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ABDOMINAL SURGERY

Official Journal of the American Society of Abdominal Surgeons, Inc.

This article originally appeared in the Winter 20011 / Spring 2012 issue of the Journal.

Pyridostigmine Administered for Myasthenia Gravis Precipitating Colonic Anastomotic Dehiscence

Deepak Kumar M.D., F.A.C.S.
Wright State University
Boonshoft School of Medicine

Anita Rao, MD


ABSTRACT

Anticholinesterase medications are the mainstay of treatment for myasthenia gravis patients. Their postoperative use in conjunction with a newly constructed bowel anastomosis has been controversial due to vigorous prokinetic effects. Anticholinesterase medications have been implicated in increasing the rate of anastomotic disruption in colonic anastomoses. It is unknown if myasthenia gravis patients with long-term exposure to anticholinesterase medication are just as susceptible as those receiving a one-time postoperative dose for reversal of anesthesia. We present a rare case of near-total colonic anastomotic disruption in a patient receiving long-term anticholinesterase therapy, and hypothesize methods to prevent it.

INTRODUCTION

Anticholinesterase medications are the foundation of treatment and crisis prevention for myasthenia gravis patients. These medications are also commonly used to reverse the action of muscle relaxants after surgery. Their postoperative use in conjunction with a newly constructed bowel anastomosis has been controversial due to vigorous prokinetic effects. Anticholinesterase medications have been implicated in increasing the rate of anastomotic disruption for this reason. However, the gastrointestinal effects of chronic, daily dosing in myasthenic patients have not been fully studied. An interesting question arises: Is the bowel of myasthenia gravis patients with long-term exposure to anticholinesterase medication just as susceptible as those receiving a one-time postoperative dose? Also, how can we possibly prevent this dire complication? We present a rare case of near-total colonic anastomotic disruption in a patient receiving long-term anticholinesterase therapy and hypothesize methods to prevent it.

CASE REPORT

Patient is a 70 year-old Caucasian female with myasthenia gravis. She was admitted to the hospital for elective closure of colostomy which was created approximately 1.5 years earlier. Of note, patient initially had sigmoid colon resection with end colostomy for acute perforated diverticulitis. Several months later, she had colostomy closure, which leaked and required subsequent end-colostomy formation. Our patient greatly desired another attempt at take-down of her colostomy. She underwent a relatively uncomplicated surgical procedure this time for closure of her colostomy. Preoperatively, her myasthenia gravis was controlled with pyridostigmine 75mg every three hours. She received neostigmine 3mg intravenous just after the end of the surgical procedure by anesthesia. Postoperatively, she was restarted on her oral pyridostigmine. She seemed to progress well in terms of gastrointestinal recovery, and had return of bowel function on post operative day 3. However, she continued to have complaints of uncontrolled abdominal pain and large volume of watery diarrhea with negative stool studies.

Our patient clinically deteriorated around post operative day 5 with delirium, and subsequent respiratory distress on day 7. This was thought to be secondary to her myasthenia gravis. She was urgently intubated and started on plasmaphoresis therapy for the believed myasthenic crisis. On post operative day 10, drainage of stool was noted from inferior portion of her wound, and she was taken back to surgery for presumed anastomotic leak and pelvic sepsis. Intraoperatively, she had a large stool collection in the pelvis and right paracolic gutter as well as near complete disruption of the colonic anastomosis. The decision was made to re-fashion an end colostomy, and her abdomen was closed using a biosynthetic mesh. It is likely that her disruption occurred well before post operative day 10. Following her last surgery, she has suffered from wound dehiscence and peristomal skin necrosis requiring additional small revisional surgery, but is headed towards slow recovery.

DISCUSSION

The use of anticholinesterase medication has been targeted in promoting colonic anastomotic breakdown. Only two other reports of anastomotic disruption in myasthenic patients exist in the medical literature, and only one of these from the United States.1, 2We present another rare case of colonic anastomotic dehiscence in a myasthenic patient receiving pyridostigmine.

