Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

International survey of antibiotic dosing and monitoring in adult intensive care units.

BACKGROUND: In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time. METHODS: A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides. RESULTS: A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%). CONCLUSIONS: We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

Incidence, predictors, and outcomes of febrile neutropenia and neutropenia in patients with metastatic castrate-resistant prostate cancer receiving docetaxel.

PURPOSE: The incidence of febrile neutropenia (FN) in adults with castrate-resistant metastatic prostate cancer (mCRPC) receiving docetaxel in real-world settings has not been well studied since the expanded role of hormonal treatments. The study objective was to determine the incidence of FN and neutropenia among adults with mCRPC receiving docetaxel. Secondary objectives were to quantify outcomes of patients who develop FN and to identify predictors for FN in this population. METHODS: A single-center retrospective cohort study was conducted which included adults with mCRPC receiving docetaxel at the Ottawa Hospital over a 5-year period. Charts were reviewed to collect clinical data to determine the incidence of FN and neutropenia. A multiple logistic regression was used to identify predictors of FN. RESULTS: In patients receiving docetaxel for mCRPC, the incidence of FN and neutropenia was 34/137 (25%) and 45/137 (33%), respectively. Among 34 patients who developed FN, 94% required hospitalization for FN for a mean of 5 days (± 2.8) and 6% died. Following FN, 53% required at least 1 treatment delay and 71% had at least 1 dose reduction. Age category (OR 2.025, 95% CI 1.13-3.627) and presence of multiple comorbidities (OR 1.466, 95% CI 1.01-2.258) increased the risk of FN. CONCLUSION: The incidence of FN and neutropenia in the clinical setting in patients receiving docetaxel for mCRPC is higher than previously reported and high enough to consider primary prophylaxis with granulocyte colony stimulating factors in high-risk groups. Age and multiple comorbidities were identified as risk factors.

Potential pharmacological confounders in the setting of death determined by neurologic criteria: a narrative review.

Guidelines for the determination of death by neurologic criteria (DNC) require an absence of confounding factors if clinical examination alone is to be used. Drugs that depress the central nervous system suppress neurologic responses and spontaneous breathing and must be excluded or reversed prior to proceeding. If these confounding factors cannot be eliminated, ancillary testing is required. These drugs may be present after being administered as part of the treatment of critically ill patients. While measurement of serum drug concentrations can help guide the timing of assessments for DNC, they are not always available or feasible. In this article, we review sedative and opioid drugs that may confound DNC, along with pharmacokinetic factors that govern the duration of drug action. Pharmacokinetic parameters including a context-sensitive half-life of sedatives and opioids are highly variable in critically ill patients because of the multitude of clinical variables and conditions that can affect drug distribution and clearance. Patient-, disease-, and treatment-related factors that influence the distribution and clearance of these drugs are discussed including end organ function, age, obesity, hyperdynamic states, augmented renal clearance, fluid balance, hypothermia, and the role of prolonged drug infusions in critically ill patients. In these contexts, it is often difficult to predict how long after drug discontinuation the confounding effects will take to dissipate. We propose a conservative framework for evaluating when or if DNC can be determined by clinical criteria alone. When pharmacologic confounders cannot be reversed, or doing so is not feasible, ancillary testing to confirm the absence of brain blood flow should be obtained.

