Special Article

Common Mechanisms and Strategies for Prevention and Treatment of Cardiac Arrest During Epidural Anesthesia
John B. Pollard, MD*
Departments of Anesthesiology Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Stanford, CA,

Cardiac arrests continue to occur during epidural anesthesia and frequently result in death or brain damage. Although unintentional total spinal anesthesia, respiratory depression, myocardial ischemia, and local anesthetic toxicity can also lead to cardiac arrest, often the arrests do not fit any of these four categories. Many of the unexplained arrests may be attributed to vagal predominance. The evidence for a vagal-linked circulatory mechanism for these arrests is reviewed, and the characteristics that are associated with an increased risk for cardiac arrest during epidural anesthesia are identified. Specific strategies to forestall vagal predominance are discussed. In case these strategies fail, multiple interventions are discussed that should increase the likelihood of a successful resuscitation in the setting of extensive sympathetic blockade. 2002 by Elsevier Science Inc. Keywords: Asystole, conduction anesthesia, pregnancy, severe bradycardia.

Introduction
Cardiac arrests during central neuraxial blockade are a major source of morbidity and mortality. At present, there are more claims in the ASA closedclaims database for injury due to cardiac arrest during spinal or epidural anesthesia (170 cases) than there are for aspiration related injury (154 cases).* The severity of injury has remained high with death or brain damage in approximately 90% of these claims.*1 Vagal-linked reflexes are believed to play an important role in arrests that occur during spinal anesthesia.2 4 The shared characteristics of spinal and epidural anesthesia make it likely that similar mechanisms are involved in the arrests that occur during epidural anesthesia.5,6 The evidence supporting an important role for vagal reflexes leading to cardiac arrest during epidural anesthesia is discussed with the expectation that a greater appreciation of these reflexes will lead to more effective strategies for prevention and treatment.

* Assistant Professor, Departments of Anesthesiology Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Stanford, California Address correspondence and reprint requests to Dr. Pollard at the VA Palo Alto Health Care System, 3801 Miranda Ave. #112A, Palo Alto CA 94304-1207, USA. Email: john.pollard@med.va.gov Received for publication July 3, 2001; revised manuscript accepted for publication October 11, 2001.

Pathophysiology
There is a growing awareness that vagal predominance in the setting of sympathetic blockade can lead to cardiac arrest.7,8 While unintentional total
*Anesthesiology News. Park Ridge, IL: American Society of Anesthesiologists, 2000:1235.

Journal of Clinical Anesthesia 14:5256, 2002 2002 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

0952-8180/02/$see front matter PII S0952-8180(00)00355-5

Cardiac arrest during epidural anesthesia: Pollard.

spinal anesthesia, respiratory depression, myocardial ischemia, and local anesthetic toxicity can also lead to cardiac arrest, often the arrests do not fit any of these four categories. Regardless of the cause of an individual arrest, one should understand the role of sympathetic blockade and vagal predominance during epidural anesthesia because these effects can make it more difficult to achieve a fully successful resuscitation.1,9 Evidence for a circulatory etiology for many of these arrests originates from studies using healthy volunteers who experienced bradycardia and cardiac arrest in settings that mimic the effects of epidural anesthesia and surgery.10,11 Most of these effects are directly or indirectly related to the blockade of sympathetic efferents during epidural anesthesia. For example, the level of sympathetic blockade during epidural anesthesia is typically higher than the sensory level, so a patient with a T5 sensory block may have completely blocked cardiac accelerator fibers that originate from T1T4. A more important effect of the inhibition of the sympathetic efferents during epidural anesthesia is vasodilatation with redistribution of blood to the lower extremities and splanchnic beds. This decreases venous return and can result in vagal predominance. Baron et al.12 demonstrated that cardiac vagal tone is enhanced primarily through reduced venous return. Vagally induced bradycardia was confirmed by Jacobsen et al.13 when they studied the effect of epidural anesthesia on left ventricular diameter with echocardiography in 8 unpremedicated, young volunteers. Two subjects developed bradycardia and hypotension after 25 minutes with anesthetic levels at T8 and T9. This finding was associated with a reduction of up to 22% in left ventricular diameter. In both cases, the changes were reversed by head-down position and rapid infusion of intravenous (IV) fluids. Human pancreatic polypeptide was used as a marker of parasympathetic activity and its simultaneous increase with the decreases in heart rate (HR) observed is consistent with vagal activation. Even without a high anesthetic level, the effects of sympathetic blockade on central venous pressure (CVP) and vagal tone can be profound. Baron et al.12 reported that without volume preloading, T8 to T12 levels of epidural anesthesia resulted in an 82% decrease in CVP. Bonica et al.11decreased preload further by removing 10 mL/kg of blood in patients with epidural anesthesia (T5 level). This action resulted in two cardiac arrests in the 20 healthy, male volunteers enrolled in the study. These reflex responses to decreases in preload can also be triggered without sympathetic blockade. A study using lower body negative pressure to cause functional hypovolemia demonstrated progressive vagal symptoms, including sweating, nausea, and syncope, and one of the healthy subjects progressed from vagal symptoms to abrupt sinus arrest.10 This arrest in a young healthy patient in the absence of sympathetic blockade and without any sedation underscores the importance of preload. These three arrests are most likely attributable to one or more of the three reflex responses to abrupt decreases in preload. The first involves the pacemaker stretch. The

