Introduction
Acute colonic pseudo-obstruction, or Ogilvie’s syndrome, occurs most often in geriatric patients (>65 years old) with underlying medical comorbidities although its exact mechanism has not been clearly identified. However, factors such as advanced age, polypharmacy and poor functional status contribute to increased risk for Ogilvie’s syndrome (Conner et al., 2022). While originally reported more than 70 years ago, there have been no systematic reviews of the condition, and it remains relatively infrequent. One randomized interventional trial identified 48 cases of Ogilvie’s over 10 years, predominantly in elderly men (Haj et al., 2018). Limited evidence to date favors conservative management with observation, gastric and/or rectal tube decompression, hydration, and electrolyte management over intervention with neostigmine, colonoscopy and/or surgery.
Case Presentation
A 78-year-old African American male was admitted to the Walter Reed National Military Medical Center with an acute heart failure exacerbation with pulmonary edema and volume overload.
His past medical history was significant for heart failure with preserved ejection fraction (HFpEF), aortic stenosis status/post transaortic valve replacement (TAVR), and atrial fibrillation. He was admitted to the cardiac care unit, treated with diuretics, and improved clinically over the next 4 days. He was started on an oral HId drug combination on hospital day 4 for improved management of his blood pressure, and also to reduce his mortality and morbidity risk associated with heart failure (Heidenreich et al., 2022). He then transitioned from the cardiac care unit to the general medicine ward to manage a pre-renal acute kidney injury that occurred during his resuscitation. The patient did not have a bowel movement for several days. On hospital day 9, he developed bloody stool, abdominal pain, and progressive abdominal distension. There was concern for bowel obstruction versus ileus with possible abdominal compartment syndrome. Figure 1 shows the patient’s hospital course.
The General Surgery team was consulted, and a non-contrast computed tomography (CT) scan of the chest and abdomen was obtained. At that time, the abdominal exam was reassuring without peritoneal signs. CT demonstrated diffuse large and small bowel dilatation without obvious transition point or mesenteric edema (Figure 2). There was no indication for acute surgical intervention. Laboratory evaluation demonstrated normal lactate (2 mmol/L) and thyroid stimulating hormone levels (TSH: 2.38 mIU/L), but elevated renal and liver function test levels (creatinine: 5.23 mg/dL, BUN: 109.6 mg/dL, AST: 57 U/L) over baseline values (creatinine: 2 mg/dL, BUN: 26 mg/dL, AST: 23 U/L). The patient developed cough and shortness of breath with decreased oxygen saturation (SaO2: 90%) at rest and with activity and the lung exam suggested bibasilar fluid collections. A Foley catheter was then introduced into the patient while awake to assess intrabdominal pressure. The elevated pressure reading (31 mmHg) was consistent with abdominal compartment syndrome, though the patient was neither sedated nor intubated, making the assessment less specific to accurately diagnose this syndrome. The most likely diagnosis was determined to be severe Ogilvie’s syndrome with possible secondary abdominal compartment syndrome since the clinical likelihood of the latter was determined to be very low.
Management
Nasogastric (NG) tube placement and flexible sigmoidoscopy with rectal tube placement for decompression were performed with significant palliation of abdominal pain and notable flatus with rectal tube placement. There was subsequent improvement in overall clinical status including decreased O2 requirement, euvolemia, improved renal and liver function tests, and return of bowel function. However, after rectal tube placement, the patient developed black, tarry stools. Pantoprazole 40 mg twice daily was added to the patient’s drug regimen due to concern for upper gastrointestinal bleed, while his chronic anticoagulation to prevent valvular thrombosis was held. The patient was made nothing by mouth (NPO) for bowel rest with intravenous fluids maintained for adequate hydration. The patient continued to have improved bowel function without reoccurrence of abdominal pain. He tolerated progression to clear liquids with NG and rectal tubes removed on hospital day 13. He was discharged to home on hospital day 14 after tolerating soft foods.
