- Email: [email protected]
Impact of Vasopressin on Hemodynamic and Metabolic Function in the Decompensatory Phase of Hemorrhagic Shock
Impact of Vasopressin on Hemodynamic and Metabolic Function in the Decompensatory Phase of Hemorrhagic Shock Ken B. Johnson, MD,* Frederick J. Pearce, PhD,† Nicole Jeffreys, MD,‡ Scott W. McJames, MS,† and Mark Cluff, BS† Objectives: To explore how the potent vasoconstrictive features of vasopressin impact the rate of cardiovascular collapse and metabolic derangements associated with prolonged hemorrhagic shock. Design: A prospective randomized trial. Setting: University hospital– based animal laboratory. Participants: Sixteen swine. Interventions: Swine were bled in an isobaric fashion to achieve a linear decrease in the mean arterial blood pressure to 40 mmHg. The mean arterial blood pressure was then maintained at 40 mmHg until the onset of cardiovascular decompensation, defined as the need to reinfuse shed blood to maintain the blood pressure at 40 mmHg. Once at the onset of cardiovascular decompensation, animals were randomly assigned to 2 resuscitation groups: the crystalloid group received lactated Ringer’s solution and the vasopressin group received lactated Ringer’s solution and arginine vasopressin. Resuscitation consisted of infusing lactated Ringer’s solution with and without vasopressin (0.05 U/kg/ min) to maintain a blood pressure of 70 mmHg for 60 minutes. Measurements and Main Results: The rate of crystalloid
infusion was compared between groups using an unpaired 2-tailed t test. Metabolic and hemodynamic parameters between groups over time were compared with a repeated measures analysis of variance. Vasopressin decreased the rate of crystalloid infusion during resuscitation by 50%. During resuscitation, the cardiac index in the crystalloid group was restored to near baseline levels and was decreased to near half of baseline levels in the vasopressin group. Animals in the vasopressin group developed a lactic acidemia, but animals in the crystalloid group revealed no change from baseline in the arterial pH and a slight decrease in the plasma lactate. Conclusions: Administration of vasopressin used as an adjunct to maintain blood pressure in the decompensatory phase of hemorrhagic shock slows cardiovascular collapse, but has an adverse effect on metabolic and hemodynamic function. Further investigation is warranted to clarify the role of vasopressin in the delayed management of severe hemorrhagic shock. © 2006 Elsevier Inc. All rights reserved.
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These mechanisms suggest that administering exogenous AVP in the late phases of hemorrhagic shock might reverse some of the adverse consequences of cardiovascular decompensation as shown by Morales et al.5 Even after severe prolonged hemorrhagic hypotension, blood pressure remained responsive to exogenous AVP. Prior work has shown the benefit of AVP administered as a continuous infusion in the management of both (1) acute severe blood loss and (2) prolonged hemorrhagic hypotension leading to cardiovascular collapse. This study sought to explore more thoroughly the metabolic and hemodynamic effects of AVP when administered after the onset of cardiovascular decompensation. The aim was to examine the value of administering exogenous AVP on (1) the rate of crystalloid infusion to maintain a target blood pressure, and (2) on hemodynamic function and metabolic homeostasis in response to volume resuscitation. It was hypothesized that exogenous AVP, used as an adjunct to volume resuscitation, would slow the rate of
XOGENOUSLY ADMINISTERED arginine vasopressin (AVP) has been found to improve survival and hemodynamic performance in animal models of severe uncontrolled blood loss. In the setting of acute large-volume blood loss, AVP, when compared with more conventional interventions, such as volume resuscitation or epinephrine, has been found to improve survival rates and neurologic function.1-3 This work suggests that AVP may become an important tool when treating hemorrhagic shock. The focus of these prior studies has explored the benefits of AVP when given early in a severe hemorrhagic insult. Several questions, however, warrant further investigation to define conditions in which AVP may be helpful or possibly harmful as an adjunct to treating hemorrhagic shock. Hemorrhagic shock is a potent stimulus for AVP release. During hemorrhage, AVP exhibits a biphasic change in plasma levels.4-6 In a canine isobaric hemorrhage model, plasma levels initially increased approximately 150-fold above baseline during early hemorrhage and then later fell after remaining in hemorrhagic shock for 2 hours.5 AVP, as a vasoconstrictor known to suppress nitric oxide production,7-9 may contribute to the compensatory cardiovascular mechanisms directed at preserving blood flow to vital organs. Waning AVP levels may play a role in the transition from reversible hypovolemia to cardiovascular decompensation. Potential AVP-related mechanisms of this transition include (1) a rise in circulating cytokines that downregulate certain types of AVP (ie, V1) receptors,10 (2) exhaustion of neurohypophyseal stores of AVP, (3) lack of autonomic stimulus to release AVP, (4) high circulating levels of norepinephrine that suppress AVP release,11 and (5) rising nitric oxide levels from the vascular endothelium within the posterior pituitary and elsewhere that inhibit AVP production and compete with its vasopressor effects.12
KEY WORDS: hemorrhagic shock, arginine vasopressin, resuscitation
From the *Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT; †Department of Resuscitative Medicine, Walter Reed Army Institute of Research, Silver Spring, MD; and ‡University of Michigan Hospitals and Health Centers, Ann Arbor, MI. Supported in part by a grant from the National Institute of Health, Bethesda, MD (grant no. K08GM00712) and by the Department of Anesthesiology, University of Utah. Address reprint requests to Ken B. Johnson, MD, Department of Anesthesiology, University of Utah School of Medicine, 30 North, 1900 East, Room 3C444, Salt Lake City, UT 84132-2304. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2002-0007$32.00/0 doi:10.1053/j.jvca.2005.11.015
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crystalloid infusion required to maintain a target resuscitation pressure but not improve other indices of hemodynamic performance and would exacerbate metabolic function already compromised from prolonged hemorrhagic hypotension. METHODS AND MATERIALS Experiments were performed using commercial farm-bred swine of either sex. The study was approved by the Institutional Animal Care and Use Committee at the University of Utah. Animals were bled to a shock state and then assigned to either a vasopressin or a control group (n ⫽ 8 for each group). In the AVP group, animals were resuscitated with a continuous AVP infusion and lactated Ringer’s solution (LR ⫹ AVP). In the control group, animals were resuscitated with only lactated Ringer’s solution (LR). Swine weighing 35.8 ⫾ 1.6 kg were commercially obtained and quarantined for 6 days in a temperature- and light-controlled environment. Animals had access to food and water ad libitum. Anesthesia was induced with an intramuscular injection of tiletamine HCl, 2.3 mg/kg, zolazepam, 2.3 mg/kg, ketamine, 2.3 mg/kg, and xylazine, 2.3 mg/kg, as described by Ko et al13 for pigs. Intravascular access was obtained from an ear vein. A continuous crystalloid infusion with lactated Ringer’s solution was administered through the peripheral ear vein to meet insensible fluid and electrolyte losses according to the following set of rules: 4 mL/kg/h for