Diagnosis and Management of Central Airway Obstruction

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Diagnosis and management of central airway obstruction Authors Armin Ernst, MD, FCCP Felix JF Herth, MD, PhD Heinrich D Becker, MD, FCCP Section Editor Praveen N Mathur, MB, BS Deputy Editor Kevin C Wilson, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: mar 30, 2010. INTRODUCTION — Central airway obstruction can occur secondary to a number of malignant and benign processes (table 1) [1]. Patients may develop symptoms suddenly (eg, obstructing foreign body) or more gradually (eg, most malignant obstructions). In many cases, patients are incorrectly diagnosed as having asthma or chronic obstructive pulmonary disease, which contributes to delayed recognition and therapy. Interventional options for central airway obstruction are subject to the availability of experienced personnel and equipment. In addition, the stability of the patient, the nature of the underlying problem, and the patient's overall prognosis and quality of life impact the choice of intervention [1-5]. The broadest range of management options are available at centers where a multidisciplinary team specializes in the evaluation and management of the impaired airway. The diagnosis and general approach to central airway obstruction will be reviewed here. Specific management modalities are discussed in detail separately. DIAGNOSIS — The hallmark of the severely compromised airway is impairment of oxygenation and ventilation. Patients with minor obstruction are often asymptomatic, since airflow limitation is mild. However, rapid deterioration may occur if swelling or secretions increase the degree of luminal impingement during a respiratory tract infection. It is not uncommon for patients with subcritical lesions to be misdiagnosed as suffering from an exacerbation of asthma or chronic obstructive pulmonary disease (COPD) while the true etiology is anatomic airway obstruction. Patients with airway obstruction also frequently present with pneumonia; if symptoms and/or radiographic infiltrates do not resolve within four to six weeks, bronchoscopy should be considered. (See "Nonresolving pneumonia".) Symptoms and signs develop when airflow impairment reaches a critical threshold. Patients complain of shortness of breath, which is often constant and unresponsive to bronchodilators. Monophonic wheezing may be present, and can be unilateral if the lesion is distal to the carina. Stridor is a sign of severe subglottic or tracheal obstruction. Breathing becomes labored in advanced phases and heralds impending respiratory failure.

The onset and progression of symptoms depend upon the nature of the problem (acute with foreign bodies, slowly progressive with an expansile goiter) and the location of the lesion (tracheal versus bronchial). Patients with long-term artificial airways are at increased risk for subglottic or tracheal stenosis and tracheomalacia. Removal of the airway or capping of a tracheostomy tube can result in shortness of breath or stridor, which should prompt a thorough airway evaluation. (See "Endotracheal tube management and complications" and "Overview of tracheostomy".) A number of studies are employed to confirm the presence of central airway obstruction and estimate its magnitude:
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Plain chest radiographs are rarely diagnostic. Chest computed tomography (CT) may detect airway compromise, but the test as generally performed is not sensitive. If an airway lesion is suspected and time permits, a high resolution CT with three-dimensional airway reconstruction can prove helpful [6]. These new imaging protocols may assist in both the initial assessment of the lesion and in objective grading of therapeutic success and followup (figure 1). (See "Radiology of the trachea".) Flow volume loops can show the characteristic changes of airway obstruction, frequently before abnormalities in the spirometric volumes are noted (figure 2A-E). (See "Flow-volume loops".) Direct bronchoscopic visualization is the gold standard for confirming the presence of airway obstruction and also aids in discerning its underlying etiology. Often the differentiation of endobronchial or extrinsic lesions can be accomplished only at bronchoscopy (figure 3). (See "Flexible bronchoscopy: Indications and contraindications".)

MANAGEMENT — Management of central airway obstruction is divided into two phases: initial stabilization and airway interventions. Initial stabilization — In a stable patient, imaging studies and pulmonary function tests should be obtained as outlined above. A patient with severe tracheal or mainstem obstruction and marginal lung function requires initial stabilization to secure ventilation and oxygenation.




Endotracheal intubation is preferred. In the presence of a compromised trachea, this is most safely performed with an awake or mildly sedated patient who is still actively breathing. The use of paralytic agents may be hazardous, since intubation may be difficult or impossible. (See "Endotracheal tube management and complications".) In cases of severe tracheal obstruction, use of the open ventilating rigid bronchoscope is the preferred method of airway control. (See "Rigid bronchoscopy: Intubation techniques".) The rigid bronchoscope not only provides a secure airway during visualization, but is also a therapeutic tool [7]. In emergent cases, the airway can be dilated with the barrel of the scope (figure 4A-B).

Bronchoscopy should be performed after the airway has been secured and appropriate gas exchange documented. During the bronchoscopic examination, the airway is inspected, lesions are assessed, distal secretions are suctioned, and diagnostic tissue is obtained if needed. This information is used to plan further interventions aimed at opening an airway and maintaining patency. If no dedicated airway team is available, patient transfer to a specialized center should be considered after the patient has been stabilized. An appropriate course of antibiotics should be administered after a patent airway has been reestablished in individuals with postobstructive infections. The usefulness of empiric antibiotic therapy after interventions in the absence of evidence of infection is unproven. Similarly, there is no evidence that corticosteroids are effective in reducing complications in this setting. It is advisable for all patients with a history of airway obstruction to carry a card or bracelet identifying them as patients with complicated airways or indwelling airway stents. Airway interventions — Further interventions are planned following the initial assessment [1]. The number and scope of therapeutic options has increased dramatically, and a given intervention must be chosen carefully in the context of an individual patient's situation [8]. Multimodality approaches featuring a combination of several interventions are preferred for their mucosal sparing effects and long term success over dilation alone (figure 5 and table 2) [1,3]. The rigid bronchoscope is the preferred instrument for unstable patients and when significant bleeding is expected. Its nonflammable nature also makes it the preferred tool for many laser bronchoscopies. For most other interventions, the flexible bronchoscope with use of conscious sedation provides a therapeutic alternative. (See "Rigid bronchoscopy: Instrumentation" and "Flexible bronchoscopy: Equipment, procedure, and complications".) Foreign body extraction — Foreign body aspiration is more common in children than adults, and can lead to sudden, catastrophic, central airway obstruction. Both flexible and rigid bronchoscopy can be used for foreign body extraction; the selection of procedure and technique of removal are discussed elsewhere. (See "Airway foreign bodies in adults".) Rigid or balloon dilation — In emergent cases, the airway may be dilated with the rigid bronchoscope. During this procedure (called bronchoplasty), the patient is intubated with the instrument under general anesthesia. The optical telescope is advanced through the stenotic airway opening and the barrel then pushed through the obstruction in a rotating motion. Bleeding is usually minimal due to compression of the lesion by the rigid instrument (figure 4A-B). In less urgent cases, sequential balloon or rigid dilators may be used, particularly when the stenosis occurs after transplantation or long term intubation. For sequential rigid dilation, the patient must be preoxygenated carefully, which may not be feasible in severe airway stenosis. Balloon dilation can safely be performed with the flexible bronchoscope (figure 6) [9]. The major advantage of sequential rigid versus balloon dilation is that there generally is less mucosal trauma. (See "Flexible fiberoptic bronchoscopy balloon dilation".)

Dilation is immediately effective for intrinsic and extrinsic lesions, but the results are usually not sustained. Mucosal disruption from these techniques may in fact produce granulation tissue and accelerate recurrent stenosis [10]. For this reason, dilation is frequently followed by laser and/or stenting procedures, as described below [11]. Laser therapy — Nd:YAG laser therapy is frequently performed utilizing the rigid bronchoscope, but can be safely performed with the flexible bronchoscope by experienced endoscopists [12]. The tissue-light interaction leads to thermal tissue damage and destruction of obstructing lesions [13]. (See "Basic principles of medical lasers" and "Bronchoscopic laser resection".) Laser therapy is indicated for short endobronchial central airway lesions with a visible distal lumen. The technique is most commonly applied in cases of malignant intrinsic airway obstruction or in postintubation tracheal stenosis. The effects upon airway lumen size are usually immediate and accompanied by excellent control of bleeding, but as is true with dilation, they are not long-lasting. Large series have demonstrated the safety of laser therapy in experienced hands [14]. Complications include combustion of the endotracheal tube or fiberoptic bronchoscope, hypoxemia, respiratory failure, and destruction of bronchial wall components. Electrocautery and argon plasma coagulation — These therapies also rely on thermal tissue destruction. With electrocautery, a high-frequency current is applied to the lesion with bipolar probes. When the current is directly applied to the tissue, heat develops and leads to tissue necrosis. (See "Endobronchial electrocautery".) Argon plasma coagulation is a related therapeutic intervention [15]. Argon gas is emitted through a Teflon tube that can be passed through a flexible bronchoscope. This gas is ionized because of exposure to high-frequency current and an electrical arc is formed which allows for desiccation and tissue destruction without direct contact. The penetration depth is reliably 2 to 3 mm, which makes the argon plasma coagulator a valuable tool in treating superficial bleeding and debulking granulation tissue and tumors such as papillomas (figure 7) [1]. Photodynamic therapy — Photodynamic therapy is approved for malignant intrinsic airway obstruction due to lung cancer that is unresponsive or unsuitable for laser therapy. After injection of a photosensitizing agent and a suitable time interval, tumor tissue that has retained the photosensitizing agent is exposed to a laser light of 630 nm wavelength. The laser is delivered through a fiber introduced through the flexible bronchoscope. A nonthermal phototoxic reaction leads to delayed cell death [1,16,17]. (See "Photodynamic therapy of lung cancer".) This therapeutic approach is also suitable for completely obstructed airways due to the predictable penetration depth of 5 to 10 mm. Follow-up bronchoscopy is necessary to remove debris and secretions. The main adverse effect of this approach is associated skin photosensitivity, which can last up to six weeks.

Cryotherapy — As opposed to the thermal effects of laser therapy, cryotherapy relies on repeated freeze/thaw cycles for tissue destruction. Cryotherapy may be performed through the flexible bronchoscope and spares cartilaginous structures due to their poor vascularity. The intervention is more time-consuming than laser therapy because of the need for repeat cycles, and a repeat bronchoscopy for clearance of debris and secretions is usually necessary [18,19]. (See "Bronchoscopic cryosurgery: Principles and technique" and "Bronchoscopic cryosurgery: Indications, contraindications, and outcomes".) Cryotherapy can be performed safely in complete mainstem obstruction, but its delayed effects do not make it a first choice in acute situations or severe tracheal stenosis. As with any tissue-destroying interventions, long-term stabilization of the airway is often necessary. Stenting or radiation in the case of malignant lesions may achieve this. External beam radiation and brachytherapy — Radiation therapy is a variably effective treatment for malignant airway obstruction, and therapeutic effects may be quite delayed. External beam radiation also may produce unwanted effects on thoracic structures outside the airway, further compromising gas exchange. Endobronchial brachytherapy is a treatment modality that has fewer of these drawbacks and is particularly useful in patients who have received previous maximal doses of external beam radiation [20]. (See "Endobronchial brachytherapy".) After a patent airway has been established by laser resection, dilation, or other methods, a hollow catheter is introduced through the flexible bronchoscope and positioned under direct vision. After the catheter is secured, it is loaded with a radioactive source [21,22]. Depending upon the results, airway stenting should be considered. Adverse effects of brachytherapy are usually minimal (tracheobronchitis, cough), but severe hemoptysis and fistula formation have been reported [22]. Airway stents — Stenting should be considered to prevent reocclusion after patency has been restored to occluded or severely stenotic airways. Stents are the intervention of choice for external obstruction and are also highly effective for persistent proximal bronchopleural fistulas and tracheoesophageal fistulas [23,24]. The first dedicated tracheobronchial stent was introduced in 1990; numerous designs with various advantages and disadvantages are now available [25-27]. (See "Airway stents".) Silicone stents generally require introduction with a rigid bronchoscope, but are comparatively inexpensive. Most metal stents can be introduced with the flexible bronchoscope; their greater expense is partially offset by the fact that neither an operating room nor general anesthesia is needed [28,29]. New stent designs combining different materials are currently being evaluated [30-32]. Stents are generally well tolerated, but patients require periodic follow-up. Patients should carry a card detailing type and size of the indwelling stent. Stents do not contraindicate subsequent intubation, but intubation should preferably be performed under fiberoptic guidance if the stent is in the tracheal position.

Meticulous follow-up is indicated to identify potential problems at an early stage. These include recurrence of obstruction, growth of granulation tissue, as well as stent occlusion and migration. If identified early, these complications can be addressed in an elective manner. At our institution, a first follow-up bronchoscopy after stent placement is performed after six to eight weeks, which allows for repositioning of migrated metallic stents. Thereafter, we perform interval bronchoscopies every three to six months and as problems arise. Surgical resection — Surgical intervention for airway obstruction is usually reserved for severe, benign, relatively short tracheal lesions. Patient selection is crucial, as the operative morbidity and mortality may be unacceptable in patients with limited cardiopulmonary reserve. Patients should be referred to a center with a large cumulative experience if surgical resection is a consideration. Techniques that are commonly employed are primary end-toend anastomosis and tracheal sleeve resection [33-35]. Anastomotic complications that result in recurrent stenosis may necessitate multiple dilations, reoperation, or permanent tracheostomy. These complications were noted in 9 percent of patients in one large single center series of over 900 procedures [36]. Risk factors for complications following tracheal resection in this study included diabetes, prior tracheal resection, and stenotic lesions longer than 4 cm [36]. Patients undergoing laryngotracheal resection were also at increased risk of anastomotic complications in this report. In the future, biological tissue engineering techniques may be used to create tracheal bioprostheses covered with mucosal tissue [37-44]. Tracheal transplantation, which has been difficult to achieve because of the limited blood supply to the airway, may also be possible as muscle flap reconstruction techniques continue to improve [45,46]. RECOMMENDATIONS — Central airway obstruction may be extrinsic or intrinsic and may cause a variety of symptoms, from shortness of breath to respiratory failure and death. In the decompensated patient, immediate restoration of ventilation and oxygenation is of vital importance. Subsequent interventions are based upon the nature of the obstruction and refined according to issues involving quality of life and the duration of expected survival. Frequently, the best therapeutic approach employs a combination of several treatment modalities, and should be chosen at any given time in such a way that leaves open options for further therapy (figure 5). Close follow-up is necessary in order to recognize complications early and intervene accordingly. The most comprehensive assessment and therapy can be provided by centers with a multidisciplinary airway team specializing in compromised airways. Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Ernst A, Feller-Kopman D, Becker HD, Mehta AC. Central airway obstruction. Am J Respir Crit Care Med 2004; 169:1278. 2. Ernst A, Silvestri GA, Johnstone D, American College of Chest Physicians. Interventional pulmonary procedures: Guidelines from the American College of Chest Physicians. Chest 2003; 123:1693. 3. Bolliger CT, Mathur PN, Beamis JF, et al. ERS/ATS statement on interventional pulmonology. European Respiratory Society/American Thoracic Society. Eur Respir J 2002; 19:356. 4. Stephens KE Jr, Wood DE. Bronchoscopic management of central airway obstruction. J Thorac Cardiovasc Surg 2000; 119:289. 5. Seijo LM, Sterman DH. Interventional pulmonology. N Engl J Med 2001; 344:740. 6. LoCicero J 3rd, Costello P, Campos CT, et al. Spiral CT with multiplanar and threedimensional reconstructions accurately predicts tracheobronchial pathology. Ann Thorac Surg 1996; 62:811. 7. Colt HG, Harrell JH. Therapeutic rigid bronchoscopy allows level of care changes in patients with acute respiratory failure from central airways obstruction. Chest 1997; 112:202. 8. Beamis JF Jr. Interventional pulmonology techniques for treating malignant large airway obstruction: an update. Curr Opin Pulm Med 2005; 11:292. 9. Hautmann H, Gamarra F, Pfeifer KJ, Huber RM. Fiberoptic bronchoscopic balloon dilatation in malignant tracheobronchial disease: indications and results. Chest 2001; 120:43. 10. Mehta AC, Lee FY, Cordasco EM, et al. Concentric tracheal and subglottic stenosis. Management using the Nd-YAG laser for mucosal sparing followed by gentle dilatation. Chest 1993; 104:673. 11. Noppen M, Schlesser M, Meysman M, et al. Bronchoscopic balloon dilatation in the combined management of postintubation stenosis of the trachea in adults. Chest 1997; 112:1136. 12. Duhamel DR, Harrell JH 2nd. Laser bronchoscopy. Chest Surg Clin N Am 2001; 11:769. 13. Ramser ER, Beamis JF Jr. Laser bronchoscopy. Clin Chest Med 1995; 16:415. 14. Cavaliere S, Venuta F, Foccoli P, et al. Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 1996; 110:1536. 15. Morice RC, Ece T, Ece F, Keus L. Endobronchial argon plasma coagulation for treatment of hemoptysis and neoplastic airway obstruction. Chest 2001; 119:781. 16. Edell ES, Cortese DA. Photodynamic therapy. Its use in the management of bronchogenic carcinoma. Clin Chest Med 1995; 16:455. 17. Cortese DA, Edell ES, Kinsey JH. Photodynamic therapy for early stage squamous cell carcinoma of the lung. Mayo Clin Proc 1997; 72:595. 18. Hetzel M, Hetzel J, Schumann C, et al. Cryorecanalization: a new approach for the immediate management of acute airway obstruction. J Thorac Cardiovasc Surg 2004; 127:1427. 19. Mathur PN, Wolf KM, Busk MF, et al. Fiberoptic bronchoscopic cryotherapy in the management of tracheobronchial obstruction. Chest 1996; 110:718. 20. Chella A, Ambrogi MC, Ribechini A, et al. Combined Nd-YAG laser/HDR brachytherapy versus Nd-YAG laser only in malignant central airway involvement: a prospective randomized study. Lung Cancer 2000; 27:169.

21. Nori D, Allison R, Kaplan B, et al. High dose-rate intraluminal irradiation in bronchogenic carcinoma. Technique and results. Chest 1993; 104:1006. 22. Suh JH, Dass KK, Pagliaccio L, et al. Endobronchial radiation therapy with or without neodymium yttrium aluminum garnet laser resection for managing malignant airway obstruction. Cancer 1994; 73:2583. 23. Freitag L, Tekolf E, Steveling H, et al. Management of malignant esophagotracheal fistulas with airway stenting and double stenting. Chest 1996; 110:1155. 24. Wood D. Airway stenting. Chest Surg Clin N Am 2003; 13:211. 25. Dumon JF. A dedicated tracheobronchial stent. Chest 1990; 97:328. 26. Becker, HD. Stenting of the central airways. J Bronchol 1995; 2:98. 27. Wood DE, Liu YH, Vallières E, et al. Airway stenting for malignant and benign tracheobronchial stenosis. Ann Thorac Surg 2003; 76:167. 28. Dasgupta A, Dolmatch BL, Abi-Saleh WJ, et al. Self-expandable metallic airway stent insertion employing flexible bronchoscopy: preliminary results. Chest 1998; 114:106. 29. Saad CP, Murthy S, Krizmanich G, Mehta AC. Self-expandable metallic airway stents and flexible bronchoscopy: long-term outcomes analysis. Chest 2003; 124:1993. 30. Bolliger CT, Breitenbuecher A, Brutsche M, et al. Use of studded Polyflex stents in patients with neoplastic obstructions of the central airways. Respiration 2004; 71:83. 31. Noppen M, Meysman M, Claes I, et al. Screw-thread vs Dumon endoprosthesis in the management of tracheal stenosis. Chest 1999; 115:532. 32. Bolliger CT, Wyser C, Wu X, et al. Evaluation of a new self-expandable silicone stent in an experimental tracheal stenosis. Chest 1999; 115:496. 33. Grillo HC. Development of tracheal surgery: a historical review. Part 1: Techniques of tracheal surgery. Ann Thorac Surg 2003; 75:610. 34. Grillo HC. Development of tracheal surgery: a historical review. Part 2: Treatment of tracheal diseases. Ann Thorac Surg 2003; 75:1039. 35. Bisson A, Bonnette P, el Kadi NB, et al. Tracheal sleeve resection for iatrogenic stenoses (subglottic laryngeal and tracheal). J Thorac Cardiovasc Surg 1992; 104:882. 36. Wright CD, Grillo HC, Wain JC, et al. Anastomotic complications after tracheal resection: prognostic factors and management. J Thorac Cardiovasc Surg 2004; 128:731. 37. Saito Y, Minami K, Kaneda H, et al. New tubular bioabsorbable knitted airway stent: feasibility assessment for delivery and deployment in a dog model. Ann Thorac Surg 2004; 78:1438. 38. Kim J, Suh SW, Shin JY, et al. Replacement of a tracheal defect with a tissueengineered prosthesis: early results from animal experiments. J Thorac Cardiovasc Surg 2004; 128:124. 39. Kojima K, Ignotz RA, Kushibiki T, et al. Tissue-engineered trachea from sheep marrow stromal cells with transforming growth factor beta2 released from biodegradable microspheres in a nude rat recipient. J Thorac Cardiovasc Surg 2004; 128:147. 40. Bugmann P, Rimensberger PC, Kalangos A, et al. Extratracheal biodegradable splint to treat life-threatening tracheomalacia. Ann Thorac Surg 2004; 78:1446.

41. Jaquet Y, Pilloud R, Lang FJ, Monnier P. Prefabrication of composite grafts for long-segment tracheal reconstruction. Arch Otolaryngol Head Neck Surg 2004; 130:1185. 42. Grimmer JF, Gunnlaugsson CB, Alsberg E, et al. Tracheal reconstruction using tissue-engineered cartilage. Arch Otolaryngol Head Neck Surg 2004; 130:1191. 43. Kamil SH, Eavey RD, Vacanti MP, et al. Tissue-engineered cartilage as a graft source for laryngotracheal reconstruction: a pig model. Arch Otolaryngol Head Neck Surg 2004; 130:1048. 44. Martinod E, Seguin A, Holder-Espinasse M, et al. Tracheal regeneration following tracheal replacement with an allogenic aorta. Ann Thorac Surg 2005; 79:942. 45. Cibantos Filho JS, de Mello Filho FV, Campos AD, Ellinguer F. Viability of a 12ring complete tracheal segment transferred in the form of a compound flap: an experimental study in dogs. Laryngoscope 2004; 114:1949. 46. Olias J, Millán G, da Costa D. Circumferential tracheal reconstruction for the functional treatment of airway compromise. Laryngoscope 2005; 115:159. Topic 4384 Version 3.0 © 2012 UpToDate, Inc. All rights reserved. | Subscription and License Agreement |Release: 20.3 - C20.4 Licensed to: UTPL |Support Tag: [ecapp1005p.utd.com-200.0.29.70-8DA7D5FDCB50339.14]

TOPIC OUTLINE
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INTRODUCTION DIAGNOSIS MANAGEMENT Initial stabilization Airway interventions - Foreign body extraction - Rigid or balloon dilation - Laser therapy - Electrocautery and argon plasma coagulation - Photodynamic therapy - Cryotherapy - External beam radiation and brachytherapy - Airway stents - Surgical resection RECOMMENDATIONS REFERENCES

GRAPHICSView All

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FIGURES CT reconstruction of trachea Upper airway obstruction Flow volume loops airway obstr Mainstem bronchial obstr Partial mainstem bronchial obs End inspiratory tail Central obstruction types Rigid bronchoscope Dilation with rigid scope Management central obstruction Balloon dilation Juvenile papillomatosis bronch TABLES Causes central airway obstruct Interventions cent obstruction

RELATED TOPICS
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Airway foreign bodies in adults Airway stents Basic principles of medical lasers Bronchoscopic cryosurgery: Indications, contraindications, and outcomes Bronchoscopic cryosurgery: Principles and technique Bronchoscopic laser resection Endobronchial brachytherapy Endobronchial electrocautery Endotracheal tube management and complications Flexible bronchoscopy: Equipment, procedure, and complications Flexible bronchoscopy: Indications and contraindications Flexible fiberoptic bronchoscopy balloon dilation Flow-volume loops Nonresolving pneumonia Overview of tracheostomy Photodynamic therapy of lung cancer Radiology of the trachea Rigid bronchoscopy: Instrumentation Rigid bronchoscopy: Intubation techniques

Help improve UpToDate. Did UpToDate answer yo The failed airway in adults Authors Ron M Walls, MD, FRCPC, FAAEM Michael F Murphy, MD, FRCPC

Section Editor John A Marx, MD Deputy Editor Jonathan Grayzel, MD, FAAEM Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: jun 14, 2010. INTRODUCTION — A failed airway exists at any time during an attempt at endotracheal intubation when there is an inability to intubate the patient (even with a single attempt) and an inability to ventilate the patient adequately with a bag and mask to maintain oxyhemoglobin saturations above 90 percent. This is the "can't intubate, can't ventilate" type of failed airway. A second form of failed airway has been defined for emergency intubation, and exists when there have been three failed attempts to intubate by an experienced operator, even when bag and mask ventilation is capable of maintaining adequate oxyhemoglobin saturation [1]. This is the "can't intubate, can ventilate" type of failed airway. When either of these two situations arises during emergency airway management, the clinician must take effective action immediately to avoid oxygen desaturation with resultant cerebral hypoxia. A failed airway can arise during a rapid sequence intubation, during management of a difficult airway, or during management of a crash airway. Regardless of the circumstances leading to the airway failure, a deliberate approach must be used to ensure that oxygenation is preserved, and that the airway is ultimately secured. This topic review will discuss management of the failed airway. Discussions of other aspects of airway management are found elsewhere. (See "Rapid sequence intubation in adults" and "The difficult airway in adults" and "The difficult pediatric airway" and "Emergent endotracheal intubation in children".) INCIDENCE OF THE FAILED AIRWAY — The incidence of the failed airway, as defined above, is not known for emergency department (ED) airway management, nor for patients undergoing anesthesia in the operating room. Analysis of nearly 9000 ED intubations in the National Emergency Airway Registry (NEAR) found that rapid sequence intubation is successful in approximately 97 percent of cases for which it is the first method chosen, and that surgical cricothyroidotomy (also called cricothyrotomy) is required in approximately 0.8 percent of all emergency intubations and 1.7 percent of intubations of trauma patients [2,3]. An earlier, single center study of 610 emergency intubations noted a cricothyroidotomy rate of 1.1 percent [4]. (See "Emergent surgical cricothyrotomy (cricothyroidotomy)".) It is likely that the incidence of failed airway, particularly of the can't intubate, can ventilate type, is much higher than this. Regardless of the incidence, the failed airway represents a potential catastrophe if not managed effectively. The failed airway scenario is best avoided

by a systematic preintubation evaluation of patients for difficult airway attributes. (See "The difficult airway in adults".) THE FAILED AIRWAY ALGORITHM© — When a failed airway occurs, the failed airway algorithm© provides a series of actions to guide management (algorithm 1) [1,5]. The critical question is whether adequate oxygenation (ie, oxyhemoglobin saturation [SpO2] above 90 percent or stable in the high 80s) can be maintained. If oxygenation is adequate, there is time to plan a series of actions to manage the airway; if the patient's oxygenation cannot be maintained, immediate rescue by (usually) cricothyrotomy is necessary. If time permits, there are a number of alternative or rescue devices that can be used when direct laryngoscopy has failed. In some cases, the rescue airway may provide a definitive airway, with a cuffed endotracheal tube (ETT) in the trachea. If the airway is secured by a cuffed ETT, the airway is considered to be managed, and general resuscitation continues. If adequate oxygenation and ventilation are achieved, but the airway is not protected by a cuffed ETT in the trachea, resuscitation can continue, but arrangements must be made to establish a definitive airway at the earliest appropriate opportunity. As with the difficult airway algorithm©, the response to the failed airway can be thought of as a series of discrete steps. Each of these steps is described in detail below. Assistance in the form of personnel, equipment, or airway devices, should be obtained as needed at the moment the failed airway is recognized. Is there time? — At the outset, the key determination is whether the patient is being adequately oxygenated (ie, oxyhemoglobin saturation [SpO2] above 90 percent or stable in the high 80s). If so, there is time to create and execute a deliberate rescue plan, perhaps customized to the patient's particular circumstances. This is the "can't intubate, can ventilate" scenario. If the patient cannot be oxygenated adequately with a bag and mask, despite use of optimal technique (ie, can't intubate, can't oxygenate), immediate cricothyrotomy is indicated. Although an alternative airway device might rescue the patient without cricothyrotomy, the extremely brief time before cerebral hypoxia ensues argues for immediate surgical intervention. Attempts to establish an alternative airway, if unsuccessful, may delay the initiation of cricothyrotomy leading to hypoxic brain injury. Thus, we equate "can't intubate, can't ventilate" with cricothyrotomy in the emergency setting. There is one modification to this approach. Placement of a single "best" alternative device, usually an extraglottic airway (eg, Laryngeal Mask Airway (LMA™) or King LT Airway™) can be attempted in parallel with preparations for the surgical airway. If the operator is able to insert an extraglottic airway and attempt ventilation, while a second clinician simultaneously prepares for a cricothyrotomy, then valuable time is not lost if ventilation using the extraglottic device is unsuccessful. Similarly, a single operator might make one attempt with an extraglottic device, then proceed directly to cricothyrotomy if ventilation is not promptly achieved. This approach

involves a single attempt using a single "go to" device, and cannot delay significantly the initiation of cricothyrotomy if ventilation is not achieved immediately. Whether this single, parallel rescue maneuver is attempted but unsuccessful or not attempted, the primary rescue technique is cricothyrotomy. The performance of cricothyrotomy is discussed separately. (See "Emergent surgical cricothyrotomy (cricothyroidotomy)".) ALTERNATIVE AIRWAY DEVICES — The initial goal for failed airway management is to provide adequate oxygenation sufficient to support the patient until a definitive airway can be achieved. So long as the patient is adequately oxygenated using a bag and mask, the clinician may use any of several alternatives to direct laryngoscopy to rescue the failed airway. The devices briefly described below are discussed in detail separately. (See "Devices for difficult emergency airway management in adults".) List of devices










Fiberoptic or video stylet - There are several rigid or semi-rigid fiberoptic and video stylets available (eg, Shikani Optical Stylet [SOS™] or Storz Bonfils™ laryngoscope). These stylets have fiberoptic or video viewers at their distal end and are inserted through the endotracheal tube (ETT). The image generated can be used to guide the ETT between the vocal cords without need of a conventional laryngoscope. Video laryngoscopes - Video laryngoscopes (eg, Glidescope™ or Storz C-MAC™) contain video cameras on the blade that generally provide an excellent view of the glottis, without the need to align the airway axes to achieve a direct view from outside the patient's mouth. These devices function well with the patient in the neutral position, and obstacles to conventional laryngoscopy, such as limited mouth opening or a large tongue, generally do not present a problem. Optical devices — Various optical devices are available for intubation of the failed airway or as an alternative to direct laryngoscopy. The best studied of these is the AirTraq™, a periscope-like device that uses prisms and mirrors to provide an indirect view of the glottis. The AirTraq™ incorporates a channel for the ETT, which is advanced when the glottis is properly sighted. Extraglottic airway - Various laryngeal mask airways (LMAs) are available, some specifically designed to facilitate subsequent intubation, some intended strictly as ventilatory devices in their own right. A second type of extraglottic airway is inserted into the esophageal inlet and has two balloons that are inflated to occlude both the esophagus and the pharynx thereby permitting sidestream ventilation of the trachea. Available devices include the Combitube™ and the King LT™ airways. Flexible bronchoscope - The flexible bronchoscope, usually an intubating bronchoscope, provides access to the glottis without having to correct for the various angles of the oropharynx, as is required for direct laryngoscopy. Intubation can be achieved nasally or orally, but by either route, attempts can be timeconsuming, making this device more appropriate for a planned approach to certain difficult airways, rather than for the rescue of a failed airway. Attempts using the fiberoptic bronchoscope may have to be abbreviated or abandoned because of the difficulty maintaining oxygenation during fiberoptic airway procedures. Flexible

bronchoscopes require training and practice, but have high success rates when time permits [6]. Was a cuffed endotracheal tube placed in the trachea? — Many of the alternative airway devices listed above result in a cuffed ETT in the trachea, in which case, the airway is secured. Others, such as the extraglottic airways, provide for ventilation and oxygenation, but do not protect the airway. If one of the nonprotective devices has been used, resuscitation can proceed, but a plan must be initiated to secure the airway at the earliest opportunity. If at any time oxygenation fails, and the patient reverts to a can't intubate, can't ventilate situation, cricothyrotomy remains the rescue technique of first resort. SUMMARY AND RECOMMENDATIONS








A failed airway exists at any time during an attempt at endotracheal intubation when there is an inability to intubate the patient (even with a single attempt) and an inability to ventilate the patient adequately using a bag and mask or an extraglottic device (ie, maintain oxyhemoglobin saturations [SpO2] above 90 percent or stable in the high 80s). This is the "can't intubate, can't ventilate" type of failed airway. A failed airway also exists when there have been three failed attempts to intubate by an experienced operator, even when ventilation with a bag and mask or an extraglottic device maintains adequate SpO2. This is the "can't intubate, can ventilate" type of failed airway. (See 'Introduction' above.) We recommend that cricothyrotomy be used as the primary rescue maneuver for the "can't intubate, can't ventilate" failed airway (Grade 1C). Cricothyrotomy has a high success rate and relatively low complication rate, and can be performed using open surgical technique or a Seldinger method. (See 'The failed airway algorithm©' above.) The critical question in failed airway management is whether adequate oxygenation (ie, SpO2 above 90 percent or stable in the high 80s) can be maintained. If oxygenation is adequate there is time to plan a series of actions to manage the airway; if the patient's oxygenation cannot be maintained, immediate rescue by (usually) cricothyrotomy is necessary. (See 'The failed airway algorithm©' above and "Emergent surgical cricothyrotomy (cricothyroidotomy)".) For the can't intubate, can ventilate patient, there are several possible rescue devices. (See 'Alternative airway devices' above.) For ventilation only: Extraglottic airway (eg, Combitube™, King LT™, Laryngeal mask airway)



For intubation:
    

Intubating LMA Rigid fiberoptic or video stylet Video laryngoscope Optical device (eg, AirTraq™) Flexible fiberoptic scope

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REFERENCES
1. Walls, RM. The Emergency Airway algorithms. In: Manual of Emergency Airway Management, Walls, RM, Murphy, MF, Luten, RF, et al (Eds). Philadelphia, Lippincott, Williams and Wilkins 2004. p 8. 2. Sagarin MJ, Barton ED, Chng YM, et al. Airway management by US and Canadian emergency medicine residents: a multicenter analysis of more than 6,000 endotracheal intubation attempts. Ann Emerg Med 2005; 46:328. 3. Walls, RM, et al. Emergency Airway Management: A Multi-center Report of 8937 Emergency Department Intubations. J Emerg Med 2010; [Epub ahead of print]. 4. Sakles JC, Laurin EG, Rantapaa AA, Panacek EA. Airway management in the emergency department: a one-year study of 610 tracheal intubations. Ann Emerg Med 1998; 31:325. 5. The airway management algorithms cited in this review are reproduced with permission from: The Difficult Airway Course™: Emergency, and Walls, RM, Murphy, MF. Manual of Emergency Airway Management, 3rd ed, Lippincott Williams & Wilkins, Philadelphia 2008. 6. Dunn S, Connelly NR, Robbins L. Resident training in advanced airway management. J Clin Anesth 2004; 16:472. Topic 274 Version 3.0 The difficult pediatric airway Author Nathan W Mick, MD Section Editor Susan B Torrey, MD Deputy Editor James F Wiley, II, MD, MPH Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: oct 12, 2011. INTRODUCTION — Effective airway management includes anticipating and planning for problems. Difficulties frequently occur as the result of patient characteristics that interfere with spontaneous breathing, bag mask ventilation, laryngoscopy, and/or intubation of the trachea. Identifying characteristics of the difficult airway and developing a plan for managing problems are essential principles of anesthesia practice [1]. These principles have been modified and effectively used to evaluate adults in the emergency department [2]. Children infrequently require aggressive airway management and difficulties do not occur often [3]. As a result, evidence specific for children regarding identification and management of difficult airways is limited [4]. Nevertheless, a reasonable, systematic approach for children can be developed from experience with adult patients in the operating room and emergency department.

