Out-of-Hospital Intranasal Ketamine as an Adjunct to Fentanyl for the Treatment of Acute Traumatic Pain: A Randomized Clinical Trial.

STUDY OBJECTIVE: To evaluate if out-of-hospital administration of fentanyl and intranasal ketamine, compared to fentanyl alone, improves early pain control after injury. METHODS: We conducted an out-of-hospital randomized, placebo-controlled, blinded, parallel group clinical trial from October 2017 to December 2021. Participants were male, aged 18 to 65 years, receiving fentanyl to treat acute traumatic pain prior to hospital arrival, treated by an urban fire-based emergency medical services agency, and transported to the region's only adult Level I trauma center. Participants randomly received 50 mg intranasal ketamine or placebo. The primary outcome was the proportion with a minimum 2-point reduction in self-described pain on the verbal numerical rating scale 30 minutes after study drug administration assessed by 95% confidence interval overlap. Secondary outcomes were side effects, pain ratings, and additional pain medications through the first 3 hours of care. RESULTS: Among the 192 participants enrolled, 89 (46%) were White, (median age, 36 years; interquartile range, 27 to 53 years), with 103 receiving ketamine and 89 receiving placebo. There was no difference in the proportion experiencing improved pain 30 minutes after treatment (46/103 [44.7%] ketamine versus 32/89 [36.0%] placebo; difference in proportions, 8.7%; 95% confidence interval, -5.1% to 22.5%; P=.22) or at any time point through 3 hours. There was no difference in secondary outcomes or side effects. CONCLUSION: In our sample, we did not detect an analgesic benefit of adding 50 mg intranasal ketamine to fentanyl in out-of-hospital trauma patients.

Simulation and qualitative analysis of glucose variability, mean glucose, and hypoglycemia after subcutaneous insulin therapy for stress hyperglycemia.

BACKGROUND: The critically ill can have persistent dysglycemia during the "subacute" recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial. METHODS: Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation. RESULTS: Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, "rebound hyperglycemia" was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes. CONCLUSIONS: Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose variability; its linear dose-response curve rendered the preparation better suited for a sliding-scale protocol. The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units; if present, their clinical effects should be evaluated.

Qualitative analysis of subcutaneous Lispro and regular insulin injections for stress hyperglycemia: a pilot numerical study.

Increased glucose variability (GV) is an independent risk factor for mortality in the critically ill; unfortunately, the optimal insulin therapy that minimizes GV is not known. We simulate the glucose-insulin feedback system to study how stress hyperglycemia (SH) states, taken to be a non-uniform group of physiologic disorders with varying insulin resistance (IR) and similar levels of hyperglycemia, respond to the type and dose of subcutaneous (SQ) insulin. Two groups of 100 virtual patients are studied: those receiving and those not receiving continuous enteral feeds. Stress hyperglycemia was facilitated by doubling the gluconeogenesis rate and IR was stepwise varied from a borderline to a high value. Lispro and regular insulin were simulated with dosages that ranged from 0 to 6 units; the resulting GV was analyzed after each insulin injection. The numerical model used consists of a set of non-linear differential equations with two time delays and five adjustable parameters. The results show that regular insulin decreased GV in both patient groups and rarely caused hypoglycemia. With continuous enteral feeds and borderline to mild IR, Lispro showed minimal effect on GV; however, rebound hyperglycemia that increased GV occurred when the IR was moderate to high. Without a nutritional source, Lispro worsened GV through frequent hypoglycemia episodes as the injection dose increased. The inferior performance of Lispro is a result of its rapid absorption profile; half of its duration of action is similar to the glucose ultradian period. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units, and if such dynamics are present, their clinical effects should be evaluated.

Impact of Rank, Provider Specialty, and Unit Sustainment Training Frequency on Military Critical Care Air Transport Team Readiness.

