Comparing the Effects of Low-Dose Ketamine, Fentanyl, and Morphine on Hemorrhagic Tolerance and Analgesia in Humans.

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73-139], fentanyl (n = 28): 95 [68-130], morphine (n = 30): 62 [35-85]; values expressed as a % of the respective placebo trial's CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R2=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

Effects of extremity trauma on physiological responses to hemorrhage in conscious rats.

Although physiological responses to hemorrhage are well-studied, hemorrhage is often accompanied by trauma, and it remains unclear how injury affects these responses. This study examined effects of extremity trauma on cardiorespiratory responses and survival to moderate (37%; H-37) or severe (50%; H-50) hemorrhage in rats. Transmitter and carotid catheter implantation and extremity trauma (fibular fracture and muscle injury) were conducted 2 wk, 24 h, and 90 min, respectively, before conscious hemorrhage. Mean arterial pressure (MAP) and heart rate (HR; via telemetry), and respiration rate (RR), minute volume (MV), and tidal volume (TV; via plethysmography) were measured throughout the 25 min hemorrhage and remainder of the 4 h observation period. There were four groups: 1) H-37, no trauma (NT; n = 17); 2) H-37, extremity trauma (T, n = 18); 3) H-50, NT (n = 20); and 4) H-50, T (n = 20). For H-37, during and after hemorrhage, T increased HR (P ≤ 0.031) and MV (P ≤ 0.048) compared with NT rats. During H-50, T increased HR (0.041) and MV (P = 0.043). After hemorrhage, T increased MV (P = 0.008) but decreased HR (P = 0.007) and MAP (P = 0.039). All cardiorespiratory differences between T and NT groups were intermittent. Importantly, both survival time (159.8 ± 78.2 min vs. 211.9 ± 60.3 min; P = 0.022; mean ± SD) and percent survival (45% vs. 80%; P = 0.048) were less in T versus NT rats after H-50. Trauma interacts with physiological systems in a complex manner and no single cardiorespiratory measure was sufficiently altered to indicate that it alone could account for increased mortality after H-50.NEW & NOTEWORTHY 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.

Patterns of Palliation: A Review of Casualties That Received Pain Management Before Reaching Role 2 in Afghanistan.

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.

A novel animal model to study delayed resuscitation following traumatic hemorrhage.

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.

Low-dose morphine reduces pain perception and blood pressure, but not muscle sympathetic outflow, responses during the cold pressor test.

Our knowledge about how low-dose (analgesic) morphine affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose morphine affects human autonomic cardiovascular responses during painful stimuli in conscious humans. Therefore, we tested the hypothesis that low-dose morphine reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-nine participants (14 females/15 males; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ∼0.4°C ice bath for 2 min) before and ∼35 min after drug/placebo administration (5 mg iv morphine or saline). We compared pain perception (100 mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography; 14 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo time points) using paired, two-tailed t tests. Before drug/placebo infusion, perceived pain (P = 0.92), ΔMSNA burst frequency (n = 14, P = 0.21), and Δmean BP (P = 0.39) during the CPT were not different between trials. After the drug/placebo infusion, morphine versus placebo attenuated perceived pain (morphine: 43 ± 20 vs. placebo: 57 ± 24 mm, P < 0.001) and Δmean BP (morphine: 10 ± 7 vs. placebo: 13 ± 8 mmHg, P = 0.003), but not ΔMSNA burst frequency (morphine: 10 ± 11 vs. placebo: 13 ± 11 bursts·min-1, P = 0.12), during the CPT. Reductions in pain perception and Δmean BP were only weakly related (r = 0.34, P = 0.07; postmorphine CPT minus postplacebo CPT). These data provide valuable information regarding how low-dose morphine affects autonomic cardiovascular responses during an experimental painful stimulus.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that low-dose morphine administration reduced pain perception and blood pressure responses during the cold pressor test via attenuated increases in heart rate and cardiac output. We also determined that muscle sympathetic outflow responses during the cold pressor test seem to be unaffected by low-dose morphine administration. Finally, our exploratory analysis suggests that biological sex does not influence morphine-induced antinociception in healthy adults.

