Severe shock resulting from uncontrolled hemorrhage unresponsive to fluid resuscitation remains a major cause of death in trauma patients. Epidemiologic studies show that hemorrhage is the cause of death in 30% to 50% of trauma patients (1, 2). The management of hemorrhagic shock has evolved considerably during the past century, and the best strategy for timing and components of resuscitation still remain to be defined. Traditionally, the standard management of a patient presumed hypotensive from hemorrhagic shock has been to infuse massive amounts of crystalloid with the goal of replacing intravascular volume (3, 4). However, in the past several years, studies have demonstrated numerous complications to be associated with large-volume fluid infusions: coagulopathy, acute lung injury, immune dysfunction, rebleeding, and multiorgan failure (5, 6). Therefore, the current practice is damage control resuscitation, which is characterized by hypotensive resuscitation; limitation of excessive crystalloid use; early transfusion of red blood cells, plasma, and platelets in a 1:1:1 ratio; and rapid control of surgical bleeding (7). The principle of hypotensive resuscitation is based on the finding that raising the blood pressure to normal limits via aggressive fluid administration may dislodge clots, causing rebleeding (8, 9).
The role of vasopressors in hemorrhagic shock remains controversial. Traditionally, the use of vasopressors has been avoided in hypovolemic shock because of concern that vasoconstriction in the absence of adequate volume replacement will lead to tissue ischemia, acidosis, and vasomotor collapse (10). However, vasopressin (VP) is emerging as a potential pharmacological adjunct to posthemorrhagic resuscitation. Both human case reports (11–13) and animal studies (14–16) suggest that VP may improve short-term survival in patients with hemorrhagic shock refractory to catecholamines and crystalloids. Indeed, we have recently reported that blunted endogenous VP response was associated with nonsurvival of acute hemorrhage (17). This finding suggests that VP deficiency may contribute to mortality via hypoxemia, in addition to promoting vasodilation in irreversible shock, which has been previously described (18).
Nonetheless, the problem with aggressive use of pressor agents with large-volume fluid resuscitation is that nondiscriminatory vasoconstriction would cause decreased perfusion through the pulmonary vascular bed and, together with fluid volume administration increasing pulmonary edema and congestion, increased pulmonary vascular resistance (PVR) would eventually cause increased pulmonary hypertension and right ventricle failure (19, 20). The ideal vasoactive agent will maintain systemic circulation while avoiding a detrimental increase in PVR that would hinder pulmonary perfusion and adequate blood oxygenation. Accordingly, a vasoconstrictor that spares the pulmonary bed of its effects may be the adjunct to low-volume crystalloid resuscitation needed to stabilize a patient in the first few hours after severe hemorrhage.
In septic shock, multiple studies have been published comparing outcomes associated with various vasopressors (21, 22). Norepinephrine (NE) is a potent α- and β-agonist that increases mean arterial pressure via both vasoconstriction and increase in cardiac output (CO). The Surviving Sepsis campaign recommends NE as the first-line vasopressor, over dopamine and epinephrine, in septic shock (22). However, NE may predispose to tachyarrhythmias as well as increase myocardial oxygen demand via β1-receptor stimulation (21). Phenylephrine (PE) is a selective α1-agonist that constricts arterioles without a compensatory increase in myocardial contractility. Although PE is not recommended as first-line therapy in septic shock, it may be helpful in cases when NE is associated with arrhythmias or when CO is known to be high (22). Thus, the effectiveness of PE versus NE in septic shock could also be evident in resuscitation of hemorrhagic shock. At present, there are no major studies comparing the effects of commonly used pressor agents on the pulmonary bed versus systemic vasculature in severe hemorrhage.
Therefore, our objective in this study was to test the hypothesis that VP has distinct effects on pulmonary versus systemic hemodynamics in posthemorrhagic resuscitation, unlike the catecholamine pressors NE and PE.
MATERIALS AND METHODS
The study protocol was approved by the Institutional Animal Care and Use Committee at Tripler Army Medical Center. Investigators complied with the policies as prescribed in the USDA Animal Welfare Act and the National Research Council’s Guide for the Care and Use of Laboratory Animals. Facilities are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC International). Animal care and use were performed by qualified individuals supervised by veterinarians. Anesthesia was used in all surgical interventions, and unnecessary suffering was avoided.
