International Analgesia and Sedation Weaning and Withdrawal Practices in Critically Ill Adults: The Adult Iatrogenic Withdrawal Study in the ICU.

OBJECTIVES: Iatrogenic withdrawal syndrome (IWS) associated with opioid and sedative use for medical purposes has a reported high prevalence and associated morbidity. This study aimed to determine the prevalence, utilization, and characteristics of opioid and sedative weaning and IWS policies/protocols in the adult ICU population. DESIGN: International, multicenter, observational, point prevalence study. SETTING: Adult ICUs. PATIENTS: All patients aged 18 years and older in the ICU on the date of data collection who received parenteral opioids or sedatives in the previous 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ICUs selected 1 day for data collection between June 1 and September 30, 2021. Patient demographic data, opioid and sedative medication use, and weaning and IWS assessment data were collected for the previous 24 hours. The primary outcome was the proportion of patients weaned from opioids and sedatives using an institutional policy/protocol on the data collection day. There were 2,402 patients in 229 ICUs from 11 countries screened for opioid and sedative use; 1,506 (63%) patients received parenteral opioids, and/or sedatives in the previous 24 hours. There were 90 (39%) ICUs with a weaning policy/protocol which was used in 176 (12%) patients, and 23 (10%) ICUs with an IWS policy/protocol which was used in 9 (0.6%) patients. The weaning policy/protocol for 47 (52%) ICUs did not define when to initiate weaning, and the policy/protocol for 24 (27%) ICUs did not specify the degree of weaning. A weaning policy/protocol was used in 34% (176/521) and IWS policy/protocol in 9% (9/97) of patients admitted to an ICU with such a policy/protocol. Among 485 patients eligible for weaning policy/protocol utilization based on duration of opioid/sedative use initiation criterion within individual ICU policies/protocols 176 (36%) had it used, and among 54 patients on opioids and/or sedatives ≥ 72 hours, 9 (17%) had an IWS policy/protocol used by the data collection day. CONCLUSIONS: This international observational study found that a small proportion of ICUs use policies/protocols for opioid and sedative weaning or IWS, and even when these policies/protocols are in place, they are implemented in a small percentage of patients.

Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system for augmented renal clearance prediction in a trauma subgroup of a mixed ICU population.

WHAT IS KNOWN AND OBJECTIVE: Augmented renal clearance is prevalent in trauma patients and leads to subtherapeutic levels of renally eliminated medications with potentially unfavourable clinical outcomes. The Augmented Renal Clearance of Trauma in Intensive Care (ARCTIC) score has been developed to predict augmented renal clearance in critically ill trauma patients. Our primary objective was to validate this score among the trauma subgroup of a mixed intensive care patient cohort. METHODS: This single-centre, retrospective, observational cohort study assessed augmented renal clearance using a timed 24-h urine collection performed weekly. ARC was defined as a measured creatinine clearance of ≥130 ml/min/1.73 m2 . ARCTIC score performance was evaluated through a receiver operator characteristic curves and analysis of sensitivities and specificities for the trauma subgroup, the medical/surgical subgroup and the pooled cohort. RESULTS AND DISCUSSION: Augmented renal clearance was observed in 33.9% (n = 58) of trauma patients (n = 171) and 15.7% (n = 24) of medical/surgical patients (n = 153). Examination of different cutoffs for the ARCTIC score in our trauma population confirmed that the optimal cutoff score was ≥6. Comparison between ROC curves for ARCTIC score and for regression model based upon our data in trauma patients indicated validation of the score in this subgroup. Comparison of sensitivities and specificities for ARCTIC score between trauma (93.1% and 41.6%, respectively) and medical/surgical subjects (87.5% and 49.6%, respectively) showed no clinical nor statistical difference, suggesting validation for the medical/surgical subgroup as well. WHAT IS NEW AND CONCLUSION: In our mixed ICU population, the ARCTIC score was validated in the trauma subgroup. We also found that the score performed well in the medical/surgical population. Future studies should assess the performance of the ARCTIC score prospectively.

A systematic review of interventions to facilitate extubation in patients difficult-to-wean due to delirium, agitation, or anxiety and a meta-analysis of the effect of dexmedetomidine.