This topic will review conditions in children that can make airway management difficult, anatomic characteristics that may identify those conditions, and management strategies. General principles of airway management in children, including rapid sequence intubation, and the adult with a difficult airway are discussed separately. (See "Basic airway management in children" and "Emergent endotracheal intubation in children" and "Rapid sequence intubation in children" and "The difficult airway in adults".) DEFINITION — A difficult airway is generally defined as a situation in which a clinician experiences difficulty with face mask ventilation, laryngoscopy, or intubation [1,2]. In an emergency setting, this also includes difficulty performing an emergency surgical airway, such as needle cricothyroidotomy. These difficulties may arise whenever any of the following maneuvers cannot be successfully performed:
    

Positioning to optimally align the pharyngeal and tracheal axes (picture 1). Achieving sufficient positive pressure with a resuscitation bag to inflate the lungs. Opening the mouth and controlling oral structures with the laryngoscope blade. Visualizing the larynx and intubating the trachea. Identifying landmarks in the neck for performing a surgical airway.

CAUSES OF THE DIFFICULT PEDIATRIC AIRWAY Normal pediatric airway — Predictable differences in the pediatric airway (as compared with adult airway anatomy) may make management difficult. These differences, most evident in children less than two to three years of age, include the following (see "Emergency airway management in children: Unique pediatric considerations"):
   

A large occiput affects positioning. A large tongue and small mouth may make laryngoscopy difficult. The larynx may be harder to locate with the laryngoscope because it is higher and more anterior than in an adult. The epiglottis is large and floppy and may difficult to control.

Anatomic features of the normal pediatric airway are reviewed elsewhere. (See "Basic airway management in children", section on 'Anatomic considerations' and "Emergent endotracheal intubation in children".) Congenital abnormalities — Numerous congenital conditions have features that may make airway management difficult (table 1). In addition, children with underlying airway abnormalities who acquire an acute condition (such as croup or an upper respiratory tract infection) may quickly develop respiratory compromise. Congenital features that may interfere with airway management include the following:


Misshapen head – Positioning of the head to optimally align the pharyngeal and tracheal axes may be difficult if the head is misshapen, as can occur with















craniosynostosis (such as Apert's or Crouzon's syndrome) or hydrocephalus. (See "Craniosynostosis syndromes" and "Hydrocephalus".) Facial abnormalities – Facial asymmetry or underdevelopment may make it difficult to achieve a good seal between the face and a mask, creating difficulties with bag mask ventilation (picture 2). As examples, maxillary hypoplasia is a feature of Apert's syndrome, while Goldenhar syndrome includes unilateral hypoplasia of the mandible. (See "Syndromes with craniofacial abnormalities".) Abnormal neck mobility – Limited neck mobility (as occurs with Klippel- Feil syndrome) or cervical spine instability (which can occur with Down syndrome and the mucopolysaccharidoses) may interfere with positioning of the head. (See "Clinical features and diagnosis of Down syndrome", section on 'Atlantoaxial instability' and "Complications and management of the mucopolysaccharidoses", section on 'Anesthesia'.) Small oral aperture – Opening the mouth for laryngoscopy may be difficult in children with microstomia, which is a feature of Freeman-Sheldon and HallermannStrieff syndromes. Small oral cavity – Children with small mandibles or palatal abnormalities (such as high arched or cleft palates) have a smaller oral cavity. This may make laryngoscopy and control of oral structures difficult. For instance, mandibular hypoplasia is a feature of the Robin sequence and Treacher Collins' syndrome (picture 3). Large tongue – A large tongue may obstruct the airway during bag mask ventilation or be difficult to control during laryngoscopy. Macroglossia occurs in several conditions (such as hypothyroidism, Beckwith-Wiedeman syndrome, and Down syndrome). It is also a feature of infiltrative diseases such as the mucopolysaccharidoses. Masses – Masses in the neck (such as cystic hygromas) may interfere with positioning. Masses within the airway (such as teratomas or hemangiomas) may obstruct the airway and interfere with visualization of the larynx. Mediastinal masses may make tube placement difficult and interfere with ventilation after successful intubation [5]. (See "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx" and "Epidemiology; pathogenesis; clinical features; and complications of infantile hemangiomas", section on 'Airway hemangiomas'.) Laryngeal and subglottic abnormalities – Abnormalities of the larynx or subglottic trachea may interfere with intubation (picture 4).

Acquired conditions — Acquired conditions that can cause difficulties with airway management may develop as the result of infection, allergic reactions, trauma, or aspiration of a foreign body. Infection — The specific difficulties in airway management that arise because of Infection depend upon where the infection is located within the airway.


Retropharyngeal and peritonsillar abscesses may interfere with laryngoscopy and visualization of the larynx. These conditions do not typically require emergency airway management. (See "Retropharyngeal infections in children".)





Epiglottitis is characterized by rapidly progressive inflammation and edema of the supraglottic structures. Airway management is difficult because laryngeal anatomy is distorted and the glottic opening may be small and difficult to identify. Since the introduction of conjugate Haemophilus influenza type B vaccines, the incidence of epiglottitis in children has declined dramatically. (See "Epiglottitis (supraglottitis): Clinical features and diagnosis".) Croup and tracheitis cause subglottic airway obstruction. As a result, it may be difficult to deliver effective bag mask ventilation or to pass an endotracheal tube through the subglottic trachea. Fortunately, both conditions generally respond to medical management. (See "Clinical features, evaluation, and diagnosis of croup", section on 'Pathogenesis' and "Approach to the management of croup".)

Anaphylaxis — Edema involving the tongue, retropharynx, and/or larynx, that can interfere with laryngoscopy and visualization of the larynx, may develop as the result of anaphylaxis. Symptoms typically respond to aggressive medical management (table 2). Trauma — Injury to the face or airway (as the result of blunt or penetrating trauma, thermal burns, or caustic ingestions) may complicate airway management. Facial burns may make it difficult to deliver bag mask ventilation because an adequate seal between the mask and face cannot be achieved. An expanding hematoma in the pharynx can interfere with laryngoscopy. Injury to the larynx or subglottic trachea may be exacerbated by intubation. Spinal immobilization with a rigid cervical collar, regardless of the presence of injury can make direct laryngoscopy difficult because the clinician is unable to optimally position the patient in the sniffing position and adequately align the visual axis. (See 'Management' below.) Foreign body — A foreign body in the airway may cause significant obstruction and require immediate treatment. Identification and removal of the foreign body during laryngoscopy can be challenging. In addition, normal anatomic landmarks may be distorted by the foreign body. (See "Emergent evaluation of acute upper airway obstruction in children", section on 'Causes'.) Piercings around the mouth and tongue may interfere with or become dislodged during laryngoscopy [6]. Other causes — Other acquired conditions in children that may make airway management difficult include tumors, previous surgery, or radiation treatment. IDENTIFICATION OF THE DIFFICULT PEDIATRIC AIRWAY — The initial evaluation of any critically ill or injured child should include a brief, systematic assessment of the airway to identify characteristics that may complicate management. These characteristics must be taken into consideration when developing an airway management plan. (See "Emergent endotracheal intubation in children" and "Rapid sequence intubation in children", section on 'Preparation'.) Anesthesiologists have used bedside evaluation tools to identify patients for whom airway management may be difficult [1]. None of these indicators has been tested in emergency

departments or in children. Nevertheless, a reasonable approach can be developed using evidence from the operating room and clinical experience in the emergency department to identify children who may have difficult airways [2]. Bag mask ventilation — Bag mask ventilation may be difficult in children with the following features:






A misshapen head (as the result of trauma or a congenital anomaly) or limited neck mobility (such as a patient whose cervical spine is immobilized) can interfere with proper positioning (picture 1). Facial burns or any disruption of lower facial continuity (as can occur with facial trauma or a congenital anomaly with facial asymmetry) can make it difficult to achieve an adequate seal between the face and the mask. Patients who are obese or who have significant lung disease (such as severe asthma) may be difficult to ventilate with a bag and mask [7].

Laryngoscopy or intubation — A combination of several clinical features appears to be a sensitive predictor of difficult laryngoscopy or intubation for adults [8-10]. These features include:






Interincisor gap is the distance between the upper and lower incisors with the mouth open as wide as possible. For adult patients, the width of three of the patient's fingers is considered an adequate distance for laryngoscopy [2]. Mallampati score assesses the view of the posterior pharynx with the mouth wide open (figure 1). Intubation may be difficult for patients with a poor view (Class III or IV). However, when used alone, the score has limited accuracy for predicting a difficult airway [11]. Thyromental distance is the distance between the tip of the chin and the thyroid notch. Typically, the width of three of the patient's fingers is considered normal for adults [2]. Difficulty visualizing the larynx may occur when the distance is longer or shorter.

Cricothyroidotomy — Needle cricothyroidotomy, which permits percutaneous transtracheal ventilation, should always be considered a difficult technique in children because normal landmarks are difficult to identify and the caliber of the airway is small. In addition, few if any practitioners are able to gain proficiency with these techniques because clinical scenarios that require them occur rarely. (See 'Surgical airway' below.) The LEMON© approach to difficult airway assessment — The mnemonic LEMON© has been developed by researchers in emergency airway management as a tool for rapidly identifying adult patients who may have a difficult airway (table 3) [2,12]. The tool has not been tested in children. Components of the mnemonic include the following:
 

L: Look externally for indicators of a difficult airway (such as a misshapen head, facial abnormalities, or neck masses). E: Evaluate mouth opening, thyromental distance, and the distance between the mandible and the thyroid cartilage (this correlates with the distance between the







base of the tongue and the larynx) (figure 2). Adequate mouth opening and thyromental distance should be the width of three of the patient's fingers. The distance between the mandible and thyroid cartilage should be the width of two fingers. M: Mallampati score: Assigning a Mallampati score may be difficult in young children. For the obtunded, supine patient, a crude assessment can be made using a tongue blade (figure 1) [2]. O: Obstruction: Signs of airway obstruction (such as stridor, a muffled voice, or difficulty handling secretions) always indicate that airway management may be difficult. Upper airway obstruction can interfere with bag mask ventilation, as well as with laryngoscopy and intubation. N: Neck mobility: Conditions that limit neck mobility (such as congenital anomalies or cervical spine immobilization) can usually be identified by observation.

ALTERNATIVE AIRWAY TECHNIQUES — Alternative strategies for providing oxygenation and ventilation must be considered for the child who may be difficult to intubate with direct laryngoscopy. These techniques may be temporizing (such as laryngeal mask airway, combitube, or a percutaneous needle cricothyrotomy) or provide alternative approaches to tracheal intubation (as with fiberoptic intubation or a lighted stylet). Several factors impact the choice of device including the clinical situation, type of airway difficulty, and experience of the operator. (See "Devices for difficult endotracheal intubation in children", section on 'Choice of device' and "Emergency rescue devices for difficult pediatric airway management", section on 'Choice of device'.) Laryngeal mask airway — The laryngeal mask airway (LMA) consists of a cuffed mask, designed to fit over the larynx, which is attached to a tube similar to an endotracheal (ET) tube. The LMA is inserted into the mouth and blindly passed along the palate into the posterior pharynx until resistance is met. The cuff is then inflated and the mask forms a partial seal around the larynx. Positive pressure ventilation can then be delivered through the tube. The procedure for placing the LMA in children is described in detail separately. (See "Emergency rescue devices for difficult pediatric airway management", section on 'Laryngeal mask airway (LMA)'.) The device is available in multiple sizes suitable for infants, children, and adults. The appropriate size is based on the patient's weight (table 4). The LMA has been used extensively by anesthesiologists in the operating room for children with normal and difficult airways [13-16]. It is relatively easy to insert, although complications with its use have been reported in infants and small children [17]. It has been used as a primary airway and as an adjunct for fiberoptic tracheal intubation [18,19]. (See 'Flexible fiberoptic intubation' below.) The LMA may provide effective airway management for adults during resuscitation [20]. In addition, successful oxygenation and ventilation with an LMA have been described in adults with upper airway obstruction from supraglottic edema [21]. However, experience with the device as a rescue airway in children is limited [22]. Case series and reports suggest that an adequate airway can be achieved with an LMA in neonates when bag-mask ventilation and tracheal intubation have failed [23].

An LMA with a modified cuff (Proseal™ LMA) appears to provide a better seal over the larynx for children, allowing for more effective delivery of positive pressure ventilation [24,25]. The device also has an esophageal drainage tube through which a gastric tube can be placed to empty the stomach. It is available in the full range of pediatric sizes. Intubating introducers (gum elastic bougie) — Intubating introducers are helpful when the epiglottis is visible but the vocal cords cannot be seen. These devices are semi-rigid solid or hollow rods with the distal tip bent at a 30 degree angle (figure 3 and figure 4). Pediatric sized introducers allow placement of endotracheal tubes as small as 4.0 mm (internal diameter). Lighted stylet — The pediatric lighted stylet is a rescue device that does not require direct visualization of the vocal cords [26]. A stylet with a fiberoptic light source is inserted into an endotracheal tube that is then blindly placed into the posterior pharynx and advanced. The tube is usually located in the trachea when a cherry-red glow is noted at the suprasternal notch. The stylet can then be carefully removed, endotracheal tube placement confirmed, and the tube secured. This technique has been used successfully for infants and children but has a relatively low success rate (75-83%) when the technique is performed by inexperienced users [27,28]. It can often be performed with minimal movement of the patient's head and neck, making it particularly useful for trauma patients whose cervical spines are immobilized [29]. (See "Devices for difficult endotracheal intubation in children", section on 'Lighted stylet'.) Fiberoptic stylets — These devices combine features of the lighted stylet with features of a flexible fiberoptic bronchoscope to create a device that can be used for blind intubation similar to a lighted stylet or visually guided intubation. With this technique an endotracheal tube is loaded onto a stylet with a fiberoptic lens that allows the clinician to visualize the glottis. The endotracheal tube is then threaded through the glottis and secured. (See "Devices for difficult endotracheal intubation in children", section on 'Fiberoptic stylets'.) Flexible fiberoptic intubation — Flexible fiberoptic techniques have been used extensively by anesthesiologists for difficult intubations [1,19]. Experience with this approach in the emergency department is almost exclusively in adult patients [30]. Typically, an endotracheal tube is threaded onto the end of a flexible fiberoptic bronchoscope. The scope is then introduced into the nose or mouth. The trachea is visualized and intubated with the scope and endotracheal tube. The scope is then withdrawn, placement of the endotracheal tube in the trachea is confirmed, and the tube is secured. (See "Devices for difficult endotracheal intubation in children", section on 'Flexible fiberoptic bronchoscope'.) Fiberoptic intubation should be considered in cases where the pre-intubation assessment suggests that orotracheal intubation via RSI (preferred in most emergency department intubation scenarios) is unlikely to be successful. Examples include congenital airway anomalies such as micrognathia or conditions where difficulty aligning the oral, pharyngeal, and laryngeal axes is predicted (such as when neck mobility is limited). The small size of the nasal passages in very young children may preclude the nasal route for intubation.

In the hands of an experienced clinician, flexible fiberoptic laryngoscopy is an excellent method for endotracheal intubation for a patient with a difficult airway who is breathing spontaneously. Availability of equipment and experienced personnel, as well as time considerations, are usually the limiting factors for using this technique for emergency airway management. Video laryngoscopy — Video laryngoscopes provide indirect laryngoscopy and display the glottic view on a video monitor during endotracheal intubation. Several devices are available in sizes appropriate for infants and children. (See "Devices for difficult endotracheal intubation in children", section on 'Video laryngoscope'.) Combitube™ — The Combitube™ is a dual-cuff, dual-lumen tube that is placed blindly in the esophagus. The distal balloon is designed to occlude the esophagus, while the proximal balloon will occlude the hypopharynx. Positive pressure ventilation can be delivered through side ports when the tube is in the esophagus, or through the tip when it is placed in the trachea, which rarely occurs. Minimal training is required to use the device effectively, and it can be placed quickly, with minimal movement of the cervical spine [31]. The Combitube™ does not provide a definitive airway. In addition, it is only available in sizes appropriate for patients taller than 48 inches (1.2 m) [32]. (See "Emergency rescue devices for difficult pediatric airway management", section on 'Combitube®'.) Complications may occur more commonly with the Combitube™ than with an LMA [33]. Reported complications with the Combitube™ include esophageal rupture, pyriform sinus perforation, and tongue engorgement [34-36]. Mucosal ischemia may occur as the result of pressure from the balloons [37]. Surgical airway — Rarely, noninvasive rescue devices fail to provide an airway. As a result, emergency healthcare providers should be familiar with surgical airway techniques, such as needle or surgical cricothyroidotomy, although in reality few if any practitioners have enough opportunity with these approaches to gain proficiency. Surgical cricothyroidotomy should be avoided in infants and young children. Equipment required for needle and surgical cricothyroidotomy, particularly a setup for delivering transtracheal ventilation, should be organized in advance and readily available in locations where emergency airway procedures are performed. Step by step instructions on how to perform needle or surgical cricothyroidotomy and on how to perform percutaneous transtracheal ventilation are discussed separately. (See "Needle cricothyroidotomy with percutaneous transtracheal ventilation" and "Emergent surgical cricothyrotomy (cricothyroidotomy)".) MANAGEMENT — Anticipating and preparing for advanced airway management, including intubation, for a critically ill or injured child who may have a difficult airway should begin before the patient arrives in the emergency department. Emergency departments should have equipment and supplies available in a readily identifiable location, such as a "difficult airway box". (See 'Alternative airway techniques' above.)

Once the child with a difficult airway is identified, a specific plan for management must be developed that includes mobilizing appropriate personnel and assembling specialized equipment (algorithm 1 and algorithm 2 and algorithm 3). The child may improve with supportive care and aggressive treatment of the underlying condition. For children who require intubation, airway management must include a rescue plan and preparation for a failed airway (algorithm 4). Supportive care — Care for all patients with respiratory difficulties who may have a difficult airway should include the following:








Provide supportive care and careful monitoring. Children who are developing respiratory compromise must be rapidly identified. (See "Initial assessment and stabilization of children with respiratory or circulatory compromise".) Aggressively treat the underlying condition. As an example, a patient with a congenitally abnormal airway who develops croup should quickly receive nebulized epinephrine and corticosteroids. In most cases, the child's condition will improve and advanced airway management will not be necessary. (See "Approach to the management of croup".) Avoid situations that could worsen airway compromise. As an example, a child with a retropharyngeal abscess who requires sedation for imaging studies should receive reversible agents, whenever possible. (See "Procedural sedation and analgesia in children".) Anticipate the need for advanced airway management. Children with conditions that rapidly and predictably progress to involve edema and distortion of normal airway anatomy despite aggressive medical management (such as thermal or chemical airway burns) should be intubated early, in as controlled a setting as possible.

Airway management — In the case of a predicted difficult airway, the first intervention should be to ―call for help‖ if such help is available. The most expert physician available may be from anesthesia or otorhinolaryngology rather than emergency medicine or pediatrics, and they may provide valuable assistance in the rare case of a difficult pediatric airway. An approach to management decisions should consider the urgency of establishing an airway ("crash airway") and the likelihood that rapid sequence intubation (RSI) will be successful. In comparison to adults, fewer interventions are available for children who have a failed airway. Crash airway — Children who are in extremis are considered a "crash airway" and should receive bag mask ventilation, followed by orotracheal intubation (algorithm 3). Numerous studies have demonstrated that effective BMV, especially in the prehospital arena, is an effective means of supporting respirations [38,39]. BMV may provide oxygenation and ventilation as personnel and equipment are being mobilized for endotracheal intubation, even in situations with significant soft tissue obstruction such as epiglottitis [40]. Alternative airway techniques (such as laryngeal mask airway or needle cricothyrotomy) should be employed when attempts to intubate the trachea are unsuccessful. (See 'Alternative airway techniques' above and 'Approach to the failed airway' below.)

Rapid sequence intubation — Rapid sequence intubation should be considered for children who are not in extremis when the clinician is confident that the child can be adequately ventilated with a bag and mask and that oral tracheal intubation will be successful (algorithm 1). Preparations should always be made for alternative airway management (such as a laryngeal mask airway). (See "Rapid sequence intubation in children" and 'Alternative airway techniques' above.) Awake intubation — Awake intubation, using sedation and local anesthesia, is an approach that is frequently used for adults [41]. With this technique, the patient is sedated but not paralyzed and continues to breath spontaneously. There are no reports describing experience with this technique for children in the emergency department. It is likely that the degree of sedation required to perform awake intubation in a frightened young child would depress airway protective reflexes and spontaneous respiration, placing the patient at risk for aspiration and hypoxia. Alternative airway techniques — Alternatives for airway management when RSI or awake intubation are not feasible include a laryngeal mask airway or fiberoptic intubation. (See 'Alternative airway techniques' above and 'Approach to the failed airway' below.) Approach to the failed airway — A child with respiratory failure for whom bag mask ventilation is not effective and the trachea cannot be intubated has a failed airway. This situation is often referred to as a "can't ventilate, can't intubate" scenario [2]. Prompt intervention to improve oxygenation and ventilation is essential (algorithm 4). The most expert clinician available should be managing the airway. There is no evidence to guide recommendations for management of these rare, but lifethreatening, situations. Therefore, any intervention that could be possibly helpful and is unlikely to worsen the patient's condition, should be considered. An LMA should be used initially for most children with failed airways who do not have complete airway obstruction. Positive pressure ventilation through a device that is sealed around the larynx may be effective for those with partial airway obstruction, even if the obstruction is subglottic (such as with croup or a subglottic foreign body). Temporary improvement in oxygenation may be life-saving, while other interventions are implemented. A surgical airway should be performed for a child with a complete upper airway obstruction. Needle cricothyroidotomy is recommended for children ≤10 years of age. A surgical airway should also be considered for children with airway conditions that could be worsened by injury from attempts to place an LMA (such as expanding hematomas, significant midface trauma, or large abscesses). (See "Needle cricothyroidotomy with percutaneous transtracheal ventilation".) SUMMARY AND RECOMMENDATIONS — Effective airway management includes anticipating and planning for difficulties. A reasonable, systematic approach for children can be developed from experience with adult patients.







Problems with airway management can occur with positioning, positive pressure ventilation, laryngoscopy, visualizing and/or intubating the trachea, or identifying landmarks for performing a surgical airway. (See 'Definition' above.) Conditions in children that may make airway management difficult include characteristics of the normal airway and congenital or acquired conditions. (See 'Causes of the difficult pediatric airway' above.) Airway characteristics that may identify a difficult airway can be rapidly assessed using the mnemonic LEMON© (table 3). (See 'The LEMON© approach to difficult airway assessment' above.) L: Look externally for indicators of a difficult airway E: Evaluate mouth opening, thyromental distance, and the distance between the mandible and the thyroid cartilage (figure 2) M: Mallampati score (figure 1) O: Obstruction: Signs of airway obstruction N: Neck mobility Alternative airway techniques that may be useful for managing a difficult airway include a laryngeal mask airway (LMA), fiberoptic laryngoscopy, video laryngoscopy, a lighted stylet, a combitube, or performing a surgical airway. (See 'Alternative airway techniques' above.) General management issues for all patients include providing supportive care, monitoring, treating the underlying condition, avoiding situations that could worsen airway compromise, and anticipating the need for advanced airway management. (See 'Management' above.) Once the child with a difficult airway is identified, a specific plan for management must be developed that includes mobilizing appropriate personnel and assembling specialized equipment (algorithm 1 and algorithm 2 and algorithm 3). The child may improve with supportive care and aggressive treatment of the underlying condition. For children who require intubation, airway management must include a rescue plan and preparation for a failed airway (algorithm 4). We suggest that an LMA be used as the initial rescue device for a child with a failed airway who does not have complete upper airway obstruction or an airway condition that could be worsened by injury from attempts to place an LMA (Grade 2B). (See 'Approach to the failed airway' above.) A surgical airway is the only option for a child who has a failed airway with complete upper airway obstruction or an airway condition that could be worsened by injury from attempts to place an LMA. Children ≤10 years of age should receive a needle cricothyrotomy. For children who are older than 10 years, the surgical approach may be dictated by experience of the clinician. (See 'Approach to the failed airway' above and "Needle cricothyroidotomy with percutaneous transtracheal ventilation".) We suggest that oxygen be delivered from a low pressure source when a needle cricothyrotomy is performed (Grade 2C). Jet ventilation is unlikely to improve ventilation and the risk of injury may be significant.

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Emergency airway management in the adult with direct airway trauma Authors Trevor J Mills, MD, MPH Peter DeBlieux, MD Section Editor Ron M Walls, MD, FRCPC, FAAEM Deputy Editor Jonathan Grayzel, MD, FAAEM Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: feb 9, 2012. INTRODUCTION — Airway management in patients who have sustained direct trauma to the airway is among the most challenging problems for emergency clinicians. Blunt or penetrating injuries to the head, oropharynx, neck, or upper chest can result in immediate or delayed airway obstruction. Immediate, definitive airway management is needed when the patient cannot protect their airway or is unable to adequately oxygenate or ventilate. Emergent or urgent airway management is indicated when a patient develops respiratory distress or when symptoms are progressing rapidly. In addition, airway management often is indicated when the patient appears clinically stable, but the clinician anticipates clinical decline (eg, smoke inhalation, edema, subcutaneous air, hematoma) or feels that an unprotected airway presents a risk to the patient who requires transport to another facility or to radiology for extensive diagnostic studies. The higher rate of complicated airways in this population mandates that the clinician be prepared to use advanced airway techniques, including a surgical airway. Airway assessment and management in adults with direct airway trauma will be reviewed here. Other aspects of airway management, including a general approach to the difficult airway, the decision to intubate, and advanced tools for airway management, are discussed separately. (See "The difficult airway in adults" and "Rapid sequence intubation in adults" and "Devices for difficult emergency airway management in adults" and "The decision to intubate" and "Basic airway management in adults".) The general management of trauma to the head and neck is also discussed separately. (See "Facial trauma in adults" and "Penetrating neck injuries" and "Skull fractures in adults".) CAUSES OF AIRWAY TRAUMA — Common causes of direct airway trauma include the following:
   

Blunt or penetrating maxillofacial injury Blunt or penetrating neck injury Smoke inhalation or facial burns Caustic ingestion

Face and neck injuries from blunt or penetrating trauma can cause severe bleeding into the oropharynx, expanding hematomas within soft tissue, and disruption of bone and soft tissue. Smoke inhalation, burns of the face and oropharynx, and caustic ingestions are all capable of causing mucosal injury and severe swelling and edema within the oropharynx, larynx, and tracheobronchial tree. It is crucial that emergency airway managers recognize that such injuries are dynamic and that conditions can deteriorate quickly. Hematomas and soft tissue swelling can expand rapidly, converting a partially obstructed airway into a completely obstructed airway. The general management of the injuries listed here is discussed separately. (See "Facial trauma in adults" and "Penetrating neck injuries" and "Smoke inhalation" and "Emergency care of moderate and severe thermal burns in adults" and "Caustic esophageal injury in adults".) AIRWAY ASSESSMENT Determining the need for immediate intervention — The first step in managing patients with direct airway trauma is to rapidly assess the patient and their airway to determine whether a definitive airway is needed emergently. Unresponsive patients and those with inadequate respiratory function are intubated during or immediately following evaluation. Patients in obvious respiratory distress also require prompt intubation. This includes patients struggling to breathe because of their injuries and those who have sustained severe burns of the face or who demonstrate blistering or edema of the oropharynx. Patients incapable of protecting their airway, as demonstrated, for example, by inability to clear debris from the oropharynx (eg, teeth, bone fragments, foreign bodies, emesis), also require prompt intubation. A simple assessment consisting of four basic questions often distinguishes patients requiring intubation from those who may be observed. An affirmative answer to any of the following questions identifies the need for intubation in nearly all scenarios involving direct airway trauma:
   

Is there failure of airway maintenance or protection? Is there failure of ventilation? Is there failure of oxygenation? Is deterioration, particularly of the airway, anticipated? (ie, What is the expected clinical course?)

