Mark van den Boogaard

Routine use of the confusion assessment method for the intensive care unit : a multicenter study

RATIONALE Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear. OBJECTIVES To investigate the diagnostic value of the CAM-ICU in daily practice. METHODS Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each others conclusions. MEASUREMENTS AND MAIN RESULTS Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8). CONCLUSIONS Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.

Haloperidol prophylaxis in critically ill patients with a high risk for delirium

IntroductionDelirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.MethodsThis study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ≥ 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.ResultsIn 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.ConclusionsOur evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.Trial registrationclinicaltrial.gov Identifier: NCT01187667.

Incidence and short-term consequences of delirium in critically ill patients: A prospective observational cohort study §

BACKGROUND Delirium is a serious and frequent psycho-organic disorder in critically ill patients. Reported incidence rates vary to a large extent and there is a paucity of data concerning delirium incidence rates for the different subgroups of intensive care unit (ICU) patients and their short-term health consequences. OBJECTIVES To determine the overall incidence and duration of delirium, per delirium subtype and per ICU admission diagnosis. Furthermore, we determined the short-term consequences of delirium. DESIGN Prospective observational study. PARTICIPANTS AND SETTING All adult consecutive patients admitted in one year to the ICU of a university medical centre. METHODS Delirium was assessed using the Confusion Assessment Method-ICU three times a day. Delirium was divided in three subtypes: hyperactive, hypoactive and mixed subtype. As measures for short-term consequences we registered duration of mechanical ventilation, re-intubations, incidence of unplanned removal of tubes, length of (ICU) stay and in-hospital mortality. RESULTS 1613 patients were included of which 411 (26%) developed delirium. The incidence rate in the neurosurgical (10%) and cardiac surgery group (12%) was the lowest, incidence was intermediate in medical patients (40%), while patients with a neurological diagnosis had the highest incidence (64%). The mixed subtype occurred the most (53%), while the hyperactive subtype the least (10%). The median delirium duration was two days [IQR 1-7], but significantly longer (P<0.0001) for the mixed subtype. More delirious patients were mechanically ventilated and for a longer period of time, were more likely to remove their tube and catheters, stayed in the ICU and hospital for a longer time, and had a six times higher chance of dying compared to non-delirium ICU patients, even after adjusting for their severity of illness score. Delirium was associated with an extended duration of mechanical ventilation, length of stay in the ICU and in-hospital, as well as with in-hospital mortality. CONCLUSIONS The delirium incidence in a mixed ICU population is high and differs importantly between ICU admission diagnoses and the subtypes of delirium. Patients with delirium had a significantly higher incidence of short-term health problems, independent from their severity of illness and this was most pronounced in the mixed subtype of delirium. Delirium is significantly associated with worse short-term outcome.

Implementation of a delirium assessment tool in the ICU can influence haloperidol use

IntroductionIn critically ill patients, delirium is a serious and frequent disorder that is associated with a prolonged intensive care and hospital stay and an increased morbidity and mortality. Without the use of a delirium screening instrument, delirium is often missed by ICU nurses and physicians. The effects of implementation of a screening method on haloperidol use is not known. The purpose of this study was to evaluate the implementation of the confusion assessment method-ICU (CAM-ICU) and the effect of its use on frequency and duration of haloperidol use.MethodsWe used a tailored implementation strategy focused on potential barriers. We measured CAM-ICU compliance, interrater reliability, and delirium knowledge, and compared the haloperidol use, as a proxy for delirium incidence, before and after the implementation of the CAM-ICU.ResultsCompliance and delirium knowledge increased from 77% to 92% and from 6.2 to 7.4, respectively (both, P < 0.0001). The interrater reliability increased from 0.78 to 0.89. More patients were treated with haloperidol (9.9% to 14.8%, P < 0.001), however with a lower dose (18 to 6 mg, P = 0.01) and for a shorter time period (5 [IQR:2–9] to 3 [IQR:1–5] days, P = 0.02).ConclusionsWith a tailored implementation strategy, a delirium assessment tool was successfully introduced in the ICU with the main goals achieved within four months. Early detection of delirium in critically ill patients increases the number of patients that receive treatment with haloperidol, however with a lower dose and for a shorter time period.

