The Daily Dose • Friday, March 18, 2022

Improving Patient Surgical Outcomes and Mental Health

Cameron Bosinski, MD, MS

Anesthesiologists are in a unique position to address the mental health of patients undergoing surgery. In this session, “Perioperative Mental Health: From Neural Circuits to Implementation,” held on Friday, March 18 at the IARS 2022 Annual Meeting, the speakers discussed the potential for mindfulness, as well as pharmacologic interventions, to improve surgical outcomes and the mental health of patients. Topic experts Boris Heifets, MD, PhDBen Palanca, MD, PhD, and Renee El-Gabalawy, MA, PhD, examined mental health through a perioperative outcomes lens to offer insights for improving mental health at the bedside and beyond.

Boris Heifets, MD, PhD, an assistant professor of anesthesiology, perioperative and pain medicine at Stanford University, focused on “Neural Circuits and Systems Implicated in the Antidepressant Effects of Ketamine.” Ketamine, methylenedioxymethamphetamine (MDMA) and psilocybin constitute a recently identified class of medications known as psychedelic therapy. In 2017, MDMA was approved by the FDA for treatment of posttraumatic stress disorder (PTSD). In 2018 and 2019, psilocybin and esketamine, respectively, were approved for the treatment of depression. These drugs can provide rapid antidepressant effects, which last even after the drug has been eliminated from the body. Although these drugs have great potential, they also come with the potential for abuse and psychosis, Dr. Heifets explained.

Prior studies have shown that a single infusion of ketamine results in an antidepressant effect that begins within hours and lasts for at least a week (Zarate, Arch Gen Psych 2006). Dr. Heifets surveyed over 500 patients receiving ketamine infusion therapy and found that there was a >50% reduction in the PHQ9 depression score and this lasted for 60 days without additional infusions (McInness, J Affect Dis 2022). The main action of ketamine is thought to be blocking the channel of NMDA receptors, which leads to an increase in glutamate in the prefrontal cortex and to upregulation of mTOR and BDNF. However, studies of direct NDMA receptor antagonists in humans have not been able to replicate the antidepressant effect of ketamine. Another possible mechanism for ketamine is via the opioid receptor. Dr. Heifets found that administration of naltrexone blocks the antidepressant of ketamine in humans (Williams, Am J Psych 2018).

In order to study the potential contribution of opioid receptor to ketamine’s antidepressant affect, Dr. Heifets further investigated a mouse model using behavioral tests of hyperlocomotion, nociception and depression. He found that the hyperlocomotion effect of ketamine can be reliably blocked by μ-opioid antagonists. In order to study this further, he administered ketamine +/- naltrexone to mice. The brains were removed and made transparent with iDISCO+. cFos+ neurons were imaged with a light sheet microscopy and analyzed via region- and voxel-based statistics. Compared to ketamine with naltrexone, ketamine alone reduced activity in the central amygdala. Additionally, direct injection of a μ-opioid antagonist into the central amygdala bilaterally blocked the hyperlocomotion effect of ketamine.

Although there are many diagnostic and therapeutic interventions for cardiopulmonary problems prior to surgery, there are few options available to address psychiatric risk factors prior to surgery. Nearly 17,000 patients undergoing surgery at Stanford Hospital were screened for depression. Approximately one-third of depressed patients were identified as high risk, in which they had moderate to severe symptoms, but were not being treated for depression. Currently, Dr. Heifets is performing a clinical trial to determine if intraoperative ketamine improves depression after surgery in this high-risk population.

Ben Palanca, MD, PhD, an associate professor, anesthesiology, at Washington University School of Medicine in St. Louis gave a talk entitled, “Seizure, Sedation, and Sleep: Novel Antidepressant Markers and Pharmacologic Interventions.” Prior studies have shown that perioperative depression is associated with higher rates of delirium (Sockalingham, Card Surg 2005) and that surgery increases the development of depression (Tully and Baker, Geriatric Cardiology 2012, Liberzon, Vascular Surgery 2006, Sukantarat, Br J Health Psychology 2007). Depression is associated with poorer physical recovery (Doering, Am J Crit Care 2005), increased readmission (Tully, J Behav Med 2008) and increased mortality (Takagi, Heart Vessels 2017). Although anesthesiologists mainly focus on the cardiovascular health of the patient, anesthesiologists may be able to positively intervene on the mental health of the patient as well. Several medications regularly used in practice can be utilized to produce positive effects on mental health after surgery.