Table 1. Potential Risk Factors For Cardiac Arrest During Epidural Anesthesia Male gender Baseline heart rate 60 bpm ASA physical status I (vs. ASA physical status III or IV) Use of beta-blocking drugs Sensory level above T6 Age 50 yrs Prolonged PR interval

rate of firing of these cells within the myocardium is proportional to the degree of stretch. Decreased venous return results in decreased stretch and a slower HR. The second reflex may be attributable to the firing of lowpressure baroreceptors in the right atrium and vena cava. The third is the paradoxical Bezold-Jarisch reflex, in which receptors in the left ventricle are stimulated by a decrease in ventricular volume and cause bradycardia.2 This slowing of the HR should allow more time for more complete filling of the heart. With severe hypovolemia, these reflex responses can result in severe bradycardia or asystole.

Identification of High-Risk Patients

These arrests often occur when patients with strong vagal tone are exposed to circumstances that trigger further increases in vagal activity.14 17 There are multiple factors that may help predict who is at risk to progress to cardiac arrest. Typically, bradycardia is noted before the onset of cardiac arrest during epidural anesthesia.16 18 Bradycardia may be a surrogate marker for extensive sympathetic blockade,17 and it may help identify patients with excessive vagal tone attributable to other causes such as those with athletic heart syndrome16 or central volume depletion.10 Since spinal anesthesia also results in sympathetic blockade and an abrupt decrease in preload, the information learned about cardiac arrest during spinal anesthesia may also apply to epidural anesthesia. For example, there are six known risk factors associated with bradycardia19 22 and cardiac arrest8 during spinal anesthesia. A seventh potential risk factor comes from the observation that male patients are more than 10 times more likely than females to develop bradycardia during epidural anesthesia.23 Taken together, these 7 risk factors for bradycardia may help identify patients at risk for cardiac arrest during epidural anesthesia. To test this hypothesis, all case reports of unexplained cardiac arrest during epidural anesthesia reported in the English literature from 1/1/88 to 12/31/ 1998 were reviewed using the seven risk factors listed in Table 1. Cases with combined spinal epidural or total spinal anesthesia were excluded from the analysis. Evaluation of the remaining 11 cases using the risk factors from Table 1 suggests that these patients do fit a high-risk profile (see Table 2).7,17,18,24 27 In nine of the 11 cases, at least two of the risk factors from Table 1 were identified. The most common risk factor was age less than 50 years. Typically, younger patients have stronger vagal tone, which may increase their risk for vagal predominance.
J. Clin. Anesth., vol. 14, February 2002 53

Original Contributions

Table 2. Risk Factors for Bradycardia Documented in Patients With Severe Bradycardia or Cardiac Arrest During Epidural Anesthesia Authors Chan and Welch18 Frerichs et al.17 Geffin and Shapiro7 Gild and Crilley26 Heidegger and Kreienbuhl27 Liguori and Sharrock24 Patient 1 1 7 1 1 1 2 3 4 11 1 Risk Factors Documented (Other information) Age 50 yrs, ASA physical status I, sensory level above T6 Age 50 yrs, male, sensory level above T6, baseline heart rate 60 bpm None (block level and gender not documented) Age 50 yrs, sensory level above T6 Male, sensory level above T6 Age 50 yrs, male, sensory level above T6 None (Minimal patient data provided) Male, prolonged PR interval Age 50 yrs, male Age 50 yrs, male Age 50 yrs, sensory level above T6

