ORIGINAL ARTICLE
Hypotensive resuscitation in combination with arginine vasopressin may prolong the hypotensive resuscitation time in uncontrolled hemorrhagic shock rats Guangming Yang, MD, Yi Hu, MD, Xiaoyong Peng, MS, Yu Zhu, MS, Jiatao Zang, MS, Tao Li, MD, and Liangming Liu, MD, PhD, Chongqing, China
BACKGROUND: The optimal resuscitation strategy for traumatic hemorrhagic shock is not completely determined. The objective of the present study was to investigate whether hypotensive resuscitation in combination with arginine vasopressin (AVP) can prolong the hypotensive resuscitation time by minimizing blood loss and stabilizing hemodynamics for uncontrolled hemorrhagic shock. METHODS: With an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions. RESULTS: Hypotensive resuscitation in combination with AVP maintenance for 3 hours significantly reduced total blood loss and fluid requirement during hypotensive resuscitation period and significantly improved the survival of shock rats as compared with hypotensive resuscitation alone. Among the four concentrations of AVP, 5 10j4 U/mL had the best effect: it significantly improved hemodynamics and increased cardiac function, oxygen delivery, as well as hepatic blood flow and hepatic function in the shock rats. However, renal blood flow in the hypotensive resuscitation + AVP group was lower than that in the hypotensive resuscitation alone group. CONCLUSION: Hypotensive resuscitation in combination with early application of AVP could prolong the tolerance time of hypotensive resuscitation and ‘‘buy’’ longer safe prehospital transport time by reducing blood loss and stabilizing hemodynamics. This strategy may be a promising strategy for the early management of trauma patients with active bleeding. (J Trauma Acute Care Surg. 2015;78: 760Y766. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved.) KEY WORDS: Uncontrolled hemorrhagic shock; hypotensive resuscitation; arginine vasopressin; rats.
T
rauma is the leading cause of death for the population younger than 40 years; it has become a global health problem, with more than 10,000 deaths per day worldwide.1,2 Hemorrhage and subsequently hemorrhagic shock remain the major cause of mortality after trauma. Fluid resuscitation is the ‘‘cornerstone’’ of the therapy of hemorrhagic shock during the last decades.1,3 However, uncontrolled bleeding is often seen in trauma patients (known as uncontrolled hemorrhagic shock), and the ‘‘classic’’ fluid resuscitation (aggressive resuscitation) is deleterious for this condition3,4 because large volume of fluid infusion before bleeding is controlled can induce further blood loss and severe hemodilution. So, hypotensive resuscitation or limited fluid resuscitation emerged and was advocated. Animal studies and clinic trials showed that hypotensive resuscitation resulted in better outcomes than did large-volume fluid resuscitation.4Y7 However, hypotensive resuscitation cannot provide a stable hemodynamics for a long time. Our previous studies suggested that for uncontrolled hemorrhagic shock, 90 minutes Submitted: September 28, 2014, Revised: November 23, 2014, Accepted: November 26, 2014, Published online: March 4, 2015. From the State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China. Address for reprints: Tao Li, PhD, and Liangming Liu, MD, PhD, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Daping, Chongqing 400042, China; email: [email protected], [email protected]. DOI: 10.1097/TA.0000000000000564
of hypotensive resuscitation was the maximal tolerance limit for the body; more than 90 minutes of hypotensive resuscitation caused severe organ damage and worse outcome.8 Unfortunately, the time required for prehospital transport may often be more than 90 minutes in some remote regions or in some disaster situations.9 So, an effective strategy that can prolong the tolerance time for hypotensive resuscitation is urgently needed. Arginine vasopressin (AVP) is an endogenous hormone, which has only a minor effect on blood pressure under physiologic condition. However, under shock state, AVP shows a potent vasoconstriction and vasopressor effect, both in vasodilatory septic shock and hemorrhagic shock patients. A recent study with a rat model of uncontrolled hemorrhagic shock by an 80% tail amputation showed improved hemodynamics and outcome after treatment with AVP or terlipressin (an analog of AVP).10 This study observed only a shorter ‘‘hypotension’’ time (40 minutes) before the active bleeding was controlled, and a bolus injection of AVP was given, which rapidly increased the mean arterial pressure (MAP) up to 120 mm Hg. However, the rapid elevation of blood pressure during uncontrolled hemorrhage is contradictory to the concept of the hypotensive resuscitation according to European trauma guidelines.11 Our previous studies revealed that AVP could significantly strengthen vasoconstriction following shock. Early application of AVP plus norepinephrine (NE) could maintain MAP at 55 mm Hg for 3 hours and win ‘‘time’’ to bring about definitive treatment for uncontrolled hemorrhagic shock.12Y15 In this study, we wanted to know if hypotensive resuscitation in combination with early J Trauma Acute Care Surg Volume 78, Number 4
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application of AVP can prolong tolerance time of hypotensive resuscitation and improve resuscitative effects, by minimizing blood loss and maintaining hemodynamics. It is aimed to search for an effective treatment strategy for traumatic hemorrhagic shock at prehospital stage. To elucidate this issue, with an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain the blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions.
