Publications by authors named "Salmaan Kanji"

90 Publications

Venous Thromboembolism Prophylaxis in Critically Ill Adults - A Systematic Review and Network Meta-Analysis.

Chest 2021 Aug 19. Epub 2021 Aug 19.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada;; Department of Medicine, McMaster University, Hamilton, ON, Canada.

Background: Critically ill adults are at increased risk of venous thromboembolism (VTE), including deep venous thrombosis (DVT), and pulmonary embolism (PE). Various agents exist for venous thromboprophylaxis in this population.

Research Question: What is the comparative efficacy and safety of prophylaxis agents for prevention of VTE in critically ill adults?

Study Design And Methods: Systematic review and network meta-analysis of randomized clinical trials (RCTs) evaluating efficacy of thromboprophylaxis agents among critically ill patients. We searched six databases (including PubMed, EMBASE, and Medline) from inception to January 2021 for RCTs of intensive care unit (ICU) patients receiving pharmacologic, mechanical, or combination therapy (pharmacologic agents and mechanical devices) for thromboprophylaxis. Two reviewers performed screening, full-text review, and extraction. We used GRADE to rate certainty of effect estimates.

Results: We included 13 RCTs (9,619 patients). Compared to control (a composite of no prophylaxis, placebo, or compression stockings only), low molecular weight heparin (LMWH) reduces the incidence of DVT (odds ratio [OR] 0.59 [95% Credible Interval [CrI]: 0.33-0.90]; high certainty) and unfractionated heparin (UFH) may reduce the incidence of DVT (OR 0.82 [95% CrI: 0.47-1.37]; low certainty). LMWH probably reduces DVT compared to UFH (OR 0.72 [95% CrI: 0.46-0.98]; moderate certainty). Compressive devices may reduce risk of DVT compared to controls, however this was based on low certainty evidence (OR 0.85 [95% CrI: 0.50-1.50]). Combination therapy had unclear effect on DVT, compared to either therapy alone (very low certainty).

Conclusion: Among critically ill adults, compared to control, LMWH reduces incidence of DVT while UFH and mechanical compressive devices may reduce risk of DVT. LMWH is probably more effective than UFH in reducing incidence of DVT, and should be considered the primary pharmacologic agent for thromboprophylaxis. The efficacy and safety of combination pharmacologic therapy and mechanical compressive devices was unclear.
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http://dx.doi.org/10.1016/j.chest.2021.08.050DOI Listing
August 2021

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.

Ann Surg 2021 Aug 13. Epub 2021 Aug 13.

Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, Canada School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, Canada Department of Emergency Medicine, University of Ottawa, Ottawa, Canada Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada Division of Acute Care Surgery, Department of Surgery, University of Southern California, Los Angeles, USA Division of General Surgery, Department of Surgery, Western University, London, Canada Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Canada Department of Medicine, Division of Critical Care, McMaster University, Hamilton, Canada Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Purpose: Trauma patients are at high risk of venous thromboembolism (VTE). We summarize the efficacy and safety of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) for the prevention of VTE in trauma patients.

Methods: We searched six databases from inception through March 12th, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH vs 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 ROBINS-I tool for observational studies and assessed certainty of findings using GRADE 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 (DVT) (relative risk [RR] 0.67, 95% confidence interval [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 (aOR) 0.56 (95% CI 0.50 to 0.62) and mortality (aOR 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).

Conclusion: Among adult trauma patients, LMWH is superior to UFH for DVT and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.
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http://dx.doi.org/10.1097/SLA.0000000000005157DOI Listing
August 2021

Pharmacological and non-pharmacological interventions to prevent delirium in critically ill patients: a systematic review and network meta-analysis.

Intensive Care Med 2021 Sep 11;47(9):943-960. Epub 2021 Aug 11.

Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK.

Purpose: To compare the effects of prevention interventions on delirium occurrence in critically ill adults.

Methods: MEDLINE, Embase, PsychINFO, CINAHL, Web of Science, Cochrane Library, Prospero, and WHO international clinical trial registry were searched from inception to April 8, 2021. Randomized controlled trials of pharmacological, sedation, non-pharmacological, and multi-component interventions enrolling adult critically ill patients were included. We performed conventional pairwise meta-analyses, NMA within Bayesian random effects modeling, and determined surface under the cumulative ranking curve values and mean rank. Reviewer pairs independently extracted data, assessed bias using Cochrane Risk of Bias tool and evidence certainty with GRADE. The primary outcome was delirium occurrence; secondary outcomes were durations of delirium and mechanical ventilation, length of stay, mortality, and adverse effects.