BACKGROUND: Delirium, agitation, and anxiety may hinder weaning from mechanical ventilation and lead to increased morbidity and healthcare costs. The most appropriate clinical approach to weaning in these contexts remains unclear and challenging to clinicians. The objective of this systematic review was to identify effective and safe interventions to wean patients that are difficult-to-wean from mechanical ventilation due to delirium, agitation, or anxiety. METHODS: A systematic review was performed using MEDLINE, EMBASE, and PubMed. Studies evaluating mechanically ventilated patients deemed difficult-to-wean due to delirium, agitation, or anxiety, and comparing the effects of an intervention with a comparator arm were sought. Time-to-extubation was the primary outcome while the secondary outcome was intensive care unit (ICU) length of stay. RESULTS: From 10,860 studies identified, eight met the inclusion criteria: six studies assessed dexmedetomidine while the remaining two assessed loxapine and biofeedback. Pooled analysis of studies assessing dexmedetomidine showed reduced time-to-extubation (six studies, n = 303) by 10.9 hr compared with controls (95% confidence interval [CI], -15.7 to -6.1; I2 = 68%) and ICU length of stay (four studies, n = 191) by 2.6 days (95% CI, 1.9 to 3.3; I2 = 0%). Nevertheless, the evidence was deemed to be of low quality given the small sample sizes and high heterogeneity. Studies assessing other interventions did not identify improvements compared with controls. Safety assessment was globally poorly reported. CONCLUSIONS: This systematic review and meta-analysis provides low quality evidence to suggest the use of dexmedetomidine in patients deemed difficult-to-wean due to agitation, delirium, or anxiety. Insufficient evidence was found regarding other interventions to provide any recommendation. TRIAL REGISTRATION: PROSPERO (CRD42016042528); registered 15 July, 2016.

RéSUMé: CONTEXTE: Le délirium, l'agitation et l'anxiété peuvent compliquer le sevrage de la ventilation mécanique et aboutir à une augmentation de la morbidité et du coût des soins de santé. L'approche clinique la plus adaptée au sevrage dans ces circonstances n'est pas claire et reste un défi pour les cliniciens. L'objectif de cette étude systématique était d'identifier des interventions efficaces et sécuritaires pour sevrer les patients « difficiles à sevrer ¼ de la ventilation mécanique en raison d'un délirium, d'une agitation ou d'anxiété. MéTHODES: Une revue systématique a été menée en utilisant les bases de données MEDLINE, EMBASE et PubMed. Les études évaluant des patients sous ventilation mécanique jugés difficiles à sevrer en raison d'un délirium, d'une agitation ou d'anxiété, comparant les effets d'une intervention à celle d'un bras comparateur ont été recherchées. Le critère d'évaluation principal a été le délai jusqu'à l'extubation et le critère d'évaluation secondaire a été la durée de séjour en unité de soins intensifs (USI). RéSULTATS: À partir de 10 860 études identifiées, huit satisfaisaient les critères d'inclusion : six études ont évalué la dexmédétomidine tandis que les deux dernières ont évalué la loxapine et le biofeedback. L'analyse groupée des études évaluant la dexmédétomidine a montré une réduction du délai d'extubation (six études, n = 303) de 10,9 heures comparativement aux contrôles (intervalle de confiance [IC] à 95 % : -15,7 à -6,1; I2 = 68 %) et de la durée du séjour en USI (quatre études, n = 191) de 2,6 jours (IC à 95 % : 1,9 à 3,3; I2 = 0 %). Néanmoins, les résultats sont de faible qualité compte tenu de la petite taille des échantillons et d'une grande hétérogénéité. Les études évaluant d'autres interventions n'ont pas identifié d'améliorations par rapport aux contrôles. D'une manière générale, les évaluations de l'innocuité ont été médiocrement décrites. CONCLUSIONS: Cette étude systématique et la méta-analyse procurent une preuve de qualité basse pour suggérer l'utilisation de la dexmédétomidine chez des patients considérés difficiles à sevrer en raison d'un délirium, d'une agitation ou d'anxiété. Les données probantes concernant les autres interventions ont été jugées insuffisantes pour permettre des recommandations quelconques. ENREGISTREMENT DE L'ESSAI CLINIQUE: PROSPERO (CRD42016042528); enregistré le 15 juillet 2016.

Frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically Ill neonates, children and adults: A systematic review of clinical studies.

