Pyridostigmine induced cardiac arrest after anesthesia induction in a patient with Myasthenia Gravis

Authors: Kyparissa M^1a, Fyntanidou B^2b*, Foroulis Ch^3c, Tsagkaropoulos S^3c, Palaska E^4a, Kotzampassi K^5d, Aggou M^6a, Grosomanidis V^1a

¹ MD, PhD, Anesthesiology
² MD, PhD, MSc Emergency Medicine
³ MD, PhD, Cardiac Surgery
⁴ MD, Anesthesiology
⁵ MD, PhD, Surgery
⁶ RN, MSc, Anesthesia

^a Clinic of Anesthesiology and Intensive Care, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.
^b Emergency Department, AHEPA Hospital, Thessaloniki, Greece.
^c Department of Cardiothoracic Surgery, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
^d Department of Surgery, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece

*Corresondence: Kautatzoglou 14A, 54639, Thessaloniki, Greece, Tel: 0030 6977427336, e-mail:

 

ABSTRACT

Myasthenia Gravis (MG) is an autoimmune disorder affecting the neuromuscular junction function and causing muscle weakness that gets worse during the day and after physical activity. The most common medication prescribed for MG treatment is pyridostigmine. Pyridostigmine is an anticholinesterase agent, which increases and prolongs the effects of acetylcholine by blocking acetylcholinesterase action. In the present study we present a patient taking pyridostigmine for MG, who was scheduled for elective thymectomy and suffered cardiac arrest (CA) after anesthesia induction. A patient 42yrs male old, ASA-PS:2, with a prior medical history of MG, was scheduled for Video Assisted Thoracoscopic (VATS) thymectomy. Patient had drooping eyelids (ptosis) and had been receiving pyridostigmine for one month (60mgx3). After drug administration and before intubation patient experienced a profound bradycardia, which immediately resulted to asystole. Advanced Cardio Pulmonary Resuscitation (CPR) was initiated and after 1min of CPR, ROSC was achieved. A decision was made to cancel the surgery and to transfer patient to the Intensive Care Unit. Patient was extubated 2 hours later in good hemodynamic and neurological status. Patient suffered a second similar episode in the evening of the same day, which was again managed successfully. A temporary transvenous cardiac pacemaker was placed and on the next day patient was transferred to the Coronary Care Unit and was scheduled for permanent pacemaker implantation. Patient did not give his consent for permanent cardiac pacemaker implantation and was self-discharged against medical advice. Pyridostigmine is an aqcetylcholinesterase (AChE) inhibitor and bradycardia is included in the side effects of these agents.

 

INTRODUCTION

Neuromuscular Junction

Acetylocholine (Ach) is the neurotransmitter in all neurons; with the exception of the postganglionic neurons of the sympathetic nervous system, where norepinephrine gets released¹. Ach release into the synapsis results in relaying the signal from the nerve and in muscle contraction. Ach gets catalyzed by the enzyme acetylcholinesterase AChE². There are two types of cholinesterase enzymes, acetylcholinesterase (true cholinesterase) and butyrylcholinesterase (pseudocholinesterase), which have similar molecular structure but different distribution³.

Anticholinesterase medications are agents which prevent both acetylcholinesterase and butyrylcholinesterase action and thereby prolong Ach action. In the anesthesia community, neostigmine was the most popular agent of this category used for antagonism of neuromuscular blockade before suggamadex³.

Myasthenia Gravis

Myasthenia Gravis (MG) is an autoimmune disorder, which affects neuromuscular junction function and it is characterized by decrease in the number of available nicotinic acetylcholine receptors at postsynaptic membrane, due to presence of pathogenic autoantibodies⁴.

MG causes a progressive muscle weakness that gets worse during the day and after physical activity. At the age of 55 the incidence of MG is greater in females (♀ to ♂ ratio is 4:1), whereas after this age incidence rates are similar for men and women⁵.

MG symptoms could be either focal and impact function of the eye (ocular myasthenia) or more general, non-focal and not specific to a certain area. In most of the cases symptoms are non-focal, nevertheless even in ocular myasthenia symptoms could become non-focal and general during disease progression.

Respiratory failure is the most severe complication of MG and is called myasthenic crisis. It occurs in 15-20% of patients, could be potentially fatal if not managed appropriately and in the vast majority of the cases mechanical ventilation support is indicated⁶.

Currently it is believed that clinical course of MG can also include cardiac manifestations, which might cause sudden cardiac death⁷. Several patients experience symptoms of cardiac disease and their incidence becomes greater in patients with concomitant thymoma⁸

Diagnosis is based on medical history, symptoms, physical examination findings and diagnostic tests⁹.

Treatment of Myasthenia Gravis

Treatment of MG is mainly medication-based. Agents used for MG treatment include anticholinesterases, which are AChE Inhibitors, corticosteroids and immunosuppressive drugs.