the first 10 kg, 2 mL/kg/h for the next 10 to 20 kg, and 1 mL/kg/h for each kilogram above 20 kg. Each animal’s trachea was then intubated, and the lungs were mechanically ventilated. Initial ventilator settings were a tidal volume of 8 to 10 mL/kg, a respiratory rate of 20 breaths per minutes, an FIO2 of 50%, and no positive end-expiratory pressure. Tissue oxygenation was monitored using continuous pulse oximetry placed on the tongue or ear. Ventilation was monitored using an inspired/expired gas analyzer that measured oxygen, carbon dioxide, and isoflurane concentrations. Ventilator settings were adjusted as needed to keep the pulse oximetry above 95% and the end-tidal CO2 at 38 ⫾ 4 mmHg. Once satisfactory ventilator settings were established, a baseline arterial blood gas was obtained. Ventilator settings were adjusted further if needed to maintain the arterial PCO2 at 40 ⫾ 4 mmHg. A continuous level of anesthesia was achieved with isoflurane and intermittent boluses of pancuronium (0.1 mg/kg). During animal instrumentation, expired isoflurane levels were monitored and kept at 1.0 minimum alveolar concentration equivalent for swine (an end-tidal isoflurane concentration of 1.6%14). Subcutaneous electrocardiograph electrodes were placed, and the electrocardiogram was monitored throughout the study. The left femoral artery was cannulated with a 16-G arterial sheath to monitor arterial blood pressure and heart rate continuously. The right femoral artery was cannulated with a 16-G arterial sheath for blood removal and subsequent reinfusion. An internal jugular vein was cannulated with a pulmonary artery catheter for intermittent measurements of central venous pressure, pulmonary capillary wedge pressure, and thermodilution estimates of cardiac output. Colonic temperatures were monitored and maintained at 37°C throughout the study with a heating/ cooling blanket and heating lamps as needed. Once access to the vascular compartment was obtained, each animal was anticoagulated with an intravenous bolus injection of heparin (100 U/kg). Cardiac index and systemic vascular resistance index were calculated by estimating the body surface area according to the following: body surface area ⫽ (K*[weight2/3])/100 m2, where K, a species constant, is 9 for swine,15 cardiac index ⫽ cardiac output/body surface area, and systemic vascular resistance index ⫽ systemic vascular resistance/body surface area. The arterial blood pressures were measured with a pressure transducer (Utah Medical, Midvale, UT). A computerized data acquisition system recorded the mean arterial blood pressure (MABP), systolic and
diastolic arterial pressures, heart rate, and shed blood volume every 5 seconds. After instrumentation, animals underwent a 30-minute stabilization period before initiating the hemorrhage resuscitation protocol. Once in the stabilization period, the isoflurane was reduced to 0.8% and maintained there for the remainder of the experiment. The hemorrhage protocol was designed to ensure that each animal was at an equivalent degree of metabolic compromise from hemorrhagic shock before initiating resuscitation. This was accomplished by using an isobaric hemorrhage model as described by Wiggers.16 Animals were bled via an arterial line feeding through a roller pump. The roller pump was controlled by a computer. Shed blood was stored in a reservoir placed on a scale. Shed blood volume was measured by weight. Via a second arterial line, MABP was continuously acquired by the computer controlling the roller pump. Blood was removed at a rate required to achieve a linear decrease in the MABP to 40 mmHg over 20 minutes. Blood was then removed or reinfused by the servo-controlled roller pump to maintain the MABP at 40 mmHg. The compensatory phase of hemorrhagic shock was defined as the time during which blood had to be removed to maintain the MABP at 40 mmHg. The decompensatory phase of hemorrhagic shock was defined as the time period during which blood had to be reinfused to maintain the MABP at 40 mmHg. The peak shed blood volume was defined as the maximum amount of blood removed during the isobaric hemorrhage process. Upon reaching the peak shed blood volume, the target MABP was changed from 40 to 70 mmHg. The shed blood volume stored in a reservoir placed on the scale was replaced with a reservoir of LR solution. In the control group, LR was intravenously infused to achieve and maintain the MABP at 70 mmHg for 60 minutes. In the experimental group, in addition to LR, AVP, 0.05 U/kg/min, was intravenously infused during the resuscitation period. The dose of 0.05 U/kg/ min was based on infusion doses found to be effective in treating hemorrhagic shock in swine and rodents1,5 and delivered using a syringe pump (Medfusion 2010i; Medex Inc, Duluth, GA). Arterial blood samples for determining pH, PO2, PCO2, bicarbonate, base excess, lactate, glucose, potassium, and hematocrit were measured using a blood gas and chemistry analyzer (Model Number ABL 725; Radiometer America, Westlake, OH). Samples were obtained before hemorrhage, upon reaching 50% of the estimated peak shed blood volume, upon achieving the actual peak shed blood volume, and after the 60-minute resuscitation period. Metrics of comparison between groups included (1) the rate of crystalloid infusion (mL/kg/min) required to maintain the target MABP at 70 mmHg, and (2) changes in hemodynamic and metabolic parameters during the resuscitation period. The rate of crystalloid infusion was compared between groups using an unpaired 2-tailed t test. A power analysis revealed that with a type I margin of error set to 0.05 and 80% power to detect a mean difference of at least 0.3 mL/kg/min in the rate of crystalloid infusion between groups, a sample size of 8 would be required in each group assuming a standard deviation of 0.3.17 Metabolic and hemodynamic parameters were compared between groups over the duration of the resuscitation period using a repeated measures analysis of variance. A p value ⬍0.05 was considered significant. Data are expressed as mean ⫾ standard error of the mean. RESULTS
Animals required 91 ⫾ 8 minutes to reach their respective peak shed blood volumes. One animal in the LR group was not resuscitated according to the study protocol and was removed from the analysis. A plot of the typical time course for MABP, shed blood volume, and resuscitation volume for animals in each group is presented in Figure 1. The peak shed blood volume and time required to reach the target MABP were
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Panel A. Lactated Ringer’s Only Crystalloid Resuscitation
Hemorrhage
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Lactated Ringer’s Resuscitation (mL/kg)
Target MABP 70 mmHg
100
Shed Blood Volume (mL/kg)
MABP (mmHg)
Target MABP 40 mmHg
Time (minutes)
Panel B. Lactated Ringer’s and Vasopressin Crystalloid Resuscitation
Hemorrhage
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Target MABP 70 mmHg
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MABP (mmHg)
Target MABP 40 mmHg
Time (minutes)
MABP Shed Blood Volume Resuscitation Volume Fig 1. Typical time course for the mean arterial blood pressure (MABP, solid line), shed blood volume (dashed line), and resuscitation volume (dash-dot line) during the study period for animals resuscitated with lactated Ringer’s solution (A) and lactated Ringer’s solution combined with a continuous infusion of vasopressin (B).
similar between groups (Table 1). The rate of crystalloid infusion was significantly slower in the LR ⫹ AVP group (Table 2). Animals resuscitated with LR required 1.7-fold more LR over the 60-minute period than the animals resuscitated with LR ⫹ AVP.