Takase et al.25

It is important to note that none of the patients listed in Table 2 received epidural anesthesia for labor or delivery. With the popularity of epidural anesthesia for obstetrics and the propensity for these arrests to occur in younger patients, the paucity of cases in the obstetric population is remarkable.28 There are several likely explanations for this situation. First, nonpregnant women are 11 to 50 times less likely to develop bradycardia during epidural anesthesia than men.23 In addition, the physiologic changes associated with pregnancy may further decrease the cardiac arrests reported for this subset of patients. Pregnancy is associated with changes in autonomic control, and at-term HRs of 90 to 95 beats per minute (bpm) are typical. These high HRs may be due to decreased parasympathetic tone during pregnancy.29 These inherent characteristics of the obstetrical patient may decrease the risk of vagally induced cardiac arrests during epidural anesthesia. Despite this lower relative risk for women, approximately one half of the claims for complications related to epidural and spinal anesthesia are from women who had an obstetric indication for regional anesthesia.30 While the risk of cardiac arrest with a single obstetric epidural is very small, the large number of patients receiving epidurals in this setting has resulted in a number of claims from this population.

Strategies for Prevention and Treatment

Although multiple factors may lead to cardiac arrest during epidural anesthesia, the evidence suggests that vagal predominance is a common mechanism. If so, more rigorous patient selection could decrease the risk of cardiac arrest during epidural anesthesia. For example, an epidural anesthetic may not be the best choice for a young, healthy, male patient with bradycardia. When epidural anesthesia is indicated for a patient with two or more of the risk factors listed in Table 1, interventions to forestall vagal predominance, including the use of vagolytic drugs, should be considered. The simplest way to decrease the risk of vagal predominance during epidural anesthesia is to maintain adequate preload. Observations from physiologic studies10,11 and multiple case reports7,27 emphasize the importance of volume loading and prompt replacement of losses. Main54 J. Clin. Anesth., vol. 14, February 2002

taining preload during epidural anesthesia might be expected to be a uniform practice of anesthetists, but the literature demonstrates otherwise. Geffin and Shapiro7 reported that prophylactic preloading was not practiced during the period when they experienced 13 cases of severe bradycardia or cardiac arrest during spinal or epidural anesthesia. Others have reported limiting fluids for a combined spinal epidural technique to an initial fluid bolus of 200 to 300 mL and then restricting the total amount of IV fluids for the entire perioperative period to 1000 mL or less.31 Minimizing fluids to this extent could increase the risk of vagal predominance and cardiac arrest. Since decreases in preload can trigger cardiac arrest during epidural anesthesia, it may be prudent to contemplate a different technique when rapid blood loss or the use of a vasodilator is anticipated. A report of bradycardia and cardiac arrest during epidural anesthesia revealed that five of these events were associated with initiating sodium nitroprusside infusions, and in two cases pulmonary artery pressures were noted to decrease just before the onset of bradycardia.24,27 In contrast, the use of a tourniquet increases afterload and has been associated with a decreased incidence of bradycardia during epidural anesthesia.23 With release of the tourniquet, a change in patient position or other common perioperative events, decreases in preload can occur so quickly that there may not be time to give sufficient volumes of fluid over several minutes. When an abrupt decrease in preload is suspected, raising the legs and rapidly infusing IV fluids can be helpful.11,13 Fluid administration should be closely monitored in patients with heart disease. In addition to concerns about volume overload and heart failure, there is also the potential to cause myocardial ischemia. In older patients, low vagal tone and relative sympathetic predominance have been documented during epidural anesthesia after administration of 20 mL/kg IV fluid bolus.32 This sympathetic predominance may be problematic for older patients with underlying coronary artery disease.33 For patients less than 50 years of age, hypovolemia and vagal predominance are typically more pressing concerns, and aggressive fluid loading can be recommended. How-

Cardiac arrest during epidural anesthesia: Pollard.

ever, fluid replacement alone may be insufficient and multiple simultaneous interventions may be necessary to prevent vagal predominance. Gratador et al.34 reported that neither volume loading nor infusion of a mixed alpha-agent and beta-agent was sufficient to prevent an increase in baroreflex activity during extensive sympathetic blockade. Hence, when nausea, bradycardia, or hypotension is evident during epidural anesthesia, additional volume loading, the use of a vasopressor, and prophylactic treatment with atropine should all be considered. When the bradycardia is profound or a full cardiac arrest occurs, the early administration of epinephrine (0.01 0.1 mg/kg) can be critical to maintain coronary perfusion pressure in the setting of extensive sympathetic blockade.9 Other treatments also may be necessary to prevent or treat cardiac arrest. Evidence that epinephrine alone may be insufficient to treat bradycardia comes from the observation that seven patients have developed severe bradycardia or cardiac arrest during epidural anesthesia while an epinephrine infusion was administered.24,27 Two possible explanations have been offered.24 One is that the increase in contractility due to the epinephrine may contribute to reflex slowing attributed to the paradoxical Bezold-Jarish reflex. Alternatively, since epinephrine is not a vagolytic drug, these failures provide additional evidence for the importance of the vagal limb in these arrests. A recent animal study designed to assess the effects of epinephrine versus vasopressin during cardiopulmonary resuscitation (CPR) during epidural anesthesia revealed better outcomes in the animals that received vasopressin.35 After 18 minutes of CPR, seven of eight vasopressintreated animals and three of eight epinephrine-treated animals survived the postresuscitation phase. After vasopressin treatment, five of the seven surviving animals with epidural block required atropine for bradycardia, while none of the six unblocked animals needed atropine after return of spontaneous circulation. These findings suggest that vasopressin and atropine may be more effective than epinephrine alone when treating cardiac arrest during epidural anesthesia.

