Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial.

BACKGROUND: The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae. METHODS: This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization. RESULTS: The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73-1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18-0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12-1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29-1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22-2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study. CONCLUSIONS: Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov (#NCT03628391), October 9, 2017.

The Effects of Low Pressure Domiciliary Non-Invasive Ventilation on Clinical Outcomes in Patients with Severe COPD Regardless Having Hypercapnia.

BACKGROUND: The effectiveness of non-invasive home ventilation in patients with severe chronic obstructive pulmonary disease (COPD) is lacking. Non-invasive home ventilation might be more effective when high ventilator settings are used. However, high ventilator settings might reduce patient adherence. We have developed a multidisciplinary approach (ventilation practitioners, 24 hours support of respiratory nurses, physicians) to non-invasive ventilation aimed at optimizing patient adherence using low ventilator settings in severe COPD patients with high disease burden irrespectively having hypercapnia. METHODS: We included in a proof of concept, prospective interventional study, 48 GOLD stage III-IV COPD patients with a high disease burden (≥2 exacerbations in a year, and Medical Research Council dyspnea scores ≥3). Outcome measures included hospital admissions, capillary pCO2, Medical Research Council dyspnea scores (MRC), Clinical COPD Questionnaire scores (CCQ) and Hospital Anxiety and Depression Scale (HADS). RESULTS: After 1 year 32 patients could be evaluated. Hospital admissions decreased by 1.0 admission (mean difference ± SD: 1.0 ± 1.48; p = 0.001). In-hospital days decreased by 10.0 days (10.0 ± 15.48; p = 0.001). Capillary pCO2 decreased by 0.33 kPa (0.33 ± 0.81: p = 0.03). The MRC dyspnea score decreased by 0.66 (0.66 ± 1.35; p = 0.02). The CCQ score decreased by 0.59 (0.59 ± 1.39; p = 0.03). The HADS anxiety score decreased by 1.64 (1.64 ± 3.12; p = 0.01). The HADS depression score decreased by 1.64 (1.64 ± 3.91; p = 0.04). CONCLUSION: A proof of concept multidisciplinary approach, using low pressure domiciliary non-invasive ventilation, aimed at optimizing patient adherence in severe COPD patients regardless having hypercapnia, reduced hospital admissions and improved symptoms and quality of life measures. This may imply that severe COPD patients with high disease burden, irrespective being hypercapnic, are candidates to be treated with low pressure domiciliary non-invasive ventilation.

Efficacy of halopeRIdol to decrease the burden of Delirium In adult Critically ill patiEnts (EuRIDICE): study protocol for a prospective randomised multi-centre double-blind placebo-controlled clinical trial in the Netherlands.

INTRODUCTION: Delirium in critically ill adults is associated with prolonged hospital stay, increased mortality and greater cognitive and functional decline. Current practice guideline recommendations advocate the use of non-pharmacological strategies to reduce delirium. The routine use of scheduled haloperidol to treat delirium is not recommended given a lack of evidence regarding its ability to resolve delirium nor improve relevant short-term and longer-term outcomes. This study aims to evaluate the efficacy and safety of haloperidol for the treatment of delirium in adult critically ill patients to reduce days spent with coma or delirium. METHODS AND ANALYSIS: EuRIDICE is a prospective, multi-centre, randomised, double-blind, placebo-controlled trial. Study population consists of adult intensive care unit (ICU) patients without acute neurological injury who have delirium based on a positive Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU) assessment. Intervention is intravenous haloperidol 2.5 mg (or matching placebo) every 8 hours, titrated daily based on ICDSC or CAM-ICU positivity to a maximum of 5 mg every 8 hours, until delirium resolution or ICU discharge. Main study endpoint is delirium and coma-free days (DCFD) up to 14 days after randomisation. Secondary endpoints include (1) 28-day and 1-year mortality, (2) cognitive and functional performance at 3 and 12 months, (3) patient and family delirium and ICU experience, (4) psychological sequelae during and after ICU stay, (4) safety concerns associated with haloperidol use and (5) cost-effectiveness. Differences in DCFDs between haloperidol and placebo group will be analysed using Poisson regression analysis. Study recruitment started in February 2018 and continues. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam (MEC2017-511) and by the Institutional Review Boards of the participating sites. Its results will be disseminated via peer-reviewed publication and conference presentations. TRIAL REGISTRATION: NCT03628391.

Improved Guideline Adherence and Reduced Brain Dysfunction After a Multicenter Multifaceted Implementation of ICU Delirium Guidelines in 3,930 Patients.