Myasthenia gravis is a rare autoimmune disorder in which antibodies are formed against the acetylcholine receptors at the neuromuscular junction. The hallmark of the disorder is a fluctuating degree of weakness in ocular, bulbar, limb, and respiratory muscles. Untreated myasthenia gravis has an associated mortality rate of 30-70%.3 Myasthenic crisis is defined as the need for respiratory assistance secondary to respiratory insufficiency. This may be precipitated by infections, over exertion, emotional or physical stress (such as surgery), acute illness, or under-dosing of cholinesterase.4 With prevention of these symptoms in the form of medical therapy, patients have a near-normal life expectancy. First line therapy is anticholinesterase medication; pyridostigmine being the most widely used followed by neostigmine or physostigmine. Cholinesterase inhibitors improve muscle weakness by prolonging the presence and availability of acetylcholine in the neuromuscular junction through delay of acetylcholine hydrolysis.3 During surgery or times of stress, an increase in dosage may be necessary. The most common adverse reactions occur due to muscarinic side effects of the drugs. These can include increased secretions, abdominal cramps, diarrhea, sweating, nausea, bradycardia, or muscle twitches.3

Pyridostigmine has a rapid onset of action (15 to 30 minutes) with peak action at about 2 hours, and its effects last for 3-4 hours.5 Neostigmine is the best studied of the anticholinesterases due to its more common usage to reverse neuromuscular blockade in anesthesia. The general mechanism of action for the two is very similar aside from some differences in pharmacokinetics. Intravenous neostigmine has a quick onset of action, after about 5 minutes, and a relatively short duration of action, anywhere from 30-120 minutes.6, 7 Neostigmine has been shown to raise intraluminal pressure by increasing smooth muscle contractility.8

Neostigmine is commonly used to reverse muscle relaxation after general anesthesia in non-myasthenic patients. For this reason, there are a greater number of reports regarding colonic disruption in this setting than in the myasthenic patient. It has been implicated that the muscarinic effects on the bowel smooth muscle cause increased peristaltic waves and diarrhea which may disrupt a newly formed colonic anastomosis in the otherwise healthy surgical patients.1 In one instance a surgeon reported visualizing the disruption ‘in vivo’ as neostigmine was given to the patient at time of re-entry for a lost sponge.9 In one retrospective study examining ileorectal anastomoses in Crohn’s patients, the group that received neostigmine immediately postoperatively had a 36% leak rate compared to 4% for those who did not receive it.9 Yet another case report describes neostigmine used immediately postoperatively in a nonmyasthenic patient, resulting in the patient having a great deal of abdominal pain followed by a large watery bowel movement. This patient became hemodynamically unstable, requiring immediate reoperation, and was found to have posterior wall disruption and feculent fluid in the abdomen.8 Reports also exist of perforation of the colon after neostigmine administration for colonic pseudoobstruction.7 Certainly, when bowel that has not been operated on perforates, as in the last example, the question arises whether a fresh anastomosis would be able to withstand the forces.

Not enough evidence exists to assume that the above results are generalizable to other gastrointestinal anastomoses. A report exists of a myasthenic patient with similar medication profile as our patient who underwent roux-en-y gastric bypass.10 This patient healed in normal fashion, implying that all of the gastric and small bowel anastomoses healed without being affected by anticholinesterase. No case reports exist to document dehiscence of various other anastomoses, but there are experimental studies on the effects of neostigmine in the small bowel as well as colon.11 The contraction amplitude and frequency in the ileum and colon in one study were both found to be enhanced by neostigmine injection. However, the amplitude and frequency increased to 300-400% in the colon. In another study, the effect on colonic motility was investigated in patients after colorectal surgery and in control patients. Effects were found to be similar between the surgical and non-surgical patients. Neostigmine evoked a dose-dependent increase in colonic motility with higher frequency and greater amplitude of colonic contractions with increasing doses of neostigmine. Also, the study indicated increased colonic tone with administration of the medication.6 This may then increase tension and mechanical traction across the anastomosis, resulting in disruption. Also likely, would be relative hypovolemia or ischemia during periods of contraction, leading to necrosis.

The use of atropine to counteract these muscarinic gastrointestinal side effects has been studied, and the results are mixed. Most studies support the fact that atropine does not reduce the risk of gastrointestinal side effects, but does prevent adverse cardiovascular side effects.11 Likewise, glucagon has been investigated in hopes of counteracting undesirable events. It has been used to offset colonic spasm during colonoscopies, but in regards to reducing postoperative peristaltic waves, the studies have been non-conclusive.1

Myasthenia gravis patients have special perioperative and anesthetic considerations. Bulbar symptoms are considered primary risk factors for postoperative respiratory difficulties.5 No evidence exists to suggest that altering a patient’s anticholinesterase regimen prior anesthesia has any effect on duration of mechanical ventilation postoperatively. 12 Myasthenia gravis patients have been shown to be relatively resistant to depolarizing neuromuscular blockade. Conversely, atracurium, rocuronium, mivacurium, cisatracurium, or other short-acting nondepolarizing drugs may be used.12 Even patients who are on oral anticholinesterase medications preoperatively responded normally to reversal with the same medications. Patients should be monitored in the post-anesthesia care unit for at least 2 hours to observe stability. Before extubation, they should demonstrate vital capacity 15mL/kg and negative inspiratory force of 25cm.5 Though several reports exist of colonic anastomotic disruption after administration of neostigmine intraoperatively, no definite perioperative guidelines exist regarding neostigmine for colonic anastomosis creation in healthy or myasthenic patients.

