COVID-19 Impact on Resident Mental Health and Well-Being.

Columbia University's Papper Symposium, a virtual event held on March 20, 2021, was dedicated to the coronavirus disease-2019 (COVID-19) pandemic. This article summarizes a lecture by Dr. Roberta Hines, Nicholas M. Greene Professor of Anesthesiology and Department Chair and Chief of Anesthesiology at Yale-New Haven Hospital titled "The impact of COVID-19 on trainees: lessons learned and unanticipated opportunities," in addition draws from experiences at Columbia University Irving Medical Center and a focused review of the literature on the toll of the pandemic on trainee well-being and mental health. Early research has demonstrated that rates of burnout and acute stress were higher among health care providers who cared for COVID-19 patients than those who did not and that COVID-19 frontline health care providers are at high risk for common psychological disorders, including depression, anxiety, and post-traumatic stress disorder. Trainees working on the frontlines may be at particularly high risk for these mental health disorders and are less likely to access resources available to them. Program directors and hospital graduate medical education leaders should be aware of the threats to physiological and psychological safety and take action to prevent further detrimental effects. The rates of burnout and mental health disorders among trainees are expected to rise as a result of the pandemic, making screening programs and increased access to mental health treatment an essential feature of all residency and fellowship programs.

The Impact of COVID-19 on Trainees: Lessons Learned and Unanticipated Opportunities.

Dr. Emanuel Martin Papper was a Professor and Department Chair at Columbia University whose top passion was training the next generation of anesthesiologists. As such, a fitting topic for discussion at Columbia University Department of Anesthesiology's Papper Symposium was the "The Impact of the COVID-19 Pandemic on Trainees: Lessons Learned and Unanticipated Opportunities," presented by Dr. Roberta L. Hines, Nicholas M. Greene Professor of Anesthesiology and Department Chair and Chief of Anesthesiology at Yale-New Haven Hospital. The pandemic led to abrupt changes at the national, hospital, and training program levels, all of which impacted trainees in anesthesiology and other disciplines. Nationally, there were sweeping regulatory changes that helped to shape the coronavirus disease-2019 response by medical front line workers. At each individual hospital, coronavirus disease-2019 units were created and teams were restructured to keep up with patient care demands. Educational programs adapted their curricula and trainees lost valuable clinical and academic opportunities. The innovative educational responses, including a pivot to virtual learning and virtual recruitment, provided a silver lining to the health care crisis. Another bright spot was that anesthesiology as a specialty rose to the forefront of patient care. Anesthesiologists displayed impactful leadership during the pandemic, paving the way for future growth and broadened reach of our specialty.

A Randomized Controlled Trial Examining the Impact of an Anorectal Surgery Multimodal Enhanced Recovery Program on Opioid Use.

BACKGROUND: Anorectal cases may be a common gateway to the opioid epidemic. Opioid reduction is inherent in enhanced recovery after surgery (ERAS) protocols, but little work has evaluated ERAS in these cases. OBJECTIVE: To determine if ERAS could reduce postoperative opioid utilization in ambulatory anorectal surgery without sacrificing patient pain or satisfaction. METHODS: A randomized controlled trial assigned ambulatory anorectal patients to ERAS (experimental) or routine care (surgeon's choice) for pain management (control) over 30-days postoperatively. Primary outcome was overall days of opioid use. Secondary outcomes included pain and satisfaction scores over multiple time points and new persistent opioid use. The Visual Analog Scale, Functional Pain Scale, and EQ-5D-3L measured patient-reported pain and satisfaction. Univariate analysis compared outcomes overall and at individual time points. Two-way mixed ANOVA evaluated pain and satisfaction measures between groups and over time. RESULTS: Thirty-two patients were randomized into each arm (64 total). The control group consumed significantly more opioids after discharge (median 121.3MME vs 23.5MME, P < 0.001). Significantly more control patients requested additional narcotics (P  =  0.004), made unplanned calls (P = 0.009), and had unplanned clinic visits (P = 0.003). The control group had significantly more days on opioids (mean 14.4 vs 2.2, P < 0.001). Three control patients (9.4%) versus no experimental patients had new persistent opioid use. The mean global health, EQ5D-3L, Visual Analog Scale, and Functional Pain scores were comparable between groups over time. CONCLUSIONS: An ERAS protocol in ambulatory anorectal surgery is feasible, and resulted in reduced opioid use, and healthcare utilization, with no difference in pain or patient satisfaction. This challenges the paradigm that extended opioids are needed for effective postoperative pain management.

Spinal Cord Protection for Thoracoabdominal Aortic Surgery.

Open and endovascular repairs of the descending thoracic and thoracoabdominal aorta are associated with a substantial risk of spinal cord injury, namely paraplegia. Endovascular repairs seem to have a lower incidence of spinal cord injury, but there have been no randomized trials comparing outcomes of open and endovascular repairs. Paraplegia occurs when collateral blood supply to the anterior spinal artery is impaired. The risk of spinal cord injury can be mitigated with perioperative protocols that include drainage of cerebrospinal fluid, avoidance of hypotension and anemia, intraoperative neurophysiologic monitoring, and advanced surgical techniques. Drainage of cerebrospinal fluid using a spinal drain decreases the risk of spinal cord ischemia by improving spinal cord perfusion pressure. However, cerebrospinal fluid drainage has risks including neuraxial and intracranial bleeding, and these risks need to be carefully weighed against its potential benefit. This review discusses current surgical management of descending thoracic and thoracoabdominal aortic disease, incidence of and risk factors for spinal cord injury, and elements of spinal cord protection protocols that pertain to anesthesiologists, with a focus on cerebrospinal fluid drainage.

Dimerization with cannabinoid receptors allosterically modulates delta opioid receptor activity during neuropathic pain.