Results: Eighty trials met eligibility criteria: 67.5% pharmacological, 31.3% non-pharmacological and 1.2% mixed pharmacological and non-pharmacological interventions. For delirium occurrence, 11 pharmacological interventions (38 trials, N = 11,993) connected to the evidence network. Compared to placebo, only dexmedetomidine (21/22 alpha agonist trials were dexmedetomidine) probably reduces delirium occurrence (odds ratio (OR) 0.43, 95% Credible Interval (CrI) 0.21-0.85; moderate certainty). Compared to benzodiazepines, dexmedetomidine (OR 0.21, 95% CrI 0.08-0.51; low certainty), sedation interruption (OR 0.21, 95% CrI 0.06-0.69; very low certainty), opioid plus benzodiazepine (OR 0.27, 95% CrI 0.10-0.76; very low certainty), and protocolized sedation (OR 0.27, 95% CrI 0.09-0.80; very low certainty) may reduce delirium occurrence but the evidence is very uncertain. Dexmedetomidine probably reduces ICU length of stay compared to placebo (Ratio of Means (RoM) 0.78, CrI 0.64-0.95; moderate certainty) and compared to antipsychotics (RoM 0.76, CrI 0.61-0.98; low certainty). Sedative interruption, protocolized sedation and opioids may reduce hospital length of stay compared to placebo, but the evidence is very uncertain. No intervention influenced mechanical ventilation duration, mortality, or arrhythmia. Single and multi-component non-pharmacological interventions did not connect to any evidence networks to allow for ranking and comparisons as planned; pairwise comparisons did not detect differences compared to standard care.

Conclusion: Compared to placebo and benzodiazepines, we found dexmedetomidine likely reduced the occurrence of delirium in critically ill adults. Compared to benzodiazepines, sedation-minimization strategies may also reduce delirium occurrence, but the evidence is uncertain.
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http://dx.doi.org/10.1007/s00134-021-06490-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356549PMC
September 2021

N-Acetylcysteine Interference With Creatinine Measurement: An In Vitro Analysis.

Kidney Int Rep 2021 Jul 19;6(7):1973-1976. Epub 2021 Apr 19.

Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1016/j.ekir.2021.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258456PMC
July 2021

Stability of Dexmedetomidine in Polyvinyl Chloride Bags Containing 0.9% Sodium Chloride Intended for Subcutaneous Infusions.

Int J Pharm Compd 2021 Jul-Aug;25(4):330-335

Department of Pharmacy, The Ottawa Hospital, The Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Dexmedetomidine is a sedative medication with co-analgesic effects that has been used primarily in critical care and anesthesia as a continuous intravenous infusion. Its utility in the treatment of refractory agitated delirium is being investigated in other settings including palliative care, but continuous intravenous infusions are not always feasible during end-of-life care. Subcutaneous infusions are more commonly used in this setting, but smaller volumes and higher concentrations are typically required. Investigations into stability at these higher concentrations are required to address preparation and administration feasibility issues. The objective of this research was to study the chemical stability of high-concentration dexmedetomidine 20 mcg/mL prepared in polyvinyl chloride bags with 0.9% sodium chloride and storage up to 9 days under refrigeration and room temperature conditions. A total of four solutions of dexmedetomidine 20 mcg/mL in 0.9% sodium chloride were prepared in polyvinyl chloride bags under sterile conditions. Two bags were stored under refrigeration and two bags at room temperature. Duplicate samples were withdrawn from each bag at hours 0, 24, 48, 72, 96, 120, 144, 168, 192, and 216 and frozen at -20°C (total of 4 samples per time point at each storage condition). These samples were thawed and transferred to glass vials prior to their analysis by high-performance liquid chromatography electrospray ionization-tandem mass spectrometry and pH testing. All samples of dexmedetomidine 20 mcg/mL met stability criteria by retaining more than 90% of the initial concentration after 9 days under refrigeration and room temperature. There was no evidence of precipitation or color change during the study period. The pH reduced slightly over time under both refrigerated (5.7 to 4.5) and room temperature conditions (5.7 to 4.6). Dexmedetomidine solutions of 20 mcg/mL intended for subcutaneous use were stable in polyvinyl chloride bags containing 0.9% sodium chloride for 9 days under refrigeration and room temperature.
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July 2021

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

BMC Med Res Methodol 2021 07 7;21(1):140. Epub 2021 Jul 7.

The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Canada.

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.
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http://dx.doi.org/10.1186/s12874-021-01269-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265144PMC
July 2021

Pharmacokinetics of Commonly Used Antimicrobials in Critically Ill Adults During Extracorporeal Membrane Oxygenation: A Systematic Review.

Drugs 2021 Jul 5;81(11):1307-1329. Epub 2021 Jul 5.

Faculté de Pharmacie, Université de Montréal, Montreal, Canada.

Purpose: Adequate dosing of antimicrobials is critical to properly treat infections and limit development of resistance and adverse effects. Limited guidance exists for antimicrobial dosing adjustments in patients requiring extracorporporeal membrane oxygenation (ECMO) therapy. A systematic review was conducted to delineate the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in critically ill adult patients requiring ECMO.

Methods: Medline, EMBASE, Global Health, and All EBM Reviews databases were searched. Grey literature was examined. All studies reporting PK/PD parameters of antimicrobials in critically ill adults treated with ECMO were included, except for case reports and congress abstracts. Ex vivo studies were included. Two independent reviewers applied the inclusion and exclusion criteria. Reviewers were then paired to independently abstract data and evaluate methodological quality of studies using the ROBINS-I tool and the compliance with ClinPK guidelines. Patients' and studies' characteristics, key PK/PD findings, details of ECMO circuits and co-treatments were summarized qualitatively. Dosing recommendations were formulated based on data from controlled studies.

Results: Thirty-two clinical studies were included; most were observational and uncontrolled. Fourteen ex vivo studies were analysed. Information on patient characteristics and co-treatments was often missing. The effect of ECMO on PK/PD parameters of antimicrobials varied depending on the studied drugs. Few dosing recommendations could be formulated given the lack of good quality data.

