Marc M. Perreault

Systematic Review of Antipsychotics for the Treatment of Hospital-Associated Delirium in Medically or Surgically III Patients

Objective: To determine which antipsychotic is associated with the greatest efficacy and safety when used for the pharmacotherapeutic management of delirium in medically or surgically ill patients. Data Sources: MEDLINE, Current Contents, Cumulative Index of Nursing and Allied Health Literature, PsyclNFO, Biological Abstracts, Cochrane Central Register of Controlled Trials, and EMBASE databases (all to July 2006) were searched for trials evaluating the pharmacologic treatment of delirium in medically or surgically ill patients. The key terms used included delirium, agitation, or acute confusion, and antipsychotics, phenothiazine, butyrophenone, perphenazine, fluphenazine, clozapine, trifluorophenazine, loxapine, thioridazine, pimozide, molindone, haloperidol, methotrimeprazine, chlorpromazine, prochlorperazine, droperidol, risperidone, quetiapine, ziprasidone, amisulpride, or olanzapine. Study Selection and Data Extraction: Prospective, randomized, controlled trials comparing the clinical effects of antipsychotic therapy with placebo or comparing 2 antipsychotic treatments in an acute care setting were selected. Studies involving dementia-associated delirium, Alzheimers disease-associated delirium, emergency department-associated acute agitation, acute brain trauma-associated agitation, or agitation secondary to underlying psychiatric afflictions such as depression or schizophrenia were excluded. All studies were evaluated independently by the 3 authors using a validated evaluation tool. Outcomes related to both efficacy and safety were collected. Four prospective trials were included in this systematic review. Data Synthesis: Antipsychotic agents, either atypical or typical, were effective compared with baseline for the treatment of delirium in medically or surgically ill patients without underlying cognitive disorders. Oral haloperidol was associated with more frequent extrapyramidal side effects, but overall, all agents were well tolerated. Interpretation of the published evidence is limited by the small sample sizes, varied patient populations, and comparative agents of the studies reviewed. Conclusions: The comparative studies evaluated here suggest that antipsychotic drugs are efficacious, when compared with baseline, and safe for the treatment of delirium. Haloperidol remains the most studied agent. Recommendation of one antipsychotic over another as a first-line pharmacologic intervention in the treatment of hospital-associated delirium is limited by the quality and quantity of data available. Better designed and larger studies evaluating the addition of antipsychotic agents to nonpharmacologic treatments are needed to measure the true effect of pharmacologic treatment.

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

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

Efficacy and Safety of Intravenous Phosphate Replacement in Critically Ill Patients

OBJECTIVE: To evaluate the efficacy and safety of intravenous potassium phosphate administered in a fixed-dose regimen in critically ill patients. DESIGN: Prospective, unblind study. SETTING: Surgical—medical intensive care unit (ICU). PARTICIPANTS: Patients who developed hypophosphatemia during their ICU admission. INTERVENTIONS: Patients with a serum phosphate concentration between 1.27 and 2.48 mg/dL (group 1) and those with a concentration of 1.24 mg/dL or less (group 2) received 15 and 30 mmol, respectively, of phosphate as a potassium salt via a central line over 3 hours. MAIN OUTCOME MEASURES: Normalization of serum phosphate within 6 hours of infusion, the development of arrhythmias during the infusion, and the development of hypocalcemia and hyperkalemia after the infusion were evaluated. Redevelopment of hypophosphatemia and the need for further therapy were also assessed. RESULTS: Thirty-seven episodes of hypophosphatemia were entered in this study: 27 in group 1 (17 patients) and 10 in group 2 (10 patients). The mean serum phosphate concentration increased significantly from 2.02 to 2.82 mg/dL in group 1 and from 0.83 to 2.17 mg/dL in group 2, with no change in calcium or potassium. Normalization of serum phosphate with this initial dose occurred in 81.5% of the episodes in group 1 and 30% in group 2. However, over the following 2 days, 45% of the patients in group 1 and 60% in group 2 required further phosphate supplementation. No arrhythmias occurred during the 3-hour infusion that were related to the potassium phosphate. A significant drop in total serum calcium concentrations occurred in 2 patients who were slightly hypercalcemic prior to the infusion. Serum calcium concentrations remained above normal, but this was not associated with any adverse effects. CONCLUSIONS: The administration of potassium phosphate 15 mmol to critically ill patients with mild-to-moderate hypophosphatemia over 3 hours is both effective and safe. The administration of potassium phosphate 30 mmol to severely hypophosphatemic patients was safe but achieved normalization of serum phosphate in a minority of patients. Either a higher dose or the subsequent administration of more potassium phosphate may be required to normalize serum phosphate concentrations. Once normalization has occurred, there is a high likelihood of redevelopment of hypophosphatemia over the following 2 days and supplementation should be given accordingly.

