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 vs. placebo for the treatment of delirium in ICU patients: a pre-planned, secondary Bayesian analysis of the AID-ICU trial.

PURPOSE: The AID-ICU trial was a randomised, blinded, placebo-controlled trial investigating effects of haloperidol versus placebo in acutely admitted, adult patients admitted in intensive care unit (ICU) with delirium. This pre-planned Bayesian analysis facilitates probabilistic interpretation of the AID-ICU trial results. METHODS: We used adjusted Bayesian linear and logistic regression models with weakly informative priors to analyse all primary and secondary outcomes reported up to day 90, and with sensitivity analyses using other priors. The probabilities for any benefit/harm, clinically important benefit/harm, and no clinically important differences with haloperidol treatment according to pre-defined thresholds are presented for all outcomes. RESULTS: The mean difference for days alive and out of hospital to day 90 (primary outcome) was 2.9 days (95% credible interval (CrI) - 1.1 to 6.9) with probabilities of 92% for any benefit and 82% for clinically important benefit. The risk difference for mortality was - 6.8 percentage points (95% CrI - 12.8 to - 0.8) with probabilities of 99% for any benefit and 94% for clinically important benefit. The adjusted risk difference for serious adverse reactions was 0.3 percentage points (95% CrI - 1.3 to 1.9) with 98% probability of no clinically important difference. Results were consistent across sensitivity analyses using different priors, with more than 83% probability of benefit and less than 17% probability of harm with haloperidol treatment. CONCLUSIONS: We found high probabilities of benefits and low probabilities of harm with haloperidol treatment compared with placebo in acutely admitted, adult ICU patients with delirium for the primary and most secondary outcomes.

Noninvasive intracranial pressure monitoring in central nervous system infections.

Intracranial pressure (ICP) monitoring constitutes an important part of the management of traumatic brain injury. However, its application in other brain pathologies such as neuroinfections like acute bacterial meningitis is unclear. Despite focus on aggressive, prompt treatment, morbidity and mortality from acute bacterial meningitis remain high. Increased ICP is well-known to occur in severe neuroinfections. The increased ICP compromise cerebral perfusion pressure and may ultimately lead to brain stem herniation. Therefore, controlling the ICP could also be important in acute bacterial meningitis. However, risk factors for complications due to invasive monitoring among these patients may be significantly increased due to higher age and levels of comorbidity compared to the traumatic brain injury patient from which the ICP treatment algorithms are developed. This narrative review evaluates the different modalities of ICP monitoring with the aim to elucidate current status of non-invasive alternatives to invasive monitoring as a decision tool and eventually monitoring. Non-invasive screening using ultrasound of the optical nerve sheath, transcranial doppler, magnetic resonance imaging or preferably a combination of these modalities, provides measurements that can be used as a decision guidance for invasive ICP measurement. The available data do not support the replacement of invasive techniques for continuous ICP measurement in patients with increased ICP. Non-invasive modalities should be taken into consideration in patients with neuroinfections at low risk of increased ICP.

Haloperidol for the Treatment of Delirium in ICU Patients.

BACKGROUND: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Agents intervening against delirium in the intensive care unit trial-Protocol for a secondary Bayesian analysis.

BACKGROUND: Delirium is highly prevalent in the intensive care unit (ICU) and is associated with high morbidity and mortality. The antipsychotic haloperidol is the most frequently used agent to treat delirium although this is not supported by solid evidence. The agents intervening against delirium in the intensive care unit (AID-ICU) trial investigates the effects of haloperidol versus placebo for the treatment of delirium in adult ICU patients. METHODS: This protocol describes the secondary, pre-planned Bayesian analyses of the primary and secondary outcomes up to day 90 of the AID-ICU trial. We will use Bayesian linear regression models for all count outcomes and Bayesian logistic regression models for all dichotomous outcomes. We will adjust for stratification variables (site and delirium subtype) and use weakly informative priors supplemented with sensitivity analyses using sceptical priors. We will present results as absolute differences (mean differences and risk differences) and relative differences (ratios of means and relative risks). Posteriors will be summarised using median values as point estimates and percentile-based 95% credibility intervals. Probabilities of any benefit/harm, clinically important benefit/harm and clinically unimportant differences will be presented for all outcomes. DISCUSSION: The results of this secondary, pre-planned Bayesian analysis will complement the primary frequentist analysis of the AID-ICU trial and facilitate a nuanced and probabilistic interpretation of the trial results.

