Anne Julie Frenette

Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials.

In the intensive care unit, dopamine agonists (DA) have been used in traumatic brain injury (TBI) patients to augment or accelerate cognitive recovery and rehabilitation. However, the efficacy and safety of DA in this population is not well established. We conducted a systematic review of randomized controlled trials (RCTs) examining the clinical efficacy and safety of DA in patients with TBI. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, comparing DA to either placebo, standard treatment, or another active comparator. There was no restriction for age, date, or language of publication. Sensitivity analyses were planned to evaluate the potential effect of timing of TBI, age, drugs, and year of publication on efficacy. Among the 790 citations identified, 20 RCTs evaluating methylphenidate, amantadine, and bromocriptine were eligible. Significant clinical heterogeneity was observed between and within studies, which precluded any pooling of data. Efficacy outcomes included mainly neuropsychological measures of cognitive functioning. A total of 76 different neuropsychological tests were used, but most of them (59%) only once. Only 5 studies systematically assessed safety. No trend could be drawn from the analysis of efficacy and safety. Important sources of bias in the studies were of major concern. Considering the absence of consensus regarding clinical outcome, the lack of safety assessment, and the high risk of bias in the included trials, more research is warranted before DA can be recommended in critically ill TBI patients.

Albumin administration is associated with acute kidney injury in cardiac surgery: a propensity score analysis

IntroductionThe risk of acute kidney injury (AKI) with the use of albumin-containing fluids compared to starches in the surgical intensive care setting remains uncertain. We evaluated the adjusted risk of AKI associated with colloids following cardiac surgery.MethodsWe performed a retrospective cohort study of patients undergoing on-pump cardiac surgery in a tertiary care center from 2008 to 2010. We assessed crystalloid and colloid administration until 36 hours after surgery. AKI was defined by the RIFLE (risk, injury, failure, loss and end-stage kidney disease) risk and Acute Kidney Injury Network (AKIN) stage 1 serum creatinine criterion within 96 hours after surgery.ResultsOur cohort included 984 patients with a baseline glomerular filtration rate of 72 ± 19 ml/min/1.73 m2. Twenty-three percent had a reduced left ventricular ejection fraction (LVEF), thirty-one percent were diabetics and twenty-three percent underwent heart valve surgery. The incidence of AKI was 5.3% based on RIFLE risk and 12.0% based on the AKIN criterion. AKI was associated with a reduced LVEF, diuretic use, anemia, heart valve surgery, duration of extracorporeal circulation, hemodynamic instability and the use of albumin, pentastarch 10% and transfusions. There was an important dose-dependent AKI risk associated with the administration of albumin, which also paralleled a higher prevalence of concomitant risk factors for AKI. To address any indication bias, we derived a propensity score predicting the likelihood to receive albumin and matched 141 cases to 141 controls with a similar risk profile. In this analysis, albumin was associated with an increased AKI risk (RIFLE risk: 12% versus 5%, P = 0.03; AKIN stage 1: 28% versus 13%, P = 0.002). We repeated this methodology in patients without postoperative hemodynamic instability and still identified an association between the use of albumin and AKI.ConclusionsAlbumin administration was associated with a dose-dependent risk of AKI and remained significant using a propensity score methodology. Future studies should address the safety of albumin-containing fluids on kidney function in patients undergoing cardiac surgery.

Corticosteroids in the management of brain-dead potential organ donors: a systematic review

Summary Current guidelines recommend the administration of hormonal combination therapy including immunosuppressive doses of corticosteroids to donors with low left ventricular ejection fractions and to consider hormonal therapy administration to all donors. However, these recommendations are largely based on observational data. The aim of this systematic review (SR) was to assess the clinical efficacy and safety of corticosteroids in brain-dead potential organ donors. MEDLINE and EMBASE were searched from the earliest accessible date up to March 2013 with a qualified librarian. Studies comparing the effects of any corticosteroid with those of placebo, standard treatment, or another active comparator were sought. Two independent reviewers evaluated each citation retrieved and selected studies independently and in duplicate. A third independent reviewer resolved any disagreement. Outcomes included donor haemodynamics and oxygenation, organ procurement, recipient survival, and graft survival. This review included 11 randomized controlled trials (RCTs) and 14 observational studies. The majority used methylprednisolone and often combined it with other hormonal therapies. Ten out of the 11 RCTs yielded neutral results. However, in observational studies, use of corticosteroids generally resulted in improved donor haemodynamics and oxygenation status, increased organ procurement, and improved recipient and graft survival. Overall quality of included studies was poor, as most of them presented high risks of confounding. This SR highlights the low quality and conflicting evidence supporting the routine use of corticosteroids in the management of organ donors. A large trial evaluating the effect of corticosteroids on outcomes such as organ recovery and graft survival is warranted.