This approach to intubation and management of the failed airway is discussed in detail separately. (See "The decision to intubate" and "The failed airway in adults".) Direct trauma to the airway can cause conditions that deteriorate precipitously leading to complete airway obstruction. Examples include expanding hematomas following blunt or penetrating trauma and soft tissue swelling following smoke inhalation or caustic ingestion. Of note, the progression of an airway injury, such as a soft tissue hematoma, may involve the deep tissue planes of the neck and therefore not become clinically apparent until airway

obstruction is nearly complete and the chance for successful intervention is slim. Therefore, the risk of rapid airway compromise is a common and important reason for early intubation in patients with direct airway trauma. Signs of airway compromise — In patients with direct trauma to the face, neck, or upper chest who do not have a crash airway, the clinician performs a careful examination looking for signs of airway compromise. These signs may include any of the following:
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Direct signs of airway compromise: Dyspnea Stridor Indirect signs of airway compromise: Drooling Trismus Painful swallowing (odynophagia) Tracheal deviation or other anatomical abnormality involving the larynx or trachea Signs of developing airway compromise: Nonsuperficial burns of the face or neck Severe bleeding in the oropharynx or nasopharynx Subcutaneous air (crepitus) in the neck or upper chest Hematoma in the neck or lower face Hoarseness or other alterations in voice Subjective sense of shortness of breath despite adequate oxygen saturation

If any such signs are identified, it is generally prudent to secure the patient's airway early, before significant further deterioration occurs. Of note, the signs listed above may not be present during the clinician's initial examination. Frequent reexamination is needed in patients who have sustained significant direct trauma to the airway but whose airway is not secured early. (See 'Patients appropriate for observation' below.) A subset of initially stable patients is at higher risk of progressing to an unstable and potentially difficult airway. Patients with any of the following signs or conditions often require early intubation to prevent subsequent airway compromise or collapse:
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Unstable mandible or midface injuries Steady bleeding into the oropharynx or nasopharynx Worsening or fluctuating level of consciousness

Determining difficulty with management — Emergency clinicians should assess the patient's airway for potential difficulty with bag-mask ventilation, endotracheal intubation, rescue device placement, and cricothyrotomy. Mnemonics that can be used for these

assessments are provided here and discussed in detail separately (table 1 and table 2 and table 3 and table 4). (See "The difficult airway in adults".) [1]. Difficulty with bag-mask ventilation should be anticipated in patients who have sustained severe maxillofacial injuries that disrupt bones and create instability or disfigurement in the middle or lower face. Such injuries make it difficult to maintain a proper mask seal. Obstruction from heavy bleeding, soft tissue swelling, or hematoma can interfere with effective bag-mask ventilation. Posterior displacement of severe fractures of the maxilla or mandible can also obstruct the patient's airway [2]. Subcutaneous air in the neck or communicating injury that establishes an external opening from any part of the airway (mouth, oropharynx, larynx, trachea) makes bag-mask ventilation impossible and also increases the likelihood that bag-mask ventilation will further distort anatomy, making subsequent airway rescue maneuvers more difficult. Bleeding and disruption of normal anatomy can make laryngoscopy and intubation extremely difficult. Mouth opening may be limited and should be carefully assessed with the anterior portion of the cervical collar removed. Bleeding, soft tissue swelling, and debris can obscure the view of the glottis during laryngoscopy, making effective suction essential. In-line stabilization of the neck is recommended in all blunt trauma patients during intubation, although it increases the difficulty of the procedure. In penetrating trauma, the role of in-line stabilization is controversial. Victims of isolated penetrating trauma who are neurologically intact rarely have unstable bony spinal columns and so are at low risk of sustaining a spinal cord injury during intubation [3]. However, a patient with penetrating injury may have concomitant blunt injury. Examples include a patient who is shot then falls down a flight of stairs or a patient who sustains a stab wound to the neck while also being beaten about the head and neck with blunt objects. Although in-line stabilization should be maintained if the clinician harbors any doubt about spinal column injury, the risk of unstable bony injury is so low in isolated penetrating injury with intact neurological examination that, if the operator is unable to see the glottis satisfactorily to intubate, it may be preferable to relax spinal immobilization somewhat to achieve a gentle intubation rather than allow hypoxemia to occur. Judgment is required to determine which of the two threats (hypoxemia caused by a failed airway versus spinal cord injury caused by spinal column movement) represents a more realistic or serious risk to the patient. Placement of a rescue device (eg, laryngeal mask airway) can be difficult if mouth opening is limited, if the airway is disrupted or distorted (eg, by swelling), or if debris such as teeth or bone fragments are present. Cricothyrotomy can be difficult if normal anatomic relationships are disrupted or a hematoma is present at the anterior neck. MANAGEMENT

Guiding principle: Secure the airway early — Injuries sustained from direct trauma to the airway are often dynamic and conditions can deteriorate quickly [4]. As examples, hematomas and soft tissue swelling can expand rapidly, converting a partially obstructed airway into a completely obstructed airway. Signs suggestive of imminent obstruction are described above. (See 'Signs of airway compromise' above.) It is best to secure the airway early whenever signs of active or impending obstruction are identified or there is doubt about the extent of the injuries or their likely course. Doing so enables clinicians to secure the airway under relatively controlled circumstances before complete obstruction occurs and a crisis ensues. The basic and advanced techniques used to manage the airway are discussed separately. (See "Rapid sequence intubation in adults" and "The difficult airway in adults" and "Basic airway management in adults" and "Devices for difficult emergency airway management in adults".) Crash airway: No time available — Patients with direct trauma to their airway may present in extremis, unresponsive to the examiner and without effective ventilation or circulation (ie, crash airway). The basic approach to the crash airway remains unchanged in such patients. Algorithms outlining the basic approach to the traumatized airway and the crash airway are provided (algorithm 1 and algorithm 2). The airway management algorithms are discussed in detail separately. (See "Advanced emergency airway management in adults" and "The failed airway in adults".) Management of the patient with an exposed trachea, most likely from a stab wound to the neck or a "clothesline" type injury, differs from the standard management of a crash airway. In such a circumstance, the airway manager prevents the inferior portion of the trachea from retracting into the chest by grasping it with a towel clip or clamp and the exposed trachea is then intubated directly. The general management of penetrating neck wounds is discussed separately. (See "Penetrating neck injuries".) Time available and difficult airway anticipated — The difficult airway algorithm© provides the fundamental approach to the patient with direct airway trauma who requires intubation and whose airway is anticipated to be difficult (algorithm 3 and algorithm 1). The specific approach selected is determined by the patient's injuries, patient attributes that suggest difficult airway management, the skills of the airway manager, and the resources available. The traumatized airway can be difficult to manage and it is important to obtain whatever help is available. The general approach to the difficult airway is discussed separately; aspects of management related to the traumatized airway are discussed below. (See "The difficult airway in adults".) The most important questions to ask when faced with a traumatized airway (or any difficult airway) are:
 

Is there time? In other words, can the patient's oxygen saturation (SpO2) be maintained above 90 percent? Is difficulty with bag-mask ventilation (BMV) anticipated?

If the SpO2 can be maintained above 90 percent, there is some time to consider different approaches and to make preparations. If adequate oxygenation cannot be maintained, a failed airway is present, and a definitive airway must be established promptly (algorithm 4). (See "The failed airway in adults".) If the SpO2 remains above 90 percent and no risk factors for difficult BMV are identified, the clinician may elect to use standard rapid sequence intubation (RSI) to secure the airway. If difficult BMV is anticipated, RSI may pose risks, and an awake approach to intubation may be best. Alternatively, RSI may be undertaken using a "double set-up" in which the patient undergoes RSI with one or two brief attempts at laryngoscopy, proceeding directly to a cricothyrotomy if intubation is not possible. Both the intubation and the cricothyrotomy are prepared for in advance. (See "Rapid sequence intubation in adults".) Of note, subcutaneous emphysema usually represents a contraindication to BMV because gases forced into the airway during BMV can expand the neck's soft tissues, compromising subsequent efforts to ventilate or to intubate. In patients with very minimal detectable subcutaneous air, gentle, controlled bag-mask ventilation might be attempted, but its effectiveness is not assured and it should be abandoned if the subcutaneous air increases in volume. The awake approach to securing the airway involves sedation to the level used for common emergency department procedures (eg, using propofol or ketamine) in conjunction with topical airway anesthesia (eg, using atomized or nebulized lidocaine, or lidocaine paste or jelly). This approach allows the patient to continue to breathe spontaneously while sedation and topical anesthesia enable the clinician to overcome the patient's protective airway reflexes. Excessive blood or secretions in the airway limit the effectiveness of topical anesthetics and may preclude use of the awake approach if adequately deep sedation without topical anesthesia cannot be achieved. (See "The difficult airway in adults", section on 'Awake look'.) The awake but sedated patient can undergo standard direct laryngoscopy, video laryngoscopy, or fiberoptic laryngoscopy. The presence of a large amount of upper airway blood will likely make flexible fiberoptic laryngoscopy difficult or impossible. If the vocal cords are visualized, the clinician can opt to intubate during the awake look without additional medications or to withdraw the laryngoscope and perform standard RSI. We believe in general it is best not to remove the laryngoscope and perform RSI in a patient with direct airway trauma due to the risk of the glottic view deteriorating during the interim. Direct, fiberoptic, and video laryngoscopy are the primary awake intubation techniques used in the setting of the traumatized airway. Flexible fiberoptics require patient stability, time, and operator expertise. Rigid fiberoptic devices (eg, optical stylet) may enable clinicians to obtain a more rapid view of the glottis. Copious blood or secretions in the airway can make fiberoptic laryngoscopy difficult or impossible. Devices used for difficult

airway management are discussed separately. (See "Devices for difficult emergency airway management in adults".) In some instances the clinician will judge RSI to be the best approach despite the presence of a potentially difficult airway, particularly if performed early before significant deterioration occurs (ie, when the anatomy is still close to normal). Several observational studies suggest that RSI is effective in patients with traumatized airways [5,6]. An approach incorporating a double set-up is often prudent when managing patients with traumatized airways, whether laryngoscopy is anticipated to be difficult or not. In this case, double set-up refers to simultaneous preparation for orotracheal intubation and cricothyrotomy. In other words, while medications and equipment are readied for RSI or an awake approach, the patient's neck is cleaned, landmarks identified, and a cricothyrotomy kit opened and prepared at the bedside. This enables the airway manager to shift instantly from an attempt at orotracheal intubation should a failed airway develop suddenly. (See "Emergent surgical cricothyrotomy (cricothyroidotomy)".) In some patients, a surgical airway may be the first and only choice for airway intervention. Severe injuries to the face, larynx, or supraglottic tissues may create an obstruction or an anatomic disruption that prevents the airway manager from gaining access to the glottis and performing orotracheal intubation. A surgical airway is also necessary in the patient with direct airway trauma that has an SpO2 below 90 percent despite optimal BMV, or in whom BMV cannot be performed. Of note, there is no absolute contraindication to cricothyrotomy in a patient who is dying of respiratory causes and who cannot be intubated orally. Supraglottic devices, such as the laryngeal mask airway (LMA), Combitube™, and King LT® airway, may be used as rescue techniques for the patient with direct airway trauma that can be effectively oxygenated by BMV. Such devices should not be used when a supraglottic airway obstruction exists, or when anatomy is significantly distorted. Blind passage of endotracheal tubes should NOT be attempted in patients with direct trauma to their airway because of the risk of exacerbating a preexisting injury. A surgical airway may be the best option in cases where the glottis cannot be seen. Time available and difficult airway NOT anticipated — The patient with direct airway trauma who requires intubation and whose airway is NOT anticipated to be difficult is best managed by rapid sequence intubation (RSI). Assessment of the traumatized airway is discussed above, while the performance of RSI is discussed separately. (See 'Airway assessment' above and "Rapid sequence intubation in adults".) When preparing to perform definitive airway management in the apparently stable patient with direct airway trauma, the clinician must remain alert for signs of early or sudden airway compromise. Traumatized airways can deteriorate unexpectedly without obvious external signs of injury. Both basic and advanced equipment for difficult airway management, including a surgical airway, must be available at the bedside. In many cases, it is best to use a double set-up, in which preparations are made to perform RSI and the

neck is prepared simultaneously for a surgical airway, with the cricothyrotomy kit open and prepared at the bedside. (See "Emergent surgical cricothyrotomy (cricothyroidotomy)".) Emergency clinicians should revert to the difficult airway management algorithm if signs of a potentially difficult airway manifest after the initial airway evaluation (algorithm 3). (See 'Time available and difficult airway anticipated' above.) Patients appropriate for observation — If the patient with direct airway trauma maintains normal vital signs, pulse oximetry, and mental status, and manifests none of the signs of impending airway compromise listed above, the patient is a candidate for observation. However, many patients who sustain direct airway trauma show no initial signs of airway instability but do show signs that suggest impending compromise. These patients need early definitive airway management. By securing the airway early, emergency clinicians avoid precipitant crises when immediate action is required to save the patient's life, the airway has become more difficult to manage, and equipment, medications, and personnel may not be ready. (See 'Airway assessment' above.) Some patients develop airway and breathing difficulties suddenly, despite the absence of external signs of airway compromise. Thus, all patients with direct airway trauma must be monitored closely, and the equipment necessary to place a definitive airway, including those necessary for a surgical airway, should be placed at the bedside. Early flexible fiberoptic examination of the upper airway is often advisable when the patient has minimal or no external signs of trauma, but there is evidence of internal injury, (eg, hoarseness). The monitoring and disposition of patients with direct airway trauma depends upon the nature and severity of injury. Most patients with airway trauma of any significance should remain in the ED or be admitted to a step down or intensive care unit overnight for monitoring. Observation should include frequent reassessment of pulse oximetry, voice quality, adequacy of respiration, swallowing, and bleeding in the airway, late developing hematoma, or any sign of worsening condition. If early fiberoptic examination reveals no internal injury and there is no external evidence of significant injury (eg, no hematoma, crepitus, or bruising) a shorter period of observation in the ED may suffice. There is no literature defining a sufficient period of observation in such cases, but we suggest a minimum of four hours. If the patient is intoxicated or otherwise displays an altered mental status, observation is continued until the mental status is normal and the patient can be reliably assessed. Again, observation is performed for a minimum of four hours following the injury. A subset of patients may undergo treatment in the ED that sufficiently stabilizes their injury such that the development of airway compromise becomes unlikely. Examples may include maxillary or alveolar ridge fractures that are immobilized by oral surgery, oropharyngeal lacerations that are repaired and show no further sign of hemorrhage or developing hematoma, and cases of minor smoke inhalation in whom upper airway endoscopy does not reveal significant edema or thermal injury.

Following treatment and a brief period of observation (eg, four hours), such patients may be discharged with clear verbal and written instructions to return to the emergency department immediately for any concerns. A responsible adult should accompany such patients for approximately 24 hours following discharge. SUMMARY AND RECOMMENDATIONS










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Common causes of direct airway trauma include: blunt or penetrating maxillofacial injury, blunt or penetrating neck injury, smoke inhalation or facial burns, and caustic ingestion. The first step in managing patients with direct airway trauma is to determine whether the airway needs to be secured immediately or urgently. If this is not the case, clinicians then determine whether there are signs of impending airway compromise and possible difficulty with management. (See 'Airway assessment' above.) Injuries sustained from direct trauma to the airway are often dynamic and conditions can deteriorate quickly. It is best to secure the airway early whenever signs of active or impending obstruction are identified or there is doubt about the extent of the injuries or their likely course. (See 'Guiding principle: Secure the airway early' above.) Management of the patient with direct airway trauma varies according to the time and resources available and the difficulties anticipated. An approach to each major scenario is described in the text. (See 'Crash airway: No time available' above and 'Time available and difficult airway anticipated' above and 'Time available and difficult airway NOT anticipated' above.) Patients with direct trauma to their airway may present in extremis, unresponsive and without effective ventilation or circulation (ie, crash airway). The basic approach to the crash airway remains unchanged in such patients. (See 'Crash airway: No time available' above.) The most important questions to ask when faced with a traumatized airway are: Is there time? In other words, can the patient's oxygen saturation (SpO2) be maintained above 90 percent? Is difficulty with bag-mask ventilation (BMV) anticipated?

If the SpO2 can be maintained above 90 percent, there is some time to consider different approaches and to make preparations. If adequate oxygenation cannot be maintained, a failed airway is present and a definitive airway must be established promptly. If the SpO2 remains above 90 percent and no risk factors for difficult BMV are identified, the clinician may elect to use standard rapid sequence intubation (RSI) to secure the airway. If difficult BMV is anticipated, RSI may pose risks and intubation using an awake approach of "double set-up" (ie, simultaneous preparation for RSI and cricothyrotomy) may be best.


If the patient with direct airway trauma maintains normal vital signs, pulse oximetry, and mental status, and manifests NONE of the signs of impending airway compromise listed above, the patient is a candidate for observation. (See 'Patients appropriate for observation' above.)

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REFERENCES
1. Murphy MF, Walls RW. Identification of the difficult and failed airway. In: Manual of Emergency Airway Management, 3rd, Walls RM, Murphy MF. (Eds), Lippincott Williams & Wilkins, Philadelphia 2008. 2. Krausz AA, El-Naaj IA, Barak M. Maxillofacial trauma patient: coping with the difficult airway. World J Emerg Surg 2009; 4:21. 3. Connell RA, Graham CA, Munro PT. Is spinal immobilisation necessary for all patients sustaining isolated penetrating trauma? Injury 2003; 34:912. 4. Walls RW. Trauma. In: Manual of Emergency Airway Management, 3rd, Walls RW, Murphy MF. (Eds), Lippincott Williams & Wilkins, Philadelphia 2008. 5. Bair AE, Filbin MR, Kulkarni RG, Walls RM. The failed intubation attempt in the emergency department: analysis of prevalence, rescue techniques, and personnel. J Emerg Med 2002; 23:131. 6. Mandavia DP, Qualls S, Rokos I. Emergency airway management in penetrating neck injury. Ann Emerg Med 2000; 35:221. Emergency airway management in the morbidly obese patient Authors Christian Arbelaez, MD, MPH Susan Bartels, MD, MPH Calvin A Brown, III, MD Section Editor Ron M Walls, MD, FRCPC, FAAEM Deputy Editor Jonathan Grayzel, MD, FAAEM Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: sep 13, 2011. INTRODUCTION — In patients presenting with acute respiratory or ventilatory failure, the emergency clinician's first responsibilities are to ensure oxygenation and secure the airway. Obesity-related anatomic and physiologic changes make airway management more difficult, and studies have shown a correlation between obesity and difficulty with endotracheal intubation [1-4]. This topic will review airway management in obese and morbidly obese patients. Other aspects of airway management are discussed separately. (See "The difficult airway in adults" and "Rapid sequence intubation in adults" and "Advanced emergency airway management in adults" and "Basic airway management in adults".) OBESITY'S EFFECTS ON THE AIRWAY

Definitions — The evaluation and classification of obesity is discussed in detail separately. A brief overview and aspects of obesity of particular relevance to airway management are reviewed here. (See "Screening for and clinical evaluation of obesity in adults", section on 'Screening'.) Overweight is defined as weight above the normal range. Obesity is defined as an abnormally high percentage of body weight as fat. Body mass index (BMI) is used to distinguish between the two terms and also determines the degree of excess weight. BMI = body weight (in kg) ÷ height (in meters) squared Using the BMI, obesity is then classified as follows:
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Overweight – BMI ≥25.0 to 29.9 kg/m2 Class I obesity – BMI of 30.0 to 34.9 kg/m2 Class II obesity (formerly known as morbid obesity) – BMI of 35.0 to 39.9 kg/m2 Class III obesity (formerly known as severe obesity) – BMI ≥40 kg/m2. This type of obesity is also referred to as severe or extreme obesity.

Physiologic and anatomic changes — The pathophysiology of obesity is discussed in detail separately. Aspects of obesity of particular relevance to airway management are reviewed here. (See "Pathogenesis of obesity", section on 'Physiologic basis for obesity'.) Several physiologic and anatomic changes occur in obese patients that are important for airway management. Both oxygen consumption and carbon dioxide production are increased. These increases result from metabolic activity in excess adipose tissue and from the increased work required of supportive tissues [5]. As a consequence, desaturation time and thus, the "safe apnea period" during rapid sequence intubation, are decreased. The attached figure illustrates time to desaturation for obese patients compared with others (figure 1). (See "Rapid sequence intubation in adults".) Morbidly obese patients have increased airway resistance, an abnormally elevated diaphragm, and increased work of breathing secondary to abnormal chest wall elasticity and resistance to caudad excursion of the diaphragm. These alterations result in shallow, rapid breathing and limited ventilatory capacity and are more pronounced when the patient is supine [2,5,6]. Obesity alters upper airway anatomy. Increased fat deposition in pharyngeal tissues increases the likelihood of pharyngeal wall collapse, which can complicate the performance of rapid sequence intubation [7]. Obesity contributes to the development of many diseases and increases not only the morbidity and mortality from such diseases, but also the incidence of complications from managing them [2,8-10]. Obesity plays a significant role in atherosclerosis, hypertension, diabetes, cardiomyopathy, and arrhythmias, such as bradycardia, second-degree heart block, and ventricular arrhythmias [1]. Obese patients are also at increased risk of

aspiration pneumonitis secondary to an excess volume of gastric acid and increased intraabdominal pressure [5,11]. (See "Health hazards associated with obesity in adults".) The metabolism and pharmacokinetics of commonly used drugs are altered by the physiologic changes of obesity. Lipophilic drugs have a larger volume of distribution (Vd), since the Vd is dependent upon the amount of adipose tissue [6]. Obese patients are known to have higher glomerular filtration rates, and renally excreted drugs may have shorter halflives since their elimination is directly proportional to creatinine clearance. Obesity does not generally affect the clearance of drugs that are metabolized by the liver. Because of the complexity of obesity-related pharmacokinetic changes and because detailed data are lacking for many drugs, individual drug dosing for obese patients remains controversial [12,13]. Drugs that depress the central nervous system, such as opioids, benzodiazepines, and propofol, can both depress respiratory drive and increase the tendency for collapse of the pharyngeal wall [1]. AIRWAY ASSESSMENT Obesity and airway difficulty — The goal of airway assessment is to identify clinical features that predict difficulty in any of the following areas of emergency airway management:
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Ventilation with bag-mask or extraglottic device Laryngoscopy and endotracheal intubation Surgical airway performance

Obesity may complicate the performance of any of these tasks, and therefore, airway management in obese patients should always be considered potentially difficult [14]. However, obese patients are also subject to the same risk factors for difficult airway management as nonobese patients, and whenever possible, a careful evaluation for such factors should be conducted before undertaking airway management. After assessing the patient, the clinician must decide whether to use an awake approach or to proceed with rapid sequence intubation (RSI). Airway assessment and the approach to the difficult airway are discussed in detail separately. (See "The difficult airway in adults".) Aspects of particular relevance to obesity are reviewed below. Bag-mask ventilation — Obesity makes bag-mask ventilation more difficult [1,2,9,10,15]. Redundant upper airway soft tissue coupled with increased body mass results in increased airway resistance. Higher pressures are required to ventilate effectively, and this can lead to difficulty maintaining a mask seal. Oxygen consumption is increased in obese patients, and target oxygen saturations may be difficult to achieve or maintain. Other predictors of difficult bag-mask ventilation are shown in the table (table 1) [16]. (See 'Physiologic and anatomic changes' above.) Endotracheal intubation — Laryngoscopy and endotracheal tube placement can be difficult in obese patients. Such patients may have altered upper airway anatomy resulting in a poor view of the glottis despite optimal laryngoscopic technique. In addition, short, thick necks

may limit mobility and make it difficult to place the patient in the optimal sniffing position. General indicators of difficult intubation are shown in the table (table 2). Studies assessing emergency airway management in obese patients are scarce. Nevertheless, a few studies in the emergency setting and multiple studies performed in the operating room have found an association between obesity and difficult laryngoscopy and endotracheal intubation [3,4,17-23]:






A large retrospective study using the Danish Anesthesia Database found that patients with a BMI above 35 were more likely to be difficult to intubate compared with those with a lower BMI [19]. When controlling for other risk factors, researchers found the odds ratio for the obese patients to be 1.34 (95% CI 1.191.51). One observational study compared the incidence of difficult endotracheal intubation in consecutive obese (n = 129) and lean (n = 134) patients undergoing elective surgery using a validated difficulty score (The Intubation Difficulty Scale, or IDS) [20]. The rate of difficult intubation was 15 percent for obese patients versus 2 percent for lean patients. In obese patients, a Mallampati score of III or IV was the only independent risk factor for difficult intubation (OR 12.51; 95% CI 2.01-77.81) (figure 2). Hypoxemia occurred more frequently in obese patients despite preoxygenation. Another study using the IDS to assess 204 elective surgery patients found endotracheal intubation to be more difficult in obese patients [21]; a study examining 100 consecutive morbidly obese surgical patients arrived at a similar conclusion [22]. The researchers of the latter study found that large neck circumference and high Mallampati score were the only predictors of difficult intubation in this population.

Surgical airway — Excessive soft tissue in the anterior neck limits access to the cricothyroid membrane and makes it difficult to identify the anatomic landmarks needed to perform a cricothyrotomy. Therefore, surgical airways can be extremely difficult in morbidly obese patients. Other limitations to performing a cricothyrotomy are described in the accompanying table (table 3) [16]. AIRWAY MANAGEMENT Bag-mask ventilation — The best method for bag-mask ventilation in obese patients is the two-person technique with oropharyngeal and nasopharyngeal airways in place, unless these airway adjuncts are contraindicated. This approach allows for better patient positioning and mask seal. The performance of bag-mask ventilation, including the twoperson technique, is described separately. (See "Basic airway management in adults".) If possible, the hospital bed is angled with the head up and foot down (reverse Trendelenburg position) to reduce pressure from the abdominal contents on the diaphragm and to shift the weight of the chest wall inferiorly, thereby improving chest wall and diaphragm excursion.

Endotracheal intubation Positioning — In preparation for intubation, the obese patient should be placed in an upright or semi-upright position (eg, reverse Trendelenburg), depending upon the degree of respiratory distress. An upright position improves respiratory function by allowing the diaphragm to fall downward and reducing the weight on the chest wall. Even in trauma patients requiring cervical spine stabilization, the stretcher can be tilted with the head elevated to improve breathing while preparations are made for intubation. (See "Direct laryngoscopy and tracheal intubation in adults", section on 'Laryngoscopy Technique'.) If there is no contraindication (eg, cervical spine precautions), the obese patient should be placed in a ramped or head-elevated position for direct laryngoscopy. In the ramped position, blankets or commercially available beds are used to elevate the head and torso such that the external auditory meatus and the sternal notch are horizontally aligned (picture 1) [24]. The sniffing position has traditionally been recommended to optimize glottic visualization during direct laryngoscopy, but the ramped position appears to be more effective in the obese patient [24-28]. Several studies have compared the positions used to optimize the glottic view:






In a blinded, randomized trial, 60 morbidly obese patients were assigned to either the ramped or to the sniffing position (7 cm head elevation) for direct laryngoscopy and endotracheal intubation prior to surgery [25]. The authors reported that the ramped position provided a significant improvement in the glottic view. A randomized trial of direct laryngoscopy in 40 anesthetized patients found that the glottic view improved by over 50 percent when the head-elevated position was used compared with supine positioning [26]. A study using fresh cadavers found significant improvement in the glottic view during direct laryngoscopy with the head in a fully elevated position compared with either a supine or partially elevated position [27].

Preoxygenation — Preoxygenation is an essential aspect of rapid sequence intubation (RSI). The significance and techniques of preoxygenation are discussed separately. (See "Rapid sequence intubation in adults", section on 'Preoxygenation'.) It can be difficult to achieve and maintain adequate oxygenation in morbidly obese patients. Furthermore, oxygen saturation levels fall faster in the obese during RSI [29]. Thus, it is important to preoxygenate as well as possible. Techniques to optimize preoxygenation include the following:


Administer the highest possible concentration of oxygen via the best available means. Remember that the traditional non-rebreather mask provides about 70 percent oxygen.





A properly configured bag-valve-mask unit can provide 90 to 100 percent oxygen during active breathing, even without bag assist. Place the obese patient in an upright position whenever possible. Use lubricated, bilateral nasal trumpets to assist with oxygenation when needed.

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Oxygen reserves can generally be maximized by administering high-flow oxygen for three to five minutes while the patient breathes their normal tidal volumes. Patients should be allowed to breathe spontaneously without assistance unless adequate oxygen saturation cannot be achieved. When time allows, noninvasive positive pressure ventilation can be used to improve preoxygenation in the morbidly obese [30,31]. This approach is best suited to patients who do not achieve adequate oxygen saturation with standard techniques. A systematic review concluded that preoxygenation in morbidly obese adults is more effective when performed with the patient in the head-up position rather than a supine position [32]. Among several studies that have investigated the effects of positioning on preoxygenation, one assessed the time necessary for desaturation to occur in 40 obese patients undergoing elective surgery [33]. After preoxygenation, induction, and intubation, patients were left apneic until their SpO2 dropped to 90 percent. Preoxygenation in the sitting position increased the mean time needed to desaturate to 90 percent by almost one minute. Other studies have reported similar results [34]. The angle of head elevation that enables optimal preoxygenation while still permitting a good intubating position remains unclear. One option is to preoxygenate with the patient positioned as close to 90 degrees as possible (ie, sitting upright) and then to intubate in the ramped position once induction and paralysis are complete. (See 'Positioning' above.) Providing oxygen by nasal cannula during the apneic phase of RSI may improve oxygenation in obese patients. In a small randomized trial, patients (n = 15) provided with oxygen at 5 L/minute by nasal cannula maintained an SpO2 above 95 percent for a mean of 5.29 minutes compared to 3.49 minutes for those not given oxygen [35]. Medication dosing — Optimal dosing for many drugs in the obese patient remains controversial. Obesity alters the pharmacokinetics and pharmacodynamics of many medications, including some of those used for rapid sequence intubation [5,12,13]. The mechanisms by which obesity alters the effects of drugs are described above. (See 'Physiologic and anatomic changes' above.) Evidence supporting the use of any particular calculation of body weight to determine the dosing of induction or neuromuscular blocking agents (NMBAs) is limited and our approach is based primarily upon clinical experience and pharmacologic considerations, although there is stronger evidence in the case of succinylcholine. In summary, we suggest

using dosing based upon lean body weight (LBW) for induction agents, ideal body weight (IBW) for rocuronium (and vecuronium), and total body weight (TBW) for succinylcholine. We believe the use of LBW for induction agents provides the best trade-off between insufficient sedation, which may occur with dosing based upon IBW, and excessive sedation (possibly leading to hemodynamic compromise), which may occur with dosing based upon TBW. Furthermore, in emergency circumstances, it can be difficult to recall which drugs should be dosed according to which body weight. For this reason as well, we suggest using LBW for all induction agents, unless there is time available to determine the best approach for a particular drug. Commonly used formulas to calculate LBW that rely on height and sex underestimate actual non-adipose tissue mass in the severely obese (Class II or III) and may be difficult to use in emergencies [13,36]. Clinicians can use the attached table or calculators to rapidly estimate LBW and calculate emergent drug doses in the severely obese (table 4) (calculator 1 and calculator 2). The characteristics of particular induction agents may also affect dosing [9]. Thiopental and benzodiazepines may have prolonged effects in obese patients due to their lipophilicity and large volumes of distribution. Dosing for propofol and opioids is generally similar for obese and nonobese patients. Data evaluating etomidate dosing in the obese is scant. Both depolarizing and nondepolarizing NMBAs have been used successfully for the intubation of morbidly obese patients. Dosing succinylcholine by TBW appears to give better results. In one randomized trial, excellent intubating conditions and full paralysis were achieved in all obese patients dosed by TBW while poor intubating conditions were found in one third of patients dosed by IBW [37]. Succinylcholine demonstrated equivalent activity in obese and nonobese adolescents when dosed by TBW [38]. Few studies have evaluated rocuronium use in the morbidly obese. Early reports suggest the duration of action is prolonged in such patients [39,40]. A small randomized trial found that recovery time (ie, time to muscle twitch recovery) was doubled in patients dosed according to TBW compared with IBW, while the time to onset of muscle relaxation was not significantly different (TBW group 77 seconds and IBW group 87 seconds) [41]. A calculator to determine IBW is provided (calculator 3). Rapid sequence intubation — Airway management in the obese patient is always potentially difficult [14]. Based upon an assessment of the patient's airway, the clinician may decide it is prudent to take an "awake look" to determine if rapid sequence intubation (RSI) is appropriate. The clinician can proceed with RSI if the vocal cords are well visualized during the awake look [42]. If the patient is combative or otherwise uncooperative due to respiratory distress and hypoxia, an awake look may not be possible and RSI may provide the best approach for securing the airway [43]. Assessment of the airway for signs of potential difficulty and the awake look are discussed separately. (See "The difficult airway in adults".) Awake intubation in the obese patient is discussed below. (See 'Awake intubation' below.)

