Objective: Novel analgesics used for acute pain relief in both the military and civilian settings must have minimal or no secondary effects, especially on the cardiovascular and respiratory systems, when the pain of trauma is associated with hemorrhage. Sparian Biosciences has developed an N-arachidonoylethanolamine receptor agonist, SBS-1000, that has “opioid-like” analgesic efficacy but lacks “opioid-like” side effects, like respiratory depression and tolerance. However, the effects of SBS-1000 on cardiovascular and respiratory responses after hemorrhage (HEM) associated with trauma are unknown. Thus, the objective of this study is to test effects of an analgesic dose of SBS-1000 on cardiorespiratory responses and survival in an animal model of battlefield trauma and HEM. We hypothesized that, when given after trauma and HEM, SBS-1000 will suppress cardiorespiratory responses to HEM by 30% or more and thereby decrease survival. Methods: Male rats were anesthetized with isoflurane and implanted with a telemetry transmitter to measure mean arterial pressure (MAP) and heart rate (HR); buprenorphine sustained release was used to relieve pain associated with surgical procedures. Following 2 weeks recovery, rats were anesthetized with isoflurane, and a carotid catheter was implanted. No analgesics were used to relieve the pain associated with catheter implantation to exclude associated confounding factors during experiment day. The next day, rats were briefly anesthetized to perform extremity trauma (ET; fibular fracture + hindlimb soft tissue crush injury) and were allowed to recover 90 min before starting conscious HEM (time = 0-25 min) within a plethysmograph to measure respiratory rate (RR), tidal volume (TV), and minute ventilation (MV). HEM was moderate and consisted of 37% of total blood volume. Rats received either 1) vehicle (VEH, 10% DMS, 10% Kolliphor, 80% Saline) or 2) SBS-1000 (1 mg/kg in VEH) via subcutaneous injection into the animal’s back after HEM (t = 25 min). The study continued for 215 minutes (time = 25-240 min). Data are mean ± standard deviation (SD). Results: There were no differences between groups in MAP, HR, RR, TV, MV at either baseline (t = 0 min), end of HEM (t = 25 min), or after VEH/SBS-1000 injection (t = 25-240 min). 100% of animals in VEH (n=8) and SBS-1000 (n=9) groups survived. Conclusion: An analgesic dose of SBS-1000 did not affect cardiorespiratory responses or survival following ET and HEM. SBS-1000 is a promising novel analgesic that may prove useful in the battlefield or civilian sector to reduce pain from trauma in the presence of moderate hemorrhage. Future studies will investigate the effects of SBS-1000 after a more severe level of hemorrhage. Funding Source: Congressionally Directed Medical Research Program (CDMRP) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Objective: Multiple analgesics are used for acute pain relief in both the military and civilian settings. However, in addition to their ability to relieve pain, medical providers must also be concerned about secondary effects of the analgesics, especially effects on the cardiovascular and respiratory systems when the pain of trauma is associated with hemorrhage. AmacaThera, Inc. has developed AMT-143, a new delivery platform for the FDA-approved anesthetic ropivacaine, a non-opioid sodium channel blocker having both local anesthetic and analgesic effects. AMT-143 is formulated as a slow releasing hydrogel that provides extended release of ropivacaine. Ropivacaine in high doses, like other local anesthetics, can have effects on the central nervous and cardiovascular systems. While a single subcutaneous dose of AMT-143 can be used to localize ropivacaine to the injection site, to provide effective pain relief over an extended period, the effects of this prolonged local concentration of ropivacaine on cardiovascular and respiratory responses after extremity trauma (ET; fibular fracture + hindlimb soft tissue crush injury) and hemorrhage (HEM) are unknown. Hypothesis: We hypothesized that AMT-143 will change cardiovascular responses to HEM by 30% or more and thereby decrease survival. Methods: Male rats were anesthetized with isoflurane and implanted with a telemetry transmitter to measure mean arterial pressure (MAP) and heart rate (HR); buprenorphine sustained release was used to relieve pain associated with surgical procedures. Following 2 weeks recovery, rats were anesthetized, and a carotid catheter was implanted. The next day, rats were briefly anesthetized to perform ET and were allowed to recover 90 min before starting conscious HEM (time = 0-25 min). HEM was either moderate (37%HEM, 37% of total blood volume) or severe (50%HEM, 50% of total blood volume). Rats received either 1) saline vehicle (VEH) or 2) AMT-143 via subcutaneous injection into the injured hind limb at end of HEM (t=25 min). The study continued for 215 minutes (time = 25-240 min). Data are mean ± standard deviation. Results: There were no differences between groups in MAP or HR at either baseline (t = 0 min), end of HEM (t = 25 min), or after VEH/AMT-143 injection (t = 25-240 min) in either the 37%HEM animals or 50%HEM animals. 