Virtual Anesthesiology Medical Student Learning Program Pilot Designed in Response to COVID-19.

Background: This learning opportunity was designed to provide an interactive, virtual, educational anesthesiology program for interested medical students and to offer an opportunity to learn more about an institutional culture through a question and answer (Q&A) with program faculty preceptors for the 2020-2021 anesthesiology residency application cycle. We sought to identify if this virtual learning program was a valuable educational tool through a survey. Methods: A short Likert-scale survey was sent to medical students before and after participation in a session using REDCap electronic data capture tool. We designed the survey to assess the program's self-reported effect on participants' anesthesiology knowledge, and whether the program design was successful in creating a collaborative experience while also providing a forum to explore residency programs. Results: All respondents found the call useful in building anesthesiology knowledge and networking, and 42 (86%) found the call helpful in deciding where to apply for residency. Overall, 100% of respondents found the call useful, collaborative, engaging, and important to define critical thinking skills. Conclusions: The framework used for this program-virtual asynchronous and synchronous problem-based learning-can be applied broadly with potential benefit to medical student participants challenged by the cancellation of clinical rotations.

Superiority of compensatory reserve measurement compared with the Shock index for early and accurate detection of reduced central blood volume status.

BACKGROUND: Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. METHODS: We measured HR, SBP, and CRM in 172 human subjects (19-55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. RESULTS: The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater ( p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94-0.97) compared with 0.91 (0.89-0.94) for SI ( p = 0.0002). CONCLUSION: Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia. LEVEL OF EVIDENCE: Diagnostic Test or Criteria; Level III.

Intralipid fails to rescue bupivacaine-induced cardiotoxicity in late-pregnant rats.

Background: Females routinely receive bupivacaine for obstetric and regional anesthesia. An accidental overdose of bupivacaine can result in cardiotoxicity and cardiac arrest. Intralipid (ILP) rescues bupivacaine-induced cardiotoxicity in male rats. However, bupivacaine cardiotoxicity and ILP rescue have not been studied in non-pregnant and late-pregnant female rats. Here, we tested the hypothesis that an appropriate dose of ILP would rescue non-pregnant and late-pregnant rats from bupivacaine-induced cardiotoxicity. Methods: Non-pregnant (n = 6) and late-pregnant (n = 7) female rats received intravenous bupivacaine (10-mg/kg bolus) to induce asystole. Resuscitation with 20% ILP (5-ml/kg actual body weight, single bolus, and 0.5-ml/kg/min maintenance) and chest compressions were continued for 10-min. Serial heart rate (HR), left ventricular ejection-fraction (LVEF%), and LV-fractional shortening (LVFS%) were recorded at baseline and 10-min after bupivacaine-induced cardiac arrest. Data are mean ± SD followed by 95% CI. P-values < 0.05 were considered statistically significant. Results: All rats developed cardiac arrest within a few seconds after bupivacaine. All non-pregnant rats were successfully rescued by ILP, with a HR of 280 ± 32 bpm at baseline vs. 212 ± 18 bpm at 10-min post ILP (p < 0.01), LVEF of 70 ± 6% vs. 68 ± 5% (p = ns), and LVFS of 41 ± 5% vs. 39 ± 4% (p = ns). Interestingly, 6 out of 7 late-pregnant rats did not recover with ILP. Baseline HR, LVEF and LVFS for late-pregnant rats were 330 ± 40 bpm, 66 ± 5% and 38 ± 4%, respectively. At 10-min post ILP, the HR, LVEF, and LVFS were 39 ± 102 bpm (p < 0.0001), 8 ± 22% (p < 0.0001), and 5 ± 12% (p < 0.001), respectively. Conclusions: ILP successfully rescued bupivacaine-induced cardiac arrest in non-pregnant rats, but failed to rescue late-pregnant rats.

Identifying critical DO2 with compensatory reserve during simulated hemorrhage in humans.