Comparison and clinical suitability of eight prediction models for cardiac surgery-related acute kidney injury

BACKGROUND Cardiac surgery-related acute kidney injury (CS-AKI) results in increased morbidity and mortality. Different models have been developed to identify patients at risk of CS-AKI. While models that predict dialysis and CS-AKI defined by the RIFLE criteria are available, their predictive power and clinical applicability have not been compared head to head. METHODS Of 1388 consecutive adult cardiac surgery patients operated with cardiopulmonary bypass, risk scores of eight prediction models were calculated. Four models were only applicable to a subgroup of patients. The area under the receiver operating curve (AUROC) was calculated for all levels of CS-AKI and for need for dialysis (AKI-D) for each risk model and compared for the models applicable to the largest subgroup (n = 1243). RESULTS The incidence of AKI-D was 1.9% and for CS-AKI 9.3%. The models of Rahmanian, Palomba and Aronson could not be used for preoperative risk assessment as postoperative data are necessary. The three best AUROCs for AKI-D were of the model of Thakar: 0.93 [95% confidence interval (CI) 0.91-0.94], Fortescue: 0.88 (95% CI 0.87-0.90) and Wijeysundera: 0.87 (95% CI 0.85-0.89). The three best AUROCs for CS-AKI-risk were 0.75 (95% CI 0.73-0.78), 0.74 (95% CI 0.71-0.76) and 0.70 (95% CI 0.73-0.78), for Thakar, Mehta and both Fortescue and Wijeysundera, respectively. The model of Thakar performed significantly better compared with the models of Mehta, Rahmanian, Fortescue and Wijeysundera (all P-values <0.01) at different levels of severity of CS-AKI. CONCLUSIONS The Thakar model offers the best discriminative value to predict CS-AKI and is applicable in a preoperative setting and for all patients undergoing cardiac surgery.

Endotoxemia-induced inflammation and the effect on the human brain

IntroductionEffects of systemic inflammation on cerebral function are not clear, as both inflammation-induced encephalopathy as well as stress-hormone mediated alertness have been described.MethodsExperimental endotoxemia (2 ng/kg Escherichia coli lipopolysaccharide [LPS]) was induced in 15 subjects, whereas 10 served as controls. Cytokines (TNF-α, IL-6, IL1-RA and IL-10), cortisol, brain specific proteins (BSP), electroencephalography (EEG) and cognitive function tests (CFTs) were determined.ResultsFollowing LPS infusion, circulating pro- and anti-inflammatory cytokines, and cortisol increased (P < 0.0001). BSP changes stayed within the normal range, in which neuron specific enolase (NSE) and S100-β changed significantly. Except in one subject with a mild encephalopathic episode, without cognitive dysfunction, endotoxemia induced no clinically relevant EEG changes. Quantitative EEG analysis showed a higher state of alertness detected by changes in the central region, and peak frequency in the occipital region. Improved CFTs during endotoxemia was found to be due to a practice effect as CFTs improved to the same extent in the reference group. Cortisol significantly correlated with a higher state of alertness detected on the EEG. Increased IL-10 and the decreased NSE both correlated with improvement of working memory and with psychomotor speed capacity. No other significant correlations between cytokines, cortisol, EEG, CFT and BSP were found.ConclusionsShort-term systemic inflammation does not provoke or explain the occurrence of septic encephalopathy, but primarily results in an inflammation-mediated increase in cortisol and alertness.Trial registrationNCT00513110.

The impact of delirium on the prediction of in-hospital mortality in intensive care patients

IntroductionPredictive models, such as acute physiology and chronic health evaluation II (APACHE-II), are widely used in intensive care units (ICUs) to estimate mortality. Although the presence of delirium is associated with a higher mortality in ICU patients, delirium is not part of the APACHE-II model. The aim of the current study was to evaluate whether delirium, present within 24 hours after ICU admission, improves the predictive value of the APACHE-II score.MethodsIn a prospective cohort study 2116 adult patients admitted between February 2008 and February 2009 were screened for delirium with the confusion assessment method-ICU (CAM-ICU). Exclusion criteria were sustained coma and unable to understand Dutch. Logistic regression analysis was used to estimate the predicted probabilities in the model with and without delirium. Calibration plots and the Hosmer-Lemeshow test (HL-test) were used to assess calibration. The discriminatory power of the models was analyzed by the area under the receiver operating characteristics curve (AUC) and AUCs were compared using the Z-test.Results1740 patients met the inclusion criteria, of which 332 (19%) were delirious at the time of ICU admission or within 24 hours after admission. Delirium was associated with in-hospital mortality in unadjusted models, odds ratio (OR): 3.22 (95% confidence interval [CI]: 2.23 - 4.66). The OR between the APACHE-II and in-hospital mortality was 1.15 (95% CI 1.12 - 1.19) per point. The predictive accuracy of the APACHE-II did not improve after adding delirium, both in the total group as well as in the subgroup without cardiac surgery patients. The AUC of the APACHE model without delirium was 0.77 (0.73 - 0.81) and 0.78 (0.74 - 0.82) when delirium was added to the model. The z-value was 0.92 indicating no improvement in discriminative power, and the HL-test and calibration plots indicated no improvement in calibration.ConclusionsAlthough delirium is a significant predictor of mortality in ICU patients, adding delirium as an additional variable to the APACHE-II model does not result in an improvement in its predictive estimates.

Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial

BACKGROUND Disturbed circadian rhythm is a potentially modifiable cause of delirium among patients in intensive-care units (ICUs). Bright-light therapy in the daytime can realign circadian rhythm and reduce the incidence of delirium. We investigated whether a high-intensity dynamic light application (DLA) would reduce ICU-acquired delirium. METHODS This was a randomised, controlled, single-centre trial of medical and surgical patients admitted to the ICU of a teaching hospital in the Netherlands. Patients older than 18 years, expected to stay in the ICU longer than 24 h and who could be assessed for delirium were randomised to DLA or normal lighting (control), according to a computer-generated schedule. The DLA was administered through ceiling-mounted fluorescent tubes that delivered bluish-white light up to 1700 lux between 0900 h and 1600 h, except for 1130-1330 h, when the light was dimmed to 300 lux. The light could only be turned off centrally by investigators. Control light levels were 300 lux and lights could be turned on and off from inside the room. The primary endpoint was the cumulative incidence of ICU-acquired delirium. Analyses were by intention to treat and per protocol. The study was terminated prematurely after an interim analysis for futility. This study is registered with Clinicaltrials.gov, number NCT01274819. FINDINGS Between July 1, 2011, and Sept 9, 2013, 734 patients were enrolled, 361 in the DLA group and 373 in the control group. Delirium occurred in 137 (38%) of 361 DLA patients and 123 (33%) of 373 control patients (odds ratio 1·24, 95% CI 0·92-1·68, p=0·16). No adverse events were noted in patients or staff. INTERPRETATION DLA as a single intervention does not reduce the cumulative incidence of delirium. Bright-light therapy should be assessed as part of a multicomponent strategy. FUNDING None.

Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial

Importance Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium. Objective To determine whether prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days. Design, Setting, and Participants Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017. Interventions Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride. Main Outcome and Measures The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. Results All 1789 randomized patients (mean, age 66.6 years [SD, 12.6]; 1099 men [61.4%]) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group). Conclusions and Relevance Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults. Trial Registration clinicaltrials.gov Identifier: NCT01785290

Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial

BackgroundDelirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Therefore, preventive treatment for delirium may be beneficial. Worldwide, haloperidol is the first choice for pharmacological treatment of delirious patients. In daily clinical practice, a lower dose is sometimes used as prophylaxis. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. The primary objective of our study is to determine the effect of haloperidol prophylaxis on 28-day survival. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis.MethodsThis will be a multicenter three-armed randomized, double-blind, placebo-controlled, prophylactic intervention study in critically ill patients. We will include consecutive non-neurological ICU patients, aged ≥18 years with an expected ICU length of stay >1 day. To be able to demonstrate a 15% increase in 28-day survival time with a power of 80% and alpha of 0.05 in both intervention groups, a total of 2,145 patients will be randomized; 715 in each group. The anticipated mortality rate in the placebo group is 12%. The intervention groups will receive prophylactic treatment with intravenous haloperidol 1 mg/q8h or 2 mg/q8h, and patients in the control group will receive placebo (sodium chloride 0.9%), both for a maximum period of 28-days. In patients who develop delirium, study medication will be stopped and patients will subsequently receive open label treatment with a higher (therapeutic) dose of haloperidol. We will use descriptive summary statistics as well as Cox proportional hazard regression analyses, adjusted for covariates.DiscussionThis will be the first large-scale multicenter randomized controlled prevention study with haloperidol in ICU patients with a high risk of delirium, adequately powered to demonstrate an effect on 28-day survival.Trial registrationClinicaltrials.gov: NCT01785290.EudraCT number: 2012-004012-66.