Conclusion: Limited data exist on the PK/PD of antimicrobials during ECMO therapy. Rigorously designed and well powered populational PK studies are required to establish empiric dosing guidelines for antimicrobials in patients requiring ECMO support.

Prospero Registration Number: CRD42018099992 (Registered: July 24th 2018).
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http://dx.doi.org/10.1007/s40265-021-01557-3DOI Listing
July 2021

Prophylaxis for patients at Risk to Eliminate Post-operative Atrial Fibrillation (PREP-AF trial): a protocol for a feasibility randomized controlled study.

Trials 2021 Jun 7;22(1):384. Epub 2021 Jun 7.

Division of Thoracic Surgery, Department of Surgery, University of Ottawa, Ottawa, Canada.

Background: Postoperative atrial fibrillation (POAF) is a frequent adverse event after thoracic surgery with associated morbidity, mortality, and healthcare costs. It has been shown to be preventable with prophylactic amiodarone, which is only recommended in high-risk individuals due to the potential associated side effects. Risk factors for POAF have been identified and incorporated into a prediction model to identify high-risk patients. Further evaluation in the form of a multicenter clinical trial is required to assess the effectiveness of prophylaxis specifically in this high-risk population. The feasibility of such a trial first needs to be assessed.

Methods: The PREP-AF trial is a double-blind randomized controlled feasibility trial. Individuals undergoing major thoracic surgery who are identified to be high-risk by the POAF prediction model will be randomized 1:1 to receive a short course of amiodarone vs. placebo in the immediate postoperative period. The primary outcome is feasibility, which will be measured by the number of eligible patients identified, consented, and randomized; intervention adherence; and measurement of future outcomes of a full trial.

Discussion: This study will determine the feasibility of a randomized controlled trial to assess the effectiveness of prophylactic amiodarone, in high-risk patients undergoing major thoracic surgery. This will inform the development of a multi-center trial to establish if prophylactic amiodarone is safe and effective at reducing the incidence of POAF. Preventing this adverse event will not only improve outcomes for patients but also reduce the associated health resource utilization and costs.

Trial Registration: ClinicalTrials.gov NCT04392921 . Registered on 19 May 2020.
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http://dx.doi.org/10.1186/s13063-021-05318-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182941PMC
June 2021

Delirium and Associated Length of Stay and Costs in Critically Ill Patients.

Crit Care Res Pract 2021 24;2021:6612187. Epub 2021 Apr 24.

Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.

Purpose: Delirium frequently affects critically ill patients in the intensive care unit (ICU). The purpose of this study is to evaluate the impact of delirium on ICU and hospital length of stay (LOS) and perform a cost analysis.

Materials And Methods: Prospective studies and randomized controlled trials of patients in the ICU with delirium published between January 1, 2015, and December 31, 2020, were evaluated. Outcome variables including ICU and hospital LOS were obtained, and ICU and hospital costs were derived from the respective LOS.

Results: Forty-one studies met inclusion criteria. The mean difference of ICU LOS between patients with and without delirium was significant at 4.77 days ( < 0.001); for hospital LOS, this was significant at 6.67 days ( < 0.001). Cost data were extractable for 27 studies in which both ICU and hospital LOS were available. The mean difference of ICU costs between patients with and without delirium was significant at $3,921 ( < 0.001); for hospital costs, the mean difference was $5,936 ( < 0.001).

Conclusion: ICU and hospital LOS and associated costs were significantly higher for patients with delirium, compared to those without delirium. Further research is necessary to elucidate other determinants of increased costs and cost-reducing strategies for critically ill patients with delirium. This can provide insight into the required resources for the prevention of delirium, which may contribute to decreasing healthcare expenditure while optimizing the quality of care.
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http://dx.doi.org/10.1155/2021/6612187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088381PMC
April 2021

The Clinician Scientist.

Can J Hosp Pharm 2021 1;74(2):130-134. Epub 2021 Apr 1.

, BScPharm, PharmD, FCCP, FCCM, is a Clinician Scientist with the Department of Pharmacy and Medicine, Sinai Health System, an Associate Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, and a PhD candidate at the University of Toronto.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042188PMC
April 2021

Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review.

BMC Complement Med Ther 2021 Apr 7;21(1):112. Epub 2021 Apr 7.

The Ottawa Hospital Research Institute (OHRI), Ottawa, Ontario, Canada.

Background: Elderberry has traditionally been used to prevent and treat respiratory problems. During the COVID-19 pandemic, there has been interest in elderberry supplements to treat or prevent illness, but also concern that elderberry might overstimulate the immune system and increase the risk of 'cytokine storm'. We aimed to determine benefits and harms of elderberry for the prevention and treatment of viral respiratory infections, and to assess the relationship between elderberry supplements and negative health impacts associated with overproduction of pro-inflammatory cytokines.

Methods: We conducted a systematic review and searched six databases, four research registers, and two preprint sites for studies. Two reviewers independently assessed studies for inclusion, extracted data from studies, assessed risk of bias using Cochrane tools, and evaluated certainty of estimates using GRADE. Outcomes included new illnesses and the severity and duration of illness.

