Brief History of Opioids in Perioperative and Periprocedural Medicine to Inform the Future.

Background: Opioids and derivatives of opium had been used as analgesics for thousands of years before the introduction of inhalational anesthetic agents. Once these early volatile agents were in widespread use, opioids were used as part of anesthetic care for premedication, as intraoperative adjuncts to general anesthesia, and for the management of postoperative pain. Evidence of growing dependence on opioids in the perioperative and periprocedural patient is supported by the ongoing research to develop synthetic opioids and to customize the pharmacokinetics and pharmacodynamics to achieve specific therapeutic goals. Methods: We explore the history of opioid use in perioperative care as a means of future management in light of new persistent opioid abuse. Results: As the opium chemical structure has been modified, newer nonopioid analgesics have been approved and brought into clinical practice. Opioid-sparing and opioid-free anesthetic techniques are not only a possibility, but a reality. Conclusion: Continuing research in neurobiology and addiction genetics will ultimately lead to a pharmacogenetic approach to patients at risk for new persistent opioid abuse.

The Modified Early Warning Score as a Predictive Tool During Unplanned Surgical Intensive Care Unit Admission.

Background: The Modified Early Warning Score (MEWS) has been proposed to warn healthcare providers of potentially serious adverse events. We evaluated this scoring system during unplanned escalation of care in hospitalized surgical patients during a 1-year period. Methods: Following institutional review board approval, all consecutive, unplanned surgical admissions into the surgical intensive care unit (SICU) during 2016 were entered into this study. MEWS and patient demographics during bedside evaluation for SICU admission were extracted from electronic medical records. Logistic regression was used to analyze the association of MEWS with the incidence of future mortality. P values were set at <0.01 for statistical significance. Results: In this series of 263 consecutive patients, the incidence of mortality following unplanned escalation of care was 29.3% (confidence interval [CI] 24.1% to 35.0%), ranging from 22% to 57%, with all positive MEWS values. The association of MEWS with future mortality was not statistically significant (P=0.0107). A misclassification rate of 0.29 (CI 0.24 to 0.35) was observed with this association. Conclusion: MEWS provided no clinical benefit as an early warning system, as mortality was elevated throughout the MEWS scale in this clinical setting. The high misclassification rate indicates MEWS does not provide discriminatory support for patients at risk for mortality.

Use of biomarkers in the prediction of culture-proven infection in the surgical intensive care unit.

PURPOSE: The purpose of this study was to prospectively analyze the predictive role of classic predictors for suspected infection (temperature, WBC and derivatives) with two biomarkers, procalcitonin and lactate, on the incidence of culture-proven infection in the surgical intensive care unit (SICU). MATERIALS AND METHODS: One hundred forty-six consecutive patients admitted for suspected infection had admission and 12-h procalcitonin values, admission and every 6-h lactate values for 24 h, and admission temperature, leukocyte count, lymphocyte count and percentage measured and analyzed in this study. RESULTS: Peak (highest measured value ≤24-h of admission) procalcitonin values were not predictive for culture-proven infection. However, a culture-negative subset was identified when peak procalcitonin values were  < 2.9 ng/mL and when peak lactate values were  < 1.3 mmol/L with a probability of 98.3% (P < .001). No other admission predictor was statistically associated with culture-proven infection. Following boosted-tree partitioning, a C-index of 0.85 was calculated with a misclassification rate of 23.3%. CONCLUSIONS: The ability to utilize procalcitonin values in the diagnosis of culture-proven infection was not realized in this study. However, the association of admission peak procalcitonin values with admission peak lactate values identified a group of patients who were culture-negative for suspected infection. No other admission predictor was associated with culture-proven infection.

An Evidence-Based Opioid-Free Anesthetic Technique to Manage Perioperative and Periprocedural Pain.

BACKGROUND: The epidemic of opioid abuse is increasing, and the number of deaths secondary to opioid overdose is also increasing. Recent attention has focused on opioid prescribing and management of chronic pain. However, opioid use in perioperative and periprocedural patients, whether they have chronic pain or exhibit new persistent opioid abuse after a procedure, has received little attention. METHODS: We present an evidence-based technique that combines subanesthetic infusions of lidocaine and dexmedetomidine supplemented with other intravenous agents and a low dose of inhaled anesthetic. RESULTS: Based on evidence of drug action and interaction, an opioid-free anesthetic can be delivered successfully. We present the cases of 2 patients in whom the opioid-free anesthetic technique was used with a successful outcome, adequate pain management, and avoidance of opioid drugs. CONCLUSION: This anesthetic prescription can be useful for opioid-naïve patients as well as for patients with chronic pain that is managed with opioids.