WHAT IS KNOWN AND OBJECTIVE: Many critically ill patients are exposed to opioids and benzodiazepines at high doses for prolonged periods, and upon discontinuation of these drugs, they may be at risk for iatrogenic withdrawal. Although this syndrome was associated with worse outcomes in the critically ill, limited guidance exists regarding its evaluation, prevention and treatment. This systematic review examined the frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and/or benzodiazepines in critically ill neonates, children and adults. METHODS: The literature search was conducted in PubMed, Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane register of systematic reviews, DARE, CINAHL, Trip database, CMA infobase and NICE evidence from inception to February 2018. Grey literature was examined. We included studies reporting frequency, risk factors or symptomatology of iatrogenic withdrawal of opioids, benzodiazepines (or both) in critically ill patients. We considered all study designs except case reports and case series. We excluded studies on neonatal abstinence syndrome, alcohol withdrawal, studies on chronic opioid and/or benzodiazepine users and studies on prevention or treatment of withdrawal in critical care patients. Two independent reviewers applied the inclusion and exclusion criteria. Pairs of reviewers independently abstracted data and evaluated methodological quality using the Cochrane Collaboration Tool, Newcastle-Ottawa or QUADAS-2. Details regarding study design, outcomes, definition, evaluation and type of withdrawal (opioid, benzodiazepine or mixed) were collected. Cumulative doses and duration of opioids and benzodiazepines were collected. RESULTS AND DISCUSSION: We identified 21 866 unique citations and 153 full texts were assessed for eligibility. Thirty-four studies were included; the majority were observational and few included adults. In prospective studies, mixed withdrawal was observed in 7.5%-100% of patients in paediatric studies and ranged from 16.7% to 55% in adults. Symptomatology of withdrawal was not well described. Risk factors included higher cumulative dose and prolonged administration of opioids and benzodiazepines. WHAT IS NEW AND CONCLUSION: Iatrogenic withdrawal appears to be a frequent syndrome in critical care patients who received regular doses of opioids and/or benzodiazepines for ≥72 hours. Larger studies are required, especially in critically ill adults, to better define the syndrome and its symptomatology.

Antipsychotics for treatment of delirium in hospitalised non-ICU patients.

BACKGROUND: Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence. OBJECTIVES: Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects. SEARCH METHODS: We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients. DATA COLLECTION AND ANALYSIS: We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes. MAIN RESULTS: We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.

Iatrogenic Opioid Withdrawal in Critically Ill Patients: A Review of Assessment Tools and Management.

OBJECTIVE: To (1) provide an overview of the epidemiology, clinical presentation, and risk factors of iatrogenic opioid withdrawal in critically ill patients and (2) conduct a literature review of assessment and management of iatrogenic opioid withdrawal in critically ill patients. DATA SOURCES: We searched MEDLINE (1946-June 2017), EMBASE (1974-June 2017), and CINAHL (1982-June 2017) with the terms opioid withdrawal, opioid, opiate, critical care, critically ill, assessment tool, scale, taper, weaning, and management. Reference list of identified literature was searched for additional references as well as www.clinicaltrials.gov . STUDY SELECTION AND DATA EXTRACTION: We restricted articles to those in English and dealing with humans. DATA SYNTHESIS: We identified 2 validated pediatric critically ill opioid withdrawal assessment tools: (1) Withdrawal Assessment Tool-Version 1 (WAT-1) and (2) Sophia Observation Withdrawal Symptoms Scale (SOS). Neither tool differentiated between opioid and benzodiazepine withdrawal. WAT-1 was evaluated in critically ill adults but not found to be valid. No other adult tool was identified. For management, we identified 5 randomized controlled trials, 2 prospective studies, and 2 systematic reviews. Most studies were small and only 2 studies utilized a validated assessment tool. Enteral methadone, α-2 agonists, and protocolized weaning were studied. CONCLUSION: We identified 2 validated assessment tools for pediatric intensive care unit patients; no valid tool for adults. Management strategies tested in small trials included methadone, α-2 agonists, and protocolized sedation/weaning. We challenge researchers to create validated tools assessing specifically for opioid withdrawal in critically ill children and adults to direct management.

Current practices and barriers impairing physicians' and nurses' adherence to analgo-sedation recommendations in the intensive care unit--a national survey.