100% of animals in 37%HEM VEH (n=8) and 37%HEM AMT-143 (n=11) survived. There was no difference (P=0.197) in survival rate between 50%HEM VEH (44.4%, n=9) and 50%HEM AMT-143 (22.2%, n=9). Summary: An analgesic dose of AMT-143 did not affect cardiovascular responses or survival following ET and HEM. Conclusion: AMT-143, a slow-release non-opioid anesthetic, may prove useful in the battlefield or civilian sector to reduce pain locally after traumatic hemorrhage. Congressionally Directed Medical Research Program (CDMRP) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Opioids are used for analgesia, but questions persist about their safety after traumatic hemorrhage. We investigated analgesic doses of three opioids (morphine, fentanyl, and sufentanil) on cardiorespiratory responses and survival to moderate or severe (37% or 50% blood volume) hemorrhage after trauma. A conscious hemorrhage model with extremity trauma (fibular fracture + soft tissue injury) was used; mean arterial pressure (MAP) and heart rate (HR) were measured by telemetry, whereas minute volume (MV) was determined by whole body plethysmography. Male rats (n = 10/group) received saline, morphine (2 mg/kg), fentanyl (10 µg/kg), or sufentanil (1 µg/kg) after traumatic hemorrhage. Neither survival times (for 37% hemorrhage: P = 0.209; for 50% hemorrhage: P = 0.88) nor survival percentages (for 37% hemorrhage: P = 0.357; for 50% hemorrhage: P = 1.0) differed among groups. For 37% hemorrhage, MAP of all opioid groups was higher than that in the saline-treated group 10 min post injection. By 75 min post injection, MAP after sufentanil was higher than saline; MAP for other opioids did not differ from saline. HR did not differ across treatments. Opioid injection decreased MV within 10 min but did not vary by treatment subsequently. For 50% hemorrhage, opioid injection did not immediately alter MAP but morphine and sufentanil were lower than saline at ≥75 min post injection, with no treatment effects on HR. Fentanyl produced an immediate (5 min) decrease in MV with no treatment effects thereafter. Opioid effects on cardiorespiratory function were therefore modest and did not alter survival during a 4-h observation period, supporting the judicious use of analgesic doses after traumatic hemorrhage.NEW & NOTEWORTHY Administration of an analgesic dose of either morphine, fentanyl, or sufentanil produced only modest and transient effects on cardiorespiratory function after either moderate (37% blood volume) or severe (50%) hemorrhage in conscious rats with extremity trauma. Under the conditions of these experiments, analgesic doses of these commonly used opioids also did not alter survival after traumatic hemorrhage.

Background: Sufentanil (SUF) is 500-fold more potent than morphine but is currently not recommended for use on the battlefield for casualties with shock or respiratory difficulties. However, there have been no controlled, preclinical studies conducted using analgesic doses of SUF to support these guidelines. We previously reported that SUF transiently and moderately depressed respiration rate and tidal volume (TV). The current study was conducted to further evaluate effects of SUF on components of the respiratory cycle after moderate hemorrhage in conscious rats with extremity trauma. Knowledge of specific respiratory-cycle components affected by SUF could provide information concerning SUF mechanisms and sites of action and may provide indices for diagnosis and treatment of compromised respiration. We hypothesized that SUF would negatively impact these respiratory components. Methods: Rats were randomly assigned to receive either 0.9% saline vehicle (VEH), or 1 µg/kg SUF (n=9-10 rats/ group). Rats (male; ~ 380 grams) were surgically implanted with a carotid catheter for hemorrhage and blood sampling. After 24 hours, rats were anesthetized (10 min) to undergo trauma (crushing of the right gastrocnemius and semimembranosus muscles for 30 sec with forceps) and fibula fracture. Rats were allowed to awaken, and 90 min later underwent a conscious hemorrhage (~37% of blood volume during 25 min) within a whole-body plethysmography chamber. After hemorrhage, rats received either VEH orSUF intra-arterially. Respiratory measures were recorded over 1 min intervals and included inspiratory time (Ti, sec), time spent inhaling during each breath; expiratory time (Te, sec), time spent exhaling during each breath); peak inspiratory flow (PIF, ml/sec), maximum inspiratory flow that occurs in one breath; mean inspiratory flow (MIF, equal to TV/Ti, ml/sec); peak expiratory flow (PEF, ml/sec), maximum expiratory flow that occurs in one breath. Data were analyzed via multiway analysis of variance (ANOVA) for repeated measures using PROC GLIMMIX of the Statistical Analysis System with adjustments for multiple comparisons provided via the Hochberg procedure. Results: Compared with VEH, for up to 10 min after SUFinjection Ti was 48% higher (P ≤ 0.025), PIF was 32% lower (P ≤ 0.017), and MIF was 40% lower (P≤0.002). Neither Te nor PEF were affected by SUF (P ≥ 0.18). In SUF-treated rats, PIF and MIF were highly negatively correlated with pCO 2 (r ≥ -0.91; P ≤ 0.03). This did not occur in VEH-treated rats (r ≤ -0.44; P ≥ 0.24). Summary & Conclusions: Maintaining appropriate respiratory function after trauma and hemorrhage is critical for welfare and survival. At the analgesic dose given ̶ previously shown to ameliorate behavioral indices of pain in rats ̶ SUFhad transient inhibitory effects on inspiration rather than expiration, causing the SUF-induced decrease in respiration rate. Such effects suggest a possible site of action of SUF at the pre-Botzinger Complex, but do not obviate other brainstem nuclei. Moreover, SUF appeared to increase association of inspiratory regulatory mechanisms with blood pCO 2. The minor and transient nature of SUF effects on respiration do not, however, provide evidence for its exclusion as a battlefield pain-relief medication. Applied Pain Research Program, US Army Clinical and Rehabilitative Medicine, and US Army Combat Casualty Care Research Program, Medical Research and Development Command. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