Outpatient medications at the time of admission included alfuzosin, amlodipine, apixaban, ascorbic acid, benazepril, cholecalciferol, docusate sodium, ferrous sulfate, furosemide, potassium chloride, simvastatin, sildenafil, multivitamins, and eye drops including ketorolac and prednisolone. Upon review of medications, there was concern that the Ogilvie’s syndrome was precipitated by HId. The HId combination drug was started on hospital day 4 for twice daily administration to maintain a systolic blood pressure less than 150 mmHg but discontinued on hospital day 9 for concerns it was contributing to paralytic ileus. This drug was the only new cardiovascular medication started during the patient’s admission. The patient remained on alfuzosin throughout admission, which may contribute to constipation but had no temporal relation to this patient’s onset of Ogilvie’s syndrome. Table 1 lists the patient’s outpatient and inpatient medications along with their relevant drug-drug interactions.
Discussion
There have been prior literature reports of paralytic ileus - alternatively referred to as Ogilvie’s syndrome in some sources – which are associated with hydralazine, isosorbide mononitrate, or isosorbide dinitrate use (Arbor Pharmaceuticals, LLC, 2019; Magdalan et al., 2004). Isosorbide mononitrate has greater oral bioavailability (close to 100%) than isosorbide dinitrate and it is also an active metabolite of the latter (AstraZeneca Canada Inc, 2008). Ogilvie’s syndrome has also been associated with scheduled administration of calcium-channel blockers, neuroleptics, antidepressants, dopaminergic medications, and opiates (Rondeau et al., 2001). Although our patient was taking amlodipine as an outpatient, this calcium-channel blocking drug was discontinued during their inpatient heart failure management. Alfuzosin can cause stomach pain but was considered an unlikely precipitating factor for this syndrome since it was a medication the patient was taking at home, and continued for the duration of his hospital stay.
In this unique case, initiation of HId for hypertension and heart failure may have precipitated, or at the very least, contributed to Ogilvie’s syndrome given the temporal association with symptom onset and HId use. That is, our strongest evidence for this appears to be that HId was the only new medication started prior to the onset of symptoms and resolved with dechallenge. Of note, the patient’s drug regimen does introduce several potential drug-drug interactions (Table 1); however, the interactions suggest a lack of clear association with the patient’s gastrointestinal symptoms. Since bowel rest and decompression are mainstays of treatment for Ogilvie’s syndrome, they surely contributed to its resolution.
Medication-induced Ogilvie’s syndrome is also plausible here given HId’s mechanisms of action. Isosorbide dinitrate is responsible for vascular smooth muscle relaxation and dilation of arteries and veins, while hydralazine selectively dilates arterial smooth muscle (NitroMed, 2005). The oral drug combination (i.e., BiDil) is marketed primarily for adjunctive treatment of heart failure in African American patients. The ability of HId to cause systemic vascular relaxation and dilation of peripheral vasculature may have contributed to colonic dilatation through venous pooling and fluid retention leading to local tissue edema. Both hydralazine and isosorbide dinitrate, as well as its active metabolites, may be eliminated more slowly in elderly patients, thus increasing its likelihood of contributing to Ogilvie’s syndrome in this patient (Arbor Pharmaceuticals, LLC, 2019).
While a clear mechanism of Ogilvie’s syndrome has not been identified, autonomic nervous system dysregulation and its impact on colonic motility are also likely culprits. To help facilitate colonic motility, acetylcholine is a stimulatory gastrointestinal neurotransmitter while nitrous oxide (N2O) and vasoactive intestinal peptide (VIP) are inhibitory to gastrointestinal motility (Daniels et al., 2015). Both isosorbide and hydralazine have anticholinergic properties and thus may have reduced the activity of acetylcholine relative to N2O and VIP levels (Conner et al., 2022; Green et al., 2019). Neostigmine therapy, which is often used to treat Ogilvie’s syndrome, is thought to reverse the parasympathetic dysregulation that occurs with drug-induced disease via reversible inhibition of acetylcholinesterase, allowing for increased strength of colonic musculature contractions (Neely et al., 2023). Notably, nitric oxide (NO) has also been reported to inhibit smooth muscle motility and contribute to ileus (Khawaja et al., 2022).
Conclusion
In summary, the at-risk patient population for Ogilvie’s syndrome is subject to the combination of significant medical comorbidities and polypharmacy. Therefore, characterizing the incidence of medication-induced Ogilvie’s syndrome, with medications such as HId, may help clinicians recognize this syndrome sooner while potentially providing insight into its exact pathophysiology.
Disclaimer
The contents of this article are the sole responsibility of the Authors and do not necessarily reflect the views, opinions, or policies of the United States Department of Defense (DoD).