INTRODUCTION: Appropriate management of analgo-sedation in the intensive care unit (ICU) is associated with improved patient outcomes. Our objectives were: a) to describe utilization of analgo-sedation regimens and strategies (assessment using scales, protocolized analgo-sedation and daily sedation interruption (DSI)) and b) to describe and compare perceptions challenging utilization of these strategies, amongst physicians and nurses. METHODS: In the 101 adult ICUs in Belgium, we surveyed all physicians and a sample of seven nurses per ICU. A multidisciplinary team designed a survey tool based on a previous qualitative study and a literature review. The latter was available in paper (for nurses essentially) and web based (for physicians). Topics addressed included: practices, perceptions regarding recommended strategies and demographics. Pre-testing involved respondents' debriefings and test re-test reliability. Four reminders were sent. RESULTS: Response rate was 60% (898/1,491 participants) representing 94% (95/101) of all hospitals. Protocols were available to 31% of respondents. Validated scales to monitor pain in patients unable to self-report and to monitor sedation were available to 11% and 75% of respondents, respectively. Frequency of use of sedation scales varied (never to hourly). More physicians than nurses agreed with statements reporting benefits of sedation scales, including: increased autonomy for nurses (82% versus 68%, P < 0.001), enhancement of their role (84% versus 66%, P < 0.001), aid in monitoring administration of sedatives (83% versus 68%, P < 0.001), and cost control (54% versus 29%, P < 0.001). DSI was used in less than 25% of patients for 75% of respondents. More nurses than physicians indicated DSI is contra-indicated in hemodynamic instability (66% versus 53%, P < 0.001) and complicated weaning from mechanical ventilation (47% versus 29%, P < 0.001). Conversely, more physicians than nurses indicated contra-indications including: seizures (56% versus 40%, P < 0.001) and refractory intracranial hypertension (90% versus 83%, P < 0.001). More nurses than physicians agreed with statements reporting DSI impairs patient comfort (60% versus 37%, P < 0.001) and increases complications such as self-extubation (82% versus 69%, P < 0.001). CONCLUSIONS: Current analgo-sedation practices leave room for improvement. Physicians and nurses meet different challenges in using appropriate analgo-sedation strategies. Implementational interventions must be tailored according to profession.

Predictors of physical restraint use in Canadian intensive care units.

INTRODUCTION: Physical restraint (PR) use in the intensive care unit (ICU) has been associated with higher rates of self-extubation and prolonged ICU length of stay. Our objectives were to describe patterns and predictors of PR use. METHODS: We conducted a secondary analysis of a prospective observational study of analgosedation, antipsychotic, neuromuscular blocker, and PR practices in 51 Canadian ICUs. Data were collected prospectively for all mechanically ventilated adults admitted during a two-week period. We tested for patient, treatment, and hospital characteristics that were associated with PR use and number of days of use, using logistic and Poisson regression respectively. RESULTS: PR was used on 374 out of 711 (53%) patients, for a mean number of 4.1 (standard deviation (SD) 4.0) days. Treatment characteristics associated with PR were higher daily benzodiazepine dose (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.00 to 1.11), higher daily opioid dose (OR 1.04, 95% CI 1.01 to 1.06), antipsychotic drugs (OR 3.09, 95% CI 1.74 to 5.48), agitation (Sedation-Agitation Scale (SAS) >4) (OR 3.73, 95% CI 1.50 to 9.29), and sedation administration method (continuous and bolus versus bolus only) (OR 3.09, 95% CI 1.74 to 5.48). Hospital characteristics associated with PR indicated patients were less likely to be restrained in ICUs from university-affiliated hospitals (OR 0.32, 95% CI 0.17 to 0.61). Mainly treatment characteristics were associated with more days of PR, including: higher daily benzodiazepine dose (incidence rate ratio (IRR) 1.07, 95% CI 1.01 to 1.13), daily sedation interruption (IRR 3.44, 95% CI 1.48 to 8.10), antipsychotic drugs (IRR 15.67, 95% CI 6.62 to 37.12), SAS <3 (IRR 2.62, 95% CI 1.08 to 6.35), and any adverse event including accidental device removal (IRR 8.27, 95% CI 2.07 to 33.08). Patient characteristics (age, gender, Acute Physiology and Chronic Health Evaluation II score, admission category, prior substance abuse, prior psychotropic medication, pre-existing psychiatric condition or dementia) were not associated with PR use or number of days used. CONCLUSIONS: PR was used in half of the patients in these 51 ICUs. Treatment characteristics predominantly predicted PR use, as opposed to patient or hospital/ICU characteristics. Use of sedative, analgesic, and antipsychotic drugs, agitation, heavy sedation, and occurrence of an adverse event predicted PR use or number of days used.

