Neostigmine for Treating Acute Colonic Pseudo-Obstruction in Neurocritically Ill Patients

by gross dilatation of the colon in the absence of a mechanical obstruction.1, 2, 3 ACPO often occurs in critically ill patients due to the disturbance of gastrointestinal motility induced by severe medical illnesses. Regardless of the underlying condition, early recognition and timely management are important to avoid life-threatening complications of ACPO such as colonic ischemia, bowel perforation, and peritonitis.1, 2, 4 Neostigmine is an acetylcholinesterase inhibitor exerting potent muscarinic effects that promote intestinal smooth-muscle contractions and augment peristalsis.5, 6, 7 Previous studies have shown that neostigmine is a safe and effective treatment option for ACPO in patients who do not respond to conservative management.5, 8, 9, 10 However, the effect of neostigmine on APCO in neurological intensive-care unit (NeuroICU) patients has rarely been studied. Gastrointestinal motility problems are common in NeuroICU patients.11, 12, 13, 14 Both the severity of neurological illnesses and the medications used such as opioids or drugs with strong anticholinergic effects put neurocritically ill patients at risk of developing ACPO. Despite this condition being observed frequently in clinical practice, very little has been published about its treatment. Therefore, we investigated the safety and effectiveness of neostigmine for the treatment of ACPO in neurocritically ill patients.

This study included 31 patients with a mean age of 46.8 years, of whom 20 (65.4%) were male. The admission diagnoses comprised stroke (ischemic stroke and hemorrhagic stroke; n=11, 35.5%), status epilepticus (n=7, 22.6%), anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (n=4, 12.9%), traumatic brain injury (n=4, 12.9%), traumatic spinal cord injury (n=3, 9.7%), anaplastic astrocytoma (n=1, 3.2%), and cardiac arrest (n=1, 3.2%; Tables 1 and 2). No patient had bradyarrhythmia at baseline (Table 2). Fifteen of the included patients (48.4%) underwent abdominal CT to exclude mechanical causes of bowel obstruction. Before the administration of neostigmine, all patients were taking more than three medications (prokinetics or laxatives) for ACPO (Supplementary Table 1 in the online-only Data Supplement). Neostigmine was administered intravenously in 90.3% patients (n=28) (Table 2).

Table 1
Characteristics of the included patients at the two centers

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Table 2
Efficacy and safety of neostigmine in the treatment of acute colonic pseudo-obstruction in all patients (n=31)

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For the primary outcome, all patients had bowel movements after the first injection of neostigmine, and the median time from the administration of neostigmine to defecation was 120 minutes (IQR, 60–210 minutes). Five patients (16.1%) received an additional dose of neostigmine on the same day as the first round of neostigmine treatment. Patients with a lower dose of neostigmine tended to require repeated neostigmine treatment (Table 3). Nine patients (29.0%) were treated using another round of neostigmine injection at a median of 1 day after the initial treatment (IQR, 1–2.5 days) due to a partial response to neostigmine treatment or the recurrence of APCO. The secondary outcome of the colon diameter on plain radiographs significantly decreased by a median of 17.5 mm (IQR, −12.8 to −26.3 mm; paired t-test: p<0.001) (Fig. 1 and Table 2). The treatment effects of neostigmine on the colon diameter were consistently significant at each center (Fig. 2 and Supplementary Tables 2 and 3 in the online-only Data Supplement). Multilevel analysis considering the center as a random effect revealed that the administration of neostigmine was significantly effective in reducing the colon diameter [least-square mean: from 66 mm (95% confidence interval, 43.9–89.2 mm) pretreatment to 47.5 mm (95% confidence interval, 24.8–70.1 mm) posttreatment, p<0.001), with an intraclass correlation coefficient of 13% for each center. Moreover, the abdomen circumference, which was measured only in Center 1 and at a median of 24 hours (IQR, 3.5–24.0 hours) after neostigmine injection, decreased by a median of 1.75 cm (IQR, 0.98 to 2.50 cm; paired t-test: p=0.001) after the administration of neostigmine (Supplementary Table 2 in the online-only Data Supplement and Supplementary Fig. 1 in the online-only Data Supplement).

Fig. 1
Treatment effect of neostigmine on ACPO. Plain abdominal radiographs obtained before (A) and after (B) the intravenous administration of neostigmine (2 mg) in a 23-year-old female with anti-N-methyl-d-aspartate receptor encephalitis. (A) Initial imaging shows massive colonic dilatation consistent with ACPO. (B) A bowel movement occurred 2.5 hours after the neostigmine injection, and follow-up imaging performed 24 hours after the injection showed an improvement in colonic dilatation with a decrease in the diameter of the colon. ACPO: acute colonic pseudo-obstruction.

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Fig. 2
Effect of neostigmine on colon diameter. Neostigmine treatment induced significant reductions in the colon diameter at the two centers.
Data are mean±standard deviation values. ^*p<0.001.

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Table 3
Association between initial dose and repeated injection on the same day

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Regarding the clinical outcomes during hospitalization, enteral feeding was initiated in 28 patients (90.3%) after neostigmine treatment, and no patient required endoscopic or surgical decompression (Table 2). In addition, 10 patients (32.3%) were being treated using opioids prior to neostigmine therapy, but the effect of neostigmine was not influenced by the use or nonuse of opioids (colon diameter: median, −21.1 mm; IQR, −27.0 to −12.6 mm in opioid nonusers vs. median, −16.3 mm; IQR, −23.5 to −11.1 mm in opioid users; p=0.569) (Supplementary Table 1 in the online-only Data Supplement). In addition, one patient was treated using quetiapine (300 mg/day, minimal anticholinergic effect), and no patient was taking beta adrenergic agonists or antagonists (Supplementary Table 1 in the online-only Data Supplement).