using vasopressors, or repositioning the patient to augment venous return. These interventions are especially important if the patient has vagal symptoms such as nausea, hypotension, or bradycardia. Based on experience with spinal anesthesia, the stepwise escalation of treatment of bradycardia during epidural anesthesia with atropine (0.4 0.6 mg), ephedrine (2550 mg), and, if necessary, epinephrine (0.2 0.3 mg), may also be appropriate.2 For cardiac arrest, full resuscitation doses of atropine, epinephrine and/or vasopressin, or transcutaneous pacing may be necessary. With the popularity of epidural anesthesia and the severe complications from these cardiac arrests, the potential impact of these early interventions on further improving the safety of epidural anesthesia could be substantial.

References
1. Caplan RA, Ward RJ, Posner K, Cheney FW: Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of predisposing factors. Anesthesiology 1988;68:511. 2. Mackey DC, Carpenter RL, Thompson GE, Brown DL, Bodily MN: Bradycardia and asystole during spinal anesthesia: a report of three cases without morbidity. Anesthesiology 1989;70:866 8. 3. Lovstad RZ, Granhus G, Hetland S: Bradycardia and asystolic cardiac arrest during spinal anaesthesia: a report of five cases. Acta Anaesthesiol Scand 2000;44:48 52. 4. Thrush DN, Downs JB: Vagotonia and cardiac arrest during spinal anesthesia. Anesthesiology 1999;91:11713. 5. Shimosato S, Etsten BE: The role of the venous system in cardiocirculatory dynamics during spinal and epidural anesthesia in man. Anesthesiology 1969;30:619 28. 6. Ward RJ, Bonica JJ, Freund FG, Akamatsu T, Danziger F, Englesson S: Epidural and subarachnoid anesthesia. Cardiovascular and respiratory effects. JAMA 1965;191:99 102. 7. Geffin B, Shapiro L: Sinus bradycardia and asystole during spinal and epidural anesthesia: a report of 13 cases. J Clin Anesth 1998;10:278 85. 8. Pollard JB: Cardiac arrest during spinal anesthesia: common mechanisms and strategies for prevention. Anesth Analg 2001;92: 252 6. 9. Rosenberg JM, Wahr JA, Sung CH, Oh YS, Gilligan LJ: Coronary perfusion pressure during cardiopulmonary resuscitation after spinal anesthesia in dogs. Anesth Analg 1996;82:84 7. 10. Murray RH, Thompson LJ, Bowers JA, Albright CD: Hemodynamic effects of graded hypovolemia and vasodepressor syncope induced by lower body negative pressure. Am Heart J 1968;76: 799 811. 11. Bonica JJ, Kennedy WF, Akamatsu TJ, Gerbershagen HU: Circulatory effects of peridural block: 3 Effects of acute blood loss. Anesthesiology 1972;36:219 27. 12. Baron JF, Decaux-Jacolot A, Edouard A, Berdeaux A, Samii K: Influence of venous return on baroreflex control of heart rate during lumbar epidural anesthesia in humans. Anesthesiology 1986;64:188 93. 13. Jacobsen J, Sofelt S, Brocks V, Fernandez A, Warberg J, Secher NH: Reduced left ventricular diameters at onset of bradycardia during epidural anaesthesia. Acta Anaesthesiol Scand 1992;36: 831 6. 14. Kennedy WF, Bonica JJ, Akamatsu TJ, Ward RJ, Martin WE, Grinstein A: Cardovascular and respiratory effects of subarachnoid block in the presence of acute blood loss. Anesthesiology 1968;29:29 35. J. Clin. Anesth., vol. 14, February 2002 55