Results: We screened 1187 records and included five randomized trials on elderberry for the treatment or prevention of viral respiratory illness. We did not find any studies linking elderberry to clinical inflammatory outcomes. However, we found three studies measuring production of cytokines ex vivo after ingestion of elderberry. Elderberry may not reduce the risk of developing the common cold; it may reduce the duration and severity of colds, but the evidence is uncertain. Elderberry may reduce the duration of influenza but the evidence is uncertain. Compared to oseltamivir, an elderberry-containing product may be associated with a lower risk of influenza complications and adverse events. We did not find evidence on elderberry and clinical outcomes related to inflammation. However, we found evidence that elderberry has some effect on inflammatory markers, although this effect may decline with ongoing supplementation. One small study compared elderberry to diclofenac (a nonsteroidal anti-inflammatory drug) and provided some evidence that elderberry is as effective or less effective than diclofenac in cytokine reduction over time.

Conclusions: Elderberry may be a safe option for treating viral respiratory illness, and there is no evidence that it overstimulates the immune system. However, the evidence on both benefits and harms is uncertain and information from recent and ongoing studies is necessary to make firm conclusions.
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http://dx.doi.org/10.1186/s12906-021-03283-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026097PMC
April 2021

A Systematic Review of the Effect of N-Acetylcysteine on Serum Creatinine and Cystatin C Measurements.

Kidney Int Rep 2021 Feb 3;6(2):396-403. Epub 2020 Dec 3.

The Ottawa Hospital, Ottawa, Ontario, Canada.

Introduction: N-acetylcysteine (NAC) is an antioxidant that can regenerate glutathione and is primarily used for acetaminophen overdose. NAC has been tested and used for preventing iatrogenic acute kidney injury or slowing the progression of chronic kidney disease, with mixed results. There are conflicting reports that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, we conducted a systematic review of the literature to determine whether there is an effect of NAC on kidney function as measured with serum creatinine and cystatin C.

Methods: A literature search was conducted to identify all study types reporting a change in serum creatinine after NAC administration. The primary outcome was change in serum creatinine after NAC administration. The secondary outcome was a change in cystatin C after NAC administration. Subgroup analyses were conducted to assess effect of creatinine assay (Jaffe vs. non-Jaffe and intravenous vs. oral).

Results: Six studies with a total of 199 participants were eligible for the systematic review and meta-analysis. There was a small but significant decrease in serum creatinine after NAC administration overall (weighted mean difference [WMD], -2.80 μmol/L [95% confidence interval {CI} -5.6 to 0.0];  = 0.05). This was greater with non-Jaffe methods (WMD, -3.24 μmol/L [95% CI -6.29 to -0.28];  = 0.04) than Jaffe (WMD, -0.51 μmol/L [95% CI -7.56 to 6.53];  = 0.89) and in particular with intravenous (WMD, -31.10 μmol/L [95% CI -58.37 to -3.83];  = 0.03) compared with oral NAC (WMD, -2.5 μmol/L [95% CI -5.32 to 0.32];  = 0.08). There was no change in cystatin C after NAC administration.

Discussion: NAC causes a decrease in serum creatinine but not in cystatin C, suggesting analytic interference rather than an effect on kidney function. Supporting this, the effect was greater with non-Jaffe methods of creatinine estimation. Future studies of NAC should use the Jaffe method of creatinine estimation when kidney outcomes are being reported. Even in clinical settings, the use of an enzymatic assay when high doses of intravenous NAC are being used may result in underdiagnosis or delayed diagnosis of acute kidney injury.
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http://dx.doi.org/10.1016/j.ekir.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879108PMC
February 2021

Clinical and pharmacokinetic/dynamic outcomes of prolonged infusions of beta-lactam antimicrobials: An overview of systematic reviews.

PLoS One 2021 22;16(1):e0244966. Epub 2021 Jan 22.

The Ottawa Hospital, Ottawa, Ontario, Canada.

Objective: This overview of reviews aims to map and compare of objectives, methods, and findings of existing systematic reviews to develop a greater understanding of the information available about prolonged beta-lactam infusions in hospitalized patients with infection.

Design: Overview of systematic reviews.

Data Sources: Medline, Embase, PROSPERO and the Cochrane Library were systematically searched from January, 1990 to June, 2019 using a peer reviewed search strategy. Grey literature was also searched for relevant reviews.

Eligibility Criteria For Selecting Reviews: Systematic reviews were sought that compared two or more infusion strategies for intravenous beta-lactam antimicrobials and report clinical cure or mortality. Populations of included reviews were restricted to hospitalized patients with infection, without restrictions on age, infection type, or disease.

Data Extraction And Analysis: Abstract screening, data extraction, quality and risk of bias assessment were conducted by two independent reviewers. Overlap between reviews was assessed using a modified corrected covered area. Overview findings are reported in accordance with Cochrane's recommendation for overview conduct. Clinical outcomes extracted included survival, clinical cure, treatment failure, microbiological cure, length of stay, adverse events, cost, and emergence of resistance.

Results: The search strategy identified 3327 unique citations from which 21 eligible reviews were included. Reviews varied by population, intervention and outcomes studied. Between reviews, overlap of primary studies was generally high, methodologic quality generally low and risk of bias variable. Nine of 14 reviews that quantitatively evaluated mortality and clinical cure identified a benefit with prolonged infusions of beta lactams when compared with intermittent infusions. Evidence of mortality and clinical cure benefit was greater among critically ill patients when compared to less sick patients and lower in randomized controlled trials when compared with observational studies.