Anticholinesterases prevent ACh destruction by cholinesterase resulting in Ach accumulation increase¹⁰. AChE Inhibitors used in the symptomatic treatment of MG include pyridostigmine, edrophonium and neostigmine. Because of edrophonium’s short term effects it is primarily used for MG diagnosis. Neostigimine (bromide) is a well-known agent in the anesthesia community since it has been used for several years for antagonism of non-depolarising neuromuscular block¹¹. It can be administered orally (neostigmine methylsulfate), intramuscularly or intravenously. These agents reduce and improve MG symptoms by increasing Ach accumulation at the neuromuscular junction. However, these agents also have side effects, which occur in one third of patients, and are attributed to stimulation of muscarinic receptors^12,13.

Pyridostigmine

Pyridostigmine bromide, available under the trade name of Mestinon, is the brand-name drug synthesized in 1945 in Switzerland by Hoffmann-La Roche AG healthcare company. At the end of 1947 it was approved for clinical use. Since 1954 it gradually became first line treatment for MG^14-16. Pyridostigmine is cholinesterase inhibitor and it is the most commonly prescribed drug for MG treatment¹⁰ and prevents acetylcholinesterase action and thereby increases Ach concentrations and prolongs its action. Pyridostigmine has a rapid onset of action after oral administration within 30min and its effects last for 3-4hrs. Maximum peak plasma concentration is reached at 1-2hrs and elimination half-life is 3-4hrs. Plasma concentrations are positively correlated with inhibition of AChE activity^17-19 and improvement of functional parameters^20-22.

Most common associated side effects include gastrointestinal disorders (30%), hypersalivation (6%), increased sweating (4%), tingling sensation in the fingers and toes (4%)¹⁰ and in most of the cases pharmacological treatment should not be discontinued. According to the available literature there are several case reports about pyridostigmine related bradycardia, atrioventricular block and asystole^23-25.

In the present study we present a case of patient who received pyridostigmine for MG, he was scheduled for elective thymectomy and suffered a profound bradycardia episode which immediately resulted to asystole. The same episode occurred once more in the evening of the same day in the ICU.

Case presentation

A 42yrs old male patient (Body Weight: 78 kg, Body Mass Index: 23, class II physical status of American Society of Anesthesiologists), with a prior medical history of MG was scheduled for VATS thymectomy. Patient had drooping eyelids (ptosis) and had been receiving pyridostigmine for one month (60mgx3). Prescribed pyridostigmine has been continued up to the day of surgery. Preoperative laboratory results, spirometry and electrocardiogram (ECG) were normal.

Monitoring was applied to the patient upon his arrival in the operating room and included ECG, SpO₂ and Invasive Arterial Blood Pressure (IABP) monitoring through cannulation of the left radial artery. Thiopental (3mg/kg), rocuronium (0,7mg/kg) and fentanyl (0,15mg) were used for anesthesia induction. After drug administration and during bag-mask ventilation patient suffered a profound bradycardia episode, which immediately and before any intervention resulted to asystole. Immediately thereafter, Advanced Cardio Pulmonary Resuscitation (CPR) was initiated, chest compressions were performed and 1mg adrenaline was administered iv. After 1min of CPR, Return of Spontaneous Circulation (ROSC) was achieved. During CPR the efficacy of chest compressions was evaluated by IBP and ETCO₂.

After ROSC patient was hemodynamically stable, without the need for vasoactive and/or inotropic support. A 12-lead ECG was performed, which did not show any myocardial ischemia. Transesophageal Εchocardiogram (TEE) showed normal cardiac function, without any myocardial wall motion abnormalities.

A decision was made to cancel the surgery and to transfer the patient to the Cardiothoracic Intensive Care Unit, where he was successfully extubated 2 hours later, presenting normal hemodynamic and neurological status.

Patient suffered a second similar episode in the evening of the same day, which was managed successfully via adrenaline administration, chest compressions and bag-mask ventilation. A temporary transvenous cardiac pacemaker (settings: demand mode 50b/min) was placed and pyridostigmine administration was discontinued.

The next day patient was transferred to the Coronary Care Unit and was scheduled for permanent cardiac pacemaker implantation, after consultation with the electrophysiologists of the cardiology department (Images 1-3).

 

Patient did not give consent for permanent cardiac pacemaker implantation and was self-discharged against medical advice. During the remaining hospitalization time he did not suffer any other episode of bradycardia.

DISCUSSION

Treatment of MG is mainly medication-based and includes AChE Inhibitors with or without immunosuppressive drugs. For MG patients with thymoma, thymectomy is part of the treatment plan²⁶.

