Journal Article Annotations
2017, 4th Quarter
Delirium
Annotations by Maalobeeka Gangopadhyay, MD, and Lex Denysenko, MD, FAPM
January 2018
- Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: a randomized clinical trial
- Delirium and benzodiazepines associated with prolonged ICU stay in critically ill infants and young children
- Perioperative gabapentin does not reduce postoperative delirium in older surgical patients: a randomized clinical trial
PUBLICATION #1 — Delirium
Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: a randomized clinical trial
Hui D, Frisbee-Hume S, Wilson A, et al
Abstract: JAMA 2017; 318(11):1047-1056
Importance: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial.
Objective: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer.
Design, Setting, and Participants: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016.
Interventions: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode.
Main Outcomes and Measures: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival.
Results: Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (-4.1 points) than placebo + haloperidol (-2.3 points) (mean difference, -1.9 points [95% CI, -2.8 to -0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, -1.0 mg [95% CI, -2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]).
Conclusions and Relevance: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects.
On PubMed: JAMA 2017; 318(11):1047-1056
Annotation
Type of study: Randomized controlled trial
The finding: In the setting of hospitalized patients with advanced cancer who have agitated delirium, a combination of lorazepam and haloperidol intravenously leads to reduction in agitation within 8 hours compared to haloperidol alone.
Strength and weaknesses: This is a double blind, parallel group, placebo-controlled randomized clinical trial including patients diagnosed with delirium. The study was powered for the primary outcome (reduction in RASS) but not the secondary outcomes of delirium severity, delirium-related distress, and communication capacity. These findings might not be generalized to patients in the home setting or with less severe illness. In addition, this only involved a single dose of lorazepam. The delirium recall questionnaire requires validation.
Relevance: Delirium and agitation management in the palliative care setting is underrepresented in the consultation-liaison literature. Using lorazepam along with haloperidol in cases of agitated delirium in the palliative care setting may be justified when the priority is to reduce agitation rather than maintaining alertness.
PUBLICATION #2 — Delirium
Delirium and benzodiazepines associated with prolonged ICU stay in critically ill infants and young children
Smith HAB, Gangopadhyay M, Goben CM, et al
Abstract: Crit Care Med 2017; 45(9):1427-1435
Objectives: Delirium is prevalent among critically ill children, yet associated outcomes and modifiable risk factors are not well defined. The objective of this study was to determine associations between pediatric delirium and modifiable risk factors such as benzodiazepine exposure and short-term outcomes.
Design: Secondary analysis of collected data from the prospective validation study of the Preschool Confusion Assessment Method for the ICU.
Setting: Tertiary-level PICU.
Patients: Critically ill patients 6 months to 5 years old.
Interventions: None.
Measurements and Main Results: Daily delirium assessments were completed using the Preschool Confusion Assessment Method for the ICU. Associations between baseline and in-hospital risk factors were analyzed for likelihood of ICU discharge using Cox proportional hazards regression and delirium duration using negative binomial regression. Multinomial logistic regression was used to determine associations between daily risk factors and delirium presence the following day. Our 300-patient cohort had a median (interquartile range) age of 20 months (11-37 mo), and 44% had delirium for at least 1 day (1-2 d). Delirium was significantly associated with a decreased likelihood of ICU discharge in preschool-aged children (age-specific hazard ratios at 60, 36, and 12 mo old were 0.17 [95% CI, 0.05-0.61], 0.50 [0.32-0.80], and 0.98 [0.68-1.41], respectively). Greater benzodiazepine exposure (75-25th percentile) was significantly associated with a lower likelihood of ICU discharge (hazard ratio, 0.65 [0.42-1.00]; p = 0.01), longer delirium duration (incidence rate ratio, 2.47 [1.36-4.49]; p = 0.005), and increased risk for delirium the following day (odds ratio, 2.83 [1.27-6.59]; p = 0.02).
Conclusions: Delirium is associated with a lower likelihood of ICU discharge in preschool-aged children. Benzodiazepine exposure is associated with the development and longer duration of delirium, and lower likelihood of ICU discharge. These findings advocate for future studies targeting modifiable risk factors, such as reduction in benzodiazepine exposure, to mitigate iatrogenic harm in pediatric patients.