BACKGROUND: The Critical Care Air Transport (CCAT) Advanced Course utilizes fully immersive high-fidelity simulations to assess personnel readiness for deployment. This study aims to determine whether simple well-defined demographic identifiers can be used to predict CCAT students' performance at CCAT Advanced. MATERIALS AND METHODS: CCAT Advanced student survey data and course status (pass/fail) between March 2006 and April 2020 were analyzed. The data included students' Air Force Specialty Code (AFSC), military status (active duty and reserve/guard), CCAT deployment experience (yes/no), prior CCAT Advanced training (yes/no), medical specialty, rank, and unit sustainment training frequency (never, frequency less often than monthly, and frequency at least monthly). Following descriptive analysis and comparative tests, multivariable regression was used to identify the predictors of passing the CCAT Advanced course for each provider type. RESULTS: A total of 2,576 student surveys were analyzed: 694 (27%) physicians (MDs), 1,051 (40%) registered nurses (RNs), and 842 (33%) respiratory therapists (RTs). The overall passing rates were 92.2%, 90.3%, and 85.4% for the MDs, RNs, and RTs, respectively. The students were composed of 579 (22.5%) reserve/guard personnel, 636 (24.7%) with CCAT deployment experience, and 616 (23.9%) with prior CCAT Advanced training. Regression analysis identified groups with lower odds of passing; these included (1) RNs who promoted from Captain to Major (post-hoc analysis, P = .03), (2) RTs with rank Senior Airman, as compared to Master Sergeants (post-hoc analysis, P = .04), and (3) MDs with a nontraditional AFSC (P = .0004). Predictors of passing included MDs and RNs with CCAT deployment experience, odds ratio 2.97 (P = .02) and 2.65 (P = .002), respectively; and RTs who engaged in unit CCAT sustainment at least monthly (P = .02). The identifiers prior CCAT Advanced training or reserve/guard military status did not confer a passing advantage. CONCLUSION: Our main result is that simple readily available metrics available to unit commanders can identify those members at risk for poor performance at CCAT Advanced readiness training; these include RNs with rank Major or above, RTs with rank Senior Airman, and RTs who engage in unit sustainment training less often than monthly. Finally, MD specialties which are nontraditional for CCAT have significantly lower CCAT Advanced passing rates, reserve/guard students did not outperform active duty students, there was no difference in the performance between different RN specialties, and for MD and RN students' previous deployment experience was a strong predictor of passing.

Hypobaria During Aeromedical Evacuation and Systemic Inflammation after Porcine Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is utilized by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation following TBI that could contribute to more severe TBI-related secondary injury. STUDY DESIGN: Thirty-six female pigs were used to test TBI vs. TBI sham, hypoxia vs. normoxia, and hypobaria vs. ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 feet were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO2 while at altitude. Serum cytokines, UCH-L1 and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein (GFAP) and phosphorylated tau (p-tau). RESULTS: Serum IL-1b, IL-6, and TNFα were significantly elevated following TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared to ground level/normoxia. No difference in TBI biomarkers following TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue GFAP or p-tau when comparing the most different conditions of sham TBI+ground/normoxia to the TBI+hypobaria/hypoxia group was noted. CONCLUSION: The hypobaric environment of AE induces systemic inflammation following TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE following TBI.

Commotio cordis, therapeutic hypothermia, and evacuation from a United States military base in Iraq.

BACKGROUND: Therapeutic hypothermia (TH) has been demonstrated to improve clinical outcomes after out-of-hospital ventricular fibrillation (VF) cardiac arrest. It remains unclear if TH can be safely and effectively used in the setting of traumatic arrest. Furthermore, the use of TH methods in the pre-hospital and transport environments remain poorly established and a domain of active investigation. OBJECTIVES: To describe a case of successful TH utilization after blunt trauma with commotio cordis and pulmonary contusion, and to describe the continuation of TH during international fixed-wing aeromedical transport. CASE REPORT: A 33-year-old active duty soldier suffered blunt chest trauma and immediate VF arrest. He was successfully resuscitated with cardiopulmonary resuscitation and defibrillation attempts. Given his ensuing comatose post-arrest state, he was therapeutically cooled and subsequently evacuated from Iraq to Germany, with cooling maintenance established in flight without the availability of training or commercial cooling equipment. The patient exhibited an eventual excellent neurologic recovery. To utilize TH for this patient, military physicians with limited local resources employed a telemedical approach to obtain a hypothermia protocol to develop a successful treatment plan. CONCLUSIONS: The patient's successful resuscitation suggests that care should not be withheld for blunt trauma patients without vital signs in the field if VF is present, until the differential diagnosis of commotio cordis has been considered.