MATERIALS AND METHODS Ethical Approval This study was approved by the Research Council and Animal Care and Use Committee of Research Institute of Surgery, Daping Hospital, Third Military Medical University. The investigation conformed to the Guide for the Care and Use of Laboratory Animals (8th ed. Washington, DC: National Academies Press; 2011).16
Animal Preparation Two hundred sixteen Sprague-Dawley rats (220Y260 g, both male and female) were anesthetized with sodium pentobarbital and Jingsongling (xylidinothiazole) using an established protocol.12,13 The right femoral arteries and veins were catheterized for monitoring the MAP and administration, respectively. The left ventricle of the heart was catheterized via the right carotid artery for monitoring hemodynamics. Uncontrolled hemorrhagic shock model was induced by transection of the splenic parenchyma and one of the branches of the splenic artery and vein as previously described.17 Briefly, after laparotomy, a crosstransection was made in splenic parenchyma between the two major branches of the splenic artery. Simultaneously, one of the major branches of the splenic artery and vein was also transected. Blood was allowed to freely flow into the abdominal cavity. When the MAP decreased to 40 mm Hg, uncontrolled hemorrhagic shock modelwas established for the following experiments. At the end of all the experiments, all animals were euthanatized with a pentobarbital-based euthanasia solution (Sleepaway, 2 mL, intravenously administered).18
Experimental Protocol Experimental Phases and Management Experiments were divided into four phases. Phase I was the uncontrolled hemorrhagic shock period (shock model stage), in which blood was allowed to freely flow into the abdominal cavity. This period was maintained for 20 minutes to 30 minutes. Phase II was the hypotensive resuscitation + AVP application period, in which the MAP was maintained at 50 mm Hg for 3 hours (target MAP) by continuous infusion of different concentrations of AVP along with the lactated Ringer’s solution plus 6% hydroxyethyl starch 130, at a ratio of 1:2 (LR + HES). The concentrations of AVP in LR + HES were 1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL. In this phase, the amount of fluid requirement and AVP administered were dependent on the maintenance of the target MAP; the control group was solely hypotensive resuscitation group. At the end of this phase, the bleeding was controlled by ligation of the spleen and vessels. Phase III was the definitive treatment period, in which rats received two volumes of blood loss of LR + whole blood (1:1), to maintain MAP at 80 mm Hg for 2 hours. Phase IV was the observation period. The hemodynamics, the cardiac function, the blood flow of liver/kidney, and their function were observed, and the time was 2 hours. In addition, the animal survival time and survival rate were also observed, and the time was 24 hours from the beginning of Phase IV (Fig. 1).
Animal Survival, Blood Loss, and Fluid Requirement Eighty Sprague-Dawley rats were randomly divided into five groups (n = 16 per group): hypotensive resuscitation control group and hypotensive resuscitation with AVP (1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL) groups. The experimental phase and fluid infusion procedures were the same as those discussed in the Experimental Phases and Management section. At the end of Phase II, blood loss during Phases I and II was recorded. The amounts of fluid infusion during Phases II and III were also noted. At the end of Phase III, the catheters were removed, the incisions were closed, and the animal survival time was observed to 24 hours after the onset of Phase IV.