When performing direct laryngoscopy in the obese patient, specific pieces of equipment may make management easier. A short laryngoscope handle may be easier to insert. Larger laryngoscope blades, such as a size four Macintosh or Grandview™, can help to control excess soft tissue and improve the glottic view. An endotracheal tube introducer may be extremely helpful in cases of a limited view despite optimal technique and is discussed immediately below. Devices for airway management — Below is a brief description of airway adjuncts that can be employed when managing a difficult airway in an obese patient, particularly a "can't intubate, can ventilate" scenario, in which bag-mask ventilation is successful, but the vocal cords cannot be adequately visualized using direct laryngoscopy to place an endotracheal tube. These devices are discussed in greater detail separately; techniques and evidence concerning their use in the obese are described here. (See "Devices for difficult emergency airway management in adults".)




Optical and video laryngoscopes – Preliminary studies suggest that optical and video laryngoscopes are useful for intubating the morbidly obese patient and have advantages over standard laryngoscopes (picture 2) [44-47]. In one small randomized trial of bariatric surgery patients, a video laryngoscope consistently provided a superior view of the glottis compared to direct laryngoscopy [44]. The Airtraq™, a novel optical laryngoscope, has also demonstrated preliminary success (picture 3) [48]. Laryngeal mask airway (LMA) and laryngeal tubes – LMAs and laryngeal tubes are supraglottic devices, placed blindly, for use in difficult airways and in failed airways as a temporizing measure before cricothyrotomy. They are easy to place, have high ventilation success rates, and have been used effectively in obese patients [49]. They are not definitive airways and likely do not protect against aspiration (picture 4). When using the LMA, patient positioning may be important as excessive resistance to ventilation in the obese may overcome the seal pressure of the LMA cuff, reducing the effectiveness of ventilation. Proper positioning is identical to that used for bag-mask ventilation. (See 'Bag-mask ventilation' above.) Intubating LMAs – The intubating LMA (ILMA) is a laryngeal mask modified to facilitate intubation directly through the mask. Prospective trials suggest it is effective for intubating morbidly obese patients [27,50]. The LMA C-Trach™ is a modified ILMA that allows for video laryngoscopy. Preliminary studies suggest it may be effective in obese patients [51]. Combitube™ – The Combitube™ is a double-lumen rescue device for blind insertion in patients who cannot be intubated. It is an easy to learn technique for untrained medical personnel providing temporary airway support. There are several case reports of its successful use in obese patients [52,53]. The pressure required to break the seal of the Combitube™ is felt to be higher than for the LMA. Endotracheal tube introducer (ETTI) – The endotracheal tube introducer (often referred to as a gum elastic bougie or bougie) is a plastic, semirigid stylet that can be useful when intubating difficult airways and should be available during any attempt to intubate a morbidly obese patient. In the event of a class III vocal cord













view, the clinician may be able to place the introducer into the trachea and then insert the endotracheal tube over it (figure 3). Use of the introducer is described separately. (See "Devices for difficult emergency airway management in adults", section on 'Intubating introducers (gum elastic bougie)'.) Lighted stylets – A light guided stylet transilluminates the soft tissues in the anterior neck and facilitates blind insertion of an endotracheal tube. It can be a useful adjunct in patients with anatomical abnormalities of the airway. However, in morbidly obese patients, transillumination is often hindered due to the extra subcutaneous tissue, particularly in patients with heavily pigmented skin. Fiberoptic stylets – Fiberoptic stylets incorporate a fiberoptic viewing element into the distal end of a metal stylet. There are case reports of their successful use in obese patients [43,54]. Flexible fiberoptic laryngoscopes – Flexible fiberoptic laryngoscopy with light sedation and topical anesthesia is the mainstay of "awake" intubation for the obese patient. (See 'Awake intubation' below.)

Awake intubation — The use of an awake approach to intubation is prudent when traits associated with difficult bag-mask ventilation or endotracheal intubation is identified in the morbidly obese patient. The awake approach is described separately; issues related to its performance in obese patients are reviewed here. (See "The difficult airway in adults".) In patients considered poor candidates for rapid sequence intubation (RSI) because of difficult airway attributes (including obesity itself), awake intubation, using flexible fiberoptic laryngoscopy via the nasal or oral route, often is the best approach, provided time and the necessary equipment and expertise are available. Awake intubation offers superior visualization without the time pressure inherent in the use of neuromuscular blockade, and intubation can be accomplished while the patient continues to maintain respiratory drive and protective airway reflexes. An awake approach usually requires sedation and topical anesthesia [55]. If time permits, topical anesthesia is preceded (by 10 minutes or so) by administration of a mucosal drying agent, such as glycopyrrolate (0.004 mg/kg IM or IV; usual adult dose 0.4 to 0.8 mg), to reduce mucosal moisture, enhance effectiveness of topical anesthetics, and minimize blockage of the fiberoptic lens by secretions. Light to moderate systemic sedation is then given, followed by inspection of the airway using video or direct laryngoscopy or fiberoptic instruments. Failure to obtain an adequate view of the glottis using direct or video laryngoscopy despite excellent technique and effective sedation and topical anesthesia argues against RSI and in favor of switching to a flexible fiberoptic method if possible [17]. When a flexible fiberoptic laryngoscope is used, the procedure continues until the glottis is traversed and the endotracheal tube is introduced over the endoscope into the trachea. If the vocal cords are adequately visualized during the "awake look," the operator may opt to proceed with intubation during awake laryngoscopy or to perform RSI. Immediate intubation may be best in dynamic situations where the airway may degenerate quickly (eg, neck trauma, thermal burns).

Awake intubation requires careful use of medications because obese patients, particularly those with obstructive sleep apnea, have an increased risk of upper airway obstruction precipitated by opioids or sedatives, particularly when these are used in combination [1]. When performing awake intubation in the obese, physicians should use medications with which they are familiar and titrate them to achieve a level of sedation similar to that needed for a painful procedure. The medication chosen should be given in reduced doses, typically 25 to 50 percent of the normal dose (based upon lean body weight), and titrated to the desired effect using small aliquots. Commonly used drugs include ketamine, propofol, midazolam, or etomidate [54,56]. These are often accompanied by fentanyl for analgesia. In more urgent circumstances when time is short or the airway of a combative patient must be assessed, haloperidol (doses of 2 to 10 mg IV) or ketamine (doses of 10 to 20 mg IV) may enable the physician to take an awake look while the patient maintains airway reflexes. Cricothyrotomy — Cricothyrotomy is the technique of choice to secure a failed airway. However, the procedure can be difficult to perform in obese patients, particularly those with a large amount of soft tissue in the anterior neck. If the clinician must perform the procedure in an obese patient, it may be necessary to have an assistant retract redundant soft tissue and to make a generous vertical midline incision [16]. The physician should also be prepared to place an endotracheal tube, rather than a standard cricothyrotomy tube, in case the latter is too short. The performance of cricothyrotomy is discussed separately. (See "Emergent surgical cricothyrotomy (cricothyroidotomy)".) Mechanical ventilation — Providing adequate ventilation and oxygenation to the intubated obese patient can be difficult. Tidal volumes are calculated based upon the patient's ideal body weight (obesity does not change underlying lung volumes) and then adjusted according to the clinical response, using airway pressures, oxygen saturation, and blood gas results. Oxygenation and ventilation can be improved in the morbidly obese by placing them in a more upright position (eg, reverse Trendelenburg). Management of mechanical ventilation in the emergency department is reviewed separately. (See "Mechanical ventilation of adults in the emergency department".) SUMMARY AND RECOMMENDATIONS






Obesity leads to a number of anatomic and physiologic changes that increase the difficulty of airway management and alter the pharmacology of many medications used for rapid sequence intubation (RSI) and awake intubation. Of note, obese patients desaturate quickly. Bag-mask ventilation, laryngoscopy and intubation, and cricothyrotomy are all more likely to be difficult in such patients. (See 'Physiologic and anatomic changes' above and 'Airway assessment' above.) The best method for bag-mask ventilation in obese patients is the two-person technique with oropharyngeal and nasopharyngeal airways in place, unless these airway adjuncts are contraindicated. Techniques for improving intubation in obese patients include preoxygenating the patient in an upright or semi-upright position and placing the patient in the ramp position (align the external auditory meatus and sternal notch) if cervical spine







precautions are not necessary (picture 1). (See 'Positioning' above and 'Preoxygenation' above.) When performing RSI in the obese patient, we use the following approach to medication dosing: We suggest using the lean body weight (LBW) to determine the dose of the induction agent (Grade 2C); we suggest using the ideal body weight (IBW) to determine the dose of rocuronium (Grade 2C); and we suggest the use of the total body weight (TBW) to determine the dose of succinylcholine (Grade 2B). Based upon the clinical circumstances and the characteristics of the airway, the clinician may decide it is prudent to manage the obese patient's airway using an "awake approach." This approach is described in the text. (See 'Rapid sequence intubation' above and 'Awake intubation' above.) A number of airway adjuncts can be employed when managing a difficult airway in the obese patient. These are described in the text. (See 'Devices for airway management' above.)

DISCLOSURE — Calvin A Brown, III, MD, an author of this topic review, has received research support from Karl Storz Endoscopy. Use of UpToDate is subject to the Subscription and License Agreement.

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11. Passannante AN, Rock P. Anesthetic management of patients with obesity and sleep apnea. Anesthesiol Clin North America 2005; 23:479. 12. Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999; 88:1. 13. Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet 2000; 39:215. 14. Butler KH, Clyne B. Management of the difficult airway: alternative airway techniques and adjuncts. Emerg Med Clin North Am 2003; 21:259. 15. Langeron O, Masso E, Huraux C, et al. Prediction of difficult mask ventilation. Anesthesiology 2000; 92:1229. 16. Murphy, MF, Walls, RM. Identification of the difficult and failed airway. In: Manual of emergency airway management, 3rd ed, Walls, RM (Eds), Lippincott, Williams and Wilkins, Philadelphia 2008. p.82. 17. Grant P, Newcombe M. Emergency management of the morbidly obese. Emerg Med Australas 2004; 16:309. 18. Voyagis GS, Kyriakis KP, Dimitriou V, Vrettou I. Value of oropharyngeal Mallampati classification in predicting difficult laryngoscopy among obese patients. Eur J Anaesthesiol 1998; 15:330. 19. Lundstrøm LH, Møller AM, Rosenstock C, et al. High body mass index is a weak predictor for difficult and failed tracheal intubation: a cohort study of 91,332 consecutive patients scheduled for direct laryngoscopy registered in the Danish Anesthesia Database. Anesthesiology 2009; 110:266. 20. Juvin P, Lavaut E, Dupont H, et al. Difficult tracheal intubation is more common in obese than in lean patients. Anesth Analg 2003; 97:595. 21. Lavi R, Segal D, Ziser A. Predicting difficult airways using the intubation difficulty scale: a study comparing obese and non-obese patients. J Clin Anesth 2009; 21:264. 22. Brodsky JB, Lemmens HJ, Brock-Utne JG, et al. Morbid obesity and tracheal intubation. Anesth Analg 2002; 94:732. 23. Holmberg TJ, Bowman SM, Warner KJ, et al. The association between obesity and difficult prehospital tracheal intubation. Anesth Analg 2011; 112:1132. 24. Rao SL, Kunselman AR, Schuler HG, DesHarnais S. Laryngoscopy and tracheal intubation in the head-elevated position in obese patients: a randomized, controlled, equivalence trial. Anesth Analg 2008; 107:1912. 25. Collins JS, Lemmens HJ, Brodsky JB, et al. Laryngoscopy and morbid obesity: a comparison of the "sniff" and "ramped" positions. Obes Surg 2004; 14:1171. 26. Lee BJ, Kang JM, Kim DO. Laryngeal exposure during laryngoscopy is better in the 25 degrees back-up position than in the supine position. Br J Anaesth 2007; 99:581. 27. Frappier J, Guenoun T, Journois D, et al. Airway management using the intubating laryngeal mask airway for the morbidly obese patient. Anesth Analg 2003; 96:1510. 28. Neligan PJ, Porter S, Max B, et al. Obstructive sleep apnea is not a risk factor for difficult intubation in morbidly obese patients. Anesth Analg 2009; 109:1182. 29. Benumof JL, Dagg R, Benumof R. Critical hemoglobin desaturation will occur before return to an unparalyzed state following 1 mg/kg intravenous succinylcholine. Anesthesiology 1997; 87:979.

30. Delay JM, Sebbane M, Jung B, et al. The effectiveness of noninvasive positive pressure ventilation to enhance preoxygenation in morbidly obese patients: a randomized controlled study. Anesth Analg 2008; 107:1707. 31. El-Khatib MF, Kanazi G, Baraka AS. Noninvasive bilevel positive airway pressure for preoxygenation of the critically ill morbidly obese patient. Can J Anaesth 2007; 54:744. 32. Solis A, Baillard C. [Effectiveness of preoxygenation using the head-up position and noninvasive ventilation to reduce hypoxaemia during intubation]. Ann Fr Anesth Reanim 2008; 27:490. 33. Altermatt FR, Muñoz HR, Delfino AE, Cortínez LI. Pre-oxygenation in the obese patient: effects of position on tolerance to apnoea. Br J Anaesth 2005; 95:706. 34. Dixon BJ, Dixon JB, Carden JR, et al. Preoxygenation is more effective in the 25 degrees head-up position than in the supine position in severely obese patients: a randomized controlled study. Anesthesiology 2005; 102:1110. 35. Ramachandran SK, Cosnowski A, Shanks A, Turner CR. Apneic oxygenation during prolonged laryngoscopy in obese patients: a randomized, controlled trial of nasal oxygen administration. J Clin Anesth 2010; 22:164. 36. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010; 49:71. 37. Lemmens HJ, Brodsky JB. The dose of succinylcholine in morbid obesity. Anesth Analg 2006; 102:438. 38. Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 2000; 90:576. 39. Pühringer FK, Keller C, Kleinsasser A, et al. Pharmacokinetics of rocuronium bromide in obese female patients. Eur J Anaesthesiol 1999; 16:507. 40. Pühringer FK, Khuenl-Brady KS, Mitterschiffthaler G. Rocuronium bromide: timecourse of action in underweight, normal weight, overweight and obese patients. Eur J Anaesthesiol Suppl 1995; 11:107. 41. Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of rocuronium when dosed according to real body weight or ideal body weight in morbidly obese patients. Anesth Analg 2004; 99:1086. 42. Levitan RM. Patient safety in emergency airway management and rapid sequence intubation: metaphorical lessons from skydiving. Ann Emerg Med 2003; 42:81. 43. Levitan RM, Chudnofsky C, Sapre N. Emergency airway management in a morbidly obese, noncooperative, rapidly deteriorating patient. Am J Emerg Med 2006; 24:894. 44. Marrel J, Blanc C, Frascarolo P, Magnusson L. Videolaryngoscopy improves intubation condition in morbidly obese patients. Eur J Anaesthesiol 2007; 24:1045. 45. Dhonneur G, Abdi W, Ndoko SK, et al. Video-assisted versus conventional tracheal intubation in morbidly obese patients. Obes Surg 2009; 19:1096. 46. Maassen R, Lee R, Hermans B, et al. A comparison of three videolaryngoscopes: the Macintosh laryngoscope blade reduces, but does not replace, routine stylet use for intubation in morbidly obese patients. Anesth Analg 2009; 109:1560. 47. Abdelmalak BB, Bernstein E, Egan C, et al. GlideScope® vs flexible fibreoptic scope for elective intubation in obese patients. Anaesthesia 2011; 66:550.

48. Ndoko SK, Amathieu R, Tual L, et al. Tracheal intubation of morbidly obese patients: a randomized trial comparing performance of Macintosh and Airtraq laryngoscopes. Br J Anaesth 2008; 100:263. 49. Zoremba M, Aust H, Eberhart L, et al. Comparison between intubation and the laryngeal mask airway in moderately obese adults. Acta Anaesthesiol Scand 2009; 53:436. 50. Combes X, Sauvat S, Leroux B, et al. Intubating laryngeal mask airway in morbidly obese and lean patients: a comparative study. Anesthesiology 2005; 102:1106. 51. Dhonneur G, Ndoko SK, Yavchitz A, et al. Tracheal intubation of morbidly obese patients: LMA CTrach vs direct laryngoscopy. Br J Anaesth 2006; 97:742. 52. Della Puppa A, Pittoni G, Frass M. Tracheal esophageal combitube: a useful airway for morbidly obese patients who cannot intubate or ventilate. Acta Anaesthesiol Scand 2002; 46:911. 53. Banyai M, Falger S, Röggla M, et al. Emergency intubation with the Combitube in a grossly obese patient with bull neck. Resuscitation 1993; 26:271. 54. Kovacs G, Law AJ, Petrie D. Awake fiberoptic intubation using an optical stylet in an anticipated difficult airway. Ann Emerg Med 2007; 49:81. 55. Wieczorek PM, Schricker T, Vinet B, Backman SB. Airway topicalisation in morbidly obese patients using atomised lidocaine: 2% compared with 4%. Anaesthesia 2007; 62:984. 56. Murphy, MF. Sedation and anesthesia for awake intubation. In: Manual of emergency airway management, 3rd ed, Walls, RM (Eds), Lippincott, Williams and Wilkins, Philadelphia 2008. p.82. Topic 283 Version 8.0 © 2012 UpToDate, Inc. All rights reserved. | Subscription and License Agreement |Release: 20.3 - C20.4 Licensed to: UTPL |Support Tag: [ecapp1005p.utd.com-200.0.29.70-8DA7D5FDCB50339.14]

TOPIC OUTLINE
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INTRODUCTION OBESITY'S EFFECTS ON THE AIRWAY Definitions Physiologic and anatomic changes AIRWAY ASSESSMENT Obesity and airway difficulty Bag-mask ventilation Endotracheal intubation Surgical airway AIRWAY MANAGEMENT Bag-mask ventilation Endotracheal intubation

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- Positioning - Preoxygenation - Medication dosing - Rapid sequence intubation - Devices for airway management - Awake intubation Cricothyrotomy Mechanical ventilation SUMMARY AND RECOMMENDATIONS DISCLOSURE REFERENCES

GRAPHICSView All
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FIGURES Time to desaturation Mallampati classification SunMed bougie PICTURES RAMP position Storz C Mac video laryngoscope Airtraq device Laryngeal mask airway TABLES MOANS mnemonic LEMON mnemonic SHORT mnemonic IBW LBW obesity approx

CALCULATORS
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Help improve UpToDate. Did UpToDate answer your questio Malignant hyperthermia: Clinical diagnosis and management of acute crisis Author Ronald S Litman, DO, FAAP Section Editor Stephanie B Jones, MD Deputy Editor Kathryn A Collins, MD, PhD, FACS Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: abr 2, 2010. INTRODUCTION — Malignant hyperthermia (MH) manifests clinically as a hypermetabolic crisis when an MH-susceptible individual is exposed to an inhalational anesthetic (eg, halothane, isoflurane, enflurane, sevoflurane, desflurane), or depolarizing muscle relaxant (eg, succinylcholine) [1-5]. This topic will discuss the incidence, clinical manifestations and acute management of MH. Susceptibility to MH is discussed elsewhere. (See "Susceptibility to malignant hyperthermia".) EPIDEMIOLOGY — The clinical incidence of acute MH for a given population depends upon the prevalence of MH-susceptibility, and use of triggering anesthetics. (See "Susceptibility to malignant hyperthermia", section on 'Genetic basis'.) The incidence of acute MH in the general population is estimated to be about 1:30,000 administered anesthetics, occurring in all ethnic groups in all parts of the world. The incidence is probably underestimated because unrecognized, mild, or atypical reactions likely occur due to variable penetrance of the inherited trait. Children under 19 years account for between 45 and 52 percent of reported events [6,7]. Reactions occur more frequently in males compared to females (2:1) [6-8]. TRIGGERING AGENTS — Nearly all known cases of MH have occurred while the patient was receiving an inhalational anesthetic agent (eg, halothane, sevoflurane, desflurane), with or without administration of succinylcholine. In MH-susceptible patients, these agents cause unregulated release of calcium from the sarcoplasmic reticulum leading to myocyte hypermetabolism. (See "Susceptibility to malignant hyperthermia", section on 'Pathophysiology'.)

Rarely, MH has also been reported following administration of succinylcholine in the absence of an inhalational agent (eg, to facilitate endotracheal intubation). MH-susceptible patients exposed to heat stress or vigorous exercise can also develop acute MH. (See "Susceptibility to malignant hyperthermia", section on 'Conditions associated with MH'.) MH-susceptible patients may not consistently develop the acute syndrome with each anesthetic exposure. An acute MH crisis may develop at first exposure to a triggering agent; however, on average, patients have had three exposures prior to having a documented reaction [6]. ANESTHESIA HISTORY — The anesthesia history should include questions about prior adverse reactions to anesthetic exposure in the patient and their family members. The majority of patients will give a negative history, however, a negative family history, or previous uneventful exposure to triggering anesthetic agents are not reliable at excluding a susceptibility for MH [9]. Approximately half of patients who develop acute MH have prior uneventful exposures to triggering agents [7,10]. On occasion a patient may offer specific information regarding a familial susceptibility with a known mutation, or may state they reportedly became rigid with anesthesia. Under these circumstances susceptibility to MH should be assumed and triggering agents avoided. Soliciting questions about temperature elevation is not useful given the common occurrence of non-MH related postoperative fever. CLINICAL DIAGNOSIS — During an acute event, diagnosis of MH is based upon clinical manifestations (table 1), most importantly the presence of a mixed metabolic and respiratory acidosis, manifested as an increased end-tidal carbon dioxide (ETCO2) level, when all other reasonable causes have been ruled out. (See 'Clinical manifestations' below and 'Approach to hypercapnia' below.) Triggering agents are discontinued and dantrolene is administered to any patient suspected of having acute MH. (See 'Acute management' below.) Following an acute event, the determination of whether a suspected clinical event represents a true MH episode is estimated using the MH clinical grading scale (calculator 1) [11,12]. (See "Susceptibility to malignant hyperthermia", section on 'MH clinical grading'.) Definitive diagnosis can be achieved through susceptibility testing. (See "Susceptibility to malignant hyperthermia", section on 'Susceptibility testing'.) Differential diagnosis — A number of conditions may present perioperatively with clinical manifestations (eg, hypercapnia, tachycardia, muscle rigidity, rhabdomyolysis, hyperthermia, arrhythmia) that are similar to those with acute MH (table 2). (See 'Clinical manifestations' below.)

Consideration of these diagnoses should not interfere with prompt treatment of suspected acute MH. (See 'Acute management' below.) Approach to hypercapnia — An unexpected rise in the ETCO2 level is the earliest sign of MH; therefore, early exclusion of technical factors, sources of decreased carbon dioxide elimination, or increased carbon dioxide production that could account for hypercapnia is important. Hypercapnia during general anesthesia or sedation is usually due to hypoventilation from shallow breathing or a diminished respiratory rate. Patients who are machine ventilated may have sub-optimal ventilation parameters or a technical malfunction of the anesthesia machine, breathing circuit, ventilator, or monitor. Carbon dioxide accumulation is identified as a rise in ETCO2. Increasing minute ventilation with supplemental bag ventilation, or correcting ventilator settings or malfunction should correct the ETCO2 in the setting of hypoventilation. Any condition that impairs the elimination of carbon dioxide, such as bronchial obstruction or pneumothorax, will increase the ETCO2. These conditions should be corrected as soon as recognized. During laparoscopic surgery, ETCO2 can also rise due to carbon dioxide retention. Temporarily releasing the pneumoperitoneum should restore CO2 levels to normal within a reasonable timeframe; however, carbon dioxide that has insufflated into the subcutaneous tissues may be slower to clear. Sources of increased carbon dioxide production may be difficult to distinguish from MH. Carbon dioxide production is increased in patients with thyrotoxicosis, pheochromocytoma, or sepsis and these conditions may be accompanied by tachycardia and alterations in blood pressure. While these signs mimic the early signs of MH, other signs of MH, such as mixed acidosis, rigidity or rhabdomyolysis, will be absent. (See 'Clinical manifestations' below.) The use of a vascular clamp (eg, aortic cross clamp), or tourniquet for prolonged periods of time leads to retention of metabolic products (ie, CO2, lactate), which are then released into the circulation when the clamp or tourniquet is released. The resulting acidosis is usually transient and not likely to be confused with the mixed acidosis of acute MH. CLINICAL MANIFESTATIONS — The clinical manifestations vary, but early clinical findings typically include hypercapnia, sinus tachycardia, and masseter or generalized muscle rigidity [7,12]. The earliest sign is an unexpected rise in the ETCO2; therefore, early exclusion of other sources of decreased carbon dioxide elimination, or increased carbon dioxide production that account for hypercapnia is important. (See 'Approach to hypercapnia' above.) There is a widespread misconception that acute MH may begin in the postoperative period with hyperthermia as the initial presenting sign. Hyperthermia is a later sign of MH and is typically absent when the diagnosis is initially suspected. Hyperthermia and signs of tissue hypoxia can be accompanied by hypotension, complex dysrhythmias, rhabdomyolysis, electrolyte abnormalities, disseminated intravascular coagulation (DIC), and mixed acidosis. (See "Susceptibility to malignant hyperthermia", section on 'Pathophysiology'.)

The clinical signs present perioperatively in one of the following patterns:
   

Intraoperatively, within one hour of anesthetic induction, though delayed intraoperative reactions do occur [13-16] After the cessation of the anesthetic agent, usually within minutes [16-20] Postoperatively, as delayed rhabdomyolysis in an otherwise asymptomatic patients [21-25] Following successful treatment, recrudescence occurs in up to 25 percent of patients and is more likely in patients with increased muscle mass [26].

Early signs Hypercapnia — The most reliable initial clinical sign heralding the development of acute MH is hypercapnia resistant to increasing the patient's minute ventilation. With acute MH, hypercapnia is due to cellular hypermetabolism, which causes metabolic acidosis. (See "Susceptibility to malignant hyperthermia", section on 'Pathophysiology'.) Disproportionate increases in minute ventilation are required to normalize ETCO2 levels in the setting of MH. The greatly increased exhaled CO2 heats the CO2 absorbent (ie, exothermic reaction) warming the ventilator absorbent canister (picture 1). (See 'Approach to hypercapnia' above.) Tachycardia — Tachycardia is another early sign of acute MH and may be associated with hypertension. However, tachycardia is relatively nonspecific. Other causes of tachycardia and hypertension that need to be distinguished from MH include inadequate depth of anesthesia, sepsis, thyrotoxicosis, pheochromocytoma, cocaine toxicity, alcohol withdrawal, amphetamine toxicity, and sympathomimetic toxicity. A discussion of these disorders is found in individual topic reviews. (See 'Differential diagnosis' above.) Calcium channel blockers are absolutely contraindicated in the acute management of MH since they can worsen hyperkalemia. Masseter muscle rigidity — Masseter muscle rigidity (MMR) is the inability to open a patient's mouth after the administration of a triggering agent. This sign is not specific enough to make a definitive diagnosis in the absence of additional signs of hypermetabolism, however, when MMR is observed, all triggering agents should be discontinued and the patient carefully monitored for additional signs that may indicate development of acute MH. (See 'Acute management' below.) Masseter muscle tension normally increases after the administration of succinylcholine, but typically lasts only a few seconds. When it persists, MMR indicates the initiation of acute MH in up to 30 percent of cases [27]. In the pediatric population, MMR has occurred in up to one percent of children who received succinylcholine, and is more common in children with strabismus or a subclinical myopathy [28].