Analgesic, sedative, antipsychotic, and neuromuscular blocker use in Canadian intensive care units: a prospective, multicentre, observational study.

PURPOSE: Our aim was to describe analgo-sedation and antipsychotic and neuromuscular blocking drug (NMBD) use in critically ill patients, management strategies, and variables associated with these practice patterns. METHODS: This prospective observational study in 51 intensive care units (ICUs) included all patients who underwent invasive mechanical ventilation (MV) over a two-week period during 2008-2009. RESULTS: We included 712 patients representing 3,620 patient-days. Median MV duration was 3.0 days (interquartile range 2-6). During MV, 92% of patients received analgo-sedation, 32% an adjunct agent (e.g., acetaminophen), 18% NMBDs, and 10% antipsychotics. Opioids were used more frequently than benzodiazepines or propofol (84.8% vs 62.2% vs 10.1% patients, respectively, P < 0.0001). Independent predictors of opioid and benzodiazepine use were a longer MV duration, assessment scales, physical restraints, and university-affiliated hospital. Although more than 50% of ICUs reported that assessment tools, protocols, and daily sedation interruption (DSI) were available for use, application was modest: sedation scale 53.0%, pain scale 19.1%, delirium scale 5.2%, protocol 25.0%, DSI 42.1%. Accidental device removal occurred in 4.6% of patients, with 75.8% of events during DSI. Daily sedation interruption was associated with protocol use, physical restraints, university-affiliated hospital, and short-duration MV. Variables associated with protocol use included assessment scales, longer MV duration, lack of physical restraints, and admission to a community hospital. CONCLUSION: Nearly all MV patients received analgo-sedation. Opioids were used more often than sedatives despite infrequent use of pain scales. Few patients received antipsychotic therapy, but physical restraint was common. Protocol use was poor compared to DSI. Duration of MV predicted the use of either.

Valproic acid for agitation in the intensive care unit: an observational study of psychiatric consults.

BACKGROUND: Agitation is a common clinical problem encountered in the intensive care unit (ICU). Treatment options are based on clinical experience and sparse quality literature. AIM: The aim of this study was to describe the effect of valproic acid (VPA) as adjuvant treatment for agitation in the ICU, identify predictors of response to VPA and evaluate the independent effect of VPA on agitation compared to standard of care (SOC). METHOD: This retrospective single center observational study evaluated adult patients admitted to the ICU for whom a psychiatric consultation was requested for agitation management, with agitation defined as a Richmond Agitation Sedation Score of 2 or greater. A descriptive analysis of the proportion of agitation-free patients per day of follow-up, the incidence of agitation-related-events, as well as the evolution of co-medications use over time are presented. A logistic regression model was used to assess predictors of VPA response, defined as being agitation-free on Day 7 and generalized estimating equations were used to evaluate the independent effect of VPA as adjuvant therapy for agitation in the critically ill. RESULTS: One hundred seventy-five patients were included in the study with 78 receiving VPA. The percentage of agitation-free patients on VPA was 6.5% (5/77) on Day 1, 14.1% (11/78) on Day 3 and 39.5% (30/76) on Day 7. Multivariate regression model for clinical and demographic variables identified female gender as predictor of response on Day 7 (OR 6.10 [1.18-31.64], p = 0.03). The independent effect of VPA was non-significant when compared to SOC. CONCLUSION: Although VPA used as adjuvant treatment was associated with a decrease in agitation, its effect when compared to SOC did not yield significant results.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Canadian survey of critical care pharmacists' views and involvement in clinical research.