After hemorrhage, there were no significant differences in hemodynamic parameters between groups. Both groups developed decreases in the cardiac index and the central venous pressure and increases in the systemic vascular resistance index and the heart rate. In response to resuscitation, the cardiac
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Table 1. Comparison of Peak Shed Blood Volume and Time Required to Reach the Target Resuscitation Mean Arterial Blood Pressure (70 mmHg) Between Groups
PSBV (mL/kg) Time to target resuscitation MABP (min)
LR Group
LR ⫹ AVP Group
p Value
42 ⫾ 2 31 ⫾ 5
40 ⫾ 2 26 ⫾ 4
0.236 0.432
NOTE. LR and LR ⫹ AVP indicate the resuscitation approach: (1) lactated Ringer’s solution and (2) lactated Ringer’s solution with arginine vasopressin, respectively. Data are expressed as mean ⫾ standard error of the mean. A p less than 0.05 is considered significant. Abbreviations: PSBV, peak shed blood volume; MABP, mean arterial blood pressure.
index in the LR group was restored to baseline levels, whereas the cardiac index in the LR ⫹ AVP group was near half of baseline values. The heart rate decreased more in the LR group than in the LR ⫹ AVP group. The pulmonary capillary wedge pressure showed no change between groups during resuscitation. The systemic vascular resistance index remained elevated in the LR ⫹ AVP group but decreased in the LR group (Table 3). Before starting, midway through, and upon completing the hemorrhage protocol, the metabolic parameters were similar between animals (data not shown). Both groups developed a rise in the plasma lactate and a decrease in the base excess from hemorrhagic shock. Animals resuscitated with LR ⫹ AVP developed a lactic acidemia, but animals resuscitated with LR had no change in the arterial pH and a slight decrease in the plasma lactate. The base excess decreased after resuscitation in the LR ⫹ AVP group and increased after resuscitation with LR. The plasma glucose and potassium and the hematocrit were unchanged between groups throughout the 60-minute resuscitation period. DISCUSSION
After a prolonged severe hemorrhagic insult leading to the onset of cardiovascular collapse, this study explored the impact of a continuous AVP infusion on the hemodynamic and metabolic function of swine during a 60-minute resuscitation period with LR. The most important finding was that AVP reduced resuscitation volume requirements to maintain a target MABP. This finding suggests that AVP may slow the rate of
Table 2. Comparison of the Rate of Crystalloid Resuscitation Volume (mL/kg/min) Between Groups Subject Number
LR Group
LR ⫹ AVP Group
1 2 3 4 5 6 7 8 Mean ⫾ SEM
1.1 1.4 1.1 0.7 0.9 0.9 0.8 1.0 ⫾ 0.1
0.3 0.7 0.6 0.3 0.7 1.0 0.6 0.2 0.5 ⫾ 0.1*
NOTE. LR and LR ⫹ AVP indicate the resuscitation approach: (1) lactated Ringer’s solution and (2) lactated Ringer’s solution with arginine vasopressin, respectively. A p less than 0.05 was considered significant. Abbreviation: SEM, standard error of the mean. *The p value between groups was less than 0.005.
cardiovascular collapse. Both conventional resuscitation with LR and resuscitation with LR ⫹ AVP improved the MABP, suggesting an improvement in cardiovascular function. However, changes in heart rate, cardiac index, and systemic vascular resistance index all revealed that hemodynamic function was more impaired after resuscitation using AVP ⫹ LR versus LR alone. Metabolic derangements as a consequence of hemorrhagic shock were worsened when vasopressin was added to the crystalloid infusion. These derangements are most likely the consequence of prolonged hypoperfusion of critical organs leading to an exacerbation of the lactic acidemia and base deficit. These findings show how AVP can be used to achieve a desired blood pressure yet exacerbate underlying metabolic and hemodynamic disturbances from prolonged hemorrhagic shock. Several investigators have explored the use of AVP in animal models as an adjunct in the management of hemorrhagic shock with encouraging results.1-3,5,18 Stadlbauer et al,1 using an elegant swine model of uncontrolled hemorrhage (liver laceration), explored prehospital resuscitation strategies after severe blood loss. In their protocol, exsanguination was rapid, requiring resuscitation within 20 to 30 minutes in order for animals to survive. They found AVP administered as an initial bolus of 0.4 U/kg followed by a continuous infusion of 0.08 U/kg/min for 30 minutes improved survival and neurologic outcome more effectively than crystalloid resuscitation or epinephrine infusions. In this setting, AVP showed a clear advantage over other more conventional approaches to resuscitation. Not all investigations using potent vasoconstrictors as an adjunct to managing hemorrhagic shock, however, have corroborated the administration of exogenous vasoconstrictors as a useful component of treatment for hemorrhagic shock. In a combined splenic laceration-brain injury hemorrhage model in swine, Alspaugh et al19 reported that early resuscitation with phenylephrine (15 g/kg for 30 minutes) improved survival rates over resuscitation with LR or no resuscitation, but that brain tissue samples revealed more extensive cerebral tissue damage in animals treated with phenylephrine. They concluded that prehospital resuscitation with LR decreases secondary brain injury compared with phenylephrine. After prolonged hemorrhage and resuscitation, the present authors found that a continuous infusion of AVP improved blood pressure at the expense of deteriorating hemodynamic and metabolic function. Hence, aggressive and/or prolonged use of a potent vasoconstrictive agent may have harmful consequences despite improving blood pressure. Morales et al5 conducted a study similar to this protocol in a canine isobaric hemorrhage model that explored the impact of
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Table 3. Hemodynamic and Metabolic Parameters After Hemorrhage and Resuscitation After Hemorrhage
Hemodynamic parameters Heart rate (beats/min) Cardiac index (L/min/m2) Central venous pressure (mmHg) Pulmonary artery occlusion pressure (mmHg) Systemic vascular resistance index (dynes/s/cm5/m2) Metabolic parameters Plasma lactate (mmol/L) Arterial pH Plasma Glucose (mg/dL) Hematocrit (%) Base Deficit (mmol/L) Potassium (meq/L)
End of Resuscitation
LR Group
LR ⫹ AVP Group
LR Group
LR ⫹ AVP Group
234 ⫾ 9 1.2 ⫾ 0.1 3⫾1 7⫾2 2549 ⫾ 200
253 ⫾ 7 1.2 ⫾ 0.1 2⫾1 7⫾2 2512 ⫾ 132
163 ⫾ 16 4.5 ⫾ 0.7 6⫾1 7⫾2 1362 ⫾ 316
221 ⫾ 7* 2.4 ⫾ 0.2* 4 ⫾ 1* 7⫾1 2386 ⫾ 295*
11 ⫾ 1.6 7.33 ⫾ 0.01 239 ⫾ 69 32.6 ⫾ 2.8 ⫺6.8 ⫾ 1.9 5.1 ⫾ 0.4
7.8 ⫾ 1.0 7.36 ⫾ 0.03 173 ⫾ 55 31.5 ⫾ 1.1 ⫺4.6 ⫾ 1.9 5.4 ⫾ 0.3
9.7 ⫾ 0.7 7.32 ⫾ 0.02 135 ⫾ 24 26.3 ⫾ 2.5 ⫺2.2 ⫾ 1.1 4.0 ⫾ 0.2
10.5 ⫾ 1.9* 7.21 ⫾ 0.07* 88 ⫾ 29 25.4 ⫾ 2.2 ⫺9 ⫾ 2.8* 4.6 ⫾ 0.3
NOTE. LR and LR ⫹ AVP indicate the resuscitation approach: (1) lactated Ringer’s solution and (2) lactated Ringer’s solution with arginine vasopressin, respectively. Data are presented as mean ⫾ standard error of the mean. Abbreviation: PSBV, peak shed blood volume. *A p value less than 0.05 between groups over the resuscitation period.