Previous studies have found that a single administration of nitrous oxide (25 or 50%) may result in a decrease in depressive symptoms days to weeks after the treatment (Nagele, Biol Psych 2015, Nagele, Sci Transl Med 2021). Although the mechanism is unclear, this may be due to modulation of nitric oxide synthase in the medial prefrontal cortex (Liu, Front Psych 2020) or neurotrophic signaling (Kohtala, Basic and Clinical Pharm and Tox 2021). Upregulation of neurotrophic signaling via BDNF and TrkB may mediate the long-term effects of nitrous oxide or ketamine administration on depression. It has been shown that a 4-day infusion of ketamine reduces hyperconnectivity in the prefrontal cortex and limbic regions (Siegel, Psychopharm 2021). In addition, ketamine increases slow wave activity during sleep (Duncan, Int J Neuropsychparhm 2013). Patients with worse sleep quality prior to receiving ketamine have a greater reduction in depression scores after treatment (Duncan, J Affect Disord 2013). Assessments of sleep quality may serve as a biomarker that can help identify patients that will be responsive to the antidepressant effects of ketamine.

Currently, Dr. Palanca is leading a study to assess the changes in sleep after electroconvulsive therapy (ECT). He found that sleep EEG and postical EEG suppression may be useful markers for identifying candidates that will respond to ECT (CET-REM Study). Isoflurane itself may be an antidepressant when it induces burst suppression (Weeks, PLOS One 2013, Michey, Int J Neuropsychpharm 2018). This antidepressant effect can last up to 4 weeks. In the future, studies will be performed to assess propofol’s ability to enhance slow waves during sleep and determine its impact on sleep quality, depression and cognitive impairment.

Renee El-Gabalawy, MA, PhD, an associate professor, Department of Anesthesiology, Perioperative and Pain Medicine at the University of Manitoba, gave a talk on “The Role of Targeted Mental Health Interventions to Improve Perioperative Outcomes.” For most people, surgery is stressful, both physically and mentally. Preoperative mental health factors may contribute to surgical outcomes. Recent systematic reviews have shown depression increases all-cause mortality after bypass surgery (Stenman 2016), anxiety increases acute pain after breast surgery (McCowat 2019) and both can lead to more complications and slower recovery after arthroplasty (Lungu 2016, Bletterman 2018, Vajapey 2019). In a 2011 systemic review by Mavros, 15/16 studies reported at least one adverse outcome in patients with preoperative mental disorders.

State anxiety refers to the amount of anxiety that an individual has as a result of being exposed to an anxiety-provoking situation. People with mental disorders are more likely to have higher levels of state anxiety. State anxiety has been associated with higher doses required for induction, persistent pain, nausea, delirium and increased length of stay (Kil 2012, Mejdahl 2015, Mitchell 2011, Montgomery and Bovbjerg 2004, Wada 2019, Fox 2013, El-Gabalaway 2019). In addition, it has been associated with reductions in functional recovery, quality of life and satisfaction with the surgery (Utrillas-Compaired 2014, Tirault 2010). Dr. El-Gabalawy found that state anxiety while in the operating room is associated with placement of the oxygen mask, lack of communication, limb restraints, intravenous catheter, cold temperature of the room and lying flat.

Psychological preparation prior to surgery, in particular mindfulness-based stress reduction (MDSR) has the potential to reduce sympathetic hyperarousal and decrease acute and chronic pain after surgery (Powell 2016). Jon Kabat-Zinn developed an 8-week mindfulness course that has some preliminary evidence of improved postsurgical outcomes. Dr. El-Gabalawy found that patients who take this course report significant reductions in pain catastrophizing, anxiety, depression and improved quality of life postoperatively at 6 weeks and at 6 months. There is a reduction in pain behavior and pain interference at 6 months postoperatively in addition to improved function after orthopedic surgery. Patients reported that MBSR led to increased self-efficacy, improved coping, facilitated relaxation, especially those that were open to mindfulness and believed that it had health-related benefits. Future directions include developing virtual interventions and apps for patients in the perioperative setting. The Center for Perioperative Mental Health at Washington University is working to investigate the utility of preoperative mental health interventions.

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