Preparation and measurements
Twenty-five healthy 4- to 6-month-old male and female Yorkshire cross pigs, weighing 30 to 40 kg, were studied. The pigs were fasted overnight with ad lib water. Before surgery, the pigs were premedicated with acepromazine (1.1 mg/kg), midazolam (1.0 mg/kg), ketamine (22–33 mg/kg), and glycopyrrolate (0.005 – 0.010 mg/kg) administered intramuscularly. Animals were then intubated orotracheally and mechanically ventilated (Servo-i; Maquet Medical Systems, Wayne, NJ) to maintain tidal volumes of 8 to 10 mL/kg, positive end-expiratory pressure of 5 mmHg, and at a rate appropriate to maintain an EtCO2 of 35 to 40 mmHg. The FiO2 was maintained at 21% throughout the experiment. Anesthesia was maintained with ketamine (8–33 mg/kg per h), fentanyl (0.3–4.0 mg/kg per h), and midazolam (0.5–1.5 mg/kg per h). Depth of anesthesia was judged according to arterial blood pressure, heart rate (HR), and response to gentle tactile stimuli; and the infusion rates of ketamine, fentanyl, and midazolam were titrated to maintain an adequate level of sedation. 1% Para-aminohippuric acid solution at 3 mL/kg per h and normal saline (NS) were administered continuously throughout the preparation period to replace fluid loss during instrumentation; the saline rate was adjusted based on the titration of anesthetics to maintain the total fluid administration rate at 6 mL/kg per h. A standard lead II electrocardiogram (IntelliVue MP70; Philips Medical Systems, Andover, Mass) was used to monitor cardiac rhythm. Body core temperature was maintained with a heating blanket (Bair Hugger; 3 M, St. Paul, Minn) between 38.0°C (100.4°F) and 39.0°C (101.2°F) during surgical preparation. Blood gases were measured with a blood gas analyzer (ABL 800; Radiometer America, Inc., Westlake, Ohio). Oxygen consumption was measured by respirometry (VMax Encore; Viasys Healthcare, Conshohocken, Pa) during the first hour after the start of hemorrhage.
A 7F 20-cm introducer sheath (Arrow, Reading, Pa) with 1/16″ Flexene FLXCI-2 tubing (Eldon James, Loveland, Colo) was placed into the abdominal aorta via the right femoral artery for hemorrhage. A 7F triple-lumen catheter (Arrowgard Blue Plus Multi-lumen CVC; Arrow) was inserted into the left femoral vein for the administration of fluids and medications, and a second triple-lumen catheter was placed into the left femoral artery for measurement of mean arterial blood pressure (MAP). Two 4F 13-cm double-lumen catheters (Arrow) were placed cephalad into the left carotid artery and right external jugular vein for measurement of blood gases and blood pressure. A 7.5F 110-cm pulmonary artery catheter (Swan-Ganz CCOmbo; Edwards LifeSciences, Irvine, Calif) was inserted through the right external jugular vein within a 9F introducer sheath (Cook, Inc., Bloomington, Ind) to measure pulmonary artery pressure (PAP), mixed venous oxygen saturation, and core temperature. Cardiac index was measured either using a Vigilance II (Edwards LifeSciences) or manually via thermodilution (IntelliVue MP70; Philips Medical Systems, Andover, Mass). Through the left carotid artery, a 1/16″ Flexene FXI-2 N tubing (Eldon James) was placed into the left ventricle for injection of microspheres. Pressure transducers were attached to the catheters in the left femoral artery, pulmonary artery, right external jugular vein, left ventricle, and cerebral carotid artery/external jugular vein. A Foley catheter (Rusch Teleflex Medical, Research Triangle Park, NC) was placed into the bladder via a midline laparotomy for urine collection.