a continuous infusion of AVP on hemodynamic performance after the onset of cardiovascular collapse. In their study, animals were bled to a target MABP of 40 mmHg. Unlike the present hemorrhage protocol, animals in their study were held at 40 mmHg until approximately 50% of the shed blood had been returned. Although not reported, this would represent approximately 20 mL/kg of whole blood if the peak shed blood volume in dogs was similar to what was observed in swine. Subsequently, a norepinephrine infusion was started and found to be ineffective, followed by an AVP infusion, which restored the MABP to levels above 100 mmHg and produced an increasing trend in the cardiac output when compared with untreated controls, although the difference was not significant. No metabolic analysis was done. A few differences between the present work and that of Morales et al5 in study methods and results merit discussion. In the present protocol, AVP was initiated before any restoration of blood volume and coadministered with LR. Furthermore, the LR infusion was held when the MABP was greater than 70 mmHg. By contrast, in the protocol used by Morales et al, the intravascular volume was partially restored with shed whole blood before the start of AVP administration and additional crystalloid was then coadministered with the AVP to maintain a central venous pressure of greater than 5 mmHg. The present authors speculate that the extent of intravascular volume depletion in animals subjected to this study protocol was substantially more than that of animals subjected to the hemorrhage protocol used by Morales et al just before receiving an AVP infusion. With the potential differences in intravascular volume in mind, it is important to point out that the dose of AVP used by Morales et al5 was approximately one tenth lower than the dose used in this protocol (0.04 v 0.05 U/kg/min, respectively). Although the dose was lower, the response in blood pressure was large. Despite a faster AVP infusion rate, the MABP in the present study protocol never reached levels reported by Morales et al. A potential explanation for this difference is that a
partially restored intravascular compartment allows for a more pronounced effect from exogenous AVP. The authors also reported a significant drop in cardiac index in animals resuscitated with LR ⫹ AVP versus LR alone, whereas Morales et al reported an increasing trend in the cardiac output when compared with untreated controls. Again, the response in cardiac output to AVP may have been a function of intravascular volume depletion and the resultant preload deficit to the heart. Perhaps the most important limitation of this study is that long-term metrics of clinical outcome, namely neurologic function and mortality rates, were not explored. One possible outcome is that a comparison of these metrics between groups would be unremarkable. A potential cause for this finding might be that in the hemorrhage protocol that was so severe, no animal would survive (ie, greater than 24 hours), or, by contrast, the hemorrhage model is too mild such that all would survive with no neurologic deficit in either resuscitative approach. This study used a resuscitation protocol that does not reflect clinical practice. Resuscitation from severe hemorrhagic shock is rarely done with crystalloid alone.20 It is not clear how resuscitation with blood products or colloids would have influenced the results, but it is anticipated that restoration of the vascular volume and tissue oxygenation would have been more complete and the adverse cardiovascular and metabolic response to AVP would have been reduced. Another shortcoming of this study relates to the use of an isobaric hemorrhage model in swine to mimic what a patient in hemorrhagic shock might experience. Isobaric hemorrhage models are often criticized as being far removed from a typical clinical scenario, in part because severe blood loss associated with trauma or surgery does not occur as a controlled hemorrhage over time with a target MABP but more so as an uncontrolled hemorrhage with a highly variable MABP.21 However, a major advantage of the isobaric model is it brings each animal to the same degree of insult, as quantified by the shed blood volume, before resuscitation is initiated. Hemorrhagic shock is
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a dynamic process involving dramatic changes in cardiovascular and metabolic states that vary with time, species, and laboratory, and it was believed to be important to examine the effects of AVP at an equivalent stage of physiologic decompensation. This was best achieved with an isobaric model. This model permitted consistent administration of AVP at the onset of cardiovascular decompensation as manifested by the transition from removal to reinfusion of blood to maintain the target MABP. Achieving a consistent pathophysiologic endpoint using hemorrhage models that better simulate hemorrhage associated with trauma or surgery (ie, isovolemic or uncontrolled hemorrhage models) is difficult. An additional limitation is that unlike humans, endogenous release of vasopressin in swine is predominantly lysine vasopressin and not AVP. Hence, the vasoactive responses to exogenous AVP in swine may be different from what would be observed in humans. AVP, however, is pharmacologically ac-
tive in swine and has been successfully used in previous studies using swine hemorrhage-resuscitation models. Furthermore, only 1 dose of AVP was evaluated. Future work along this line of investigation should explore additional infusion rates to establish the dose response of AVP at the onset of cardiovascular decompensation. In conclusion, a continuous infusion of AVP decreased the crystalloid requirements to maintain a target MABP but exacerbated the hemodynamic and metabolic consequences of severe blood loss. Further investigation exploring the impact of AVP on mortality and neurologic function is warranted to clarify the role of AVP as a treatment in the delayed management of severe hemorrhagic shock. The results of this study show a potential drawback to the otherwise attractive features of AVP-assisted volume resuscitation and indicate that judicious use may be warranted, especially if prolonged infusions are required to maintain perfusion to vital organs.