RéSUMé: Les lignes directrices pour la détermination du décès selon des critères neurologiques (DCN) exigent une absence de facteurs confondants si l'examen clinique seul doit être utilisé. Les médicaments qui dépriment le système nerveux central suppriment les réponses neurologiques et la respiration spontanée et doivent être exclus ou neutralisés avant de procéder. Si ces facteurs confondants ne peuvent être éliminés, un examen auxiliaire est nécessaire. Ces médicaments peuvent être présents après avoir été administrés dans le cadre du traitement de patients en état critique. Bien que la mesure des concentrations sériques de médicaments puisse guider l'horaire des évaluations pour un DCN, ces mesures ne sont pas toujours disponibles ou réalisables. Dans cet article, nous passons en revue les médicaments sédatifs et opioïdes qui peuvent confondre un DCN, ainsi que les facteurs pharmacocinétiques qui régissent la durée d'action de ces médicaments. Les paramètres pharmacocinétiques, y compris une demi-vie des sédatifs et des opioïdes sensible au contexte, sont très variables chez les patients gravement malades en raison de la multitude de variables cliniques et de conditions qui peuvent affecter la diffusion et l'élimination des médicaments. Les facteurs liés au patient, à la maladie et au traitement qui influencent la diffusion et l'élimination de ces médicaments sont discutés, notamment la fonction des organes cibles, l'âge, l'obésité, les états hyperdynamiques, l'augmentation de la clairance rénale, l'équilibre liquidien, l'hypothermie et le rôle des perfusions prolongées de médicaments chez les patients gravement malades. Dans ces contextes, il est souvent difficile de prédire combien de temps après l'arrêt du médicament les effets confusionnels prendront pour se dissiper. Nous proposons un cadre conservateur pour évaluer quand ou si un DCN peut être déterminé selon des critères cliniques uniquement. Lorsque les facteurs confondants pharmacologiques ne peuvent pas être neutralisés, ou que cela n'est pas possible, un examen auxiliaire pour confirmer l'absence de circulation sanguine cérébrale doit être réalisé.

Association of age with death and withdrawal of life-sustaining therapy after severe traumatic brain injury.

BACKGROUND: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention. METHODS: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy. RESULTS: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions. CONCLUSION: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear.

Efficacy and Safety of Low Molecular Weight Heparin Versus Unfractionated Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-analysis.

PURPOSE: Trauma patients are at high risk of VTE. We summarize the efficacy and safety of LMWH versus UFH for the prevention of VTE in trauma patients. METHODS: We searched 6 databases from inception through March 12, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH versus UFH for thromboprophylaxis in adult trauma patients. We pooled effect estimates across RCTs and observational studies separately, using random-effects model and inverse variance weighting. We assessed risk of bias using the Cochrane tool for RCTs and the Risk of Bias in Non-Randomized Studies (ROBINS)-I tool for observational studies and assessed certainty of findings using Grading of Recommendations, Assessment, Development and Evaluations methodology. RESULTS: We included 4 RCTs (879 patients) and 8 observational studies (306,747 patients). Based on pooled RCT data, compared to UFH, LMWH reduces deep vein thrombosis (RR 0.67, 95% CI 0.50 to 0.88, moderate certainty) and VTE (RR 0.68, 95% CI 0.51 to 0.90, moderate certainty). As compared to UFH, LMWH may reduce pulmonary embolism [adjusted odds ratio from pooled observational studies 0.56 (95% CI 0.50 to 0.62)] and mortality (adjusted odds ratio from pooled observational studies 0.54, 95% CI 0.45 to 0.65), though based on low certainty evidence. There was an uncertain effect on adverse events (RR from pooled RCTs 0.80, 95% CI 0.48 to 1.33, very low certainty) and heparin induced thrombocytopenia [RR from pooled RCTs 0.26 (95% CI 0.03 to 2.38, very low certainty)]. CONCLUSIONS: Among adult trauma patients, LMWH is superior to UFH for deep vein thrombosis and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.

The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Managing overlap of primary study results across systematic reviews: practical considerations for authors of overviews of reviews.