Febuxostat as a Novel Option to Optimize Thiopurines’ Metabolism in Patients With Inadequate Metabolite Levels

Objective: To report the use of febuxostat in order to potentiate thiopurines’ metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels. Case Summary: A 44-year-old woman with a history of anti–signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped. Discussion: AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines’ metabolism. Conclusion: It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines’ metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines’ metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.

A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension

PurposeClinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients.MethodsWe searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects.ResultsOf 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01).ConclusionCurrent evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.RésuméObjectifLes cliniciens doivent équilibrer les risques liés à l’hypotension aux complications potentielles des vasopresseurs. Des experts ont recommandé de cibler une tension artérielle moyenne (TAM) d’au moins 65 mmHg, et une TAM plus élevée chez les patients atteints d’hypertension chronique, d’athérosclérose ou plus âgés. Nous avons réalisé une revue systématique des études randomisées contrôlées comparant des cibles de tension artérielle plus élevées à plus basses chez des patients hypotendus en état critique recevant un traitement vasopresseur.MéthodeNous avons fait des recherches dans les bases de données Medline, EMBASE et dans le registre central des études contrôlées Cochrane afin d’en extraire les études comparant des cibles de tension artérielle plus élevées ou plus basses chez des patients adultes hypotendus et en état critique recevant un traitement vasopresseur. Deux examinateurs ont évalué de façon indépendante l’éligibilité des études selon leur titre et leur résumé, puis sélectionné les articles intégraux. Les critères d’évaluation, sous-groupes et analyses étaient spécifiés au préalable. Nous avons utilisé le système GRADE (Grading of Recommendations Assessment, Development and Evaluation) afin d’évaluer la confiance globale dans les estimations des effets de l’intervention.RésultatsParmi les 8001 citations, nous avons extrait 57 articles intégraux et finalement inclus deux études randomisées contrôlées (894 patients). Les cibles de tension artérielle plus élevées n’étaient pas associées à une mortalité plus basse (risque relatif [RR] 1,05; intervalle de confiance [IC] 95 %, 0,90 à 1,23; P = 0,54), et ni l’âge (P = 0,17) ni l’hypertension chronique (P = 0,32) n’ont modifié l’effet global. Cependant, les cibles de tension artérielle plus élevées étaient associées à un risque plus élevé de nouvelle apparition d’une arythmie cardiaque supraventriculaire (RR, 2,08; IC 95 %, 1,28 à 3,38; P < 0,01).ConclusionLes données probantes actuelles n’appuient pas une cible de TAM supérieure à 70 mmHg chez les patients adultes hypotendus et gravement malades nécessitant un traitement vasopresseur.

Stability of levothyroxine injection in glass, polyvinyl chloride, and polyolefin containers

PURPOSE The 24-hour stability of a levothyroxine solution admixed and stored in three common infusion containers and infused through polyvinyl chloride (PVC) tubing was evaluated. METHODS Levothyroxine sodium 1-μg/mL injection prepared in glass bottles and PVC and polyolefin bags were assayed using high-performance liquid chromatography at 0, 1, 3, 6, 12, and 24 hours; samples drawn directly from the containers, as well as from the distal end of attached PVC tubing, were assayed. The area under the time-versus-concentration curve (AUC) for predicted and delivered doses was calculated; analysis of variance was used for comparison of the percentages of predicted and actual AUC values. RESULTS The levothyroxine concentration was stable in glass bottles and polyolefin bags through 24 hours (mean ± S.D. percentage of initial concentration remaining, 103.5% ± 2.5% and 100.0% ± 2.9%, respectively). In the PVC infusion bags, the amount of drug decreased to 90% of the initial concentration within 1 hour and then rose and remained within acceptability limits. The levothyroxine concentration of the samples infused through PVC line from glass and polyolefin containers decreased after 1 hour by about 13%; the loss of the drug from the samples infused from PVC bags was higher (18%), presumably due to additive adsorptive effects. In all samples tested, the drug concentration rebounded and remained above 90% to the end of the study. CONCLUSION Levothyroxine sodium 1-μg/mL solution was stable for 24 hours in glass bottles and polyolefin bags but when stored in PVC bags, the concentration decreased by 10% after 1 hour.

Thiopental-associated dyskalemia in severe head trauma.