BACKGROUND: Based on previous experiments in nonhuman primates, we hypothesized that DO2 crit in humans is 5-6 ml O2 ·kg-1  min-1 . STUDY DESIGN AND METHODS: We measured the compensatory reserve (CRM) and calculated oxygen delivery (DO2 ) in 166 healthy, normotensive, nonsmoking subjects (97 males, 69 females) during progressive central hypovolemia induced by lower body negative pressure as a model of ongoing hemorrhage. Subjects were classified as having either high tolerance (HT; N = 111) or low tolerance (LT; N = 55) to central hypovolemia. RESULTS: HT and LT groups were matched for age, weight, BMI, and vital signs, DO2 and CRM at baseline. The CRM-DO2 relationship was best fitted to a logarithmic model in HT subjects (amalgamated R2  = 0.971) and a second-order polynomial model in the LT group (amalgamated R2  = 0.991). Average DO2 crit for the entire subject cohort was estimated at 5.3 ml O2 ·kg-1  min-1 , but was ~14% lower in HT compared with LT subjects. The reduction in DO2 from 40% CRM to 20% CRM was 2-fold greater in the LT compared with the HT group. CONCLUSIONS: Average DO2 crit in humans is 5.3 ml O2 ·kg-1  min-1 , but is ~14% lower in HT compared with LT subjects. The CRM-DO2 relationship is curvilinear in humans, and different when comparing HT and LT individuals. The threshold for an emergent monitoring signal should be recalibrated from 30% to 40% CRM given that the decline in DO2 from 40% CRM to 20% CRM for LT subjects is located on the steepest part of the CRM-DO2 relationship.

An Analysis of Outcomes and Interventions for Female Pediatric Casualties in Iraq and Afghanistan.

BACKGROUND: Traumatic injuries were the most common reason for admission of pediatric patients to military hospitals during the recent wars in Iraq and Afghanistan. We compare survival and interventions between female and male pediatric casualties. MATERIALS AND METHODS: This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry. We requested pediatric encounters from January 2007 to January 2016 within Iraq and Afghanistan. We separated casualties by sex to compare injury and mortality patterns. RESULTS: Our initial dataset included 3439 pediatric encounters-784 (22.8%) females and 2655 (77.2%) males. Females were less likely to sustain injuries by explosive (38.0% versus 44.5%) but more likely to sustain injuries via alternative mechanisms of injury (28.9% versus 21.5%). Both sexes had similar ISS (females median 10 [5-17], males 10 [4-17]). Fewer females underwent tourniquet application (4.2% versus 7.2%; all findings were significant). In unadjusted and adjusted regression analyses, females under age 8 had lower odds of survival to hospital discharge (OR 0.67, 95% CI 0.51-0.89) compared to males. CONCLUSIONS: Among pediatric patients treated by U.S. medical personnel in Iraq and Afghanistan, females had a lower survival to hospital discharge despite similar severity of injury. Further studies are necessary to elucidate causes for this finding.

Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis.

Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.

Physiology of Human Hemorrhage and Compensation.

Hemorrhage is a leading cause of death following traumatic injuries in the United States. Much of the previous work in assessing the physiology and pathophysiology underlying blood loss has focused on descriptive measures of hemodynamic responses such as blood pressure, cardiac output, stroke volume, heart rate, and vascular resistance as indicators of changes in organ perfusion. More recent work has shifted the focus toward understanding mechanisms of compensation for reduced systemic delivery and cellular utilization of oxygen as a more comprehensive approach to understanding the complex physiologic changes that occur following and during blood loss. In this article, we begin with applying dimensional analysis for comparison of animal models, and progress to descriptions of various physiological consequences of hemorrhage. We then introduce the complementary side of compensation by detailing the complexity and integration of various compensatory mechanisms that are activated from the initiation of hemorrhage and serve to maintain adequate vital organ perfusion and hemodynamic stability in the scenario of reduced systemic delivery of oxygen until the onset of hemodynamic decompensation. New data are introduced that challenge legacy concepts related to mechanisms that underlie baroreflex functions and provide novel insights into the measurement of the integrated response of compensation to central hypovolemia known as the compensatory reserve. The impact of demographic and environmental factors on tolerance to hemorrhage is also reviewed. Finally, we describe how understanding the physiology of compensation can be translated to applications for early assessment of the clinical status and accurate triage of hypovolemic and hypotensive patients. © 2021 American Physiological Society. Compr Physiol 11:1531-1574, 2021.