Conclusions: Findings from our review demonstrate a consistent and reproducible lack of harm with prolonged infusions of beta-lactam antibiotics with variability in effect size and significance of benefits. Despite 21 systematic reviews addressing prolonged infusions of beta-lactams, this overview supports the continued need for a definitive systematic review given variability in populations, interventions and outcomes in the current systematic reviews. Subsequent systematic reviews should have more rigorous and transparent methods, only include RCTs and evaluate the proposed benefits found in various subgroup-analyses-i.e. high risk of mortality.

Trial Registration: Prospero registry, CRD42019117118.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244966PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822342PMC
May 2021

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

Healthc Q 2021 Jan;23(4):17-22

A physician in Mississauga, ON, and was previously associated with the Ontario Palliative Care Network, Ontario Health. During the COVID-19 pandemic, he represented the Ontario Palliative Care Network in working with the Ontario Ministry of Health to develop the province's approach to managing the palliative care drug supply in community settings.

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.
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http://dx.doi.org/10.12927/hcq.2020.26398DOI Listing
January 2021

Chemotherapy in the Intensive Care Unit: An Evaluation of Context and Outcomes.

Can J Hosp Pharm 2020 1;73(4):279-287. Epub 2020 Oct 1.

, MD, MHA, FRCPC, is with The Ottawa Hospital, Ottawa, Ontario.

Background: Administration of chemotherapy to highly vulnerable, critically ill patients in the intensive care unit (ICU) is becoming more common, but the process requires significantly more resources than chemotherapy administration in specialized oncology settings.

Objective: To describe the context, complications, and outcomes of chemotherapy administration for cancer-related indications in ICU patients.

Methods: For this retrospective observational study, consecutive patients receiving parenteral chemotherapy in the ICU at the General Campus of The Ottawa Hospital between January 1, 2014, and December 31, 2017, were identified using pharmacy records. The clinical characteristics of these patients, details of their chemotherapy regimens, and outcomes were analyzed.

Results: A total of 32 patients were included in the study. Of these, 27 patients (84%) had a hematological malignancy, 16 (50%) had a documented infection at the time of chemotherapy administration, and 29 (91%) received their first cycle of chemotherapy on an urgent basis during the ICU admission rather than as a scheduled or planned treatment. Severity of illness was high both at ICU admission and at the time of chemotherapy treatment; regimen modifications, drug interactions, and adverse events were common. Remission and survival data were available for 28 patients at 12 months. Eighteen (56%) of the 32 patients survived to hospital discharge, and 12 (38%) survived to 6 months; at 12 months, survival was 25% (7 of 28 patients with available data). About one-quarter of the patients were in remission at 6 and 12 months.

Conclusion: Administering chemotherapy in the ICU is feasible, but the process is resource-intensive. Patients with aggressive hematological cancers who require treatment on an urgent basis represent the most commonly observed scenario. This study highlights the complexity of management and the importance of multidisciplinary care teams for this patient population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556399PMC
October 2020

It Takes a Village…: Contending With Drug Shortages During Disasters.

Chest 2020 12 14;158(6):2414-2424. Epub 2020 Aug 14.

The University of Arizona College of Pharmacy, Tucson, AZ.

Critical drug shortages have been widely documented during the coronavirus disease 2019 (COVID-19) pandemic, particularly for IV sedatives used to facilitate mechanical ventilation. Surges in volume of patients requiring mechanical ventilation coupled with prolonged ventilator days and the high sedative dosing requirements observed quickly led to the depletion of "just-in-time" inventories typically maintained by institutions. This manuscript describes drug shortages in the context of global, manufacturing, regional and institutional perspectives in times of a worldwide crisis such as a pandemic. We describe etiologic factors that lead to drug shortages including issues related to supply (eg, manufacturing difficulties, supply chain breakdowns) and variables that influence demand (eg, volatile prescribing practices, anecdotal or low-level data, hoarding). In addition, we describe methods to mitigate drug shortages as well as conservation strategies for sedatives, analgesics and neuromuscular blockers that could readily be applied at the bedside. The COVID-19 pandemic has accentuated the need for a coordinated, multi-pronged approach to optimize medication availability as individual or unilateral efforts are unlikely to be successful.
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http://dx.doi.org/10.1016/j.chest.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426714PMC
December 2020

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.

Can J Anaesth 2020 10 26;67(10):1405-1416. Epub 2020 May 26.

The Ottawa Hospital, Ottawa, ON, Canada.

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.
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http://dx.doi.org/10.1007/s12630-020-01713-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297429PMC
October 2020

Drug induced pancreatitis: A systematic review of case reports to determine potential drug associations.

PLoS One 2020 17;15(4):e0231883. Epub 2020 Apr 17.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Objective: A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations.

Methods: A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency.

Results: Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis.

Discussion: Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations.

Registration: CRD42017060473.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231883PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164626PMC
July 2020

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.

Clin Infect Dis 2021 04;72(8):1369-1378

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1093/cid/ciaa224DOI Listing
April 2021

Effects of medical and non-medical cannabis use in older adults: protocol for a scoping review.

