Journal Article Annotations
2018, 3rd Quarter

Delirium

Annotations by Maalobeeka Gangopadhyay, MD; and Lex Denysenko, MD, FACLP
October 2018

Intraoperative ketamine administration to prevent delirium or postoperative cognitive dysfunction: A systematic review and meta-analysis
Does dexmedetomidine ameliorate postoperative cognitive dysfunction? a brief review of the recent literature
Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

PUBLICATION #1 — Delirium

Intraoperative ketamine administration to prevent delirium or postoperative cognitive dysfunction: a systematic review and meta-analysis

Hovaguimian F, Tschopp C, Beck-Schimmer B, Puhan M

Abstract: Acta Anaesthesiol Scand 2018; 62(9):1182-1193

BACKGROUND: Postoperative cognitive complications are associated with substantial morbidity and mortality. Ketamine has been suggested to have neuroprotective effects in various settings. This systematic review evaluates the effects of intraoperative ketamine administration on postoperative delirium and postoperative cognitive dysfunction (POCD).

METHODS: Medline, Embase and Central were searched to 4 March 2018 without date or language restrictions. We considered randomized controlled trials (RCTs) comparing intraoperative ketamine administration versus no intervention in adults undergoing surgery under general anaesthesia. Primary outcomes were postoperative delirium and POCD. Non-cognitive adverse events, mortality and length of stay were considered as secondary outcomes. Data were independently extracted. The quality of the evidence (GRADE approach) was assessed following recommendations from the Cochrane collaboration. Risk ratios were calculated for binary outcomes, mean differences for continuous outcomes. We planned to explore the effects of age, specific anesthesia regimen, depth of anesthesia and intraoperative haemodynamic events through subgroup analyses.

RESULTS: Six RCTs were included. The incidence of postoperative delirium did not differ between groups (4 trials, 557 patients, RR 0.83, 95% CI [0.25, 2.80]), but patients receiving ketamine seemed at lower risk of POCD (3 trials, 163 patients, RR 0.34, 95% CI [0.15, 0.73]). However, both analyses presented limitations. Therefore, the quality of the evidence (GRADE) was deemed low (postoperative delirium) and very low (POCD).

CONCLUSION: The effect of ketamine on postoperative delirium remains unclear but its administration may offer some protection towards POCD. Large, well-designed randomized trials are urgently needed to further clarify the efficacy of ketamine on neurocognitive outcomes.

On PubMed: Acta Anaesthesiol Scand 2018; 62(9):1182-1193

Annotation

Type of study: Systematic review/meta-analysis

The finding: From the 6 RCTs (928 patients) analyzed, there was no difference in 4 trials in the incidence of postoperative delirium between the group exposed to ketamine and those in the control arm; in 3 trials there was lower risk of postoperative cognitive dysfunction (POCD) in patients receiving a single bolus of ketamine at the induction of anesthesia. In the delirium assessment, the quality of the evidence was low and in the POCD assessment, the quality of evidence was deemed very low.

Strength and weaknesses: This is the first systematic review looking at effects of intraoperative ketamine on neurocognitive outcomes; it included only RCTs and excluded trials using ketamine for sedation or pain control and where there was an active comparator. Generalizability of findings is limited as patient population mean age was >60 years old in 5 of the 6 trials. The findings can be a result of chance, as the population size for adequate power is only 8% of what is needed to reach significance. Also, the trials were heterogenous in terms of types of surgery, comorbidities, and reporting of adverse events, so the safety of ketamine could not be fully explored.

Relevance: Research is still needed in studying the effects of ketamine on neurocognitive function.