The threat and consequences of nuclear or radiological events remain a military concern today. It is estimated that 65–70% of weapon-related injuries after a nuclear event will be radiation combined injuries, i. e., acute radiation injury along with hemorrhage and traumatic injuries such as blast or other burns, bone fractures, soft tissue injuries, blood loss, and/or hypoxia. However, little is known about most types of traumatic injuries associated with blood loss, as might occur during combat operations. The primary objective of this pilot study was to develop a new animal model that incorporates both hemorrhage and traumatic injury, combined with radiation exposure. Male Sprague-Dawley rats were divided into four groups (6/group): 1. sham; 2. radiation injury (RI); 3. traumatic hemorrhage (TH), which is hemorrhage combined with extremity trauma; and 4. RI+TH. Radiation injury consisted of a single X-ray dose of 5. 5.5 Gy delivered at a rate of 1 Gy/min. Hemorrhage involved a stepwise reduction of 37% of the estimated blood volume. Extremity trauma consisted of fibular fractures and penetrating and soft tissue injuries to a single extremity. Heart rate, mean arterial blood pressure (MAP), and blood indices were analyzed at intervals corresponding to pre-hemorrhage, end of hemorrhage, and 4 h after hemorrhage, with survival observed for 14 days. Radiation injury alone had little impact on the measured variables. Hemorrhage resulted in a 60% and 67% reduction in MAP in the traumatic hemorrhage and RI+TH groups, respectively, immediately after hemorrhage, which recovered by 4 h in the traumatic hemorrhage group but not in RI+TH group. A similar pattern was observed for blood lactate levels. Traumatic hemorrhage and radiation injury resulted in 50% mortality, although mortality occurred earlier after traumatic hemorrhage. RI+TH produced 80% mortality by day 4. No mortality was observed in the sham group. By combining a high dose of X-ray radiation with our established model of traumatic hemorrhage, we have developed a new rodent model that mimics combat casualties during nuclear or radiological events.

INTRODUCTION:Definitive management of non-compressible intra-abdominal hemorrhage (NCIAH) currently requires a surgeon and operating room capable of performing damage control surgery. In a wartime scenario or a geographically remote environment, these may not be readily available. In this study, we sought to test the safety of 2 emerging injectable hemostatic agents (CounterFlow and Fast Onset Abdominal Management, or FOAM, poloxamer component) versus normal saline control over a prolonged monitoring duration following administration by a non-surgical provider. MATERIALS AND METHODS:The Institutional Animal Care and Use Committee approved all research conducted in this study. We randomized male New Zealand white rabbits into 2 monitoring cohorts of 24 hours and 2 weeks. Each cohort contained 3 treatment groups (n = 4 rabbits/group): CounterFlow, the testable poloxamer component of FOAM, and normal saline control. We injected each treatment intraperitoneally in the left lower abdominal quadrant. Doses were 15 mL/kg for CounterFlow, 6.3 mL/kg for the poloxamer component of FOAM, and 15 mL/kg for normal saline. We conducted all injections under isoflurane anesthesia monitored by trained veterinary staff. Animals were euthanized at each cohort end point, and a veterinary pathologist blinded to treatment type performed necropsy. The primary outcome was incidence of intra-abdominal adhesions at necropsy. Quantitatively, adhesions when present were graded by the veterinary pathologist on a 1 to 4 scale, where "1" represented adhesions involving from 1 to 25% of the examined abdomen, "2" represented from 26 to 50%, "3" represented from 51 to 75%, and "4" represented from 76 to 100%. Qualitatively, adhesions present were graded by degree ("1" = minimal, "2" = mild, "3" = moderate, and "4" = severe) and chronicity ("1" = acute, "2" = subacute, and "3" = chronic). We also drew d-dimer blood values and measured body weights for each animal. Statistical analysis included either repeated measures 2-way ANOVA or a mixed-effects model (in the case of missing data) with Geisser-Greenhouse correction. We adjusted multiple comparisons using Tukey statistical hypothesis tests. RESULTS:In the 2-week cohort, 3 CounterFlow animals showed adhesions judged to be "1" quantitatively. Qualitatively, 2 of these were assessed as "1" for degree of adhesions and the other demonstrated a "2." On the chronicity of adhesions scale, 1 animal demonstrated a "2" and 2 demonstrated a "3." No animals in other groups (FOAM and control) demonstrated adhesions. CounterFlow-treated animals showed a statistically significant rise in d-dimer values in the 24-hour cohort only. In the 2-week cohort, CounterFlow-treated animals showed a decrease in body weight at 24 hours after injection but returned to their baseline (normal) body weights at 7 days. CONCLUSIONS:Findings from this study demonstrate that the tested ingredients of FOAM poloxamer component are safe for intraperitoneal injection and hold potential for further study directed toward prehospital non-compressible intra-abdominal hemorrhage management by non-surgical providers. Although CounterFlow produced abdominal adhesions in 3 of 4 rabbits in the 2-week cohort, these were determined to be "minimal" or "mild" in degree.