Hemodynamics Another forty Sprague-Dawley rats were also randomly divided into five groups and treated identically as described
Figure 1. Experimental protocol (schematic). Phase I, establishment of a model of uncontrolled hemorrhagic shock. Phase II, continuous infusion of AVP along with LR + HES to maintain MAP at 50 mm Hg for 3 hours. Phase III, control of bleeding and maintenance of MAP at 80 mm Hg for 2 hours. Phase IV, observation period. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
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earlier (n = 8 per group). Hemodynamic parameters including MAP, left intraventricular systolic pressure (LVSP), and the maximal change rate of left intraventricular pressure (Tdp/dtmax) were determined at baseline; at the end of Phases I, II, and III; and at 2 hours in Phase IV, with a polygraph physiologic recorder (SP844, AD Instruments, Castle Hill, Australia).
Cardiac Function, Oxygen Delivery, and Oxygen Use
According to the results mentioned earlier, 5 10j4 U/mL AVP showed a better effect among the four doses of AVP, so, this dose of AVP was used in further experiments. Sixteen rats in this experiment were divided into two groups (n = 8 per group): hypotensive resuscitation control group and hypotensive resuscitation + AVP (5 10j4 U/mL) group. The experimental phase and procedures were the same as those discussed in the Experimental Phases and Management section. Cardiac output (CO), cardiac index (CI), oxygen delivery (DO2), and oxygen use (VO2) were observed at baseline; at the end of Phases I, II, and III; and at 2 hours in Phase IV. CO was measured by a Cardiomax-III machine (Columbus Instruments, Columbus, OH). The values of CI, DO2, and VO2 were calculated based on CO and arterial and venous blood gases as described in our previous work.8 Blood gases were measured with a blood gas analyzer (Phox plus L, Nova Biomedical, Waltham, MA). The formulas of DO2 and VO2 were as follows: DO2 = CI 13.4 hemoglobin SaO2 and VO2 = CI 13.4 hemoglobin (SaO2 j SvO2) (where SaO2 is the oxygen saturation of the artery and SvO2 is the oxygen saturation of the vein).
Blood Flow of Liver and Kidney and Their Functions Including Mitochondrial Function An additional eighty Sprague-Dawley rats were also divided into two groups (n = 8 for each group at each time point): hypotensive resuscitation control group and hypotensive resuscitation + AVP (5 10j4 U/mL) group. In this experiment, at each time point (at baseline; at the end of Phases I, II, and III; and at 2 hours in Phase IV), a laparotomy was performed for the measurement of blood flow in the liver and kidney with a laser Doppler blood flowmeter (Feriflux system 5000, Perimed, Stockholm, Sweden). The blood sample was withdrawn for the determination of liver and kidney function (including aspartate aminotransferase [AST], alanine aminotransferase [ALT], blood urea nitrogen [BUN], and serum creatinine [Scr]) by a biochemical analyzer (Beckman, Fullerton, CA). Thereafter, the rats were killed by a pentobarbital-based euthanasia solution (Sleepaway, 2 mL, intravenously administered) to remove the liver and kidney for the measurement of their mitochondrial function by a mitochondrial function analyzer (MT 200, Strathkelvin, Lanarkshire, Scotland). The mitochondrial function was reflected by the respiration control rate (consumed oxygen rate with and without adenosine diphosphate), which was determined as described in our previous work.7
Statistical Analysis Data are presented as mean (SD). The difference between the experimental groups was analyzed by one- or two-factor analyses of variance using SPSS 13.0 software, followed by post hoc Tukey tests. p G 0.05 was considered significant. 762
RESULTS Animal Survival, Blood Loss, and Fluid Requirement Survival The 24-hour survival rate for shock rats in the hypotensive resuscitation control group was 1 (6%) of 16, and the survival time was 2.8 (3.3) hours. AVP (5 10j4 U/mL) in combination with hypotensive resuscitation significantly increased the survival time (13.7 [7.9] hours) and 24-hour survival rate (7 of 16, 44%) for uncontrolled hemorrhagic shock rats as compared with the hypotensive resuscitation control rats. The other three doses of AVP only slightly increased the survival time and 24-hour survival rate, which were 4.3 (3.9) hours and 3 (19%) of 16; 9.0 (8.4) hours and 4 (25%) of 16; and 8.0 (6.6) hours and 2 (13%) of 16 in AVP 1 10j4, 1 10j3, and 5 10j3 U/mL groups, respectively (Fig. 2A and B).