Low-dose morphine reduces tolerance to central hypovolemia in healthy adults without affecting muscle sympathetic outflow.

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Low-dose (i.e., an analgesic dose) morphine is recommended for use in the prehospital (i.e., field) setting. Morphine administration reduces hemorrhagic tolerance in rodents. However, it is unknown whether morphine impairs autonomic cardiovascular regulation and consequently reduces hemorrhagic tolerance in humans. Thus, the purpose of this study was to test the hypothesis that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thirty adults (15 women/15 men; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, double-blinded, placebo-controlled trial. One minute after intravenous administration of morphine (5 mg) or placebo (saline), we used a presyncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (mmHg·min), which was compared between trials using a Wilcoxon matched-pairs signed-rank test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat blood pressure (photoplethysmography) during the LBNP test using mixed-effects analyses [time (LBNP stage) × trial]. Median LBNP tolerance was lower during morphine trials (placebo: 692 [473-997] vs. morphine: 385 [251-728] mmHg·min, P < 0.001, CI: -394 to -128). Systolic blood pressure was 8 mmHg lower during moderate central hypovolemia during morphine trials (post hoc P = 0.02; time: P < 0.001, trial: P = 0.13, interaction: P = 0.006). MSNA burst frequency responses were not different between trials (time: P < 0.001, trial: P = 0.80, interaction: P = 0.51). These data demonstrate that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that tolerance to simulated hemorrhage was lower after low-dose morphine administration. Such reductions in hemorrhagic tolerance were observed without differences in MSNA burst frequency responses between morphine and placebo trials. These data, the first to be obtained in conscious humans, demonstrate that low-dose morphine reduces hemorrhagic tolerance. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.

Pathophysiology of Hemorrhage as It Relates to the Warfighter.

Saving lives of wounded military warfighters often depends on the ability to resolve or mitigate the pathophysiology of hemorrhage, specifically diminished oxygen delivery to vital organs that leads to multiorgan failure and death. However, caring for hemorrhaging patients on the battlefield presents unique challenges that extend beyond applying a tourniquet and giving a blood transfusion, especially when battlefield care must be provided for a prolonged period. This review describes these challenges and potential strategies for treating hemorrhage on the battlefield in a prolonged casualty care situation.

Low-dose fentanyl reduces pain perception, muscle sympathetic nerve activity responses, and blood pressure responses during the cold pressor test.

Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10 females/13 males; 27 ± 7 yr; 26 ± 3 kg·m-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ∼0.4°C ice bath for 2 min) before and 5 min after drug/placebo administration (75 µg fentanyl or saline). We compared pain perception (100-mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo timepoints) using paired, two-tailed t tests. Before drug/placebo administration, perceived pain (P = 0.8287), ΔMSNA burst frequency (P = 0.7587), and Δmean BP (P = 0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, P < 0.0001), ΔMSNA burst frequency (9 vs. 17 bursts/min, P = 0.0054), and Δmean BP (7 vs. 13 mmHg, P = 0.0174) during the CPT compared with placebo. Fentanyl-induced reductions in pain perception and Δmean BP were moderately related (r = 0.40, P = 0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.

Extremity trauma exacerbates acute kidney injury following prolonged hemorrhagic hypotension.

