Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model

Abstract

Objectives: Analgesia and sedation are common therapies in pediatric critical care, and rapid titration of these medications is associated with iatrogenic withdrawal syndrome. We performed a systematic review of the literature to identify all common and salient risk factors associated with iatrogenic withdrawal syndrome and build a conceptual model of iatrogenic withdrawal syndrome risk in critically ill pediatric patients.

Data sources: Multiple databases, including PubMed/Medline, EMBASE, CINAHL, and the Cochrane Central Registry of Clinical Trials, were searched using relevant terms from January 1, 1980, to August 1, 2014.

Study selection: Articles were included if they were published in English and discussed iatrogenic withdrawal syndrome following either opioid or benzodiazepine therapy in children in acute or intensive care settings. Articles were excluded if subjects were neonates born to opioid- or benzodiazepine-dependent mothers, children diagnosed as substance abusers, or subjects with cancer-related pain; if data about opioid or benzodiazepine treatment were not specified; or if primary data were not reported.

Data extraction: In total, 1,395 articles were evaluated, 33 of which met the inclusion criteria. To facilitate analysis, all opioid and/or benzodiazepine doses were converted to morphine or midazolam equivalents, respectively. A table of evidence was developed for qualitative analysis of common themes, providing a framework for the construction of a conceptual model. The strongest risk factors associated with iatrogenic withdrawal syndrome include duration of therapy and cumulative dose. Additionally, evidence exists linking patient, process, and system factors in the development of iatrogenic withdrawal syndrome.

Findings: Most articles were prospective observational or interventional studies.

Conclusions: Given the state of existing evidence, well-designed prospective studies are required to better characterize iatrogenic withdrawal syndrome in critically ill pediatric patients. This review provides data to support the construction of a conceptual model of iatrogenic withdrawal syndrome risk that, if supported, could be useful in guiding future research.

Figure 1

Systematic search and selection process

Figure 2

Proportion of subjects with IWS relative to the total number of subjects among included studies (Mixed includes studies where the subjects received both opioids and benzodiazepines.)

Figure 3

Risk for Iatrogenic Withdrawal Syndrome (IWS). Conceptual model relating three levels of risk factors for IWS in critically ill children

Figure 4

Cross-study comparison of duration of opioid therapy in opioid-only and mixed agent (i.e. opioid and benzodiazepine administration) studies, among subjects with IWS Reference for 5 day threshold: Katz, Kelly, & Hsi (1994)

Figure 5

Cross-study comparison of duration of benzodiazepine therapy among subjects with IWS *Duration includes medication taper. **Reported duration only applies to nine patients receiving lorazepam. ***Authors did not specify medication for the listed duration of sedation. Reference for 10 day threshold: Ista, et al. (2008)

Figure 6

Cross-study comparison of cumulative dose of opioids among subjects with IWS *Provided dose range for total study group, not IWS subjects specifically. **Values not calculated in original study. Reference for 106.7 mg/kg (morphine equivalents) threshold: Arnold, Truog, & Orav (1994)

Figure 7

Cross-study comparison of cumulative dose of benzodiazepines among subjects with IWS *Values not calculated in original study. **Provided dose range for total study group, not IWS subjects specifically. Reference for 60 mg/kg (midazolam equivalents) threshold: Fonsmark, Rasmussen, & Carl (1999)