Kathy L. Ryan

Hemostatic Efficacy of Two Advanced Dressings in an Aortic Hemorrhage Model in Swine

BACKGROUND An effective hemostatic agent capable of stopping severe arterial bleeding and sustaining hemostasis over a prolonged time is required. The U.S. Army recently distributed fibrin sealant (under an Investigational New Drug-approved protocol) and chitosan dressings among deployed medics for treating severe external hemorrhage on the battlefield. The purpose of this study was to evaluate the efficacy of these dressings, as compared with the standard gauze army field dressing, to provide initial and sustained hemostasis up to 96 hours in a lethal uncontrolled arterial hemorrhage model. METHODS Anesthetized pigs were splenectomized and chronically instrumented for fluid/drug administration and continuous monitoring of vital signs. An infrarenal aortotomy was created using a 4.4-mm aortic hole punch and free bleeding was allowed for 5 seconds. While bleeding profusely, a dressing was applied and pressed into the wound for 4 minutes (occluding the distal flow) and then released. If hemostasis was not obtained, the dressing was replaced with a new one (maximum, two dressings per experiment) with another 4-minute compression. If hemostasis was achieved, the abdomen was closed; the animal was then recovered and monitored up to 96 hours. Initial hemostasis, duration of hemostasis, survival time, blood loss, and other variables were measured. RESULTS Application of army field dressing (gauze) did not stop the arterial hemorrhage and led to exsanguination of all the pigs (n = 6) within 10 to 15 minutes of the injury. Chitosan dressing produced initial hemostasis in five of seven pigs. However, the dressings failed to maintain hemostasis for more than 1.6 hours (range, 28-102 minutes), resulting in secondary bleeding and death of the animals. Fibrin sealant dressing produced initial hemostasis in all the pigs (n = 6) and maintained hemostasis in five cases, with one failure at 2.2 hours. These pigs resumed normal activities and lived for the 96-hour experiment duration. Computed tomographic images and histologic sections of the aortas from surviving fibrin sealant dressing-treated animals showed formation of pseudoaneurysms and early granulation tissue at the aortotomy site. The posttreatment blood loss, duration of hemostasis, and survival time were significantly different in the fibrin sealant dressing group than the chitosan dressing and army field dressing groups. CONCLUSION Both chitosan dressing and fibrin sealant dressing stopped initial arterial bleeding that could not be controlled by the standard army field dressing. However, although the fibrin sealant dressing secured hemostasis for up to 4 days, the chitosan dressing consistently failed within 2 hours after application. There may be a risk of rebleeding for high-pressure arterial wounds treated with chitosan dressings, particularly in situations where definitive care is delayed substantially.

Application of a Granular Mineral-Based Hemostatic Agent (QuikClot) to Reduce Blood Loss After Grade V Liver Injury in Swine

BACKGROUND Uncontrolled hemorrhage is a leading cause of death in cases of trauma. Many products currently are under development to control traumatic bleeding. One such Food and Drug Administration (FDA)-approved product is QuikClot. This study determined the efficacy of QuikClot, a hemostatic agent, in reducing blood loss and mortality in a standardized model of severe liver injury as well as the consequences of its use. METHODS Swine received either QuikClot or gauze treatment after induction of grade V liver injuries. Hemostasis, blood loss, resuscitation volume, 60-minute survival, and peak tissue temperatures were measured. RESULTS Hemostasis was improved with QuikClot (p < 0.05), and resuscitation volume was consequently reduced (p < 0.05). Posttreatment blood loss was reduced (p < 0.01) with QuikClot (1,397 mL), as compared with gauze (5,338 mL). The survival rate was seven of eight in the QuikClot group and one of eight in the gauze group (p < 0.01). Peak temperature at the tissue interface was increased (p < 0.01) with QuikClot (93.3 +/- 10.5 degrees C), as compared with gauze (37.5 +/- 6.5 degrees C). QuikClot use was associated with both macro- and microscopic tissue damage caused by the exothermic reaction. CONCLUSION QuikClot provides hemostasis and decreased mortality in this model of severe liver injury. The beneficial aspects of QuikClot treatment must, however, be balanced against the tissue-damaging effects of the exothermic reaction.