Quality of Integration of Air Force Trauma Surgeons Within the Center for Sustainment of Trauma and Readiness Skills, Cincinnati: A Pilot Study.

INTRODUCTION: While previous studies have analyzed military surgeon experience within military-civilian partnerships (MCPs), there has never been an assessment of how well military providers are integrated within an MCP. The Center for Sustainment of Trauma and Readiness Skills, Cincinnati supports the Critical Care Air Transport Advanced Course and maintains the clinical skills of its staff by embedding them within the University of Cincinnati Medical Center. We hypothesized that military trauma surgeons are well integrated within University of Cincinnati Medical Center and that they are exposed to a similar range of complex surgical pathophysiology as their civilian partners. MATERIALS AND METHODS: After Institutional Review Board approval, Current Procedural Terminology (CPT) codes were abstracted from billing data for trauma surgeons covering University of Cincinnati Hospitals in 2019. The number of trauma resuscitations and patient acuity metrics were abstracted from the Trauma Registry and surgeon Knowledge, Skills, and Abilities clinical activity (KSA-CA) scores were calculated using their CPT codes. Finally, surgeon case distributions were studied by sorting their CPT codes into 23 categories based on procedure type and anatomic location. Appropriate, chi-squared or Mann-Whitney U-tests were used to compare these metrics between the military and civilian surgeon groups and the metrics were normalized by the group's full-time equivalent (FTE) to adjust for varying weeks on service between groups. RESULTS: Data were available for two active duty military and nine civilian staff. The FTEs were significantly lower in the military group: military 0.583-0.583 (median 0.583) vs. civilian 0.625-1.165 (median 1.0), P = 0.04. Per median FTE and surgeon number, both groups performed a similar number of trauma resuscitations (civilian 214 ± 54 vs. military 280 ± 13, P = 0.146) and KSA-CA points (civilian 55,629 ± 25,104 vs. military 36,286 ± 11,267; P = 0.582). Although the civilian surgeons had a higher proportion of hernia repairs (P < 0.001) and laparoscopic procedures (P = 0.006), the CPT code categories most relevant to combat surgery (those relating to solid organ, hollow viscus, cardiac, thoracic, abdominal, and tissue debridement procedures) were similar between the surgeon groups. Finally, patient acuity metrics were similar between groups. CONCLUSION: This is the first assessment of U.S. Air Force trauma surgeon integration relative to their civilian partners within an MCP. Normalized by FTE, there was no difference between the two groups' trauma experience to include patient acuity metrics and KSA-CA scores. The proportion of CPT codes that was most relevant to expeditionary surgery was similar between the military and civilian partners, thus optimizing the surgical experience for the military trauma surgeons within University of Cincinnati Medical Center. The methods used within this pilot study can be generalized to any American College of Surgeons verified Trauma Center MCP, as standard databases were used.

The Ability of Military Critical Care Air Transport Members to Visually Estimate Percent Systolic Pressure Variation.