Virtues Education in Medical School: The Foundation for Professional Formation.

BACKGROUND: Studies have shown that medical students have high rates of burnout accompanied by a loss of empathy as they progress through their training. This article describes a course for medical students at The University of Queensland-Ochsner Clinical School in New Orleans, LA, that focuses on the development of virtues and character strengths necessary in the practice of medicine. Staff of the Ochsner Clinical School and of the Institute of Medicine, Education, and Spirituality at Ochsner, a research and consulting group of Ochsner Health System, developed the course. It is a curricular innovation designed to explicitly teach virtues and their associated prosocial behaviors as a means of promoting professional formation among medical students. Virtues are core to the development of prosocial behaviors that are essential for appropriate professional formation. METHODS: Fourth-year medical students receive instruction in the virtues as part of the required Medicine in Society (MIS) course. The virtues instruction consists of five 3-hour sessions during orientation week of the MIS course and a wrapup session at the end of the 8-week rotation. Six virtues-courage, wisdom, temperance, humanity, transcendence, and justice-are taught in a clinical context, using personal narratives, experiential exercises, contemplative practices, and reflective practices. RESULTS: As of July 2015, 30 medical students had completed and evaluated the virtues course. Ninety-seven percent of students felt the course was well structured. After completing the course, 100% of students felt they understood and could explain the character strengths that improve physician engagement and patient care, 100% of students reported understanding the importance of virtues in the practice of medicine, and 83% felt the course provided a guide to help them deal with the complexities of medical practice. Ninety-three percent of students stated they would use the character strengths for their own well-being, and 90% said they would change their approach to the practice of medicine as a result of this course. Overall, 92% of students rated the course as outstanding or good. CONCLUSION: We developed a course to teach virtues and their associated prosocial behaviors that are important for the practice of medicine. After completing the course, students self-reported improved understanding of the virtues and their importance to the practice of medicine. We plan further studies to determine if participation in the course leads to less burnout and improved resilience.

Multigenerational Challenges and the Future of Graduate Medical Education.

BACKGROUND: Demographics are changing on a global scale. In the United States, an aging population continues to work, either by preference or because of insufficient resources to retire. Of even greater importance, a younger generation, referred to as the Millennial Generation, will soon predominate in the workforce and even now accounts for nearly 100% of resident physicians. By the year 2020, there will be 5 generations in the workplace. METHODS: This paper defines and details the characteristics of the 5 generations and examines how the vision, attitudes, values, and expectations of the most recent generations will reshape the workforce and graduate medical education. RESULTS: The need for change is imminent to educate the next generation of physicians. Among the changes necessary to adapt to the multigenerational challenges ahead are adopting mobile devices as preferred communication tools; using social networking sites to recruit residents; adding games, simulations, and interactive videos to the curriculum to engage students; breaking down departmental silos and forming learning teams that come from different specialties; developing benchmarks and milestones to measure progress; extending the social learning ecosystem beyond the resident years; embracing diversity as the norm for both practice and learning; and providing both coaching and mentoring. CONCLUSION: For decades, resident physicians have shown commitment, tenacity, and selflessness while shouldering the dual responsibility of patient care and the pursuit of their own education and skills development. Resident engagement has been shown to drive change in undergraduate medical education and in the learning and performance of their teachers. The latter is evidence of reverse mentoring that will be a major factor for improvement in this digital age. We have only to embrace this opportunity to the benefit of our patients, our learners, and ourselves.

Just culture: a foundation for balanced accountability and patient safety.

BACKGROUND: The framework of a just culture ensures balanced accountability for both individuals and the organization responsible for designing and improving systems in the workplace. Engineering principles and human factors analysis influence the design of these systems so they are safe and reliable. METHODS: Approaches for improving patient safety introduced here are (1) analysis of error, (2) specific tools to enhance safety, and (3) outcome engineering. CONCLUSION: The just culture is a learning culture that is constantly improving and oriented toward patient safety.

Changing the culture in medical education to teach patient safety.

In 1999 a seminal Institute of Medicine report estimated that preventable medical errors accounted for 44,000-98,000 patient deaths annually in U.S. hospitals. In response to this problem, the nation's medical schools, teaching hospitals, and health systems recognized that achieving greater patient safety requires more than a brief course in an already crowded medical school curriculum. It requires a fundamental culture change across all phases of medical education. This includes graduate medical education, which is already teaching the next generation of physicians to approach patient safety in a new way. In this paper the authors explore five factors critical to transforming the culture for patient safety and reflect on one real-world example at the University of North Carolina School of Medicine.

