Are dexmedetomidine and olanzapine suitable to control delirium in critically ill elderly patients? A retrospective cohort study. Liu SB, Zhao R, Yang RL, et al. Biomedicine & Pharmacotherapy 2021;39:111617.
The authors performed a retrospective review of patients 75 years of age and older who developed delirium in a medical ICU setting, who were not intubated and had not undergone a surgical procedure. One-hundred eighteen patients who had their delirium treated with intravenous dexmedetomidine were compared to 145 patients who were treated with oral olanzapine. Dexmedetomidine was dosed and adjusted by the bedside nurse based on Richmond Agitation-Sedation Scale targets. Olanzapine was administered at a starting dose of 2.5 mg/day for those patients with dementia and 5.0 mg/day for those patients without dementia. The demographics of the two groups were similar, with a similar distribution of ages from 75 to over 90 years of age.
While dexmedetomidine appeared to be more effective in controlling the symptoms of delirium than olanzapine, it was also associated with significantly higher incidence of respiratory depression, hypoxia, hypotension, and need for intubation. The authors concluded that olanzapine was safer for elderly high-risk patients with critical illness.
This is an interesting paper which addresses the challenge of managing delirium in elderly patients in the ICU after non-operative injury, and possibly after hip fracture repair. It appears the challenges of dexmedetomidine in the non-intubated elderly patient with delirium arise from the intravenous nature of administration and ease with which agitation can be sedated by increasing the infusion rate.
Hyperoxemia during resuscitation of trauma patients and increased intensive care unit length of stay: Inverse probability of treatment weighting analysis. Yamamoto R, Fujishima S, Sasaki J, et al. World Journal of Emergency Surgery 2021;16:19.
A post hoc analysis of a prospective observational study was performed of 240 adult patients with trauma and an ISS >15. Hyperoxemia was defined as a PaO2 of 300 mmHg or greater on arrival to the hospital and/or 3 hours after arrival. Compared to the non-hyperoxemia group (n=186), the hyperoxemia group (n=58) had a lower GCS (6 vs. 14) and higher ISS (29 vs. 26). Eighty-one percent of the hyperoxemia group were intubated upon arrival or in the ED compared to 31% for the non-hyperoxemia group. The hyperoxemia group required more blood products, craniotomies, and angiographies.
The authors performed inverse probability of treatment weighting (IPW) on subgroup analysis based on intubation status. For patients intubated in the ED they found no difference in ICU-free days or ventilator-free days between patients who experienced hyperoxemia and those who did not. However, for patients not intubated in the ED they found the hyperoxemia group had statistically significantly less ICU-free days and ventilator-free days. Mortality for the two groups were similar.
At first glance this paper seems to state that hyperoxemia is deleterious to non-intubated trauma patients. However, it gets more confusing the deeper into the details of the paper one goes. This paper is a post hoc analysis of nationwide multicenter prospective descriptive study conducted by the Japanese Association for Acute Medicine Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (JAAM FORECAST) study group. The number of patients from which the 244 patients in this study were drawn is not given in the manuscript. Further the number of patients in each subgroup of the IPW analysis is not provided. Based on the information provided in the tables and supplemental information, it appears the total number of patients who were intubated in the ED were similar for the hyperoxemia group (n=47) and the non-hyperoxemia group (n=58). However, there were only 11 non-intubated patients in the hyperoxemia group, compared to 128 non-intubated patients in the non-hyperoxemia group. These numbers do not seem adequate to draw any conclusions.
Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. Hughes CG, Mailloux PT, Devlin JW, et al. N Engl J Med. 2021 Apr 15;384(15):1424-1436.
Sepsis guidelines advocate for light sedation with either dexmedetomidine or propofol but their individual effect on outcomes is unknown. The MENDS2 (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study investigators conducted a multicenter, double-blind, randomized, controlled trial designed to answer whether dexmedetomidine (alpha2 receptor agonist), based on its anti-inflammatory and bacterial clearance properties, leads to better short and long-term outcomes than propofol (GABA agonist) for mechanically ventilated patients with sepsis.
Dexmedetomidine or Propofol were dosed and adjusted by bedside nurses based on Richmond Agitation-Sedation scale targets. Of note, the FDA approved an Investigation New Drug application for prolonged administration of dexmedetomidine. The study primary endpoint was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age adjusted score on the Telephone Interview for Cognitive Status questionnaire (TICS-T) at 6 months. 432 patients were enrolled. Ultimately no difference was found between the two drugs in the number of days alive without delirium or coma, ventilator free days, death at 90 days or TICS-T score, thus supporting current guidelines and other comparative trials recommending the use of either drug for light sedation.
Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients with Sepsis: The VICTAS Randomized Clinical Trial. Sevransky JE, Rothman RE, Hager DN, et al. JAMA. 2021 Feb 23;325(8):742-750.
The VICTAS (Vitamin C, Thiamine, and Steroids in Sepsis) trial hypothesized that vitamin C, thiamine and hydrocortisone would improve clinically important outcomes in patients with sepsis-induced respiratory and/or circulatory failure; specifically, it questioned whether the cocktail given every 6 hours increased ventilator- and vasopressor-free days (VVFDs) and days alive as compared to placebo as suggested and subsequently challenged in prior studies. This was a United States multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in the ED and ICU. The study was terminated early for administrative reasons (the sponsor pulled funding due to shifting priorities) after enrollment of only 501 of the planned 2000 participants potentially leading to the study being underpowered to detect a clinically important difference. Initially scheduled interim analyses were performed after 200, 300, and 400 patients were enrolled and reportedly the sponsor did not have access to this interim data. The treatment group received hydrocortizone (50mg), intravenous vitamin C (1.5g), and thiamine (100mg), every 6 hours for 96 hours or until ICU discharge or death. Patients were randomized within 24 hours of the onset of sepsis-induced organ dysfunction and could receive open-label corticosteroids. Compared to placebo, there was no significant difference in the median VVFDs (25 vs 26 days, respectfully) within the 30 days following randomization. Similarly, there was no significant difference in overall mortality between the groups.
This study adds to the debate over hydrocortisone, vitamin C and thiamine (HAT) therapy in sepsis. The VICTAS trial’s conclusions support the other three single center clinical trials and two multicenter randomized trials of HAT recently released debunking its efficacy claim, but also confirms its safety in critically ill patients even if not directly beneficial. Despite the irregularity that occurred with the study’s funder leading to early termination, this trial remains the largest on the question and its design was otherwise sophisticated and rigorously conducted.