BACKGROUND: The incidence of and mortality due to acute kidney injury is high in patients with traumatic shock. However, it is unclear how hemorrhage and trauma synergistically affect renal function, especially when timely volume resuscitation is not available. METHOD: We hypothesized that trauma impairs renal tolerance to prolonged hemorrhagic hypotension. Sprague-Dawley rats were randomized into six groups: control, extremity trauma (ET), hemorrhage at 70 mm Hg (70-H), hemorrhage at 55 mm Hg (55-H), ET + 70 mm Hg (70-ETH), and ET + 55 mm Hg (55-ETH). Animals were anesthetized, and ET was induced via soft tissue injury and closed fibula fracture. Hemorrhage was performed via catheters 5 minutes after ET with target mean arterial pressure (MAP) clamped at 70 mm Hg or 55 mm Hg for up to 3 hours. Blood and urine samples were collected to analyze plasma creatinine (Cr), Cr clearance (CCr), renal oxygen delivery (DO2), urinary albumin, and kidney injury molecule-1 (KIM-1). RESULTS: Extremity trauma alone did not alter renal hemodynamics, DO2, or function. In 70-H, CCr was increased following hemorrhage, while Cr, renal vascular resistance (RVR), KIM-1, and albumin levels remained unchanged. Compared with 70-H, ET + 70 mm Hg exhibited increases in Cr and RVR with decreases in CCr and DO2. In addition, ET decreased the blood volume loss required to maintain MAP = 70 mm Hg by approximately 50%. Hemorrhage at 55 mm Hg and ET + 55 mm Hg exhibited a marked and similar decrease in CCr and increases in RVR, Cr, KIM-1, and albumin. However, ET greatly decreased the blood volume loss required to maintain MAP at 55 mm Hg and led to 50% mortality. CONCLUSION: These results suggest that ET impairs renal and systemic tolerance to prolonged hemorrhagic hypotension. Thus, traumatic injury should be considered as a critical component of experimental studies investigating outcomes and treatment following hemorrhagic shock. LEVEL OF EVIDENCE: This is an original article on basic science and does not require a level of evidence.

Effects of ketamine analgesia on cardiorespiratory responses and survival to trauma and hemorrhage in rats.

Ketamine is the recommended analgesic on the battlefield for soldiers with hemorrhage, despite a lack of supportive evidence from laboratory or clinical studies. Hence, this study determined the effects of ketamine analgesia on cardiorespiratory responses and survival to moderate (37% blood volume; n = 8/group) or severe hemorrhage (50% blood volume; n = 10/group) after trauma in rats. We used a conscious hemorrhage model with extremity trauma (fibular fracture + soft tissue injury) while measuring mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) by telemetry, and respiration rate (RR), minute volume (MV), and tidal volume (TV) via whole body plethysmography. Male rats received saline (S) or 5.0 mg/kg ketamine (K) (100 µL/100 g body wt) intra-arterially after trauma and hemorrhage. All rats survived 37% hemorrhage. For 50% hemorrhage, neither survival times [180 min (SD 78) vs. 209 min (SD 66)] nor percent survival (60% vs. 80%) differed between S- and K-treated rats. After 37% hemorrhage, K (compared with S) increased MAP and decreased Tb and MV. After 50% hemorrhage, K (compared with S) increased MAP but decreased HR and MV. K effects on cardiorespiratory function were time dependent, significant but modest, and transient at the analgesic dose given. K effects on Tb were also significant but modest and more prolonged. With the use of this rat model, our data support the use of K as an analgesic in injured, hypovolemic patients.NEW & NOTEWORTHY Ketamine administration at a dose shown to alleviate pain in nonhemorrhaged rats with extremity trauma had only modest and transient effects on multiple aspects of cardiorespiratory function after both moderate (37%) and severe (50%) traumatic hemorrhages. Such effects did not alter survival.

Low dose ketamine reduces pain perception and blood pressure, but not muscle sympathetic nerve activity, responses during a cold pressor test.

KEY POINTS: Low dose ketamine is a leading medication used to provide analgesia in pre-hospital and hospital settings. Low dose ketamine is increasingly used off-label to treat conditions such as depression. In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans. Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans. These mechanistic, physiological results inform risk-benefit analysis for clinicians administering low dose ketamine in humans. ABSTRACT: Low dose ketamine is an effective analgesic medication. However, our knowledge of the effects of ketamine on autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low dose ketamine influences autonomic cardiovascular responses during painful stimuli in humans. We tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. Twenty-two adults (10F/12M; 27 ± 6 years; 26 ± 3 kg m-2 , mean ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed cold pressor tests (CPT; hand in ∼0.4°C ice bath for 2 min) pre- and 5 min post-drug administration (20 mg ketamine or saline). We compared pain perception (100 mm visual analogue scale), muscle sympathetic nerve activity (MSNA; microneurography, 12 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) during the pre- and post-drug CPTs separately using paired, two-tailed t tests. For the pre-drug CPT, perceived pain (P = 0.4378), MSNA burst frequency responses (P = 0.7375), and mean BP responses (P = 0.6457) were not different between trials. For the post-drug CPT, ketamine compared to placebo administration attenuated perceived pain (P < 0.0001) and mean BP responses (P = 0.0047), but did not attenuate MSNA burst frequency responses (P = 0.3662). Finally, during the post-drug CPT, there was a moderate relation between cardiac output and BP responses after placebo administration (r = 0.53, P = 0.0121), but this relation was effectively absent after ketamine administration (r = -0.12, P = 0.5885). These data suggest that low dose ketamine administration attenuates perceived pain and pressor, but not MSNA burst frequency, responses during a CPT.

