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From the Department of Anesthesia, Brantford General Hospital, Brantford, Ontario, Canada.
Address correspondence to: Dr. Robert Martinek, Brantford General Hospital, 200 Terrace Hill Street, Brantford, Ontario N3R 1G9, Canada. Fax: 519-751-2658; E-mail: dr.martinek{at}sympatico.ca
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Abstract |
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Clinical features: A 50-yr-old, 97-kg, healthy male presented for elective left high tibial osteotomy. Spinal anesthesia was induced uneventfully at L3–4 with 11.25 mg of hyperbaric 0.75% bupivacaine and morphine 0.25 mg. Thirteen minutes after induction, the incision site was infiltrated with 20 mL of 0.5% bupivacaine with epinephrine 5 µg•mL-1 for intraoperative hemostasis, resulting in an increase in heart rate from 74 to 90 beats•min-1. Three minutes after infiltration of the incision site, the patient’s heart rate dropped to 48 beats•min-1, accompanied by a blood pressure of 107/51 mmHg, SpO2 97%, and a sinus bradycardia on the electrocardiogram. The electrocardiographic complexes suddenly disappeared with loss of the pulse oximeter waveform. Pre-drawn atropine 0.6 mg iv and ondansetron 4 mg iv were administered within seven seconds of the event. After an asystolic period of 30 to 40 sec, but before chest compressions were initiated, vital signs returned to normal with no other sequelae.
Conclusion: Exogenous epinephrine may have triggered the Bezold-Jarisch reflex and subsequent asystole. It is postulated that the combination of atropine and ondansetron may have played a key role in resuscitation by blocking the serotonergic and cholinergic receptors in the afferent and efferent limbs of this vagally-mediated reflex.
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Introduction |
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Current recommendations to treat asystole during spinal block include immediate restoration of volume by gravity or fluid bolus, early use of atropine, ephedrine, epinephrine, vasopressin, and thump pacing. The early use of epinephrine and volume restoration (and the relative inefficacy of atropine) have been emphasized previously.4–8,12
The following is a case of witnessed asystole during spinal anesthesia treated with a combination of iv atropine and ondansetron.
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Case report |
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Following volume loading with lactated Ringer’s 500 mL and sedation with iv remifentanil 25 µg, spinal anesthesia was induced at L3–4 with hyperbaric 0.75% bupivacaine 11.25 mg and morphine 0.25 mg. Vital signs were normal (HR 70 beats•min-1, systolic BP 130 mmHg). Thirteen minutes after induction, the surgeon injected the incision site with 20 mL of 0.5% bupivacaine with epinephrine 5 ug•mL-1 for intraoperative hemostasis. Over the next three minutes, the HR increased from 74 to 90 beats•min-1. The patient stated that he was relaxed. He was supine and his lower extremities remained horizontal. Surgery had not commenced.
One minute later, the patient’s HR suddenly dropped from 92 to 48 beats•min-1. The BP was 107/51 mmHg, SpO2 was 97%, and the ECG showed a sinus bradycardia. The patient repeated that he felt fine. Atropine and ondansetron were drawn up and the atropine syringe was inserted into the iv tubing. Suddenly, while the author was watching the monitor, the ECG complex and pulse oximeter waveform disappeared. Atropine 0.6 mg iv was given, followed immediately by ondansetron 4 mg iv. Both drugs were given within seven seconds. Near the end of drug administration, the patient lost consciousness and one breath of 100% O2 was given by mask. After a total asystolic period of 30 to 40 sec, but before chest compressions were initiated, a HR of 96 beats•min-1 was registered by the pulse oximeter and confirmed by palpation.
The patient regained full consciousness and denied any chest pain, dyspnea, nausea, paresthesia, or tinnitus. His initial BP was 151/80 mmHg. The ECG showed a sinus rhythm without ST changes and a rate of 84 beats•min-1, which did not increase further. Pupil size and grip strength were normal. Sensory block to ice extended to the T6 dermatome bilaterally. The patient remained hemodynamically stable (HR > 69 beats•min-1, systolic BP > 110 mmHg) without the use of vasopressors. The surgery was performed uneventfully under spinal anesthesia. The postoperative ECG was normal. Tilt-table testing was suggested for follow-up but the patient declined further investigations.