The compensatory reserve: potential for accurate individualized goal-directed whole blood resuscitation.

Hemorrhagic shock can be mitigated by timely and accurate resuscitation designed to restore adequate delivery of oxygen (DO2 ). Current doctrine of using systolic blood pressure (SBP) as a guide for resuscitation can be associated with increased morbidity. The compensatory reserve measurement (CRM) is a novel vital sign based on the recognition that the sum of all mechanisms that contribute to the compensatory response to hemorrhage reside in features of the arterial pulse waveform. CRM can be assessed continuously and non-invasively in real time. Compared to standard vital signs, CRM provides an early, as well as more sensitive and specific, indicator of patient hemorrhagic status since the activation of compensatory mechanisms occurs immediately at the onset of blood loss. Recent data obtained from our laboratory experiments on non-human primates have demonstrated that CRM is linearly related to DO2 during controlled progressive hemorrhage and subsequent whole blood resuscitation. We used this relationship to determine that the time of hemodynamic decompensation (i.e., CRM = 0%) is defined by a critical DO2 at approximately 5.3 mL O2 ∙kg-1 ∙min-1 . We also demonstrated that a target CRM of 35% during whole blood resuscitation only required replacement of 40% of the total blood volume loss to adequately sustain a DO2 more than 50% (i.e., 8.1 mL O2 ∙kg-1 ∙min-1 ) above critical DO2 (i.e., threshold for decompensated shock) while maintaining hypotensive resuscitation (i.e., SBP at ~90 mmHg). Consistent with our hypothesis, specific values of CRM can be used to accurately maintain DO2 thresholds above critical DO2 , avoiding the onset of hemorrhagic shock with whole blood resuscitation.

Combat medic testing of a novel monitoring capability for early detection of hemorrhage.

BACKGROUND: Current out-of-hospital protocols to determine hemorrhagic shock in civilian trauma systems rely on standard vital signs with military guidelines relying on heart rate and strength of the radial pulse on palpation, all of which have proven to provide little forewarning for the need to implement early intervention prior to decompensation. We tested the hypothesis that addition of a real-time decision-assist machine-learning algorithm, the compensatory reserve measurement (CRM), used by combat medics could shorten the time required to identify the need for intervention in an unstable patient during a hemorrhage profile as compared with vital signs alone. METHODS: We randomized combat medics from the Army Medical Department Center and School Health Readiness Center of Excellence into three groups: group 1 viewed a display of no simulated hemorrhage and unchanging vital signs as a control (n = 24), group 2 viewed a display of simulated hemorrhage and changing vital signs alone (hemorrhage; n = 31), and group 3 viewed a display of changing vital signs with the addition of the CRM (hemorrhage + CRM; n = 22). Participants were asked to push a computer key when they believed the patient was becoming unstable and needed medical intervention. RESULTS: The average time of 11.0 minutes (95% confidence interval, 8.7-13.3 minutes) required by the hemorrhage + CRM group to identify an unstable patient (i.e., stop the video sequence) was less by more than 40% (p < 0.01) compared with 18.9 minutes (95% confidence interval, 17.2-20.5 minutes) in the hemorrhage group. CONCLUSION: The use of a machine-learning monitoring technology designed to measure the capacity to compensate for central blood volume loss resulted in reduced time required by combat medics to identify impending hemodynamic instability. LEVEL OF EVIDENCE: Diagnostic, level IV.

Predictors of hemodynamic decompensation in progressive hypovolemia: Compensatory reserve versus heart rate variability.