BMJ Open 2020 02 28;10(2):e034301. Epub 2020 Feb 28.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Introduction: With its legalisation and regulation in Canada in 2018, the proportion of Canadians reporting cannabis use in 2019 increased substantially over the previous year, with half of new users being aged 45+ years. While use in older adults has been low historically, as those born in the 1950s and 1960s continue to age, this demographic will progressively have more liberal attitudes, prior cannabis exposure and higher use rates. However, older adults experience slower metabolism, increased likelihood of polypharmacy, cognitive decline and chronic physical/mental health problems. There is a need to enhance knowledge of the effects of cannabis use in older adults. The following question will be addressed using a scoping review approach: what evidence exists regarding beneficial and harmful effects of medical and non-medical cannabis use in adults >50 years of age? Given that beneficial and harmful effects of cannabis may be mediated by patient-level (eg, age, sex and race) and cannabis-related factors (eg, natural vs synthetic, consumption method), subgroup effects related to these and additional factors will be explored.

Methods And Analysis: Methods for scoping reviews outlined by Arksey & O'Malley and the Joanna Briggs Institute will be used. A librarian designed a systematic search of the literature from database inception to June 2019. Using the OVID platform, Ovid MEDLINE will be searched, including Epub Ahead of Print and In-Process and Other Non-Indexed Citations, Embase Classic+Embase, and PsycINFO for reviews, randomised trials, non-randomised trials and observational studies of cannabis use. The Cochrane Library on Wiley will also be searched. Eligibility criteria will be older adult participants, currently using cannabis (medical or non-medical), with studies required to report a cannabis-related health outcome to be eligible. Two reviewers will screen citations and full texts, with support from artificial intelligence. Two reviewers will chart data. Tables/graphics will be used to map evidence and identify evidence gaps.

Ethics And Dissemination: This research will enhance awareness of existing evidence addressing the health effects of medical and non-medical cannabis use in older adults. Findings will be disseminated through a peer-reviewed publication, conference presentations and a stakeholder meeting.

Trial Registration Number: DOI 10.17605/OSF.IO/5JTAQ.
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http://dx.doi.org/10.1136/bmjopen-2019-034301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050329PMC
February 2020

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial.

Trials 2020 Jan 8;21(1):42. Epub 2020 Jan 8.

Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada.

Background: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis.

Methods: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned.

Discussion: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis.

Trial Registration: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.
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http://dx.doi.org/10.1186/s13063-019-3834-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950903PMC
January 2020

Benefits and harms of medical cannabis: a scoping review of systematic reviews.

Syst Rev 2019 12 10;8(1):320. Epub 2019 Dec 10.

Knowledge Synthesis Group, Ottawa Methods Centre, Ottawa Hospital Research Institute, The Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, Ontario, K1H 8 L6, Canada.

Background: There has been increased interest in the role of cannabis for treating medical conditions. The availability of different cannabis-based products can make the side effects of exposure unpredictable. We sought to conduct a scoping review of systematic reviews assessing benefits and harms of cannabis-based medicines for any condition.

Methods: A protocol was followed throughout the conduct of this scoping review. A protocol-guided scoping review conduct. Searches of bibliographic databases (e.g., MEDLINE®, Embase, PsycINFO, the Cochrane Library) and gray literature were performed. Two people selected and charted data from systematic reviews. Categorizations emerged during data synthesis. The reporting of results from systematic reviews was performed at a high level appropriate for a scoping review.

Results: After screening 1975 citations, 72 systematic reviews were included. The reviews covered many conditions, the most common being pain management. Several reviews focused on management of pain as a symptom of conditions such as multiple sclerosis (MS), injury, and cancer. After pain, the most common symptoms treated were spasticity in MS, movement disturbances, nausea/vomiting, and mental health symptoms. An assessment of review findings lends to the understanding that, although in a small number of reviews results showed a benefit for reducing pain, the analysis approach and reporting in other reviews was sub-optimal, making it difficult to know how consistent findings are when considering pain in general. Adverse effects were reported in most reviews comparing cannabis with placebo (49/59, 83%) and in 20/24 (83%) of the reviews comparing cannabis to active drugs. Minor adverse effects (e.g., drowsiness, dizziness) were common and reported in over half of the reviews. Serious harms were not as common, but were reported in 21/59 (36%) reviews that reported on adverse effects. Overall, safety data was generally reported study-by-study, with few reviews synthesizing data. Only one review was rated as high quality, while the remaining were rated of moderate (n = 36) or low/critically low (n = 35) quality.

Conclusions: Results from the included reviews were mixed, with most reporting an inability to draw conclusions due to inconsistent findings and a lack of rigorous evidence. Mild harms were frequently reported, and it is possible the harms of cannabis-based medicines may outweigh benefits.

Systematic Review Registration: The protocol for this scoping review was posted in the Open Access (https://ruor.uottawa.ca/handle/10393/37247).
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http://dx.doi.org/10.1186/s13643-019-1243-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905063PMC
December 2019

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

Can J Anaesth 2020 03 3;67(3):369-376. Epub 2019 Dec 3.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

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).
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http://dx.doi.org/10.1007/s12630-019-01546-xDOI Listing
March 2020

Methods for the early detection of drug-induced pancreatitis: a systematic review of the literature.

BMJ Open 2019 11 5;9(11):e027451. Epub 2019 Nov 5.

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Objectives: We systematically reviewed the literature to identify evidence-informed recommendations regarding the detection of drug-induced pancreatitis (DIP) and, secondarily, to describe clinical processes for the diagnosis of DIP.

Design: Systematic review.

Data Sources: Ovid MEDLINE, including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase Classic+Embase, the Cochrane Library.