Summary
While many factors can contribute to cardiac arrest during epidural anesthesia, vagal responses to decreases in preload often play a key role. Patients with multiple risk factors for bradycardia, or with overt vagal symptoms during epidural anesthesia, appear to be at increased risk for cardiac arrest. This information has important implications. For example, the potential for vagal predominance should be remembered when considering epidural anesthesia for a patient with two or more of the risk factors listed in Table 1. When an epidural anesthetic is used, maintaining preload must be a priority and prophylactic preloading with a bolus of IV fluid should not be omitted. Standard regimens for volume preloading may not be sufficient to maintain adequate preload, so anesthetists should have a low threshold for administering additional fluid boluses,

Original Contributions 15. Sapire DW, Casta A: Vagotonia in infants, children, adolescents and young adults. Int J Cardiol 1985;9:21124. 16. Kreutz JM, Mazuzan JE: Sudden asystole in a marathon runner: the athletic heart syndrome and its anesthetic implications. Anesthesiology 1990;73:1266 8. 17. Frerichs, RL, Campbell, J, Bassell GM: Psychogenic cardiac arrest during extensive sympathetic blockade. Anesthesiology 1988;68: 943 4. 18. Chan K, Welch KJ: Cardiac arrest during segmental thoracic epidural anesthesia. Anesthesiology 1997;86:5035. 19. Tarkkila PJ, Kaukinen S: Complications during spinal anesthesia: a prospective study. Reg Anesth 1991;16:101 6. 20. Tarkkila P, Isola J: A regression model for identifying patients at high risk of hypotension, bradycardia and nausea during spinal anesthesia. Acta Anaesthesiol Scand 1992;36:554 8. 21. Carpenter RL, Caplan RA, Brown DL, Stephenson C, Wu R: Incidence and risk factors for side effects of spinal anesthesia. Anesthesiology 1992;76:906 16. 22. Liu S, Paul GE, Carpenter RL, Stephenson C, Wu R: Prolonged PR interval is a risk factor for bradycardia during spinal anesthesia. Reg Anesth 1995;20:41 4. 23. Curatolo M, Scaramozzino P, Venuti FS, Orlando A, Zbinden AM: Factors associated with hypotension and bradycardia after epidural blockade. Anesth Analg 1996;83:1033 40. 24. Liguori GA, Sharrock NE: Asystole and severe bradycardia during epidural anesthesia in orthopedic patients. Anesthesiology 1997;86: 250 7. 25. Takase B, Goto T, Nagai T, et al.: Use of head-up tilt testing to determine a possible cause of unexpected cardiac asystole during epidural anesthesia. Jpn Circ J 1997;61:52530. 26. Gild W, Crilley P: Sudden cardiac arrest during epidural anesthesia [Letter]. Anesthesiology 1990;73:1296. 27. Heidegger T, Kreienbuhl G: Unsuccessful resuscitation under hypotensive epidural anesthesia during elective hip arthroplasty. Anesth Analg 1998;86:8479. 28. Hawkins JL, Koonin LM, Palmer SK, Gibbs CP: Anesthesiarelated deaths during obstetric delivery in the United States, 1979 1990. Anesthesiology 1997;86:277 84. 29. Ekholm EM, Erkkola RU, Piha SJ, Jalonen JO, Metsala TH, Antila KJ: Changes in autonomic cardiovascular control in mid-pregnancy. Clin Physiol 1992;12:52736. 30. Morisot P: Complications of local and regional anesthesia. An analysis of closed files of insurance companies. Cah Anesthesiol 1991;39:239 42. 31. Pawlowski J, Sukhani R, Pappas HL, et al.: The anesthetic and recovery profile of two doses (60 and 80 mg) of plain mepivacaine for ambulatory spinal anesthesia. Anesth Analg 2000;91: 580 4. 32. Fleisher LA, Frank SM, Shir Y, Estafanous M, Kelly S, Raja SN: Cardiac sympathovagal balance and peripheral sympathetic vasoconstriction: epidural versus general anesthesia. Anesth Analg 1994;79:16571. 33. Sprung J, Lesitsky MA, Jagetia A, Tucker C, Saffian M, Gottlieb A: Cardiac arrest caused by coronary spasm in two patients during recovery from epidural anesthesia. Reg Anesth 1996;21:253 60. 34. Gratadour P, Viale JP, Parlow J, et al.: Sympathovagal effects of spinal anesthesia assessed by the spontaneous cardiac baroreflex. Anesthesiology 1997;87:1359 67. 35. Krismer AC, Hogan QH, Wenzel V, et al.: The efficacy of epinephrine or vasopressin for resuscitation during epidural anesthesia. Anesth Analg 2001;93:734 42.

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