INTRODUCTION: Inappropriate fluid management during patient transport may lead to casualty morbidity. Percent systolic pressure variation (%SPV) is one of several technologies that perform a dynamic assessment of fluid responsiveness (FT-DYN). Trained anesthesia providers can visually estimate and use %SPV to limit the incidence of erroneous volume management decisions to 1-4%. However, the accuracy of visually estimated %SPV by other specialties is unknown. The aim of this article is to determine the accuracy of estimated %SPV and the incidence of erroneous volume management decisions for Critical Care Air Transport (CCAT) team members before and after training to visually estimate and utilize %SPV. MATERIAL AND METHODS: In one sitting, CCAT team providers received didactics defining %SPV and indicators of fluid responsiveness and treatment with %SPV ≤7 and ≥14.5 defining a fluid nonresponsive and responsive patient, respectively; they were then shown ten 45-second training arterial waveforms on a simulated Propaq M portable monitor's screen. Study subjects were asked to visually estimate %SPV for each arterial waveform and queried whether they would treat with a fluid bolus. After each training simulation, they were told the true %SPV. Seven days post-training, the subjects were shown a different set of ten 45-second testing simulations and asked to estimate %SPV and choose to treat, or not. Nonparametric limits of agreement for differences between true and estimated %SPV were analyzed using Bland-Altman graphs. In addition, three errors were defined: (1) %SPV visual estimate errors that would label a volume responsive patient as nonresponsive, or vice versa; (2) incorrect treatment decisions based on estimated %SPV (algorithm application errors); and (3) incorrect treatment decisions based on true %SPV (clinically significant treatment errors). For the training and testing simulations, these error rates were compared between, and within, provider groups. RESULTS: Sixty-one physicians (MDs), 64 registered nurses (RNs), and 53 respiratory technicians (RTs) participated in the study. For testing simulations, the incidence and 95% CI for %SPV estimate errors with sufficient magnitude to result in a treatment error were 1.4% (0.5%, 3.2%), 1.6% (0.6%, 3.4%), and 4.1% (2.2%, 6.9%) for MDs, RNs, and RTs, respectively. However, clinically significant treatment errors were statistically more common for all provider types, occurring at a rate of 7%, 10%, and 23% (all P < .05). Finally, students did not show clinically relevant reductions in their errors between training and testing simulations. CONCLUSIONS: Although most practitioners correctly visually estimated %SPV and all students completed the training in interpreting and applying %SPV, all groups persisted in making clinically significant treatment errors with moderate to high frequency. This suggests that the treatment errors were more often driven by misapplying FT-DYN algorithms rather than by inaccurate visual estimation of %SPV. Furthermore, these errors were not responsive to training, suggesting that a decision-making cognitive aid may improve CCAT teams' ability to apply FT-DYN technologies.

Association of Hypocalcemia With Mortality of Combat Casualties With Brain Injury and Polytrauma Transported by Critical Care Air Transport Teams.

INTRODUCTION: Hypocalcemia at hospital presentation is associated with increased mortality in trauma patients with hemorrhagic shock. The 2019 updates to the Joint Trauma System Damage Control Resuscitation (DCR) Clinical Practice Guideline recommend calcium supplementation for ionized calcium (iCa) measurements <1.2 mmol/L. Ionized calcium goals for en route critical care (ERCC) following DCR are less defined, and the impact of in-flight hypocalcemia events among critically injured combat wounded is unknown. This study aimed to describe the association between hypocalcemia and mortality for combat-wounded with brain injury and polytrauma requiring transport by Critical Care Air Transport Teams (CCATT). METHODS: We performed a secondary analysis of a retrospective cohort of patients with moderate-to-severe traumatic brain injury transported by CCATT out of combat theater between January 2007 and May 2014. Additional inclusion criteria included polytrauma and at least one documented in-flight iCa measurement. We categorized exposures based on the minimum in-flight iCa measurement as severe hypocalcemia (iCa <0.9 mmol/L), hypocalcemia (iCa 0.9-1.11 mmol/L), and never hypocalcemic (iCa ≥1.12 mmol/L). The primary outcome measure was mortality. We calculated descriptive statistics and performed multivariate logistic regression to assess the association between hypocalcemia and mortality. RESULTS: We analyzed 190 subjects, with a median age of 24 years (interquartile range [IQR] 21 to 29 years) and 97.7% male gender. Explosive injuries (82.1%) and gunshot wounds (6.3%) were the most common mechanisms of injury. The median injury severity score was 34 (IQR 27 to 43). During the flight, 11.6% of patients had severe hypocalcemia, and 39.5% had hypocalcemia. Among patients with any hypocalcemia measurement in-flight (n = 97), 41.2% had hypocalcemia on pre-flight iCa, 28.9% received blood products in-flight, and 23.7% received in-flight calcium supplementation. Only 32.4% of patients with hypocalcemia or severe hypocalcemia in the setting of vasopressor administration received in-flight calcium supplementation. There was no significant difference in mortality between severe hypocalcemia (9.1%), hypocalcemia (5.3%), and never hypocalcemic (3.2%) patients even after controlling for pre-flight variables. CONCLUSION: In-flight hypocalcemia events were common among critically ill combat-wounded polytrauma patients transported by CCATT but were not associated with differences in mortality. Future training should emphasize the need for calcium correction among ERCC patients requiring vasopressors. Future studies with larger sample sizes of patients receiving ERCC are needed to assess the association between in-flight calcium supplementation with clinical outcomes.