Anesthesia-related perioperative adverse events during in-patient and out-patient procedures.

PURPOSE: This paper aims to determine the one-year incidence of, and risk factors for, perioperative adverse events during in-patient and out-patient anesthesia-assisted procedures. DESIGN/METHODOLOGY/APPROACH: A quality assurance database was the primary data source. Outcome variables were death and the occurrence of any adverse event. Risk factors were ASA physical status (PS), age, duration and type of anesthesia care, number of operating rooms running, concurrency level and medical staff. Data were stratified by in-patient or out-patient, surgical (e.g. thoracotomy) or non-surgical (e.g. electroconvulsive therapy), and were analyzed using Chi square, Fisher's exact test and generalized estimating equations. FINDINGS: Of 27,970 procedures, 49.8 percent were out-patient and greater than 80 percent were surgical. For surgical procedures, adverse event rates were higher for in-patient than out-patient procedures (2.11 percent vs. 1.45 percent; p < 0.001). For non-surgical procedures, adverse event rates were similar for in-patients and out-patients (0.54 percent vs. 0.36 percent). The types of adverseevents differed for in-patient and out-patient surgical procedures (p < 0.001), but not for non-surgical procedures. ASA PS, age, duration of anesthesia care, anesthesia type and medical staff assigned to the case were each associated with adverse event rates, but the association depended on the type of procedure. PRACTICAL IMPLICATIONS: In-patient and out-patient surgical procedures differ in the incidence of perioperative adverse events, and in risk factors, suggesting a need to develop separate monitoring strategies. ORIGINALITY/VALUE: The paper is the first to assess perioperative adverse events amongst in-patient and out-patient procedures.

Postoperative mortality after inpatient surgery: Incidence and risk factors.

PURPOSE: This study determined the incidence of and identified risk factors for 48 hour (h) and 30 day (d) postoperative mortality after inpatient operations. METHODS: A retrospective cohort study was conducted using Anesthesiology's Quality Indicator database as the main data source. The database was queried for data related to the surgical procedure, anesthetic care, perioperative adverse events, and birth/death/operation dates. The 48 h and 30 d cumulative incidence of postoperative mortality was calculated and data were analyzed using Chi-square or Fisher's exact test and generalized estimating equations. RESULTS: The 48 h and 30 d incidence of postoperative mortality was 0.57% and 2.1%, respectively. Higher American Society of Anesthesiologists physical status scores, extremes of age, emergencies, perioperative adverse events and postoperative Intensive Care Unit admission were identified as risk factors. The use of monitored anesthesia care or general anesthesia versus regional or combined anesthesia was a risk factor for 30 d postoperative mortality only. Time under anesthesia care, perioperative hypothermia, trauma, deliberate hypotension and invasive monitoring via arterial, pulmonary artery or cardiovascular catheters were not identified as risk factors. CONCLUSIONS: Our findings can be used to track postoperative mortality rates and to test preventative interventions at our institution and elsewhere.

Cardioprotection with adenosine A2 receptor activation at reperfusion.

Pre-ischemic treatment is seldom possible in the clinical setting of acute myocardial infarction. Thus, to successfully save myocardium from infarction, it is required that protective interventions must be effective when applied after ischemia has begun or at the onset of reperfusion. Unfortunately, in spite of a large body of experimental data showing that various interventions are cardioprotective at reperfusion, no specific therapy has yet been established to be clinically applicable. However, recent data from several laboratories have shown that adenosine and its analogues given at reperfusion can markedly protect the heart from ischemia/reperfusion injury. While the experimental data suggest that factors such as adenosine A2 receptor activation, anti-neutrophil effect, attenuation of free radical generation, increased nitric oxide (NO) availability, activation of the PI3-kinase/Akt pathway and ERK, prevention of mitochondrial damage, and anti-apoptotic effects may be involved in the protective effect of adenosine or its analogues, the exact receptor subtype(s), the detailed signaling mechanisms, and interaction between those individual factors are still unknown. A definite answer to these unsolved problems will offer insights into the mechanisms of cardioprotection at reperfusion, and will be critical for developing a successful therapeutic strategy to salvage ischemic myocardium in patients with acute myocardial infarction.

Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes.