BACKGROUND: The involvement of Canadian critical care pharmacists in clinical research is not well documented. OBJECTIVE: To describe the clinical research experience of Canadian critical care pharmacists, describe their views about clinical research, and identify factors that facilitate their involvement in clinical research. METHODS: A cross-sectional electronic survey of Canadian critical care pharmacists was developed through an iterative process and conducted from July to October 2010. We invited 325 pharmacists from 129 hospitals across Canada to participate. Surveys with more than 30% of questions unanswered were discarded. RESULTS: Analyzable response rate was 66.2%. Overall, 33 pharmacists (15.7%) were highly involved in research, 54 (25.7%) were moderately involved, and 123 (58.6%) were minimally involved. Most respondents (97.2%) believed that critical care pharmacist involvement in research was desirable, and many (80.4%) expressed interest to be more involved in research. Nearly all respondents (99.5%) agreed that more support should be provided to pharmacists interested in conducting research. Pharmacists currently involved in research have obtained higher academic degrees (adjusted OR 11.23; p < 0.001), express a strong interest in research (adjusted OR 7.44; p < 0.001), report a higher level of training for involvement in research (adjusted OR 2.23; p = 0.047), and practice more often in a university hospital (adjusted OR 3.68; p = 0.004) within an intensive care unit where involvement in research is valued (adjusted OR 5.61; p < 0.001). Support from pharmacy departments is not related to involvement in research (adjusted OR 1.22; p = 0.633). CONCLUSIONS: Canadian critical care pharmacists are involved to varying degrees in clinical research and are very interested in initiating and supporting research activities. Opportunities are present but significant barriers exist. The value of pharmacist-initiated research needs recognition as a priority within hospital pharmacy administration.

Risk factors associated with augmented renal clearance in a mixed intensive care unit population: a retrospective study.

BACKGROUND: Augmented renal clearance is increasingly recognized in critically ill patients. This condition may lead to suboptimal dosing of renally excreted medications. AIM: Our primary objective was to identify demographic and clinical factors associated with augmented renal clearance in a mixed critically ill population. METHOD: This retrospective single center observational cohort study evaluated patients admitted in a mixed adult intensive care unit for augmented renal clearance, defined as a creatinine clearance of ≥ 130 ml/min/1.73m2, through weekly 24-h urine collection. Variables associated with augmented renal clearance were identified using univariate analysis, then served as covariates in a backward stepwise logistic regression. Goodness-of-fit of the model was assessed and receiver operating characteristic curve was generated. RESULTS: Augmented renal clearance was observed in 25.3% of the study cohort (n = 324). Age below 50 years (adjusted odds ratio 7.32; 95% CI 4.03-13.29, p < 0.001), lower serum creatinine at intensive care admission (adjusted odds ratio 0.97; 95% CI 0.96-0.99, p < 0.001) and trauma admission (adjusted odds ratio 2.26; 95% CI 1.12-4.54, p = 0.022) were identified as independent risk factors. Our model showed acceptable discrimination in predicting augmented renal clearance (Area under receiver operating characteristic curve (0.810; 95% CI 0.756-0.864, p < 0.001)). CONCLUSION: We identified age below 50 years, lower serum creatinine upon intensive care admission and trauma as independent risk factors for augmented renal clearance, consistent with the literature suggesting that patients with low serum creatinine upon admission could have a higher risk of developing augmented renal clearance.

The relationship between Candida species cultured from the respiratory tract and systemic inflammation in critically ill patients with ventilator-associated pneumonia.

PURPOSE: In patients with ventilator-associated pneumonia (VAP), the isolation of Candida species (spp.) in respiratory secretions has been associated with worse outcomes. It is unclear whether Candida colonization is causally related or is a marker of disease severity. The objective of this study was to compare systemic inflammatory markers in patients with a clinical suspicion of VAP with Candida in respiratory tract (RT) cultures vs patients who have bacteria and those with no pathogens. METHODS: This was a prospective observational study in adults with a clinical suspicion of VAP who were enrolled within 24 hr of intensive care unit (ICU) admission. Patients were divided into four groups according to RT cultures, i.e., bacterial pathogens only, Candida spp. only, culture negative, and a control group with no clinical suspicion of VAP. Clinical outcomes were collected and compared as were systemic inflammatory and coagulation markers, including procalcitonin (PCT), C-reactive protein (CRP) and interleukin (IL)-6. RESULTS: The PCT, CRP, and IL-6 levels were similar in the Candida, bacterial pathogen, and culture negative groups but were significantly increased between the Candida group and the control group (P < 0.05). In the first 28 days, the number of ICU free days was significantly lower in the Candida group compared with the other groups, and mortality at 28 days was greater (Candida 42.9%, bacterial pathogen 25.0%, culture negative 19.8%, control 0.0%; P < 0.05). CONCLUSIONS: In patients with a clinical suspicion of VAP, the presence of Candida spp. only in the RT is associated with similar levels of inflammation and worse clinical outcomes compared with patients without Candida in RT secretions.