REFERENCES 1. Stadlbauer KH, Wagner-Berger HG, Raedler C, et al: Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs. Anesthesiology 98:699-704, 2003 2. Voelckel WG, Lurie KG, Lindner KH, et al: Vasopressin improves survival after cardiac arrest in hypovolemic shock. Anesth Analg 91:627-634, 2000 3. Voelckel WG, Raedler C, Wenzel V, et al: Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med 31:1160-1165, 2003 4. Wang B, Flora-Ginter G, Leadley RJ: Ventricular receptors stimulate vasopressin release during hemorrahge. Am J Physiol 254:R204R211, 1988 5. Morales D, Madigan J, Cullinane S, et al: Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock. Circulation 100:226-229, 1999 6. Arnauld E, Czernichow P, Fumoux F: The effects of hypotension and hypovolaemia on the liberation of vasopressin during hemorrhage in the unanaesthetized monkey (Macaca Mulatta). Pflugers Arch Eur J Physiol 371:193-200, 1977 7. Kusano E, Tian S, Umino T, et al: Arginine vasopressin inhibits interleukin-1 beta-stimulated nitric oxide and cyclic guanosine monophosphate production via the V1 receptor in cultured rat vascular smooth muscle cells. J Hypertens 15:627-632, 1997 8. Umino T, Kusano E, Muto S, et al: AVP inhibits LPS- and IL-1beta-stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells. Am J Physiol 276:F433-F441, 1999 9. Moreau R, Barriere E, Tazi KA, et al: Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis. Hepatology 36:1070-1078, 2002 10. Bucher M, Hobbhahn J, Taeger K, et al: Cytokine-mediated downregulation of vasopressin V1a receptors during acute endotoxemia in rats. Am J Physiol Regul Integr Comp Physiol 282:R979-R984, 2002
11. Holmes CI, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock. Chest 120:989-1002, 2001 12. Chu CJ, Wu SL, Lee FY, et al: Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: Role of nitric oxide and bradykinin. Clin Sci (Lond) 99:475-482, 2000 13. Ko J, Williams B, Smith V, et al: Comparison of telazolketamine, telazol-xylazine, and telazol-ketamine-xylazine as chemical restraint and anesthetic induction combination in swine. Lab Anim Sci 43:476-480, 1993 14. Lundeen G, Manohar M, Parks C: Systemic distribution of blood flow in swine while awake and during 1.0 and 1.5 MAC isoflurane anesthesia with or without 50% nitrous oxide. Anesth Analg 62:499512, 1983 15. Holt J, Rhode E, Kines H: Ventricular volumes and body weight in mammals. Am J Physiol 215:704-715, 1968 16. Wiggers CJ: Physiology of Shock. New York, Oxford University Press, 1950, pp 121-146 17. Machin D, Campbell MJ: Statistical Tables for the Design of Clinical Trials. Oxford, Blackwell Scientific Publications, 1987 18. Voelckel WG, Lurie KG, McKnite S, et al: Comparison of epinephrine with vasopressin on bone marrow blood flow in an animal model of hypovolemic shock and subsequent cardiac arrest. Crit Care Med 29:1587-1592, 2001 19. Alspaugh DM, Sartorelli K, Shackford SR, et al: Prehospital resuscitation with phenylephrine in uncontrolled hemorrhagic shock and brain injury. J Trauma 48:851-863, 2000; discussion 863-864 20. American College of Surgeons Committee on Trauma: Advanced Trauma Life Support Course Handbook. Chicago, IL, American College of Surgeons, 1989 21. Bellamy RF, Maningas PA, Wenger BA: Current shock models and clinical correlations. Ann Emerg Med 15:1392-1395, 1986
infusion was compared between groups using an unpaired 2-tailed t test. Metabolic and hemodynamic parameters between groups over time were compared with a repeated measures analysis of variance. Vasopressin decreased the rate of crystalloid infusion during resuscitation by 50%. During resuscitation, the cardiac index in the crystalloid group was restored to near baseline levels and was decreased to near half of baseline levels in the vasopressin group. Animals in the vasopressin group developed a lactic acidemia, but animals in the crystalloid group revealed no change from baseline in the arterial pH and a slight decrease in the plasma lactate. Conclusions: Administration of vasopressin used as an adjunct to maintain blood pressure in the decompensatory phase of hemorrhagic shock slows cardiovascular collapse, but has an adverse effect on metabolic and hemodynamic function. Further investigation is warranted to clarify the role of vasopressin in the delayed management of severe hemorrhagic shock. © 2006 Elsevier Inc. All rights reserved.
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These mechanisms suggest that administering exogenous AVP in the late phases of hemorrhagic shock might reverse some of the adverse consequences of cardiovascular decompensation as shown by Morales et al.5 Even after severe prolonged hemorrhagic hypotension, blood pressure remained responsive to exogenous AVP. Prior work has shown the benefit of AVP administered as a continuous infusion in the management of both (1) acute severe blood loss and (2) prolonged hemorrhagic hypotension leading to cardiovascular collapse. This study sought to explore more thoroughly the metabolic and hemodynamic effects of AVP when administered after the onset of cardiovascular decompensation. The aim was to examine the value of administering exogenous AVP on (1) the rate of crystalloid infusion to maintain a target blood pressure, and (2) on hemodynamic function and metabolic homeostasis in response to volume resuscitation. It was hypothesized that exogenous AVP, used as an adjunct to volume resuscitation, would slow the rate of
XOGENOUSLY ADMINISTERED arginine vasopressin (AVP) has been found to improve survival and hemodynamic performance in animal models of severe uncontrolled blood loss. In the setting of acute large-volume blood loss, AVP, when compared with more conventional interventions, such as volume resuscitation or epinephrine, has been found to improve survival rates and neurologic function.1-3 This work suggests that AVP may become an important tool when treating hemorrhagic shock. The focus of these prior studies has explored the benefits of AVP when given early in a severe hemorrhagic insult. Several questions, however, warrant further investigation to define conditions in which AVP may be helpful or possibly harmful as an adjunct to treating hemorrhagic shock. Hemorrhagic shock is a potent stimulus for AVP release. During hemorrhage, AVP exhibits a biphasic change in plasma levels.4-6 In a canine isobaric hemorrhage model, plasma levels initially increased approximately 150-fold above baseline during early hemorrhage and then later fell after remaining in hemorrhagic shock for 2 hours.5 AVP, as a vasoconstrictor known to suppress nitric oxide production,7-9 may contribute to the compensatory cardiovascular mechanisms directed at preserving blood flow to vital organs. Waning AVP levels may play a role in the transition from reversible hypovolemia to cardiovascular decompensation. Potential AVP-related mechanisms of this transition include (1) a rise in circulating cytokines that downregulate certain types of AVP (ie, V1) receptors,10 (2) exhaustion of neurohypophyseal stores of AVP, (3) lack of autonomic stimulus to release AVP, (4) high circulating levels of norepinephrine that suppress AVP release,11 and (5) rising nitric oxide levels from the vascular endothelium within the posterior pituitary and elsewhere that inhibit AVP production and compete with its vasopressor effects.12
KEY WORDS: hemorrhagic shock, arginine vasopressin, resuscitation
From the *Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT; †Department of Resuscitative Medicine, Walter Reed Army Institute of Research, Silver Spring, MD; and ‡University of Michigan Hospitals and Health Centers, Ann Arbor, MI. Supported in part by a grant from the National Institute of Health, Bethesda, MD (grant no. K08GM00712) and by the Department of Anesthesiology, University of Utah. Address reprint requests to Ken B. Johnson, MD, Department of Anesthesiology, University of Utah School of Medicine, 30 North, 1900 East, Room 3C444, Salt Lake City, UT 84132-2304. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2002-0007$32.00/0 doi:10.1053/j.jvca.2005.11.015