BACKGROUND: Overviews often identify and synthesise a large number of systematic reviews on the same topic, which is likely to lead to overlap (i.e. duplication) in primary studies across the reviews. Using a primary study result multiple times in the same analysis overstates its sample size and number of events, falsely leading to greater precision in the analysis. This paper aims to: (a) describe types of overlapping data that arise from the same primary studies reported across multiple reviews, (b) describe methods to identify and explain overlap of primary study data, and (c) present six case studies illustrating different approaches to manage overlap. METHODS: We first updated the search in PubMed for methods from the MOoR framework relating to overlap of primary studies. One author screened the studies titles and abstracts, and any full-text articles retrieved, extracted methods data relating to overlap of primary studies and mapped it to the overlap methods from the MOoR framework. We also describe six case studies as examples of overviews that use specific overlap methods across the steps in the conduct of an overview. For each case study, we discuss potential methodological implications in terms of limitations, efficiency, usability, and resource use. RESULTS: Nine methods studies were found and mapped to the methods identified by the MOoR framework to address overlap. Overlap methods were mapped across four steps in the conduct of an overview - the eligibility criteria step, the data extraction step, the assessment of risk of bias step, and the synthesis step. Our overview case studies used multiple methods to reduce overlap at different steps in the conduct of an overview. CONCLUSIONS: Our study underlines that there is currently no standard methodological approach to deal with overlap in primary studies across reviews. The level of complexity when dealing with overlap can vary depending on the yield, trends and patterns of the included literature and the scope of the overview question. Choosing a method might be dependent on the number of included reviews and their primary studies. Gaps in evaluation of methods to address overlap were found and further investigation in this area is needed.

Shortages of Palliative Care Medications in Canada during the COVID-19 Pandemic: Gambling with Suffering.

Patients with serious illnesses such as cancer, advanced organ failure, dementia and COVID-19 rely on medications to alleviate suffering from uncontrolled symptoms. Numerous actual or threatened shortages of key medications used to provide palliation have been reported during the COVID-19 pandemic. This article explores the nature of these shortages, factors that have contributed to them and strategies to mitigate them. It calls on all levels of the healthcare system and the government to address this problem. Shortages in these medications are as serious as shortages in medications used to cure or control diseases.

Therapeutic alternatives and strategies for drug conservation in the intensive care unit during times of drug shortage: a report of the Ontario COVID-19 ICU Drug Task Force.

During the coronavirus disease (COVID-19) global pandemic, urgent strategies to alleviate shortages are required. Evaluation of the feasibility, practicality, and value of drug conservation strategies and therapeutic alternatives requires a collaborative approach at the provincial level. The Ontario COVID-19 ICU Drug Task Force was directed to create recommendations suggesting drug conservation strategies and therapeutic alternatives for essential drugs at risk of shortage in the intensive care unit during the COVID-19 pandemic. Recommendations were rapidly developed using a modified Delphi method and evaluated on their ease of implementation, feasibility, and supportive evidence. This article describes the recommendations for drug conservation strategies and therapeutic alternatives for drugs at risk of shortage that are commonly used in the care of critically ill patients. Recommendations are identified as preferred and secondary ones that might be less desirable. Although the impetus for generating this document was the COVID-19 pandemic, recommendations should also be applicable for mitigating drug shortages outside of a pandemic. Proposed provincial strategies for drug conservation and therapeutic alternatives may not all be appropriate for every institution. Local implementation will require consultation from end-users and hospital administrators. Competing equipment shortages and available resources should be considered when evaluating the appropriateness of each strategy.

RéSUMé: Pendant la pandémie mondiale du coronavirus (COVID-19), des stratégies urgentes pour réduire les pénuries sont nécessaires. L'évaluation de la faisabilité, de l'aspect pratique et du mérite des stratégies de préservation des médicaments et des alternatives thérapeutiques nécessite une approche collaborative au niveau provincial. Le Groupe de travail ontarien sur les médicaments à l'USI pendant la COVID-19 a reçu comme mandat d'élaborer des recommandations proposant des stratégies de préservation des médicaments et des alternatives thérapeutiques pour les médicaments essentiels utilisés dans les unités de soins intensifs courant un risque de pénurie pendant la pandémie de COVID-19. Des recommandations ont été rapidement élaborées en utilisant une méthode Delphi modifiée, puis évaluées selon leur facilité de mise en œuvre, leur faisabilité et les données probantes les préconisant. Cet article décrit les recommandations quant aux stratégies de préservation des médicaments et aux alternatives thérapeutiques aux médicaments possiblement à risque de pénurie fréquemment utilisés pour les soins des patients en état critique. Les recommandations sont identifiées comme 'à privilégier' ou 'secondaires' si moins souhaitables. Bien que la pandémie de la COVID-19 ait été l'impulsion incitant la création de ce document, ces recommandations devraient également être applicables pour réduire les pénuries de médicaments en contexte normal. Les stratégies provinciales proposées pour la préservation des médicaments et les alternatives thérapeutiques pourraient ne pas être adaptées pour toutes les institutions. La mise en œuvre locale nécessitera la consultation des utilisateurs et des administrateurs hospitaliers. Il faudrait tenir compte des pénuries de matériel concurrentes et des ressources disponibles lors de l'évaluation de la faisabilité de chaque stratégie.

