Atrio-ventricular Block Following Neostigmine-Glycopyrrolate Reversal in Non-heart Transplant Patients: Case Report

Abstract

Neostigmine is the anticholinesterase drug most commonly used to reverse blockade or speed up recovery from neuromuscular blockade from nondepolarizing neuromuscular blocking drugs. Because of its cardiac muscarinic effects, prior or simultaneous administration of glycopyrrolate or atropine is usually recommended. There have been a few case reports of bradycardia, atrio-ventricular (AV) block, and cardiac arrest following neostigmine/glycopyrrolate administration to reverse neuromuscular block affecting several patients.

In this report, we describe a case of 21-year-old with a history of seizure disorder and developmental delay that presented for dental surgery under general anesthesia and developed type I AV block following the simultaneous administration of neostigmine and glycopyrrolate to reverse a nondepolarizing neuromuscular block with rocuronium at the end of his surgery.

We suggest that the chronic use of antiepileptic drugs in this patient in combination with neostigmine and glycopyrrolate lead to AV block in this patient. We also review similar cases reported in the literature and suggest an explanation for this observed phenomenon.

Following the use of nondepolarizing neuromuscular blocking drugs (NDMB), appropriate reversal of the effect of these drugs at the neuromuscular junction (NMJ) is essential after reversibility has been established to avoid adverse patient outcomes. An anticholinergic drug is usually administered followed by a cholinesterase inhibitor or both are given concurrently. The cholinesterase inhibitor prevents the breakdown of acetylcholine, thus increasing its competitiveness on the post synaptic acetylcholine receptors in caparison to the NDMB. Due to their pharmacokinetic properties, the combination of neostigmine and glycopyrrolate or atropine and edrophonium is recommended. The purpose of the anticholinergic drug is to counteract the indirect muscarinic effects of the cholinesterase inhibiting drug, which when given alone can lead to significant bradycardia.

We describe a case of heart block that occur following reversal of neuromuscular blockade with clinical doses of neostigmine and glycopyrrolate. We then summarize previous cases that have been reported in the literature and conclude by exploring possible causes of heart block following administration of reversal agents.

CASE DESCRIPTION

A 20-year-old, 65-kg male was admitted for dental examination, scaling, and multiple teeth extraction under general anesthesia. He had a history of autism, global developmental delay, and well-controlled epilepsy. His medications included lamotrigine and carbamazepine. His previous anesthetic history was unremarkable. The preoperative physical examination revealed a heart rate of 64 beats/min and a blood pressure of 121/65 mm Hg. He was saturating oxygen at 100% on room air. Preoperative laboratory values were unremarkable. A preoperative 12-lead electrocardiogram (ECG) was not performed following institutional guidelines.

The patient was brought into the operating room and general anesthesia was induced by inhalation via a firmly placed facemask after the circuit had been primed with 50% N2O, O2 and 8% sevoflurane. With loss of consciousness, O2 was increased and N2O decreased. Intravenous (IV) access was gained and 50 mcg of fentanyl and 30 mg of rocuronium were administered intravenously. The trachea was intubated nasally, and the patient was mechanically ventilated. The patient was maintained with sevoflurane at 1.9 to 2.4%.

In addition to standard Canadian Anesthesiologists' Society (CAS) monitoring, a peripheral nerve stimulator was placed on his left ulnar nerve. The patient was stable throughout the approximately 70-minute operation with a heart rate of 63 to 78 beats/min and systolic arterial blood pressures ranging from 120 to 140 mm Hg.

At the end of an uneventful surgery, three successive fading twitches were observed on the left abductor pollicis muscle after ulnar nerve stimulation. A mixture of neostigmine (2.5 mg) and glycopyrrolate (0.4 mg) was given IV to reverse neuromuscular blockade. Two to 3 minutes later, the patient's heart rate dropped to 32 beats/min and his ECG revealed a Mobitz type I atrio-ventricular (AV) block. Atropine (0.6 mg) was draw but not given as the patient blood pressure and oxygen saturation remained stable. His heart rate gradually returned to a prereversal range of 63 to 70 beats/min over a 6-minute period and remained stable over the next 10 minutes.