Eligibility Criteria: We included clinical practice guidelines, systematic reviews, narrative reviews and observational studies with a focus of establishing incidence, prevalence or diagnostic approaches for DIP. Clinical trials that diagnosed DIP as an outcome were also included.

Data Extraction And Synthesis: Two reviewers screened citations and performed data extraction. A narrative synthesis of the evidence was prepared.

Results: Fifty-nine studies were included. Early published evidence suggested serial pancreatic ultrasound could detect subclinical pancreatitis; however, subsequent studies demonstrated no utility of serial ultrasound or serial monitoring of pancreatic enzymes in the early detection of DIP. Two small studies conducted in patients with a high baseline risk of acute pancreatitis concluded serial monitoring of pancreatic enzymes may be useful to guide early discontinuation of medications with known associations with pancreatitis. Early discontinuation of medication was not advised for lower-risk patients because some medications cause transient elevations of pancreatic enzymes that do not progress to acute pancreatitis. Eight of 52 studies (15%) reporting a clinical diagnostic process for DIP reported using currently accepted criteria for the diagnosis of acute pancreatitis. A variety of methods were used to assess drug-related causality.

Conclusions: There is minimal evidence to support the use of serial monitoring by ultrasound or pancreatic enzymes to detect cases of DIP. Serial monitoring may be useful to guide early discontinuation of DIP-associated drugs in high-risk patients, but not in lower-risk patients. Greater uptake of standardised diagnostic and causality criteria for DIP is needed.

Trial Registration Number: CRD42017060473.
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http://dx.doi.org/10.1136/bmjopen-2018-027451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858245PMC
November 2019

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

Clin Pharmacokinet 2020 03;59(3):327-334

The Ottawa Hospital, The Ottawa Hospital Research Institute, 501 Smyth Rd, Ottawa, ON, Canada.

Background: Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking.

Objective: The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies.

Methods: Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses.

Results: From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46) L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration-time curve from time zero to 24 h [AUC]/minimum inhibitory concentration [MIC] ≥ 400) and safety (AUC ≥ 700), a loading dose of 2400 mg followed by daily doses of 1600 mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels.

Conclusions: In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels.
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http://dx.doi.org/10.1007/s40262-019-00817-6DOI Listing
March 2020

Administration of Intravenous Ascorbic Acid-Practical Considerations for Clinicians.

Nutrients 2019 Aug 23;11(9). Epub 2019 Aug 23.

Department of Critical Care Medicine, Sunnybrook Health Sciences Centre and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON M4N 3M5, Canada.

Emerging data suggest that intravenous ascorbic acid (AA) may be beneficial in patients with sepsis. Clinicians require data on stability of diluted AA for safe administration. We evaluated the stability of AA diluted in normal saline (NS) or 5% dextrose in water (D5W) solutions over 14 days at 25 °C and at 4 °C, protected from light, using concentrations of 37 mg/mL and 77 mg/mL (Sandoz) and 40 mg/mL and 92 mg/mL (Mylan). We also assessed stability of a 40 mg/mL solution (Mylan) at 25 °C exposed to light for 75 h. Concentrations were measured using liquid chromatographic separation with ultraviolet light detection on days 0, 0.33, 1, 1.33, 2, 3, 4, 7, 10 and 14. By day 14, solutions at 4 °C retained >97.72% of the initial concentration; at 25 °C, solutions retained >88.02% of the initial concentration, but visual changes were evident after day 2. Multiple linear regression demonstrated that study day and temperature ( < 0.001) but not solution type ( = 0.519), concentration ( = 0.677) or manufacturer ( = 0.808) were associated with the percentage remaining. At 75 h, degradation rates were similar in solutions protected from vs. exposed to light. In conclusion, AA solutions are stable for at least 14 days at 4 °C, with protection from light.
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http://dx.doi.org/10.3390/nu11091994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769642PMC
August 2019

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

Palliat Med 2019 09 11;33(8):865-877. Epub 2019 Jun 11.

1 Division of Palliative Care, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.

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 ( = 34) and mixed diagnoses ( = 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 ( = 8) was 42%-88%. Pooled point prevalence on admission to inpatient palliative care units was 35% (confidence interval = 0.29-0.40,  = 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.
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http://dx.doi.org/10.1177/0269216319854944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691600PMC
September 2019

Intervention Development Process for a Pragmatic Randomized Controlled Trial: The Thoracic Peri-Operative Integrative Surgical Care Evaluation Trial.

J Altern Complement Med 2019 Mar;25(S1):S112-S123

3 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.

Background: Use of complementary therapies is high among people with cancer despite research gaps. The Thoracic Peri-Operative Integrative Surgical Care Evaluation (POISE) Trial will evaluate the impact of an integrative care intervention delivered by naturopathic doctors (NDs) in conjunction with usual care for patients undergoing surgery for lung, gastric, and esophageal cancer.

Objectives: To describe the multistep, multidisciplinary process of defining the integrative care intervention to be used in the Thoracic POISE trial using a principle-based approach that is pragmatic, holistic, safe, feasible, evidence driven, and consensus based.