OBJECTIVES: Implementation of delirium guidelines at ICUs is suboptimal. The aim was to evaluate the impact of a tailored multifaceted implementation program of ICU delirium guidelines on processes of care and clinical outcomes and draw lessons regarding guideline implementation. DESIGN: A prospective multicenter, pre-post, intervention study. SETTING: ICUs in one university hospital and five community hospitals. PATIENTS: Consecutive medical and surgical critically ill patients were enrolled between April 1, 2012, and February 1, 2015. INTERVENTIONS: Multifaceted, three-phase (baseline, delirium screening, and guideline) implementation program of delirium guidelines in adult ICUs. MEASUREMENTS AND MAIN RESULTS: The primary outcome was adherence changes to delirium guidelines recommendations, based on the Pain, Agitation and Delirium guidelines. Secondary outcomes were brain dysfunction (delirium or coma), length of ICU stay, and hospital mortality. A total of 3,930 patients were included. Improvements after the implementation pertained to delirium screening (from 35% to 96%; p < 0.001), use of benzodiazepines for continuous sedation (from 36% to 17%; p < 0.001), light sedation of ventilated patients (from 55% to 61%; p < 0.001), physiotherapy (from 21% to 48%; p < 0.001), and early mobilization (from 10% to 19%; p < 0.001). Brain dysfunction improved: the mean delirium duration decreased from 5.6 to 3.3 days (-2.2 d; 95% CI, -3.2 to -1.3; p < 0.001), and coma days decreased from 14% to 9% (risk ratio, 0.5; 95% CI, 0.4-0.6; p < 0.001). Other clinical outcome measures, such as length of mechanical ventilation, length of ICU stay, and hospital mortality, did not change. CONCLUSIONS: This large pre-post implementation study of delirium-oriented measures based on the 2013 Pain, Agitation, and Delirium guidelines showed improved health professionals' adherence to delirium guidelines and reduced brain dysfunction. Our findings provide empirical support for the differential efficacy of the guideline bundle elements in a real-life setting and provide lessons for optimization of guideline implementation programs.

Attitudes, knowledge and practices concerning delirium: a survey among intensive care unit professionals.

BACKGROUND: Delirium is a common form of vital organ dysfunction in intensive care unit (ICU) patients and is associated with poor outcomes. Adherence to guideline recommendations pertaining to delirium is still suboptimal. AIMS: We performed a survey aimed at identifying barriers for implementation that should be addressed in a tailored implementation intervention targeted at improved ICU delirium guideline adherence. DESIGN: The survey was conducted among ICU professionals. METHODS: An online survey was conducted among 360 ICU health care professionals (nurses, physicians and delirium consultants) from six ICUs in the southwest of the Netherlands as part of a multicentre prospective implementation project [response rate: 64% of 565 invited; 283 (79%) were nurses]. RESULTS: Although the majority (83%) of respondents considered delirium a common and major problem in the ICU, we identified several barriers for implementation of a delirium guideline. The most important barriers were knowledge deficit, low delirium screening rate, lack of trust in the reliability of delirium screening tools, belief that delirium is not preventable, low familiarity with delirium guidelines, low satisfaction with physician-described delirium management, poor collaboration between nurses and physicians, reluctance to change delirium care practices, lack of time, disbelief that patients would receive optimal care when adhering to the guideline and the perception that the delirium guideline is cumbersome or inconvenient in daily practice. CONCLUSION: Although ICU professionals consider delirium a serious problem, several important barriers to adhere to guidelines on delirium management are still present today. RELEVANCE TO CLINICAL PRACTICE: Identification of implementation barriers for adherence to guidelines pertaining to delirium is feasible with a survey. Results of this study may help to design-targeted implementation strategies for ICU delirium management.

Paracetamol for intravenous use in medium--and intensive care patients: pharmacokinetics and tolerance.

PURPOSE: We studied the pharmacokinetics of paracetamol and determine the incidence of hypotension after intravenous administration in medium- (MCU) and intensive care (ICU) patients. METHODS: All patients on the ICU/MCU starting with paracetamol i.v. were included, yielding 38 patients. Blood samples were collected at predetermined time points to determine paracetamol serum concentration. The number of patients with a clinically relevant reduction in systolic blood pressure (SBP) and the number of patients that needed intervention to regain an acceptable blood pressure level were assessed. RESULTS: Overall, pharmacokinetic data were roughly comparable with earlier publications, but differences were noted in the subgroup ICU patients. Also, there was a trend to a larger peak serum concentration (p = 0.052) and a significantly smaller volume of distribution (p = 0.033) in MCU patients compared with ICU patients. Twenty-two percent (22%) and 33% of patients had a clinically relevant reduction in systolic blood pressure (SBP) 15 and 30 min after start of paracetamol infusion, respectively. In six patients (16%), an intervention was needed to correct blood pressure. Overall, SBP was significantly reduced at T = 15 min and 30 min postinfusion (p < 0.003 at both time points) when compared with SBP at the start of paracetamol infusion. CONCLUSIONS: Further research on differences in paracetamol pharmacokinetics between ICU and MCU patients is warranted, as these differences might result in differences in efficacy. Furthermore, administration of paracetamol i.v. as potential cause of hypotension in the critically ill patient must not be overlooked.