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Strategies for the Prevention and Treatment of Iatrogenic Withdrawal from Opioids and Benzodiazepines in Critically Ill Neonates, Children and Adults: A Systematic Review of Clinical Studies.

ABSTRACT: BACKGROUND:Critically ill patients are at high risk of iatrogenic withdrawal syndrome (IWS), due to exposure to high doses or prolonged periods of opioids and benzodiazepines. PURPOSE:To examine pharmacological management strategies designed to prevent and/or treat IWS from opioids and/or benzodiazepines in critically ill neonates, children and adults. METHODS:We included non-randomised studies of interventions (NRSI) and randomised controlled trials (RCTs), reporting on interventions to prevent or manage IWS in critically ill neonatal, paediatric and adult patients. Database searching included: PubMed, CINAHL, Embase, Cochrane databases, TRIP, CMA Infobase and NICE evidence. Additional grey literature was examined. Study selection and data extraction were performed in duplicate. Data collected included: population, definition of opioid, benzodiazepine or mixed IWS, its assessment and management (drug or strategy, route of administration, dosage and titration), previous drug exposures and outcomes measures. Methodological quality assessment was performed by two independent reviewers using the Cochrane risk of bias tool for RCTs and the ROBINS-I tool for NRSI. A qualitative synthesis of the results is provided. For the subset of studies evaluating multifaceted protocolised care, we meta-analysed results for 4 outcomes and examined the quality of evidence using GRADE post hoc. RESULTS:Thirteen studies were eligible, including 10 NRSI and 3 RCTs; 11 of these included neonatal and paediatric patients exclusively. Eight studies evaluated multifaceted protocolised interventions, while 5 evaluated individual components of IWS management (e.g. clonidine or methadone at varying dosages, routes of administration and duration of tapering). IWS was measured using an appropriate tool in 6 studies. Ten studies reported upon occurrence of IWS, showing significant reductions (n?=?4) or no differences (n?=?6). Interventions failed to impact duration of mechanical ventilation, ICU length of stay, and adverse effects. Impact on opioid and/or benzodiazepine total doses and duration showed no differences in 4 studies, while 3 showed opioid and benzodiazepine cumulative doses were significantly reduced by 20-35% and 32-66%, and treatment durations by 1.5-11 and 19 days, respectively. Variable effects on intervention drug exposures were found. Weaning durations were reduced by 6-12 days (n?=?4) for opioids and/or methadone and by 13 days (n?=?1) for benzodiazepines. In contrast, two studies using interventions centred on transition to enteral routes or longer tapering durations found significant increases in intervention drug exposures. Interventions had overall non-significant effects on additional drug requirements (except for one study). Included studies were at high risk of bias, relating to selection, detection and reporting bias. CONCLUSION:Interventions for IWS management fail to impact duration of mechanical ventilation or ICU length of stay, while effect on occurrence of IWS and drug exposures is inconsistent. Heterogeneity in the interventions used and methodological issues, including inappropriate and/or subjective identification of IWS and bias due to study design, limited the conclusions.

SUBMITTER: Sneyers B

PROVIDER: S-EPMC7317263 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Strategies for the Prevention and Treatment of Iatrogenic Withdrawal from Opioids and Benzodiazepines in Critically Ill Neonates, Children and Adults: A Systematic Review of Clinical Studies.

Sneyers Barbara B Duceppe Marc-Alexandre MA Frenette Anne Julie AJ Burry Lisa D LD Rico Philippe P Lavoie Annie A Gélinas Céline C Mehta Sangeeta S Dagenais Maryse M Williamson David R DR Perreault Marc M MM

Drugs 20200801 12

<h4>Background</h4>Critically ill patients are at high risk of iatrogenic withdrawal syndrome (IWS), due to exposure to high doses or prolonged periods of opioids and benzodiazepines.<h4>Purpose</h4>To examine pharmacological management strategies designed to prevent and/or treat IWS from opioids and/or benzodiazepines in critically ill neonates, children and adults.<h4>Methods</h4>We included non-randomised studies of interventions (NRSI) and randomised controlled trials (RCTs), reporting on in ...[more]

PMID: 32592134

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Project description: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.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.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.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.Most articles were prospective observational or interventional studies.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.