Low-dose ketamine affects blood pressure, but not muscle sympathetic nerve activity, during progressive central hypovolemia without altering tolerance.

KEY POINTS: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. ABSTRACT: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20 mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage] × drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360 mmHg‧min, p = 0.77). Increases in MSNA burst frequency (time: P < 0.01, trial: p = 0.27, interaction: p = 0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P < 0.01, trial: P < 0.01, interaction: p = 0.01) and heart rate (time: P < 0.01, trial: P < 0.01, interaction: P < 0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P < 0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.

Similar hemostatic responses to hypovolemia induced by hemorrhage and lower body negative pressure reveal a hyperfibrinolytic subset of non-human primates.

BACKGROUND: To study central hypovolemia in humans, lower body negative pressure (LBNP) is a recognized alternative to blood removal (HEM). While LBNP mimics the cardiovascular responses of HEM in baboons, similarities in hemostatic responses to LBNP and HEM remain unknown in this species. METHODS: Thirteen anesthetized baboons were exposed to progressive hypovolemia by HEM and, four weeks later, by LBNP. Hemostatic activity was evaluated by plasma markers, thromboelastography (TEG), flow cytometry, and platelet aggregometry at baseline (BL), during and after hypovolemia. RESULTS: BL values were indistinguishable for most parameters although platelet count, maximal clot strength (MA), protein C, thrombin anti-thrombin complex (TAT), thrombin activatable fibrinolysis inhibitor (TAFI) activity significantly differed between HEM and LBNP. Central hypovolemia induced by either method activated coagulation; TEG R-time decreased and MA increased during and after hypovolemia compared to BL. Platelets displayed activation by flow cytometry; platelet count and functional aggregometry were unchanged. TAFI activity and protein, Factors V and VIII, vWF, Proteins C and S all demonstrated hemodilution during HEM and hemoconcentration during LBNP, whereas tissue plasminogen activator (tPA), plasmin/anti-plasmin complex, and plasminogen activator inhibitor-1 did not. Fibrinolysis (TEG LY30) was unchanged by either method; however, at BL, fibrinolysis varied greatly. Post-hoc analysis separated baboons into low-lysis (LY30 <2%) or high-lysis (LY30 >2%) whose fibrinolytic state matched at both HEM and LBNP BL. In high-lysis, BL tPA and LY30 correlated strongly (r = 0.95; P<0.001), but this was absent in low-lysis. In low-lysis, BL TAFI activity and tPA correlated (r = 0.88; P<0.050), but this was absent in high-lysis. CONCLUSIONS: Central hypovolemia induced by either LBNP or HEM resulted in activation of coagulation; thus, LBNP is an adjunct to study hemorrhage-induced pro-coagulation in baboons. Furthermore, this study revealed a subset of baboons with baseline hyperfibrinolysis, which was strongly coupled to tPA and uncoupled from TAFI activity.

Fentanyl impairs but ketamine preserves the microcirculatory response to hemorrhage.

