A double blind, placebo controlled, randomized control trial studying the safety and efficacy of pyridostigmine as a rescue therapy for postoperative ileus. Patients who undergo elective colorectal resection with or without creation of an ostomy, and subsequently develop postoperative ileus will be eligible for enrollment. Patients will be randomized to receive either pyridostigmine or placebo in addition to the current elements of standard of care. Patients will also complete the pyridostigmine bromide side effects scale (PBSES) upon enrollment and following each administration of either intervention or placebo to monitor treatment safety and evaluate for the development of side effects.

Inclusion Criteria:

1. Adult (age 18 and over) patients with benign or malignant colonic or rectal disease who have undergone elective laparoscopic, robotic, or open colorectal resections with or without ostomy construction at our center, and subsequently developed POI, defined as symptoms of bloating with or without nausea and vomiting, with absence of passage of flatus or stool for at least 48 hours postoperatively and require return to NPO status after initial diet attempts with or without placement of an NGT.

2. Radiographic confirmation of POI diagnosis either via abdominal radiography (KUB), computed tomography abdomen/pelvis (CT A/P), or both

3. ECOG Performance status < 4

4. Laboratory evidence of normal organ function, defined as:

   1. Hemoglobin ≥ 7.0 g/dL
   2. WBC ≤ 20,000/mcL and ≥ 4,000/mcL
   3. Platelet count ≥ 100,000/mcL or ≤ 100,000,000/mcL
   4. AST (SGOT) ≤ 2.5 times the institutional upper limit of normal
   5. ALT (SGPT) ≤ 2.5 times the institutional upper limit of normal
   6. Total bilirubin within the upper limit of institutional normal range
   7. Serum Creatinine within the upper limit of institutional normal range

Exclusion Criteria:

1. Radiographic evidence of bowel obstruction
2. Documented intraabdominal septic complications (IASC, such as abdominopelvic abscess, peritonitis, anastomotic leak) at any time prior to or after enrollment
3. Isolated small bowel or ostomy surgery without colon or rectal resection
4. ASA score 5
5. Pregnant or breastfeeding females as PYR is classified by the FDA as a pregnancy risk category C medication with the potential for teratogenic or abortifacient effects and demonstrated secretion into breastmilk with an unknown but potential risk for adverse effects in the nursing infants
6. Current use of any other investigational agents including: neostigmine or other acetylcholine esterase inhibitors, alvimopan, metoclopramide, erythromycin, methylnaltrexone, naloxegol, cisapride, and laxatives or cathartics (i.e. milk of magnesia, polyethylene glycol)
7. History of allergic reactions attributed to PYR or other acetylcholine esterase inhibitors
8. Patients with any of the following uncontrolled, concurrent illnesses: active or latent MG, bronco-constrictive disease (asthma/reactive airway disease), chronic obstructive lung disease (COPD), symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia including bradycardia, renal failure, hepatic failure, gastroparesis, short bowel syndrome (small bowel < 200cm), preexisting short or large bowel dysmotility or pseudo-obstruction, chronic constipation/laxative use, peritoneal carcinomatosis, and psychiatric illness/social situations that would limit compliance with study requirements