Canadian Critical Care Society clinical practice guideline: The use of vasopressin and vasopressin analogues in critically ill adults with distributive shock.

PURPOSE: Hemodynamic management of adults with distributive shock often includes the use of catecholamine-based vasoconstricting medications. It is unclear whether adding vasopressin or vasopressin analogues to catecholamine therapy is beneficial in the management of patients with distributive shock. The purpose of this guideline was to develop an evidence-based recommendation regarding the addition of vasopressin to catecholamine vasopressors in the management of adults with distributive shock. METHODS: We summarized the evidence informing this recommendation by updating a recently published meta-analysis. Then, a multidisciplinary panel from the Canadian Critical Care Society developed the recommendation using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: The updated systematic review identified 25 randomized controlled trials including a total of 3,737 patients with distributive shock. Compared with catecholamine therapy alone, the addition of vasopressin or its analogues was associated with a reduced risk of mortality (relative risk [RR], 0.91; 95% confidence interval [CI], 0.85 to 0.99; low certainty), reduced risk of atrial fibrillation (RR, 0.77; 95% CI, 0.67 to 0.88; high certainty), and increased risk of digital ischemia (RR, 2.56; 95% CI, 1.24 to 5.25; moderate certainty). CONCLUSIONS: After considering certainty in the evidence, values and preferences, cost, and other factors, the expert guideline panel suggests using vasopressin or vasopressin analogues in addition to catecholamines over catecholamine vasopressors alone for the management of distributive shock (conditional recommendation, low certainty evidence).

The incidence and prevalence of delirium across palliative care settings: A systematic review.

BACKGROUND: Delirium is a common and distressing neurocognitive condition that frequently affects patients in palliative care settings and is often underdiagnosed. AIM: Expanding on a 2013 review, this systematic review examines the incidence and prevalence of delirium across all palliative care settings. DESIGN: This systematic review and meta-analyses were prospectively registered with PROSPERO and included a risk of bias assessment. DATA SOURCES: Five electronic databases were examined for primary research studies published between 1980 and 2018. Studies on adult, non-intensive care and non-postoperative populations, either receiving or eligible to receive palliative care, underwent dual reviewer screening and data extraction. Studies using standardized delirium diagnostic criteria or valid assessment tools were included. RESULTS: Following initial screening of 2596 records, and full-text screening of 153 papers, 42 studies were included. Patient populations diagnosed with predominantly cancer (n = 34) and mixed diagnoses (n = 8) were represented. Delirium point prevalence estimates were 4%-12% in the community, 9%-57% across hospital palliative care consultative services, and 6%-74% in inpatient palliative care units. The prevalence of delirium prior to death across all palliative care settings (n = 8) was 42%-88%. Pooled point prevalence on admission to inpatient palliative care units was 35% (confidence interval = 0.29-0.40, n = 14). Only one study had an overall low risk of bias. Varying delirium screening and diagnostic practices were used. CONCLUSION: Delirium is prevalent across all palliative care settings, with one-third of patients delirious at the time of admission to inpatient palliative care. Study heterogeneity limits meta-analyses and highlights the future need for rigorous studies.

Piperacillin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis.