The trachea was extubated in the operating room, and the patient was transported to the postanesthesia care unit (PACU). A repeat ECG in the PACU revealed normal sinus tracings. He remained hemodynamically stable and was discharged after 4 hours of observation.

DISCUSSION AND CONCLUSION

In 1986, Triantafillou et al¹ described a case (patient 1 in Table) of refractory bradycardia and hypotension requiring epinephrine and external cardiac massage in an elderly male diabetic after reversal of neuromuscular blockade with clinical doses of neostigmine and glycopyrrolate.¹ This patient who had chronic renal failure responded to epinephrine and external cardiac massage and he was subsequently found to have severe diabetic vagal neuropathy. The authors suggested this unusual occurrence to be due to hypersensitivity of the vagal postsynaptic receptor to the dose of the anticholinergic administered for reversal.¹ Five cases (Table), including our case, have recently been described in which patients developed AV block following administration of clinical doses of a combination of neostigmine and glycopyrrolate for neuromuscular block reversal. Patient 2 was a previously healthy 21-year-old female who developed AV-dissociation following reversal, which the authors attributed to the ineffectiveness of glycopyrrolate to overcome a combination of cardiac conduction-depression provoked by the cumulative drug interaction due to combination of midazolam, fentanyl, propofol, ranitidine, and neostigmine.² Patient 3, a morbidly obese patient, developed second-degree AV-block and Q-Tc prolongation following reversal, which responded to atropine. Morbid obesity, female gender, and a combination of drugs was implicated by the authors.³ Patient 4, a 6-year-old female with renal failure of unknown etiology and normal electrolytes, developed a first-degree AV block following reversal, which the authors attributed to increased vagal tone as seen in pediatric patients in part due to the use of neostigmine.⁴ Patient 5, a midaged obese, diabetic and hypertensive (on beta-blockers) patient, developed complete AV block within a minute after reversal and required atropine. It is not reported if this patient had any complications from diabetes; the authors, however, suggested that the concurrent use of beta-blockers and the muscarinic actions of neostigmine may have synergistically contributed to the AV blockade. Conversion of type I to type II AV block was reported in patient 6, a previously healthy elderly patient following neuromuscular block reversal with recommended doses of neostigmine and glycopyrrolate. The author suggested this to be as a consequence of a vasovagal reflex triggered by extubation under the effect of neostigmine.⁶ This patient recovered without any pharmacological management intervention. All of these 6 patients were between the ages of 6 and 78, 3 of which were male. In this small group of patients, age, type of volatile used, and the type of surgery did not appear to correlate with this observation.

Patient Characteristics

Patient 7, an 18-month-old male with no history of cardiac pathology, developed asystole within 1 minute following reversal after a successful congenital glaucoma surgery. Cardiopulmonary resuscitation and adrenaline were administered and the patient recovered fully. The authors attributed this to the anticholinergic blockage of a parasympathetically dominated autonomic nervous system in infants making them more susceptible to reversal agents.⁷ We suggest that an excessive oculo-cardiac reflex response may have contributed to asystole in this patient.

Asystole has also been described in 8 patients following neuromuscular block reversal with neostigmine and glycopyrrolate. Seven of these patients were heart transplant recipients with variability in their demographics and years post transplant, 6 of the 7 patients had experienced some transplant-related complication, and 4 of these 6 received a permanent pacemaker.⁸

It has previously been suggested that an AV block observed during neostigmine/glycopyrrolate may be due to the combinatory suppressive effects of the concurrent use of volatile anesthetics and/or opioids on cardiac parasympathetic tone. Diabetic autonomic dysregulation, premedication with beta-blockers, and muscarinic effects of neostigmine or the synergistic effects of multiple medications administered to the patient have also been implicated as possible causes of this observation.^1–6

Our patient (patient 8) was stable hemodynamically with optimal oxygenation and ventilation throughout the procedure and no prior history of cardiac pathology. However, he developed bradycardia, and AV-block occurred 2 to 3 minutes following neostigmine/glycopyrrolate (2.5 mg/0.4 mg) administration.