PUBLICATION #2 — Delirium

Does dexmedetomidine ameliorate postoperative cognitive dysfunction? a brief review of the recent literature

Carr ZJ, Cios TJ, Potter KF, Swick JT

Abstract: Curr Neurol Neurosci Rep 2018; 18(10):64

PURPOSE OF REVIEW: Postoperative cognitive dysfunction (POCD) occurs in 20-50% of postsurgical patients with a higher prevalence in elderly patients and patients with vascular disease and heart failure. In addition, POCD has been associated with many negative outcomes, such as increased hospital length of stay, increased rates of institutionalization, and higher patient mortality. This brief review discusses select evidence suggesting an association between neuroinflammation and POCD and whether the use of dexmedetomidine, a short-acting alpha 2 agonist, may ameliorate the incidence of POCD. We review the recent evidence for neuroinflammation in POCD, dexmedetomidine’s properties in reducing inflammatory-mediated brain injury, and clinical studies of dexmedetomidine and POCD.

RECENT FINDINGS: There is evidence to support the anti-inflammatory and immunomodulatory effects of dexmedetomidine in animal models. Several clinical investigations have demonstrated favorable outcomes using dexmedetomidine over placebo for the reduction of postoperative delirium. Few studies have used high-quality endpoints for the assessment of POCD and no demonstrable evidence supports the use of dexmedetomidine for the prevention of POCD. While evidence exists for the neural anti-inflammatory properties of dexmedetomidine, human trials have yielded incomplete results concerning its use for the management of POCD. Dexmedetomidine may reduce acute postoperative delirium, but further studies are needed prior to recommending the use of dexmedetomidine for the direct reduction of POCD.

On PubMed: Curr Neurol Neurosci Rep 2018; 18(10):64

Annotation

Type of study: Systematic review/meta-analysis

The finding: In examining nine studies (meta-analysis and RCTs), there is mixed evidence supporting intraoperative dexmedetomidine to reduce POCD risk and there is limited support for its management of postoperative delirium.

Strength and weaknesses: This review paper concisely reviews the clinical pharmacology of dexmedetomidine, describes the relationship of neuroinflammation and POCD, reviews the effects of dexmedetomidine on neuroinflammation in animal models, and presents the human trials examining dexmedetomidine’s effect on POCD and delirium. The trials included were of differing age and surgical cohorts and demonstrated a range of timing of neurocognitive testing, variable primary endpoints (MMSE vs CAM-ICU), and variability of how dexmedetomidine was administered.

Relevance: This review suggests there are delirum protective effects when using dexmedetomidine, but large scale clinical studies are still needed.

PUBLICATION #3 — Delirium

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

Devlin JW, Skrobik Y, Gélinas C, et al

Abstract: Crit Care Med 2018; 46(9):e825-e873

OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.

DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines’ development. A general content review was completed face-to-face by all panel members in January 2017.

METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as “strong,” “conditional,” or “good” practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified.

RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation.

CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

On PubMed: Crit Care Med 2018; 46(9):e825-e873

Annotation

Type of study: Systematic review

The finding: The reader is invited to review the practice guidelines themselves for details. The guidelines do not provide any new findings, but they do offer a systematic review of various topics that would be of interest for critical care unit consultation-liaison psychiatry.

Strength and weaknesses: This was a multidisciplinary professional international group that gathered evidence, reviewed the literature, and discussed the findings over a 3.5 year period; this expanded from the 2013 guidelines on pain, agitation/sedation, and delirium guidelines and they had a high threshold for good evidence. Many common practices are challenged in this paper (e.g., use of antipsychotics in delirium). The scope of the evidence reviewed is large.

However, the guidelines need to be taken as opinion. The inclusion or exclusion of some topics appeared to be arbitrary, for example: the use of melatonin agonists for delirium prevention were overlooked in receiving a dedicated comment or position statement (not included in the section on delirium prevention). Not all guidelines received positive or negative recommendation—many were ungraded statements. Some sections were confusing, for example: the committee decided to not recommend antipsychotics for routine treatment of delirium, but parameters for “routine” were not defined; the committee agreed that the use of antipsychotics could be helpful for patients for whom their delirium has caused “distress”—essentially the symptoms of hyperactive delirium.

Relevance: The structure of this article and examination of many co-related topics in critical illness highlights the gaps in evidence and gaps between evidence and common practices when it comes to delirium. It challenges the reader to consider multimodal interventions for pain, delirium, and sleep disruption management.