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.

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.

Validation of the Withdrawal Assessment Tool-1 in Adult Intensive Care Patients.

BACKGROUND: The Withdrawal Assessment Tool-1 (WAT-1) has been validated for assessing iatrogenic withdrawal syndrome in critically ill children receiving mechanical ventilation, but little is known about this syndrome in critically ill adults. OBJECTIVE: To evaluate the validity and reliability of the WAT-1 in critically ill adults. METHODS: A prospective, observational, open-cohort pilot study of critically ill adults receiving mechanical ventilation and regular administration of opioids for at least 72 hours. Patients were assessed for withdrawal twice daily on weekdays and once daily on weekends using the WAT-1 after an opioid weaning episode. The presence of iatrogenic withdrawal syndrome was evaluated once daily using modified Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) criteria. All evaluations were blinded and performed independently. The criterion validity of the WAT-1 and the interrater reliability for WAT-1 and DSM-5 evaluations were determined. RESULTS: During 8 months, 52 adults (median age, 51.5 years) were enrolled. Eight patients (15%) had at least 1 positive assessment during their intensive care unit stay using the DSM-5, compared with 19 patients (37%) using the WAT-1. The overall sensitivity of the WAT-1 was 50%, and its specificity was 65.9%. Agreement between WAT-1 and DSM-5 assessments was poor (κ = 0.102). The interrater reliability for the WAT-1 was 89.1% and for the DSM-5 was 90.1%. CONCLUSION: Despite showing reliability, the WAT-1 is not a valid tool for assessing the presence of iatrogenic withdrawal syndrome in adults.

The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients.

PURPOSE: Clinical uncertainty exists regarding the significance of colonization confined to respiratory tract secretions with Candida sp in critically ill patients. Our objectives were to describe such colonization, its associated risk factors, and to examine the clinical outcomes in patients with a clinical suspicion of ventilator-associated pneumonia with isolated Candida colonization compared to those without. MATERIALS AND METHODS: In a retrospective analysis of the Canadian ventilator-associated pneumonia study, patients were divided into 2 groups according to the isolated presence or absence of Candida in the respiratory tract enrollment culture. We compared length of mechanical ventilation, intensive care unit and hospital stay, and mortality outcomes between groups. We used multiple logistic regression analysis to determine factors independently associated with Candida colonization and hospital mortality. RESULTS: Of the 639 eligible patients, 114 (17.8%) were colonized with Candida in the enrollment culture. A multivariate analysis identified female sex (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.02-2.65), number of comorbidities (OR, 1.35; 95% CI, 1.08-1.71), worsening or persistent infiltrate at randomization (OR, 1.92; 95% CI, 1.09-1.38), antibiotics started within 3 days of randomization (OR, 3.16; 95% CI, 1.71-5.83), and on antibiotics at randomization but all started more than 3 days before randomization (OR, 3.04; 95% CI, 1.68-5.50) as variables associated with Candida respiratory tract colonization. A significant increase in median hospital stay (59.9 vs 38.6 days, P = .006) and hospital mortality (34.2% vs 21.0%, P = .003) was observed in patients with Candida colonization. In a multivariate model, Candida colonization of the respiratory tract was independently associated with hospital mortality (OR, 2.47; 95% CI, 1.39-4.37). CONCLUSION: Respiratory tract Candida colonization is associated with worse clinical outcomes and is independently associated with increased hospital mortality. However, it is unclear whether Candida colonization is causally related to poor outcomes or whether it is a marker for increased morbidity and mortality.

Evaluating the use of Drotrecogin alfa (activated) in adult severe sepsis: a Canadian multicenter observational study.