We suggest that his chronic use of anticonvulsive lamotrigine and carbamazepine that have been shown to cause heart block^9,10 may have predisposed this patient to heart block. The primary target of these anticonvulsive drugs is the inhibition of neuronal voltage-gated sodium channels. Both drugs, however, can potentially block cardiac sodium channels and interfere with cardiac depolarization leading to cardiac arrhythmia. Either neostigmine or glycopyrrolate or a combination of both caused AV block in this patient.

By binding to the anionic site of cholinesterase, neostigmine blocks the active site of acetylcholinesterase thereby preventing the hydrolysis of tonically released acetylcholine (Ach) by parasympathetic neurons in the cardiac parasympathetic pathway before they reach the postsynaptic membrane receptors. The accumulation of acetylcholine at the NMJ allows the competitive antagonism of any nondepolarizing relaxant. By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates both nicotinic and muscarinic receptors. The activation of muscarinic cholinergic receptors in the cardiac parasympathetic pathway by acetylcholine and the blocking of cholinesterase activity in the presence of acetylcholine from a reinnervated ganglion in heart transplant patients have been suggested as the cause of neostigmine-induced bradycardia.^11–13

It has also been suggested that the immaturity of the vagal system in infants and diabetic autonomic dysregulation render ventricular electrical conductance less stable and therefore prone to the paradoxical effect of neostigmine.¹⁴ Our patient had global developmental delay and likely an immature autonomic nervous system, which may have made his cholinergic receptors hypersensitive to neostigmine, a cholinergic agonist. It is unclear to us whether his epilepsy was temporal. Ictal bradycardia can be experienced by people with temporal lobe epilepsy.¹⁵

Glycopyrrolate, a nonselective muscarinic antagonist, is used in conjunction with neostigmine during neuromuscular block reversal to prevent the muscarinic effects of neostigmine such as bradycardia. Glycopyrrolate interferes with heart actions and to do so to a lesser degree when compared to atropine. The sensitivity of the receptor subtypes seems to vary in such a way that the inhibition of salivation (M₁-receptors) can be produced with low doses (and low plasma concentrations, consequently), whereas much higher doses are needed for heart effects (M₂-subtypes).⁸ We suggest that glycopyrrolate may paradoxically inhibit the activation of inwardly rectifying k+ channels by blocking the M₂ receptors at low doses. M₂ antagonism has been shown to slow the heart rate. This observation has been described with atropine, at low dose, atropine decrease heart rate, whereas at high doses it increases heart rate.¹⁶

Sugammadex, a modified y-cyclodextrin, is a selective reversal agent that encapsulates and effectively removes the neuromuscular blocking agent from the NMJ, forming an inactive complex. This drug can be used in place of an anticholinesterase/anticholinergic combination at a dose of 2 to 4 mg/kg; anaphylaxis and QT prolongations are serious side effects of this drug. Recently, however, Osaka et al¹⁷ reported AV block in a patient 9 (Table) following reversal with sugammadex, which the authors attributed to parasympathetic stimulation or from the drug it self.¹⁷ Heart block following reversal with edrophonium has not been reported. Edrophonium may be an alternative reversal agent in high-risk patients. It is a prosthetic anticholinesterase drug. Prosthetic cholinesterase inhibitors are short-acting competitive reversible inhibitors of acetylcholinesterase and act by preventing acetylcholine from accessing the anionic site of the enzyme. In contrast, neostigmine, an acid-transferring inhibitor reacts with acetylcholinesterase to form an intermediate compound that cannot be rapidly hydrolyzed as the acetylated enzyme form from acetylcholine.

CONCLUSION

AV block and asystole may result following reversal of neuromuscular block by neostigmine and glycopyrrolate. Heart transplant patients seem to be at high risk of this phenomenon while other risk factors may include long-standing autonomic neuropathy, hypersensitivity of immature autonomic nervous system in which the parasympathetic tone dominates, the use of neostigmine, and a paradoxical effect of glycopyrrolate on muscarinic receptors. Patients taking antiepileptic drugs with sodium blocking or other effects that may impact the cardiac conduction system may also be at risk. Close monitoring following administration of a reversal is recommended.