BACKGROUND: Hemorrhage remains the leading cause of death following traumatic injury in both civilian and military settings. Heart rate variability (HRV) and heart rate complexity (HRC) have been proposed as potential "new vital signs" for monitoring trauma patients; however, the added benefit of HRV or HRC for decision support remains unclear. Another new paradigm, the compensatory reserve measurement (CRM), represents the integration of all cardiopulmonary mechanisms responsible for compensation during relative blood loss and was developed to identify current physiologic status by estimating the progression toward hemodynamic decompensation. In the present study, we hypothesized that CRM would provide greater sensitivity and specificity to detect progressive reductions in central circulating blood volume and onset of decompensation as compared with measurements of HRV and HRC. METHODS: Continuous, noninvasive measurements of compensatory reserve and electrocardiogram signals were made on 101 healthy volunteers during lower-body negative pressure (LBNP) to the point of decompensation. Measures of HRV and HRC were taken from electrocardiogram signal data. RESULTS: Compensatory reserve measurement demonstrated a superior sensitivity and specificity (receiver operator characteristic area under the curve [ROC AUC] = 0.93) compared with all HRV measures (ROC AUC ≤ 0.84) and all HRC measures (ROC AUC ≤ 0.86). Sensitivity and specificity values at the ROC optimal thresholds were greater for CRM (sensitivity = 0.84; specificity = 0.84) than HRV (sensitivity, ≤0.78; specificity, ≤0.77), and HRC (sensitivity, ≤0.79; specificity, ≤0.77). With standardized values across all levels of LBNP, CRM had a steeper decline, less variability, and explained a greater proportion of the variation in the data than both HRV and HRC during progressive hypovolemia. CONCLUSION: These findings add to the growing body of literature describing the advantages of CRM for detecting reductions in central blood volume. Most importantly, these results provide further support for the potential use of CRM in the triage and monitoring of patients at highest risk for the onset of shock following blood loss.

Tracking DO2 with Compensatory Reserve During Whole Blood Resuscitation in Baboons.

Hemorrhagic shock can be mitigated by timely and accurate resuscitation designed to restore adequate delivery of oxygen (DO2) by increasing cardiac output (CO). However, standard care of using systolic blood pressure (SBP) as a guide for resuscitation may be ineffective and can potentially be associated with increased morbidity. We have developed a novel vital sign called the compensatory reserve measurement (CRM) generated from analysis of arterial pulse waveform feature changes that has been validated in experimental and clinical models of hemorrhage. We tested the hypothesis that thresholds of DO2 could be accurately defined by CRM, a noninvasive clinical tool, while avoiding over-resuscitation during whole blood resuscitation following a 25% hemorrhage in nonhuman primates. To accomplish this, adult male baboons (n = 12) were exposed to a progressive controlled hemorrhage while sedated that resulted in an average (±â€ŠSEM) maximal reduction of 508 ±â€Š18 mL of their estimated circulating blood volume of 2,130 ±â€Š60 mL based on body weight. CRM increased from 6 ±â€Š0.01% at the end of hemorrhage to 70 ±â€Š0.02% at the end of resuscitation. By linear regression, CRM values of 6% (end of hemorrhage), 30%, 60%, and 70% (end of resuscitation) corresponded to calculated DO2 values of 5.9 ±â€Š0.34, 7.5 ±â€Š0.87, 9.3 ±â€Š0.76, and 11.6 ±â€Š1.3 mL O2·kg·min during resuscitation. As such, return of CRM to ∼65% during resuscitation required only ∼400 mL to restore SBP to 128 ±â€Š6 mmHg, whereas total blood volume replacement resulted in over-resuscitation as indicated by a SBP of 140 ±â€Š7 mmHg compared with an average baseline value of 125 ±â€Š5 mmHg. Consistent with our hypothesis, thresholds of calculated DO2 were associated with specific CRM values. A target resuscitation CRM value of ∼65% minimized the requirement for whole blood while avoiding over-resuscitation. Furthermore, 0% CRM provided a noninvasive metric for determining critical DO2 at approximately 5.3 mL O2·kg·min.

Physiological comparison of hemorrhagic shock and V˙ O2max: A conceptual framework for defining the limitation of oxygen delivery.

IMPACT STATEMENT: Disturbance of normal homeostasis occurs when oxygen delivery and energy stores to the body's tissues fail to meet the energy requirement of cells. The work submitted in this review is important because it advances the understanding of inadequate oxygen delivery as it relates to early diagnosis and treatment of circulatory shock and its relationship to disturbance of normal functioning of cellular metabolism in life-threatening conditions of hemorrhage. We explored data from the clinical and exercise literature to construct for the first time a conceptual framework for defining the limitation of inadequate delivery of oxygen by comparing the physiology of hemorrhagic shock caused by severe blood loss to maximal oxygen uptake induced by intense physical exercise. We also provide a translational framework in which understanding the fundamental relationship between the body's reserve to compensate for conditions of inadequate oxygen delivery as a limiting factor to V˙ O2max helps to re-evaluate paradigms of triage for improved monitoring of accurate resuscitation in patients suffering from hemorrhagic shock.