Blood Loss At the end of Phase II, blood loss in the hypotensive resuscitation control group was 19.8 (5.2) mL. Hypotensive resuscitation + AVP (1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL) significantly decreased blood loss as compared with the hypotensive resuscitation control group; they were 13.2 (3.3) mL, 14.4 (2.7) mL, 14.1 (4.0) mL, and 13.2 (3.9) mL, respectively (p G 0.05) (Fig. 2C).
Fluid Requirement The fluid requirement in the hypotensive resuscitation control group during Phase II (hypotensive resuscitation period, maintenance of MAP at 50 mm Hg for 3 hours) and Phase III (definitive treatment period, maintenance of MAP at 80 mm Hg for 2 hours) was 22.9 (3.3) mL and 26.5 (4.3) mL, respectively. Application of AVP significantly reduced the fluid requirement
Figure 2. Effects of hypotensive resuscitation + AVP on animal survival, blood loss, and fluid requirement in uncontrolled hemorrhagic shock rats. Data are presented as mean (SD) (n = 16 per group). A and B, Survival number and survival time. C, Blood loss during Phase I plus Phase II. D, Fluid requirement during Phases II and III. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
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as compared with the control group ( p G 0.05 È 0.01). In the hypotensive resuscitation + AVP 1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL groups, the fluid requirement during Phase II was 11.4 (3.2) mL, 10.4 (2.2) mL, 10.7 (4.0) mL, and 10.3 (3.0) mL, respectively, and it was 16.2 (6.3) mL, 16.5 (2.4) mL, 17.3 (4.9) mL, and 16.2 (5.0) mL during Phase III, respectively (Fig. 2D).
resuscitation control group were slightly increased during Phase III and then gradually decreased during Phase IV, while they were significantly increased and maintained at a higher level in hypotensive resuscitation + AVP groups. Among the AVP groups, 5 10j4 U/mL AVP had the best effect (Table 1).
Hemodynamics MAP
At the end of Phase I, the CO and CI were significantly decreased in all groups. They were only slightly increased in the hypotensive resuscitation group during Phases II, III, and IV, while they were significantly increased in the hypotensive resuscitation + AVP group and were significantly higher than those in the hypotensive resuscitation control group ( p G 0.01) (Fig. 3A and B).
Cardiac Function, DO2, and VO2 CO and CI
During Phase II and Phase III, the MAP in all groups was maintained at the target pressure (50 mm Hg and 80 mm Hg, respectively). After Phase III, the MAP could not be maintained in the hypotensive resuscitation control group and gradually decreased to 66 mm Hg at 2 hours during Phase IV. The MAP in the hypotensive resuscitation + AVP groups maintained a stable and higher level during Phase IV. Among all groups, the hypotensive resuscitation + AVP at the concentration of 5 10j4 U/mL had the best effect for improving the MAP, which was close to the normal MAP level during Phase IV.
DO2 and VO2 DO2 and VO2 were also decreased after shock. At the end of Phases II, III and IV, hypotensive resuscitation + AVP infusion significantly restored the DO2 and VO2, which were significantly higher than those in the hypotensive resuscitation control group ( p G 0.01) (Fig. 3C and D).