Extremity trauma, including ischemia (e.g., prolonged tourniquet application or crush), is common among battlefield injuries. Injured muscle releases toxins leading to rhabdomyolysis and, potentially, acute kidney injury (AKI). The goal of this study was to characterize sequelae of ischemic extremity injury over 72 h, focusing on time courses of rhabdomyolysis and AKI. Male Sprague Dawley rats were placed into two groups. Ischemic injury was produced in anesthetized rats using bilateral tourniquets (TK; n = 10) for 5 h; control (CON; n = 9) rats were treated identically without TK application. Indicators of rhabdomyolysis and renal function were measured in conscious rats 1 day preinjury (baseline, BL) and then at 1.5, 24, 48, and 72 h post-TK release. Prolonged TK application produced necrosis in both muscle and bone marrow but not in kidney. The wet/dry weights indicated edema in injured limbs at 72 h (4.1 (0.5) (TK) vs. 2.9 (0.1) (CON); p < 0.001). TK rats exhibited a 100-fold increase in creatine kinase activity compared to CON at 1.5 h (20,040 (7265) U/L vs. 195 (86) U/L (mean (SD); p < 0.0001). TK decreased the mean glomerular filtration rate (GFR; p < 0.001) at 1.5 h, but these values recovered by 24 h in concert with elevated urinary flow and alkalinization. Prolonged ischemic extremity injury therefore produced severe rhabdomyolysis without irreversible renal damage.

Objective: Traumatic hemorrhage (HEM) is often associated with pain. The use of ketamine (KET) has increased both on the battlefield and in civilian emergency care for analgesia and sedation. We have reported that an analgesic dose of KET does not impact cardiorespiratory responses or survival after HEM (JAP 130: 1583-1593, 2021). In this study, we measured the effects of a larger, sedative, dose of KET on cardiovascular responses and survival to moderate (37% blood volume) HEM combined with extremity trauma (ET), and whether midazolam (MDZ), a drug often given in combination with KET alters these responses. Hypothesis: We hypothesized that either KET (50 mg/kg) or KET+MDZ (5 mg/kg) would compromise cardiovascular responses to HEM and thereby decrease survival. Methods: Male rats were implanted with a telemetry transmitter to measure mean arterial pressure (MAP) and heart rate (HR); buprenorphine SR was used to relieve pain associated with surgical procedures. Following 2 weeks recovery, rats were anesthetized using isoflurane, and a carotid catheter was implanted. The next day, rats were briefly anesthetized using isoflurane to perform ET (fibular fracture + hindlimb soft tissue crush injury) and were allowed to recover 90 min before starting conscious HEM (time = 0-25 min). Rats received either 1) saline vehicle (VEH, n=8); 2) KET (n=8); or 3) KET followed by MDZ (KET+MDZ; n=9) during a 15 min infusion (t = 25-40 min). The study continued for 200 minutes (time = 40-240 min). Data are mean ± SD. Results: There were no differences between groups in MAP or HR at either baseline (t = 0 min) or at end of HEM (t = 25 min). However, during the 20 min after treatment (t = 40-60 min), MAP and HR were significantly lower (P≤0.05) in KET (46 ± 3 mmHg; 220 ± 11 bpm) and KET+MDZ (45 ± 10 mmHg; 212 ± 24 bpm) compared to VEH (68 ± 20 mmHg; 297 ± 37 bpm). During this time, only 3 of 8 rats in the KET group survived HEM, while all rats survived in VEH and KET+MDZ groups. At the end of the study (t = 240 min), survival rate was significantly lower (P=0.003) in KET (37.5%) compared to VEH (87.5%) or KET+MDZ (100%). Similarly, survival time was significantly lower (P=0.004) in KET (115 ± 103 min) compared to VEH (227 ± 37 min) or KET+MDZ (240 ± 0 min). Summary of Results: A sedative dose of KET decreased survival following HEM, but the same dose of KET followed by MDZ was protective. The MDZ effect was not due to improvements in cardiovascular responses to the HEM. Conclusion: Sedation with ketamine alone after trauma and moderate HEM decreased survival. Further studies of the effects of sedation with KET alone or KET+MDZ on respiration and metabolic responses to HEM may provide insight on the overall effect on survival. Congressionally Directed Medical Research Program (CDMRP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

There is a strong association between vitamin D levels and periodontal disease based on numerous epidemiological studies. We have previously shown that experimental deficiency of serum vitamin D in mice leads to gingival inflammation and alveolar bone loss. Treatment of cultured oral epithelial cells with the active form of vitamin D, 1,25(OH)2 vitamin D3 (1,25(OH)2D3), inhibits the extracellular growth and intracellular invasion of bacteria associated with periodontal disease. Maintenance of periodontal health may be due in part to the anti-inflammatory activities of vitamin D. Furthermore, this hormone can induce the expression of an antimicrobial peptide in cultured oral epithelial cells. We have shown that oral epithelial cells are capable of converting inactive vitamin D to the active form, suggesting that topical treatment of