Thiopental is an ultra short-acting barbiturate that is used mainly as an induction agent for anesthesia. In addition, its potent agonistic action on the -aminobutyric acid (GABA) receptor A makes it a useful agent in refractory status epilepticus. Thiopental also acts as a neuroprotectant by decreasing the activity of the neuroexcitatory glutamatergic system, decreasing the intracellular calcium accumulation, and potentially scavenging reactive oxygen species. Globally, these effects result in a decrease in cerebral metabolic rate of oxygen consumption (CMRO2) as well as cerebral blood flow (CBF), and may be beneficial in the treatment of elevated intracranial pressure (ICP) states complicating head traumas and subarachnoid hemorrhage (SAH). However, this therapy is associated with serious side effects and is generally used as a last resort. Severe dyskalemia is now being recognized as a serious and potentially lethal complication of thiopental infusions. It has been associated with both hypokalemia during the infusion and rebound postinfusion hyperkalemia. We describe three cases of patients manifesting severe postinfusion hyperkalemia.

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

Because the pharmacokinetic evaluation of valproic acid (VPA) based on total drug concentration may be misleading in patients with hypoalbuminemia as a result of saturable protein binding and saturable metabolism, we sought to investigate the usefulness of therapeutic drug monitoring of unbound VPA concentration in a real‐world clinical context, with a focus on clinically significant neurologic adverse outcomes.

Early vasopressor use following traumatic injury: a systematic review

Objectives Current guidelines suggest limiting the use of vasopressors following traumatic injury; however, wide variations in practice exist. Although excessive vasoconstriction may be harmful, these agents may help reduce administration of potentially harmful resuscitation fluids. This systematic review aims to compare early vasopressor use to standard resuscitation in adults with trauma-induced shock. Design Systematic review. Data sources We searched MEDLINE, EMBASE, ClinicalTrials.gov and the Central Register of Controlled Trials from inception until October 2016, as well as the proceedings of 10 relevant international conferences from 2005 to 2016. Eligibility criteria for selecting studies Randomised controlled trials and controlled observational studies that compared the early vasopressor use with standard resuscitation in adults with acute traumatic injury. Results Of 8001 citations, we retrieved 18 full-text articles and included 6 studies (1 randomised controlled trial and 5 observational studies), including 2 published exclusively in abstract form. Across observational studies, vasopressor use was associated with increased short-term mortality, with unadjusted risk ratios ranging from 2.31 to 7.39. However, the risk of bias was considered high in these observational studies because patients who received vasopressors were systematically sicker than patients treated without vasopressors. One clinical trial (n=78) was too imprecise to yield meaningful results. Two clinical trials are currently ongoing. No study measured long-term quality of life or cognitive function. Conclusions Existing data on the effects of vasopressors following traumatic injury are of very low quality according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. With emerging evidence of harm associated with aggressive fluid resuscitation and, in selected subgroups of patients, with permissive hypotension, the alternatives to vasopressor therapy are limited. Observational data showing that vasopressors are part of usual care would provide a strong justification for high-quality clinical trials of early vasopressor use during trauma resuscitation. Trial registration number CRD42016033437.

Pharmacological interventions for agitation in patients with traumatic brain injury: protocol for a systematic review and meta-analysis.

BackgroundTraumatic brain injury (TBI) is a worldwide leading cause of mortality and disability. Among TBI complications, agitation is a frequent behavioural problem. Agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. Pharmacological treatments are often considered for agitation management following TBI. Several types of agents have been proposed for the treatment of agitation. However, the benefit and safety of these agents in TBI patients as well as their differential effects and interactions are uncertain. In addition, animal studies and observational studies have suggested impaired cognitive function with the use of certain antipsychotics and benzodiazepines. Hence, a safe and effective treatment for agitation, which does not interfere with neurological recovery, remains to be identified.Methods/designWith the help of Health Sciences librarian, we will design a search strategy in the following databases: PubMed, Ovid MEDLINE®, EMBASE, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science, and Prospero. A grey literature search will be performed using the resources suggested in CADTH’s Grey Matters. We will include all randomized controlled, quasi-experimental, and observational studies with control groups. The population of interest is all patients, including children and adults, who have suffered a TBI. We will include studies in which agitation, not further defined, was the presenting symptom or one of the presenting symptoms. We will also include studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in TBI patients. We will include studies evaluating all pharmacological interventions including beta-adrenergic blockers, typical and atypical antipsychotics, anticonvulsants, dopamine agonists, psychostimulants, antidepressants, alpha-2-adrenergic agonists, hypnotics, and anxiolytics.DiscussionAlthough agitation is frequent following TBI and pharmacological agents that are often used, there is no consensus on the most efficacious and safest strategy to treat these complications. There is a need for an updated systematic review to summarize the evidence in order to inform practice and future research.Systematic review registrationPROSPERO CRD42016033140