Our October 2008 back-to-back columns “Managing Delirium” and “Preventing Delirium” talked about high cost of delirium in both human and financial terms, the risk factors and precipitating factors, methods of identifying delirium, and principles of management. Drugs are extremely common precipitating factors and use of sedating agents is one of the biggest contributors to the occurrence of delirium. Patients who develop postoperative delirium often have received a variety of drugs during surgery that may predispose to delirium (anesthetics, sedating agents, opioids, etc.). So it should be logical to investigate whether modifications in use of these agents might reduce the likelihood of postoperative delirium. And, in fact, there are a couple recent studies doing just that.
Sieber and colleagues at Johns Hopkins Bayview Medical Center this month published the results of a study testing their hypothesis that reducing the depth of sedation during surgery might reduce the incidence of postoperative delirium (Sieber et al 2010). They looked at elderly patients undergoing hip fracture repair under spinal anesthesia with propofol sedation. Patients with severe dementia (MMSE score less than 15) were excluded but those with mild to moderate dementia were included, as were those lacking obvious cognitive impairment prior to surgery. They randomized patients to receive either light or deep sedation with propofol, using the bispectral index (BIS) on EEG monitoring to assess depth of sedation. Their findings were striking. Those in the light sedation group developed postoperative delirium half as often as those in the deep sedation group (19% vs. 40%). The number needed to treat (NNT) to avoid one case of postoperative delirium was 4.7. And for those without significant cognitive impairment (MMSE score greater than 24) the NNT was 3.5. That is one of the most successful interventions in prevention of delirium.
Though the total dose of propofol was significantly higher in the deep sedation group, the total dose did not predict the occurrence of postoperative delirium. Rather, the depth of sedation appears to be the most important predictor of postoperative delirium in this patient population.
The results may not be generalizable to other populations or other agents used for sedation. As noted above, patients with pre-existing severe dementia were excluded from the study. And propofol was the only sedating agent studied. But this is certainly a starting point for further studies in those other circumstances.
The accompanying editorial by Crosby et al discusses some of the problems interpreting the results and extrapolating the results to other populations. In particular, they discuss the issue of using the BIS to distinguish between light and deep sedation. Whether the cutoffs are arbitrary, the use of the BIS in propofol titrations has been fairly well accepted in clinical anesthesiology practice. Crosby et al. raise the interesting possibility that the “delirium-susceptible” brain might develop lower BIS scores than the normal brain at any given dose of propofol. Regardless, the basic tenet is a good one, i.e. that minimizing procedural sedation where possible is a logical means of reducing the chance of postoperative delirium. Crosby et al. also stress a point we have made over and over: the preoperative evaluation (aka “medical clearance”) all too often results in ordering many unnecessary studies and overlooks some very simple things (eg. the MMSE or other bedside measure of cognitive status) that may be very helpful in predicting postoperative problems (see our March 31, 2009 Patient Safety Tip of the Week “Screening Patients for Risk of Delirium”).
A second recent paper (Radtke et al 2009) looked at potentially modifiable risk factors for early postoperative delirium, that is delirium occurring in the recovery room and on the first postoperative day. Though early postoperative delirium (often known as “emergence” delirium) is predictive of ultimate postoperative delirium, the incidence of this is considerably lower than we’d expect for ultimate postoperative delirium. Nevertheless, they identified two modifiable factors that significantly influenced the freqnency of early postoperative delirium. The first was the duration of preoperative fluid fasting. Those patients having preoperative fluid fasting for greater than 6 hours had over twice the incidence of delirium as those whose fasting was 2-6 hours prior to surgery. Dehydration has long been known to be one of the factors associated with an increased risk of delirium but this is the first study to actually demonstrate that the timeframe of fluid fasting is important. The second factor was the type of opioid used intraoperatively. Those patients who received fentanyl rather than remifentanil, an opioid metabolized differently and having a shorter half-life, had a higher rate of early postoperative delirium. The study was an observational study, not a randomized controlled trial, did not look at total occurrence of postoperative delirum, and was not restricted to elderly patients. However, the findings lay the foundation for randomized controlled trials of those two strategies to reduce the occurrence of postoperative delirium.
There were also some recent articles on the assessment and management of delirium. A study done in Germany (Leutz et al 2010) compared several delirium assessment tools commonly used in the ICU setting in a population of postoperative patients in a surgical ICU. They concluded that the Confusion Assessment Method for the ICU (CAM-ICU) and the Nursing Delirium Screening Scale (Nu-DESC) tools had comparable sensitivities in this population, identifying 81% and 83% respectively of cases meeting DSM-IV criteria for delirium. However, the specificity of CAM-ICU was considerably higher than the Nu-DESC (95% vs. 81%). Both tests performed better than the Delirium Detection Score (DSS) tool. They conclude that the CAM-ICU is the best tool in this population but that the Nu-DESC is an acceptable alternative and the DSS should not be used. Interstingly, the accompanying editorial (Young 2010) raises the interesting concept of whether tools having lower specificities might actually be better because they may detect cases of subsyndromal delirium better.
The Luetz paper includes a nice algorithm for delirium screening in the ICU. They recommend screening each ICU patient every 8 hours. If a patient is scored delirium-positive, symptom-oriented therapy is begun. The algorithm includes good advice on what to do when the RASS score indicates the patient is either oversedated or agitated or when confounders such as language barriers are present.