the oral epithelium with inactive vitamin D could prevent the development of periodontitis. We subjected mice to ligature-induced periodontitis (LIP), followed by daily treatment with inactive vitamin D or 1,25(OH)2D3. Treatment with both forms led to a reduction in ligature-induced bone loss and inflammation. Gingival tissues obtained from vitamin D-treated LIP showed production of specialized proresolving mediators (SPM) of inflammation. To examine the mechanism, we demonstrated that apical treatment of 3-dimensional cultures of primary gingival epithelial cells with vitamin D prevented lipopolysaccharide-induced secretion of proinflammatory cytokines and led to a similar production of SPM. Analysis of the oral microbiome of the mice treated with vitamin D showed significant changes in resident bacteria, which reflects a shift toward health-associated species. Together, our results show that topical treatment of oral tissues with inactive vitamin D can lead to the maintenance of periodontal health through the regulation of a healthy microbiome and the stimulation of resolution of inflammation. This strongly supports the development of a safe and effective vitamin D-based topical treatment or preventive agent for periodontal inflammation and disease.

The objective of this study was to evaluate whether the presence of radiation injury (RI) decreases survival in an established model of battlefield trauma and hemorrhage in rats. We hypothesized that the addition of radiation to our established traumatic hemorrhage model would increase mortality. Methods: On day zero (D0), male Sprague Dawley rats (n=6/group) received Buprenorphine SR prior to being anesthetized with isoflurane to perform catheterization of a carotid artery. Twenty-four hours later (day 1 or D1), rats were randomly assigned to 1 of 4 groups: 1- sham (no injury; no radiation); 2- RI only; 3- traumatic hemorrhage alone (ET+HEM); or 4- RI combined with traumatic hemorrhage (RI+ET+HEM). For RI and RI+ET+HEM groups, rats were anesthetized and placed inside a cabinet X-ray irradiator (MultiRad 350, Precision, CT) to receive a single sub-lethal X-ray dose of 5.5 Gy, delivered at 1 Gy/min, to induce acute radiation injury. For ET+HEM and RI+ET+HEM groups, under isoflurane, rat then received a unilateral extremity trauma injury. After 90 minutes, a conscious hemorrhage of 37% of the rat estimated blood volume was withdrawn. Rats were monitored for 14 days following injury or sham procedures and provided Buprenorphine SR as needed for pain. Rats remained un-resuscitated and renal function was assessed in vivo by glomerular filtration rate (GFR). GFR was measured with a probe non-invasively and securely strapped to the belly of the rat for about 2.5h. Samples for GFR were collected on D1, day 3 (D3), and day 15 (D15) (or terminal day) from the injury. Result: Sham rats had 100% survival at D15, while RI and ET+HEM rats both had 50% mortality. RI+ET+HEM rats, however, demonstrated 100% mortality by D15; differences in survival proportions were significant (P=0.005). Sham rats showed no significant decrease in GFR (1.0-1.2 ml/min/100g) from D1 to D15. Rats from RI group showed a slight decrease in GFR from D1 to D3 (1.2 to 0.9 ml/min/100g, respectively) at the D3 of measurement. By D15, GFR was 33% lower than D1 in RI group. ET+HEM group showed significant decline in GFR on D1 and D3. However, RI+ET+HEM group showed the most significant decline in GFR ( i.e., >50% lower than sham group on D1 and D3), with little to no improvement over time. Conclusion: We developed a new rodent model of RI+ET+HEM by combining high dose of X-ray irradiation with traumatic hemorrhage, which allows acute (hours) as well as chronic (days) observation. While RI or ET+HEM alone produced significant mortality, the combination of traumatic hemorrhage with RI increased mortality to 100% before D15. Radiation injury combined with extremity trauma and hemorrhage results in significant impairment of renal function. Extremity trauma and hemorrhage impaired renal function more than radiation injury alone. Disclaimer: The views expressed in this abstract are those of the author(s) and do not reflect the offcial policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or the U.S. Government. Supported by Biomedical Advanced Research and Development Authority (BARDA). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BACKGROUND Advances in tourniquet development must meet new military needs for future large-scale combat operations or civilian mass casualty scenarios. This includes the potential use of engineering and automation technologies to provide advanced tourniquet features. A comprehensive set of design capabilities and requirements for an intelligent or smart tourniquet needed to meet the challenges currently does not exist. The goal of this project was to identify key features and capabilities that should be considered for the development of next-generation tourniquets. METHODS We used a modified Delphi consensus technique to survey a panel of 34 tourniquet subject matter experts to rate various statements and potential design characteristics relevant to tourniquets systems and their use scenarios. Three iterative rounds of surveys were held, followed by virtual working group meetings, to determine importance or agreement with any given statement. We used a tiered consensus system to determine final agreement over key features that were viewed as important or unimportant features or capabilities. This information was used to refine and clarify the necessary tourniquet design features and adjust questions for the following surveys. RESULTS Key features and capabilities of various were agreed upon by the panelists when consensus was reached. Some tourniquet features that were agreed upon included but are not limited to: Capable of being used longer than 2 hours, applied and monitored by anyone, data displays, semiautomated capabilities with inherent overrides, automated monitoring with notifications and alerts, and provide recommended actions. CONCLUSION We were able to identify key tourniquet features that will be important for future device development. These consensus results can guide future inventors, researchers, and manufacturers to develop a portfolio of next-generation tourniquets for enhancing the capabilities of a prehospital medical provider. LEVEL OF EVIDENCE Prognostic and Epidemiological; Level V.

INTRODUCTION:Battlefield pain management changed markedly during the first 20 years of the Global War on Terror. Morphine, long the mainstay of combat analgesia, diminished in favor of fentanyl and ketamine for military pain control, but the options are not hemodynamically or psychologically equivalent. Understanding patterns of prehospital analgesia may reveal further opportunities for combat casualty care improvement.MATERIALS AND METHODS:Using Department of Defense Trauma Registry data for the Afghanistan conflict from 2005 to 2018, we examined 2,402 records of prehospital analgesia administration to assess temporal trends in medication choice and proportions receiving analgesia, including subanalysis of a cohort screened for an indication with minimal contraindication for analgesia. We further employed frequency matching to explore the presence of disparities in analgesia by casualty affiliation.RESULTS:Proportions of documented analgesia increased throughout the study period, from 0% in 2005 to 70.6% in 2018. Afghan casualties had the highest proportion of documented analgesia (53.0%), versus U.S. military (31.9%), civilian/other (23.3%), and non-U.S. military (19.3%). Fentanyl surpassed morphine in the frequency of administration in 2012. The median age of those receiving ketamine was higher (30 years) than those receiving fentanyl (26 years) or nonsteroidal anti-inflammatory drugs (23 years). Among the frequency-matched subanalysis, the odds ratio for ketamine administration with Afghan casualties was 1.84 (95% CI, 1.30-2.61).CONCLUSIONS:We observed heterogeneity of prehospital patient care across patient affiliation groups, suggesting possible opportunities for improvement toward an overall best practice system. General increase in documented prehospital pain management likely reflects efforts toward complete documentation, as well as improved options for analgesia. Current combat casualty care documentation does not include any standardized pain scale.

ABSTRACT:A solution of high concentration albumin has been used for temporal volume expansion when timely resuscitation was unavailable after hemorrhagic shock. However, during prolonged hemorrhagic shock, cell edema and interstitial dehydration can occur and impede the volume expansion effect of albumin. Polyethylene glycol-20K (PEG) can establish an osmotic gradient from swollen cells to capillary lumens and thus facilitate capillary fluid shift and volume expansion. We hypothesized that with similar osmolality, 7.5% PEG elicits more rapid and profound compensatory responses after hemorrhagic shock than 25% albumin. Rats were randomized into three groups (n = 8/group) based on treatment: saline (vehicle), PEG (7.5%), and albumin (25%). Trauma was induced in anesthetized rats with muscle injury and fibula fracture, followed by pressure-controlled hemorrhagic shock (MAP = 55 mm Hg) for 45 min. Animals then received an intravenous injection (0.3 mL/kg) of saline, PEG, or albumin. MAP, heart rate, blood gases, hematocrit, skeletal muscle capillary flow, renal blood flow, glomerular filtration rate, urinary flow, urinary sodium concentration, and mortality were monitored for another 2 hours. Polyethylene glycol-20K and albumin both improved MAP, renal and capillary blood flow, and renal oxygen delivery, and decreased hyperkalemia, hyperlactatemia, hematocrit, and mortality (saline: 100% PEG: 12.5%; albumin: 38%) over saline treatment. Compared with albumin, PEG had a more rapid decrease in hematocrit and more profound increases in MAP, diastolic pressure, renal blood flow, glomerular filtration rate, and urinary flow. These results suggest that PEG may be a better option than albumin for prolonged prehospital care of hemorrhagic shock.