The diversity of receptor signaling is increased by receptor heteromerization leading to dynamic regulation of receptor function. While a number of studies have demonstrated that family A G-protein-coupled receptors are capable of forming heteromers in vitro, the role of these heteromers in normal physiology and disease has been poorly explored. In this study, direct interactions between CB(1) cannabinoid and delta opioid receptors in the brain were examined. Additionally, regulation of heteromer levels and signaling in a rodent model of neuropathic pain was explored. First we examined changes in the expression, function and interaction of these receptors in the cerebral cortex of rats with a peripheral nerve lesion that resulted in neuropathic pain. We found that, following the peripheral nerve lesion, the expression of both cannabinoid type 1 receptor (CB(1)R) and the delta opioid receptor (DOR) are increased in select brain regions. Concomitantly, an increase in CB(1)R activity and decrease in DOR activity was observed. We hypothesize that this decrease in DOR activity could be due to heteromeric interactions between these two receptors. Using a CB(1)R-DOR heteromer-specific antibody, we found increased levels of CB(1)R-DOR heteromer protein in the cortex of neuropathic animals. We subsequently examined the functionality of these heteromers by testing whether low, non-signaling doses of CB(1)R ligands influenced DOR signaling in the cortex. We found that, in cortical membranes from animals that experienced neuropathic pain, non-signaling doses of CB(1)R ligands significantly enhanced DOR activity. Moreover, this activity is selectively blocked by a heteromer-specific antibody. Together, these results demonstrate an important role for CB(1)R-DOR heteromers in altered cortical function of DOR during neuropathic pain. Moreover, they suggest the possibility that a novel heteromer-directed therapeutic strategy for enhancing DOR activity, could potentially be employed to reduce anxiety associated with chronic pain.

Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord.

An increasing body of evidence suggests that endothelin-converting enzyme-2 (ECE-2) is a non-classical neuropeptide processing enzyme. Similar to other neuropeptide processing enzymes, ECE-2 exhibits restricted neuroendocrine distribution, intracellular localization, and an acidic pH optimum. However, unlike classical neuropeptide processing enzymes, ECE-2 exhibits a non-classical cleavage site preference for aliphatic and aromatic residues. We previously reported that ECE-2 cleaves a number of neuropeptides at non-classical sites in vitro; however its role in peptide processing in vivo is poorly understood. Given the recognized roles of neuropeptides in pain and opiate responses, we hypothesized that ECE-2 knockout (KO) mice might show altered pain and morphine responses compared with wild-type mice. We find that ECE-2 KO mice show decreased response to a single injection of morphine in hot-plate and tail-flick tests. ECE-2 KO mice also show more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analyses revealed changes in the levels of a number of spinal cord peptides in ECE-2 KO as compared to wild-type mice. Taken together, our findings suggest a role for ECE-2 in the non-classical processing of spinal cord peptides and morphine responses; however, the precise mechanisms through which ECE-2 influences morphine tolerance and withdrawal remain unclear.

The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications.

Alterations in the endogenous cannabinoid system have been described in almost every category of disease. These changes can alternatively be protective or maladaptive, such as producing antinociception in neuropathic pain or fibrogenesis in liver disease, making the system an attractive therapeutic target. However, the challenge remains to selectively target the site of disease while sparing other areas, particularly mood and cognitive centers of the brain. Identifying regional changes in cannabinoid receptor-1 and -2 (CB(1)R and CB(2)R) expression is particularly important when considering endocannabinoid system-based therapies, because regional increases in cannabinoid receptor expression have been shown to increase potency and efficacy of exogenous agonists at sites of disease. Although there have been extensive descriptive studies of cannabinoid receptor expression changes in disease, the underlying mechanisms are only just beginning to unfold. Understanding these mechanisms is important and potentially relevant to therapeutics. In diseases for which cannabinoid receptors are protective, knowledge of the mechanisms of receptor up-regulation could be used to design therapies to regionally increase receptor expression and thus increase efficacy of an agonist. Alternatively, inhibition of harmful cannabinoid up-regulation could be an attractive alternative to global antagonism of the system. Here we review current findings on the mechanisms of cannabinoid receptor regulation in disease and discuss their therapeutic implications.

Estrogen receptor (ER)beta isoforms rather than ERalpha regulate corticotropin-releasing hormone promoter activity through an alternate pathway.

The hypothalamic-pituitary-adrenal axis regulates mammalian stress responses by secreting glucocorticoids. The magnitude of the response is in part determined by gender, for in response to a given stressor, circulating glucocorticoids reach higher levels in female rats than in males. This gender difference could result from estrogen regulation of the corticotropin-releasing hormone (CRH) promoter via either of its receptors: estrogen receptor (ER)alpha or ERbeta. Immunocytochemistry revealed that a subset (12%) of medial parvocellular CRH neurons in the rat hypothalamus contain ERbeta but not ERalpha. To determine whether ERs could regulate CRH promoter activity, we cotransfected cells with a CRH promoter construct and either ERalpha or individual ERbeta isoforms. ERalpha weakly stimulated CRH promoter transcriptional activity in a ligand-independent manner. Conversely, all ERbeta isoforms tested stimulated CRH promoter activity with different ligand profiles. ERbeta1 and ERbeta2delta3 displayed constitutive activity (ERbeta1 more than ERbeta2delta3). Ligand-dependent activity of beta isoforms 1 and 2 was altered by an Exon3 splice variant (delta3) or by the additional 18 amino acids in the ligand-binding domain of ERbeta2 isoforms. Lastly, we suggest that ER regulation of CRH takes place through an alternate pathway, one that requires protein-protein interactions with other transcription factors or their associated complexes. However, a pure ER-activator protein-1 alternate pathway does not appear to be involved.