Animals were assigned to one of four groups: Normal saline alone (n = 7), saline + lysine VP (n = 6), saline + NE (n = 6), and saline + PE (n = 6). Lysine VP was chosen instead of arginine VP because LVP is the form that exists in pigs. Thirty minutes before hemorrhage, fentanyl and midazolam were stopped because of their dose-dependent effect on CO; ketamine was continued to maintain adequate sedation. To mimic a period of rapid uncontrolled hemorrhage followed by a period of relative hemostasis, animals were bled to a MAP of 35 mmHg at a rate of 3 mL/kg per min for 7 min, and then 1 mL/kg per min until the target shed blood volume of 30 mL/kg was reached. Animals were kept at a MAP of 30 to 35 mmHg by withdrawing or infusing shed blood that was stored in a citrated glucose solution. After 60 min of hemorrhagic shock, animals were resuscitated with normal saline at a rate of 3 mL/kg per min for 7 min followed by 1 mL/kg per min to reach a target MAP of 60 mmHg but not to exceed one shed blood volume. One hour after the start of saline resuscitation, the NS group received additional saline not to exceed two shed blood volumes total, whereas the saline + VP group received a VP infusion titrated between 10 and 30 ng/kg per min, the saline + NE group received an NE infusion titrated between 0.05 and 0.15 μg/kg per min, and the saline + PE group received a PE infusion titrated between 5 and 15 μg/kg per min. Norepinephrine administration was also titrated to prevent HR from exceeding 200 beats/min. After 60 min of vasopressor administration, vasopressors were discontinued and the pigs were observed for 3 h. Hemodynamics, cardiodynamics, pulse oximetry, and near-infrared spectroscopy of the cerebral, renal, and mesenteric vascular beds were monitored continuously throughout the experiment. Arterial blood gases, venous blood gases, and urinalyses were measured at baseline, 1 h after the start of hemorrhage, 1 h each after the administration of normal saline and vasopressor, and then each hour after the withdrawal of vasopressors until euthanasia. At the conclusion of the experiment, euthanasia was carried out with a solution of pentobarbital sodium and phenytoin sodium at a dose of 1 mL/4.5 kg.
Quantification of V1R mRNA expression
Pulmonary, carotid, celiac, renal, and small mesenteric arteries were harvested from each pig immediately after euthanasia. Vessels were submerged in RNAlater (Ambion, Austin, Tex) and stored at −70°C until RNA extraction. Total RNA was extracted from harvested pig arteries using the Aurum Total RNA Fatty and Fibrous Tissue Kit (Bio-Rad Laboratories, Inc., Hercules Calif) according to the manufacturer’s instructions. Briefly, cells were disrupted thoroughly using a 7-mm stainless steel GLH homogenizer (Omni International, Kennesaw, Ga). RNA from homogenized tissue was passed through a silica membrane, DNase treated, washed, and eluted with 80 μL of supplied elution buffer.
Total RNA concentration and purity were determined by spectrophotometry (A260/280). Complementary DNA from 1 μg RNA per 20-μL reaction volume for each tissue sample was produced using the High-Capacity RNA-to-cDNA kit (Life Technologies, Grand Island, NY) according to the manufacturer’s instructions.
Primers and probes targeting V1a (target gene) and HPRT (housekeeping gene) were designed in-house and ordered through Biosearch Technologies (Novato, Calif). Probes were FAM labeled with a Black Hole Quencher at the 3′ end. Primer and probe sequences used for target gene (V1a) and housekeeping gene (HPRT) were as follows:
The amplicon was verified by gel electrophoresis and sequencing (Sequetech, Mountain View, Calif). Real-time polymerase chain reaction was performed using the iCycler iQ Real-Time PCR Detection System (Bio-Rad Laboratories, Inc.) in a 20-μL reaction volume. Polymerase chain reactions were prepared using iQ Supermix (Bio-Rad Laboratories, Inc.) provided as a 2× concentration (100 mM KCl, 40 mM Tris-HCl pH 8.4, 0.4 mM each dNTP, 50 U/mL iTaq DNA polymerase, 6 mM MgCl2, stabilizers) according to the manufacturer’s instructions. Primer and probe concentrations in the final reaction volume for V1a were 500 nM and 50 nM, respectively. Primer and probe concentrations in the final reaction volume for HPRT were both 100 μM. Lastly, 5 μL of cDNA diluted 10-fold was added to the reaction mixture. Amplifications were performed starting with a 3-min denaturation step at 95°C, followed by 47 cycles of 95°C for 20 s and 60°C for 45 s. Data collection through the FAM channel was obtained at the 60°C step. All samples were run in duplicate, and all artery samples from the same pig were assayed on the same plate. A positive control sample was run on every plate to assess interassay variability. The coefficient of variation for this assay was 9.6%.
JMP software for Windows 7 was used for statistical analysis. Differences between treatment groups were analyzed with two-way analysis of variance (ANOVA) with repeated measures across time and, within groups, differences were analyzed with one-way ANOVA. Values are expressed as mean ± SEM. Statistical significance was considered at P ≤ 0.05.