BACKGROUND: Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking. OBJECTIVE: To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations. METHODS: This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses. RESULTS: From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC ≤16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC ≤32 mg/L. CONCLUSIONS AND RELEVANCE: In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen.

Triiodothyronine replacement in critically ill adults with non-thyroidal illness syndrome.

PURPOSE: Non-thyroidal illness syndrome is commonly encountered in critically ill patients, many of whom are treated with thyroid hormones despite uncertainty regarding their safety and effectiveness. This retrospective observational study sought to evaluate the utilization, safety, and effectiveness of triiodothyronine (T3) supplementation in critically ill adults admitted to either of two non-cardiac surgery mixed-medical/surgical intensive care units (ICU). METHODS: Consecutive adults admitted to an ICU and treated with enterally administered T3 were identified over a two-year period. Data pertaining to demographics, T3 utilization, safety, and clinical outcomes were collected. RESULTS: Data were extracted from the medical records of 70 consecutive patients. All had baseline serum free T3 concentrations below the lower limit of our laboratory's reference range and 22 (31%) patients also had low thyroxine (T4) concentrations. The most commonly prescribed replacement doses were 25 and 50 µg for a median of seven days and almost half of the patients also received concomitant T4 supplementation. Serum thyroid hormones were available in 48 of 70 patients (69%) at a median [interquartile range (IQR)] of 7 [6-38] days. Normalization of free T3 serum concentrations occurred in 30 of 48 patients (63%) at a median [IQR] of 8 [7-33] days. A dose-response relationship was identifiable. New adverse events (atrial fibrillation/flutter, hypertension, sinus tachycardia, myocardial infarction) during therapy were less frequent than at baseline. CONCLUSIONS: This study suggests that with T3 supplementation there was evidence of serum free T3 normalization without evidence of associated harms. A definitive trial is needed to evaluate clinical effectiveness.

Validation of the Critical Care Pain Observation Tool in Critically Ill Patients With Delirium: A Prospective Cohort Study.

OBJECTIVES: The 2013 clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the ICU suggest that pain be routinely assessed using a validated pain assessment tool. Currently available tools have only been evaluated in nondelirious critically ill patients, yet delirium can affect as many as 80% of ICU patients. The validated pain assessment tool adopted by our institution is the Critical Care Pain Observation Tool, and the objective of this study was to investigate the validity of this tool in patients with evidence of delirium. DESIGN: Prospective cohort study. SETTING: Two ICUs within a Canadian tertiary healthcare center. PATIENTS: Forty consecutive adult patients deemed delirious on the day of enrollment using the Confusion Assessment Method for ICU. MEASUREMENTS AND MAIN RESULTS: Serial Critical Care Pain Observation Tool assessments were conducted simultaneously by study personnel and objective nurses at baseline and after nonpainful and painful stimuli. Subjective opinions about pain and objective physical variables (including mean arterial pressure, heart rate, respiratory rate, and oxygen saturation) were collected at the same time points. Discriminant validity was described using paired t tests, whereas internal consistency was described using the Cronbach α statistic. Responsiveness of the Critical Care Pain Observation Tool was measured by effect size, and reliability was described as the agreement between raters. Comparisons between the Critical Care Pain Observation Tool and the subjective assessments and objective measurements were based on positive and negative percent agreement. Critical Care Pain Observation Tool demonstrated excellent discriminant validity as evidenced by a highly statistically and clinically significant change in mean Critical Care Pain Observation Tool scores between baseline and painful procedures (mean difference, 3.13 ± 1.56; p < 0.001; Cohen D, 2.0). Interrater agreement was also excellent (κ > 0.6), and scores between raters were highly correlated (r = 0.957). The Critical Care Pain Observation Tool possessed a high level of internal consistency (overall Cronbach α, 0.778). Percent agreement was found to be greater between the Critical Care Pain Observation Tool and the nurse's subjective opinion of the presence or absence of pain when compared with that between the Critical Care Pain Observation Tool and physiologic variables (80.5% vs 67.5%, respectively). CONCLUSIONS: The Critical Care Pain Observation Tool is a valid pain assessment tool in noncomatose, delirious adult ICU patients who are unable to reliably self-report the presence or absence of pain.