Methods: An Intervention Development Committee (IDC) made up of a multidisciplinary team of health care providers (NDs, surgeons, oncologists, nurses, dietitians, physiotherapists, pharmacists, and psychologists), researchers, and patients was established to oversee the process. Potential intervention components were identified through a clinical practice survey and expert opinion. Systematic literature reviews were conducted and scores assigned based on the following criteria: usage, safety, goals, feasibility/scalability, and evidence. The IDC selected an intervention to be piloted that consists of a standard palette including core and optional components. Safety, known risks, and interactions with pharmaceuticals were evaluated using industry and professional monographs, a scoping literature review, and consultations with hospital pharmacists.

Results: The clinical practice survey and expert opinion identified 28 components for consideration. Following literature reviews, scoring, consensus from the IDC, and safety and interaction considerations, an intervention palette consisting of core and optional components was defined. The intervention options vary based on the patient's phase of treatment and symptom-specific needs. The intervention includes supplements, physical recommendations (exercise), nutritional counseling, and psychological support (audio scripts).

Conclusion: Through a multistep, multidisciplinary process an integrative care intervention was developed for the Thoracic POISE trial. The intervention will be piloted in a single-arm feasibility study, followed by a single-center randomized controlled trial (RCT), and finally a multicenter RCT.
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http://dx.doi.org/10.1089/acm.2018.0419DOI Listing
March 2019

Outcomes after toxic alcohol poisoning: a systematic review protocol.

Syst Rev 2018 12 28;7(1):250. Epub 2018 Dec 28.

The Ottawa Hospital - Riverside Campus, 1967 Riverside Drive, Ottawa, Ontario, K1H 7W9, Canada.

Background: Toxic alcohols have been implicated in accidental ingestions and intentional exposures. Recognition of toxic alcohol poisoning is challenging. The main treatment modalities include antidotes with alcohol dehydrogenase inhibitors and dialysis. Current guidelines exist for both methanol and ethylene glycol intoxication. However, treatment consensus related to other toxic alcohols is limited. Furthermore, uncertainties regarding thresholds for when to initiate antidotes and dialysis persist. As a consequence, variations exist in the interventions utilized for management of all toxic alcohol poisonings. To our knowledge, no prior systematic review of clinical outcomes of toxic alcohols exists. The objective of this study is to summarize existing evidence on short- and long-term outcomes of patients following toxic alcohol poisonings, including methanol, ethylene glycol, isopropanol, propylene glycol, and diethylene glycol.

Methods: A literature search in PubMed, MEDLINE, and EMBASE will be performed based on pre-determined criteria. There will be no restrictions on publication dates or languages. The search will be supplemented by manual scan of bibliographies of eligible studies and gray literature assessment. Observational studies and clinical trials will be included in this review. Once eligible studies have been selected based on pre-specified criteria, two investigators will extract relevant data independently and perform quality assessment per validated tools. A pooled analysis of mortality and short- and long-term secondary outcomes will be performed. Pre-specified subgroup analyses will be performed according to the type of toxic alcohol intoxication, mode of renal replacement therapy, and medical interventions received. A meta-analysis will be performed if three or more studies with similar populations, type of toxic alcohol poisoning, and outcome measures, as well as adequate quality, are identified. This review will be reported according to the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Statement.

Discussion: This systematic review aims to synthesize current evidence in the short- and long-term outcomes of post-toxic alcohol poisoning. The results will enhance the understanding of patient morbidity and mortality after toxic alcohol poisoning, help inform uniform concrete management guideline development, identify gaps in the current state of knowledge, and provide evidence to help implement post-treatment follow-up.

Systematic Review Registration: PROSPERO CRD42018101955.
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http://dx.doi.org/10.1186/s13643-018-0926-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309090PMC
December 2018

A Scoping Review to Map Empirical Evidence Regarding Key Domains and Questions in the Clinical Pathway of Delirium in Palliative Care.

J Pain Symptom Manage 2019 03 12;57(3):661-681.e12. Epub 2018 Dec 12.

Division of Palliative Care, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Bruyère Continuing Care, Ottawa, Ontario, Canada; Bruyère Research Institute, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Context: Based on the clinical care pathway of delirium in palliative care (PC), a published analytic framework (AF) formulated research questions in key domains and recommended a scoping review to identify evidence gaps.

Objectives: To produce a literature map for key domains of the published AF: screening, prognosis and diagnosis, management, and the health-related outcomes.

Methods: A standard scoping review framework was used by an interdisciplinary study team of nurse- and physician-delirium researchers, an information specialist, and review methodologists to conduct the review. Knowledge user engagement provided context in refining 19 AF questions. A peer-reviewed search strategy identified citations in Medline, PsycINFO, Embase, and CINAHL databases between 1980 and 2018. Two reviewers independently screened records for inclusion using explicit study eligibility criteria for the population, design, delirium diagnosis, and investigational intent.

Results: Of 104 studies reporting empirical data and meeting eligibility criteria, most were conducted in patients with cancer (73.1%) and in inpatient PC units (52%). The most frequent study design was a one or more group, nonrandomized trial or cohort (67.3%). Evidence gaps were identified: delirium risk prediction; comparative effectiveness and harms of prevention, variability in delirium management across PC settings, advanced directive and substitute decision-maker input, and transition of care location; and estimating delirium reversibility. Future rigorous primary studies are required to address these gaps and preliminary concerns regarding the quality of extant literature.

Conclusion: Substantial evidence gaps exist, providing opportunities for future research regarding the assessment, prognosis, and management of delirium in PC settings.
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http://dx.doi.org/10.1016/j.jpainsymman.2018.12.002DOI Listing
March 2019
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