Safety outcomes were monitored for up to 24 hours following the administration of the last dose of neostigmine. Four patients (12.9%) experienced adverse events including hypersalivation, sweating, and vomiting, which did not require additional management. Among them, one patient had an episode of transient bradycardia (42 beats/minute) at 1 hour after the IV administration of neostigmine (2 mg), which subsided after injecting atropine (0.5 mg). There was no sudden decrease in the blood pressure or respiration rate. None of the patients experienced syncope, bronchospasm, or cardiac arrest after the administration of neostigmine.

This study found that the IV or SC injection of neostigmine facilitated bowel movements and reduced the colon diameter on radiographic imaging in neurocritically ill patients with ACPO that were refractory to conventional medical management. The effect was consistent regardless of the route of injection and the treatment center. Moreover, adverse effects were transient and minor, and hence did not raise significant clinical concerns.

While the exact pathophysiology of ACPO remains to be elucidated, it is regarded as a dysfunctional colonic motility disorder caused by an imbalance in the gastrointestinal autonomic nervous system.1, 6, 8, 9 Neurocritically ill patients are at high risk of ACPO because they are frequently treated using drugs that have anticholinergic effects, such as barbiturates or opioids. In addition, most of these patients have a serious brain injury such as severe stroke, status epilepticus, traumatic brain injury, or encephalitis, which often leads to excessive parasympathetic suppression, sympathetic stimulation, and impairment of colonic autonomic regulation.1, 11, 12, 13, 14, 17, 18 Together these factors could disturb gastrointestinal motility and result in the development of ACPO.

The traditional management of ACPO includes bowel rest with the placement of a nasogastric tube or the use of prokinetics. 1, 3 Colonoscopic decompression can be attempted if conventional treatment fails. Our study suggests that neostigmine can be a safe and effective option for medical treatment. Neostigmine is a parasympathomimetic agent that reversibly inhibits acetylcholinesterase activity and thereby increases the concentration of acetylcholine at synapses. Moreover, neostigmine indirectly stimulates nicotinic and muscarinic receptors, which help contract colonic smooth muscles and increase colonic motility.6, 7, 9, 10 In the present study, the administration of neostigmine via either IV or SC injection rapidly resolved colonic dilatation in all patients with ACPO who had failed to respond to multiple prokinetics or laxatives. In addition, 20 patients (71.6%) responded to the first round of treatment, regardless of age, dosage, route, or treatment center, despite neostigmine having a short elimination half-life (about 80 minutes), which is consistent with previous reports. 7, 9, 10 However, another round of treatment was required when the dose was lower than 2 mg. We also found a low rate of significant adverse events. Only one patient (3.2%) experienced an episode of bradycardia, which was successfully managed by the IV injection of atropine. The percentage of patients with adverse events was similar or even lower than in previous studies.5, 6, 7, 9, 10

Our study was subject to several limitations. First, it had a retrospective design, and so there was a risk of unmeasured bias. Second, we did not include control groups with which to compare the effect of neostigmine on ACPO. However, a bowel movement occurred in all patients and their colon diameter decreased by 25% (from 76.0 mm before treatment to 57.0 mm after treatment). Given that none of the patients responded to conventional medical treatment, we consider this effect of neostigmine on ACPO to be noteworthy. Third, this study included a relatively small number of patients, although the number is comparable to those in previous studies.5, 6, 7, 8, 9, 10 Fourth, abdominal CT scans were performed in 15 patients (48.4%) to rule out mechanical causes of bowel obstruction. ACPO was diagnosed in the remaining patients based on clinical presentations and serial abdominal plain radiographs based on previous studies.6, 7, 8, 9, 10, 16 Fifth, 11 patients (35.5%) were being treated using opioids or anticholinergics prior to neostigmine administration. However, the effect of neostigmine on APCO was similar regardless of the presence or absence of other drugs. Sixth, neostigmine was administered at the discretion of the neurointensivists in charge according to the treatment protocols at each center. Notably, the effect of neostigmine on bowel movements was similar in the two centers. In addition, the relationship between neostigmine and improvement of ACPO remained significant after adjusting for the center effect.

In conclusion, neostigmine may be a safe and effective treatment option for neurocritically ill patients with ACPO who fail to respond to conventional medical management. Monitoring of adverse events should be considered despite their low probability. Future clinical trials and larger studies are needed to validate the use of neostigmine and identify the optimal dose and route of administration in neurocritically ill patients.

The online-only Data Supplement is available with this article at https://doi.org/10.3988/jcn.2021.17.4.563.

Supplementary Table 1

Comorbidities and concurrent medications of the included patients at the two centers

Supplementary Table 2

Efficacy and safety of neostigmine in the treatment of acute colonic pseudo-obstruction in Center 1 (n=15)

Supplementary Table 3

Efficacy and safety of neostigmine in the treatment of acute colonic pseudo-obstruction in Center 2 (n=16)

Supplementary Fig. 1

Effect of neostigmine on acute colonic pseudo-obstruction.