BACKGROUND: Peripheral vasoconstriction is the most critical compensating mechanism following hemorrhage to maintain blood pressure. On the battlefield, ketamine rather than opioids is recommended for pain management in case of hemorrhage, but effects of analgesics on compensatory vasoconstriction are not defined. We hypothesized that fentanyl impairs but ketamine preserves the peripheral vasoconstriction and blood pressure compensation following hemorrhage. METHOD: Sprague-Dawley rats (11-13 weeks) were randomly assigned to control (saline vehicle), fentanyl, or ketamine-treated groups with or without hemorrhage (n = 8 or 9 for each group). Rats were anesthetized with Inactin (i.p. 10 mg/100 g), and the spinotrapezius muscles were prepared for microcirculatory observation. Arteriolar arcades were observed with a Nikon microscope, and vessel images and arteriolar diameters were recorded by using Nikon NIS Elements Imaging Software (Nikon Instruments Inc. NY). After baseline perimeters were recorded, the arterioles were topically challenged with saline, fentanyl, or ketamine at concentrations relevant to intravenous analgesic doses to determine direct vasoactive effects. After arteriolar diameters returned to baseline, 30% of total blood volume was removed in 25 minutes. Ten minutes after hemorrhage, rats were intravenously injected with an analgesic dose of fentanyl (0.6 µg/100 g), ketamine (0.3 mg/100 g), or a comparable volume of saline. For each drug or vehicle administration, the total volume injected was 0.1 mL/100 g. Blood pressure, heart rate, and arteriolar responses were monitored for 40 minutes. RESULTS: Topical fentanyl-induced vasodilation (17 ± 2%), but ketamine caused vasoconstriction (-15 ± 4%, p < 0.01). Following hemorrhage, intravenous ketamine did not affect blood pressure or respiratory rate, while fentanyl induced a slight and transient (<5 minutes, p = 0.03 vs. saline group) decrease in blood pressure, with a profound and prolonged suppression in respiratory rate (>10 minutes, with a peak inhibition of 57 ± 8% of baseline, p < 0.01). The compensatory vasoconstriction observed after hemorrhage was not affected by ketamine treatment. However, after fentanyl injection, although changes in blood pressure were transiently present, arteriolar constriction to hemorrhage was absent and replaced with a sustained vasodilation (78 ± 25% to 36 ± 22% of baseline during the 40 minutes after injection, p < 0.01). CONCLUSION: Ketamine affects neither systemic nor microcirculatory compensatory responses to hemorrhage, providing preclinical evidence that ketamine may help attenuate adverse physiological consequences associated with opioids following traumatic hemorrhage. Microcirculatory responses are more sensitive than systemic response for evaluation of hemodynamic stability during procedures associated with pain management.

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.

Dexamethasone Causes Hypertension in Rats Even Under Chemical Blockade of Peripheral Sympathetic Nerves.

Synthetic glucocorticoids (GCs) are widely used to treat inflammatory conditions. However, chronic use of GCs can lead to hypertension. The cause of this undesired side effect remains unclear. Previously, we developed an in vivo rat model to study the mechanisms underlying hypertension induced by the chronic administration of the potent synthetic GC, dexamethasone (DEX) and found that the catecholamine biosynthetic pathway plays an important role. In the current study, we used this model to investigate the role of the adrenal medulla, renal nerves, and other peripheral sympathetic nerves in DEX-induced hypertension. After 5 days of baseline telemetric recording of mean arterial pressure (MAP) and heart rate (HR), rats were subjected to one of the following treatments: renal denervation (RDNX), adrenal medullectomy (ADMX), 6-hydroxydopamine (6-OHDA, 20 mg/kg, i.p.) to induce chemical sympathectomy, or a combination of ADMX and 6-OHDA. On day 11, the animals received vehicle (VEH) or DEX in drinking water for 7 days, with the latter causing an increase in MAP in control animals. ADMX and RDNX by themselves exacerbated the pressor effect of DEX. In the chemical sympathectomy group, DEX still caused a rise in MAP but the response was lower (ΔMAP of 6-OHDA/DEX < VEH/DEX, p = 0.039). However, when ΔMAP was normalized to day 10, 6-OHDA + DEX did not show any difference from VEH + DEX, certainly not an increase as observed in DEX + ADMX or RDNX groups. This indicates that sympathetic nerves do not modulate the pressor effect of DEX. TH mRNA levels increased in the adrenal medulla in both VEH/DEX (p = 0.009) and 6-OHDA/DEX (p = 0.031) groups. In the 6-OHDA group, DEX also increased plasma levels of norepinephrine (NE) (p = 0.016). Our results suggest that the activation of catecholamine synthetic pathway could be involved in the pressor response to DEX in animals even under chemical sympathectomy with 6-OHDA.