LVSP and Tdp/dtmax
Blood Flow and Mitochondrial Function of Liver and Kidney
LVSP and Tdp/dtmax in all groups was significantly reduced after shock. Hypotensive resuscitation alone only had a minor effect on LVSP and Tdp/dtmax during Phase II, while hypotensive resuscitation + AVP significantly increased the LVSP and Tdp/dtmax. LVSP and Tdp/dtmax in the hypotensive
Blood flow in the liver and kidney was significantly reduced at the end of Phase I. Hypotensive resuscitation increased the blood flow both in the liver and kidney to some
TABLE 1. Effects of Hypotensive Resuscitation + AVP on Hemodynamic Parameters After Uncontrolled Hemorrhagic Shock Baseline MAP, mm Hg Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 hypotensive resuscitation control LVSP, mm Hg Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 Hypotensive resuscitation control +dp/dtmax, mm Hg/s Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 Hypotensive resuscitation control -dp/dtmax, mm Hg/s Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 Hypotensive resuscitation control
Phase I
Phase II
Phase III
Phase IV
121.6 (8.9)
40.5 (2.1)
51.2 (3.3) 50.8 (2.6) 53.3 (3.7) 52.4 (4.5) 51.4 (2.2)
80.8 (4.2) 81.7 (5.1) 83.6 (4.4) 81.8 (3.6) 80.4 (5.3)
98.6 (8.5)* 111.2 (7.1)** 104.6 (7.4)* 78.3 (5.8) 65.7 (6.2)
146.8 (11.6)
78.9 (6.2)
104.2 (8.2)* 107.3 (8.5)** 98.6 (7.8)* 89.1 (7.0) 76.2 (6.0)
136.2 (10.8)* 142.9 (11.3)** 131.6 (10.4)* 121.8 (9.6) 108.2 (8.6)
124.5 (9.8)* 135.2 (10.7)** 131.1 (10.4)* 107.3 (8.5) 92.5 (7.3)
6,687 (1,437)
3,024 (650)
3,486 (749) 4,638 (875)* 4,379 (941) 2,824 (607) 2,906 (624)
4,928 (959) 6,136 (968)* 5,023 (1,079) 3,923 (843) 4,012 (862)
5,102 (696) 5,938 (711)* 4,936 (1,061) 4,008 (861) 4,105 (882)
j5,023 (1,079)
j2,247 (483)
j3,124 (762) j3,982 (971)** j3,108 (758) j2,086 (509) j2,136 (521)
j4,863 (1,186) j5,325 (899)** j4,965 (1,211) j2,786 (680) j3,206 (782)
j4,673 (1,140) j5,089 (741)** j4,896 (894) j3,108 (758) j3,236 (789)
*p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Data are presented as mean (SD) (n = 8 per group). Tdp/dtmax, Maximal change rate in left intraventricular pressure.
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Figure 3. Effects of hypotensive resuscitation + AVP on cardiac function, DO2, and VO2 after uncontrolled hemorrhagic shock in rats. Data are presented as mean (SD) (n = 8 per group). A, CO. B, CI. C, DO2. D, VO2. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control.
extent. Hypotensive resuscitation + AVP infusion significantly improved the hepatic blood flow but did not improve the renal blood flow. At the end of Phases II, III, and IV, the hepatic blood flow in the hypotensive resuscitation + AVP group was significantly higher than that in the hypotensive resuscitation control group ( p G 0.05); however, renal blood flow in the hypotensive resuscitation + AVP group was significantly lower than that in the hypotensive resuscitation control group ( p G 0.05 È 0.01). At the end of Phase I, the mitochondrial function in the liver and kidney was significantly reduced. Hypotensive resuscitation + AVP infusion significantly improved the mitochondrial function in the liver but did not improve the mitochondrial function in the kidney during Phases III and IV (Fig. 4AYD).
Figure 4. Effects of hypotensive resuscitation + AVP on blood flow in the liver and kidney and their mitochondrial function after uncontrolled hemorrhagic shock in rats. Data are presented as mean (SD) (n = 8 per group). A and B, Blood flow in the liver and kidney. C and D, Mitochondrial function (RCR) in the liver and kidney. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control; RCR, respiratory control rate.
studies attempting to answer this question; unfortunately, the optimal resuscitative strategy has not been determined, and the controversy continues. Current research indicates that permissive hypotension resuscitation can improve the survival outcome for traumatic hemorrhagic shock as compared with the high-volume fluid resuscitation.4Y7 The hypotensive resuscitation strategy, however, is still a subject of debate. It is hard to provide stable hemodynamics for trauma patients with active hemorrhage for a long time by hypotensive resuscitation alone, and a longer prehospital transport time is needed in some remote regions or
Liver and Kidney Function There were no significant changes in liver and kidney function parameters at the end of Phase I in all groups as compared with the baseline level. The liver function parameters (AST and ALT) in the hypotensive resuscitation + AVP group were significantly lower than those in the hypotensive resuscitation control group during Phases II and III ( p G 0.05). However, there were no significant differences for the kidney function parameters (BUN and Scr) between the hypotensive resuscitation + AVP group and the hypotensive resuscitation control group at each time point (Fig. 5AYD).
