Pulmonary Complications from Neostigmine Use for Management of Ileus in Lung Transplant Recipient

Introduction:

Neostigmine is a reversible acetylcholinesterase inhibitor that functions as a parasympathomimetic drug that has an on-label use for reversing neuromuscular paralytics. In addition, it is indicated in the off-label treatment of acute colonic pseudo-obstruction and critical illness associated ileus. Neostigmine is associated with side effects such as bradycardia, asystole, and pulmonary side effects including bronchospasm and increased pulmonary secretions^1,2.  There are no studies or case reports describing the use of neostigmine in lung transplant patients. Presented is the case of a 68-year-old comorbid male who underwent bilateral lung transplantation with a post operative course complicated by ileus that was treated with a series of IV neostigmine boluses resulting in increased pulmonary secretions and oxygen requirements.

Case Presentation:

Case presented is a 68-year-old male with a past medical history of hypertension (HTN), asthma, obstructive sleep apnea (OSA), history of prostate cancer (s/p prostatectomy), atrial fibrillation (on Flecainide at home, unresponsive to beta blockers), and progressive interstitial pneumonia with autoimmune features who presented for bilateral lung transplantation.

After an uneventful intraoperative course, he was extubated on postoperative day (POD) #1 to continuous positive airway pressure (CPAP) given his significant OSA. This was expeditiously weaned to low flow nasal canula within few hours.  Per our institution’s lung transplantation postoperative care guidelines, patient was kept nil per oral (NPO) after extubation and a postoperative bowel regiment was initiated through his post pyloric small bore feeding access.  POD #2 was also eventful due to the recurrence of his known Atrial Fibrillation with rapid response rate (RVR). Despite beta blockers and amiodarone boluses, due to refractory RVR, it necessitated cardioversion with subsequent amiodarone infusion.

On POD #3, patient had increased abdominal distension and pain with preliminary diagnosis of ileus. Subsequent abdominal x-ray showed bowel dilation concerning enough to prompt placement of nasogastric (NG) tube for gastric & bowel decompression.  Patient’s abdominal discomfort extended into POD #4 in which repetitive abdominal x-rays displayed worsening dilatation of bowel loops. A follow up computerized tomography (CT) of abdomen and pelvis displayed significant air with stool burden and without evidence of any mechanical obstruction.  Due to ongoing clinical concern for ileus and failure to respond to conservative treatments with existent bowel regimen, decision was made to treat patient with Neostigmine.

Patient was given a cumulative dose of 7.5 mg of neostigmine in 2.5 mg increments over 30 minutes. Patient had a starting heart rate of 75 and reached a nadir of 50 during treatment. Patient had copious amounts of flatus and liquid bowel movements that started during the 30 minute period of neostigmine administration resulting in improvement of the abdominal distension and abdominal complaints subsided dramatically. However, several hours after treatment with neostigmine, patient started having copious pulmonary secretions and associated dyspnea in effort to clear his airways. Patient was switched from NC to HFNC to improve dyspnea. Aggressive pulmonary toilet was provided by Respiratory Therapists. Secretions and dyspnea slowly improved with adequate pulmonary toilet and HFNC approximately 12 hours after neostigmine administration.

Discussion:

Neostigmine is an effective method to treat ileus in the ICU but can be accompanied by side effects. In the presented case, the patient did have a successful decompression of his bowels from Neostigmine administration, but it was accompanied by significant pulmonary side effects. Several different dosing strategies have been shown in the literature in the ICU of neostigmine administration for the treatment of ileus, varying from 0.4-0.8 mg/hr for 8 hours³ to a bolus of 2.5 mg over an hour⁴ to 2 mg over 3-5 minutes⁵.  The response to treatment does vary mildly depending on bolus or infusion dosing. In patients who were given a bolus dose of Neostigmine they had 80% response to treatment after two doses in comparison to continuous neostigmine infusions having a 70% response. There is a small amount of data to suggest that the safety and efficacy of bolus and infusion dosing of neostigmine are similar⁶.