Patients who exhibit MMR subsequent to succinylcholine administration should undergo diagnostic testing for MH-susceptibility. Up to 50 percent of these patients will have a positive contracture test [29]. (See 'Counseling after acute MH' below and "Susceptibility to malignant hyperthermia", section on 'MH-susceptibility testing'.) Generalized muscle rigidity — Generalized muscle rigidity in the presence of neuromuscular blockade is considered pathognomonic for MH, provided other confirmatory signs of hypermetabolism are also present. Later signs ECG changes — ECG changes and arrhythmias due to elevated potassium levels from muscle breakdown can occur rapidly in muscular patients. The presence of hyperkalemia greatly strengthens a diagnosis of MH. (See "Susceptibility to malignant hyperthermia", section on 'Pathophysiology'.) The presence of premature ventricular contractions may indicate life-threatening hyperkalemia, and is an ominous sign as it may degrade into ventricular tachycardia or ventricular fibrillation. (See "Treatment and prevention of hyperkalemia".) Rhabdomyolysis — Peak creatine kinase (CK) levels depend upon the muscle mass of the patient, and severity of muscle breakdown. Plasma CK and urine myoglobin levels peak around 14 hours after an acute MH episode. A postoperative (within 24 hours) rise in CK (>20,000 U/L) is predictive of MH-susceptibility in over 80 percent of patients who had an episode suspicious for acute MH [30]. In muscular patients, levels may exceed 100,000 units/L. Brownish or tea-colored urine indicates the presence of myoglobinuria, which should be treated. (See "Prevention and treatment of heme pigment-induced acute kidney injury (acute renal failure)", section on 'Prevention'.) There are a number of reports of seemingly normal patients with postoperative rhabdomyolysis and myoglobinuria without any of the other classic signs of MH. MH contracture testing in these patients may be positive, however, it is unclear whether they have true MH-susceptibility or a subclinical muscle disease resulting in false-positive test results [21-24]. (See "Susceptibility to malignant hyperthermia", section on 'MHsusceptibility testing'.) Hyperthermia — As discussed above, there is a widespread misconception that acute MH may begin in the postoperative period with hyperthermia as the initial presenting sign, but hyperthermia is a later sign of MH and is typically absent when the diagnosis is initially suspected. Sustained muscle contraction from unregulated calcium release generates more heat than the body is able to dissipate. Marked hyperthermia occurs minutes to hours following the initial onset of symptoms. In some cases, core body temperature may rise 1ºC every 5

minutes. Severe hyperthermia (up to 45ºC [113ºF]) leads to a marked increase in carbon dioxide production, and increased oxygen consumption can cause widespread vital organ dysfunction. Severe hyperthermia is associated with development of disseminated intravascular coagulation (DIC), a poor prognostic indicator and often terminal event [31]. (See 'Mortality' below.) Causes of fever other than acute MH are much more common perioperatively. Fever can be due to transient bacteremia or the effects of anesthetics and/or surgery on the hypothalamic thermoregulatory system [32,33]. Patients undergoing surgery involving endothelial surfaces (GI tract, urogenital tract, etc) are particularly prone to develop fever. Sepsis may be accompanied by fever, metabolic acidosis and elevations in CK, making it difficult to distinguish from MH. Consideration of these diagnoses should not interfere with proceeding to an acute MH management protocol based upon the developing clinical scenario. (See 'Acute management' below and "Postoperative fever" and "Management of severe sepsis and septic shock in adults".) ACUTE MANAGEMENT — Acute MH is strongly suspected when the anesthesiologist cannot control a rising ETCO2 level despite compensatory increases in minute ventilation. The diagnosis is further supported by muscle rigidity (masseter muscle or generalized), or an otherwise unexplained metabolic acidosis. When these clinical signs occur, dantrolene is administered immediately and triggering agents are discontinued. Additional anesthesia personnel are summoned to assist in preparing the dantrolene and initiating the MH protocol. As recommended by the Malignant Hyperthermia Association of the United States (MHAUS), an appropriately stocked MH treatment cart should be immediately available at all times (table 3). Efficient management of the patient suspected of having malignant hyperthermia includes all of the following (table 4): Optimize oxygenation and ventilation — Increase inspired oxygen to 100 percent. Increase ventilation rate and/or tidal volume to maximize ventilation and reduce the ETCO2. If the patient is not intubated, endotracheal tube placement should be performed simultaneously with the remainder of the protocol. Discontinue triggering agents — Immediately discontinue triggering agents and inform the operating surgeon of the diagnosis and the need to complete the surgical procedure as quickly as possible. If the surgical procedure cannot be aborted, it should be completed while the patient receives intravenous anesthesia with non triggering agents, usually propofol. (See "Susceptibility to malignant hyperthermia", section on 'Anesthesia in MHsusceptible patients'.) Administer dantrolene — Dantrolene is the only known antidote for MH. Dantrolene binds to ryanodine receptors (RYR1) and directly inhibits sarcoplasmic reticulum calcium release thereby reversing skeletal muscle hypermetabolism [34-36]. Prior to the introduction of dantrolene, mortality was as high as 70 percent, but is now estimated to be between 1 and 17 percent [37,38]. (See "Susceptibility to malignant hyperthermia", section on 'Pathophysiology'.)

Dantrolene is supplied as a lyophilized powder (20 mg) vial that also contains 3 g of mannitol and sodium hydroxide to maintain pH of 9 to 10. It should be mixed in warmed sterile water to enhance its solubility [39]. A newer formulation is available that solubilizes much more readily [40]. The importance of summoning additional personnel to assist with drug preparation and administration, and to assist with patient management cannot be overstated. Dantrolene is administered as a loading bolus of 2.5 mg/kg intravenously, with subsequent bolus doses of 1 mg/kg intravenously until the signs of acute MH have abated; the ETCO2 should normalize as the dantrolene takes effect. In most cases, dantrolene reverses the acute hypermetabolic process within minutes. The need to use higher doses is uncommon and the clinician should question the accuracy of the diagnosis if a rapid response is not seen; however, some patients, especially muscular males, may require initial dantrolene doses approaching 10 mg/kg intravenously. All facilities where general anesthesia is administered should have an adequate stock of dantrolene in the event that MH occurs. The Malignant Hyperthermia Association of the United States (MHAUS) recommends each facility have a treatment protocol, and dedicated MH treatment cart containing dantrolene (36 vials available at all times), along with other medications and equipment needed to immediately treat an acute episode (table 3). (See 'Acute management' above.) Monitor for hyperkalemia — Hyperkalemia is treated (ie, calcium, bicarbonate, and insulinglucose) based upon the presence of abnormal ECG waveforms (ie, peaked t waves) to prevent the development of life-threatening arrhythmias or cardiac arrest. Individuals with greater muscle mass are at an increased risk for hyperkalemia from rhabdomyolysis. (See "Treatment and prevention of hyperkalemia".) Calcium channel blockers are absolutely contraindicated in the acute management of MH since they can worsen hyperkalemia. Check labs — Measure electrolytes, acid/base status, creatine kinase (CK), coagulation parameters and fibrin split products. Arterial or venous blood gases should be collected initially as needed until pH and potassium levels trend toward normal values. Initiate supportive care




Continue to monitor the patient's core temperature (eg, esophageal, ear, rectal probe). Institute cooling measures and continue them until the patient's temperature drops below approximately 38.5ºC (101.3ºF). In a review of the North American MH Registry database, the median maximal temperature of patients who developed disseminated intravascular coagulation (DIC) was significantly greater than those who did not (40.3ºC versus 39.0ºC) [7]. (See "Severe hyperthermia (heat stroke) in adults", section on 'Cooling measures'.) Place a Foley catheter (if not in place) to monitor urine color and volume. In the absence of red blood cells, a urine dipstick positive for heme indicates myoglobinuria. Urine output should be kept at 1 to 2 mL/kg/hour until the urine





color returns to normal and the CK begins to decrease (See "Red to brown urine: Hematuria; hemoglobinuria; myoglobinuria".) Creatinine kinase (CK) values will usually peak around 14 hours after the initiation of MH and should be measured twice daily until decreasing levels are observed. The patient's muscle compartments should be monitored carefully; rhabdomyolysis can result in acute compartment syndrome especially if the patient has developed DIC. Muscle compartment release (ie, four compartment fasciotomy) may be required. (See "Acute compartment syndrome of the extremities".) Institute measures to prevent myoglobinuria-induced renal failure (ie, hydration, diuretics, bicarbonate). (See "Prevention and treatment of heme pigment-induced acute kidney injury (acute renal failure)", section on 'Prevention'.)

MHAUS hotline and support — 24 hour support is available from consultants at the Malignant Hyperthermia Association of the United States (MHAUS) 1-800-MH-HYPER.


medical.mhaus.org/index.cfm/fuseaction/Hotline.Home.cfm

Their acute management algorithm can be found at:


medical.mhaus.org/PubData/PDFs/treatmentposter.pdf

Additional information about MHAUS is found elsewhere. (See "Susceptibility to malignant hyperthermia", section on 'MH resources'.) ONGOING CARE — With the completion of the surgical procedure, the patient should be transferred to an intensive care unit for ventilatory support and hemodynamic monitoring. Because recrudescence occurs in up to 25 percent of patients after initial treatment, maintenance doses of dantrolene (1 mg/kg every 6 hours) should continue for 48 hours after the last observed sign of acute MH [26,41]. If recurrent signs appear in spite of ongoing treatment, additional dantrolene boluses may be required. Alternatively, a dantrolene infusion (0.1 to 0.3 mg/kg/hour) can be used. Dantrolene has no effect on cardiac or smooth muscle. Its most common local adverse reaction is venous irritation or thrombosis at the site of administration due to its high pH. Side effects include nausea, malaise, lightheadedness, and mild to moderate muscle weakness. Respiratory muscle weakness may occur when larger doses are used especially in patients who are debilitated. MORTALITY — Mortality from MH has declined significantly and is estimated to be between 1 and 17 percent [37,38]. A study from the North American Malignant Hyperthermia Registry (NAHMR) reported a mortality rate of 1.4 percent [37]. Patients with advancing age, greater comorbidities, heavy muscular build (eg, young males), and those who develop disseminated intravascular coagulation are at greater risk for cardiac arrest or death.

COUNSELING AFTER ACUTE MH — Following recovery from an acute MH event, patients are informed that until evaluation for MH-susceptibility can be performed they should:
  

Not have anesthesia with triggering agents. Avoid excessive heat and humidity as these may trigger an event. Inform their family members. MH-susceptibility is a genetic condition and family members may also need to be evaluated.

MH-susceptible patients are encouraged to learn as much as possible about the nature of their condition and should be directed to the appropriate educational resources. (See "Susceptibility to malignant hyperthermia", section on 'Anesthesia in MH-susceptible patients' and "Susceptibility to malignant hyperthermia", section on 'MH resources'.) SUMMARY AND RECOMMENDATIONS








Malignant hyperthermia (MH) is a genetic disorder of skeletal muscle metabolism that can manifest clinically as a hypermetabolic crisis in genetically predisposed individuals who are exposed to inhalational anesthetics or depolarizing muscle relaxants. (See 'Introduction' above.) The anesthesia history should include questions about prior adverse reactions to anesthetic exposure in the patient or their family members in an effort to identify potentially MH-susceptible individuals. (See 'Anesthesia history' above.) Approximately half of patients who develop acute MH have had prior uneventful exposure to the anesthetic agents known to trigger MH (ie, inhalational agents, depolarizing neuromuscular blockers). (See 'Triggering agents' above.) MH typically occurs intraoperatively with initial clinical signs occurring within one hour of anesthesia induction; delayed reactions can occur. (See 'Clinical manifestations' above.)

Clinical diagnosis




The diagnosis of acute MH is based upon clinical signs, the most reliable of which is hypercapnia that is due to a mixed metabolic and respiratory acidosis and is resistant to increasing the patient's minute ventilation. Other early clinical signs include sinus tachycardia and muscle rigidity. Hyperthermia is a later sign of MH and is typically absent when the diagnosis is initially suspected. (See 'Clinical manifestations' above.) The early exclusion of technical factors as a cause of decreased carbon dioxide elimination, or increased carbon dioxide production that could account for hypercapnia is important. Many other conditions also have clinical signs (ie, hypercapnia, tachycardia, muscle rigidity, rhabdomyolysis, hyperthermia, arrhythmia) in common with acute MH, but consideration of these diagnoses should not interfere with proceeding to an acute MH management protocol based upon the developing clinical scenario and clinician judgment. (See 'Differential diagnosis' above.)

Acute management








In patients with suspected acute MH, triggering agents are immediately discontinued and additional anesthesia personnel are summoned to assist with initiation of the MH protocol. If the surgery must continue, nontriggering agents (eg, propofol) are used. (See 'Acute management' above.) In patients with suspected acute MH, we recommend immediate administration of dantrolene (Grade 1A). The initial dose of dantrolene is 2.5 mg/kg intravenously, with subsequent bolus doses of 1 mg/kg intravenously until the signs of acute MH have abated; the end-tidal carbon dioxide (ETCO2) should normalize as the dantrolene takes effect. (See 'Administer dantrolene' above.) Following the administration of dantrolene, the patient's oxygenation and ventilation are optimized. Blood gases, potassium, core temperature, creatine kinase, urine output, urine color, electrolytes, coagulation parameters and fibrin split products are monitored for the remainder of the operation, and postoperatively in the intensive care unit. (See 'Acute management' above and 'Ongoing care' above.) Following an acute event, the determination of whether a suspected clinical event represents a true MH episode is estimated using the MH clinical grading scale. Definitive diagnosis is achieved with susceptibility testing. While waiting for further evaluation, the patient is counseled to not have anesthesia with triggering agents, limit exposure to excessive heat and humidity, and to inform their family members. (See 'Clinical diagnosis' above and 'Counseling after acute MH' above.)

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10. Bendixen D, Skovgaard LT, Ording H. Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test. Acta Anaesthesiol Scand 1997; 41:480. 11. Rubiano R, Chang JL, Carroll J, et al. Acute rhabdomyolysis following halothane anesthesia without succinylcholine. Anesthesiology 1987; 67:856. 12. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771. 13. Simon HB. Hyperthermia. N Engl J Med 1993; 329:483. 14. Hadad E, Weinbroum AA, Ben-Abraham R. Drug-induced hyperthermia and muscle rigidity: a practical approach. Eur J Emerg Med 2003; 10:149. 15. Papadimos TJ, Almasri M, Padgett JC, Rush JE. A suspected case of delayed onset malignant hyperthermia with desflurane anesthesia. Anesth Analg 2004; 98:548. 16. Litman RS, Flood CD, Kaplan RF, et al. Postoperative malignant hyperthermia: an analysis of cases from the North American Malignant Hyperthermia Registry. Anesthesiology 2008; 109:825. 17. Beldavs J, Small V, Cooper DA, Britt BA. Postoperative malignant hyperthermia: a case report. Can Anaesth Soc J 1971; 18:202. 18. Newson AJ. Malignant hyperthermia: three case reports. N Z Med J 1972; 75:138. 19. Britt BA. Combined anesthetic- and stress-induced malignant hyperthermia in two offspring of malignant hyperthermic-susceptible parents. Anesth Analg 1988; 67:393. 20. Kalow W, Britt BA, Terreau ME, Haist C. Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet 1970; 2:895. 21. Evans TJ, Parent CM, McGunigal MP. Atypical presentation of malignant hyperthermia. Anesthesiology 2002; 97:507. 22. Harwood TN, Nelson TE. Massive postoperative rhabdomyolysis after uneventful surgery: a case report of subclinical malignant hyperthermia. Anesthesiology 1998; 88:265. 23. McKenney KA, Holman SJ. Delayed postoperative rhabdomyolysis in a patient subsequently diagnosed as malignant hyperthermia susceptible. Anesthesiology 2002; 96:764. 24. Birmingham PK, Stevenson GW, Uejima T, Hall SC. Isolated postoperative myoglobinuria in a pediatric outpatient. A case report of malignant hyperthermia. Anesth Analg 1989; 69:846. 25. Fierobe L, Nivoche Y, Mantz J, et al. Perioperative severe rhabdomyolysis revealing susceptibility to malignant hyperthermia. Anesthesiology 1998; 88:263. 26. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology 2007; 106:901. 27. Van der Spek AF, Fang WB, Ashton-Miller JA, et al. The effects of succinylcholine on mouth opening. Anesthesiology 1987; 67:459. 28. Carroll JB. Increased incidence of masseter spasm in children with strabismus anesthetized with halothane and succinylcholine. Anesthesiology 1987; 67:559. 29. O'Flynn RP, Shutack JG, Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility in pediatric patients. An update on management and diagnosis. Anesthesiology 1994; 80:1228.

30. Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility. Anesth Analg 1986; 65:161. 31. Nelson TE. Porcine malignant hyperthermia: critical temperatures for in vivo and in vitro responses. Anesthesiology 1990; 73:449. 32. Frank SM, Kluger MJ, Kunkel SL. Elevated thermostatic setpoint in postoperative patients. Anesthesiology 2000; 93:1426. 33. Halsall PJ, Ellis FR. Does postoperative pyrexia indicate malignant hyperthermia susceptibility? Br J Anaesth 1992; 68:209. 34. Paul-Pletzer K, Yamamoto T, Bhat MB, et al. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem 2002; 277:34918. 35. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth 1975; 47:62. 36. Kolb ME, Horne ML, Martz R. Dantrolene in human malignant hyperthermia. Anesthesiology 1982; 56:254. 37. Larach MG, Brandom BW, Allen GC, et al. Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States. Anesthesiology 2008; 108:603. 38. Rosero EB, Adesanya AO, Timaran CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology 2009; 110:89. 39. Mitchell LW, Leighton BL. Warmed diluent speeds dantrolene reconstitution. Can J Anaesth 2003; 50:127. 40. www.dantrium.com/faq.php (Accessed on February 08, 2010). 41. Podranski T, Bouillon T, Schumacher PM, et al. Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work? Anesth Analg 2005; 101:1695. Topic 401 Version 8.0 Susceptibility to malignant hyperthermia Author Ronald S Litman, DO, FAAP Section Editor Stephanie B Jones, MD Deputy Editor Kathryn A Collins, MD, PhD, FACS Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: sep 8, 2011. INTRODUCTION — Malignant hyperthermia (MH) is a complex genetic disorder of skeletal muscle typically manifesting clinically as a hypermetabolic crisis when a susceptible individual receives an inhalational anesthetic agent or succinylcholine [1-3]. Susceptibility to MH is inherited in an autosomal dominant fashion and is suspected in individuals with a clinical event strongly suspicious for MH, a family history of proven

susceptibility or hypermetabolism with anesthesia, or conditions associated with MH. The mainstay of prevention is the identification of these genetically susceptible individuals. Avoidance of anesthetic triggers in MH-susceptible patients, and prompt administration of dantrolene when an acute event occurs has reduced the mortality associated with malignant hyperthermia from historic rates of 70 percent to about 5 percent [4,5]. This topic will review the pathophysiology, genetic basis of, and testing for MHsusceptibility. The clinical manifestations, diagnosis, and management of an acute MH crisis are discussed elsewhere. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis".) PATHOPHYSIOLOGY — MH-susceptible patients have genetic skeletal muscle receptor abnormalities allowing excessive calcium accumulation in the presence of certain anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis [6-8]. Normal muscle physiology — Depolarization spreads throughout the muscle cell via the transverse tubule system which activates dihydropyridine (DHP) receptors located within the t-tubule membrane (figure 1). These receptors are coupled to ryanodine receptors (RYR1) which are homo-tetrameric calcium channels embedded in the wall of the sarcoplasmic reticulum (SR). Calcium release through the DHP receptor's voltagedependent calcium channels triggers the RYR1 receptors to release calcium from the sarcoplasmic reticulum into the intracellular space [9,10]. Calcium combines with troponin allowing actin and myosin to cross-link, resulting in muscle cell contraction. Reuptake of calcium by the sarco(endo)plasmic reticulum calcium ATPase (SERCA) leads to muscle cell relaxation. Malignant hyperthermia — The majority of MH-susceptible patients have mutations encoding for abnormal RYR1 or DHP receptors that trigger unregulated passage of calcium from the sarcoplasmic reticulum into the intracellular space, which may lead to an acute MH crisis (figure 1) [9-18]. The accumulation of myoplasmic calcium causes sustained muscle contraction which, over time, generates heat. Accelerated levels of aerobic metabolism sustain the muscle for a time, but produce carbon dioxide and cellular acidosis, and deplete oxygen and adenosine triphosphate (ATP) [19-21]. A change to anaerobic metabolism worsens acidosis with the production of lactate. Once energy stores are depleted, the muscle fibers die, with rhabdomyolysis leading to hyperkalemia and myoglobinuria. (See 'Genetic basis' below and "Clinical manifestations and diagnosis of rhabdomyolysis" and "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Clinical manifestations'.) Administration of certain anesthetic agents in MH-susceptible patients can trigger these events. Prolonged RYR1 channel opening has been demonstrated in an experimental model [22]. Volatile anesthetics potentiate sarcoplasmic calcium release in patients with MH sensitivity. Halothane, for example, increases the fluidity of the lipid membrane activating sarco(endoplasmic) calcium dependent ATPase, limiting reuptake of calcium from the cytosol [23]. Succinylcholine is an analog of acetylcholine and stimulates the motor endplate to initiate muscle depolarization, which in MH-susceptible patients can become

sustained. (See "Neuromuscular blocking agents (NMBA) for rapid sequence intubation in adults", section on 'Succinylcholine'.) Dantrolene binds to the RYR1 receptor inhibiting the release of calcium from the sarcoplasmic reticulum reversing the negative cascade of effects [24-26]. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Acute management'.) GENETIC BASIS — Susceptibility to MH can be conferred by any inherited (or spontaneous) mutation of genes associated with proteins that control levels of cytosolic calcium and therefore skeletal muscle contraction [27]. Genes responsible for coding proteins of the RYR1 and DHP receptors are most commonly affected. The likelihood of developing MH in susceptible patients depends upon the specific type of receptor mutation [28]. Approximately one half of cases are inherited in an autosomal dominant fashion. Because of incomplete genetic penetrance and variable expressivity, considerable inter- and intra-individual variability exists in the clinical expression of the syndrome [29]. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Clinical manifestations'.) Approximately 50 percent of known cases of MH are caused by mutations on chromosome 19 in regions that encode the hydrophilic, amino-terminal portion of the RYR1 receptor [8,18]. Over 40 distinct mutations in this region have been described [15,30-38]. A small number (approximately 1 percent) are caused by a mutation of the CACNA1S gene, which encodes the alpha-subunit of the voltage-gated DHP receptor located on chromosome 1 [15,34-38]. (See 'Pathophysiology' above.) Classification — Six types of MH-susceptibility (MHS1-6) have been described, based upon the chromosomal locus affected:
     

MHS1 — Associated with the RYR1 gene on chromosome 19q13.1 MHS2 — Associated with the DHP receptor isolated to the 17q11.2-q24 locus MHS3 — Associated with the alpha-2/gamma subunit of the DHP receptor, linked to 7q21-q22 locus MHS4 — Linked to the 3q13.2 locus MHS5 — Encoding of the alpha-1 subunit of the DHP receptor and locus 1q32 MHS6 — Linked to chromosomal locus 5p

PREVALENCE OF SUSCEPTIBILITY — The prevalence of susceptibility for malignant hyperthermia in the general population is unknown. Published prevalence rates vary widely depending upon the characteristics of the population studied and the manner in which MH-susceptibility was determined. Prevalence is most often studied in family cohorts known to have susceptibility for MH; rates range from 1:200 to 1:5000 in these cohorts [39,40]. The variable penetrance of genetic inheritance leads to far fewer cases of clinically significant MH than prevalence rates would suggest. Many patients with susceptibility for

MH have received general anesthetic triggering agents without developing an acute crisis. (See 'Genetic basis' above and "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Epidemiology'.) CONDITIONS ASSOCIATED WITH MH — A number of conditions have been associated with malignant hyperthermia (table 1). Myopathies — Some individuals with preexisting muscle diseases due to genetic abnormalities in RYR1 or DHP receptors are at higher than normal risk for developing MH; therefore triggering agents are contraindicated in these individuals [15,34,41-51]. These conditions include:
   

Central core myopathy [16,34,41,51,52] Multicore myopathy [53] King-Denborough syndrome [1,54] Native American myopathy [15,55]

These patients can be safely anesthetized using non-triggering agents. (See 'Anesthesia in MH-susceptible patients' below.) Conditions associated with rhabdomyolysis — Some conditions characterized by muscle atrophy are associated with an increased risk for life-threatening rhabdomyolysis or hyperkalemia following administration of inhalational anesthetics [42-49,56-73]. This clinical syndrome can closely resemble acute MH. These patients are also at risk for developing rhabdomyolysis and life-threatening hyperkalemia following exposure to succinylcholine [64,65]. Evidence of causation is limited and while these patients do not appear to have a higher risk of developing fulminant MH compared to the general population, we suggest withholding MH triggering agents from patients with the following conditions.
     

Heat induced rhabdomyolysis [57-59,74,75] Exercise-related rhabdomyolysis [56,60,75] Dystrophinopathies [42-46,61-67,69,70,76,77] Myoadenylate deaminase deficiency [47] McArdle's disease [49,71] Carnitine palmitoyl transferase type 2 deficiency [72,78]

Other conditions — A number of other genetic syndromes have been associated with MHsusceptibility but without sufficient evidence [79-89]. These include:
    

Osteogenesis imperfecta [79-82] Arthrogryposis [83-85] Myotonia [90] Noonan syndrome Neuroleptic malignant syndrome [86-89]

Triggering agents can be administered to patients with these conditions. MH CLINICAL GRADING — The MH clinical grading scale is used to judge the likelihood that a prior event represents true MH which helps provide guidance in patient counseling. The MH clinical grading scale assigns points to previous clinical events (table 2) [91]. The total number of points determines an MH rank between one and six (calculator 1). The more clinical criteria fulfilled, the more likely an MH episode has occurred; an MH rank of 6 (50+ points) indicates an almost certain likelihood that the event represented MH. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Clinical manifestations'.) Important clinical indicators associated with an event and valued at more than 10 points each include:


 

   

Respiratory acidosis — The presence of end-tidal CO2 >55 mmHg or PaCO2 >60 mm Hg with controlled ventilation, PETCO2 >60 mmHg or PaCO2 >65 mmHg with spontaneous ventilation. Metabolic acidosis — Base deficit >8 mEq, pH <7.25 Muscle rigidity — Either severe masseter muscle rigidity or generalized rigidity. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Masseter muscle rigidity'.) Muscle breakdown — Serum CK >20,000 IU/L or >10,000 IU/L without the use of succinylcholine, cola colored urine in the postoperative period. Temperature — Rapidly increasing temperature, or core temperature >38.8º C (101.8ºF). Elevated resting serum CK Family history of MH (autosomal dominant inheritance)

SCREENING General population — Nearly all new cases of MH occur in phenotypically normal patients who were not previously known to be at risk. Unfortunately, there are no practical MHsusceptibility screening tests for the general population. While resting plasma creatinine kinase (CK) levels may be elevated in up to 70 percent of MH-susceptible individuals, preoperative testing of CK levels is not useful because CK may be elevated for multiple other reasons (eg, muscle trauma) [1]. It is customary to screen preoperative patients for any adverse reactions to prior anesthesia; however, a negative history does not provide assurance that an event will not occur. Up to 50 percent of patients who develop acute MH after anesthetic exposure have prior uneventful exposures to triggering agents. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Anesthesia history'.) Family members — Family members of a newly diagnosed MH-susceptible patient (ie, positive MH-susceptibility testing [muscle contracture or genetic testing], or history of

acute MH crisis) are evaluated since most MH-susceptibility is inherited. The patient's parents are generally evaluated first. (See 'MH-susceptibility testing' below.) The benefit in evaluating the parents is the identification of the side of the family (maternal or paternal) carrying the mutation, eliminating the need to screen the unaffected half. If the parents are negative for MH-susceptibility, suggesting a spontaneous mutation, the risk to family members other than the patient's children is low. The patient's children should be screened as transmission is typically autosomal dominant. Conditions associated with MH — Individuals who should undergo MH-susceptibility testing include those with conditions at high risk for MH but for which a specific receptor abnormality is not yet known (eg, Native American myopathy), and some conditions at risk for rhabdomyolysis, particularly exercise- or heat-related rhabdomyolysis. (See 'MHsusceptibility testing' below and 'Myopathies' above and 'Conditions associated with rhabdomyolysis' above.) Inherited conditions such as central core myopathy, multiminicore disease, and KingDenborough syndrome are known to have genetic abnormalities in receptors controlling muscle calcium regulation. Anesthetic triggering agents are absolutely contraindicated in this group of individuals so MH-susceptibility testing is not required. (See 'Myopathies' above.) MH-SUSCEPTIBILITY TESTING — All patients with a clinical event suspicious for MH should undergo MH-susceptibility testing, ideally with a contracture test; however, only a minority of patients and their families are willing or able to travel to the few centers where the test is performed, and some insurance plans may not cover muscle biopsy and contracture testing which costs about $5000. In lieu of contracture testing, some patients with suspected MH-susceptibility will opt for molecular genetic testing (sensitivity 30 to 50 percent), or simply consider themselves (and their family members) MH-susceptible. Although this strategy is practical, it may not provide guidance or specific answers to the patient or their family members who are then labeled as MH-susceptible forever. Future anesthetic options are then limited. Contracture tests — MH-susceptibility can be confirmed using contracture testing, which is an in vitro muscle bioassay. Contracture testing has a low false negative rate (sensitivity >97 percent), thus negative results generally rule out a diagnosis of MH-susceptibility [92,93]. Some individuals with known MH mutations have a negative response to this test [34]. In the face of equivocal test results, the decision to withhold anesthetic triggering agents in the future depends upon the results of genetic tests or the clinical scenario prompting contracture testing. (See 'Genetic tests' below and 'MH clinical grading' above.) Up to 22 percent of patients with positive contracture tests have a false positive results [92]. Methods to enhance the test (eg, 4-chloro-m-cresol test, ryanodine contracture testing) have been reported but are not yet routinely used [93,94].

The contracture test is performed at specific centers around the world (four in the United States) [37]. Following testing, the referring physician receives a report indicating whether testing was positive, negative, or equivocal. Positive or equivocal results should be followed-up with genetic testing. Referral information can be found on the Malignant Hyperthermia Association of the United States (MHAUS) website. (See 'MH resources' below.) Indications for contracture testing — Contracture testing is not usually needed when genetic testing within a family is positive. (See 'Genetic tests' below.) Contracture testing is indicated for:
  

Patients with a history suspicious for MH (high MH clinical grade). (See 'MH clinical grading' above.) First degree relatives of a patient with a suspicious history if the clinically affected patient is unwilling or unable to travel to a testing center. Patients with a suspicious history who are contemplating military service since MHsusceptible individuals are not eligible for military service.

Other clinical scenarios in which contracture testing may be helpful include:
  

Unexplained rhabdomyolysis following anesthesia Mild to moderate masseter muscle rigidity following succinylcholine administration Severe or recurrent exercise- or heat-induced rhabdomyolysis

Protocols — Contracture tests evaluate the in vitro response of a fresh sample of the patient's muscle tissue to caffeine and halothane. Two different protocols were developed independently by the North American Malignant Hyperthermia Group (NAMHG) and the European Malignant Hyperthermia Group (EMHG). These protocols differ slightly in the concentrations of halothane and caffeine used in testing, and number of muscle strips used. The sensitivity and specificity of these protocols are different due to the different criteria each has for indicating a positive result [38]. The caffeine-halothane contracture test (CHCT) is available in the United States and Canada while the in-vitro contracture (IVCT) test is performed in Europe. For both protocols, an excisional muscle biopsy is required (3 to 4 inches from the thigh) and is obtained under general anesthesia with non-triggering agents or regional anesthesia [95]. Next the fresh muscle specimen is placed into a physiologic solution and taken immediately to the laboratory where it is divided into smaller strips. The muscle is placed in physiologic solution (no drugs), attached to a strain gauge, and first carefully stretched to a standard baseline tension. The muscle is then electrically stimulated (60 Hz) causing it to contract and the generated tension is measured. Separate strips are tested with either halothane or caffeine which is added to the physiologic solution at specific concentrations depending upon the protocol. Contractile responses to these pharmacologic agents are measured relative to baseline tension. Varying the threshold of contractile response considered for a

positive result (ie, 0.2 to 0.7 g relative to baseline) alters the level of sensitivity and specificity.


Caffeine-halothane contracture test — The caffeine-halothane contracture test (CHCT) is used in the United States and Canada. A minimum of three separate muscle strips for each pharmacologic agent are used in testing. Following electrical stimulation, muscle strips are exposed to a 3 percent halothane solution or gradually increasing concentrations of caffeine solution beginning at 0.5 mM (figure 2). A positive response is indicated if the contractile tension is greater than or equal to 0.7 g relative to baseline tension for halothane (tension between 0.5 and 0.69 g are considered equivocal), and 0.3 g for caffeine at 0.5, 1, or 2 mM. The sensitivity and specificity achieved with these thresholds are 97 and 78 percent, respectively. If any one of the three strips exposed to halothane or all strips exposed to caffeine exhibit a positive contracture response, the test is positive and indicates MHsusceptibility. Otherwise the test is negative.



In vitro contracture test — A slightly different protocol referred to as the in vitro contracture test (IVCT) is used in Europe [38,96,97]. The criteria for a positive test are different because the protocol differs from CHCT; two muscle fiber strips, and different concentrations of halothane and caffeine are used. The sensitivity and specificity achieved with the IVCT are 99 and 94 percent, respectively. Information on specific details of this protocol can be found on the European malignant hyperthermia group website [98].