Indices of muscle and liver dysfunction after surviving hemorrhage and prolonged hypotension.

BACKGROUND: This study determined the long-term effects of prolonged hypotension (PH) on liver, muscle, and kidney dysfunction. The hypothesis was that longer duration of PH after hemorrhage will result in greater organ dysfunction. METHODS: Baboons were sedated and hemorrhaged (30% blood volume). Systolic blood pressure greater than 80 mm Hg was maintained for 1 hour (1 hr-PH; n = 5), 2 hours (2 hr-PH; n = 5), or 3 hours (3 hr-PH; n = 5). After PH, hemorrhage volume was replaced. Animals were recovered and monitored for 21 days. Control animals were hemorrhaged and immediately resuscitated (0 hr-PH, n = 3). Data are Mean ± Standard Deviation, and analyzed by 2-way repeated measures ANOVA and Holm-Sidak test. RESULTS: Hemorrhage resulted in mild hypotension. Minimal resuscitation was required during the hypotensive phase, and survival rate was 100%. Significant increases (p < 0.001) in alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, and lactate dehydrogenase occurred on Day 1 after PH, and were significantly greater (p < 0.001) in the 2 hr- and 3 hr-PH groups than the 0 hr-PH group. Maximum alanine aminotransferase levels (U/L) were 140 ± 56 (0 hr-PH), 170 ± 130 (1 hr-PH), 322 ± 241 (2 hr-PH), and 387 ± 167 (3 hr-PH). Maximum aspartate aminotransferase levels (U/L) were 218 ± 44 (0 hr-PH), 354 ± 219 (1 hr-PH), 515 ± 424 (2 hr-PH), and 711 ± 278 (3 hr-PH). Maximum creatine phosphokinase values (U/L) were 7834 ± 3681 (0 hr-PH), 24336 ± 22268 (1 hr-PH), 50494 ± 67653 (2 hr-PH), and 59857 ± 32408 (3 hr-PH). Maximum lactic acid dehydrogenase values (U/L) were 890 ± 396 (0 hr-PH), 2055 ± 1520 (1 hr-PH), 3992 ± 4895 (2 hr-PH), and 4771 ± 1884 (3 hr-PH). Plasma creatinine and blood urea nitrogen were unaffected by PH (p > 0.10). CONCLUSION: These results indicate that PH up to 3 hours in duration results in transient liver and muscle dysfunction that was most severe after 2 hr-PH and 3 hr-PH. Prolonged hypotension produced minimal effects on the kidney. LEVEL OF EVIDENCE: Basic science research, Level of evidence not required for basic science research.

Capacity to Compensate for Central Hypovolemia and Effects of Menstrual Cycle Phases.

BACKGROUND: Tolerance to central hypovolemia is dictated by exhaustion of the physiological capacity to compensate called the compensatory reserve. Such physiological compromise can have detrimental impact on performance in aerospace environments as well as survival from hemorrhage on the battlefield. We induced central hypovolemia using progressively stepwise lower body negative pressure (LBNP) in women during various phases of the menstrual cycle to test the hypothesis that similar tolerance across all menstrual cycle phases would be reflected by similar changes in compensatory reserve.METHODS: Based on self-reporting of the last menstrual period, 40 healthy women, matched by demographics, were classified into 1 of 5 menstrual cycle phases: early follicular (EF, Days 1-7; N = 10), late follicular and ovulatory (LF, Days 9-15, N = 6), early luteal (EL, Days 16-18, N = 6), midluteal (ML, Days 19-25, N = 8), and late luteal (LL, Days 26-30, N = 10). All subjects had a 28-30 d menstrual cycle and were not taking oral contraceptives. Tolerance to central hypovolemia was measured as time (seconds) from baseline to the onset of presyncopal symptoms induced by LBNP.RESULTS: Time to presyncope as well as hemodynamic and compensatory reserve responses were statistically indistinguishable across all menstrual cycle phases.DISCUSSION: Consistent with our hypothesis, compensatory reserve with associated hemodynamic responses and tolerance to central hypovolemia was not affected by menstrual cycle phases. Our findings indicate experimental comparisons of responses to central hypovolemia involving the participation of healthy women with normal menstrual cycles and not taking oral contraceptives can be conducted independent of menstrual cycle phase.Convertino VA, Schlotman TE, Stacey W, Hinojosa-Laborde C. Capacity to compensate for central hypovolemia and effects of menstrual cycle phases. Aerosp Med Hum Perform. 2019; 90(4):378-383.

