Article

Outcomes and Adverse Effects With Peramivir for the Treatment of Influenza H1N1 in Critically Ill Pediatric Patients

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Abstract

OBJECTIVES Influenza is an environmental pathogen and infection presents as a range from asymptomatic to fulminant illness. Though treatment is supportive, antiviral agents have a role in the management of infection. Pediatric use of peramivir is largely based on reports and extrapolations of pharmacokinetic data. We seek to describe efficacy and safety of peramivir in critically ill pediatric patients. METHODS This is a retrospective, institutional review board–approved chart review of all patients under 21 years of age, admitted to the PICU, and treated with peramivir for influenza H1N1 infection between January 1, 2016, and March 31, 2016, at a single-center, 12-bed PICU. The primary outcome was time to sustained resolution of fever; secondary outcomes included dose, duration, and adverse effects of peramivir therapy. RESULTS Seven patients were included with median age of 3.7 years. Median time to sustained resolution of fever was 49.3 hours, median duration of mechanical ventilation was 14.2 days, median ICU LOS was 18.7 days, and hospital LOS was 24.7 days. No patients suffered mortality. Three patients experienced leukopenia, one of which experienced a concurrent neutropenia. Three patients experienced hyperglycemia, 2 experienced hypertension, 1 experienced increased aspartate aminotransferase and increased alanine aminotransferase, and 1 experienced diarrhea. All adverse events assessed were classified as possible using published adverse event causality assessments. CONCLUSIONS Peramivir has been shown to be an effective therapy for the treatment of influenza H1N1 in critically ill pediatric patients. In our experience with 7 pediatric patients, peramivir was well tolerated at typical durations of therapy; however, increased vigilance is warranted during prolonged courses or in patients with reasons for altered pharmacokinetics and pharmacodynamics.

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... [40][41][42][43][44][45][46] In some studies, peramivir shortened median duration of fever and fasten viral titers reduction. 29,31,47 Moreover, a small number of studies assessed its efficacy and safety in specific populations such as pediatric patients, 29,48 and patients with diabetes, chronic respiratory diseases, and those exposed to immunosuppressive therapy, 41 finding no serious adverse events linked to peramivir administration and no meaningful modification of clinical outcomes related to different dosage (►Table 4). ...
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  • C Paules
  • K Subbarao
  • Influenza
Paules C, Subbarao K. Influenza. Lancet. 2017;390(10095): 697-708.
  • N J Cox
  • K Subbarao
Cox NJ, Subbarao K. Influenza. Lancet. 1999;354(9186): 1277-1282.
Pediatric and neonatal Lexi-drugs
  • Lexicomp Online
Lexicomp Online. Pediatric and neonatal Lexi-drugs. Hudson, OH: 2017. online.lexi.com. Accessed December 26, 2017.