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crystalloid infusion required to maintain a target resuscitation pressure but not improve other indices of hemodynamic performance and would exacerbate metabolic function already compromised from prolonged hemorrhagic hypotension. METHODS AND MATERIALS Experiments were performed using commercial farm-bred swine of either sex. The study was approved by the Institutional Animal Care and Use Committee at the University of Utah. Animals were bled to a shock state and then assigned to either a vasopressin or a control group (n ⫽ 8 for each group). In the AVP group, animals were resuscitated with a continuous AVP infusion and lactated Ringer’s solution (LR ⫹ AVP). In the control group, animals were resuscitated with only lactated Ringer’s solution (LR). Swine weighing 35.8 ⫾ 1.6 kg were commercially obtained and quarantined for 6 days in a temperature- and light-controlled environment. Animals had access to food and water ad libitum. Anesthesia was induced with an intramuscular injection of tiletamine HCl, 2.3 mg/kg, zolazepam, 2.3 mg/kg, ketamine, 2.3 mg/kg, and xylazine, 2.3 mg/kg, as described by Ko et al13 for pigs. Intravascular access was obtained from an ear vein. A continuous crystalloid infusion with lactated Ringer’s solution was administered through the peripheral ear vein to meet insensible fluid and electrolyte losses according to the following set of rules: 4 mL/kg/h for the first 10 kg, 2 mL/kg/h for the next 10 to 20 kg, and 1 mL/kg/h for each kilogram above 20 kg. Each animal’s trachea was then intubated, and the lungs were mechanically ventilated. Initial ventilator settings were a tidal volume of 8 to 10 mL/kg, a respiratory rate of 20 breaths per minutes, an FIO2 of 50%, and no positive end-expiratory pressure. Tissue oxygenation was monitored using continuous pulse oximetry placed on the tongue or ear. Ventilation was monitored using an inspired/expired gas analyzer that measured oxygen, carbon dioxide, and isoflurane concentrations. Ventilator settings were adjusted as needed to keep the pulse oximetry above 95% and the end-tidal CO2 at 38 ⫾ 4 mmHg. Once satisfactory ventilator settings were established, a baseline arterial blood gas was obtained. Ventilator settings were adjusted further if needed to maintain the arterial PCO2 at 40 ⫾ 4 mmHg. A continuous level of anesthesia was achieved with isoflurane and intermittent boluses of pancuronium (0.1 mg/kg). During animal instrumentation, expired isoflurane levels were monitored and kept at 1.0 minimum alveolar concentration equivalent for swine (an end-tidal isoflurane concentration of 1.6%14). Subcutaneous electrocardiograph electrodes were placed, and the electrocardiogram was monitored throughout the study. The left femoral artery was cannulated with a 16-G arterial sheath to monitor arterial blood pressure and heart rate continuously. The right femoral artery was cannulated with a 16-G arterial sheath for blood removal and subsequent reinfusion. An internal jugular vein was cannulated with a pulmonary artery catheter for intermittent measurements of central venous pressure, pulmonary capillary wedge pressure, and thermodilution estimates of cardiac output. Colonic temperatures were monitored and maintained at 37°C throughout the study with a heating/ cooling blanket and heating lamps as needed. Once access to the vascular compartment was obtained, each animal was anticoagulated with an intravenous bolus injection of heparin (100 U/kg). Cardiac index and systemic vascular resistance index were calculated by estimating the body surface area according to the following: body surface area ⫽ (K*[weight2/3])/100 m2, where K, a species constant, is 9 for swine,15 cardiac index ⫽ cardiac output/body surface area, and systemic vascular resistance index ⫽ systemic vascular resistance/body surface area. The arterial blood pressures were measured with a pressure transducer (Utah Medical, Midvale, UT). A computerized data acquisition system recorded the mean arterial blood pressure (MABP), systolic and
diastolic arterial pressures, heart rate, and shed blood volume every 5 seconds. After instrumentation, animals underwent a 30-minute stabilization period before initiating the hemorrhage resuscitation protocol. Once in the stabilization period, the isoflurane was reduced to 0.8% and maintained there for the remainder of the experiment. The hemorrhage protocol was designed to ensure that each animal was at an equivalent degree of metabolic compromise from hemorrhagic shock before initiating resuscitation. This was accomplished by using an isobaric hemorrhage model as described by Wiggers.16 Animals were bled via an arterial line feeding through a roller pump. The roller pump was controlled by a computer. Shed blood was stored in a reservoir placed on a scale. Shed blood volume was measured by weight. Via a second arterial line, MABP was continuously acquired by the computer controlling the roller pump. Blood was removed at a rate required to achieve a linear decrease in the MABP to 40 mmHg over 20 minutes. Blood was then removed or reinfused by the servo-controlled roller pump to maintain the MABP at 40 mmHg. The compensatory phase of hemorrhagic shock was defined as the time during which blood had to be removed to maintain the MABP at 40 mmHg. The decompensatory phase of hemorrhagic shock was defined as the time period during which blood had to be reinfused to maintain the MABP at 40 mmHg. The peak shed blood volume was defined as the maximum amount of blood removed during the isobaric hemorrhage process. Upon reaching the peak shed blood volume, the target MABP was changed from 40 to 70 mmHg. The shed blood volume stored in a reservoir placed on the scale was replaced with a reservoir of LR solution. In the control group, LR was intravenously infused to achieve and maintain the MABP at 70 mmHg for 60 minutes. In the experimental group, in addition to LR, AVP, 0.05 U/kg/min, was intravenously infused during the resuscitation period. The dose of 0.05 U/kg/ min was based on infusion doses found to be effective in treating hemorrhagic shock in swine and rodents1,5 and delivered using a syringe pump (Medfusion 2010i; Medex Inc, Duluth, GA). Arterial blood samples for determining pH, PO2, PCO2, bicarbonate, base excess, lactate, glucose, potassium, and hematocrit were measured using a blood gas and chemistry analyzer (Model Number ABL 725; Radiometer America, Westlake, OH). Samples were obtained before hemorrhage, upon reaching 50% of the estimated peak shed blood volume, upon achieving the actual peak shed blood volume, and after the 60-minute resuscitation period. Metrics of comparison between groups included (1) the rate of crystalloid infusion (mL/kg/min) required to maintain the target MABP at 70 mmHg, and (2) changes in hemodynamic and metabolic parameters during the resuscitation period. The rate of crystalloid infusion was compared between groups using an unpaired 2-tailed t test. A power analysis revealed that with a type I margin of error set to 0.05 and 80% power to detect a mean difference of at least 0.3 mL/kg/min in the rate of crystalloid infusion between groups, a sample size of 8 would be required in each group assuming a standard deviation of 0.3.17 Metabolic and hemodynamic parameters were compared between groups over the duration of the resuscitation period using a repeated measures analysis of variance. A p value ⬍0.05 was considered significant. Data are expressed as mean ⫾ standard error of the mean. RESULTS
Animals required 91 ⫾ 8 minutes to reach their respective peak shed blood volumes. One animal in the LR group was not resuscitated according to the study protocol and was removed from the analysis. A plot of the typical time course for MABP, shed blood volume, and resuscitation volume for animals in each group is presented in Figure 1. The peak shed blood volume and time required to reach the target MABP were
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Panel A. Lactated Ringer’s Only Crystalloid Resuscitation
Hemorrhage
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10
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40
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160
Lactated Ringer’s Resuscitation (mL/kg)
Target MABP 70 mmHg
100
Shed Blood Volume (mL/kg)
MABP (mmHg)
Target MABP 40 mmHg
Time (minutes)
Panel B. Lactated Ringer’s and Vasopressin Crystalloid Resuscitation
Hemorrhage
30
80
25 70 20 60 15 50
10
40
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Lactated Ringer’s Resuscitation (mL/kg)
Target MABP 70 mmHg
Shed Blood Volume (mL/kg)
MABP (mmHg)
Target MABP 40 mmHg
Time (minutes)
MABP Shed Blood Volume Resuscitation Volume Fig 1. Typical time course for the mean arterial blood pressure (MABP, solid line), shed blood volume (dashed line), and resuscitation volume (dash-dot line) during the study period for animals resuscitated with lactated Ringer’s solution (A) and lactated Ringer’s solution combined with a continuous infusion of vasopressin (B).
similar between groups (Table 1). The rate of crystalloid infusion was significantly slower in the LR ⫹ AVP group (Table 2). Animals resuscitated with LR required 1.7-fold more LR over the 60-minute period than the animals resuscitated with LR ⫹ AVP.