DISCUSSION The most optimal therapeutic strategy for trauma patients with active bleeding is rapid control of bleeding and moderate fluid resuscitation to restore the efficient circulating blood volume. However, in most military and civilian situations, the definitive control of bleeding immediately after trauma or in the prehospital phase is difficult. So, what is the optimal strategy for these patients before surgical bleeding control? Numerous attempts have been made, with clinical investigation and animal 764
Figure 5. Effects of hypotensive resuscitation + AVP on liver and kidney function after uncontrolled hemorrhagic shock in rats. Data are presented as mean (SD) (n = 8 per group). A, AST. B, ALT. C, BUN. D, Scr. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
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special conditions. Vasoactive agents are often used to maintain blood pressure and tissue perfusion, such as NE, dopamine, and anisodamine, but most of these agents play effects depending on large-volume fluid infusion.19 Our present study showed that hypotensive resuscitation in combination with early application of AVP at the ‘‘prehospital stage’’ could prolong the tolerance time to hypotensive resuscitation and get a better resuscitation effect on uncontrolled hemorrhagic shock than hypotensive resuscitation alone. Hypotensive resuscitation + AVP could significantly reduce total blood loss and fluid requirements, improve hemodynamics, and increase DO2. Our previous study found that 90 minutes of hypotensive resuscitation was the maximal tolerance limit of tissues in uncontrolled hemorrhagic shock rats; 120 minutes of hypotensive resuscitation can cause severe organ damage and deleterious outcome.8 In the present study, we found that early application of AVP could significantly prolong the tolerance time of shock rats to hypotensive resuscitation (3 hours). These results suggested that hypotensive resuscitation + AVP may provide a longer safe time for the prehospital transport for trauma patients. This may be a promising strategy for the early treatment of trauma patients with active hemorrhage, especially in some remote areas or some military or disaster situations. Recently, more and more attention has been paid to the remarkable ability of vasoconstriction of AVP and its blood pressureYmaintaining effect under pathologic states. Our previous study found that AVP could improve the vascular hyporeactivity and strengthen the vasoconstriction of NE to play an antishock effect.12Y15 Our present study found that blood loss during Phase II in the hypotensive resuscitation + AVP group was significantly lower than that in the hypotensive resuscitation alone group. This result suggested that early application of AVP could reduce the bleeding from the transected spleen and splenic vessels by its vasoconstriction effect, and through this effect and hemodynamic maintaining effects, AVP in combination with hypotensive resuscitation played the beneficial effect on uncontrolled hemorrhagic shock. What is the optimal dose of AVP for the treatment of traumatic shock? Most studies and the Surviving Sepsis Campaign (2012) recommend a continuous infusion of small doses of AVP (0.01Y0.03 U/min) for septic shock.20,21 High doses of AVP may be associated with the increased adverse effects in advanced vasodilatory shock and septic shock, such as impairment of intestinal microcirculation and hepatic function.22,23 Our previous studies showed that low-dose AVP (an initial bolus of 0.4 U/kg followed by an infusion of 0.04 U/kg/min) could improve the decreased vascular responsiveness following controlled hemorrhagic shock,13 and AVP (0.4 U/kg) + NE was beneficial for uncontrolled hemorrhagic shock.14 The present study observed the effects of four doses of AVP (1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL) in combination with hypotensive resuscitation and found that all the four doses of AVP could decrease blood loss and improve hemodynamics. Among these doses, 5 10j4 U/mL had the best effects in improving hemodynamics and survival outcome for the hemorrhagic shock rats. Of course, further studies and clinical trials are needed to further confirm the exact dose of AVP beneficial for traumatic patients. Another ongoing debate was on the effects of AVP on cardiac function and myocardial contractility. Indrambarya