Stress ulcer prophylaxis in critical illness: a Canadian survey.

PURPOSE: Stress ulcer prophylaxis (SUP) using histamine-2-receptor antagonists has been a standard of care in intensive care units (ICUs) for four decades. Proton pump inhibitors (PPIs) are increasingly used despite apparently lower background rates of gastrointestinal bleeding and growing concerns about PPI-associated complications. Our objective was to understand the views and prescribing habits amongst Canadian physicians regarding SUP in the ICU and to gauge interest in a future randomized-controlled trial (RCT). METHODS: We created a short self-administered survey about SUP for critically ill adults, evaluated its clinical sensibility, and pilot tested the instrument. We surveyed all physician members of the Canadian Critical Care Trials Group (CCCTG) by e-mail and sent reminders three and five weeks later. RESULTS: We received 94 of 111 (85%) surveys from the validated respondent pool between May and June, 2015. Respondents reported use of SUP most commonly in patients 1) receiving invasive mechanical ventilation (62, 66%), 2) expected to be ventilated for ≥ two days (25, 27%), or 3) receiving mechanical ventilation but nil per os (NPO) (20, 21%). Stress ulcer prophylaxis is discontinued when patients no longer receive mechanical ventilation (75%), no longer are NPO (22%), or are discharged from the ICU (19%). Stress ulcer prophylaxis involves PPIs in 68% of centres. Most respondents endorsed the need for a large rigorous RCT of PPI vs placebo to understand the risks and benefits of this practice. CONCLUSIONS: Stress ulcer prophylaxis is reportedly used primarily for the duration of mechanical ventilation. The CCCTG physicians believe that a placebo-controlled RCT is needed to evaluate the effectiveness and safety of contemporary SUP with PPIs.

Prolactin-related adverse events and change in prolactin levels in pediatric patients given antipsychotics for schizophrenia and schizophrenia spectrum disorders: A systematic review.

BACKGROUND: Second-generation antipsychotics are commonly prescribed for pediatric patients with schizophrenia and schizophrenia spectrum disorders despite their lack of approval for use in children. Although considered a safer alternative to first-generation antipsychotics, there is evidence to suggest that second-generation antipsychotics may be associated with some adverse events as well as an increase in prolactin levels. The purpose of this review is to examine the risk of prolactin-related adverse events in pediatric patients using antipsychotics and to quantify changes in prolactin for this population. METHODS: Literature searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO databases, supplemented with review of select gray literature to identify both randomized controlled trials and observational studies on pediatric patients prescribed antipsychotic medications for schizophrenia or schizophrenia spectrum disorders. Using a narrative approach, data on adverse events were recorded and changes from baseline in prolactin were pooled, where possible, from the randomized trials. Change from baseline in prolactin was evaluated for each treatment, as well as in comparison to placebo and to other treatments. Where data was available, these changes were evaluated separately for male and female patients. RESULTS: Six randomized controlled trials and five observational studies, all examining the effects of second-generation antipsychotics, were selected. Literature reporting the effects of risperidone, quetiapine, aripiprazole, olanzapine, and paliperidone was identified, with varying doses. Prolactin-related adverse events were sparsely reported across studies. In evidence gathered from randomized controlled trials, risperidone, olanzapine, and two doses of paliperidone (3-5 mg/day and 6-12 mg/day) were associated with increased prolactin levels compared to baseline. With the exception of paliperidone, similar trends were observed in males and females, separately. The findings of the observational evidence served to both complement and run contrary to the randomized trials, with discrepancies attributed to differences in patient and treatment characteristics. CONCLUSIONS: No definitive conclusions between second-generation antipsychotic use and prolactin-related adverse events can be made based on the available literature. While some trends in prolactin level changes emerged, this was based on few trials with small sample sizes. Future investigations should emphasize reporting on treatment safety. TRIAL REGISTRATION: PROSPERO CRD42014009506 .