In both civilian and military settings, severe hemorrhage rarely occurs in the absence of tissue trauma, yet many animal models for the study of hemorrhage do not include significant tissue trauma. This study using conscious unrestrained rats clearly demonstrates that extremity trauma worsens the probability of survival after a severe hemorrhage. Although no single cardiorespiratory factor accounted for the increased mortality, multiple modest time-related cardiorespiratory responses to the trauma were observed suggesting that their combined dysfunction may have contributed to the reduced survival.

Objective: To determine the impact of analgesic doses of opioids on cardiovascular function and survival time in a severe hemorrhage and extremity trauma rat model. Hypothesis: Using opioids for appropriate pain management, not sedation, will not exacerbate the pathophysiological shock process in a model of polytrauma. Background: Morphine has been doctrinally discarded for use in pain management following battlefield hemorrhage due to its effects on cardiovascular suppression. However, the effects of new opioids, Fentanyl and Sufentanil, on cardiovascular function have yet to be fully described. The current study was conducted to evaluate and compare effects of three opioid analgesics on cardiovascular function and survival after severe hemorrhage in conscious rats in the presence of extremity trauma (ET). Methods: Male rats (n=10/group) were randomly assigned to receive either 0.9% saline (S), 2.0 mg/kg morphine (M), 10 μg/kg fentanyl (F) or 1 μg/kg sufentanil (SuF). Two weeks prior to experimentation, rats were surgically implanted with a telemetry unit to measure mean arterial pressure (MAP) and heart rate (HR). A carotid catheter was then placed. After 24 hours, rats were anesthetized briefly to undergo soft tissue injury and fibula fracture. Rats were allowed to awaken, and 90 min later underwent a conscious hemorrhage (~50% of blood volume). At the end of hemorrhage, rats received one dose of either S, M, F, or SuF via the carotid catheter. Rats were observed for a maximum of 4 hr after the start of hemorrhage. Results: From 70 to 195 min after the end of hemorrhage, there was a significant (p≤0.04) decrease in the MAP of M rats relative to that of V rats, while SuF decreased MAP (p≤0.02) only at t=100, 220 and 240 min. There was no significant effect of treatment on HR (p=0.37) throughout the experiment. Neither survival times (p=0.88) nor percent survival (p=1.0) differed between treatment groups. Conclusions: At the analgesic dose previously shown to ameliorate behavioral indices of pain in rats, both M and SuF depressed blood pressure following severe traumatic hemorrhage. Despite this hypotensive effect, none of the opioids tested decreased survival time or survival rate. Funding disclosure: Applied Pain Research Program, US Army Clinical and Rehabilitative Medicine/Joint Program Committee 8, and US Army Combat Casualty Care Research Program, US Army Medical Research and Development Command. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Multiple analgesics are used for acute pain relief following trauma in both the military and civilian settings. However, in addition to their ability to relieve pain, medical providers must also be concerned about secondary effects of the analgesics, especially effects on the cardiovascular and respiratory systems when the pain of trauma is associated with hemorrhage. Kalyra Pharmaceuticals has developed novel analogs of APAP to circumvent liver toxicity and improve analgesic efficacy. These analogs have the potential to replace opioids for severe pain while minimizing adverse effects. The objective of this study is to test a pain-reducing dose of D-112, an APAP analog, for its effects on survival to hemorrhage after extremity trauma (ET). We hypothesize that D-112 will not affect survival after either moderate or severe hemorrhage. Methods: Male Rats (~360 grams) were randomly assigned to receive either 0.9% saline (V) or 50 mg/kg D-112 (D) after either ~37% or ~50% of blood volume hemorrhage. All rats were surgically implanted with a carotid catheter under anesthesia. Carotid catheters were used for blood withdrawal and for injection of V or D. 24 hrs later, rats were briefly (~10 min) anesthetized again and ET consisting of soft tissue injury (crushing of the right gastrocnemius and semimembranosus muscles for 30 sec with forceps) and fibula fracture was performed. After completion of ET, rats were allowed to recover. 90 min after ET, rats underwent a conscious hemorrhage via the indwelling catheter. At the end of hemorrhage, rats received either V or D via the carotid catheter. Rats were observed for a maximum of 4 hrs after the start of the 25 min hemorrhage. Results: Survival after hemorrhage was recorded in the 4 groups: V-37% (n=13), D-37% (n=11), V-50% (n=10), D-50% (n=11). The survival proportions at 240 min were 92.3% for V-37%, 81.8% for D-37%, 60.0% for V-50%, and 18.1% for D-50%. While there was no significant difference in the survival curves of V-37% and D-37%, the survival curves of V-50% and D-50% were significantly different ( p = 0.036). Conclusions: The analgesic dose of D-112 tested decreased survival after ET and severe hemorrhage (~50% of blood volume), but not after ET and moderate hemorrhage (~37%). These results suggest that D-112 may not be an appropriate analgesic following traumatic hemorrhage. Applied Pain Research Program, US Army Clinical and Rehabilitative Medicine/Joint Program Committee 8, and US Army Combat Casualty Care Research Program, US Army Medical Research and Development Command. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