Trends in Prehospital Analgesia Administration by US Forces From 2007 Through 2016.

BACKGROUND: Tactical Combat Casualty Care (TCCC) guidelines regarding prehospital analgesia agents have evolved. The guidelines stopped recommending intramuscular (IM) morphine in 1996, recommending only intravenous (IV) routes. In 2006, the guidelines recommended oral transmucosal fentanyl citrate (OTFC), and in 2012 it added ketamine via all routes. It remains unclear to what extent prehospital analgesia administered on the battlefield adheres to these guidelines. We seek to describe trends in analgesia administration patterns on the battlefield during 2007-2016. METHODS: This is a secondary analysis of a Department of Defense Trauma Registry data set from January 2007 to August 2016. Within that group, we searched for subjects who received IM morphine, IV morphine, OTFC, parenteral fentanyl, or ketamine (all routes). RESULTS: Our predefined ED search codes captured 28,222 subjects during the study period. Of these, 594 (2.1%) received IM morphine; 3,765 (13.3%) received IV morphine; 589 (2.1%) received OTFC; and 1,510 (5.4%) subjects received ketamine. Annual rates of administration of IM morphine were relatively stable during the study period, while those for OTFC and ketamine generally trended upward starting in 2012. In particular, the proportion of subjects receiving ketamine rose from 3.9% (n = 995/25,618) during the study period preceding its addition to the TCCC guidelines (2007 to 2012) to 19.8% thereafter (2013-2016, n = 515/2,604, p < 0.001). CONCLUSIONS: During the study period, rates of prehospital administration of IM morphine remained relatively stable while those for OTFC and ketamine both rose. These findings suggest that TCCC guidelines recommending the use of these agents had a material impact on prehospital analgesia patterns.

Time course of compensatory physiological responses to central hypovolemia in high- and low-tolerant human subjects.

Lower body negative pressure (LBNP) simulates hemorrhage in human subjects. Most subjects (67%) exhibited high tolerance (HT) to hypovolemia, while the remainder (33%) had low tolerance (LT). To investigate the mechanisms for decompensation to central hypovolemia in HT and LT subjects, we characterized the time course of total peripheral resistance (TPR), heart rate (HR), and muscle sympathetic nerve activity (MSNA) during LBNP to tolerance determined by the onset of decompensation (presyncope, PS). We hypothesized that 1) maximum (Max) TPR, HR, and MSNA would coincide, and 2) PS would result from simultaneous decreases in TPR, HR, and MSNA in LT and HT subjects but occur earlier in LT than in HT subjects. Max TPR was lower and occurred earlier in LT ( n = 59) than in HT ( n = 113) subjects (LT: 24 ± 1 mmHg·min·1-1 at 756 ± 31 s; HT: 28 ± 1 mmHg·min·1-1 at 1,265 ± 37 s, P < 0.01). Max TPR occurred several minutes before PS. During subsequent decrease in TPR, HR and MSNA continued to increase. Max HR (LT: 111 ± 2 beat/min at 923 ± 27 s; HT: 130 ± 2 beats/min at 1489 ± 23 s, P < 0.01) occurred several seconds before PS. Higher MSNA ( P < 0.01) was attained in HT ( n = 10; 51 ± 5 bursts/min at max TPR; 54 ± 5 bursts/min at max HR) than LT subjects ( n = 4; 41 ± 8 bursts/min at max TPR; 39 ± 8 bursts/min at max HR). The onset of cardiovascular decompensation is a biphasic process in which vasodilation occurs before bradycardia and sympathetic withdrawal. This pattern was similar in LT and HT but occurred earlier in LT subjects. We conclude that sudden bradycardia plays a critical role in the determination of tolerance to central hypovolemia.