Long-term outcomes with haloperidol versus placebo in acutely admitted adult ICU patients with delirium.

PURPOSE: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. METHODS: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. RESULTS: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS. CONCLUSIONS: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. METHODS: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. RESULTS: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. CONCLUSIONS: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. TRIAL REGISTRATION: CRD42017081133, date of registration 28 November 2017.

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids.

BACKGROUND: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. METHODS: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. CONCLUSION: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

Delirium in Intensive Care.

Purpose of Review: Delirium in the intensive care unit (ICU) has become increasingly acknowledged as a significant problem for critically ill patients affecting both the actual course of illness as well as outcomes. In this review, we focus on the current evidence and the gaps in knowledge. Recent Findings: This review highlights several areas in which the evidence is weak and further research is needed in both pharmacological and non-pharmacological treatment. A better understanding of subtypes and their different response to therapy is needed and further studies in aetiology are warranted. Larger studies are needed to explore risk factors for developing delirium and for examining long-term consequences. Finally, a stronger focus on experienced delirium and considering the perspectives of both patients and their families is encouraged. Summary: With the growing number of studies and a better framework for research leading to stronger evidence, the outcomes for patients suffering from delirium will most definitely improve in the years to come.

The Danish chronic subdural hematoma study-predicting recurrence of chronic subdural hematoma.

BACKGROUND: An increasing incidence of chronic subdural hematoma (CSDH) and an unchanging high recurrence rate of 10-20% call for individualized treatment. The aim of this study was to establish individualized prediction models for the risk of recurrence treating death as a competing risk. METHODS: A retrospective national cohort of unilateral CSDH was included for analysis. Using competing risk survival analysis, we tested whether available covariates were associated with the risk of recurrence. We further established a pre- and a postoperative prediction model, where predictors were chosen using a LASSO approach. The models were visualized in nomograms. Predictive performance was evaluated by c index and calibrations plots. RESULTS: A total of 763 patients with surgically evacuated unilateral CSDH were included for analysis. The recurrence rate was 14% while 12% of patients died during follow-up (1 year). In our association model, hematoma size, drain type, drainage time, presence of complications, and Glasgow Coma Score were significantly associated to recurrence. Subdural drain was associated with a lower recurrence risk than subgaleal drain. The preoperative model included hematoma size, hematoma density, and history of hypertension. The postoperative model included further drain type, drainage time, and surgical complications. CONCLUSION: The nomograms allow easy assessment of the recurrence risk for the individual patient, providing a better possibility for individual adjustment of treatment and follow-up. The predictive performance indicates that significant unaccounted or unknown factors still remain. The association test found passive subdural drain superior to passive subgaleal drain in minimizing the risk of CSDH recurrence.

Bilateral chronic subdural hematoma: unilateral or bilateral drainage?

OBJECTIVE Bilateral chronic subdural hematoma (bCSDH) is a common neurosurgical condition frequently associated with the need for retreatment. The reason for the high rate of retreatment has not been thoroughly investigated. Thus, the authors focused on determining which independent predictors are associated with the retreatment of bCSDH with a focus on surgical laterality. METHODS In a national database of CSDHs (Danish Chronic Subdural Hematoma Study) the authors retrospectively identified all bCSDHs treated in the 4 Danish neurosurgical departments over the 3-year period from 2010 to 2012. Univariate and multivariate analyses were performed to determine the relationship between retreatment of bCSDH and clinical, radiological, and surgical variables. RESULTS Two hundred ninety-one patients with bCSDH were identified, and 264 of them underwent unilateral (136 patients) or bilateral (128 patients) surgery. The overall retreatment rate was 21.6% (57 of 264 patients). Cases treated with unilateral surgery had twice the risk of retreatment compared with cases undergoing bilateral surgery (28.7% vs 14.1%, respectively, p = 0.002). In accordance with previous studies, the data also showed that a separated hematoma density and the absence of postoperative drainage were independent predictors of retreatment. CONCLUSIONS In bCSDHs bilateral surgical intervention significantly lowers the risk of retreatment compared with unilateral intervention and should be considered when choosing a surgical procedure.