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Discussion |
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The BJR originally referred to bradycardia, hypotension, and apnea caused by the iv injection of veratrum alkaloids. The cardiac and respiratory effects were found to be mediated via cardiac and pulmonary vagal afferents respectively. Later, bradycardia and hypotension from the stimulation of cardiac chemoreceptors and mechanoreceptors were established.7,8,15 Cardiac vagal afferents are located mainly in the inferoposterior wall of the left ventricle1 but are present in all cardiac chambers.15 Stimulation of these receptors increases parasympathetic activity and inhibits sympathetic activity producing bradycardia, vasodilation, hypotension, and inhibition of renal sympathetic activity.11,16 The reflex can be abolished by cervical vagotomy and the bradycardia can be blocked with anticholinergic drugs, but the efferent pathway of the sympathoinhibition remains unknown.8,17 The mechanoreceptors are normally triggered by distention. However, a decrease in venous return in combination with an increased inotropic state may deform the cardiac wall sufficiently to trigger the mechanically sensitive receptors in the same way as stretching and initiate a paradoxical vasodepressor response.1,8 Since a BJR-like reflex causing syncope has been shown in cardiac transplant patients, non-cardiac peripheral triggers and other mechanisms may also be involved.7,8,18
Head-up tilt (HUT) testing is used to simulate hypovolemia and can precipitate the BJR in susceptible individuals.18,19 When HUT fails to elicit syncope, isoproterenol may be used to provoke the response. Conversely, beta blockers have been used successfully to prevent subsequent syncopal episodes in these patients.19 The sitting position can cause venous pooling similar to a HUT test, and the BJR has been implicated as a cause of significant bradycardia and hypotension in patients undergoing shoulder arthroscopy under interscalene block.19 In Liguori’s prospective study, prophylactic metoprolol given after the interscalene block reduced the incidence of these episodes from 28% to 5%, suggesting that unopposed beta-adrenergic effects of epinephrine may play a role in the development of this reflex.19 In animals, exogenous epinephrine has been noted to augment the BJR induced by veratridine.15 In addition, significantly elevated epinephrine levels preceding syncope have been demonstrated in susceptible individuals during tilt-table testing.20 Hence, the combination of hypovolemia and increased plasma epinephrine levels appear to be associated with imminent neurocardiogenic syncope in susceptible individuals.
Serotonin (5-HT) has been implicated in the pathogenesis of sympathoinhibition, both centrally via 5-HT1 and 5-HT2 receptors and peripherally via 5-HT3 receptors.10,16–18,21,22 Direct stimulation of the cardiac 5-HT3 chemoreceptors located on cardiac vagal afferents with 5-HT or with 5-HT3 agonists will elicit the BJR in several mammals.9,11 Conversely, in rats, epicardial injection of the 5-HT3 antagonist MDL 72222 has been shown to completely abolish the reflex.16 Pretreatment with iv ondansetron (a 5-HT3 antagonist) also abolished the BJR even when scorpion venom was used to augment the initial reflex.21 Furthermore, in a hemorrhagic rabbit model, granisetron was effective at preventing inappropriate HR slowing and allowed significantly more blood to be removed before reaching the target BP compared to the saline control.10 Interestingly, non-cardiac 5-HT3 receptors have been demonstrated also in the rat lung,23 gastrointestinal mucosa24 and rabbit carotid sinus.25 All could be blocked with 5-HT3 antagonists to prevent bradycardia and hypotension induced by 5-HT or phenyl biguanide (a 5-HT3 agonist). Taken together these animal studies clearly demonstrate a role for peripheral 5-HT3 receptors in producing bradycardia and sympathoinhibition.
Serotonin released during low-volume or ischemic states has been suggested as a possible trigger for the BJR.11,16,22 Activated platelets appear to be a source of 5-HT in animal models23,25,26 and epinephrine is well known to activate platelets. In some volunteers it has been demonstrated that catecholamine levels were elevated and platelets were depleted of their 5-HT content, suggesting that elevated concentrations of circulating catecholamines may induce platelet activation and 5-HT release.27 Interestingly, in a rabbit fat embolism model, pretreatment with a 5-HT3 antagonist, cervical vagotomy, or antibody-induced thrombocytopenia prevented the usual hypotension and bradycardia. The survival rate reached 100% in the MDL 72222 group vs 25% in the saline group.23 If this applies to humans as well, 5-HT3 chemoreceptor stimulation by release of 5-HT from platelets may explain the sudden bradycardia and hypotension sometimes seen during cemented hip arthroplasty (often done under spinal anesthesia), and 5-HT3 antagonists may have a potential therapeutic role.