For more than 70yrs pyridostigmine bromide has been used as first line treatment for MG²⁷. Pyridostigmine is an AChE Inhibitor, which is a well-known drug category in the anesthesia community since it has been used for several years for antagonism of non-depolarising neuromuscular block and it is generally well tolerated. However, as all medications, it has some side effects. According to the Scientific Statement from the American Heart Association, both pyridostigmine and neostigmine are included in the drugs associated with bradyarrhythmias, by causing dysfunction of the sinus node automaticity²⁸. Drug related bradyarrhythmias and heart blocks have been described and documented in several case reports^24,29-31. There are also reports, in current literature, of CA in patients receiving pyridostigmine³². Moreover, there is a case study of CA after pyridostigmine administration for neuromuscular block reversal in a 60yrs old patient, who had undergone uvulopalatopharyngoplasty^24,25. In this case, CA was attributed to coronary spasm, a hypothesis which was confirmed in the cardiac catheterization laboratory, by ergonovine maleate administration³².

In our case, the profound bradycardia episode, which immediately resulted in asystole, occurred after drug administration for anesthesia induction. Bradycardia associated with pyridostigmine is managed by administration of anticholinergic agents (Hyoscyamine, Atropine), which counteract actions of acetylcholine on muscarinic receptors^23,24,25. In the present case, treatment included immediate initiation of chest compressions and administration of 1mg adrenaline since bradycardia immediately resulted in asystole and therefore it was managed as CA with a non-shockable rhythm. According to the European Resuscitation Council Guidelines for the management of CA with a non-shockable rhythm, adrenaline should be administered as soon as venous line has been placed³³. In our patient, a peripheral venous catheter and an arterial catheter had been placed before anesthesia induction. Thereby, immediate adrenaline administration and continuous evaluation of chest compressions efficacy was feasible. ROSC was succeeded after 2min of CPR.

Initially, the profound bradycardia episode in our case was not associated with pyridostigmine, which our patient received for MG treatment, despite the fact that bradycardia induced by neostigmine administration is common knowledge for anesthesiologists (and therefore neostigmine is always co-administered with atropine). CA during anesthesia induction is not common and in most of the cases it is attributed to hypovolemia, hypoxemia and inability to intubate the patient³⁴. Anesthetic drugs decrease heart rate, due to reduction in sympathetic activity but not to the extent that pharmacological treatment is indicated²⁸. Initial cardiac rhythm, normal TEE and absence of abnormal ECG findings suggested that the CA in our patient was of non-cardiac origin. Immediate and effective management contributed to patient’s successful early extubation, 2hrs after the incidence of CA. Patient’s hemodynamic and neurological status were normal after extubation.

The incident of a second similar episode in the evening of the same day, which was managed successfully via adrenaline administration, chest compressions and bag-mask ventilation raised suspicion about the potential  involvement of pyridostigmine in the occurrence of bradycardia and CA.

After the second episode of CA, placement of a temporary transvenous cardiac pacemaker was decided, since this management approach was considered safer for the patient compared to continuous infusion of a beta adrenergic agonist³⁵ along with pyridostigmine discontinuation. Discontinuation of pyridostigmine therapy is adequate treatment in most but not in all cases³⁶. Permanent cardiac pacemaker implantation is the optimal treatment regime in MG patients under pyridostigmine, who suffer symptomatic or asymptomatic bradycardia but should continue to receive pyridostigmine for MG management²⁴.

Literature has confirmed that MG is affecting the heart⁷ and the autonomic nerve system^37,38. Co-administration of pyridostigmine with anesthetic drugs could evoke a profound bradycardia, due to the muscarinic effects of pyridostigmine and the central vagotonic effects of the anesthetics³⁹. However the re-occurrence of the same bradycardia episode a few hours later is eliminating the potential involvement of this pathophysiological mechanism in our case.

Since our patient was self-discharged against medical advice, we do not have any follow up information about whether he continued treatment with pyridostigmine and his clinical course.

Limitations: Since our patient did not give consent for permanent pacemaker implantation and was self-discharged against medical advice we do not have any information about patient’s clinical course.

Conclusions

Pyridostigmine can induce profound bradycardia, which can result in asystole. This side effect of pyridostigmine should be taken into account during the perioperative management of patients under pyridostigmine.

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Addittional materials: No

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Acknowledgements: Not applicable

Authors’ contributions: KM drafted the paper and is the lead author. FB contributed to planning and the critical revision of the paper. FCh contributed to planning and the critical revision of the paper. TS contributed to planning and the critical revision of the paper. PE contributed to planning and the critical revision of the paper. KK contributed to planning and the critical revision of the paper. AM contributed to planning and the critical revision of the paper. GV contributed to planning and the critical revision of the paper. All authors read and approved the final manuscript.

Funding: Not applicable.

Availability of supporting data: The datasets analyzed during the current article are available from the corresponding author on reasonable request.

Ethical approval and consent to participate: Ethics committee approval required. Patient’s consent was obtained

Competing interests: The authors declare that they have no competing interests.

Received: January 2024, Accepted: January 2024, Published: February 2024

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Citation: Kyparissa M, Fyntanidou B, Foroulis Ch, Tsagkaropoulos S, Palaska E, Kotzampassi K, Aggou M, Grosomanidis V. Pyridostigmine induced cardiac arrest after anesthesia induction in a patient with Myasthenia Gravis. Greek e j Perioper Med. 2024;23(a): 33-43.

 

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