After hemorrhage, there were no significant differences in hemodynamic parameters between groups. Both groups developed decreases in the cardiac index and the central venous pressure and increases in the systemic vascular resistance index and the heart rate. In response to resuscitation, the cardiac
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Table 1. Comparison of Peak Shed Blood Volume and Time Required to Reach the Target Resuscitation Mean Arterial Blood Pressure (70 mmHg) Between Groups
PSBV (mL/kg) Time to target resuscitation MABP (min)
LR Group
LR ⫹ AVP Group
p Value
42 ⫾ 2 31 ⫾ 5
40 ⫾ 2 26 ⫾ 4
0.236 0.432
NOTE. LR and LR ⫹ AVP indicate the resuscitation approach: (1) lactated Ringer’s solution and (2) lactated Ringer’s solution with arginine vasopressin, respectively. Data are expressed as mean ⫾ standard error of the mean. A p less than 0.05 is considered significant. Abbreviations: PSBV, peak shed blood volume; MABP, mean arterial blood pressure.
index in the LR group was restored to baseline levels, whereas the cardiac index in the LR ⫹ AVP group was near half of baseline values. The heart rate decreased more in the LR group than in the LR ⫹ AVP group. The pulmonary capillary wedge pressure showed no change between groups during resuscitation. The systemic vascular resistance index remained elevated in the LR ⫹ AVP group but decreased in the LR group (Table 3). Before starting, midway through, and upon completing the hemorrhage protocol, the metabolic parameters were similar between animals (data not shown). Both groups developed a rise in the plasma lactate and a decrease in the base excess from hemorrhagic shock. Animals resuscitated with LR ⫹ AVP developed a lactic acidemia, but animals resuscitated with LR had no change in the arterial pH and a slight decrease in the plasma lactate. The base excess decreased after resuscitation in the LR ⫹ AVP group and increased after resuscitation with LR. The plasma glucose and potassium and the hematocrit were unchanged between groups throughout the 60-minute resuscitation period. DISCUSSION
After a prolonged severe hemorrhagic insult leading to the onset of cardiovascular collapse, this study explored the impact of a continuous AVP infusion on the hemodynamic and metabolic function of swine during a 60-minute resuscitation period with LR. The most important finding was that AVP reduced resuscitation volume requirements to maintain a target MABP. This finding suggests that AVP may slow the rate of
Table 2. Comparison of the Rate of Crystalloid Resuscitation Volume (mL/kg/min) Between Groups Subject Number
LR Group
LR ⫹ AVP Group
1 2 3 4 5 6 7 8 Mean ⫾ SEM
1.1 1.4 1.1 0.7 0.9 0.9 0.8 1.0 ⫾ 0.1
0.3 0.7 0.6 0.3 0.7 1.0 0.6 0.2 0.5 ⫾ 0.1*
NOTE. LR and LR ⫹ AVP indicate the resuscitation approach: (1) lactated Ringer’s solution and (2) lactated Ringer’s solution with arginine vasopressin, respectively. A p less than 0.05 was considered significant. Abbreviation: SEM, standard error of the mean. *The p value between groups was less than 0.005.
cardiovascular collapse. Both conventional resuscitation with LR and resuscitation with LR ⫹ AVP improved the MABP, suggesting an improvement in cardiovascular function. However, changes in heart rate, cardiac index, and systemic vascular resistance index all revealed that hemodynamic function was more impaired after resuscitation using AVP ⫹ LR versus LR alone. Metabolic derangements as a consequence of hemorrhagic shock were worsened when vasopressin was added to the crystalloid infusion. These derangements are most likely the consequence of prolonged hypoperfusion of critical organs leading to an exacerbation of the lactic acidemia and base deficit. These findings show how AVP can be used to achieve a desired blood pressure yet exacerbate underlying metabolic and hemodynamic disturbances from prolonged hemorrhagic shock. Several investigators have explored the use of AVP in animal models as an adjunct in the management of hemorrhagic shock with encouraging results.1-3,5,18 Stadlbauer et al,1 using an elegant swine model of uncontrolled hemorrhage (liver laceration), explored prehospital resuscitation strategies after severe blood loss. In their protocol, exsanguination was rapid, requiring resuscitation within 20 to 30 minutes in order for animals to survive. They found AVP administered as an initial bolus of 0.4 U/kg followed by a continuous infusion of 0.08 U/kg/min for 30 minutes improved survival and neurologic outcome more effectively than crystalloid resuscitation or epinephrine infusions. In this setting, AVP showed a clear advantage over other more conventional approaches to resuscitation. Not all investigations using potent vasoconstrictors as an adjunct to managing hemorrhagic shock, however, have corroborated the administration of exogenous vasoconstrictors as a useful component of treatment for hemorrhagic shock. In a combined splenic laceration-brain injury hemorrhage model in swine, Alspaugh et al19 reported that early resuscitation with phenylephrine (15 g/kg for 30 minutes) improved survival rates over resuscitation with LR or no resuscitation, but that brain tissue samples revealed more extensive cerebral tissue damage in animals treated with phenylephrine. They concluded that prehospital resuscitation with LR decreases secondary brain injury compared with phenylephrine. After prolonged hemorrhage and resuscitation, the present authors found that a continuous infusion of AVP improved blood pressure at the expense of deteriorating hemodynamic and metabolic function. Hence, aggressive and/or prolonged use of a potent vasoconstrictive agent may have harmful consequences despite improving blood pressure. Morales et al5 conducted a study similar to this protocol in a canine isobaric hemorrhage model that explored the impact of
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Table 3. Hemodynamic and Metabolic Parameters After Hemorrhage and Resuscitation After Hemorrhage
Hemodynamic parameters Heart rate (beats/min) Cardiac index (L/min/m2) Central venous pressure (mmHg) Pulmonary artery occlusion pressure (mmHg) Systemic vascular resistance index (dynes/s/cm5/m2) Metabolic parameters Plasma lactate (mmol/L) Arterial pH Plasma Glucose (mg/dL) Hematocrit (%) Base Deficit (mmol/L) Potassium (meq/L)
End of Resuscitation
LR Group
LR ⫹ AVP Group
LR Group
LR ⫹ AVP Group
234 ⫾ 9 1.2 ⫾ 0.1 3⫾1 7⫾2 2549 ⫾ 200
253 ⫾ 7 1.2 ⫾ 0.1 2⫾1 7⫾2 2512 ⫾ 132
163 ⫾ 16 4.5 ⫾ 0.7 6⫾1 7⫾2 1362 ⫾ 316
221 ⫾ 7* 2.4 ⫾ 0.2* 4 ⫾ 1* 7⫾1 2386 ⫾ 295*
11 ⫾ 1.6 7.33 ⫾ 0.01 239 ⫾ 69 32.6 ⫾ 2.8 ⫺6.8 ⫾ 1.9 5.1 ⫾ 0.4
7.8 ⫾ 1.0 7.36 ⫾ 0.03 173 ⫾ 55 31.5 ⫾ 1.1 ⫺4.6 ⫾ 1.9 5.4 ⫾ 0.3
9.7 ⫾ 0.7 7.32 ⫾ 0.02 135 ⫾ 24 26.3 ⫾ 2.5 ⫺2.2 ⫾ 1.1 4.0 ⫾ 0.2
10.5 ⫾ 1.9* 7.21 ⫾ 0.07* 88 ⫾ 29 25.4 ⫾ 2.2 ⫺9 ⫾ 2.8* 4.6 ⫾ 0.3
NOTE. LR and LR ⫹ AVP indicate the resuscitation approach: (1) lactated Ringer’s solution and (2) lactated Ringer’s solution with arginine vasopressin, respectively. Data are presented as mean ⫾ standard error of the mean. Abbreviation: PSBV, peak shed blood volume. *A p value less than 0.05 between groups over the resuscitation period.