Intermittent gastric feeds lower insulin requirements without worsening dysglycemia: A pilot randomized crossover trial.

INTRODUCTION: We hypothesized that critically ill medical patients would require less insulin when fed intermittently. METHODS: First, 26 patients were randomized to receive intermittent or continuous gastric feeds. Once at goal nutrition, data were collected for the first 4-hr data collection period. Next, the enteral feed type was switched, goal nutrition was repeated, and a second 4-h data collection period was completed. The primary endpoint was the total amount of insulin infused; secondary endpoints were glucose concentration mean, maximum, minimum, and standard deviation, as well as episodes of hypoglycemia. RESULTS: Sixteen of the 26 patients successfully completed the protocol. One patient experienced a large, rapid, and sustained decline in insulin requirement from liver failure, creating a bias of lesser insulin in the intermittent arm; this patient was removed from the analysis. For the remaining 15 patients, the average total amount of insulin infused was 1.4 U/patient/h less following intermittent feeds: P =0.027, 95% confidence interval (0.02, 11.17), and effect size 0.6. Secondary endpoints were statistically similar. CONCLUSIONS: Critically ill medical patients who require an insulin infusion have a reduced insulin requirement when fed intermittently, whereas dysglycemia metrics are not adversely affected. A larger clinical study is required to confirm these findings.

Comparison of Subcutaneous Regular Insulin and Lispro Insulin in Diabetics Receiving Continuous Nutrition: A Numerical Study.

BACKGROUND: Optimal management of non-critically ill patients with diabetes maintained on continuous enteral feeding (CEN) is poorly defined. Subcutaneous (SQ) lispro and SQ regular insulin were compared in a simulated type 1 and type 2 diabetic patient receiving CEN. METHOD: A glucose-insulin feedback mathematical model was employed to simulate type 1 and type 2 diabetic patients on CEN. Each patient received 25 SQ injections of regular insulin or insulin lispro, ranging from 0-6 U. Primary endpoints were the change in mean glucose concentration (MGC) and change in glucose variability (GV); hypoglycemic episodes were also reported. The model was first validated against patient data. RESULTS: Both SQ insulin preparations linearly decreased MGC, however, SQ regular insulin decreased GV whereas SQ lispro tended to increase GV. Hourly glucose concentration measurements were needed to capture the increase in GV. In the type 2 diabetic patient, "rebound hyperglycemia" occurred after SQ lispro was rapidly metabolized. Although neither SQ insulin preparation caused hypoglycemia, SQ lispro significantly lowered MGC compared to SQ regular insulin. Thus, it may be more likely to cause hypoglycemia. Analyses of the detailed glucose concentration versus time data suggest that the inferior performance of lispro resulted from its shorter duration of action. Finally, the effects of both insulin preparations persisted beyond their duration of actions in the type 2 diabetic patient. CONCLUSIONS: Subcutaneous regular insulin may be the short-acting insulin preparation of choice for this subset of diabetic patients. Clinical trial is required before a definitive recommendation can be made.