Hemorrhage end points
At baseline, there were no differences in HR, MAP, CO, or SpO2 between groups. After 60 min of controlled bleeding, weight-based shed blood volume was 35.1 ± 1.4 mL/kg in the NS group, 34.1 ± 2.3 mL/kg in the VP group, 30.8 ± 1.8 mL/kg in the NE group, and 32.3 ± 0.3 mL/kg in the PE group. Cumulative oxygen debt was 73.9 ± 8.5 mL/kg in the NS group, 64.7 ± 2.3 mL/kg in the VP group, 79.1 ± 13.5 mL/kg in the NE group, and 67.9 ± 15.8 mL/kg in the PE group. There were no significant differences in weight-based shed blood volume or cumulative oxygen debt in any group (P < 0.05), demonstrating an equivalent severity of hemorrhage among all groups.
The baseline MAP ranged between 69.0 ± 2.5 mmHg and 74.7 ± 3.5 mmHg, with no significant difference in any group (Fig. 1A). All treatment groups had an equivalent decrease in MAP after 1 h of hemorrhage, ranging between 33.2 ± 2.0 mmHg and 40.1 ± 3.2 mmHg. Vasopressin administration produced the greatest increase in MAP to 68.5 ± 7.2 mmHg; only VP and not the catecholamine pressors demonstrated a statistically significant difference from saline control, which raised the MAP to 53.9 ± 2.6 mmHg. Baseline PAP ranged between 15.4 ± 1.0 mmHg and 17.0 ± 1.2 mmHg, with no significant difference between groups (Fig. 1B). All treatment groups had an equivalent decrease in PAP after 1 h of hemorrhage, ranging between 12.6 ± 1.0 mmHg and 15.2 ± 1.7 mmHg. In contrast with the MAP, NE administration produced the greatest increase in PAP, to 23.8 ± 3.5 mmHg, whereas VP maintained the PAP at 14.7 ± 1.3 mmHg. Only NE and not VP or PE produced a statistically significant difference compared with saline control, which raised the PAP to 17.4 ± 0.9 mmHg. During hemorrhage, HR rose in all groups, whereas stroke volume (SV) and CO decreased (Table 1). Although NE tended to increase HR (159.8 ± 16.6 beats/min vs. 129.1 ± 11.4 beats/min in saline controls) and decrease SV (0.66 ± 0.11 mL/kg per beat vs. 0.85 ± 0.14 mL/kg per beat in saline controls), there was no statistically significant difference between any of the treatment groups at baseline, during hemorrhage, or resuscitation. Left ventricular stroke work index (LVSWI) significantly decreased with hemorrhage (36 ± 2 vs. 6 ± 1 g*m/m2 at baseline and hemorrhage, respectively) and improved with fluid resuscitation before pressor administration in all groups (16 ± 1 g*m/m2). Pressors helped keep the LVSWI elevated, and there were no statistically significant differences between pressor agents.
Pulmonary and systemic vasoconstriction
Systemic vascular resistance decreased in all treatment groups during hemorrhage and early resuscitation with NS and then increased to varying degrees with vasopressor administration (Table 2). Only VP had a statistically significant positive effect on the SVR compared with the saline control (660 ± 76 mmHg/[L/min per kg] vs. 528 ± 76 mmHg/[L/min per kg], P < 0.05). On the other hand, PVR increased in all treatment groups during hemorrhage and decreased during early resuscitation. The administration of NE increased PVR and was the only treatment to differ significantly from that of the saline control group. These findings are summarized by the PVR/SVR ratio (Fig. 2). Whereas NE increased the PVR/SVR ratio, the administration of VP decreased the PVR/SVR ratio by 45% compared with the saline control (P < 0.05). The shunt fraction (QS/QT, Table 2) decreased with hemorrhage and was not altered by resuscitation.
Arterial blood parameters
Arterial blood parameters are summarized in Table 3. Hemoglobin levels began at a range of 7.18 ± 0.28 g/dL to 8.26 ± 0.32 g/dL, decreased to a range of 5.25 ± 0.21 g/dL to 6.31 ± 0.31 g/dL during early crystalloid resuscitation, and ranged between 5.08 ± 0.38 g/dL and 6.10 ± 0.49 g/dL at the conclusion of the observation period. Arterial blood oxygenation is depicted in Figure 3, A and B. Administration of NE led to a decrease in both PaO2 and SaO2, whereas administration of PE led to a decrease in SaO2 (P < 0.05). Both PaO2 and SaO2 recovered after catecholamines were withdrawn. The increased PVR/SVR ratio with NE translated to a decrease in the PaO2/FiO2 ratio (Table 2), indicating predisposition of developing respiratory distress despite controlled ventilation. Groups treated with VP and crystalloid maintained blood oxygenation at baseline throughout. Hemorrhage caused base excess to decrease and lactate to increase, indicating overall systemic hypoperfusion (Table 3). There were no significant differences between treatments, and these indicators did not worsen with treatment.