Although animal studies strongly support a role for 5-HT3 antagonists in preventing the BJR, limited human data appear less promising. In one study, iv granisetron decreased the change in HR and prevented recurrence of tilt-table syncope in 47% of 17 patients but did not alter the time to syncope or presyncope.28 In another study (n = 7) ondansetron did not alter the time to syncope, HR or BP changes during HUT.29 One case report described a patient with a thoracic epidural anesthetic who was given ondansetron 4 mg iv for nausea yet still developed sudden bradycardia and asystole 15 min later.30 On the other hand, ondansetron and cardiac 5-HT3 blockade has been implicated as a possible cause of tachycardia, hypertension and ischemia.31 Hence in humans, the role of 5-HT3 antagonists in preventing bradycardia and sympathoinhibition is unclear.
In this patient, the BJR, triggered by epinephrine, could explain the observed sequence of events. The immediate drop in HR, followed by asystole, is consistent with a cardiac reflex. The rapid resolution without any residual sequelae also supports a reflex mechanism. The initial rise in HR shortly after the injection of bupivacaine with epinephrine, in the absence of any obvious emotional or surgical stimuli, suggests beta-adrenergic stimulation from systemic absorption of epinephrine. Increased cardiac contractility from epinephrine combined with central hypovolemia from the spinal block, may have initiated the BJR via the cardiac mechanoreceptors. Alternatively, epinephrine may have caused endogenous 5-HT release, triggering the cardiac (or non-cardiac) chemoreceptors. Furthermore, low-dose epinephrine could have aggravated hypovolemia by shunting more blood to the muscle and viscera (beta2 effect) and could explain the rapidity of the observed HR changes. Increasing vagal tone from stimulation of vagal afferent receptors may have initiated the sudden HR drop and, as hypovolemia and cardiac contractility increased, ultimately resulted in asystole. In retrospect, atropine should have been given during the initial bradycardia even though the BP was still stable at the time. The reversal of asystole and subsequent hemodynamic stability, without additional fluid volume suggests that the BJR was successfully inhibited following administration of atropine and ondansetron.
A vagally-mediated cardiodepressor reflex appears to be the best explanation of events. The hypothesis assumes the initial rise in HR was due to the beta-adrenergic effects of systemically absorbed epinephrine, but since plasma levels were not measured the cause remains speculative. Although a slight rise in HR may be seen in the compensatory phase of hypovolemia during tilt-testing,18 a period of bradycardia usually precedes cardiac arrest in patients under spinal anesthesia.4,5,8 The augmentation of the BJR by exogenous epinephrine could explain the sudden (rather than gradual) onset of bradycardia. Bupivacaine toxicity does not appear to have played a role since there were no central neurological sequelae or ventricular arrhythmias and the asystole resolved rapidly. Spontaneous reversal of the asystole is a possible explanation; however, tachycardia would have been expected once the atropine had reached its effector sites. The HR and BP increased immediately after the asystole resolved and remained stable for the duration of the case, implying that atropine (and ondansetron) had reached their effector sites. Since both drugs were given rapidly, the iv was running well, and there would be an initial venous pressure gradient to wind down, sufficient venous flow to deliver the drugs to the right heart without chest compressions was presumed.
Although atropine alone has been used to treat these cardiac arrests,1,30 it is usually given with ephedrine or epinephrine in successfully treated cases.1–3,12 Atropine can reverse the bradycardia but may fail to prevent the drop in BP and syncope caused by the sudden withdrawal of sympathetic tone.5,7,8,13,22 Santagostino reported two patients who arrested under spinal anesthesia despite the use of atropine (0.7 mg and 1.0 mg).12 He specifically commented on the efficacy of epinephrine and the relative inefficacy of atropine. Liguori et al.19 compared glycopyrrolate or metoprolol in preventing bradycardia and hypotension in the sitting position, and showed only a minimal decrease in incidence with the use of an anticholinergic compared to placebo (22% vs 28%). Other than the atropine, none of the other recommended treatments for spinal cardiac arrests were used. Specifically, no vasopressors or additional fluid volume were required to restore a normal BP. In the absence of other interventions, ondansetron, via its 5-HT3 antagonism, may have been therapeutic in this patient.
In summary, the asystole in this patient could be explained by exogenous epinephrine triggering the BJR. Ondansetron may have antagonized the afferent vagal 5-HT3 receptors sufficiently to block the reflex. The concomitant use of atropine and its anticholinergic action on the efferent vagal limb of this reflex may have played a key role as well. Hence it is postulated that the afferent and efferent limbs of the vagally-mediated BJR may be significantly blocked by combined serotonergic and cholinergic receptor blockade. The role, if any, of ondansetron during cardiac arrest under spinal anesthesia in humans requires further study.
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Acknowledgments |
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Footnotes |
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2 Liguori GA, Sharrock NE. Asystole and severe bradycardia during epidural anesthesia in orthopedic patients. Anesthesiology 1997; 86: 250–7.[Medline]
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