Physiological and Medical Monitoring for En Route Care of Combat Casualties

BACKGROUND Most prehospital medical interventions during civilian and military trauma casualty transport fail to utilize advanced decision-support systems for treatment and delivery of medical interventions, particularly intravenous fluids and oxygen. Current treatment protocols are usually based on standard vital signs (eg, blood pressure, arterial oxygen saturation) which have proven to be of limited value in detecting the need to implement an intervention before cardiovascular collapse. A primary objective of the US Army combat casualty care research program is to reduce mortality and morbidity during casualty transport from the battlefield through advanced development of a semiautomated decision-support capability for closed-loop resuscitation and oxygen delivery. METHODS To accomplish this goal, the Trauma Informatics Research Team at the US Army Institute of Surgical Research has developed two models for evidence-based decision support 1) a trauma patient database for capture and analysis of prehospital vital signs for identification of early, novel physiologic measurements that could improve the control of closed-loop systems in trauma patients; and, 2) a human experimental model of central hypovolemia using lower body negative pressure to improve the understanding and identification of physiologic signals for advancing closed-loop capabilities with simulated hemodynamic responses to hemorrhage. RESULTS In the trauma patient database and lower body negative pressure studies, traditional vital sign measurements such as systolic blood pressure and oxygen saturation fail to predict mortality or indicate the need for life saving interventions or reductions in central blood volume until after the onset of cardiovascular collapse. We have evidence from preliminary analyses, however, that indicators of reduced central blood volume in the presence of stable vital signs include 1) reductions in pulse pressure; 2) changes in indices of autonomic balance derived from calculation of heart period variability (ie, linear and non-linear analyses of R-R intervals); and 3) reductions in tissue oxygenation. CONCLUSIONS We propose that derived indices based on currently available technology for continuous monitoring of specific hemodynamic, autonomic, and/or metabolic responses could provide earlier recognition of hemorrhage than current standard vital signs and allow intervention before the onset of circulatory shock. Because of this, such indices could provide improved feedback for closed-loop control of patient resuscitation and oxygen delivery. These technological advances could prove instrumental in advancing decision-support capabilities for prehospital trauma care during transport to higher levels of care in both the military and civilian environments.

Oxygen saturation determined from deep muscle, not thenar tissue, is an early indicator of central hypovolemia in humans

Objective:To compare the responses of noninvasively measured tissue oxygen saturation (Sto2) and calculated muscle oxygen tension (Pmo2) to standard hemodynamic variables for early detection of imminent hemodynamic instability during progressive central hypovolemia in humans. Design:Prospective study. Setting:Research laboratory. Subjects:Sixteen healthy human volunteers. Interventions:Progressive lower body negative pressure (LBNP) to onset of cardiovascular collapse. Measurements and Main Results:Noninvasive measurements of blood pressures, heart rate, and stroke volume were obtained during progressive LBNP with simultaneous assessments of Sto2, Pmo2, and muscle oxygen saturation (Smo2). Forearm Smo2 and Pmo2 were determined with a novel near infrared spectroscopic measurement device (UMMS) and compared with thenar Sto2 measured by a commercial device (HT). All values were normalized to the duration of LBNP exposure required for cardiovascular collapse in each subject (i.e., LBNP maximum). Stroke volume was significantly decreased at 25% of LBNP maximum, whereas blood pressure was a late indicator of imminent cardiovascular collapse. Pmo2 (UMMS) was significantly decreased at 50% of maximum LBNP while Smo2 (UMMS) decreased at 75% of maximum LBNP. Thenar Sto2 (HT) showed no statistical change throughout the entire LBNP protocol. Conclusions:Spectroscopic assessment of forearm muscle Po2 and Smo2 provides noninvasive and continuous measures that are early indicators of impending cardiovascular collapse resulting from progressive reductions in central blood volume.

Tolerance to central hypovolemia: the influence of oscillations in arterial pressure and cerebral blood velocity

Higher oscillations of cerebral blood velocity and arterial pressure (AP) induced by breathing with inspiratory resistance are associated with delayed onset of symptoms and increased tolerance to central hypovolemia. We tested the hypothesis that subjects with high tolerance (HT) to central hypovolemia would display higher endogenous oscillations of cerebral blood velocity and AP at presyncope compared with subjects with low tolerance (LT). One-hundred thirty-five subjects were exposed to progressive lower body negative pressure (LBNP) until the presence of presyncopal symptoms. Subjects were classified as HT if they completed at least the -60-mmHg level of LBNP (93 subjects; LBNP time, 1,880 ± 259 s) and LT if they did not complete this level (42 subjects; LBNP time, 1,277 ± 199 s). Middle cerebral artery velocity (MCAv) was measured by transcranial Doppler, and AP was measured at the finger by photoplethysmography. Mean MCAv and mean arterial pressure (MAP) decreased progressively from baseline to presyncope for both LT and HT subjects (P < 0.001). However, low frequency (0.04-0.15 Hz) oscillations of mean MCAv and MAP were higher at presyncope in HT subjects compared with LT subjects (MCAv: HT, 7.2 ± 0.7 vs. LT, 5.3 ± 0.6 (cm/s)(2), P = 0.075; MAP: HT, 15.3 ± 1.4 vs. 7.9 ± 1.2 mmHg(2), P < 0.001). Consistent with our previous findings using inspiratory resistance, high oscillations of mean MCAv and MAP are associated with HT to central hypovolemia.

