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.

Prognostic significance of delirium subtypes in critically ill medical and surgical patients: a secondary analysis of a prospective multicenter study.

BACKGROUND: The prognostic implication of delirium subtypes in critically ill medical and surgical patients is scarcely investigated. The objective was to determine how delirium subtypes are associated with hospital mortality and other clinical outcomes. METHODS: We performed a secondary analysis on data from a prospective multicenter study aimed at implementation of delirium-oriented measures, conducted between 2012 and 2015 in The Netherlands. We included adults (≥ 18 years) admitted to the medical or surgical intensive care unit (ICU). Exclusion criteria were neurological admission diagnosis, persistent coma or ICU readmissions. Delirium was assessed using the Confusion Assessment Method-ICU or Intensive Care Delirium Screening Checklist, and delirium subtypes (hypoactive, hyperactive, or mixed) were classified using the Richmond Agitation-Sedation Scale. The main outcome was hospital mortality. Secondary outcomes were ICU mortality, ICU length of stay, coma, mechanical ventilation, and use of antipsychotics, sedatives, benzodiazepines and opioids. RESULTS: Delirium occurred in 381 (24.4%) of 1564 patients (52.5% hypoactive, 39.1% mixed, 7.3% hyperactive). After case-mix adjustment, patients with mixed delirium had higher hospital mortality than non-delirious patients (OR 3.09, 95%CI 1.79-5.33, p = 0.001), whereas hypoactive patients did not (OR 1.34, 95%CI 0.71-2.55, p = 0.37). Similar results were found for ICU mortality. Compared to non-delirious patients, both subtypes had longer ICU stay, more coma, increased mechanical ventilation frequency and duration, and received more antipsychotics, sedatives, benzodiazepines and opioids. Except for coma and benzodiazepine use, the most unfavourable outcomes were observed in patients with mixed delirium. CONCLUSIONS: Patients with mixed delirium had the most unfavourable outcomes, including higher mortality, compared with no delirium. These differences argue for distinguishing delirium subtypes in clinical practice and future research. Trial registration ClinicalTrials.gov NCT01952899.

Prospective multicentre multifaceted before-after implementation study of ICU delirium guidelines: a process evaluation.

OBJECTIVE: We aimed to explore: the exposure of healthcare workers to a delirium guidelines implementation programme; effects on guideline adherence at intensive care unit (ICU) level; impact on knowledge and barriers, and experiences with the implementation. DESIGN: A mixed-methods process evaluation of a prospective multicentre implementation study. SETTING: Six ICUs. PARTICIPANTS: 4449 adult ICU patients and 500 ICU professionals approximately. INTERVENTION: A tailored implementation programme. MAIN OUTCOME MEASURE: Adherence to delirium guidelines recommendations at ICU level before, during and after implementation; knowledge and perceived barriers; and experiences with the implementation. RESULTS: Five of six ICUs were exposed to all implementation strategies as planned. More than 85% followed the required e-learnings; 92% of the nurses attended the clinical classroom lessons; five ICUs used all available implementation strategies and perceived to have implemented all guideline recommendations (>90%). Adherence to predefined performance indicators (PIs) at ICU level was only above the preset target (>85%) for delirium screening. For all other PIs, the inter-ICU variability was between 34% and 72%. The implementation of delirium guidelines was feasible and successful in resolving the majority of barriers found before the implementation. The improvement was well sustained 6 months after full guideline implementation. Knowledge about delirium was improved (from 61% to 65%). The implementation programme was experienced as very successful. CONCLUSIONS: Multifaceted implementation can improve and sustain adherence to delirium guidelines, is feasible and can largely be performed as planned. However, variability in delirium guideline adherence at individual ICUs remains a challenge, indicating the need for more tailoring at centre level.

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.

Pharmacogenomic response of low dose haloperidol in critically ill adults with delirium.

