Objective Analgesia and sedation are common therapies in pediatric critical care, and rapid titration of these medications is associated with iatrogenic withdrawal syndrome (IWS). We performed a systematic review of the literature to identify all common and salient risk factors associated with IWS and build a conceptual model of IWS 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 IWS 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 and synthesis In total 1395 papers 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 IWS include duration of therapy and cumulative dose. Additionally, evidence exists linking patient, process and system factors in the development of IWS. Findings Most papers were prospective observational or interventional studies. Conclusions Given the state of existing evidence, well-designed prospective studies are required to better characterize IWS in critically ill pediatric patients. This review provides data to support the construction of a conceptual model of IWS risk that, if supported, could be useful in guiding future research.

Iatrogenic withdrawal syndrome is common in children recovering from critical illness, and several risk factors are predictive, including patient characteristics, sedative exposure, additional sedative agents, and system-level factors. High-risk patients could be identified before weaning to better prevent iatrogenic withdrawal syndrome among at-risk patients.

Traumatic brain injury (TBI) is associated with aberrant network hyperexcitability in the dentate gyrus. GABA A ergic parvalbumin-expressing interneurons (PV-INs) in the dentate gyrus regulate network excitability with strong, perisomatic inhibition, though the post-traumatic effects on PV-IN function after TBI are not well understood. In this study, we investigated physiological alterations in PV-INs one week after mild lateral fluid percussion injury (LFPI) in mice. PV-IN cell loss was observed in the dentate hilus after LFPI, with surviving PV-INs showing no change in intrinsic membrane properties. Whole-cell voltage clamp recordings in PV-INs revealed alterations in both excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs). Evoked EPSCs in PV-INs from perforant path electrical stimulation were diminished after injury but could be recovered with application of a GABA A-receptor antagonist. Furthermore, currentclamp recordings using minimal perforant path stimulation demonstrated a decrease in evoked PV-IN action potentials after LFPI, which could be restored by blocking GABA A ergic inhibition. Together, these findings suggest that injury alters synaptic input onto PV-INs, resulting in a net inhibitory effect that reduces feedforward PV-IN activation in the dentate gyrus. Decreased PV-IN activation suggests a potential mechanism of dentate gyrus network hyperexcitability contributing to hippocampal dysfunction after TBI. Significance Statement Traumatic brain injury (TBI) damages the hippocampus and causes long-lasting memory deficits. After TBI, the dentate gyrus, a crucial regulator of cortical input to the hippocampus, undergoes a dysfunctional net increase in excitation, though the circuit mechanisms underlying this network excitatory-inhibitory (E/I) imbalance are unclear. In this study, we found that TBI alters synaptic inputs onto an inhibitory interneuron population (PV-INs) in the dentate gyrus which results in 3 the decreased firing activity of these neurons due to a net inhibitory influence. The inhibition of PV-INs demonstrates a potential mechanism contributing to dentate gyrus network hyperexcitability and hippocampal dysfunction after TBI.

Objective To characterize sedation weaning patterns in typical practice settings among children recovering from critical illness. Design A descriptive secondary analysis of data that were prospectively collected during the pre-randomization phase (January to July 2009) of a clinical trial of sedation management. Setting Twenty-two pediatric intensive care units across the United States. Patients The sample included 145 patients, aged 2 weeks to 17 years, mechanically ventilated for acute respiratory failure who received ≥5 consecutive days of opioid exposure. Measurements and Main Results Group comparisons were made between patients with an intermittent weaning pattern, defined as a ≥20% increase in daily opioid dose after the start of weaning, and the remaining patients defined as having a steady weaning pattern. Demographic and clinical characteristics, tolerance to sedatives, and iatrogenic withdrawal symptoms were evaluated. Sixty-six patients (46%) were intermittently weaned; 79 patients were steadily weaned. Prior to weaning, intermittently weaned patients received higher peak and cumulative doses and longer exposures to opioids and benzodiazepines, demonstrated more sedative tolerance (58% vs. 41%), and received more chloral hydrate and barbiturates compared to steadily weaned patients. During weaning, intermittently weaned patients assessed for withdrawal had a higher incidence of Withdrawal Assessment Tool-Version 1 scores ≥3 (85% vs. 46%) and received more sedative classes compared to steadily weaned patients. Conclusions This study characterizes sedative administration practices for pediatric patients prior to and during weaning from sedation after critical illness. It provides a novel methodology for describing weaning in an at-risk pediatric population that may be helpful in future research on weaning strategies to prevent iatrogenic withdrawal syndrome.

Objective: To compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy. Study design: This study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit (PICU) and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category (PCPC) ≥3 were defined as CI subjects, and differences between groups were explored using regression methods accounting for PICU as a cluster variable. Results: This study identified 412 subjects (17%) with CI. Compared with NT subjects, CI subjects were older (median, years, 6.2 vs 1.4; P<.001) with more severe pediatric acute respiratory distress syndrome (40% vs 33%; P=.009). They received significantly lower cumulative doses of opioids (median, mg/kg, 14.2 vs 16.2; P<.001) and benzodiazepines (10.6 vs 14.4; P<.001). Three non-verbal CI subjects received no analgesia or sedation. Subjects with CI were assessed as having more study days awake and calm and fewer study days with an episode of pain. They were less likely to be assessed as having inadequate pain/sedation management or unplanned endotracheal/invasive tube removal. CI subjects had more documented iatrogenic withdrawal symptoms than NT subjects. Conclusions: Subjects with CI in this study received less medication, but it is unclear whether they have authentically lower analgesic and/or sedative requirements or are vulnerable to inadequate assessment of discomfort due to the lack of validated assessment tools. We recommend the development of pain and sedation assessment tools specific to this patient population.

No abstract

No abstract

No abstract