CONCLUSIONS

In myasthenic patients, cholinesterase inhibitors are the mainstay of daily crisis prevention. These medications are often escalated in the postoperative period to facilitate early extubation.1 In this setting, anticholinesterases should be utilized in extreme caution due to the vulnerability of a fresh anastomosis. Most studies reflect outcomes after single postoperative ‘reversal’ dosages of anticholinesterase inhibitors. The effects of chronic preoperative and postoperative dosing, as in the typical myasthenic patient, are undetermined, but in our experience, also pose a serious risk. If bowel resection is unavoidable, and anastomosis is desired, one strategy to reduce the incidence of anastomotic dehiscence is to discontinue the medication preoperatively and immediately postoperatively. Patients could receive perioperative plasmapheresis as a bridge during this time frame. As the most worrisome complication in the myasthenic patient is myasthenic crisis in the form of respiratory failure, patients should remain on mechanical ventilatory support until the anastomosis has had time to begin the healing process (5-7 days). After an adequate period of time has passed, the medications should be resumed, and patients may be weaned off the ventilator. Another anesthetic option may be to perform surgery with a combination of light general and regional, such as epidural, anesthesia. However, intra-abdominal surgery in this setting would be more difficult. Yet another line of attack is to always perform a protective ileostomy in these patients, regardless of ease of operation. This may not prevent anastomotic dehiscence, but might prevent an intra-abdominal catastrophe. The safest course of action remains to approach these patients non-operatively when possible.

SUMMARY

Anticholinesterase medications are the foundation of treatment and crisis prevention for myasthenia gravis patients. These medications have vigorous prokinetic effects which have been directly related to colonic anastomotic disruption. In the immediate postoperative setting, anticholinesterases should be utilized in extreme caution due to the vulnerability of a fresh anastomosis.

 

REFERENCES

1. Herz B. Colonic Anastomotic Disruption in Myasthenia Gravis, Report of Two Cases. Dis. Col & Rect 1987; 30:809-811

2. Destri GL, Scilletta B et al. Myasthenia gravis and intestinal resection: is dehiscence likely to occur? Minerva Chri 2006; 6:525-528

3. Agnes JA, Lisak RP. Myasthenia Gravis. Current Treatment Options in Neurology 2010; 12:231-243

4. Jamal BT, Herb K. Perioperative management of patients with myasthenia gravis: prevention, recognition, treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 107:612-6194.

5. Yu QS, Holloway HW et al. Long-acting anticholinesterases for myasthenia gravis: synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine and physostigmine. Bioorganic & Medicinal Chemistry 2010; 18:4687-4693

6. Kreis ME, Kasparek M et al. Neostigmine Increases Postoperative Colonic Motility in Patients Undergoing Colorectal Surgery. Surgery 2001; 130:449-456

7. Mollema R, Japp SJ. Perforation of the colon after administration of neostigmine. Intensive Care Med 2004; 30:730

8. Hirst GR, Karandikar SS, Brown G et al. Colonic anastomotic disruption in the immediate postoperative period. Int J Colorectal Dis 2004; 19:281-282

9. Bell CM, Lewis CB. Effect of Neostigmine on Integrity of Ileorectal Anastomoses. British Medical Journal 1968; 3:587-58890-o

10. Arias F, Szomstein S. Myasthenia Gravis Improvement after Laparoscopic Roux-en-Y Gastric Bypass. Obesity Surgery 2005; 15:591-594

11. Wilkins JL, Hardcastle JD. Effects of Neostigmine and Atropine on Motor Activity of Ileum, Colon, and Rectum of Anaesthetized Subjects. British Medical Journal 1970; 793-794

12. Dillon FX. Anesthesia Issues in the Perioperative Management of Myasthenia Gravis. Seminars in Neurology 2004; 24:83-94



Journal CoverOFFICIAL PUBLICATION OF:
The American Board of Abdominal Surgery
The American Society of Abdominal Surgeons, Inc.
Foundation for Abdominal Surgery

Louis F. Alfano, Jr., M.D., Editor-in-Chief
Diane M. Pothier, Executive Editor and
Director of Continuing Medical Education


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