Project description:IntroductionSmoking is highly addictive, and nicotine abstinence is associated with withdrawal syndrome in hospitalized patients. In this study, we aimed to evaluate the impact of sudden nicotine abstinence on the development of agitation and delirium, and on morbidities and outcomes in critically ill patients who required respiratory support, either noninvasive ventilation or intubation, and mechanical ventilation.MethodsWe conducted a prospective, observational study in two intensive care units (ICUs). The 144 consecutive patients admitted to ICUs and requiring mechanical ventilation for >48 hours were included. Smoking status was assessed at ICU admission by using the Fagerström Test of Nicotine Dependence (FTND). Agitation, with the Sedation-Agitation Scale (SAS), and delirium, with the Intensive Care Delirium Screening Checklist (ICDSC), were tested twice daily during the ICU stay. Agitation and delirium were defined by SAS >4 and ICDSC >4, respectively. Nosocomial complications and outcomes were evaluated.ResultsSmokers (n = 44) were younger and more frequently male and were more likely to have a history of alcoholism and to have septic shock as the reason for ICU admission than were nonsmokers. The incidence of agitation, but not delirium, increased significantly in the smoker group (64% versus 32%; P = 0.0005). Nicotine abstinence was associated with higher incidences of self-removal of tubes and catheters, and with more interventions, including the need for supplemental sedatives, analgesics, neuroleptics, and physical restraints. Sedation-free days, ventilator-free days, length of stay, and mortality in ICUs did not differ between groups. Multivariate analysis identified active smoking (OR, 3.13; 95% CI, 1.45-6.74; P = 0.003) as an independent risk factor for agitation. Based on a subgroup of 56 patients, analysis of 28 pairs of patients (smokers and nonsmokers in a 1:1 ratio) matched for age, gender, and alcoholism status found similar results regarding the role of nicotine withdrawal in increasing the risk of agitation during an ICU stay.ConclusionsNicotine withdrawal was associated with agitation and higher morbidities in critically ill patients. These results suggest the need to look specifically at those patients with tobacco dependency by using the FTND in ICU settings. Identifying patients at risk of behavioral disorders may lead to earlier interventions in routine clinical practice.

Project description:BackgroundResearch on acute kidney injury (AKI) has focused on identifying early biomarkers. However, whether AKI could be diagnosed in the absence of the classic signs of clinical AKI and whether the condition of subclinical AKI, identified by damage or functional biomarkers in the absence of oliguria or increased serum creatinine (sCr) levels, is clinically significant remains to be elucidated in critically ill children. The aims of the study were to investigate the associations between urinary cystatin C (uCysC) levels and AKI and mortality and to determine whether uCysC-positive subclinical AKI is associated with adverse outcomes in critically ill neonates and children.MethodsIn this prospective cohort study, uCysC levels were serially measured during the first week after intensive care unit (ICU) admission in a heterogeneous group of patients (n = 510) presenting to a tertiary neonatal and pediatric ICU. The diagnosis of neonatal AKI that developed during the first week after admission was based on neonatal KDIGO criteria or sCr >1.5 mg/dL, and pediatric AKI was based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The term "uCysC(-)" or "uCysC(+)", indicating the absence or presence of tubular injury, was defined by the optimal peak uCysC cutoff value for predicting ICU mortality.ResultsThe initial and peak uCysC levels were significantly associated with AKI and mortality, and had an area under the receiver operating characteristic curve of 0.76 and 0.81, respectively, for predicting mortality. At the optimal cutoff value of 1260 ng/mg uCr, the peak uCysC displayed sensitivity of 79.2% and specificity of 72.3% for predicting mortality. Among all patients, 130 (25.5%) developed uCysC(+)/AKI(-) status during the first week after admission. The adjusted odds ratio for patients with uCysC(+)/AKI(-) status in association with an increased risk of mortality compared with that for patients with uCysC(-)/AKI(-) was 9.34 (P <?0.001). Patients with uCysC(+)/AKI(-) spent 2.8 times as long in the ICU as those with uCysC(-)/AKI(-) (P <?0.001).ConclusionsBoth initial and peak uCysC levels are associated with AKI and mortality and are independently predictive of mortality in critically ill neonates and children. Subclinical AKI may occur without detectable loss of kidney function, and uCysC-positive subclinical AKI is associated with worse clinical outcomes in this population.

Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyteÂ® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyteÂ® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyteÂ® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyteÂ® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyteÂ® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyteÂ® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator

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Strategies for the Prevention and Treatment of Iatrogenic Withdrawal from Opioids and Benzodiazepines in Critically Ill Neonates, Children and Adults: A Systematic Review of Clinical Studies.

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Strategies for the Prevention and Treatment of Iatrogenic Withdrawal from Opioids and Benzodiazepines in Critically Ill Neonates, Children and Adults: A Systematic Review of Clinical Studies.

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