Genetic tests — Genetic analysis is performed to confirm the presence of a known causative mutation [32-36]. Molecular genetic testing for known MH-causing mutations, implemented in the United States and Europe, consists of a genetic panel evaluating 17 of the most common RYR1 mutations [29,31,50,74,97,99]. A blood sample can be sent to one of two testing centers in the United States and costs around $800 [11]. Because testing evaluates only a relatively small percentage of possible mutations, the overall sensitivity of RYR1 panel testing is low. Individual mutations known to occur within a family can be specifically evaluated and cost $200 dollars per mutation tested [99]. Compared to contracture testing, the advantages of genetic testing are that it is convenient for the patient, minimally invasive, and typically covered by insurance. However, because the panel evaluates primarily RYR1 mutations, it has a high false negative rate for MHsusceptibility (about 30 to 50 percent). Thus, a disadvantage is that a negative test does not rule out MH-susceptibility [74,97]. Indications for genetic testing — Genetic testing is indicated for:


Patients with a positive or equivocal contracture test to determine the presence of a specific mutation.

 

Individuals with a positive genetic test for MH in a family member. Patients with a clinical history suspicious for MH (acute MH episode, masseter muscle rigidity, postoperative myoglobinuria, heat or exercise induce rhabdomyolysis) who are unable or unwilling to undergo contracture testing.

PATIENT AND FAMILY COUNSELING — Patients and family members of individuals testing positive for susceptibility to MH should be counseled about this disorder. They are advised that agents that can trigger MH should never be given to them, and of the importance of informing future anesthesiologists of their susceptibility. A letter from the anesthesiologist who supervised the initial incident should be obtained and kept in the patient's personal records and electronic medical record for future reference. MH-susceptible patients are also cautioned about the possibility of developing heat stroke in extremely hot and humid environments. (See "Severe hyperthermia (heat stroke) in adults".) Because susceptibility to MH has an autosomal dominant inheritance, all first-degree family members are considered potentially MH-susceptible and should be counseled and referred for MH consultation. (See 'MH resources' below.) The patient and anyone in their family confirmed positive for MH-susceptibility should obtain and wear alert identification indicating his or her susceptibility. Identification bracelets specific for MH can be obtained through the Malignant Hyperthermia Association of the United States (MHAUS). (See 'MH resources' below.) The MH-susceptible patient and his or her family are encouraged to learn as much as possible about the nature of the disorder and should be directed to appropriate educational resources. (See 'MH resources' below.) ANESTHESIA IN MH-SUSCEPTIBLE PATIENTS — MH-susceptible patients can be safely anesthetized using non-triggering agents. Prophylactic pharmacologic intervention (ie, dantrolene) is not indicated. End-tidal carbon dioxide (ETCO2) levels, minute ventilation, and core body temperature are monitored closely in MH-susceptible patients. Preventive measures — The anesthesiologist can "clean" the anesthesia machine by flushing it with high-flow oxygen to ensure that the MH-susceptible patient will not be exposed to trace anesthetic gases. Tape is placed over the vaporizer canisters to avoid accidental administration of volatile anesthetic or the canisters can be removed altogether (picture 1). Alternatively, a charcoal filter (picture 2) can be attached to the inspiratory and/or expiratory breathing circuits to absorb any traces of anesthetic gas [100]. The use of charcoal filters eliminates the need for prolonged oxygen flushing [101].

Safe anesthetic agents — The most common non-triggering agent used in MH-susceptible patients is propofol via continuous infusion. Regional anesthesia is also appropriate when feasible. (See "Overview of anesthesia and anesthetic choices" and "Overview of peripheral nerve blocks".) Agents that can be safely administered to MH-susceptible patients include:
    

All intravenous anesthetic, and sedative agents including propofol, ketamine, etomidate, dexmedetomidine, and barbiturates. All local anesthetics (eg, lidocaine, bupivacaine, ropivacaine) Nondepolarizing neuromuscular blockers (eg, vecuronium) Inhalational agents limited to nitrous oxide and xenon Pain relievers and anxiolytics including opioids and benzodiazepines

Ambulatory surgery — Routine day surgery discharge criteria are applicable to MHsusceptible patients who have not received anesthetic triggering agents. Upon discharge, the patient is instructed to call their physician or go to the emergency room if elevated temperature or brown urine develop. MH RESOURCES — The Malignant Hyperthermia Association of the United States (MHAUS) was formed to educate the medical and lay communities about MH and serve as a resource for affected families. A wide variety of educational information for health professionals and the public is available at the MHAUS Web site (www.mhaus.org). In 1987, the North American MH Registry (www.mhaus.org/index.cfm/fuseaction/Content.Display/PagePK/NARegistry.cfm) was established to collect and analyze information about clinical episodes of MH and the results of laboratory tests. These organizations merged in 1995. MHAUS maintains a free, 24-hour "hot line" for acute cases (1-800-MH HYPER) that is continuously staffed by anesthesiologists who are experts in managing cases of MH, answering questions about prospective management of MH-susceptible patients, and directing callers to appropriate resources. General information is available through the MHAUS office located at 39 East State St., Sherburne, NY 13460, 607-674-7901. MHAUS also sponsors and supports the Neuroleptic Malignant Syndrome Information Service (www.nmsis.org). The European malignant hyperthermia group was established in 1983 and information on European protocols can be found on their website (www.emhg.org). SUMMARY AND RECOMMENDATIONS


Malignant hyperthermia (MH) is a genetic disorder of skeletal muscle metabolism (MH) that can manifest clinically as a hypermetabolic crisis in MH-susceptible individuals exposed to inhalational anesthetics or depolarizing muscle relaxants (ie, succinylcholine). (See 'Introduction' above.)













Susceptibility to MH is inherited in an autosomal dominant fashion and is suspected in individuals with a clinical event strongly suspicious for MH, a family history of proven susceptibility or hypermetabolism with anesthesia, or conditions associated with MH. The mainstay of prevention is the identification of MH-susceptible individuals. (See 'Introduction' above.) MH-susceptible individuals have skeletal muscle receptor abnormalities allowing excessive intracellular calcium to accumulate in response to volatile anesthetic agents or succinylcholine which can trigger intracellular events leading to skeletal muscle hypermetabolism. (See 'Pathophysiology' above.) Genes responsible for coding proteins of the sarcolemmal membrane RYR1 and DHP receptors are responsible for approximately 30 to 50 percent of the mutations known to cause MH-susceptibility. (See 'Genetic basis' above.) Preexisting muscle diseases known to be linked to MH-susceptibility due to genetic abnormalities in RYR1 or DHP receptors include central core myopathy, multiminicore myopathy, Native American myopathy, and King-Denborough syndrome. Some conditions characterized by muscle atrophy are associated with an increased risk for life-threatening rhabdomyolysis or hyperkalemia following inhalational anesthetic administration which resembles MH. These include heat- or exerciseinduced rhabdomyolysis, dystrophinopathies, myoadenylate deaminase deficiency, McArdle's disease, and carnitine palmitoyl transferase type 2 deficiency (CPT2) deficiency. There are no practical MH-susceptibility screening tests for the general population. (See 'General population' above.)

Susceptibility testing






Two tests are available for MH-susceptibility evaluation: contracture testing and molecular genetic testing. These tests are indicated only under specific circumstances. (See 'Indications for contracture testing' above and 'Indications for genetic testing' above.) Contracture testing has few false negatives; a negative test effectively rules out MHsusceptibility. Contracture testing is the preferred initial test for individuals with an event suspicious for MH, and some pre-existing conditions. However, contracture testing is invasive and offered at only a limited number of centers. (See 'Contracture tests' above.) Genetic testing is indicated in individuals with a positive or equivocal contracture test, positive family history for a gene mutation, and those who are unable or unwilling to undergo contracture testing. Genetic testing identifies only about 50 percent of MH-susceptible individuals. (See 'Genetic tests' above.)

Withholding triggering agents


Individuals at high risk for acute malignant hyperthermia crisis are not given triggering agents. Included are patients with confirmed susceptibility to malignant hyperthermia through either contracture or genetic testing, and patients with certain genetic disorders (ie, central core myopathy, multiminicore myopathy, King-





Denborough syndrome and Native American myopathy). (See 'MH-susceptibility testing' above and 'Myopathies' above.) We suggest withholding triggering agents from individuals with conditions characterized by muscle atrophy and associated with an increased risk for lifethreatening rhabdomyolysis or hyperkalemia (Grade 2C). These include: heat or exercise induced rhabdomyolysis, dystrophinopathies, myoadenylate deaminase deficiency, McArdle's disease, and carnitine palmitoyl transferase type 2 deficiency. (See 'Conditions associated with rhabdomyolysis' above.) For patients with a prior perioperative event strongly suspicious for MH but negative MH-susceptibility testing, or who have been unable to be tested, the decision to withhold triggering agents is individualized and based upon the MH clinical grading score (see 'MH clinical grading' above).

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REFERENCES
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15. Stewart SL, Hogan K, Rosenberg H, Fletcher JE. Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet 2001; 59:178. 16. Quane KA, Healy JM, Keating KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 1993; 5:51. 17. Censier K, Urwyler A, Zorzato F, Treves S. Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors. J Clin Invest 1998; 101:1233. 18. Sambuughin N, Holley H, Muldoon S, et al. Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population. Anesthesiology 2005; 102:515. 19. Gronert GA, Theye RA. Halothane-induced porcine malignant hyperthermia: metabolic and hemodynamic changes. Anesthesiology 1976; 44:36. 20. Mickelson JR, Louis CF. Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects. Physiol Rev 1996; 76:537. 21. Louis CF, Zualkernan K, Roghair T, Mickelson JR. The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum. Anesthesiology 1992; 77:114. 22. Dirksen RT, Avila G. Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1. Biophys J 2004; 87:3193. 23. Schuster F, Müller R, Hartung E, et al. Inhibition of sarcoplasmic Ca2+-ATPase increases caffeine- and halothane-induced contractures in muscle bundles of malignant hyperthermia susceptible and healthy individuals. BMC Anesthesiol 2005; 5:8. 24. Paul-Pletzer K, Yamamoto T, Bhat MB, et al. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem 2002; 277:34918. 25. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth 1975; 47:62. 26. Kolb ME, Horne ML, Martz R. Dantrolene in human malignant hyperthermia. Anesthesiology 1982; 56:254. 27. Davis PJ, Brandom BW. The association of malignant hyperthermia and unusual disease: when you're hot you're hot or maybe not. Anesth Analg 2009; 109:1001. 28. Carpenter D, Robinson RL, Quinnell RJ, et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth 2009; 103:538. 29. Robinson RL, Anetseder MJ, Brancadoro V, et al. Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing? Eur J Hum Genet 2003; 11:342. 30. MacLennan DH, Duff C, Zorzato F, et al. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 1990; 343:559. 31. McCarthy TV, Healy JM, Heffron JJ, et al. Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2. Nature 1990; 343:562.

32. Yang T, Ta TA, Pessah IN, Allen PD. Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling. J Biol Chem 2003; 278:25722. 33. Broman M, Gehrig A, Islander G, et al. Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases. Br J Anaesth 2009; 102:642. 34. Brandt A, Schleithoff L, Jurkat-Rott K, et al. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. Hum Mol Genet 1999; 8:2055. 35. Girard T, Urwyler A, Censier K, et al. Genotype-phenotype comparison of the Swiss malignant hyperthermia population. Hum Mutat 2001; 18:357. 36. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 1997; 60:1316. 37. Rueffert H, Olthoff D, Deutrich C, et al. Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta Anaesthesiol Scand 2002; 46:692. 38. Sei Y, Sambuughin NN, Davis EJ, et al. Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824. 39. Bachand M, Vachon N, Boisvert M, et al. Clinical reassessment of malignant hyperthermia in Abitibi-Témiscamingue. Can J Anaesth 1997; 44:696. 40. Monnier N, Krivosic-Horber R, Payen JF, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 2002; 97:1067. 41. Sewry CA, Müller C, Davis M, et al. The spectrum of pathology in central core disease. Neuromuscul Disord 2002; 12:930. 42. Bush A, Dubowitz V. Fatal rhabdomyolysis complicating general anaesthesia in a child with Becker muscular dystrophy. Neuromuscul Disord 1991; 1:201. 43. Tang TT, Oechler HW, Siker D, et al. Anesthesia-induced rhabdomyolysis in infants with unsuspected Duchenne dystrophy. Acta Paediatr 1992; 81:716. 44. Obata R, Yasumi Y, Suzuki A, et al. Rhabdomyolysis in association with Duchenne's muscular dystrophy. Can J Anaesth 1999; 46:564. 45. Kerr TP, Duward A, Hodgson SV, et al. Hyperkalaemic cardiac arrest in a manifesting carrier of Duchenne muscular dystrophy following general anaesthesia. Eur J Pediatr 2001; 160:579. 46. Girshin M, Mukherjee J, Clowney R, et al. The postoperative cardiovascular arrest of a 5-year-old male: an initial presentation of Duchenne's muscular dystrophy. Paediatr Anaesth 2006; 16:170. 47. Fricker RM, Raffelsberger T, Rauch-Shorny S, et al. Positive malignant hyperthermia susceptibility in vitro test in a patient with mitochondrial myopathy and myoadenylate deaminase deficiency. Anesthesiology 2002; 97:1635. 48. Isaacs H, Badenhorst ME, Du Sautoy C. Myophosphorylase B deficiency and malignant hyperthermia. Muscle Nerve 1989; 12:203.

49. Lobato EB, Janelle GM, Urdaneta F, Malias MA. Noncardiogenic pulmonary edema and rhabdomyolsis after protamine administration in a patient with unrecognized McArdle's disease. Anesthesiology 1999; 91:303. 50. Mitchell LW, Leighton BL. Warmed diluent speeds dantrolene reconstitution. Can J Anaesth 2003; 50:127. 51. Klingler W, Rueffert H, Lehmann-Horn F, et al. Core myopathies and risk of malignant hyperthermia. Anesth Analg 2009; 109:1167. 52. Zhang Y, Chen HS, Khanna VK, et al. A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet 1993; 5:46. 53. Guis S, Figarella-Branger D, Monnier N, et al. Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol 2004; 61:106. 54. D'Arcy CE, Bjorksten A, Yiu EM, et al. King-denborough syndrome caused by a novel mutation in the ryanodine receptor gene. Neurology 2008; 71:776. 55. Stamm DS, Aylsworth AS, Stajich JM, et al. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am J Med Genet A 2008; 146A:1832. 56. Köchling A, Wappler F, Winkler G, Schulte am Esch JS. Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anaesth Intensive Care 1998; 26:315. 57. Tobin JR, Jason DR, Challa VR, et al. Malignant hyperthermia and apparent heat stroke. JAMA 2001; 286:168. 58. Denborough M, Hopkinson KC, O'Brien RO, Foster PS. Overheating alone can trigger malignant hyperthermia in piglets. Anaesth Intensive Care 1996; 24:348. 59. Chelu MG, Goonasekera SA, Durham WJ, et al. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J 2006; 20:329. 60. Wappler F, Fiege M, Steinfath M, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001; 94:95. 61. Kleopa KA, Rosenberg H, Heiman-Patterson T. Malignant hyperthermia-like episode in Becker muscular dystrophy. Anesthesiology 2000; 93:1535. 62. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51:919. 63. Gronert GA. Cardiac arrest after succinylcholine: mortality greater with rhabdomyolysis than receptor upregulation. Anesthesiology 2001; 94:523. 64. Larach MG, Rosenberg H, Gronert GA, Allen GC. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila) 1997; 36:9. 65. Goresky GV, Cox RG. Inhalation anesthetics and Duchenne's muscular dystrophy. Can J Anaesth 1999; 46:525. 66. Rubiano R, Chang JL, Carroll J, et al. Acute rhabdomyolysis following halothane anesthesia without succinylcholine. Anesthesiology 1987; 67:856. 67. Boba A. Fatal postanesthetic complications in two muscular dystrophic patients. J Pediatr Surg 1970; 5:71. 68. Marchildon MB. Malignant hyperthermia. Current concepts. Arch Surg 1982; 117:349.

69. McKishnie JD, Muir JM, Girvan DP. Anaesthesia induced rhabdomyolysis--a case report. Can Anaesth Soc J 1983; 30:295. 70. Kelfer HM, Singer WD, Reynolds RN. Malignant hyperthermia in a child with Duchenne muscular dystrophy. Pediatrics 1983; 71:118. 71. Bollig G, Mohr S, Raeder J. McArdle's disease and anaesthesia: case reports. Review of potential problems and association with malignant hyperthermia. Acta Anaesthesiol Scand 2005; 49:1077. 72. Katsuya H, Misumi M, Ohtani Y, Miike T. Postanesthetic acute renal failure due to carnitine palmityl transferase deficiency. Anesthesiology 1988; 68:945. 73. Schaer H, Steinmann B, Jerusalem S, Maier C. Rhabdomyolysis induced by anaesthesia with intraoperative cardiac arrest. Br J Anaesth 1977; 49:495. 74. Ellis FR, Harriman DG, Keaney NP, et al. Halothane-induced muscle contracture as a cause of hyperpyrexia. Br J Anaesth 1971; 43:721. 75. Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg 2009; 109:1065. 76. Gurnaney H, Brown A, Litman RS. Malignant hyperthermia and muscular dystrophies. Anesth Analg 2009; 109:1043. 77. Benca J, Hogan K. Malignant hyperthermia, coexisting disorders, and enzymopathies: risks and management options. Anesth Analg 2009; 109:1049. 78. Hogan KJ, Vladutiu GD. Malignant hyperthermia-like syndrome and carnitine palmitoyltransferase II deficiency with heterozygous R503C mutation. Anesth Analg 2009; 109:1070. 79. Ryan CA, Al-Ghamdi AS, Gayle M, Finer NN. Osteogenesis imperfecta and hyperthermia. Anesth Analg 1989; 68:811. 80. Kill C, Leonhardt A, Wulf H. Lacticacidosis after short-term infusion of propofol for anaesthesia in a child with osteogenesis imperfecta. Paediatr Anaesth 2003; 13:823. 81. Rampton AJ, Kelly DA, Shanahan EC, Ingram GS. Occurrence of malignant hyperpyrexia in a patient with osteogenesis imperfecta. Br J Anaesth 1984; 56:1443. 82. Porsborg P, Astrup G, Bendixen D, et al. Osteogenesis imperfecta and malignant hyperthermia. Is there a relationship? Anaesthesia 1996; 51:863. 83. Martin S, Tobias JD. Perioperative care of the child with arthrogryposis. Paediatr Anaesth 2006; 16:31. 84. Baines DB, Douglas ID, Overton JH. Anaesthesia for patients with arthrogryposis multiplex congenita: what is the risk of malignant hyperthermia? Anaesth Intensive Care 1986; 14:370. 85. Hopkins PM, Ellis FR, Halsall PJ. Hypermetabolism in arthrogryposis multiplex congenita. Anaesthesia 1991; 46:374. 86. Smego RA Jr, Durack DT. The neuroleptic malignant syndrome. Arch Intern Med 1982; 142:1183. 87. Caroff SN, Rosenberg H, Fletcher JE, et al. Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 1987; 67:20. 88. Ward A, Chaffman MO, Sorkin EM. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986; 32:130.

89. Bello N, Adnet P, Saulnier F, et al. [Lack of sensitivity to per-anesthetic malignant hyperthermia in 32 patients who developed neuroleptic malignant syndrome]. Ann Fr Anesth Reanim 1994; 13:663. 90. Parness J, Bandschapp O, Girard T. The myotonias and susceptibility to malignant hyperthermia. Anesth Analg 2009; 109:1054. 91. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771. 92. Rosenberg H, Antognini JF, Muldoon S. Testing for malignant hyperthermia. Anesthesiology 2002; 96:232. 93. Hopkins PM, Hartung E, Wappler F. Multicentre evaluation of ryanodine contracture testing in malignant hyperthermia. The European Malignant Hyperthermia Group. Br J Anaesth 1998; 80:389. 94. Ording H, Glahn K, Gardi T, et al. 4-Chloro-m-cresol test--a possible supplementary test for diagnosis of malignant hyperthermia susceptibility. Acta Anaesthesiol Scand 1997; 41:967. 95. Serfas KD, Bose D, Patel L, et al. Comparison of the segregation of the RYR1 C1840T mutation with segregation of the caffeine/halothane contracture test results for malignant hyperthermia susceptibility in a large Manitoba Mennonite family. Anesthesiology 1996; 84:322. 96. Deufel T, Sudbrak R, Feist Y, et al. Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. Am J Hum Genet 1995; 56:1334. 97. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. The European Malignant Hyperpyrexia Group. Br J Anaesth 1984; 56:1267. 98. www.emhg.org/en/emhg/mh-diagnosis/. 99. Fortunato G, Carsana A, Tinto N, et al. A case of discordance between genotype and phenotype in a malignant hyperthermia family. Eur J Hum Genet 1999; 7:415. 100. Birgenheier N, Stoker R, Westenskow D, Orr J. Activated charcoal effectively removes inhaled anesthetics from modern anesthesia machines. Anesth Analg 2011; 112:1363. 101. Gunter JB, Ball J, Than-Win S. Preparation of the Dräger Fabius anesthesia machine for the malignant-hyperthermia susceptible patient. Anesth Analg 2008; 107:1936. Topic 403 Version 4.0 Severe hyperthermia (heat stroke) in adults Author C Crawford Mechem, MD, FACEP Section Editor Daniel F Danzl, MD Deputy Editor Jonathan Grayzel, MD, FAAEM Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: nov 22, 2010.

INTRODUCTION — Hyperthermia is defined as elevation of core body temperature above the normal diurnal range of 36ºC to 37.5ºC due to failure of thermoregulation. Hyperthermia is not synonymous with the more common sign of fever, which is induced by cytokine activation during inflammation, and regulated at the level of the hypothalamus. The evaluation and management of severe hyperthermia in adults will be reviewed here. Malignant hyperthermia and fever in adults are discussed separately. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis" and "Pathophysiology and treatment of fever in adults".) PATHOPHYSIOLOGY — Body temperature is maintained within a narrow range by balancing heat load with heat dissipation [1-3]. The body's heat load results from both metabolic processes and absorption of heat from the environment. As core temperature rises, the preoptic nucleus of the anterior hypothalamus stimulates efferent fibers of the autonomic nervous system to produce sweating and cutaneous vasodilation. Evaporation is the principal mechanism of heat loss in a hot environment, but this becomes ineffective above a relative humidity of 75 percent [4]. The other major methods of heat dissipation – radiation (emission of infrared electromagnetic energy), conduction (direct transfer of heat to an adjacent, cooler object), and convection (direct transfer of heat to convective air currents) – cannot efficiently transfer heat when environmental temperature exceeds skin temperature. Temperature elevation is accompanied by an increase in oxygen consumption and metabolic rate, resulting in hyperpnea and tachycardia [2]. Above 42ºC (108ºF), oxidative phosphorylation becomes uncoupled, and a variety of enzymes cease to function. Hepatocytes, vascular endothelium, and neural tissue are most sensitive to these effects, but all organs may be involved. As a result, these patients are at risk of multiorgan system failure [5]. DIFFERENTIAL DIAGNOSIS — The differential diagnosis of hyperthermia is extensive and includes infectious, endocrine, central nervous system, and toxic etiologies (table 1). The most important causes of severe hyperthermia (greater than 40ºC or 104ºF) caused by failure of thermoregulation are heat stroke, neuroleptic malignant syndrome, and malignant hyperthermia. Each of these conditions may be associated with severe systemic complications and death. (See "Neuroleptic malignant syndrome" and "Malignant hyperthermia: Clinical diagnosis and management of acute crisis".) Malignant hyperthermia — Malignant hyperthermia is a rare autosomal dominant disorder that manifests following treatment with anesthetic agents, most commonly succinylcholine and halothane. The onset of malignant hyperthermia is usually within one hour of the administration of general anesthesia, but rarely may be delayed up to 10 hours after induction. Early clinical findings include muscle rigidity (especially masseter stiffness), sinus tachycardia, hypercarbia, and skin cyanosis with mottling. Marked hyperthermia (up to 45ºC [113ºF]) occurs minutes to hours later. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis".)

Neuroleptic malignant syndrome — Neuroleptic malignant syndrome (NMS) is an idiosyncratic reaction most frequently associated with classic and atypical antipsychotic agents. In addition to hyperthermia, NMS is also characterized by "lead pipe" muscle rigidity, altered mental status, choreoathetosis, tremors, and evidence of autonomic dysfunction, such as diaphoresis, labile blood pressure, and dysrhythmias. (See "Neuroleptic malignant syndrome".) DEFINITIONS AND CLINICAL FINDINGS — Heat stroke is defined as a core body temperature usually in excess of 40.5ºC (105ºF) with associated central nervous system dysfunction in the setting of a large environmental heat load that cannot be dissipated [3,4,6]. Frequently encountered complications include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), acute kidney injury (ie, acute renal failure), hepatic failure, hypoglycemia, rhabdomyolysis, and seizures [3,7]. There are two types of heat stroke:




Classic (nonexertional) heat stroke — Classic heat stroke affects individuals, most often the elderly, with underlying chronic medical conditions that either impair thermoregulation or prevent removal from a hot environment [8]. These conditions include cardiovascular disease, neurologic or psychiatric disorders, obesity, anhidrosis, extremes of age, and use of drugs, such as anticholinergic agents or diuretics [2,9-11]. Exertional heat stroke — Exertional heat stroke generally occurs in young, otherwise healthy individuals who engage in heavy exercise during periods of high ambient temperature and humidity. Typical patients are athletes and military recruits in basic training [2,12]. In vitro muscle fiber testing reveals evidence of susceptibility to malignant hyperthermia in some patients who present in this fashion [13,14].

Physical findings in heat stroke may include flushing (cutaneous vasodilation), tachypnea, crackles due to noncardiogenic pulmonary edema, excessive bleeding due to DIC, and evidence of neurologic dysfunction such as altered mentation or seizures. The skin may be moist or dry, depending upon underlying medical conditions, the speed with which the heat stroke developed, and hydration status [7]. Not all victims of heat stroke are volumedepleted [15]. RISK FACTORS FOR INCREASED MORTALITY — Patients who present to the hospital with heatstroke have high mortality, with rates ranging from 21 to 63 percent [1618]. Mortality correlates with the degree of temperature elevation, time to initiation of cooling measures, and the number of organ systems affected [19]. According to one prospective cohort study, the risk of death increases substantially in patients who present with anuria (HR 5.24; 95 percent CI 2.29-12.03), coma (HR 2.95; 95 percent CI 1.26-6.91), or cardiovascular failure (HR 2.43; 95 percent CI 1.14-5.17) [17]. Patients who take longterm antihypertensive medications, lack access to air conditioning, or are socially isolated or unable to care for themselves are also at high risk [17,20-22].

DIAGNOSTIC EVALUATION — The diagnosis of heat stroke, neuroleptic malignant syndrome (NMS), or malignant hyperthermia is based upon a careful history and physical examination. The full differential diagnosis of hyperthermia should be considered in each patient (table 1). The context in which symptoms develop usually suggests the etiology (eg, exertional heat stroke following exercise in high ambient temperature; malignant hyperthermia after anesthetic agents; NMS among patients treated with antipsychotic agents). Rectal temperature should be obtained in all patients. Abnormalities of vital signs in severe hyperthermia include sinus tachycardia, tachypnea, a widened pulse pressure, and hypotension [7]. The chest radiograph may demonstrate pulmonary edema, while the electrocardiogram may reveal dysrhythmias, conduction disturbances, nonspecific ST-T wave changes, or heatrelated myocardial ischemia or infarction [23-25]. Laboratory studies may reveal coagulopathy, acute renal failure, acute hepatic necrosis, respiratory alkalosis, and a leukocytosis as high as 30,000 to 40,000/mm3 [1]. Laboratory studies to obtain in the patient with heat stroke include:
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Complete blood count, electrolytes, blood urea nitrogen, plasma creatinine concentration, and liver enzymes. Prothrombin time (PT) and partial thromboplastin time (PTT) because of the risk of disseminated intravascular coagulation [26]. Studies to detect rhabdomyolysis (eg, serum creatine kinase) and its complications (eg, hypocalcemia, hyperphosphatemia, myoglobinuria, and acute renal failure) [27]. Myoglobinuria should be suspected in any patient with brown urine supernatant that is heme-positive, and clear plasma. (See "Clinical manifestations and diagnosis of rhabdomyolysis" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)".) Toxicologic screening may be indicated if a medication effect is suspected. A head CT and lumbar puncture should be performed as indicated if central nervous system etiologies are suspected [7].

MANAGEMENT General treatment and monitoring — Management of heat stroke requires ensuring adequate airway protection, breathing, and circulation; initiation of rapid cooling; and treatment of complications. A table summarizing emergency management of severe hyperthermia is provided. Tracheal intubation is needed for patients unable to protect their airway or with deteriorating respiratory function. Central venous pressure monitoring is useful for assessing volume status and determining the need for fluid resuscitation [15]. Alphaadrenergic agonists should be avoided, since the resultant vasoconstriction decreases heat dissipation. Instead, hypotension or volume depletion is treated with discrete intravenous

(IV) boluses of isotonic crystalloid (eg, isotonic saline 500 mL). Continuous core temperature monitoring with a rectal or esophageal probe is mandatory, and cooling measures should be stopped once a temperature of 38 to 39ºC (100.4 to 102.2ºF) has been achieved in order to reduce the risk of iatrogenic hypothermia [7]. Seizures are treated with benzodiazepines (eg, diazepam 5 mg IV). Cooling measures — Evaporative cooling is the method used most often to treat heat stroke because it is effective, noninvasive, easily performed, and does not interfere with other aspects of patient care. When used to treat elderly patients with classic heat stroke, evaporative cooling is associated with decreased morbidity and mortality [5]. With evaporative cooling, the naked patient is sprayed with a mist of lukewarm water while fans are used to blow air over the moist skin. Special beds called body cooling units have been made for this purpose [5]. Shivering induced by evaporative cooling or other treatments may be suppressed with IV benzodiazepines such as diazepam (5 mg IV) or lorazepam (1-2 mg IV) or, if NMS is not suspected, with chlorpromazine (25 to 50 mg IV). Benzodiazepines may also improve core body cooling [28]. Other effective cooling methods are less commonly used. Immersing the patient in ice water (cold water immersion) is an efficient, noninvasive method of rapid cooling [29], but it complicates monitoring and access. An alternative method that allows greater access to the patient is water ice therapy (WIT), in which the patient is placed supine on a porous stretcher positioned on top of a tub of ice water. Medical personnel continuously pour ice water from the bath onto the patient and massage major muscle groups with ice packs to increase skin vasodilation [30]. Applying ice packs to the axillae, neck, and groin, areas adjacent to major blood vessels, is another effective cooling technique, but may be poorly tolerated by the awake patient. Cold thoracic and peritoneal lavage results in rapid cooling. However, it is invasive and peritoneal lavage is contraindicated in pregnant patients and those with previous abdominal surgery. Cooled oxygen, cooling blankets, and cold (ie, room temperature, or approximately 22°C) intravenous fluids may be helpful adjuncts. Cold gastric lavage may cause water intoxication [3]. Recommendations for the treatment of heat stroke are based primarily upon small observational studies. A systematic review of clinical studies investigating the treatment of heat stroke noted the following [5]:
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There are no definitive studies supporting any particular approach to cooling in classic heat stroke. Evaporative cooling methods in the treatment of classic heat stroke are better tolerated. Immersion in ice water is rapid and effective in young patients with exertional heat stroke. However, immersion therapy is associated with increased mortality when used to treat elderly patients with classic heat stroke. Pharmacologic therapy (eg, dantrolene) is ineffective and not indicated in the treatment of exertional or classic heat stroke.