Oxygen metabolism at baseline, during hemorrhage, and resuscitation is depicted in Figure 4, A to C. In compensation for the decrease in O2 delivery during hemorrhage, O2 extraction increased. By the end of resuscitation, O2 delivery, extraction, and consumption approached baseline levels for the remainder of the experiment. There was no significant difference in O2 delivery, extraction, or consumption associated with the administration of VP or NE compared with saline controls, although PE was associated with a higher O2 consumption and extraction compared with values at hemorrhage.
V1R mRNA distribution
Consistent with the relatively less vasoconstrictive action VP had on the pulmonary bed, V1R mRNA expression in the pulmonary artery was considerably less than that found in the celiac, mesenteric, and carotid arteries (Fig. 5).
In the critical care setting, inability to control pulmonary hypertension in the face of systemic hypotension such as in hemorrhage presents an urgent crisis in patient management because the patients have little cardiovascular reserve, do not tolerate hypotension and hypoxemia, and quickly decompensate to heart failure (19).
Our results demonstrate that VP used in early hemorrhagic shock maintains blood oxygenation by sparing the pulmonary vasculature of vasoconstriction while raising the mean arterial pressure. The administration of VP decreased the PVR/SVR ratio by 45%. This effect was not seen with crystalloid or catecholamine administration. Instead, NE administration increased the PVR/SVR ratio and induced pulmonary hypertension. Correspondingly, the PaO2 and SaO2 were maintained at baseline levels during resuscitation with VP but dropped with administration of NE. Given that we did not find any differences in peripheral O2 consumption with the administration of VP or NE, the differences in blood oxygenation were most likely attributable to the variable vasoconstriction in the pulmonary and systemic vascular beds. Notably, VP was able to achieve the most significant increases in MAP and SVR. Although both NE and PE were titrated with the goal of returning to baseline MAP during posthemorrhagic resuscitation, the dose of NE was limited by the development of tachyarrhythmias, whereas the effectiveness of PE reached a plateau at doses of 12 to 15 μg/kg per min. Heart rate, SV, and CO did not vary significantly between treatment groups, suggesting that the differences noted in MAP and PAP were mostly attributable to changes in the resistance across the systemic and pulmonary vascular beds.
The effectiveness of VP in raising MAP and SVR without causing pulmonary vasoconstriction has been previously described (23) and suggested to be attributed to VP-mediated vasodilatory action via stimulation of nitric oxide production in the pulmonary vasculature (24). It is also likely that the selective sparing of the pulmonary vasculature of vasoconstriction is related to the distribution and characteristics of its receptors, in contrast with the catecholamine vasopressors. Vasopressin mediates vasoconstriction via V1 receptors, whereas NE is an α- and β-agonist, and PE is a pure α-agonist. It has been established that, in a low pH environment, such as that seen in shock states, α and β receptors are inactivated whereas VP maintains vascular responsiveness in hemorrhage by inhibiting K+ ATP channels (11, 16, 25, 26). In addition, whereas the density of α1 receptors in the pulmonary vasculature matches if not exceeds that in the systemic vasculature (27), our data show a decreased level of V1R mRNA expression in the pulmonary versus systemic vasculature. This may explain the differential effects of VP on the pulmonary and systemic vascular beds in contrast with catecholamine pressors in our study.
Vasopressin has shown potential in the treatment of cardiorespiratory arrest and pulmonary hypertension (28–30). However, long-term outcomes after use of VP in vasodilatory shock remain controversial. Some studies have shown that the addition of VP to NE is associated with a clinically significant increase in mortality (31, 32), but VP was not used as a first-line drug in those studies and it is unclear whether the patients were too far along a downward spiral of poor perfusion to allow VP to be effective. The VP in Septic Shock Trial showed that 28-day mortality was not improved (33) nor worsened. It is unclear whether the use of VP is itself detrimental or simply a marker of poor outcome in these patients independent of treatment. The clinical concern with using VP as a first-line agent is the long-known strong dose-dependent effect of VP on visceral blood flow. Indeed, VP has traditionally been used to stem blood loss in gastrointestinal bleeding.