It is anticipated that both ionizing radiation and traumatic injury may occur simultaneously in future terrorist attacks and battlefield scenarios. However, it is not known how radiation combined with injuries (RCI) will impact physiological compensatory responses to traumatic hemorrhage and survival. We hypothesized that the addition of radiation to our established traumatic hemorrhage model (Klemcke et al., J Appl Physiol 2021) would increase mortality. Male rats (n=6/group) were randomly assigned to 1 of 4 groups: sham (no injury; no radiation); radiation injury (RI) only; traumatic hemorrhage alone (CI); or RI combined with traumatic hemorrhage (RCI). For RI and RCI rats, whole-body irradiation was performed with a single, sub-lethal X-ray dose of 5.5 Gy delivered at 1 Gy/min (MultiRad 350). CI consisted of extremity trauma (fibular fracture + penetrating and soft tissue injury, performed under isoflurane anesthesia) followed by conscious hemorrhage of 37% of blood volume. Rats were monitored for 14 days following injury or sham procedures. Sham rats had 100% survival to Day 14, while RI and CI rats had 50% and 50% mortality, respectively, at this point. RCI rats, however, demonstrated 100% mortality at Day 14; differences in survival proportions were significant (P=0.005). We therefore developed a new rat model of RCI by combining X-ray irradiation with traumatic hemorrhage which allows acute (hours) as well as chronic (days) observations. While RI alone produced significant mortality, the addition of traumatic hemorrhage increased mortality to 100%. Future work will elucidate physiological mechanisms potentiating the lethal effect of either RI or CI alone. Biomedical Advanced Research and Development Authority (BARDA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

A focus of combat casualty care research is to develop treatments for when full resuscitation after hemorrhage is delayed. However, few animal models exist to investigate such treatments. Given the kidney's susceptibility to ischemia, we determined how delayed resuscitation affects renal function in a model of traumatic shock. Rats were randomized into three groups: resuscitation after 1 h (ETH-1) or 2 h (ETH-2) of extremity trauma and hemorrhagic shock, and sham control. ETH was induced in anesthetized rats with muscle injury and fibula fracture, followed by pressure-controlled hemorrhage [mean arterial pressure (MAP) = 55 mmHg] for 1 or 2 h. Rats were then resuscitated with whole blood until MAP stabilized between 90 and 100 mmHg for 30 min. MAP, glomerular filtration rate (GFR), creatinine, blood gases, and fractional excretion of sodium (nFENa+) were measured for 3 days. Compared with control, ETH-1 and ETH-2 exhibited decreases in GFR and nFENa+, and increases in circulating lactate, creatinine, and blood urea nitrogen (BUN) before and within 30 min after resuscitation. The increases in creatinine, BUN, and potassium were greater in ETH-2 than in ETH-1, whereas lactate levels were similar between ETH-1 and ETH-2 before and after resuscitation. All measurements were normalized in ETH-1 within 2 days after resuscitation, with 22% mortality. However, ETH-2 exhibited a prolonged impairment of GFR, increased nFENa+, and a 66% mortality. Resuscitation 1 h after injury therefore preserves renal function, whereas further delay of resuscitation irreversibly impairs renal function and increases mortality. This animal model can be used to explore treatments for prolonged prehospital care following traumatic hemorrhage.NEW & NOTEWORTHY A focus of combat casualty care research is to develop treatment where full resuscitation after hemorrhage is delayed. However, animal models of combat-related hemorrhagic shock in which to determine physiological outcomes of such delays and explore potential treatment for golden hour extension are lacking. In this study, we filled this knowledge gap by establishing a traumatic shock model with reproducible development of AKI and shock-related complications determined by the time of resuscitation.

Tracheal intubation is the preferred method of airway management, a common emergency trauma medicine problem. Currently, methods for confirming tracheal tube placement are lacking, and we propose a novel technology, spectral reflectance, which may be incorporated into the tracheal tube for verification of placement. Previous work demonstrated a unique spectral profile in the trachea, which allowed differentiation from esophageal tissue in ex vivo swine, in vivo swine, and human cadavers. The goal of this study is to determine if spectral reflectance can differentiate between trachea and other airway tissues in living humans and whether the unique tracheal spectral profile persists in the presence of an inhalation injury. Reflectance spectra were captured using a custom fiber-optic probe from the buccal mucosa, posterior oropharynx, and trachea of healthy humans intubated for third molar extraction and from the trachea of patients admitted to a burn intensive care unit with and without inhalation injury. Using ratio comparisons, we found that the tracheal spectral profile was significantly different from buccal mucosa or posterior oropharynx, but the area under the curve values are not high enough to be used clinically. In addition, inhalation injury did not significantly alter the spectral reflectance of the trachea. Further studies are needed to determine the utility of this technology in a clinical setting and to develop an algorithm for tissue differentiation.