Breathing through an inspiratory threshold device improves stroke volume during central hypovolemia in humans

Inspiratory resistance induced by breathing through an impedance threshold device (ITD) reduces intrathoracic pressure and increases stroke volume (SV) in supine normovolemic humans. We hypothesized that breathing through an ITD would also be associated with a protection of SV and a subsequent increase in the tolerance to progressive central hypovolemia. Eight volunteers (5 men, 3 women) were instrumented to record ECG and beat-by-beat arterial pressure and SV (Finometer). Tolerance to progressive lower body negative pressure (LBNP) was assessed while subjects breathed against either 0 (sham ITD) or -7 cmH(2)O inspiratory resistance (active ITD); experiments were performed on separate days. Because the active ITD increased LBNP tolerance time from 2,014 +/- 106 to 2,259 +/- 138 s (P = 0.006), data were analyzed (time and frequency domains) under both conditions at the time at which cardiovascular collapse occurred during the sham experiment to determine the mechanisms underlying this protective effect. At this time point, arterial blood pressure, SV, and cardiac output were higher (P < or = 0.005) when breathing on the active ITD rather than the sham ITD, whereas indirect indicators of autonomic activity (low- and high-frequency oscillations of the R-to-R interval) were not altered. ITD breathing did not alter the transfer function between systolic arterial pressure and R-to-R interval, indicating that integrated baroreflex sensitivity was similar between the two conditions. These data show that breathing against inspiratory resistance increases tolerance to progressive central hypovolemia by better maintaining SV, cardiac output, and arterial blood pressures via primarily mechanical rather than neural mechanisms.

Inspiratory resistance maintains arterial pressure during central hypovolemia: Implications for treatment of patients with severe hemorrhage

Objective:To test the hypothesis that an impedance threshold device would increase systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure and delay the onset of symptoms and cardiovascular collapse associated with severe central hypovolemia. Design:Prospective, randomized, blinded trial design. Setting:Human physiology laboratory. Patients:Nine healthy nonsmoking normotensive subjects (five males, four females). Interventions:Central hypovolemia and impending cardiovascular collapse were induced in human volunteers by applying progressive lower body negative pressure (under two experimental conditions: a) while breathing with an impedance threshold device set to open at −7 cm H2O pressure (active impedance threshold device); and b) breathing through a sham impedance threshold device (control). Measurements and Main Results:Systolic blood pressure (79 ± 5 mm Hg), diastolic blood pressure (57 ± 3 mm Hg), and mean arterial pressure (65 ± 4 mm Hg) were lower (p < .02) when subjects (n = 9) breathed through the sham impedance threshold device than when they breathed through the active impedance threshold device at the same time of cardiovascular collapse during sham breathing (102 ± 3, 77 ± 3, 87 ± 3 mm Hg, respectively). Elevated blood pressure was associated with 23% greater lower body negative pressure tolerance using an active impedance threshold device (1639 ± 220 mm Hg-min) compared with a sham impedance threshold device (1328 ± 144 mm Hg-min) (p = .02). Conclusions:Use of an impedance threshold device increased systemic blood pressure and delayed the onset of cardiovascular collapse during severe hypovolemic hypotension in spontaneously breathing human volunteers. This device may provide rapid noninvasive hemodynamic support in patients with hypovolemic hypotension once the blood loss has been controlled but before other definitive therapies are available.