Pharmacologic therapy — Pharmacologic therapy is not required in heat stroke. There is no role for antipyretic agents such as acetaminophen or aspirin in the management of heat stroke, since the underlying mechanism does not involve a change in the hypothalamic setpoint and these medications may exacerbate complications such as hepatic injury or DIC [2,7]. Alcohol sponge baths should be avoided because large amounts of the drug may be absorbed through dilated cutaneous vessels and produce toxicity [1]. Dantrolene has been found to be ineffective in patients with severe temperature elevation not caused by malignant hyperthermia [31,32]. Treatment of complications — Severe hyperthermia may lead to a wide range of complications. These are generally treated in standard fashion while cooling measures are instituted. Complications may include:
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Respiratory dysfunction (See "Advanced emergency airway management in adults" and "Rapid sequence intubation in adults".) Seizures (See "Status epilepticus in adults", section on 'Benzodiazepines'.) Vomiting and diarrhea Rhabdomyolysis (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)".) Acute kidney injury Hepatic injury Disseminated intravascular coagulation (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults".)

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Basics topic (see "Patient information: Heat stroke (The Basics)")

SUMMARY AND RECOMMENDATIONS


Body temperature is maintained within a narrow range by balancing heat load with heat dissipation. Evaporation is the principal mechanism of heat loss in a hot environment, but becomes ineffective above a relative humidity of 75 percent. The other major methods of heat dissipation, including conduction and convection, cannot efficiently transfer heat when environmental temperature exceeds skin temperature. (See 'Pathophysiology' above.)













The differential diagnosis of hyperthermia is extensive and includes infectious, endocrine, central nervous system, and toxic etiologies (table 1). The most important causes of severe hyperthermia (greater than 40ºC) caused by failure of thermoregulation are heat stroke, neuroleptic malignant syndrome, and malignant hyperthermia. (See "Neuroleptic malignant syndrome" and "Malignant hyperthermia: Clinical diagnosis and management of acute crisis".) Severe hyperthermia carries a high mortality rate. Mortality correlates with the degree of temperature elevation, time to initiation of cooling measures, and the number of organ systems affected. (See 'Risk factors for increased mortality' above.) The diagnosis of heat stroke is based upon a careful history and physical examination. The full differential diagnosis of hyperthermia should be considered in each patient (table 1). The context in which symptoms develop usually suggests the etiology (eg, exertional heat stroke following exercise in high ambient temperature). Diagnostic studies are generally nonspecific but may reflect cardiovascular, renal or hepatic dysfunction or coagulopathy. Studies to be obtained are described in the text. (See 'Definitions and clinical findings' above and 'Diagnostic evaluation' above.) The management of heat stroke consists of ensuring adequate airway protection, breathing, and circulation; initiation of rapid cooling; and treatment of complications. A table summarizing emergency management of severe hyperthermia is provided. (See 'General treatment and monitoring' above.) We suggest that rapid cooling of patients with heat stroke be performed using evaporative techniques (Grade 2C). Evaporative cooling techniques are safe and effective in both exertional and classic heat stroke and do not interfere with patient access or monitoring. Among young healthy patients with exertional heat stroke, rapid cooling with ice water immersion is also an acceptable therapy. (See 'Cooling measures' above.) Hypotension or volume depletion is treated with discrete intravenous boluses of isotonic crystalloid. Continuous core temperature monitoring with a rectal or esophageal probe is mandatory in all patients being treated for heat stroke.

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REFERENCES
1. 2. 3. 4. Khosla R, Guntupalli KK. Heat-related illnesses. Crit Care Clin 1999; 15:251. Simon HB. Hyperthermia. N Engl J Med 1993; 329:483. Bouchama A, Knochel JP. Heat stroke. N Engl J Med 2002; 346:1978. Bross MH, Nash BT Jr, Carlton FB Jr. Heat emergencies. Am Fam Physician 1994; 50:389. 5. Bouchama A, Dehbi M, Chaves-Carballo E. Cooling and hemodynamic management in heatstroke: practical recommendations. Crit Care 2007; 11:R54. 6. Centers for Disease Control and Prevention (CDC). Heat-related deaths--Chicago, Illinois, 1996-2001, and United States, 1979-1999. MMWR Morb Mortal Wkly Rep 2003; 52:610. 7. Tek D, Olshaker JS. Heat illness. Emerg Med Clin North Am 1992; 10:299.

8. Klenk J, Becker C, Rapp K. Heat-related mortality in residents of nursing homes. Age Ageing 2010; 39:245. 9. Brody GM. Hyperthermia and hypothermia in the elderly. Clin Geriatr Med 1994; 10:213. 10. Dann EJ, Berkman N. Chronic idiopathic anhydrosis--a rare cause of heat stroke. Postgrad Med J 1992; 68:750. 11. Flynn A, McGreevy C, Mulkerrin EC. Why do older patients die in a heatwave? QJM 2005; 98:227. 12. Rav-Acha M, Hadad E, Epstein Y, et al. Fatal exertional heat stroke: a case series. Am J Med Sci 2004; 328:84. 13. Denborough M. Malignant hyperthermia. Lancet 1998; 352:1131. 14. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al. A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001; 93:683. 15. Seraj MA, Channa AB, al Harthi SS, et al. Are heat stroke patients fluid depleted? Importance of monitoring central venous pressure as a simple guideline for fluid therapy. Resuscitation 1991; 21:33. 16. Dematte JE, O'Mara K, Buescher J, et al. Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med 1998; 129:173. 17. Argaud L, Ferry T, Le QH, et al. Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France. Arch Intern Med 2007; 167:2177. 18. Misset B, De Jonghe B, Bastuji-Garin S, et al. Mortality of patients with heatstroke admitted to intensive care units during the 2003 heat wave in France: a national multiple-center risk-factor study. Crit Care Med 2006; 34:1087. 19. Pease S, Bouadma L, Kermarrec N, et al. Early organ dysfunction course, cooling time and outcome in classic heatstroke. Intensive Care Med 2009; 35:1454. 20. Bouchama A, Dehbi M, Mohamed G, et al. Prognostic factors in heat wave related deaths: a meta-analysis. Arch Intern Med 2007; 167:2170. 21. Naughton MP, Henderson A, Mirabelli MC, et al. Heat-related mortality during a 1999 heat wave in Chicago. Am J Prev Med 2002; 22:221. 22. Semenza JC, Rubin CH, Falter KH, et al. Heat-related deaths during the July 1995 heat wave in Chicago. N Engl J Med 1996; 335:84. 23. al-Harthi SS, Nouh MS, al-Arfaj H, et al. Non-invasive evaluation of cardiac abnormalities in heat stroke pilgrims. Int J Cardiol 1992; 37:151. 24. Akhtar MJ, al-Nozha M, al-Harthi S, Nouh MS. Electrocardiographic abnormalities in patients with heat stroke. Chest 1993; 104:411. 25. García-Rubira JC, Aguilar J, Romero D. Acute myocardial infarction in a young man after heat exhaustion. Int J Cardiol 1995; 47:297. 26. al-Mashhadani SA, Gader AG, al Harthi SS, et al. The coagulopathy of heat stroke: alterations in coagulation and fibrinolysis in heat stroke patients during the pilgrimage (Haj) to Makkah. Blood Coagul Fibrinolysis 1994; 5:731. 27. Becker BN, Ismail N. The neuroleptic malignant syndrome and acute renal failure. J Am Soc Nephrol 1994; 4:1406. 28. Hostler D, Northington WE, Callaway CW. High-dose diazepam facilitates core cooling during cold saline infusion in healthy volunteers. Appl Physiol Nutr Metab 2009; 34:582.

29. Smith JE. Cooling methods used in the treatment of exertional heat illness. Br J Sports Med 2005; 39:503. 30. McDermott BP, Casa DJ, O'Connor FG, et al. Cold-water dousing with ice massage to treat exertional heat stroke: a case series. Aviat Space Environ Med 2009; 80:720. 31. Zuckerman GB, Singer LP, Rubin DH, Conway EE Jr. Effects of dantrolene on cooling times and cardiovascular parameters in an immature porcine model of heatstroke. Crit Care Med 1997; 25:135. 32. Bouchama A, Cafege A, Devol EB, et al. Ineffectiveness of dantrolene sodium in the treatment of heatstroke. Crit Care Med 1991; 19:176. Management of anticoagulation before and after elective surgery Author Gregory YH Lip, MD, FRCPE, FESC, FACC Section Editor Lawrence LK Leung, MD Deputy Editor Stephen A Landaw, MD, PhD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: sep 14, 2011. INTRODUCTION — The role for warfarin and other anticoagulants in many cardiovascular disorders is well established and their use as prophylaxis against stroke or thromboembolism is increasing. As a result, many patients undergoing elective surgery or an invasive procedure may be taking anticoagulants. The management of anticoagulation in such patients both before and after such procedures will be reviewed here [1]. Rapid, temporary reversal of excess warfarin anticoagulation, and the possible use of medications affecting hemostasis in the perioperative period are discussed separately. (See "Correcting excess anticoagulation after warfarin", section on 'Temporary reversal of warfarin' and "Perioperative medication management", section on 'Medications affecting hemostasis'.) Issues concerning the risks of continuing warfarin or antiplatelet agents during eye surgery are discussed separately. (See "Cataract in adults", section on 'Antithrombotic agents' and "Anticoagulant, antiplatelet, and fibrinolytic (thrombolytic) therapy in patients at high risk for ocular hemorrhage", section on 'Ophthalmic surgery'.) PROBLEM OVERVIEW — Although continuation of anticoagulation increases the risk of bleeding following invasive procedures, interruption of such therapy increases the risk of thromboembolism in patients taking anticoagulants to prevent thrombosis [2-4]. Accordingly, individual circumstances should be carefully reviewed before an informed decision on modifying anticoagulation therapy is made in the patient undergoing surgery or an invasive procedure. There is also concern about the following issues in anticoagulated patients:

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There is a requirement of several days for the anticoagulant effect to resolve after warfarin therapy is discontinued, potentially delaying more urgent surgery. Rebound hypercoagulability may occur following the abrupt cessation of anticoagulation. Several days may be required after warfarin therapy is resumed to reestablish a therapeutic and adequate level of anticoagulation.

The importance of these issues varies in part with the indication for anticoagulation (eg, prophylaxis for thromboembolism versus actual treatment for an acute thrombotic episode). Accordingly, there is no general consensus regarding management strategy in patients undergoing elective surgery who are currently taking long-term anticoagulation. The type of procedure may also be important (see 'Type of surgery or procedure' below). THROMBOTIC RISK IF ANTICOAGULATION IS STOPPED — Patients may be taking oral anticoagulation as prophylaxis against the development of new thrombi or embolism (eg, atrial fibrillation, severe myocardial dysfunction, prosthetic heart valve) or as actual treatment of acute thrombus-related problems (eg, deep venous thrombosis or pulmonary embolism). Cessation of oral anticoagulation used to treat an acute thrombotic event may exacerbate the condition, which may itself be life-threatening. The risk of underanticoagulation varies with the type of thromboembolic event. While recurrent DVT carries some risk of fatal pulmonary embolism, the consequences of arterial thromboembolism from atrial fibrillation or prosthetic heart valves are much more serious, with 20 percent of episodes being fatal and 40 percent causing permanent disability [5-8]. Appropriate use of alternative strategies, such as intravenous heparin or subcutaneous low molecular weight heparin (LMW heparin) to provide antithrombotic coverage (ie, "bridging" anticoagulation) during the period when warfarin is withdrawn or reintroduced has been utilized in an attempt to minimize the risks involved. (See 'Use of bridging anticoagulation' below.) Venous thromboembolism — Long-term anticoagulation is the recommended treatment for patients at high risk of recurrence of venous thromboembolism. Discontinuation of warfarin in such patients is associated with a significant risk of thromboembolism as high as 15 percent per year; warfarin probably reduces this risk by about 80 percent [9-11]. After an acute episode of venous thromboembolism, the recurrence risk is much reduced over the following three months [12]. Without anticoagulation, the early risk of recurrent venous thromboembolism is approximately 50 percent, but treatment with warfarin for one month reduces this risk to 8 to 10 percent, and to 4 to 5 percent after three months of warfarin therapy [11,13]. Thus, discontinuing oral anticoagulation within the first month after an acute venous thromboembolic episode is associated with a high risk of recurrent venous thromboembolism [14]; this risk is reduced if surgery is delayed and there is a longer period of warfarin treatment.

Patients at risk for arterial thromboembolism — The risk of recurrent arterial embolism from any cardiac source is approximately 0.5 percent per day in the first month after an acute event [15]. This risk is reduced by two-thirds with warfarin. Arterial thromboembolism is most commonly associated with atrial fibrillation; embolic stroke is fatal or associated with a severe neurologic deficit in over 60 percent of these patients [5,6]. Patients with atrial fibrillation not due to valvular heart disease have an overall risk of systemic embolism of 4 to 5 percent per year in the absence of warfarin therapy; anticoagulation reduces the risk of embolization by about two-thirds in this setting [7,16]. However, patients with atrial fibrillation are not a homogeneous group and the risk of stroke and thromboembolism varies. Management should therefore be tailored to an individual patient's risk of thromboembolism as compared to the risk of bleeding during surgery. It is possible to risk stratify such patients based upon clinical and echocardiographic criteria. (See "Risk of embolization in atrial fibrillation".) Other causes of thromboembolism include a dilated and poorly contractile left ventricle or a left ventricular aneurysm in which intraventricular thrombi may form and embolize [1719].




Among patients with left ventricular dysfunction, one report found an 18 percent increase in stroke risk for every 5 percent reduction in left ventricular ejection fraction, although the absolute short-term risk was low [18]. Anticoagulation with warfarin was associated with an 81 percent reduction in total stroke risk while aspirin therapy reduced the risk by 56 percent. (See "Indications for anticoagulation in heart failure".) Among patients with left ventricular aneurysm, the frequency of left ventricular thrombi in aneurysms reported by postmortem studies can range between 14 and 68 percent, a value consistent with findings at the time of surgical aneurysmectomy (50 to 95 percent) [17].

Recommendations are available elsewhere for the management of patients with atrial fibrillation when temporary cessation of warfarin is considered. (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation", section on 'Temporary cessation of anticoagulation'.) Prosthetic heart valves — Systemic embolization (predominantly cerebrovascular events) occurs at a frequency of approximately 0.7 to 1.0 percent per patient per year in patients with mechanical valves who are treated with warfarin, 2.2 percent per patient per year with aspirin, and 4.0 percent with no anticoagulation. A major advantage of the bioprosthetic valve is freedom from anticoagulation. The management of anticoagulation in such patients, both in general and in the perioperative period, is discussed in depth separately. (See "Antithrombotic therapy in patients with prosthetic heart valves", section on 'Discontinuing warfarin for surgical procedures'.)

BLEEDING RISK IF ANTICOAGULATION IS CONTINUED — The risk of bleeding occurring with surgery in patients taking anticoagulant therapy is dependent upon patient age, the presence of other disease states, the type of surgery [20], the anticoagulant regimen and intensity, the length of warfarin therapy, the use of other drugs that affect hemostasis (eg, heparin, aspirin, antiplatelet agents), the stability of anticoagulation, and the degree of anticoagulation as measured by the INR [2,21,22]. Type of surgery or procedure — Prolonged, complex, and major surgery is much more likely to cause significant bleeding problems than short, simple, and minor surgical procedures. As examples:




Low bleeding risk procedures — Most patients can undergo low-risk surgical procedures (eg, arthrocentesis, cataract surgery, coronary arteriography, outpatient dental surgery, other minor outpatient procedures) without alteration of their anticoagulation regimen [23,24]. In such patients, oral anticoagulation with a vitamin K antagonist can be continued at or below the low end of the therapeutic range (INR ≤2.0). (See "Cataract in adults", section on 'Antithrombotic agents' and "Anticoagulant, antiplatelet, and fibrinolytic (thrombolytic) therapy in patients at high risk for ocular hemorrhage", section on 'Ophthalmic surgery'.) High bleeding risk procedures — More complex or high-risk surgical procedures (eg, open-heart surgery, abdominal vascular surgery, intracranial or spinal surgery, major cancer surgery, urologic procedures) require discontinuation of oral anticoagulation, followed by temporary perioperative coverage with unfractionated heparin or LMW heparin in those patients who are at high risk of thromboembolism [25]. (See 'Cessation and resumption of anticoagulation' below.)

Gastroenterologic procedures — Management of anticoagulation in patients undergoing gastroenterologic procedures depends upon the estimated bleeding risk for the contemplated procedure as well as the estimated thrombotic risk if the patient is temporarily taken off anticoagulation (table 1 and table 2 and table 3) [26]. This subject is discussed in detail separately. (See "Management of anticoagulants in patients undergoing endoscopic procedures", section on 'Elective procedures in anticoagulated patients'.) Dental or excisional cutaneous procedures — In patients undergoing dental extraction, warfarin anticoagulation is associated with a minimal risk of serious bleeding if the INR is within the therapeutic range just prior to the contemplated surgery [27-32]. Tranexamic acid or aminocaproic acid mouthwash, if available (eg, 4.8 to 5 percent aqueous solutions used four times per day for at least two days), can be used to limit local postoperative bleeding [32-37]. The use of aspirin, NSAIDS, or Cox-2 inhibitors for analgesia should be avoided. However, there are documented cases of serious embolic events when warfarin has been withdrawn prior to dental procedures. In a literature review of 542 documented cases in 493 patients in whom continuous anticoagulation was withdrawn for a dental procedure (without heparin replacement), there were five serious embolic complications (0.9 percent of cases) [28].

Anticoagulation is generally safe in patients undergoing excisional cutaneous surgery (eg, Mohs surgery) if the INR is maintained within the therapeutic range [20,38-40]. As with dental procedures, cessation of prophylactic anticoagulation (warfarin or antiplatelet therapy) has been associated with a risk of thromboembolic events [38-40]. Use of heparin — The risk of bleeding after the use of heparin is variable. A two-day course of intravenous heparin before surgery is unlikely to cause much in the way of preoperative bleeding. The general risk of bleeding associated with continuous intravenous heparin is less than 5 percent in patients with acute venous thromboembolism; however, in patients with deep vein thrombosis who are judged to be at high risk for bleeding, the incidence of major bleeding is approximately 11 percent during the first five days of intravenous heparin therapy [22,41]. CESSATION AND RESUMPTION OF ANTICOAGULATION Warfarin Overview — After the cessation of oral warfarin, it usually takes a few days for the INR to fall to below 2.0. One study prospectively evaluated 22 patients with a baseline INR of 2.6 in whom it was deemed safe to discontinue warfarin [42]. In these patients the mean INR was 1.6 and 1.2 at 2.7 and 4.7 days after discontinuation of warfarin, respectively. Once the INR is 2.0 or below, surgery can be performed with relative safety in most cases. Following surgery and after warfarin is restarted, it takes about three to four days for the INR to rise above 2.0. It is therefore estimated that if warfarin is withheld for four days before surgery and is restarted as soon as possible afterwards, patients would have a subtherapeutic INR for approximately two days before surgery and two days after surgery [14]. A slight elevation of the INR to about 1.5 should theoretically provide partial protection against thromboembolism [43,44]. In support of this hypothesis, ultra-low dose warfarin (1 mg/day) has been successfully used to prevent deep venous thrombosis in patients with malignancy in association with a marginal rise in the INR [44]. (See "Drug-induced thrombosis and vascular disease in patients with malignancy", section on 'Prophylactic anticoagulation'.) If the patient has been adequately anticoagulated for some time prior to cessation of warfarin, it is generally assumed that almost any preexisting thrombus would have either resolved or be endothelialized, thereby minimizing the risk of embolism [18]. Among patients with nonvalvular atrial fibrillation, for example, over 85 percent of thrombi resolve after four weeks of warfarin therapy as determined by transesophageal echocardiography [45]. Nevertheless, although the INR itself may not be a good guide to a reduced risk of thromboembolism, some patients have a significant reduction in their usual anticoagulant intensity during surgery and a minor increase in the risk of thromboembolism is probably unavoidable [42]. Among patients with atrial fibrillation, chronic low dose warfarin plus

aspirin is much less effective than adjusted dose warfarin in preventing embolic events (figure 1 and figure 2), demonstrating that such lesser degrees of anticoagulation do not provide optimal protection [46]. (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation".) Reversing warfarin — Reversing the activity of vitamin K antagonists depends upon the amount of time available before the surgical or invasive procedure. The following guidelines are most appropriate [37]: Fully elective surgery — In patients with an INR between 2.0 and 3.0 who are undergoing elective surgery that requires temporary cessation of anticoagulation, warfarin should be withheld for approximately three to four days to allow the INR to fall to a level of 1.5 to 2.0 before surgery [14,42,47]. Warfarin should be withheld for approximately five days if the surgeon feels it is necessary to reduce the INR to a lower or normal level in order to reduce the risk of bleeding (eg, less than 1.5) [42]. Semi-urgent surgery — If more rapid reversal of warfarin anticoagulation is required (eg, over one to two days), warfarin should be withheld and a small dose (eg, 1.0 to 3.0 mg) of intravenous vitamin K1 administered. (See "Correcting excess anticoagulation after warfarin", section on 'Temporary reversal of warfarin'.) Urgent surgery — If urgent reversal of warfarin anticoagulation is required (eg, less than one day), warfarin should be withheld and a higher dose (eg, 2.5 to 5.0 mg) of intravenous vitamin K1 administered. If more immediate correction is required (eg, minutes to hours), this can be achieved via the use of those prothrombin complex concentrates which contain adequate amounts of factor VII or fresh frozen plasma, in addition to vitamin K [48]. A discussion of how such rapid reversal of the warfarin effect can be accomplished can be found elsewhere. (See "Correcting excess anticoagulation after warfarin", section on 'Significant or life-threatening bleeding'.) The risk of rebound hypercoagulability — As mentioned above, rebound hypercoagulability may occur following the abrupt cessation of anticoagulation. Accordingly, alternative preoperative and/or postoperative prophylaxis against thromboembolism with unfractionated heparin (UFH) or LMW heparin should be considered in high risk patients (eg, prosthetic valve in the mitral position, venous thromboembolism within the previous four weeks, or active malignancy) for the period during which the INR is less than 2.0 [49-51]. The clinical effects of rebound hypercoagulability after stopping warfarin are unlikely to be significant, despite biochemical evidence for this phenomenon and the recommendation by some investigators that warfarin should be withdrawn gradually [52-54].




In one study of 19 patients, for example, thrombin and fibrin formation increased after abrupt cessation of warfarin therapy but no patient had a thromboembolic event [54]. In another report, however, 32 patients were randomly assigned to receive abrupt or gradual withdrawal of warfarin [53]. Very high levels of thrombin activation were

seen in a few patients treated with abrupt withdrawal, two of whom developed a thrombotic event (one recurrent deep vein thrombosis and one thrombosis in a varicose vein). Surgery itself increases the risk of thromboembolism as documented by changes in hemostatic markers, which are also part of the acute phase response and wound healing process [55]. High levels of hemostatic markers, such as fibrin D-dimer, an index of intravascular thrombogenesis and fibrin turnover, are predictive of postoperative thrombosis [56,57]. Although there is evidence that surgery increases the risk of venous thromboembolism, there is no evidence that surgery itself increases the risk of arterial thromboembolism, apart from risks associated with particular procedures, such as carotid surgery [58]. Use of bridging anticoagulation — The risk of a short period of underanticoagulation is uncertain, especially since randomized studies of heparin versus placebo bridging among warfarin-treated patients who need procedures have not been conducted. Because of the lack of evidence-based information indicating those patients in whom bridging anticoagulation is or is not warranted, there is considerable variation in the use of this modality [59]. Of the available non-randomized studies of this question [25,49,60-68], the following prospective observational cohort studies are instructive concerning the thrombotic and hemorrhagic risks attendant to the use or non-use of bridging therapy in this setting. The first study involved a cohort of 1024 individuals whose warfarin therapy was temporarily withheld on 1293 different occasions for an outpatient invasive procedure (colonoscopy; oral, dental, or ophthalmic surgery; epidural injection; prostate or breast biopsy; dermatologic procedure). The following observations were made [62]:






The duration of warfarin therapy interruption was variable, although >80 percent had warfarin therapy withheld for ≤5 days. Bridging therapy with heparin or LMW heparin was given in only 8.3 percent of the procedures. Six patients (0.6 percent; 95% CI 0.2-1.3) experienced major bleeding and an additional 17 patients (1.7 percent; 95% CI 1.0-2.6) experienced a clinically significant, nonmajor bleeding episode. Four of the six patients with major bleeding and 10 of the 17 patients with nonmajor clinically significant bleeding had received periprocedural bridging therapy, for an overall bleeding rate in bridged patients of 13 percent. Postprocedural thromboembolism within 30 days occurred in seven patients (0.7 percent; 95% CI 0.3-1.4). None of the seven patients had received periprocedural bridging therapy; two of these patients would have been considered to be at high risk for thromboembolism (ie, recent VTE or active malignancy).

The authors concluded that perioperative anticoagulation may be unnecessary for a significant proportion of low- to intermediate-risk outpatients who have undergone longterm anticoagulation, whose warfarin therapy must be interrupted for a brief period (ie, ≤5

days), and that bridging therapy with unfractionated or LMW heparin may result in significant and potentially avoidable perioperative hemorrhage. Similar conclusions were reached in a second study involving a cohort of 345 individuals with nonvalvular atrial fibrillation undergoing an invasive procedure. Warfarin therapy was temporarily withheld on 342 different occasions for a mean period of 6.6 days. The decision to use bridging anticoagulation with therapeutic doses of either intravenous unfractionated heparin or LMW heparin was individualized, but was generally given only to those patients deemed to be at high risk for stroke. The following observations were made [25]:






The three-month cumulative incidence of thromboembolism was 1.1 percent and did not differ significantly between those who did or did not receive bridging therapy. Of interest, despite not receiving bridging therapy after brief warfarin cessation, none of the 43 patients with a prior thromboembolic event, and none of the 51 patients with a CHADS2 score ≥3 developed postoperative thromboembolism during the three-month follow-up period. The three-month cumulative incidence of major bleeding was 2.7 percent for those receiving bridging therapy. Of the 10 episodes of major bleeding, six occurred in five patients given bridging therapy with LMW heparin.

The authors indicated that they currently utilize bridging with LMW heparin only for those patients at highest risk (eg, prior stroke, CHADS2 score ≥4) while taking into account the procedure-associated risk of bleeding. (See 'Type of surgery or procedure' above.) Use of subtherapeutic doses of LMW heparin — Two nonrandomized studies employing bridging with sub-therapeutic doses of LMW heparin are discussed below. In the first study, subtherapeutic doses of LMW heparin (eg, 3800 IU of nadroparin or 4000 IU of enoxaparin once daily the night before the procedure for those at low risk of thrombosis or 3800 or 4000 IU of these agents twice daily for those at high thrombotic risk) were employed in 103 patients undergoing surgery and in 225 non-major invasive procedures. Results included [63]:




The overall incidence of a thromboembolic event was 1.8 percent and was not significantly different between those in the low-risk (0.54 percent) or high-risk (3.4 percent) groups. The overall incidence of major bleeding was 2.1 percent and was not significantly different between those in the low-risk (0.5 percent) or high-risk (4.1 percent) groups. All of the major bleeding events occurred in those undergoing major surgery.

The second study was a report from a prospective registry of 198 consecutive patients receiving oral anticoagulation with phenprocoumon and a planned surgery [69]. The majority of patients (88 percent) were judged to be at intermediate thromboembolic risk. Phenprocoumon was stopped seven days before surgery. All patients received enoxaparin

in a half-therapeutic dose (1 mg/kg per day) starting when the INR was <2.0 and continuing until the day before surgery. Enoxaparin was restarted after the procedure at the same total daily dose (in two divided doses) and phenprocoumon was resumed within the first 14 postoperative days, depending upon the bleeding risk. Only one patient (0.5 percent) developed a postoperative arterial thromboembolic event, and one patient (0.5 percent) required a second surgical intervention due to severe bleeding. Both sets of authors concluded that the use of bridging anticoagulation with subtherapeutic doses of LMW heparin was safe and effective. Resumption of warfarin — Warfarin therapy should be restarted 12 to 24 hours postsurgery, provided that surgical hemostasis has been achieved [37]. Heparin products Unfractionated heparin — The biologic half-life of intravenous unfractionated heparin (UFH) is approximately 45 minutes [37,70]. Thus, most bridging anticoagulation studies have suggested that intravenous UFH should be stopped 4 to 5 hours before the planned surgery or procedure, a time interval that is approximately 5 elimination half-lives of UFH. LMW heparin — The biologic half-life of subcutaneous LMW heparin is approximately 4 to 6 hours [37,70]. Thus, most bridging anticoagulation guidelines have suggested that the last dose of subcutaneous LMW heparin should be given 24 hours before the planned surgery or procedure, a time interval that is approximately 5 elimination half-lives of LMW heparin. However, because some studies have shown residual anticoagulant effect at 24 hours after stopping therapeutic-dose LMW heparin [12,71], it has been recommended that, on the day before surgery or the procedure, therapeutic-dose LMW heparin should be administered at one-half of the usual total daily dose [37]. Resumption of treatment — The onset of anticoagulation after both UFH and LMW heparin is similar, at around one hour after administration, with peak anticoagulant activity at around three to five hours. Thus, if post-operative or post-procedural anticoagulation is contemplated, these agents should not be employed too early following the operation, in order to insure that hemostasis has been secured at the operative or procedural site [72]. This requires both a pre-procedural estimate of the anticipated risk of bleeding as well as a post-procedural determination of the adequacy of hemostasis [37]. However, for most minor procedures associated with a low bleeding risk, therapy with LMW heparin or UFH can usually be resumed at 24 hours post-procedure, whereas for those undergoing major surgery or those with a high bleeding risk procedure, such treatment should be delayed for 48 to 72 hours after hemostasis has been secured [37]. Dabigatran — Dabigatran is an orally active thrombin inhibitor. It has a time to peak anticoagulant activity of two to three hours after ingestion and a half-life elimination of 12

to 14 hours in normal subjects and approximately 28 hours in those with severe renal impairment [73]. (See "Anticoagulants other than heparin and warfarin", section on 'Dabigatran'.) These pharmacokinetic parameters affect the timing of cessation and resumption of treatment with this agent, as follows [74,75]:




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Cessation prior to invasive or surgical procedures: For those with a creatinine clearance ≥ 50 mL/minute, discontinue dabigatran 1 to 2 days before the procedure. For those with a creatinine clearance <50 mL/minute, discontinue this agent 3 to 5 days before the procedure. Longer periods should be considered for those undergoing major surgery, spinal puncture, placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required. Conversion to a parenteral anticoagulant: Wait 12 hours (Clcr ≥30 mL/minute) or 24 hours (Clcr <30 mL/minute) after the last dose of dabigatran before initiating a parenteral anticoagulant. Resumption following procedure: Therapy with dabigatran should be initiated when hemostasis has been achieved, since its onset of action (2 to 3 hours) is rapid. Resumption following use of heparin or LMW heparin: Initiate dabigatran ≤2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant (eg, enoxaparin) or at the time of discontinuation for a continuously administered parenteral drug (eg, intravenous heparin)

SPECIAL CONSIDERATIONS — A number of clinical situations require special consideration. These are discussed below. Venous thromboembolism — The management of anticoagulation in patients with previous venous thromboembolic disease depends upon the temporal relationship to surgery or an invasive procedure (table 4).






Within the first month after an acute episode of venous thromboembolism, the incidence of recurrence without anticoagulation is about 1 percent per day. While postoperative intravenous heparin doubles the rate of bleeding, there is a net reduction in serious morbidity in such patients, since the risk of postoperative recurrent venous thromboembolism is high. Thus, heparin therapy is recommended both before and after surgery [14]. By two to three months after an acute episode of venous thromboembolism, the risk of recurrence is significantly reduced so that preoperative heparin therapy is probably not justified unless there are other risk factors for thromboembolism (eg, prolonged hospitalization and confinement to bed) [14]. However, because of an expected increase in the risk of venous thromboembolism after surgery, these patients should be treated postoperatively with heparin. At more than three months after an episode of venous thromboembolism, preoperative anticoagulation is not needed and postoperative intravenous heparin is also probably not necessary. (See "Treatment of lower extremity deep vein thrombosis", section on 'Length of treatment'.)