a continuous infusion of AVP on hemodynamic performance after the onset of cardiovascular collapse. In their study, animals were bled to a target MABP of 40 mmHg. Unlike the present hemorrhage protocol, animals in their study were held at 40 mmHg until approximately 50% of the shed blood had been returned. Although not reported, this would represent approximately 20 mL/kg of whole blood if the peak shed blood volume in dogs was similar to what was observed in swine. Subsequently, a norepinephrine infusion was started and found to be ineffective, followed by an AVP infusion, which restored the MABP to levels above 100 mmHg and produced an increasing trend in the cardiac output when compared with untreated controls, although the difference was not significant. No metabolic analysis was done. A few differences between the present work and that of Morales et al5 in study methods and results merit discussion. In the present protocol, AVP was initiated before any restoration of blood volume and coadministered with LR. Furthermore, the LR infusion was held when the MABP was greater than 70 mmHg. By contrast, in the protocol used by Morales et al, the intravascular volume was partially restored with shed whole blood before the start of AVP administration and additional crystalloid was then coadministered with the AVP to maintain a central venous pressure of greater than 5 mmHg. The present authors speculate that the extent of intravascular volume depletion in animals subjected to this study protocol was substantially more than that of animals subjected to the hemorrhage protocol used by Morales et al just before receiving an AVP infusion. With the potential differences in intravascular volume in mind, it is important to point out that the dose of AVP used by Morales et al5 was approximately one tenth lower than the dose used in this protocol (0.04 v 0.05 U/kg/min, respectively). Although the dose was lower, the response in blood pressure was large. Despite a faster AVP infusion rate, the MABP in the present study protocol never reached levels reported by Morales et al. A potential explanation for this difference is that a
partially restored intravascular compartment allows for a more pronounced effect from exogenous AVP. The authors also reported a significant drop in cardiac index in animals resuscitated with LR ⫹ AVP versus LR alone, whereas Morales et al reported an increasing trend in the cardiac output when compared with untreated controls. Again, the response in cardiac output to AVP may have been a function of intravascular volume depletion and the resultant preload deficit to the heart. Perhaps the most important limitation of this study is that long-term metrics of clinical outcome, namely neurologic function and mortality rates, were not explored. One possible outcome is that a comparison of these metrics between groups would be unremarkable. A potential cause for this finding might be that in the hemorrhage protocol that was so severe, no animal would survive (ie, greater than 24 hours), or, by contrast, the hemorrhage model is too mild such that all would survive with no neurologic deficit in either resuscitative approach. This study used a resuscitation protocol that does not reflect clinical practice. Resuscitation from severe hemorrhagic shock is rarely done with crystalloid alone.20 It is not clear how resuscitation with blood products or colloids would have influenced the results, but it is anticipated that restoration of the vascular volume and tissue oxygenation would have been more complete and the adverse cardiovascular and metabolic response to AVP would have been reduced. Another shortcoming of this study relates to the use of an isobaric hemorrhage model in swine to mimic what a patient in hemorrhagic shock might experience. Isobaric hemorrhage models are often criticized as being far removed from a typical clinical scenario, in part because severe blood loss associated with trauma or surgery does not occur as a controlled hemorrhage over time with a target MABP but more so as an uncontrolled hemorrhage with a highly variable MABP.21 However, a major advantage of the isobaric model is it brings each animal to the same degree of insult, as quantified by the shed blood volume, before resuscitation is initiated. Hemorrhagic shock is
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a dynamic process involving dramatic changes in cardiovascular and metabolic states that vary with time, species, and laboratory, and it was believed to be important to examine the effects of AVP at an equivalent stage of physiologic decompensation. This was best achieved with an isobaric model. This model permitted consistent administration of AVP at the onset of cardiovascular decompensation as manifested by the transition from removal to reinfusion of blood to maintain the target MABP. Achieving a consistent pathophysiologic endpoint using hemorrhage models that better simulate hemorrhage associated with trauma or surgery (ie, isovolemic or uncontrolled hemorrhage models) is difficult. An additional limitation is that unlike humans, endogenous release of vasopressin in swine is predominantly lysine vasopressin and not AVP. Hence, the vasoactive responses to exogenous AVP in swine may be different from what would be observed in humans. AVP, however, is pharmacologically ac-
tive in swine and has been successfully used in previous studies using swine hemorrhage-resuscitation models. Furthermore, only 1 dose of AVP was evaluated. Future work along this line of investigation should explore additional infusion rates to establish the dose response of AVP at the onset of cardiovascular decompensation. In conclusion, a continuous infusion of AVP decreased the crystalloid requirements to maintain a target MABP but exacerbated the hemodynamic and metabolic consequences of severe blood loss. Further investigation exploring the impact of AVP on mortality and neurologic function is warranted to clarify the role of AVP as a treatment in the delayed management of severe hemorrhagic shock. The results of this study show a potential drawback to the otherwise attractive features of AVP-assisted volume resuscitation and indicate that judicious use may be warranted, especially if prolonged infusions are required to maintain perfusion to vital organs.
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11. Holmes CI, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock. Chest 120:989-1002, 2001 12. Chu CJ, Wu SL, Lee FY, et al: Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: Role of nitric oxide and bradykinin. Clin Sci (Lond) 99:475-482, 2000 13. Ko J, Williams B, Smith V, et al: Comparison of telazolketamine, telazol-xylazine, and telazol-ketamine-xylazine as chemical restraint and anesthetic induction combination in swine. Lab Anim Sci 43:476-480, 1993 14. Lundeen G, Manohar M, Parks C: Systemic distribution of blood flow in swine while awake and during 1.0 and 1.5 MAC isoflurane anesthesia with or without 50% nitrous oxide. Anesth Analg 62:499512, 1983 15. Holt J, Rhode E, Kines H: Ventricular volumes and body weight in mammals. Am J Physiol 215:704-715, 1968 16. Wiggers CJ: Physiology of Shock. New York, Oxford University Press, 1950, pp 121-146 17. Machin D, Campbell MJ: Statistical Tables for the Design of Clinical Trials. Oxford, Blackwell Scientific Publications, 1987 18. Voelckel WG, Lurie KG, McKnite S, et al: Comparison of epinephrine with vasopressin on bone marrow blood flow in an animal model of hypovolemic shock and subsequent cardiac arrest. Crit Care Med 29:1587-1592, 2001 19. Alspaugh DM, Sartorelli K, Shackford SR, et al: Prehospital resuscitation with phenylephrine in uncontrolled hemorrhagic shock and brain injury. J Trauma 48:851-863, 2000; discussion 863-864 20. American College of Surgeons Committee on Trauma: Advanced Trauma Life Support Course Handbook. Chicago, IL, American College of Surgeons, 1989 21. Bellamy RF, Maningas PA, Wenger BA: Current shock models and clinical correlations. Ann Emerg Med 15:1392-1395, 1986