Interrelationship Between Sex, Age, Blood Volume, and Vo2max.

BACKGROUND: Circulating blood volume (BV) and maximal oxygen uptake (Vo2max) are physiological characteristics important for optimal human performance in aerospace and military operational environments. We tested the hypothesis that BV and Vo2max are lower in older people independent of sex.METHODS: To accomplish this, a "data mining" effort of an historic database generated from NASA and U.S. Air Force experiments was conducted. BV, red cell volume, plasma volume, hematocrit, and Vo2max were measured in 84 healthy individuals (24 women, 60 men) across an age range of 23 to 65 yr to assess the interrelationship between sex, age, BV, and Vo2max. Subjects were classified in age groups by < 40 yr and ≥ 40 yr; these groups identified women as pre- vs. postmenopausal.RESULTS: Consistent with our hypothesis, comparisons revealed that men had higher BV, red cell volume, hematocrit, and Vo2max than women when standardized for body mass. Against expectations, BV was not different in older compared with younger men and women. Vo2max was not different in older compared with younger women, while Vo2max was lower in older men.CONCLUSION: We conclude that physiological mechanisms other than BV associated with aging appear to be responsible for a decline in Vo2max of our older men. Furthermore, factors other than menopause may also influence the control of BV in the women. Our results provide evidence that aging may not compromise men or women in scenarios where BV can affect performance in aerospace and military environments.Koons NJ, Suresh MR, Schlotman TE, Convertino VA. Interrelationship between sex, age, blood volume, and Vo2max. Aerosp Med Hum Perform. 2019; 90(4):362-368.

Hemostatic responses to exercise, dehydration, and simulated bleeding in heat-stressed humans.

Heat stress followed by an accompanying hemorrhagic challenge may influence hemostasis. We tested the hypothesis that hemostatic responses would be increased by passive heat stress, as well as exercise-induced heat stress, each with accompanying central hypovolemia to simulate a hemorrhagic insult. In aim 1, subjects were exposed to passive heating or normothermic time control, each followed by progressive lower-body negative pressure (LBNP) to presyncope. In aim 2 subjects exercised in hyperthermic environmental conditions, with and without accompanying dehydration, each also followed by progressive LBNP to presyncope. At baseline, pre-LBNP, and post-LBNP (<1, 30, and 60 min), hemostatic activity of venous blood was evaluated by plasma markers of hemostasis and thrombelastography. For aim 1, both hyperthermic and normothermic LBNP (H-LBNP and N-LBNP, respectively) resulted in higher levels of factor V, factor VIII, and von Willebrand factor antigen compared with the time control trial (all P < 0.05), but these responses were temperature independent. Hyperthermia increased fibrinolysis [clot lysis 30 min after the maximal amplitude reflecting clot strength (LY30)] to 5.1% post-LBNP compared with 1.5% (time control) and 2.7% in N-LBNP ( P = 0.05 for main effect). Hyperthermia also potentiated increased platelet counts post-LBNP as follows: 274 K/µl for H-LBNP, 246 K/µl for N-LBNP, and 196 K/µl for time control ( P < 0.05 for the interaction). For aim 2, hydration status associated with exercise in the heat did not affect the hemostatic activity, but fibrinolysis (LY30) was increased to 6-10% when subjects were dehydrated compared with an increase to 2-4% when hydrated ( P = 0.05 for treatment). Central hypovolemia via LBNP is a primary driver of hemostasis compared with hyperthermia and dehydration effects. However, hyperthermia does induce significant thrombocytosis and by itself causes an increase in clot lysis. Dehydration associated with exercise-induced heat stress increases clot lysis but does not affect exercise-activated or subsequent hypovolemia-activated hemostasis in hyperthermic humans. Clinical implications of these findings are that quickly restoring a hemorrhaging hypovolemic trauma patient with cold noncoagulant fluids (crystalloids) can have serious deleterious effects on the body's innate ability to form essential clots, and several factors can increase clot lysis, which should therefore be closely monitored.