PURPOSE: To characterize the pharmacogenomic response of low-dose haloperidol for delirium treatment in critically ill adults. MATERIALS AND METHODS: Single-center, pilot study of a convenience sample of ICU adults with delirium treated with low-dose IV haloperidol. Patients were evaluated for delirium with the ICDSC every 8 h. Serum haloperidol concentrations were collected on ICU days 2-6, CYP2D6 and CYP3A4 genotypes were characterized and patients were categorized as extensive (EM), intermediate (IM) or poor metabolizers (PM). RESULTS: The 22 patients (median age 67 [IQR 48,77] years; median APACHE III 81[IQR 54,181]; CYP2D6 [EM = 12, IM = 7, PM = 3], CYP3A [EM = 18, IM = 4]) received a median [IQR] daily haloperidol dose of 3.0 [2.4, 4.5] mg. After adjusting for age, SOFA, and ICU day, neither an association between CYP2D6 (IM p = .67/PM p = .25) or CYP3A4 (IM p = .44) metabolizer status and serum haloperidol concentrations was found. After adjusting for age, SOFA, and ICU day, neither an association between daily haloperidol dose (p = .77) or ICDSC score (p = .13) and serum haloperidol concentrations was found. No patient experienced QTc interval prolongation (≥500 ms). CONCLUSIONS: This pilot study, the first to evaluate the pharmacogenomic response of low-dose haloperidol when used to treat delirium in the ICU, suggests CYP2D6/CYP3A4 metabolizer status does not affect the serum haloperidol concentrations.

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.

TREATMENT OF PROGRESSION OF DIFFUSE ASTROCYTOMA BY HERBAL MEDICINE: CASE REPORT.

BACKGROUND: The paper presents the results of the use of phytotherapy in a 33-year-old woman who, after finishing the oncological treatment of diffuse astrocytoma, had tumour progression. MATERIAL AND METHODS: Phytotherapy was introduced after the tumour had progressed. It consisted of 4 types of herbal medicine which the subject was taking in form of tea once a day at regular intervals. The patient started phytotherapy along with temozolomide, which was the only oncological treatment she was under after the tumour had progressed. Following the finished chemotherapy, the patient continued the treatment with herbal medicine only. She regularly took phytotherapy without interruption and to the fullest extent for 30 months, and the results of treatment were monitored by periodic scanning using nuclear magnetic resonance technique. RESULTS: The control scanning that was conducted after the end of combined treatment with temozolomide and phytotherapy showed tumour regression. The patient continued with phytotherapy after finishing chemotherapy and, during the following 24 months, it was the sole treatment option. In that period, the regression of the tumour continued, until a control examination 30 months after the introduction of phytotherapy showed no clinical and radiological signs of tumour. CONCLUSION: The results presented in this research paper clearly indicate the potential of phytotherapy in the treatment of some types of brain tumours. A complete regression of tumour following the treatment with nothing but herbal medicine offers support for such claim. Future research should demonstrate the effectiveness of phytotherapy, as a supplementary form of brain tumour treatment, and the results of this research should be compared with the existing information on the effectiveness of the protocols currently used in the treatment of these types of tumour.

A systematic review of implementation strategies for assessment, prevention, and management of ICU delirium and their effect on clinical outcomes.

INTRODUCTION: Despite recommendations from professional societies and patient safety organizations, the majority of ICU patients worldwide are not routinely monitored for delirium, thus preventing timely prevention and management. The purpose of this systematic review is to summarize what types of implementation strategies have been tested to improve ICU clinicians' ability to effectively assess, prevent and treat delirium and to evaluate the effect of these strategies on clinical outcomes. METHOD: We searched PubMed, Embase, PsychINFO, Cochrane and CINAHL (January 2000 and April 2014) for studies on implementation strategies that included delirium-oriented interventions in adult ICU patients. Studies were suitable for inclusion if implementation strategies' efficacy, in terms of a clinical outcome, or process outcome was described. RESULTS: We included 21 studies, all including process measures, while 9 reported both process measures and clinical outcomes. Some individual strategies such as "audit and feedback" and "tailored interventions" may be important to establish clinical outcome improvements, but otherwise robust data on effectiveness of specific implementation strategies were scarce. Successful implementation interventions were frequently reported to change process measures, such as improvements in adherence to delirium screening with up to 92%, but relating process measures to outcome changes was generally not possible. In meta-analyses, reduced mortality and ICU length of stay reduction were statistically more likely with implementation programs that employed more (six or more) rather than less implementation strategies and when a framework was used that either integrated current evidence on pain, agitation and delirium management (PAD) or when a strategy of early awakening, breathing, delirium screening and early exercise (ABCDE bundle) was employed. Using implementation strategies aimed at organizational change, next to behavioral change, was also associated with reduced mortality. CONCLUSION: Our findings may indicate that multi-component implementation programs with a higher number of strategies targeting ICU delirium assessment, prevention and treatment and integrated within PAD or ABCDE bundle have the potential to improve clinical outcomes. However, prospective confirmation of these findings is needed to inform the most effective implementation practice with regard to integrated delirium management and such research should clearly delineate effective practice change from improvements in clinical outcomes.

