Annotated Abstracts of Journal Articles
2013, 3rd Quarter
Annotations by Shamim Nejad, MD
September 2013
ANNOTATION (Shamim Nejad)
The Finding: In a double-blind, placebo-controlled randomised trial in a general adult mixed-type ICU, there was no significant statistical difference between low dose IV haloperidol administration versus placebo in delirium free and coma free days, ventilator-free days, mortality, length of critical care and hospital stay, safety with regard to prolonged QTc, extrapyramidal effects, and serious adverse events.
Strength and Weaknesses:: The primary strength of this study was that it was a randomized, double-blind, placebo-controlled trial which can be difficult to perform in this patient population. Limitations of the study include that it was a single site study, the reason for ICU admission was varied (and included medical and surgical patients), premorbid neurocognitive function was largely unknown, and there was no information regarding history of alcohol substance use prior to admission.
Relevance: This study highlights the importance that delirium is a syndrome with multiple different etiologies resulting in varied pathophysiological derangements of which a hyperdopaminergic state may or not be present. Continued assessment and management of underlying physiological derangements should always be pursued, with the use of IV haloperidol likely being the most beneficial for patients with underlying hyperactive agitated delirium.
Background: Delirium is frequently diagnosed in critically ill patients and is associated with poor clinical outcomes. Haloperidol is the most commonly used drug for delirium despite little evidence of its effectiveness. The aim of this study was to establish whether early treatment with haloperidol would decrease the time that survivors of critical illness spent in delirium or coma.
Methods: We did this double-blind, placebo-controlled randomised trial in a general adult intensive care unit (ICU). Critically ill patients (=18 years) needing mechanical ventilation within 72 h of admission were enrolled. Patients were randomised (by an independent nurse, in 1:1 ratio, with permuted block size of four and six, using a centralised, secure web-based randomisation service) to receive haloperidol 2·5 mg or 0·9% saline placebo intravenously every 8 h, irrespective of coma or delirium status. Study drug was discontinued on ICU discharge, once delirium-free and coma-free for 2 consecutive days, or after a maximum of 14 days of treatment, whichever came first. Delirium was assessed using the confusion assessment method for the ICU (CAM-ICU). The primary outcome was delirium-free and coma-free days, defined as the number of days in the first 14 days after randomisation during which the patient was alive without delirium and not in coma from any cause. Patients who died within the 14 day study period were recorded as having 0 days free of delirium and coma. ICU clinical and research staff and patients were masked to treatment throughout the study. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN83567338.
Findings: 142 patients were randomised, 141 were included in the final analysis (71 haloperidol, 70 placebo). Patients in the haloperidol group spent about the same number of days alive, without delirium, and without coma as did patients in the placebo group (median 5 days [IQR 0—10] vs 6 days [0—11] days; p=0·53). The most common adverse events were oversedation (11 patients in the haloperidol group vs six in the placebo group) and QTc prolongation (seven patients in the haloperidol group vs six in the placebo group). No patient had a serious adverse event related to the study drug.
Interpretation: These results do not support the hypothesis that haloperidol modifies duration of delirium in critically ill patients. Although haloperidol can be used safely in this population of patients, pending the results of trials in progress, the use of intravenous haloperidol should be reserved for short-term management of acute agitation.
ANNOTATION (Shamim Nejad)
The Finding: Few patients had PTSD immediately after experiencing physical trauma and while overall PTSD incidence at 3, 12, and 24 months was 8.5%, 9.5%, and 6.8%, respectively, diagnoses fluctuated between no PTSD, subsyndromal PTSD and full PTSD during this time period. Severity of PTSD at 24 months was predicted by mild traumatic brain injury, intercurrent adverse events, and severity of initial PTSD.
Strength and Weaknesses: Most evidence in this area is limited by cross-sectional design relying on retrospective recall of symptoms, small sample sizes, or self-reported measurement of PTSD symptoms. This particular study is a multisite, longitudinal investigation of patients with physical trauma assessed for PTSD symptoms over a 24 month period clinical-administered scales. Limitations include that patients with pre-existing trauma and PTSD were not excluded or accounted for, the contribution of subsequent trauma to symptomatology on follow-up, sample size was restricted to physical injury (mostly from motor vehicle accidents) requiring hospital admission (and thus may not be applicable to other types of trauma), and that the authors did not index delayed-onset PTSD to DSM-IV criteria.
Relevance: Although most patients did not exhibit PTSD, in those that did, clinicians should be aware of the fluctuating course of PTSD following physical trauma. The development of PTSD may in part be explained by subsequent stressors that retrigger previously extinguished fear conditioning, sensitization to further stress, and decreased resiliency and increased mood lability secondary to head injury. Within the first year, patients with increased initial acute stress reactions, head injury and concomitant stressors, seem to be at higher risk for development of chronic PTSD and should be followed closely.
Objective: To test the roles of initial psychiatric reactions, mild traumatic brain injury (MTBI), and ongoing stressors on delayed-onset PTSD.
