title: Opioid and Benzodiazepine Withdrawal Syndrome in PICU Patients: Which Risk Factors Matter?
abstract: OBJECTIVE
  Although iatrogenic withdrawal syndrome (IWS) has been recognized in patients exposed to opioids and benzodiazepines, very few studies have used a validated tool for diagnosis and assessment of IWS in critically ill children. We sought to determine IWS rate, risk factors, and outcomes of IWS patients.
  
  
  METHODS
  Prospective observational study conducted in a pediatric intensive care unit. A total of 137 patients (31 with IWS and 106 with no IWS) received a continuous infusion of fentanyl and midazolam for 3 or more days. The Sophia Observation withdrawal Symptoms scale was repeatedly applied when children were weaned off sedation/analgesia.
  
  
  RESULTS
  The overall incidence of IWS was 22.6%. Of the 31 IWS patients, 6 showed IWS with less than 5 days sedation or analgesia. Logistic regression showed that the median peak dose of midazolam was associated with IWS development (odds ratio 1.4). Receiver-operating curve showed a cut-off value of 0.35 mg/kg/h for midazolam peak dose (sensitivity 96.7%, specificity 51%, positive predictive value 36.6%, and negative predictive value 98.2%), with area under the curve of 0.80. IWS patients had a longer time on mechanical ventilation, prolonged pediatric intensive care unit, and hospital stays, and required prolonged period to have drugs discontinued.
  
  
  CONCLUSIONS
  Although length of sedation/analgesia for at least5 days has been widely proposed for monitoring IWS, our data suggest that initiating monitoring after 3 sedation days is highly recommended. In addition, patients requiring infusion rates of midazolam above 0.35 mg/kg/h should be considered at high risk for IWS.
authors.affiliation: Pediatric Intensive Care Unit, Department of Pediatrics, Hospital do Servidor Público Municipal, São Paulo, Brazil (PSLS); Hospital e Maternidade Santa Joana, São Paulo, Brazil (MER); Faculdade de Medicina do ABC, Santo André, Brazil (TSMF); Health Technologies Assessment Center - Federal University of São Paulo, São Paulo, Brazil (MCMF).
authors.forename: Paulo Sérgio Lucas
authors.initials: PS
authors.lastname: da Silva
authors.forename: Maria Eunice
authors.initials: ME
authors.lastname: Reis
authors.forename: Thais Suelotto Machado
authors.initials: TS
authors.lastname: Fonseca
authors.forename: Marcelo Cunio Machado
authors.initials: MC
authors.lastname: Fonseca
mesh_terms: D000293:Adolescent; D000701:Analgesics, Opioid / Q000009:adverse effects; D001569:Benzodiazepines / Q000009:adverse effects; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D003422:Critical Care / Q000379:methods*; D005260:Female; D005283:Fentanyl / Q000009:adverse effects*; D006801:Humans; D007049:Iatrogenic Disease / Q000453:epidemiology*; D015994:Incidence; D007223:Infant; D015278:Intensive Care Units, Pediatric; D008297:Male; D008874:Midazolam / Q000009:adverse effects*; D011446:Prospective Studies; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome / Q000453:epidemiology*
chemical_list: D000701:Analgesics, Opioid; D001569:Benzodiazepines; D008874:Midazolam; D005283:Fentanyl