Improvement of care for ICU patients with delirium by early screening and treatment: study protocol of iDECePTIvE study.

BACKGROUND: Delirium in critically ill patients has a strong adverse impact on prognosis. In spite of its recognized importance, however, delirium screening and treatment procedures are often not in accordance with current guidelines. This implementation study is designed to assess barriers and facilitators for guideline adherence and next to develop a multifaceted tailored implementation strategy. Effects of this strategy on guideline adherence as well as important clinical outcomes will be described. METHODS: Current practices and guideline deviations will be assessed in a prospective baseline measurement. Barriers and facilitators will be identified from a survey among intensive care health care professionals (intensivists and nurses) and focus group interviews with selected health care professionals (n=60). Findings will serve as a foundation for a tailored guideline implementation strategy. Adherence to the guideline and effects of the implementation strategies on relevant clinical outcomes will be piloted in a before-after study in six intensive care units (ICUs) in the southwest Netherlands. The primary outcomes are adherence to screening and treatment in line with the Dutch ICU delirium guideline. Secondary outcomes are process measures (e.g. attendance to training and knowledge) and clinical outcomes (e.g. incidence of delirium, hospital-mortality changes, and length of stay). Primary and secondary outcome data will be collected at four time points including at least 924 patients. Furthermore, a process evaluation will be done, including an economical evaluation. DISCUSSION: Little is known on effective implementation of delirium management in the critically ill. The proposed multifaceted implementation strategy is expected to improve process measures such as screening adherence in line with the guideline and may improve clinical outcomes, such as mortality and length of stay. This ICU Delirium in Clinical Practice Implementation Evaluation study (iDECePTIvE-study) will generate important knowledge for ICU health care providers on how to improve their clinical practice to establish optimum care for delirious patients. TRIALS REGISTRATION: Clinical Trials NCT01952899.

The influence of phytotherapy on prolactin level in macroprolactinoma patients.

The study aims at demonstrating the efficiency of phytotherapy in regulation of prolactin levels in patients diagnosed with pituitary macroprolactinoma. The study made use of workup outcomes submitted by treating healthcare facilities where the patients were first diagnosed with macroprolactinomas based on diagnostic imaging (MRI and/or CT), laboratory workup, and hormone status estimation. The data in reference served as the baseline for a comparative follow-up of phytotherapeutic efficiency in terms of comparison of medical data obtained prior to phytotherapy and those submitted following herbal remedy use. The study displays the results of a five-year follow-up of macroprolactinoma patients undergoing phytotherapy. In well-responding patients, the benefit of phytotherapy in terms of prolactin level putdown can be seen 3-5 months following the phytotherapy commencement. A special attention should be paid to the favourable results obtained with patients who chose to resort to phytotherapy only. The primary outcome measure used to monitor the efficiency of the administered phytotherapy was prolactin level determined prior to, during the course of, and following phytotherapy. Implementation of phytotherapy to the effect of prolactin level regulation in patients diagnosed with macroprolactinoma, represents a completely novel therapeutic approach. The majority of the diseased resorted to phytotherapy once they were left out of any other therapeutic option offered by their treating healthcare facilities. This fact gives a substantial rise to the significance of the results presented herein and justifies the role of phytotherapy in macroprolactinoma-induced hyperprolactinaemia treatment.

The influence of phytotherapy on macroprolactinoma size.

The study aims at demonstrating the efficiency of phytotherapy in macroprolactinoma downsizing. The comparison of phytotherapeutic (PT) efficiency leant on medical records submitted by the patients prior to the PT launch, indicating the diagnosis established based on the outcome of the nuclear magnetic resonance imaging (NMRI) and/or computed tomography (CT) of the affected site and bringing the results of field-of-vision examination and hormonal status determination. The insight into the documentation in reference provided the information on tumour size and prolactin levels. The data in reference were compared against medical records submitted following phytotherapy completion. This study brings the results of a five-year investigation into the influence of phytotherapy on the size of macroprolactinomas. In patients responsive to this kind of treatment, tumour regression was witnessed within 6 months of herbal remedy use. A substantial tumour downsizing was accompanied by vision restitution;namely, in a number of cases, sight impairments are the first indicators of tumour presence. The basic parameters used for phytotherapeutic efficiency estimation and follow-up were the size of the tumour and the state of the field-of-vision, established both prior to and following phytotherapy. The results of the study presented herein unequivocally demonstrated the efficiency of phytotherapy in macroprolactinoma tumour mass downsizing, providing therefore solid grounds for the implementation of phytotherapy as a novel treatment modality of this tumour cluster.