The protracted use of any vasopressor could result in multiple metabolic and hemodynamic derangements, for example, gut/liver ischemia with VP and NE, arrhythmias and myocardial demand ischemia with NE, and eventual tachyphylaxis with PE (21). Vasopressors should be used to acutely stabilize perfusion pressure and then withdrawn. Our data demonstrate that effects of short exposure to vasoconstrictors are reversible, and further that VP may provide the advantage over catecholamines in improving relative pulmonary perfusion and blood oxygenation.
This study was designed to address the short-term effects of vasopressors on perfusion and oxygenation and not designed to address extended use of pressors and the effects of prolonged vasoconstriction on long-term survival. Therefore, we are unable to specifically assess the longer-term effects of each resuscitation method on outcomes such as 30-day mortality, length of hospital stay, or the development of multiorgan dysfunction. We also were not able to evaluate the longer-term immune/inflammatory effects that have been associated with tissue trauma. However, our data can be applied to evaluating the short-term use of VP as bridging therapy from the initiation of hemorrhage until surgical intervention can be obtained in a hospital setting to correct the injury and control the source of bleeding, as well as the effect of removal of vasoconstriction during a 2-h period after 2 h of resuscitation. Our results indicate that the temporary use of vasopressors for the 2-h period of resuscitation and subsequent release of vasoconstriction with removal of pressor treatment for 2 h did not worsen the hemodynamic or oxygenation condition compared with the start of hemorrhage. Although long-term vasoconstriction is not advocated, short-term vasoconstriction of hemorrhaging vascular beds of damaged tissue would be beneficial, with the added benefit of maintaining perfusion pressure without the need for overload of fluid volume administration that increases the risk of coagulopathy.
Although the reduced gut/liver perfusion seen with VP may be a detriment if used at high doses in septic shock, in hemorrhagic shock, VP has been found to have a hemostatic effect on intra-abdominal bleeding in both animals (16) and humans (34). The mesenteric vasoconstriction may serve to help control noncompressible sources of hemorrhage. The variation in reported outcomes with VP in hemorrhagic shock may in part be related to failure to control for bleeding source (e.g., intra-abdominal versus extremity). Several animal models have been described for the evaluation of hemorrhagic shock. The uncontrolled hemorrhage model uses standardized tissue injury, such as crush/laceration of liver/spleen, aortic injury, and so on (35). We chose a controlled fixed-pressure hemorrhage model that mimics uncontrolled bleeding followed by a period of relative hemostasis without the tissue damage of trauma. The advantage of controlled hemorrhage is standardization of the degree and duration of hypotension among test groups (35). The main disadvantage of this model is that we cannot address the risk of rebleeding or “popping the clot” associated with raising the blood pressure as in damage control resuscitation (8, 9). We also were not able to assess the potential hemostatic effect of VP on intra-abdominal bleeding.
This study shows that VP can effectively maintain blood oxygenation by sparing the pulmonary vasculature while raising MAP via systemic vasoconstriction. In addition to blood oxygenation, end-organ perfusion is the major goal in the management of hemorrhagic shock, and further studies will be needed to specifically evaluate organ-specific perfusion during the use of vasopressors. Although future work in the form of randomized clinical trials are needed to define the role of VP in posthemorrhagic resuscitation, our results demonstrate that VP administered during early hemorrhagic shock can be useful as early supportive therapy. The ability of VP to maintain blood oxygenation indicates that VP may reduce hypoxemia and oxygen debt accumulation if used early in the management of hemorrhagic shock.
The authors thank all of the members of the laboratory staff: Aileen Sato, Wayne Ichimura, Wendy Kurata, Claudia Hernandez, Gustavo Alvarado, and Christina Ware for their assistance with experiment logistics, data recording, and specimen processing. The authors also thank the Animal Research staff: Thomas Eggleston, LVM (attending veterinarian), Jacob Espinosa, Katherine Titus, and Nicole Correa for their assistance with animal care and comfort.
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Keywords:© 2015 by the Shock Society
Vasopressin; norepinephrine; phenylephrine; hemorrhage; resuscitation; pulmonary hypertension; PVR; SVR; vasoconstriction; oxygenation