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.

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.

Pancreatitis Associated with Simvastatin Plus Fenofibrate

OBJECTIVE: To report a case of acute necrotizing pancreatitis associated with simvastatin and fenofibrate use. CASE SUMMARY: A 70-year-old white man presenting with rapid onset of abdominal pain, nausea, and vomiting was diagnosed with acute pancreatitis. On bowel rest, his condition deteriorated secondary to systemic inflammatory response syndrome, and he was transferred to a tertiary hospitals intensive care unit (ICU). He had been taking fenofibrate for 1 year; 6 months prior to this admission, he had been taking simvastatin 3 days of the week and fenofibrate the other 4 days of the week. The pancreatic tissue became necrotic, requiring surgical debridement. After a hospital stay of 121 days, including multiple ICU admissions, the patient died secondary to a bowel perforation. DISCUSSION: Although idiopathic pancreatitis cannot be ruled out in this patient, no causes of pancreatitis were identified other than drug induced. Five cases of acute pancreatitis caused by simvastatin have been reported; no case reports were found for fenofibrate. The onset of pancreatitis relative to the duration of therapy with simvastatin supports this medication as a possible cause of the pancreatitis. CONCLUSIONS: Drug-induced pancreatitis is well established as an adverse effect of some medications, although most are substantiated only with case reports. Given the absence of other apparent causes, simvastatin and fenofibrate should be considered as possible causes of pancreatitis in this patient.

Successful treatment of lithium toxicity with sodium polystyrene sulfonate: a retrospective cohort study

Context. Lithium (Li) is a first-line treatment for bipolar disorder but has a narrow therapeutic index. Treatment of Li toxicity includes supportive measures and hemodialysis in severe cases, but this modality is not always immediately available. Sodium polystyrene sulfonate (SPS, Kayexalate™), a cation exchanger, has been promising in animal models and human reports to reduce absorption and enhance elimination of Li. Material and methods. A retrospective cohort study was conducted. All cases of chronic Li intoxication were reviewed in two adult-care hospitals from 2000 to 2009. A group comparison and a within-patient comparison were performed to compare the effect of SPS on the median Li half-life (T1/2). For this study, at least three serum Li levels were required for T1/2 calculations. Results. Forty-eight patients met inclusion requirements, 12 of whom had taken SPS. Median Li T1/2 in the treated and control groups was 20.5 and 43.2 hours, respectively (p = 0.0006). In the 12 treated patients, Li T1/2 during SPS was on average 48.9% shorter than without SPS. Furthermore, in one subject in whom urinary Li data were available, Li clearance with SPS was superior to Li renal clearance. Prolonged constipation was noted in one patient whereas mild hypokalemia was noted in six patients treated with SPS. Conclusion. This study shows that SPS reduced Li T1/2 and suggests that SPS is capable of promoting Li elimination in chronic intoxications. These results warrant a prospective trial looking at the use of SPS in the treatment of Li overdose as an adjunct to supportive measures and hemodialysis.

Impact of Candida Species on Clinical Outcomes in Patients with Suspected Ventilator-Associated Pneumonia

BACKGROUND The significance of Candida species in respiratory tract (RT) secretions in critically ill patients is unclear. METHODS A retrospective analysis of the Canadian ventilator-associated pneumonia (VAP) trial was conducted. Only patients with suspected VAP whose initial cultures failed to grow any known pathogens were included. Using two fundamentally different statistical techniques that adjusted for important confounding variables, the clinical outcomes of patients with Candida species recovered from RT cultures were compared with patients whose RT cultures were not positive for Candida species. RESULTS RT cultures yielded no identifiable bacterial pathogens in 274 patients; 68 patients had Candida species in the RT alone, while 206 patients did not have Candida species recovered from any site. The unadjusted OR of hospital mortality for patients with Candida species was 2.9 (95% CI 1.6 to 5.2; P<0.001). The hazard ratio of time to hospital discharge was 0.54 (95% CI 0.38 to 0.77; P=0.001). Logistic regression analysis demonstrated that age, Acute Physiology score and Chronic Health Evaluation (APACHE) II score, primary diagnosis of respiratory failure, two or more comorbidities and Candida species were independently associated with increased hospital mortality. Similar trends were observed with time to hospital discharge. The association between Candida species and increased mortality remained after controlling for potential confounders using both propensity score stratification and multivariable modelling approaches. CONCLUSIONS Patients with suspected VAP, in whom no bacterial pathogen was identified and in whom Candida species were isolated from RT cultures, exhibited a greater burden of illness compared with similar patients without Candida. Whether Candida species colonization of RT secretions is a marker of disease severity or actually contributes to poorer clinical outcomes remains unclear.

Impact of a Protocol for Prevention of Ventilator-Associated Pneumonia

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

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

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