Oxygen transport characterization of a human model of progressive hemorrhage

BACKGROUND Hemorrhage continues to be a leading cause of death from trauma sustained both in combat and in the civilian setting. New models of hemorrhage may add value in both improving our understanding of the physiologic responses to severe bleeding and as platforms to develop and test new monitoring and therapeutic techniques. We examined changes in oxygen transport produced by central volume redistribution in humans using lower body negative pressure (LBNP) as a potential mimetic of hemorrhage. METHODS AND RESULTS In 20 healthy volunteers, systemic oxygen delivery and oxygen consumption, skeletal muscle oxygenation and oral mucosa perfusion were measured over increasing levels of LBNP to the point of hemodynamic decompensation. With sequential reductions in central blood volume, progressive reductions in oxygen delivery and tissue oxygenation and perfusion parameters were noted, while no changes were observed in systemic oxygen uptake or markers of anaerobic metabolism in the blood (e.g., lactate, base excess). While blood pressure decreased and heart rate increased during LBNP, these changes occurred later than the reductions in tissue oxygenation and perfusion. CONCLUSIONS These findings indicate that LBNP induces changes in oxygen transport consistent with the compensatory phase of hemorrhage, but that a frank state of shock (delivery-dependent oxygen consumption) does not occur. LBNP may therefore serve as a model to better understand a variety of compensatory physiological changes that occur during the pre-shock phase of hemorrhage in conscious humans. As such, LBNP may be a useful platform from which to develop and test new monitoring capabilities for identifying the need for intervention during the early phases of hemorrhage to prevent a patients progression to overt shock.

Tracking central hypovolemia with ecg in humans: cautions for the use of heart period variability in patient monitoring.

Heart period variability (HPV) metrics have been suggested for use in medical monitoring of trauma patients. This study sought to ascertain the use of various HPV metrics in tracking central blood volume during simulated hemorrhage in individual humans. One hundred one healthy nonsmoking volunteers (58 men, 43 women) were instrumented for continuous measurement of electrocardiogram and beat-by-beat finger arterial blood pressure. Stroke volume (SV) was estimated from the arterial pulse wave and used to reflect central blood volume. Progressive lower body negative pressure (LBNP) was applied in 5-min stages until the onset of impending hemodynamic decompensation (systolic blood pressure <70 mmHg and/or presyncopal symptoms). HPV was assessed with analysis of R-to-R intervals using both linear (time and frequency domains) and nonlinear (e.g., complexity, fractality) methods. Application of increasing LBNP caused progressive reductions of SV, whereas arterial pressures changed only minimally and late. Group LBNP stage means for each HPV metric changed progressively and were strongly correlated with the mean decrease in SV (|r| ≥ 0.87). To ascertain the utility of the HPV metrics to track individual responses to central hypovolemia, the difference scores for each HPV metric were correlated at each successive LBNP level, with percentage change in SV at the subject level. This cross-correlation of difference scores revealed that none of the HPV metrics showed strong and consistent correlations (|r| ≤ 0.49) with percentage change in SV across successive LBNP levels. Although aggregate group mean values for HPV metrics are well correlated with SV changes during central hypovolemia, these metrics are less reliable when tracking individual reductions in central volume during LBNP. HPV metrics, therefore, may not be useful in monitoring hemorrhagic injuries in individual patients.

Validation of a computational platform for the analysis of the physiologic mechanisms of a human experimental model of hemorrhage

Computational models of integrative physiology may serve as a framework for understanding the complex adaptive responses essential for homeostasis in critical illness and resuscitation and may provide insights for design of diagnostics and therapeutics. In this study a computer model of human physiology was compared to results obtained from experiments using Lower Body Negative Pressure (LBNP) analog model of human hemorrhage. LBNP has been demonstrated to produce physiologic changes in humans consistent with hemorrhage. The computer model contains over 4000 parameters that describe the detailed integration of physiology based upon basic physical principles and established biologic interactions. The LBNP protocol consisted of a 5min rest period (0mmHg) followed by 5min of chamber decompression of the lower body to -15, -30, -45, and -60mmHg and additional increments of -10mmHg every 5min until the onset of hemodynamic decompensation (n=20). Physiologic parameters recorded include mean arterial pressure (MAP), cardiac output (CO), and venous oxygen saturation (SVO(2); from peripheral venous blood), during the last 30s at each LBNP level. The computer model analytic procedure recreates the investigational protocol for a virtual individual in an In Silico environment. After baseline normalization, the model predicted measurements for MAP, CO, and SVO(2) were compared to those observed through the entire range of LBNP. Differences were evaluated using standard statistical performance error measurements (median performance error (PE) <5%). The simulation results closely tracked the average changes observed during LBNP. The predicted MAP fell outside the standard error measurement for the experimental data at only LBNP -30mmHg while CO was more variable. The predicted SVO(2) fell outside the standard error measurement for the experimental data only during the post-LBNP recovery point. However, the statistical median PE measurement was found to be within the 5% objective error measure (1.3% for MAP, -3.5% for CO, and 3.95% for SVO(2)). The computer model was found to accurately predict the experimental results observed using LBNP. The model should be explored as a platform for studying concepts and physiologic mechanisms of hemorrhage including its diagnosis and treatment.