Design, Setting, and Participants:
In this prospective cohort study, patients were selected from recent admissions to 4 major trauma hospitals across Australia. A total of 1084 traumatically injured patients were assessed during hospital admission from April 1, 2004, through February 28, 2006, and 785 (72.4%) were followed up at 3, 12, and 24 months after injury.
Main Outcome and Measure: Severity of PTSD was determined at each assessment with the Clinician-Administered PTSD Scale.
Results: Of those who met PTSD criteria at 24 months, 44.1% reported no PTSD at 3 months and 55.9% had subsyndromal or full PTSD. In those who displayed subsyndromal or full PTSD at 3 months, PTSD severity at 24 months was predicted by prior psychiatric disorder, initial PTSD symptom severity, and type of injury. In those who displayed no PTSD at 3 months, PTSD severity at 24 months was predicted by initial PTSD symptom severity, MTBI, length of hospitalization, and the number of stressful events experienced between 3 and 24 months.
Conclusions and Relevance: These data highlight the complex trajectories of PTSD symptoms over time. This study also points to the roles of ongoing stress and MTBI in delayed cases of PTSD and suggests the potential of ongoing stress to compound initial stress reactions and lead to a delayed increase in PTSD symptom severity. This study also provides initial evidence that MTBI increases the risk of delayed PTSD symptoms, particularly in those with no acute symptoms.
ANNOTATION (Shamim Nejad)
The Finding:
In this retrospective administrative data–driven research, evaluating the association between SSRI use and postoperative events in 530,416 adult patients undergoing elective surgery in 375 hospitals in the United States, patients receiving SSRIs had a higher adjusted odds ratio (AOR) for in-hospital mortality (AOR, 1.20 [95% CI, 1.07-1.36]), bleeding (1.09 [1.04-1.15]), and readmission at 30 days (1.22 [1.18-1.26]). The findings were consistent across methods and largely irrespective of the specific perioperative timing of administration of SSRIs.
Strength and Weaknesses: A significant strength of this study is that more than 500,000 patients underwent analysis allowing for better evaluation of drug-outcome associations, particularly for a relatively rare event in a very specific setting. In addition, perioperative SSRI exposure was carefully ascertained, and vigorous statistical methods were utilized, adjusting for known confounders. However, causality can be difficult to evaluate from observational studies. Undercoding from administrative databases may exist, decreasing the yield of all known confounding variables. SSRI users were typically less healthy than nonusers, and, the mortality signal was abolished when the analysis was restricted to patients with a diagnosis of depression (AOR, 1.00 [95% CI, 0.72-1.37]).
Relevance: This study highlights the prevalence of SSRI use in perioperative setting and that while it does seem to be associated with some increased risk, it is unclear if the data should change clinical practice. The increase in absolute risk for patients would be very small and the number needed to harm quite large. Clinicians should be aware of potential bleeding risks in patients receiving SSRIs perioperatively coupled with the risks of discontinuing the medication, which may exacerbate underlying psychiatric illness or post-operative pain, particularly for chronic pain patients. Further studies will be needed to delineate this associated risk.
Importance: Single-site studies have described an association between use of selective serotonin reuptake inhibitors (SSRIs) and adverse outcomes of surgery. Multicenter studies including a broad range of surgical procedures that explore rare outcomes, such as bleeding and mortality, and that account for indications for administration of SSRIs are needed.
Objective: To determine whether perioperative use of SSRIs is associated with adverse outcomes of surgery in a national sample of patients.
Design: Retrospective study of patients 18 years or older who underwent major surgery from January 1, 2006, through December 31, 2008, at 375 US hospitals. We used multivariable hierarchical models to estimate associations between SSRI use and our outcomes. Pharmacy data were used to determine whether a patient received an SSRI in the perioperative period.
Setting: Three hundred seventy-five US hospitals.
Participants: Five hundred thirty thousand four hundred sixteen patients 18 years or older.
Exposure: Perioperative use of SSRIs.
Main Outcomes and Measures: In-hospital mortality, length of stay, readmission at 30 days, bleeding events, transfusions, and incidence of ventricular arrhythmias.
Results: Patients receiving SSRIs were more likely to have obesity, chronic pulmonary disease, or hypothyroidism (P < .001 for each) and more likely to have depression (41.0% vs 6.2%, P < .001). After adjustment, patients receiving SSRIs had higher odds of in-hospital mortality (adjusted odds ratio, 1.20 [95% CI, 1.07-1.36]), bleeding (1.09 [1.04-1.15]), and readmission at 30 days (1.22 [1.18-1.26]). Similar results were observed in propensity-matched analyses, although the risk of inpatient mortality was attenuated among patients with depression. Sensitivity analyses suggest that, to invalidate our results, an unmeasured covariate would have to have higher prevalence and be more strongly associated with mortality than any covariate included in our models.
Conclusions and Relevance: Receiving SSRIs in the perioperative period is associated with a higher risk for adverse events. Determining whether patient factors or SSRIs themselves are responsible for elevated risks requires prospective study.