Side effects of neostigmine include, bradycardia, bronchospasm, hypoxia, increased respiratory secretions, and increased gastrointestinal secretions and motility⁷. In the respiratory system the increase in acetylcholine from neostigmine leads to bronchial smooth muscle contraction that results in bronchospasm and hypoxia. It has additionally been shown that, neostigmine use for treatment of bowel dysfunction in patients with Spinal cord injuries will increase pulmonary resistance and that the addition of glycopyrrolate pretreatment significantly decreases neostigmine’s bronchospasm effect and can cause bronchodilation¹. In the presented case, patient’s copious airway secretions as well as hypoxemia was not an immediate side effect and worsened by peak effect at 4-6 hours after Neostigmine administration. Differential diagnosis included evolving primary graft dysfunction, ileus related regurgitation, hospital acquired pneumonia, as well as iatrogenic side effect of neostigmine. Due to refractory nature of his atrial fibrillation within 24 hours, glycopyrrolate was chosen not to be administered.

In summary the presented case, the post-surgical lung transplant patient did have successful decompression of his bowels with neostigmine treatment but at the cost of having increased secretions that caused an increased oxygen requirement and work of breathing for majority of an ICU shift for the patient. In future cases, glycopyrrolate could be utilized as a pretreatment to help mitigate neostigmine’s cardiovascular and pulmonary side effects. Careful selection of patient population should be utilized in the treatment of ileus with neostigmine to ensure that patients can tolerate the side effect profile associated with neostigmine. Bolus dosing vs continuous infusion dosing of neostigmine appear to have similar efficacy and incidences of side effects.

References:

1. Radulovic M, Spungen AM, Wecht JM, Korsten MA, Schilero GJ, Bauman WA, Lesser M. Effects of neostigmine and glycopyrrolate on pulmonary resistance in spinal cord injury. J Rehabil Res Dev. 2004 Jan-Feb;41(1):53-8. doi: 10.1682/jrrd.2004.01.0053. PMID: 15273897.
2. Ruetzler K, Li K, Chhabada S, Maheshwari K, Chahar P, Khanna S, Schmidt MT, Yang D, Turan A, Sessler DI. Sugammadex Versus Neostigmine for Reversal of Residual Neuromuscular Blocks After Surgery: A Retrospective Cohort Analysis of Postoperative Side Effects. Anesth Analg. 2022 May 1;134(5):1043-1053. doi: 10.1213/ANE.0000000000005842. PMID: 35020636.
3. van der Spoel JI, Oudemans-van Straaten HM, Stoutenbeek CP, Bosman RJ, Zandstra DF. Neostigmine resolves critical illness-related colonic ileus in intensive care patients with multiple organ failure--a prospective, double-blind, placebo-controlled trial. Intensive Care Med. 2001 May;27(5):822-7. doi: 10.1007/s001340100926. PMID: 11430537.
4. Paran H, Silverberg D, Mayo A, Shwartz I, Neufeld D, Freund U. Treatment of acute colonic pseudo-obstruction with neostigmine. J Am Coll Surg. 2000 Mar;190(3):315-8. doi: 10.1016/s1072-7515(99)00273-2. PMID: 10703857.
5. Abeyta BJ, Albrecht RM, Schermer CR. Retrospective study of neostigmine for the treatment of acute colonic pseudo-obstruction. Am Surg. 2001 Mar;67(3):265-8; discussion 268-9. PMID: 11270887.
6. İlban Ö, Çiçekçi F, Çelik JB, Baş MA, Duman A. Neostigmine treatment protocols applied in acute colonic pseudo-obstruction disease: A retrospective comparative study. Turk J Gastroenterol. 2019 Mar;30(3):228-233. doi: 10.5152/tjg.2018.18193. PMID: 30541715; PMCID: PMC6428512.
7. Nair, P. Hunter J. Anticholinesterases and anticholinergic drugs. Continuing Education in Anaesthesia Critical Care & Pain. 2004 Oct:4(5):164-168

Authors

Tyler Beattie, MD

Division of Critical Care Medicine

Department of Anesthesiology

School of Medicine and Public Health

University of Wisconsin-Madison

Madison, Wisconsin

Douglas R. Adams, MD

Division of Critical Care Medicine

Department of Anesthesiology

School of Medicine and Public Health

University of Wisconsin-Madison

Madison, Wisconsin

Gozde Demiralp, MD

Division of Critical Care Medicine

Department of Anesthesiology

School of Medicine and Public Health

University of Wisconsin-Madison

Madison, Wisconsin