BACKGROUND: The purpose of this study was to characterize the usage patterns and clinical outcomes of DAA in Ontario and Quebec over a 1-year period. METHODS: All hospitals with DAA on formulary in Ontario and Quebec were invited to participate. Consecutive patients who received DAA from 1 March 2003 to 29 February 2004 were identified retrospectively. Demographic, treatment, and outcome variables were collected via chart review. Descriptive statistics on relevant variables were performed, along with logistic regression to determine relevant risk factors for survival and bleeding. RESULTS: Thirty-seven sites participated with a total of 261 courses of DAA administered. The overall mortality rate was 45%; age (> 65 years), multiple organ system failure (> 3), and nosocomial source of sepsis were predictors of mortality, whereas early DAA administration (< 12 h) was associated with lower mortality. Serious bleeding events occurred in 10% of the patients. Only 1 case (0.4%) of fatal intracranial bleed was observed. Multiple organ system failure (>/= 4)and relative contraindications to DAA were predictors of bleeding events. INTERPRETATION: Mortality and bleeding complications associated with the use of DAA were higher than that reported in randomized trials but similar to other usage database. This may be due to the higher severity of illness seen in this cohort of patients. Modifiable risks associated with mortality and bleeding, such as time to treatment, and knowledge of relative contraindications should be targets of further research and future educational efforts in order to optimize the risk-to-benefit ratio of DAA.

Thiopental-induced neutropenia in two patients with severe head trauma.

Thiopental has been used for decades in the treatment of refractory intracranial hypertension in patients with traumatic and nontraumatic head injuries. Commonly reported adverse effects include hypotension, hypokalemia, respiratory complications, and hepatic dysfunction. Neutropenia has rarely been reported as an adverse effect of thiopental. We witnessed probable thiopental-induced neutropenia in two patients with traumatic brain injuries who developed increased intracranial hypertension that was refractory to standard therapy. Based on a MEDLINE search of published case reports and literature, we propose two mechanisms by which thiopental-related neutropenia might be explained. The first is inhibition of inflammatory mediator nuclear factor-kappa B (NF-kappa B), leading to granulocyte apoptosis. The second mechanism involves inhibition of calcineurin. Although the precise link between these two mechanisms has not been elucidated, calcineurin is known to regulate NF-kappa B activity. Development of neutropenia does not appear to be correlated with time but may correlate with plasma concentrations of thiopental. The optimum management of drug-induced neutropenia is unclear. The decision to discontinue thiopental in patients who develop neutropenia should be made by weighing the risks versus benefits. Broad-spectrum antibiotics may be required in the presence of fever. The role of hematopoietic growth factors such as granulocyte colony-stimulating factor is not yet defined. Given the adverse infectious consequences of neutropenia, it is essential to closely monitor neutrophil counts in patients receiving thiopental.

Impact of a protocol for prevention of ventilator-associated pneumonia.

BACKGROUND: Several interventions have been shown to be effective in reducing the incidence of ventilator-associated pneumonia (VAP), but their implementation in clinical practice has not gained widespread acceptance. OBJECTIVE: To determine the impact of a protocol that incorporates evidence-based interventions shown to reduce the frequency of VAP on the overall rate of VAP, early-onset VAP, and late-onset VAP in the intensive care unit (ICU) of a tertiary care adult teaching hospital. METHODS: This pre- and postintervention observational study included mechanically ventilated patients admitted to the Montreal General Hospital ICU between November 2003 and May 2004 (preintervention) and between November 2004 and May 2005 (postintervention). A multidisciplinary prevention protocol was developed, implemented, and reinforced. Rates of VAP per 1000 ventilator-days were calculated pre- and postprotocol implementation for all patients, for patients with early-onset VAP, and for those with late-onset VAP. RESULTS: In the pre- and postintervention groups, 349 and 360 patients, respectively, were mechanically ventilated. Twenty-three VAP episodes occurred in 925 ventilator-days (crude incidence rate 25 per 1000) in the preintervention period. Following implementation, the VAP rate decreased to 22 episodes in 988 ventilator-days (crude incidence rate 22.3 per 1000), corresponding to a relative reduction in rate of 10.8% (p < 0.001). The incidence of early-onset VAP decreased from 31.0 to 18.5 VAP per 1000 ventilator-days (p < 0.001), while the incidence of late-onset VAP increased from 21.9 to 24.1 VAP per 1000 ventilator-days (p < 0.001). However, when all covariates were adjusted, the impact of the prevention protocol was not statistically significant. CONCLUSIONS: Implementation of a VAP prevention protocol incorporating evidence-based interventions reduced the crude incidence of VAP, early-onset VAP, and late-onset VAP. However, when covariates were adjusted, the beneficial effect was no longer observed. Further research is needed to assess the impact of such measures on VAP, early-onset VAP, and late-onset VAP.