The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis.

OBJECTIVE: To evaluate the efficacy and safety of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection. DESIGN: Systematic review and metaanalysis. DATA SOURCES: Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles. STUDY SELECTION AND DATA EXTRACTION: Two reviewers independently identified and extracted trial-level data from randomized trials investigating unfractionated or low molecular heparin administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Internal validity was assessed in duplicate using the Risk of Bias tool. The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology. Our primary outcome was mortality. Safety outcomes included hemorrhage, transfusion, and thrombocytopenia. MEASUREMENTS AND MAIN RESULTS: We included nine trials enrolling 2,637 patients. Eight trials were of unclear risk of bias and one was classified as having low risk of bias. In trials comparing heparin to placebo or usual care, the risk ratio for death associated with heparin was 0.88 (95% CI, 0.77-1.00; I2 = 0%; 2,477 patients; six trials; moderate strength of evidence). In trials comparing heparin to other anticoagulants, the risk ratio for death was 1.30 (95% CI, 0.78-2.18; I2 = 0%; 160 patients; three trials; low strength of evidence). In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (risk ratio, 0.79; 95% CI, 0.53-1.17; I2 = 0%; 2,392 patients; three trials). In one small trial of heparin compared with other anticoagulants, the risk of major hemorrhage was significantly increased (2.14; 95% CI, 1.07-4.30; 48 patients). Important secondary and safety outcomes, including minor bleeding, were sparsely reported. CONCLUSIONS: Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock.

Guidelines for reporting case studies on extracorporeal treatments in poisonings: methodology.

A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two-round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty-one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision-making.

Environmentally sustainable opportunities for health systems: metered-dose inhaler prescribing, dispensing, usage, and waste at The Ottawa Hospital.

BACKGROUND: The carbon footprint of Canada's health sector is among the worst in the world, responsible for 4·6% of Canada's total greenhouse gas emissions. A quarter of emissions from Canada's health sector are linked to pharmaceuticals, including metered dose inhalers (MDIs). MDIs use propellants, such as hydrofluorocarbons, which act as greenhouse gas emissions and contribute to the health-care sector's overall carbon footprint. The objective of this study was to describe MDI prescribing, dispensing, usage, and waste patterns at The Ottawa Hospital (Ottawa, ON, Canada). Secondary objectives included estimating the monetary and carbon cost of current practice and the potential benefits and costs of switching to the more environmentally friendly dry powder inhalers. METHODS: In this retrospective point-prevalence cohort study, we identified 100 consecutive patients from medical and surgical services at both campuses of The Ottawa Hospital from health records discharged from medical and surgical services and who were prescribed at least one MDI during their admission. Medical records were reviewed and data related to demographics, MDI prescribing, dispensing, usage, and wastage were collected using a pre-piloted electronic case report form. Financial cost was calculated using local costing estimates and carbon cost was calculated using published estimates. FINDINGS: Between Jan 1, 2023, and June 1, 2023, we collected data for 100 eligible patients, of whom 60 (60%) were female and 90 (90%) were admitted to hospital medicine wards (10% from surgical wards). The median length of stay was 7 (range 1-47) days. The most common inpatient diagnoses were respiratory tract infections in 43 (43%) of 100 patients and chronic obstructive pulmonary disease exacerbations in 28 (28%) of 100 patients. The median number of MDIs prescribed during a patients stay was two (range one to 15) and the median number dispensed was one (range one to seven). For formulary options of MDIs, of the 200 (range 30-1400) actuations dispensed per patient, 8% were used, representing 92% wastage. During the audit, 315 MDIs were dispensed in total, of which 97 were not used at all. INTERPRETATION: MDIs are significant contributors to the carbon footprint attributed to pharmaceutical use in hospitals. This study suggests that 90% of MDI doses are wasted, showing that there is substantial room for improvement. FUNDING: None.