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

BACKGROUND: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONS: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID-ICU trial): A detailed statistical analysis plan.

BACKGROUND: The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial. METHODS: The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables. CONCLUSION: The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.

Initial experiences from patients with COVID-19 on ventilatory support in Denmark.

INTRODUCTION: The coronavirus disease 2019 (COVID-19)pandemic reached Denmark in early 2020. This paper presents initial intensive-care unit (ICU) experiences with COVID-19 patients at Roskilde Hospital, which was the primary recipient of COVID-19 patients in need of intensive care in the Zealand Region, Denmark. METHODS: An evaluation was conducted of the COVID-19 patients admitted to the ICU due to respiratory failure from 11 March 2020 to 01 April 2020. The number of ICU beds was increased from eight to 22 beds during this period. RESULTS: Sixteen patients (four women) were evaluated. The median age was 69.5 years (range: 56-84 years). All the patients were admitted to the ICU for hypoxemic respiratory failure and all needed mechanical ventilation by orotracheal intubation. By 16 April, six patients were still admitted to the ICU, four patients had been discharged from the ICU and seven had died. At present, the average length of ICU stay is 14 ± 9 days (mean ± standard deviation). One patient has remained on ventilatory support for 31 days. The evaluation revealed four key themes. COVID-19 patients 1) had greatly increased C-reactive protein levels, 2) needed a significant inspiratory O2fraction, 3) were highly positive end-expiratory pressure (PEEP) dependent on ventilatory support and 4) suffered highly fluctuating respiratory failure requiring ventilatory support for a significantly longer period of time than non-COVID-19 patients. CONCLUSIONS: COVID-19 patients have characteristic reproducible laboratory findings and present a major challenge due to their illness severity and required treatment length. FUNDING: none. TRIAL REGISTRATION: not relevant.

[Tetanus in Denmark - a forgotten but dangerous disease].

In this review of tetanus in Denmark, it is discussed, why tetanus cases continue to occur especially in elderly people, although it is a preventable disease. The phenomenon is due to a lack of primary or booster vaccination and waning immunity with age, and immediate diagnosis and treatment are crucial to prevent deadly outcome. In Denmark, booster vaccination is recommended every tenth year. Estimation of immunisation status by medical interview is unreliable, and a future solution may be the use of a tetanus quick test and focus on booster vaccination in a primary care setting.

[Survival following lightning strike and treatment of sequelae]. / Overlevelse efter lynnedslag og behandling af tilstødende komplikationer.

Lightning strike is an unpredictable weather phenomenon which can cause a variety of injuries to the human body. We present a case report with a 24-year-old male football player, who survived prolonged cardiac arrest after a lighting strike and then presented with multiple organ dysfunction due to cellular swelling, extreme rhabdomyolysis and global hypoperfusion. We describe the clinical observations, therapy and injuries which may be expected. Furthermore, the pathophysiology and factors influencing the survival of this patient are discussed.

[Extracorporeal membrane oxygenation in Legionella pneumonia]. / Ekstrakorporal oxygenering ved legionellapneumoni.

We present a case report with a 49-year-old woman with legionella pneumonia and fulminant respiratory failure. Despite maximal conventional respirator treatment with positive pressure ventilation, 100% oxygen and pharmacological treatment in an intensive care unit, further deterioration with hypoxemia and multi-organ failure occurred. The patient was referred to ECMO as a last option of treatment. Eight days of treatment with ECMO was completed without any complications except critical illness polyneuropathia (CIP) for which she was treated for an additional four weeks in the ICU.

Fatal left cardiac failure caused by external compression of left internal mammary artery graft in an accident: a case report.

We report for the first time a case of a 54 years old man with a fatal motorcycle accident due to an external bleeding compression of left internal mammary artery graft to the left anterior descending artery. The possibility of cardiac failure in trauma caused by external compression or traumatic injury of the graft should be considered in people who previously underwent coronary artery bypass graft surgery.