OBJECTIVE: To examine if adenosine prevents oxidant-induced mitochondrial dysfunction by producing nitric oxide (NO) in cardiomyocytes. METHODS AND RESULTS: Adenosine significantly enhanced the fluorescence of DAF-FM, a dye specific for NO, implying that adenosine induces synthesis of NO. Adenosine-induced NO production was blocked by both the nonspecific NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and N(5)-(1-Iminoethyl)-l-ornithine dihydrochloride (l-NIO), an inhibitor of endothelial NOS (eNOS), but not by N(6)-(1-Iminoethyl)-l-lysine hydrochloride (l-NIL), an inhibitor of inducible NOS (iNOS), indicating that adenosine activates eNOS. Adenosine also enhances eNOS phosphorylation and its activity. The adenosine A(2) receptor antagonist 8-(3-chlorostyryl)caffeine but not the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine prevented the increase in NO production. CGS21680, an adenosine A(2) receptor agonist, markedly increased NO, further supporting the involvement of A(2) receptors. Adenosine-induced NO production was blocked by 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine (PP2), a selective Src tyrosine kinase inhibitor, suggesting that Src tyrosine kinase is crucial for adenosine-induced NO production. Adenosine-induced NO production was partially reversed by both wortmannin and Akt inhibitor indicating an involvement of PI3-kinase/Akt. Pretreatment of cells with adenosine prevented H(2)O(2)-induced depolarization of mitochondrial membrane potential (DeltaPsi(m)). The protective effect was blocked by l-NAME and l-NIO but not by l-NIL, indicating that eNOS plays a role in the action of adenosine. The protective effect of adenosine was further suppressed by KT5823, a specific inhibitor of protein kinase G (PKG), indicating the PKG may serve as a downstream target of adenosine. CONCLUSION: Adenosine protects mitochondria from oxidant damage through a pathway involving A(2) receptors, eNOS, NO, PI3-kinase/Akt, and Src tyrosine kinase.

Propyl paraben inhibits voltage-dependent sodium channels and protects cardiomyocytes from ischemia-reperfusion injury.

The effects of propyl paraben, an antimicrobial preservative, on voltage-dependent sodium current and myocardial ischemia-reperfusion injury were investigated in isolated adult rat cardiomyocytes. Whole cell voltage-clamp recording showed that propyl paraben reversibly blocked the voltage-gated sodium channel both in concentration- and voltage-dependent manners. Propyl paraben (500 microM but not 100 microM) significantly shifted the steady-state inactivation of the sodium channel toward the hyperpolarizing direction at the V(1/2) point. Consistent with the above result, the propidium iodide (PI) uptake test revealed that pretreatment with 500 microM but not 100 microM of propyl paraben significantly reduced cell death induced by 45 min of sustained ischemia followed by 15 h of reperfusion (42.37 +/- 7.01% of cell viability in control and 71.05 +/- 7.06% in the propyl paraben group), suggesting that propyl paraben can protect myocytes from ischemia-reperfusion injury. These results indicate a possible correlation between the inhibition of sodium current and cardioprotection against ischemia-reperfusion injury.

Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial KATP channels, and ERK.

We examined whether cGMP-dependent protein kinase (PKG) and mitochondrial ATP-sensitive potassium (K(ATP)) channels are involved in S-nitroso-N-acetyl penicillamine (SNAP)-induced reactive oxygen species (ROS) generation. SNAP significantly increased ROS generation in cardiomyocytes. This increase was suppressed by both 5-hydroxydecanoate (5-HD) and glibenclamide. Direct opening of mitochondrial K(ATP) channels with diazoxide led to ROS generation. The increased ROS generation was reversed by N-(2-mercaptopropionyl)glycine (MPG), a scavenger of ROS. Myxothiazol partially suppressed the ROS generation. KT-5823, an inhibitor of PKG, prevented ROS generation, indicating that PKG is required for ROS generation. In addition, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), an activator of PKG, induced ROS generation. The effect of 8-BrcGMP was reversed by either 5-HD or MPG. YC-1, an activator of guanylyl cyclase, also increased ROS production, which was reversed by 5-HD. Neither LY-294002 nor wortmannin, the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase), affected SNAP's action. In a whole heart study, SNAP significantly reduced infarct size. The anti-infarct effect of SNAP was abrogated by either MPG or 5-HD. This effect was also blocked by PD-98059, an ERK inhibitor, but not by LY-294002. A Western blotting study showed that SNAP significantly enhanced phosphorylation of ERK, which was reversed by MPG. These results suggest that SNAP-induced ROS generation is mediated by activation of PKG and mitochondrial K(ATP) channels and that opening of mitochondrial K(ATP) channels is the downstream event of PKG activation. ROS and mitochondrial K(ATP) channels participate in the anti-infarct effect of SNAP. Moreover, phosphorylation of ERK is the downstream signaling event of ROS and plays a role in the cardioprotection of SNAP.