Also published this month are some of the first randomized controlled trials on pharmacologic management of delirium. Despite a paucity of evidence of either their efficacy or safety, haloperidol or some of the newer atypical antipsychotics are often used in management of delirium and consensus guidelines for managing delirium (Jacobi et al 2002) even include such as a recommendation despite the lack of a solid evidence base.
The MIND (Modifying the Incidence of Delirium) trial (Girard et al 2010) was a multicenter controlled trial in ICU patients with delirium randomized to 3 treatment arms (haloperidol, ziprasidone, or placebo). The study failed to demonstrate any difference in primary or secondary endpoints among the three groups. Safety profiles were similar in all three groups except that akathisia was more frequent in the haloperidol group. However, the stated primary goal of MIND was to demonstrate the feasibility of randomized controlled trials of pharmacologic agents in ICU patients with delirium and the study was really underpowered to statistically demonstrate differences between treatment groups. The mere fact that the study was done (though they had significant problems recruiting participants) shows that such trials are feasible and would need to be done on a much larger scale.
A second study (Devlin et al 2010) was a randomized controlled trial of an escalating dose of the atypical antipsychotic agent quetiapine vs. placebo in ICU patients with delirium who were allowed to be treated with “rescue” haloperidol for persistent symptoms. The quetiapine group demonstrated a shorter time to first resolution of delirium, fewer hours of delirium, and fewer hours of agitation. However, there were no significant differences in outcomes such as duration of mechanical ventilation, length of ICU or total hospital stay, or mortality. More patients in the quetiapine group were discharged to home or a rehab facility rather than a chronic care facility. Note that the small sample size (36 total patients) meant the study was not powered to show differences in outcomes other than the primary outcome. Importantly, the safety profile of quetiapine was reasonable in this population. Though it caused more sedation than placebo, the incidence of serious side effects did not differ from the placebo group and no episodes of extrapyramidal symptoms were seen. The study highlights many of the challenges in doing a study of this nature. Though this was a multicenter study, they had considerable difficulty recruiting patients for participation. In addition, the lack of a consensus standard definition of resolution of delirium was problematic. Thus, they chose the time until the first assessment using the Intensive Care Delirium Screening Checklist (ICDSC) score was equal to or less than 4. The authors suggest that their study be considered a “pilot” study and that further larger trials be undertaken to determine the effect of this approach on some of the more relevant outcome measures like mortality, ICU and total hospital LOS, cognitive function, ultimate disposition, and safety. But this is certainly a step in the right direction and shows that studies of this sort may be done, albeit with considerable logistical difficulty.
So for the time being, we can’t make any good evidence-based recommendations regarding pharmacologic management of delirium. Prevention remains our best way to manage delirium. Our best approach is still to identify patients at risk for development of delirium and take steps to avoid factors that may precipitate delirium.
Our other Patient Safety Tips of the Week on the topic of delirium:
October 14, 2008 “Managing Delirium”
October 21, 2008 “Preventing Delirium”
February 10, 2009 “Sedation in the ICU: The Dexmedetomidine Study”
March 31, 2009 “Screening Patients for Risk of Delirium”
Sieber FE, Zakriya, KJ, Gottschalk A et al. Sedation Depth During Spinal Anesthesia and the Development of Postoperative Delirium in Elderly Patients Undergoing Hip Fracture Repair. Mayo Clin Proc. 2010; 85(1): 18-26
Crosby G, Culley DJ, Marcantonio ER. Delirium: A Cognitive Cost of the Comfort of Procedural Sedation in Elderly Patients? Mayo Clin Proc. 2010; 85(1): 12-14
Radtke, Finn M *; Franck, Martin *; MacGuill, Martin; Seeling, Matthes; Lutz, Alawi; Westhoff, Sarah; Neumann, Ulf; Wernecke, Klaus D; Spies, Claudia D. Duration of fluid fasting and choice of analgesic are modifiable factors for early postoperative delirium.
European Journal of Anaesthesiology 2009; 26: 000–000
Luetz, Alawi; Heymann, Anja; Radtke, Finn M.; Chenitir, Chokri; Neuhaus, Ulrike; Nachtigall, Irit; von Dossow, Vera; Marz, Susanne; Eggers, Verena; Heinz, Andreas; Wernecke, Klaus D.; Spies, Claudia D. Different assessment tools for intensive care unit delirium: Which score to use? Critical Care Medicine 2010; 38(2): 409-418
Young CC, Flanagan EM. Delirium: The struggle to vanquish an ancient foe. Critical Care Medicine 2010; 38(2): 693-694
Jacobi J, Fraser GL, Coursin DB et al. Clinical practice guidelines for the sustained use
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Girard, Timothy D.; Pandharipande, Pratik P.; Carson, Shannon S.; Schmidt, Gregory A.; Wright, Patrick E.; Canonico, Angelo E.; Pun, Brenda T.; Thompson, Jennifer L.; Shintani, Ayumi K.; Meltzer, Herbert Y.; Bernard, Gordon R.; Dittus, Robert S.; Ely, E Wesley; for the MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial. Critical Care Medicine 2010; 38(2): 428-437
Devlin, John W.; Roberts, Russel J.; Fong, Jeffrey J.; Skrobik, Yoanna; Riker, Richard R.; Hill, Nicholas S.; Robbins, Tracey; Garpestad, Erik. Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Critical Care Medicine 2010; 38(2): 419-427