In this setting, the bleeding associated with postoperative intravenous heparin offsets any beneficial effect from the prevention of major thromboembolic events [14]. Prophylactic measures that reduce the thrombotic risk, such as subcutaneous LMW heparin or compression stockings, are associated with a lower risk of bleeding than intravenous heparin and are safer alternatives [3]. Arterial thromboembolism — The approach is somewhat different in patients at risk for arterial thromboembolism, because the thromboembolic risk is similar both before and after surgery. Furthermore, the risk of bleeding is much higher in such patients after surgery if heparin is continued or the INR is maintained at around 2.0. Thus, preoperative treatment with intravenous heparin is advised if oral anticoagulation is stopped. Postoperative therapy with intravenous heparin is probably useful for patients undergoing minor surgery where the risk of bleeding is low. In contrast, the net benefit of using intravenous heparin in reducing long-term disability after major surgery is small because of the high risk of serious bleeding. If the risk of acute arterial thromboembolism is low, as in patients with nonvalvular atrial fibrillation receiving warfarin for thromboprophylaxis, postoperative intravenous heparin therapy probably increases, rather than decreases, serious morbidity. Restarting warfarin on the second postoperative day and the use of low risk regimens, such as subcutaneous heparin, if warfarin was discontinued preoperatively, are preferable to minimize the risk of bleeding.


Unfractionated heparin should be stopped four hours before surgery with the expectation that the anticoagulation effect will have worn off at the time of surgery [76]. If LMW heparin has been used, it should be stopped, preferably 24 hours before surgery [77], with the same expectation. These recommendations may not apply to patients undergoing minor procedures such as skin biopsy or dental extractions [28,34,38]. However, it is important to confirm that the INR does not exceed the therapeutic range. Although uninterrupted anticoagulation may be continued in most patients, we and many other clinicians withhold warfarin for two to four days prior to the procedure, and reinstitute therapy after the procedure [76]. Elective surgery should be avoided in the first month after arterial thromboembolism. If surgery is essential, preoperative and postoperative heparin therapy is recommended as described above for venous thromboembolism, but only if the risk of postoperative bleeding is low. In patients receiving warfarin as prophylaxis against arterial embolization, such as low risk patients with a prosthetic heart valve or nonvalvular atrial fibrillation, the risk of thromboembolism is not high enough to warrant routine preoperative or postoperative therapy with intravenous heparin, especially in view of the bleeding risk [7,78].





If the surgical intervention itself is associated with a high risk of postoperative venous thromboembolism (VTE), the brief use of subcutaneous low-dose heparin or LMW heparin in doses used for prophylaxis against VTE has been suggested [76]. (See "Antithrombotic

therapy to prevent embolization in nonvalvular atrial fibrillation", section on 'Temporary cessation of anticoagulation' and "Prevention of venous thromboembolic disease in surgical patients", section on 'Risk factors for VTE'.) The approach is different in high risk patients with atrial fibrillation (eg, prior thromboembolism, rheumatic heart disease, left ventricular dysfunction) or prosthetic heart valves (eg, those with older generation mechanical valves or atrial fibrillation), in whom there is a delicate balance between the risks of bleeding and thromboembolism [7,78]. In this setting, a number of options exist and the appropriate treatment of such patients is unclear and controversial [76,78]. However, it is our preference in this setting to administer intravenous heparin until five to six hours before the procedure, to be restarted as soon as surgical hemostasis has been assured [76]; the dose is adjusted to achieve an activated PTT that is 2.0 times control. Warfarin is then reinstituted prior to discharge from the hospital; the INR should be in the therapeutic range for at least 48 hours before heparin is discontinued. Pacemaker insertion — A substantial number of patients who require the insertion of a permanent pacemaker are receiving oral anticoagulation and/or antiplatelet therapy for various reasons. Elective pacemaker insertion is often performed in the outpatient setting and the issue of anticoagulation is an important concern [79]. One study compared the outcome of 37 patients undergoing outpatient pacemaker implantation while continuing on warfarin therapy with 113 patients not receiving warfarin; there was no difference in the incidence of any complications, including those related to the wound [80]. The use of a cutdown technique, rather than a subclavian puncture, to gain venous access is preferred and a catheter electrode with a small cross sectional area and small introducer should be used to reduce the probability of venous damage; pocket hemostasis must be meticulous. Mechanical prosthetic heart valves — Recommendations regarding the perioperative management of anticoagulation in patients with prosthetic heart valves are presented separately. (See "Antithrombotic therapy in patients with prosthetic heart valves", section on 'Discontinuing warfarin for surgical procedures'.) Percutaneous coronary intervention — Management of anticoagulation as well as antiplatelet therapy in patients undergoing percutaneous coronary intervention is discussed separately. (See "Antithrombotic therapy for intracoronary stent implantation: General use", section on 'Patients who require warfarin'.) SUMMARY AND RECOMMENDATIONS — The risk of thromboembolism in patients who discontinue anticoagulation before an invasive procedure must be weighed against the risk of bleeding if these agents are continued or bridging anticoagulation is employed. Accordingly, individual circumstances should be carefully reviewed before an informed decision on modifying anticoagulation therapy is made in the patient undergoing surgery or an invasive procedure. (See 'Problem overview' above.) Low risk surgical procedures — Most patients can undergo low-risk surgical procedures without alteration of their anticoagulation regimen, provided that their INR is within the

therapeutic range. (See 'Type of surgery or procedure' above and 'Bleeding risk if anticoagulation is continued' above.) Patients at risk for bleeding — For patients with a high risk of procedural bleeding, the preprocedural INR should be ≤1.5. We recommend that patients at low risk for thrombosis stop warfarin five days preoperatively rather than for a shorter interval (Grade 1B). This will allow adequate time for the INR to normalize. (See 'Warfarin' above.) Once surgical hemostasis has been achieved, we recommend that warfarin therapy be resumed 12 to 24 hours post-surgery, rather than for a shorter or longer interval (Grade 1C). (See 'Resumption of warfarin' above.) Patients at risk for thrombosis
 







Elective surgery should be avoided, if at all possible, in the first month after an acute episode of venous thromboembolism. For patients at high or intermediate risk for thrombosis, we recommend the use of bridging anticoagulation with intravenous heparin or LMW heparin over no bridging during temporary interruption of oral anticoagulation (Grade 1C). Clinical judgement is required to determine the dose of these agents (ie, therapeutic, subtherapeutic, or prophylactic dosing) as the quality of evidence for making this choice is poor. (See 'Venous thromboembolism' above and 'Use of bridging anticoagulation' above.) For patients at low risk for thrombosis, we suggest either bridging anticoagulation with prophylactic dose or subtherapeutic dose LMW heparin or no bridging anticoagulation over bridging with therapeutic dose LMW heparin (Grade 2C). (See 'Use of bridging anticoagulation' above.) If acute venous thromboembolism has occurred within two weeks AND the risk of bleeding associated with the use of bridging anticoagulation is high, the temporary use of a vena caval filter should be considered. (See "Inferior vena cava filters".) Elective surgery should be avoided, if at all possible, in the first month after arterial thromboembolism. If surgery is essential, bridging anticoagulation is recommended as described above for venous thromboembolism. (See 'Arterial thromboembolism' above and 'Use of bridging anticoagulation' above.)

Stopping and starting bridging anticoagulation






Bridging anticoagulation with unfractionated heparin should be stopped four to five hours before surgery. If LMW heparin has been used, it should be stopped 24 hours before surgery. (See 'Heparin products' above.) We suggest that heparin or LMW heparin in therapeutic doses should not be restarted postoperatively until at least 24 hours after surgery and delayed longer if there is any evidence of bleeding (Grade 2C). (See 'Heparin products' above.) Guidelines for stopping and restarting dabigatran have been formulated on the known pharmacokinetics of this agent, and are described in the text. (See 'Dabigatran' above.)

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71. Douketis JD, Woods K, Foster GA, Crowther MA. Bridging anticoagulation with low-molecular-weight heparin after interruption of warfarin therapy is associated with a residual anticoagulant effect prior to surgery. Thromb Haemost 2005; 94:528. 72. Strebel N, Prins M, Agnelli G, Büller HR. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002; 162:1451. 73. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an openlabel, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259. 74. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116. 75. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011; 123:1436. 76. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:204S. 77. O'Donnell MJ, Kearon C, Johnson J, et al. Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin. Ann Intern Med 2007; 146:184. 78. Salem DN, O'Gara PT, Madias C, et al. Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:593S. 79. Korantzopoulos P, Letsas KP, Liu T, et al. Anticoagulation and antiplatelet therapy in implantation of electrophysiological devices. Europace 2011; 13:1669. 80. Goldstein DJ, Losquadro W, Spotnitz HM. Outpatient pacemaker procedures in orally anticoagulated patients. Pacing Clin Electrophysiol 1998; 21:1730. Anticoagulation during pregnancy Authors Jess Mandel, MD William H Gaasch, MD Kenneth A Bauer, MD Section Editors Lawrence LK Leung, MD Charles J Lockwood, MD Deputy Editors Stephen A Landaw, MD, PhD Kevin C Wilson, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: jun 9, 2011. INTRODUCTION — Clinicians are occasionally faced with the dilemma of managing pregnant patients who require ongoing anticoagulation for the prophylaxis or treatment of

thrombotic complications. Examples include women with mechanical heart valves, venous thromboembolism (VTE) immediately prior to or during pregnancy, heart failure, and symptomatic antiphospholipid antibody syndrome (see appropriate topic reviews). Strategies to maintain therapeutic anticoagulation while avoiding maternal or fetal harm due to antithrombotic agents are based largely upon retrospective data because ethical and legal considerations make large prospective trials among pregnant women difficult to conduct. This topic review will describe the experience with major antithrombotic agents among pregnant women and discuss the management of several common conditions that require anticoagulation during pregnancy. General issues related to the clinical use of warfarin and heparin are discussed separately. (See "Therapeutic use of warfarin" and "Therapeutic use of heparin and low molecular weight heparin".) Due to the unique nature of managing pregnant women with mechanical prosthetic valves, anticoagulation in this setting is discussed in detail separately. (See "Management of pregnant women with prosthetic heart valves".) COMMON ANTITHROMBOTIC AGENTS — Unfractionated heparin (UFH) and lowmolecular-weight heparin (LMWH) are the antithrombotic agents most commonly considered for use in pregnant women. Oral anticoagulants (OACs), usually warfarin, are generally not used during pregnancy for the reasons outlined below. Warfarin — The anticoagulant effect of warfarin is mediated by interference with the vitamin K-dependent gamma-carboxylation of coagulation factors II, VII, IX, and X [1]. This results in the synthesis of immunologically detectable but biologically inactive forms of these coagulation proteins. (See "Therapeutic use of warfarin".) The anticoagulant effect of warfarin is delayed until the normal clotting factors are cleared from the circulation [2]. During the first few days of warfarin therapy, the prolongation of the prothrombin time (PT) mainly reflects the depression of factor VII, which has a half-life of five to seven hours. This does not represent adequate anticoagulation, because the intrinsic and common clotting pathways remain intact until factors II, IX, and X are sufficiently reduced, which takes about five days with adequate dosing (figure 1). Warfarin is the long-term anticoagulant of choice in nonpregnant patients, but its great disadvantage in pregnancy is that it freely crosses the placental barrier because of its low molecular weight and can harm the fetus [3,4]. For this reason, the drug is classified by the United States Food and Drug Administration (FDA) as pregnancy category X (table 1). However, nursing mothers can safely take the drug because there is no convincing evidence that warfarin exerts an anticoagulant effect on the breast-fed infant [5]. Adverse fetal effects from warfarin may result from the teratogenicity of the drug and its propensity to cause bleeding in the fetus.

Teratogenic effects — There is convincing evidence that warfarin administration is potentially teratogenic. Embryopathy is most likely with exposure during the sixth to ninth weeks of gestation, but toxicity after this period is still possible [6-9]. Exposure is also associated with higher rates of spontaneous abortion and stillbirth [10,11]. The teratogenic effect appears to be dose related, with doses less than 5 mg/day providing the highest margin of safety [12,13]. The most common developmental abnormalities affect bone and cartilage; these simulate chondromalacia punctata, with stippled epiphyses and nasal and limb hypoplasia [14]. The mechanism of this type of warfarin teratogenicity has not been established, but may be related to the drug's interference with the post-translational modification of calciumbinding proteins that are important for the normal growth and development of bony structures [15]. As an example, osteocalcin carboxylation in human subjects is a vitamin Kdependent process, and circulating osteocalcin is structurally altered by warfarin [16]. (See "Vitamin K and the synthesis of gamma carboxyglutamic acid".) Less well-documented are reports of central nervous system (CNS) abnormalities (including optic atrophy, microcephaly, mental retardation, spasticity, and hypotonia) associated with warfarin use at any stage during pregnancy [3,17-20]. This complication may be related to fetal anticoagulation leading to CNS hemorrhage. Fetal or neonatal hemorrhage is a concern when warfarin is administered in the second and third trimesters; however, this complication has rarely been observed [12,21-24]. The risk is thought to be greatest during and immediately after delivery [19,20]. The precise risk of warfarin embryopathy is unknown. While different series have reported widely ranging incidences among fetuses exposed to warfarin between the sixth and twelfth weeks of gestation [14], the best overall estimate of the risk is less than 10 percent [25]. (See "Management of pregnant women with prosthetic heart valves".) One study, for example, found no congenital abnormalities in 46 women with prosthetic valves who took warfarin during the first trimester [22]. However, other reports have not found such a benign outcome, primarily in patients taking warfarin between the six and twelfth weeks of pregnancy. As an example, the following findings were noted in report of 72 pregnancies in women with valve prostheses [23]:


 

Virtually no embryopathic events occurred in the 23 pregnancies in which warfarin was discontinued by the sixth week of gestation and not restarted until after the twelfth week. Warfarin embryopathy occurred in 25 percent of the 12 pregnancies in which warfarin was not stopped until after the seventh week. Embryopathy occurred in 30 percent of the 37 pregnancies in which warfarin was continued throughout the entire pregnancy.

Another smaller study noted embryopathy in 12 of 18 infants born to mothers who took warfarin throughout pregnancy [24]. The most common event was a minor cosmetic defect (nasal hypoplasia); major complications were rare.

There may be a relationship between the warfarin dose and fetal complications that is independent of the INR [12,13]. This association was illustrated in a report of 71 pregnancies in 52 women with mechanical heart valves who were treated with warfarin throughout pregnancy [12]. There were 30 fetal complications, including 23 spontaneous abortions, four warfarin embryopathies, and five stillbirths. Women taking more than 5 mg of warfarin daily were at much higher risk of fetal complications than those taking a lower dose (82 versus 8 percent), regardless of INR. A similar increase in risk with warfarin doses above 5 mg/day (88 versus 15 percent) was noted in another study [13]. The actual risk of warfarin embryopathy resulting in a deformed, mentally retarded infant is believed to be relatively low [11], but warfarin-related central nervous system abnormalities probably occur at an incidence greater than first trimester embryopathy, although they are clinically less severe. In light of the possibility that the risk of warfarin embryopathy, central nervous system maldevelopment, and optic injury might increase with warfarin dose and the degree of anticoagulation, therapy should be monitored meticulously using the INR to achieve a therapeutic response at the lowest possible dose. (See "Therapeutic use of warfarin".) The long-term physical and neurologic development after prenatal coumarin exposure during pregnancy was evaluated in a case-control study of 274 such children (7 to 15 years of age) who were compared with 231 unexposed controls [26]. Only 5 percent of the children were exposed to coumarins during the sixth to ninth week of development. Data were analyzed by both single and combined effects models to look for adverse outcomes in the coumarin-exposed group. No major differences in growth or overall neurologic status were found. Exposed children were at mildly increased risk for minor neurologic dysfunction and lower IQ. There was a suggestion that the risk of adverse outcome was related to maternal coumarin dose; however, this was not statistically significant. Fetal hemorrhage — The immaturity of fetal enzyme systems and the relatively low concentration of vitamin K-dependent clotting factors render the fetus more sensitive than the mother to the anticoagulant effects of warfarin [3,17,18]. Thus, the transplacental passage of warfarin increases the risk of hemorrhagic fetal death during vaginal delivery. To minimize this risk, warfarin should be discontinued after 34 to 36 weeks of gestation and/or cesarean delivery should be considered [14]. Management is more complex if preterm labor develops in a patient on warfarin, because both the mother and the fetus are anticoagulated. Vitamin K administration does not achieve immediate reversal of maternal anticoagulation, which may persist for 24 hours; more rapid reversal requires the transfusion of fresh frozen plasma. Importantly, fetal levels of coagulation factors do not correlate with maternal levels, and infusion of fresh frozen plasma into the mother does not reliably reverse fetal anticoagulation. A cesarean delivery may prevent hemorrhagic fetal death, and fresh frozen plasma should be administered to the neonate. Maternal subcutaneous heparin generally should be resumed no later than six hours after delivery in anticipation of an early return to warfarin. Because only an inactive warfarin metabolite finds its way into breast milk, lactation does not result in neonatal anticoagulation [27,28].

Unfractionated heparin — Heparin is an indirect thrombin inhibitor that complexes with antithrombin and converts this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa [29,30]. (See "Therapeutic use of heparin and low molecular weight heparin".) Unfractionated heparin (as distinguished from low-molecular-weight heparin) has a high molecular weight, which precludes transplacental transfer. Heparin is in FDA pregnancy category C (table 1); it is devoid of known teratogenic risk and does not anticoagulate the fetus [3,4]. Early estimates of heparin-related fetal wastage were believed to approximate those of pregnant women receiving warfarin (ie, maternal anticoagulation was considered the major risk factor, regardless of the agent used). However, subsequent studies found a significantly lower heparin-related risk of fetal wastage that was similar to that of untreated women [31]. A number of concerns are related to sustained administration of unfractionated heparin during pregnancy, including the relative difficulty of maintaining a stable therapeutic response, the inconvenience of parenteral administration, and the complications of heparininduced thrombocytopenia and bone demineralization in patients treated for more than seven weeks [14,32-36]. Demineralization can result in the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible [35-37]. (See "Therapeutic use of heparin and low molecular weight heparin" and "Drugs that affect bone metabolism", section on 'Heparin'.) Higher doses of heparin are necessary for pregnant women to achieve therapeutic levels for both prophylaxis and therapy. The increased requirement is a result of increases in heparinbinding proteins, plasma volume, renal clearance, coagulation factors, and heparin degradation by the placenta during pregnancy [38-40]. When full anticoagulation is desired, the dose can be adjusted based upon the activated partial thromboplastin time (aPTT) or heparin levels, as in nonpregnant individuals. However, there is no consensus regarding the optimal dose of prophylactic heparin for pregnant women. In these patients, 5000 units given subcutaneously every 12 hours probably is not sufficient to maintain a mid-interval level of 0.05 to 0.25 U/mL [39,41]. The appropriate dose of prophylactic heparin should be determined based on mid-interval heparin levels; if this is not possible, a dose of 7500 to 10,000 units given subcutaneously every 12 hours is a reasonable alternative [42]. Women who are anticoagulated with heparin until the onset of labor generally experience vaginal delivery with no greater blood loss than nonanticoagulated gravidas. However, cesarean delivery in heparinized patients is accompanied by a significantly greater blood loss than would otherwise be anticipated. The heparin infusion should be stopped approximately four hours before cesarean delivery. If preterm labor develops in a patient receiving heparin, only the mother is anticoagulated, and protamine sulfate has been used to reverse maternal heparinization. LMW heparin — Low-molecular-weight heparin (LMW heparin) represents a class of anticoagulants possessing a shorter polysaccharide chain and therefore a lower molecular

weight than standard, unfractionated heparin [43-45]. The commercially available LMW heparins are made via different processes, including nitrous acid, alkaline, or enzymatic depolymerization. These agents differ chemically and pharmacokinetically; however, the clinical significance of these differences and their potential importance in pregnancy are unclear [43,46]. Enoxaparin, the most commonly used LMW heparin in the United States, is listed by the FDA in pregnancy category B (table 1). (See "Therapeutic use of heparin and low molecular weight heparin".) LMW heparin may resolve the difficulty in achieving a sustained, stable therapeutic response and may reduce the inconvenience of parenteral administration because increased bioavailability and a longer half-life produce a more predictable anticoagulant response to fixed doses administered once or twice daily [44,45]. Laboratory monitoring of the anticoagulant effect of LMW heparin is generally not performed in nonpregnant patients, but some authors recommend measuring anti-factor Xa levels four hours after injection in pregnant patients [5]. The dose of LMW heparin is then titrated to achieve the manufacturer's recommended peak anti-Xa level. Pregnant women may need dose adjustments as the pregnancy continues because of weight gain and other factors [47-51]. One study of LMW heparin pharmacokinetics in 24 women at 12, 24, and 36 weeks of gestation and 6 weeks postpartum found peak anti-X activity levels during pregnancy were lower than in nonpregnant (postpartum) women and occurred later after injection, 4 versus 2 hours [52]. LMW heparin causes less in vitro clot inhibition while retaining its in vivo antithrombotic effect, theoretically making the risk of bleeding less than with unfractionated heparin; it also appears less likely to precipitate heparin-associated thrombocytopenia [43]. It is unclear whether bone loss may be significantly reduced or prevented by using LMW instead of unfractionated heparin. A study that randomly assigned 44 pregnant women to receive either dalteparin (target anti-Xa greater than 0.20 IU/mL three hours after injection) or unfractionated heparin (mean dose 17,250 units/day) found that mean bone density (BMD) in the lumbosacral spine was significantly lower one week to three years postpartum among women receiving unfractionated heparin [37]. In addition, there was no difference in the BMD of women treated with LMW heparin compared with controls (healthy postpartum women not exposed to either heparin therapy). However, other studies have not found a difference in BMD changes between the two heparin preparations (enoxaparin versus unfractionated heparin) [53], or among patients treated with LMW heparin and matched controls [54]. Therefore, significant uncertainty remains regarding the relationship between different heparin preparations and maternal bone loss. Accordingly, more large studies are needed to clarify whether LMW heparin is less deleterious to BMD than unfractionated heparin in pregnant women. (See "Drugs that affect bone metabolism".) Clinical experience with LMW heparin during pregnancy largely has been favorable [14,55-59], and the American College of Obstetricians and Gynecologists has stated that LMW heparin can be considered in women who are candidates for prophylactic or therapeutic anticoagulation during pregnancy [60]. One study, for example, evaluated the efficacy of enoxaparin (20 to 40 mg/day) in 69 pregnancies in 61 women at high risk for

venous thromboembolism (VTE); one woman (1.6 percent) had a postpartum pulmonary embolus [56]. In addition, a 1999 review found that, after adjustment for comorbid conditions, the incidence of adverse pregnancy outcomes of 486 women treated with LMW heparin was comparable to that in the general population [46]. Danaparoid has been used in pregnant patients who require continuing anticoagulation despite the development of heparin-associated thrombocytopenia or other heparin-induced complications [32,61]. A systematic review of 64 studies involving 2777 pregnancies reported on the safety and efficacy of LMW heparin when used to treat or prevent VTE or for prior adverse pregnancy outcomes [59]:
 



VTE and arterial thrombosis were reported in 0.86 and 0.50 percent, respectively. There were no maternal deaths. Significant bleeding, generally associated with obstetric causes, occurred in 1.98 percent, allergic skin reactions in 1.80 percent, and osteoporotic fractures in 0.04 percent. There were no cases of heparin-induced thrombocytopenia. Live births were reported in 94.7 percent, including 85.4 percent in those receiving LMW heparin for recurrent pregnancy loss.

The report concluded that LMWH is both safe and effective to prevent or treat VTE in pregnancy. Some reports in nonpregnant patients have described a higher incidence of epidural hematoma associated with LMW heparin administration near the time of epidural catheter placement or removal [62,63]. For this reason, patients should be switched to subcutaneous unfractionated heparin about two weeks prior to the expected delivery; this will permit regional anesthesia for labor and possible operative delivery. Use of LMW heparins has not been associated with a risk of birth defects above the baseline risk in the general population or with a specific type of anomaly. Prefilled, single dose syringes are preservative free. The multidose vial contains benzyl alcohol, which can have adverse fetal effects and is contraindicated in pregnancy. Mechanical prosthetic heart valves — Concern has been raised about the safety and efficacy of LMWH in pregnant women with mechanical prosthetic heart valves. Small observational studies and case reports have suggested that the serious complication of valve thrombosis may be more common in women treated with LMWH than with UFH or warfarin. (See "Complications of prosthetic heart valves", section on 'Valve thrombosis'.) In July 2002, the United States Food and Drug Administration issued an addition to the warnings section of product labeling for enoxaparin, indicating that this product is not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves. Similar warnings have been given by the American College of Obstetricians and Gynecologists and the European Society of Cardiology. However, other expert panels disagree, and the American College of Chest Physicians recommended that LMWH remain a therapeutic option in this setting. Detailed discussion of the management of pregnant

women with prosthetic heart valves is presented separately. (See "Management of pregnant women with prosthetic heart valves".) MANAGEMENT OF SPECIFIC CONDITIONS REQUIRING ANTICOAGULATION — The need for anticoagulation during pregnancy is most commonly related to valvular heart disease or venous thromboembolism. The optimal management of these conditions during pregnancy remains controversial because of the absence of definitive clinical trials. General recommendations — The 2008 ACCP Guidelines for antithrombotic therapy recommended one of three approaches for anticoagulation during pregnancy [5]:






Aggressive adjusted-dose unfractionated heparin throughout the pregnancy; heparin is administered subcutaneously every 12 hours in doses adjusted to keep the midinterval aPTT at least twice control or to attain an anti-Xa level of 0.35 to 0.70 U/mL. After a stable dose is achieved, the aPTT should be measured at least weekly. Adjusted-dose subcutaneous LMW heparin therapy throughout the pregnancy in doses adjusted according to weight to achieve the manufacturer's recommended anti-Xa level four hours after subcutaneous injection. Unfractionated or LMW heparin therapy (as above) until the thirteenth week, a change to warfarin until the middle of the third trimester, and then restarting unfractionated or low molecular weight heparin until delivery.

Long-term anticoagulation should be resumed postpartum regardless of which regimen is used. Heparin can be restarted 12 hours post-cesarean delivery and 6 hours post-vaginal birth, if no significant bleeding has occurred. Heparin is either continued or replaced with warfarin (stopping the heparin when the INR is therapeutic). (See "Management of anticoagulation before and after elective surgery".) Women attempting to become pregnant — For women who are taking long-term vitamin K antagonists and are attempting to become pregnant, the 2008 ACCP Guidelines suggest performing frequent pregnancy tests and substituting treatment with a heparin preparation (unfractionated or LMW heparin) as soon as pregnancy is achieved [5]. We believe that this is a reasonable option for a woman who meets all of the following criteria:
 





She has regular monthly menstrual cycles. She agrees to have a blood pregnancy test within the first seven days of the missed first day of expected menses. This can be facilitated by having a standing order at a laboratory or giving her laboratory requisitions in advance. She can be switched to a heparin preparation promptly if the pregnancy test is positive, and will have a second blood pregnancy test if the first test is negative and menses have not begun within 10 days of the missed first day of expected menses. She understands the baseline risk of birth defects (3 percent [64]) in the population and the further increased risk and types of embryopathy if she continues to take her

long-term vitamin K antagonist during or after the sixth week of pregnancy (ie, ≥14 days after the missed first day of expected menses). (See 'Teratogenic effects' above.) Prosthetic heart valves — In pregnant women with mechanical prosthetic valves, anticoagulants are, with few exceptions, obligatory, especially in light of the hypercoagulable state during late pregnancy. This important issue is discussed in detail separately. (See "Management of pregnant women with prosthetic heart valves".) Venous thromboembolism — The risk of venous thromboembolism (VTE) is increased in association with pregnancy, occurring primarily during the postpartum period [5]. This phenomenon may relate in part to the progressive increase in resistance to activated protein C that is normally observed in the second and third trimesters [65]. Other coagulation changes that contribute to the development of VTE include: a progressive increase in several coagulation factors, such as factors I, II, VII, VIII, and X [66-68]; increased activity of the fibrinolytic inhibitors PAI-1 and PAI-2 [69,70]; increased venous stasis; and vascular damage at the time of delivery. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis".) The risk during both the intrapartum and the postpartum periods appears to be accentuated in those women who have an inherited abnormality or deficiency of a naturally occurring anticoagulant, such as factor V Leiden, prothrombin G20210A, antithrombin, protein C, or protein S [71]. In several studies, for example, the frequency of developing VTE during pregnancy or the postpartum period was at least eightfold greater in women with protein C or S deficiency, factor V Leiden, or prothrombin gene mutation G20210A than in normals [72,73]. LMW heparin is the prophylactic regimen of choice for pregnant patients who are at high risk for deep venous thrombosis and pulmonary embolism; however, data on efficacy from controlled trials are lacking [74,75]. Anti-factor Xa monitoring is not required. The advantages of LMW heparin are a good safety profile with less thrombocytopenia, bleeding, and osteopenia than unfractionated heparin and more predictable and rapidly achieved anticoagulation [74]. Included among this high-risk group are women with:
  

An inherited deficiency of a naturally occurring anticoagulant A prior episode of venous thromboembolism Antiphospholipid antibodies and a prior fetal death, pregnancy loss, or thrombotic event [76]

Prophylactic dosing of subcutaneous unfractionated heparin is an alternative [5,14,75]. Data on efficacy from controlled trials are lacking. Despite the absence of firm clinical data, it has been suggested that such women might benefit from use of LMH or unfractionated heparin prophylaxis until delivery, followed by warfarin for four to six weeks postpartum [5,72,75]. LMW heparins should be switched to

unfractionated heparin two weeks prior to the expected delivery and followed with warfarin postpartum as previously described. Another approach that has been advocated is clinical surveillance of such women during pregnancy, followed by four to six weeks of postpartum warfarin therapy, particularly in women with prior VTE that occurred in the setting of a known risk factor such as trauma [5]. Acute deep venous thrombosis or pulmonary embolism which is diagnosed during pregnancy should be managed initially in an identical fashion to that used when these conditions occur in nonpregnant patients; the mainstay of initial therapy is heparin to rapidly achieve a heparin level of 0.2 to 0.4 U/mL by the protamine titration assay (usually with a PTT that is 1.5 to 2.0 times the control value). (See "Treatment of acute pulmonary embolism".) Subcutaneous heparin (preferably LMW heparin) at treatment doses should be continued until delivery, and a four to six week course of warfarin should be completed after delivery [5,14]. Alternatively, LMW heparin can be given until two weeks prior to the expected delivery, followed by subcutaneous unfractionated heparin and warfarin as described previously. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) Other — Anticoagulation may be warranted in several other conditions during pregnancy which are discussed in detail elsewhere. These include:


   

Atrial fibrillation associated with significant underlying heart disease, but not lone atrial fibrillation (see "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation") Antiphospholipid antibody syndrome (see "Treatment of the antiphospholipid syndrome") Heart failure, particularly in the presence of a ventricular thrombus (see "Management of heart failure in pregnancy" and "Peripartum cardiomyopathy") Eisenmenger syndrome (see "Medical management of Eisenmenger syndrome", section on 'Pregnancy') Paroxysmal nocturnal hemoglobinuria (see "Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria", section on 'Prophylactic anticoagulation').

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