Preventing Postoperative Delirium After Major Noncardiac Thoracic Surgery

A Randomized Clinical Trial

Babar A. Khan, MD, MS; Anthony J. Perkins, MS; Noll L. Campbell, PharmD; Sujuan Gao, PhD; Sikandar H. Khan, DO; Sophia Wang, MD; Mikita Fuchita, MD; Daniel J. Weber, MD; Ben L. Zarzaur, MD, MPH; Malaz A. Boustani, MD, MPH; Kenneth Kesler, MD

Disclosures

J Am Geriatr Soc. 2018;66(12):2289-2297. 

In This Article

Discussion

Our results demonstrate the feasibility of conducting a randomized, placebo-controlled clinical trial in individuals undergoing major thoracic surgery. The low-dose postoperative haloperidol intervention did not reduce delirium incidence, duration, or severity in the overall population, although prespecified esophagectomy subgroup experienced modest benefits; the haloperidol intervention reduced the incidence of delirium by 17% and reduced ICU length of stay. Similar to the overall group, hospital length of stay was shorter, although not statistically significant, in the esophagectomy subgroup when the analysis was limited to participants with delirium.

Our study results had similarities to and differences from those of other delirium prevention studies in the surgical literature.[27,28] One study[27] showed a decrease in delirium incidence, delirium duration, and ICU length of stay with haloperidol prophylaxis in elderly individuals—predominantly individuals undergoing abdominal surgery. The other study[28] did not show a reduction in delirium incidence in elderly individuals undergoing hip surgery, but prophylaxis reduced delirium duration, severity, and hospital length of stay in individuals with delirium. Both studies used low-dose haloperidol (1.2 mg/d for 3 days,[28] 1.7-mg 1-time postoperative infusion[27]). We used a similar low-dose strategy based on the evidence from the aforementioned studies and prior work from our group[40] demonstrating that low-dose haloperidol conferred efficacy similar to that of higher haloperidol doses with less risk of extrapyramidal symptoms. Our results were similar to those of the Hope-ICU[41] and (REDUCE) trials.[42] Both compared haloperidol with placebo in traditional medical and surgical ICU populations and used delirium- and coma-free days as one of the outcomes. They tested a slightly higher dose of haloperidol (Hope-ICU: 2.4 mg every 8 hours, REDUCE: 2 mg 3 times daily) than the 0.5 mg 3 times daily that we used. No differences in delirium- or coma-free days were observed in either trial between the intervention and placebo groups. REDUCE also evaluated the effect of haloperidol on delirium incidence and did not find any difference between the intervention and placebo groups. The incidence rate was 33% in both groups. Our low-dose haloperidol approach could not reduce delirium incidence either, but we were able to reduce the length of ICU stay in individuals undergoing esophagectomy, in contrast to the Hope-ICU and REDUCE studies. Because there were no differences in delirium duration between the intervention and control groups, the reduction in the ICU length of stay could not be attributed to shorter delirium duration. Other factors, although statistically nonsignificant, such as high benzodiazepine use in the placebo group and ondansetron in the intervention group, may have contributed to these results. A potential protective effect of haloperidol that could have been mediated through its antiinflammatory and immunomodulatory properties could not be discounted;[25] especially in individuals undergoing esophagectomy, who may have a higher cytokine burden.

The esophagectomy subgroup differed from participants undergoing other thoracic surgeries in multiple aspects. Individuals undergoing esophagectomy had higher APACHE II scores and poorer function at baseline. Surgery was twice as long in the esophagectomy group (mean 5 hours), and participants undergoing esophagectomy had twice the blood loss during surgery and received higher doses of opioids and benzodiazepines intraoperatively. The high risk profile explains the higher delirium incidence of 32.1% in esophagectomy subgroup than the 13.7% in other thoracic surgeries. In addition, the duration of ICU stay was twice as long in the esophagectomy subgroup. These differences suggest a targeted strategy of low-dose haloperidol for the high-risk esophagectomy subgroup and do not justify use of prophylaxis in all individuals undergoing thoracic surgery, especially uncomplicated cases with short ICU stays. The mechanisms for a potential therapeutic benefit are unclear, but the extent of surgery combined with the severity of illness predisposing to high cytokine levels might respond better to the antiinflammatory properties of haloperidol. Larger studies with serial biomarkers focusing on high-risk subgroups such as individuals undergoing esophagectomy could elucidate the efficacy of haloperidol prophylaxis and underlying pathogenic mechanisms.

One of the main lessons we learned from our pilot investigation is the inherent difficulty in conducting longitudinal postsurgical follow-up. We could not achieve adequate postdischarge follow-up to collect the neurocognitive outcomes. Hence, improvements in cognitive scores in the placebo group could represent a lack of regression of the scores to the mean given the small sample size. Many of our participants were referred from out of the hospital system and did not return for follow-up and in-person cognition assessments. In designing future studies, researchers should consider allocating extra resources for study personnel travel to conduct these assessments at homes of trial participants. With the increasing availability of Internet-connected telephones, better options could be to use Tele-health for cognitive assessments (Skype, Zoom, Face Time) or conduct assessments that could be performed over the telephone.

Our study had several limitations. We had a small sample size for a prevention study. We were unable to achieve the target of 106 esophagectomies as specified in our power calculation because of the limited resources afforded to us through a small local grant. We observed lower delirium incidence rate in the low dose haloperidol group (23.8%) compared to delirium incidence in the placebo group (40.5%) in esophagectomy patients. We estimate that a larger study with 266 total participants would have 80% power to detect the effect size observed in our study. It was a single-site study with results shaped by local practice patterns, which may not be replicable at other institutions. The CAM-ICU was used throughout hospitalization, which may have resulted in missing cases of delirium outside the ICU.

Our study had several strengths. We used a double-blind placebo-controlled design with validated data assessment tools. Trained research staff monitored for delirium twice daily. Information on all relevant baseline, intraoperative, and postoperative variables was collected, including baseline cognitive and psychological assessments, information not routinely collected. We achieved high fidelity to our intervention, with a mean of 10 administered postoperative doses. Inclusion of a prespecified esophagectomy subgroup provides relevant contrast and comparison with individuals undergoing other types of thoracic surgery, which could allow development of surgery-specific approaches.

In conclusion, use of low-dose haloperidol postoperatively does not reduce delirium incidence, duration, or severity in individuals undergoing major thoracic surgery. Low-dose haloperidol prophylaxis may be efficacious in reducing delirium incidence in individuals undergoing esophagectomy, but this finding needs to be confirmed in a multiinstitutional randomized trial with adequate sample size.

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