Anesth Analg 2008; 107:1965-1967
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31818556d3
CRITICAL CARE AND TRAUMA
Reversal of Opioid-Induced Gastric Dysfunction in a Critically Ill Burn Patient After Methylnaltrexone
Michael Woo, MD,
Michael O'Connor, MD,
Chun-Su Yuan, MD, PhD, and
Jonathan Moss, MD, PhD
From the Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois.
Address correspondence and reprint requests to Jonathan Moss, MD, PhD, Department Anesthesia and Critical Care, The University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. Address e-mail to jm47{at}midway.uchicago.edu.
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Abstract
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Peripheral-acting mu opiate receptor antagonists have been extensively studied for the treatment of opiate-induced constipation in advanced illness for the prophylaxis of postoperative ileus. We document the first intensive care patient to receive methylnaltrexone in an attempt to facilitate enteral nutrition. Gastric residuals markedly decreased and enteral feeding increased after administration of IV methylnaltrexone. The patient's ileus resolved coincident with the first injection.
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Introduction
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Enteral nutrition is important in critically ill patients to promote healing. Many of these patients have decreased intestinal motility and gastric emptying. These gut effects can occur as a consequence of both the underlying disease (e.g., diabetic gastroparesis) and pharmacotherapy. Opioids, which are commonly used to treat pain and sedate in critically ill patients, can impede gastric motility1 and limit enteral nutrition.2,3 In addition to its impact on nutrition, gastrointestinal (GI) dysmotility in this setting has been associated with bacterial transmigration,4 pneumonia,5 and sepsis.6
Methylnaltrexone is a peripheral mu opioid receptor antagonist being developed for treatment of opioid-induced constipation in patients receiving palliative care and for prevention of postoperative ileus in patients undergoing open laparotomy.7 Methylnaltrexone has shown activity in reversing the peripheral effects of opioids but, because of its quaternary structure and positive charge, it has limited ability to cross the blood-brain barrier and therefore has not shown reversal of the central analgesic effects of opioids. In addition to its effects in reversing opioid-induced constipation when given subcutaneously to palliative care patients with advanced illness,8–10 volunteer studies with IV methylnaltrexone have demonstrated that it may reverse the effects of morphine on gastric emptying.11,12 We therefore reasoned that methylnaltrexone might play a useful role in facilitating enteral feeding in intensive care unit (ICU) patients receiving opioids. Although methylnaltrexone had been investigated in opioid-induced constipation and postoperative ileus, it had not been given to ICU patients to facilitate feeding. We report here our observations of a critically ill burn patient who received IV methylnaltrexone to accomplish this goal. Because of funding limitations we did not extend this study to other patients.
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CASE DESCRIPTION
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A 21-yr old-man (79 kg, 182 cm, body mass index 22.3) had been admitted to the ICU for a 30% total body surface area with partial and full thickness burn injury subsequent to house fire and explosion. The patient underwent excision and skin grafting in hospital on days 2 and 5, and was receiving 60–100 mg/d of morphine via continuous infusion and intermittent boluses. He was tracheally extubated on hospital day 8. Although enteral feeding was attempted with up to 1200 mL/d, gastric residuals of up to 700 mL/d prevented adequate nutrition. At our hospital, enteral nutrition is interrupted for gastric residuals of more than 150 mL over 4 h, or more than half of the volume of the previous intermittent feeding. We reasoned that methylnaltrexone would prevent interruptions in enteral feeding, especially in the face of a persistent opioid requirement. The patient had no bowel sounds until hospital day 9.
After approval from the University of Chicago IRB, the patient was enrolled into a trial of IV methylnaltrexone. In this study, methylnaltrexone (0.3 mg/kg) was to be infused over 10 min every 6 h for 2 days. He also continued to receive morphine, initially via a combination of infusion (up to 2 mg/h) and bolus, then bolus alone. In total he received eight doses of methylnaltrexone over 48 h on hospital days 9 and 10.
