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.

A Predominant Cause of Recurrence of Ventilator-Associated Pneumonia in Patients with COVID-19 Are Relapses.

The diagnosis of ventilator-associated pneumonia (VAP) recurrence in patients with coronavirus disease 2019 (COVID-19) pneumonia is challenging, and the incidence of recurrence is high. This study aimed to investigate the incidence and recurrence of VAP. Furthermore, we investigated the causative microorganisms of VAP and recurrent VAPs in patients with COVID-19. This retrospective, single-centre case series study was conducted during the COVID-19 pandemic from October 2020 to June 2021 at VieCuri MC Venlo. VAP and recurrent VAP were defined based on three criteria (clinical, radiological, and microbiological). During the study period, 128 mechanically ventilated patients with COVID-19 were included. The incidence ranged from 9.2 to 14 VAP/1000 ventilator days, which was higher than that in the non-COVID-19 controls. The most commonly cultured microorganisms in VAP were Pseudomonas (9/28; 32%), Klebsiella (8/28; 29%), Escherichia coli (5/28; 18%), and Staphylococcus aureus (5/28; 18%). VAP recurred often (5/19, 26%). The overall VAP rate confirmed previous findings of an increased incidence of VAP in critically ill patients with severe COVID-19 requiring mechanical ventilation. VAP recurrences occur often and are mainly relapses. A duration of antibiotic therapy longer than 7 days and therapeutic drug monitoring should be considered for VAP caused by Gram-negative microorganisms.

Novel quantitative immunofluorescent technique reveals improvements in epidermal cell populations after mild treatment of psoriasis.

A novel antibody labelling technique, the Zenon technique, was used in fluorescent immunohistochemistry for a better characterization of epidermal cell populations in a quantitative approach. With this technique, differences in proliferation and differentiation characteristics were shown between psoriatic and normal epidermis. The sensitivity of the method was investigated by assessing the effect of a mild topical treatment versus an emollient. Frozen sections of non-treated psoriatic epidermis and psoriatic epidermis treated once daily with either an emollient or betamethasone-17-valerate for only 2 weeks were compared immunohistochemically. Antibodies against keratin 6, 10 and 15 were labelled with the Zenon technique, whereas antibodies against the Ki-67 antigen and beta-1 integrin were covalently FITC-labelled. Using image analysis, these markers were measured in the epidermis in a standardized manner. Treatment of psoriasis with short-term topical steroid resulted towards normalization of Ki-67 antigen, beta-1 integrin, keratin 10 and keratin 6 expression, which are parameters for proliferation and differentiation. Although treatment with an emollient showed hardly any clinical response, changes towards a more normal phenotype could already be detected in several epidermal markers using this method.

The combination of the Zenon labeling technique and microscopic image analysis to study cell populations in normal and psoriatic epidermis.

BACKGROUND: In order to better characterize epidermal cell populations in psoriatic vs. normal skin, fluorescent immunohistochemical techniques were extended with a new labeling technique. The Zenon technique conjugates primary antibodies rapidly and quantitatively after which they are used in the same manner as covalently labeled primary antibodies. Digital microscopic images of epidermal expression of keratin 10 and keratin 6 (differentiation), Ki-67 antigen (proliferation), and keratin 15 and beta-1 integrin (basal layer) were analyzed in a standardized way. Co-expression of different proteins was demonstrated. METHODS: Sections of normal skin and psoriatic lesions were compared immunohistochemically. Antibodies against keratin 6, 10, and 15 were labeled with the Zenon technique. Antibodies against the Ki-67 antigen and beta-1 integrin were covalently fluorescein isothiocyanate-labeled. Using standardized image analysis, intensity and positive surface area of the different antibodies in the epidermis were measured. RESULTS: The number of Ki-67-antigen positive cells was significantly increased in lesional psoriatic skin. Intensity and positive surface area of keratin 10 and beta-1 integrin were significantly decreased in comparison to normal epidermis. Differential expression of keratin 6 and keratin 15 was demonstrated. CONCLUSIONS: Using Zenon technology and image analysis, a description of morphology, co-expression, and quantification of representative markers for epidermal cell populations is possible.