On PubMed: Crit Care Med 2017; 45(9):1427-1435
Annotation
Type of study: Cohort study
The finding: Benzodiazepine exposure is associated with delirium and longer lengths of stay in the PICU in infants and young children. Younger age and hypoxia are also with longer length of stay and dexmedetomidine exposure was associated with increased likelihood of ICU discharge. Benzodiazepine exposure is predictive of delirium diagnosis the next day and average duration of delirium was 1-2 days.
Strength and weaknesses: This is an analysis of a prospective observational study validating the psCAM-ICU in a population of 300 patients who were 6 months to 5 years old. Multiple risk factors for delirium were examined, however, environmental issues such as sleep deprivation, restraint, and social isolation were not examined. Limits of the study are that the findings might not generalize to older children. Benzodiazepine exposure was measure by dose administration not by blood levels. Since this was a single center study, it is not clear if the population study is representative for all PICUs. Delirium diagnoses may be a reflection of severity of illness and not just benzodiazepine exposure and so the severity of illness could be contributing to the longer length of stay in the PICU. Also presence of delirium might not be considered or identified by the medical team when discharging the patient from the PICU.
Relevance: This is the largest prospective study evaluating delirium and risk factors in a preschool population. This study suggests that just as with adults, benzodiazepine exposure in the critically ill infants and young children is predictive of negative short term outcomes.
Disclosure Note: MG was one of the authors of the publication and also one of the authors of this annotation.
PUBLICATION #3 — Delirium
Perioperative gabapentin does not reduce postoperative delirium in older surgical patients: a randomized clinical trial
Leung JM, Sands LP, Chen N, et al
Abstract: Anesthesiology 2017; 127(4):633-644
Background: Postoperative pain and opioid use are associated with postoperative delirium. We designed a single-center, randomized, placebo-controlled, parallel-arm, double-blinded trial to determine whether perioperative administration of gabapentin reduced postoperative delirium after noncardiac surgery.
Methods: Patients were randomly assigned to receive placebo (N = 347) or gabapentin 900 mg (N = 350) administered preoperatively and for the first 3 postoperative days. The primary outcome was postoperative delirium as measured by the Confusion Assessment Method. Secondary outcomes were postoperative pain, opioid use, and length of hospital stay.
Results: Data for 697 patients were included, with a mean ± SD age of 72 ± 6 yr. The overall incidence of postoperative delirium in any of the first 3 days was 22.4% (24.0% in the gabapentin and 20.8% in the placebo groups; the difference was 3.20%; 95% CI, 3.22% to 9.72%; P = 0.30). The incidence of delirium did not differ between the two groups when stratified by surgery type, anesthesia type, or preoperative risk status. Gabapentin was shown to be opioid sparing, with lower doses for the intervention group versus the control group. For example, the morphine equivalents for the gabapentin-treated group, median 6.7 mg (25th, 75th quartiles: 1.3, 20.0 mg), versus control group, median 6.7 mg (25th, 75th quartiles: 2.7, 24.8 mg), differed on the first postoperative day (P = 0.04).
Conclusions: Although postoperative opioid use was reduced, perioperative administration of gabapentin did not result in a reduction of postoperative delirium or hospital length of stay.
On PubMed: Anesthesiology 2017; 127(4):633-644
Annotation
Type of study: Randomized controlled trial
The finding: Gabapentin 900mg before non-cardiac surgery followed by 300mg TID for 72 hours after surgery did not reduce delirium incidence in patients over 65 years old compared to the control group.
Strength and weaknesses: The study used the CAM tool for delirium screening, but did not specify frequency of screening, and appears to have only been conducted once daily, which may have been insufficient for detecting delirium. Patients with significant sedation measured on the Richmond Agitation and Sedation Scale scores were excluded from delirium evaluation. A significant number of subjects (n=102) did not receive CAM screening on at least one of the three post-surgical days. For these reasons, the incidence of delirium may have been inaccurate and underestimated. Documentation on the use of benzodiazepines, antipsychotics, alpha agonists, or other medications apart from opioids were not included in the study, and may have been different in study groups.
Relevance: Perioperative and post-operative gabapentoid use may be of interest to consultation-liaison psychiatrists concerned as to the deliriogenic potential of these sedating medications. This study also showed only a mild opioid-sparing effect that may not be clinically significant, consistent with another recent study that showed only a modest increase in opioid cessation rates weeks after surgery but no major effect on pain cessation. More research is needed on the effect of gabapentoids on reducing pain, opioid use, and delirium in the postoperative setting.