Flatus occurred immediately during the first infusion of methylnaltrexone, along with return of bowel sounds, which persisted over the next 48 h. Gastric residuals decreased from approximately 280 mL/d immediately before the trial to 0 mL/d. The patient was able to tolerate enteral feeds (Perative, Abbott Laboratories, 1.3 kcal/mL) and flushes of over 2400 mL/d. By hospital day 14, he was taking solid food by mouth. Methylnaltrexone did not elicit pain or withdrawal symptoms at any time.
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DISCUSSION
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Enteral feeding in the ICU is a high priority. Nutritional support is often difficult because of the diminished peristalsis resulting from the opioids that ICU patients receive, and the decreased GI motility that may be associated with their critical illness. Nutrition is particularly important for extensive burn injury patients, and enteral nutrition is preferable. Enteral nutrition maintains gut perfusion and integrity, promoting an immunologic barrier and preventing bacterial translocation.13 Enteral formulations may have immunomodulatory advantages and may lead to decreased infection rates.14 Additionally, enteral nutrition is much less expensive than parenteral nutrition and decreases the risk associated with central access and sepsis. In this patient, there was significant improvement of feeding, both by the amount of enteral nutrition that was possible and by the decreased gastric residuals (Fig. 1).
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Figure 1. Oral (PO) and nasogastric (NG) feeding and gastric residuals were measured and recorded during 12 h shifts over a 6 day period and recorded as mL. IV methylnaltrexone was initiated on day 2 and given as described in Methods.
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Previous studies with methylnaltrexone have demonstrated its ability to facilitate gastric emptying in volunteers receiving opioids.12 The acetaminophen test was used to document facilitation of gastric emptying in volunteers.12 In another volunteer study using impedance methodology,11 morphine increased gastric emptying time from 5 to 28 min. Upon receiving methylnaltrexone, the gastric emptying time returned to 7 min. These studies demonstrated that control of gastric emptying was mediated by peripheral mu-opioid receptors and therefore suggested that methylnaltrexone could be investigated to facilitate gastric emptying in the population of critically ill patients receiving opioid infusions.
Although feeding and residuals were the primary end-points of our study, it was remarkable that the patient's intestinal dysmotility resolved during the 10 min administration of methylnaltrexone, despite having 4 days of quiescent bowel. The effect of peripheral opioid antagonists on postoperative ileus is the subject of active investigation, although there are no reports of their use in the ICU setting. Several studies using the oral peripheral opioid antagonist, alvimopan, have demonstrated significant benefit after GI surgery.15–17 IV methylnaltrexone was shown to facilitate recovery of bowel function and hospital discharge in a small study of 65 open colectomy patients,18 although results of an international study of 542 patients undergoing colectomy did not achieve the primary end-point, a reduction in time to recovery of GI function (time to first bowel movement) compared to placebo. Although the purpose of this study was to determine whether methylnaltrexone could be used to augment feeding in ICU patients, the ability to reverse ileus and enhance intestinal motility in patients with high doses of opioids is consistent with the overall action of the drug. One recent study demonstrated that early defecation was associated with decreased length of stay in ICU patients.19
Our observations of facilitated feeding and resolution of ileus in this patient suggest further study of methylnaltrexone in this clinical setting is warranted.
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Footnotes
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Accepted for publication May 7, 2008.
Dr. Moss serves as a paid consultant to Progenics Pharmaceuticals, has a financial interest in methylnaltrexone as a patent holder through the University of Chicago, and receives stock options from Progenics.
Methylnaltrexone was originally formulated and subsequently modified by faculty at the University of Chicago. It is currently being developed by Progenics Pharmaceuticals and Wyeth Pharmaceuticals, for which Dr. Yuan serves as a consultant. The University of Chicago and Dr. Yuan stand to benefit financially from the development of methylnaltrexone.
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Abstract
Introduction
