The

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but also because HEV infection has recently been Jacques Izopet, Pharm.D., Ph.D. associated with several neurologic symptoms, CHU Purpan such as Guillain–Barré syndrome and neuralgic Toulouse, France Since publication of their article, the authors report no furamyotrophy, in immunocompetent patients.3 ther potential conflict of interest. However, the concentration of anti-HEV antibody 1. Brochot E, Bodeau S, Nguyen-Khac E, Duverlie G. DHEA and that can protect immunocompromised patients progesterone have a protective effect on ribavirin-induced hemolysis. J Hepatol 2014;60:897-8. against infection remains to be determined.4 2. Vanrenterghem Y, Ponticelli C, Morales JM, et al. Prevalence

Nassim Kamar, M.D., Ph.D. Centre Hospitalier Universitaire (CHU) Rangueil Toulouse, France [email protected]

Vincent Mallet, M.D., Ph.D. Institut Cochin Paris, France

and management of anemia in renal transplant recipients: a European survey. Am J Transplant 2003;3:835-45. 3. Kamar N, Dalton HR, Abravanel F, Izopet J. Hepatitis E virus infection. Clin Microbiol Rev 2014;27:116-38. 4. Abravanel F, Lhomme S, Chapuy-Regaud S, et al. Hepatitis E virus reinfections in solid-organ-transplant recipients can evolve into chronic infections. J Infect Dis 2014 March 11 (Epub ahead of print). DOI: 10.1056/NEJMc1405191

Sirolimus in Severe Hyperinsulinemic Hypoglycemia To the Editor: The study by Senniappan et al. (March 20 issue)1 shows that four infants with severe hyperinsulinemic hypoglycemia had a clear glycemic response to sirolimus, and there were no major adverse events during 1 year of followup. Toxic effects on the lung have been recognized as an underlying complication with sirolimus therapy, particularly in persons with immunodeficiency.2 In the study by Senniappan et al., the monitoring of adverse events associated with sirolimus therapy did not include monitoring of lung function. In addition, because sirolimus is an immunosuppressive agent, its longterm use will probably induce certain adverse effects of immunosuppression. Consequently, 1 year of follow-up seems insufficient to us. Song Mao, M.D., Ph.D. Aihua Zhang, M.D., Ph.D. Songming Huang, M.D., Ph.D. Nanjing Children’s Hospital Nanjing, China No potential conflict of interest relevant to this letter was reported. 1. Senniappan S, Alexandrescu S, Tatevian N, et al. Sirolimus

therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014;370:1131-7. 2. Molinari L, Rosenbaum T, Aruj P, et al. Sirolimus-associated interstitial pneumonia in four renal transplant recipients. Chest 2014;145:630A. abstract. DOI: 10.1056/NEJMc1404716

children undergoing renal transplantation, and to our knowledge there have been no reports of increased toxic effects on the lung in these children. The risk of toxic effects on the lung with mTOR inhibitors is increased among elderly patients with impaired pretreatment pulmonary function or a history of lung disease.1 Monitoring of pulmonary function is recommended in patients with underlying lung disease who are receiving mTOR inhibitors.2 In our study, we closely monitored patients for respiratory symptoms, and no adverse effect on respiratory function has so far been observed. Because sirolimus can induce immunosuppression, we continue to monitor the patients in our study very closely, which includes measurement of neutrophil and lymphocyte counts. To date we have not observed any abnormalities in these levels or any adverse events resulting from immunosuppression. We agree that long-term follow-up will be essential to identify potential risks. We aim to taper and ultimately discontinue treatment with sirolimus, since the natural history of the disease indicates that most forms of hyperinsulinism become milder over time. Senthil Senniappan, M.D., Ph.D. University College London Institute of Child Health London, United Kingdom

Robert E. Brown, M.D. The Authors Reply: The mammalian target of rapamycin (mTOR) inhibitors are widely used in 2448

University of Texas Medical School Houston, TX

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correspondence 1. Bernard V, Lombard-Bohas C, Taquet MC, et al. Efficacy of

Khalid Hussain, M.D. University College London Institute of Child Health London, United Kingdom [email protected] Since publication of their article, the authors report no further potential conflict of interest.

everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur J Endocrinol 2013;168:665-74. 2. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol 2009;4:135-42. DOI: 10.1056/NEJMc1404716

Nutrition in the Acute Phase of Critical Illness To the Editor: With respect to the article by Casaer and Van den Berghe (March 27 issue)1 on nutrition in the acute phase of critical illness: we suggest the use of the peripherally acting μ opiate antagonist methylnaltrexone bromide (Relistor, Salix Pharmaceuticals) to facilitate enteral nutrition in patients in the intensive care unit (ICU) who are receiving mu opiates for analgesia and sedation.2,3 This agent has been approved for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care when standard agents prove inadequate. However, we and others have used it in critically ill patients in the burn unit, the cardiovascular unit, and the medical ICU to facilitate upper and lower gastrointestinal motility.4,5 In our own retrospective study,4 six of seven patients without bowel motility for 3 to 5 days had almost instant restoration of bowel function after the subcutaneous administration of methyl­ naltrexone — 3.5 days before eight patients who received conventional therapy. There was also a clinically significant effect on gastric residuals. We believe that there is justification for a prospective study designed to determine whether methylnaltrexone facilitates feeding in these critically ill patients. Jonathan Moss, M.D., Ph.D. University of Chicago Chicago, IL [email protected]

Parind Patel, M.B., B.S. Imperial College London, United Kingdom Dr. Moss reports receiving consulting fees from Progenics Pharmaceuticals and Salix Pharmaceuticals and receiving royalties through the University of Chicago. No other potential conflict of interest relevant to this letter was reported.

3. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guide-

lines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263-306. 4. Sawh SB, Selvaraj IP, Danga A, Cotton AL, Moss J, Patel PB. Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients. Mayo Clin Proc 2012;87:255-9. 5. Hewitt K, Lin H, Faraklas I, Morris S, Cochran A, Saffle J. Use of methylnaltrexone to induce laxation in acutely injured patients with burns and necrotizing soft-tissue infections. J Burn Care Res 2014;35(2):e106-e111. DOI: 10.1056/NEJMc1404896

To the Editor: Body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) can be used to select patients for nutrition support. In a prospective, observational study1 of more than 2700 patients who were receiving mechanical ventilation, an increase of 1000 calories per day reduced mortality and increased the number of ventilator-free days; these effects were seen only in patients with a BMI of 35 or more or less than 25. No benefit was seen in patients with a BMI in the range between 25 and less than 35. A prospective, randomized trial2 showed that the administration of parenteral nutrition in severely malnourished patients reduced noninfectious surgical complications. The article by Casaer and Van den Berghe cites five studies with conflicting results. None of these studies were stratified according to BMI. I interpret these data to mean that patients with high or low BMIs, as noted above, should receive nutritional supplementation, whereas those in the middle range should receive no or minimal nutrition support for the first 7 days of their illness. James M. Cohen, M.D., C.N.S.P.

1. Casaer MP, Van den Berghe G. Nutrition in the acute phase

Memorial Regional Hospital Hollywood, FL [email protected] No potential conflict of interest relevant to this letter was reported.

2. Moss J, Rosow CE. Development of peripheral opioid antag-

1. Alberda C, Gramlich L, Jones N, et al. The relationship be-

of critical illness. N Engl J Med 2014;370:1227-36.

onists’ new insights into opioid effects. Mayo Clin Proc 2008; 83:1116-30.

tween nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study.

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Sirolimus in severe hyperinsulinemic hypoglycemia.

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