et al.24 reported that AVP infusion reduced left ventricular ejection fraction and increased the 7-day mortality in ischemic/ reperfusion injury mice. A similar result was observed in a porcine model of septic shock.25 In contrast, Wenzel et al.26 reported that AVP significantly increased left anterior descending coronary artery cross-sectional area during ventricular fibrillation with cardiopulmonary resuscitation. Our present study found that hypotensive resuscitation in combination with early application of AVP significantly restored the CO and DO2 in uncontrolled hemorrhagic shock rats. These conflicting findings may be due to the different doses and application time of AVP and the different pathophysiologic state. The results of this study suggested that hypotensive resuscitation + AVP could protect the cardiovascular function for traumatic hemorrhagic shock in rats. Rats receiving AVP in the present study had a significant improvement in the blood flow of the liver and its function including mitochondrial function. However, the blood flow and mitochondrial function in the kidney in rats receiving AVP did not improve. A potential explanation for this finding may be the heterogeneous vasoconstriction of AVP on splanchnic beds. A trial of AVP in postYcardiac surgery patients showed that AVP could induce the renal vasoconstriction and result in a decrease in renal blood flow and an increase in glomerular filtration rate.27 However, another study showed that in neonates and children with septic shock, vasopressin has the potential to improve organ perfusion with preservation of renal blood flow as well as increase urine production and creatinine clearance.28 Further studies are needed to define the roles of AVP on the renal function in shock patients, including effectiveness, safety, and adverse effects. There were some limitations in the present study. First, the animal we used in the present study is a small animal (rat); that this result can be extrapolated to large animals or even humans needs further confirmation. Second, although we hoped for AVP to prolong the tolerance time to hypotensive resuscitation and increase the safe time for prehospital transportation, 3 hours of hypotensive resuscitation used in the present study seems little bit long. The ideal safe time of prehospital transportation needs further investigation. In conclusion, the present study showed that hypotensive resuscitation in combination with early application of AVP can significantly prolong the tolerance time to hypotensive resuscitation and increase the safe time of prehospital transportation. The beneficial effect of this strategy is closely related to AVP reducing blood loss, stabilizing hemodynamics, and improving tissue perfusion and vital organ function. Future studies are needed to define the effectiveness and safety of hypotensive resuscitation + AVP in traumatic shock patients. AUTHORSHIP G.Y. participated in the design of the study, statistical analysis, entire experiment, and preparation of the manuscript. Y.H., XP., Y.Z., and J.Z. participated in the entire experiment as well as data collection and analysis. T.L. and L.L. oversaw all aspects of the study, participated in the design and coordination, and edited the manuscript. All authors read and approved the final manuscript. DISCLOSURE This work was supported by the National Natural Science Foundation of China (81270400 and 30901559), Natural Science Foundation of Chongqing (Cstc2013jcyjA10012), and Foundation of State Key Laboratory of Trauma, Burns and Combined Injury (SKLZZ201020).
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REFERENCES 1. Harris T, Thomas GO, Brohi K. Early fluid resuscitation in severe trauma. Br Med J. 2012;345:e5752. 2. World Health Organization. Global Forum on Trauma Care. Available at: http://www.who.int/violence_injury_prevention/media/events/gftc/en. Accessed October 29, 2009. 3. Bougle´ A, Harrois A, Duranteau J. Resuscitative strategies in traumatic hemorrhagic shock. Ann Intensive Care. 2013;3:1. 4. Morrison CA, Carrick MM, Norman MA, Scott BG, Welsh FJ, Tsai P, Liscum KR, Wall MJ Jr, Mattox KL. Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma. 2011;70:652Y663. 5. Li T, Zhu Y, Fang Y, Liu L. Determination of the optimal mean arterial pressure for postbleeding resuscitation after hemorrhagic shock in rats. Anesthesiology. 2012;116:103Y112. 6. Li T, Lin X, Zhu Y, Li L, Liu L. Short-term, mild hypothermia can increase the beneficial effect of permissive hypotension on uncontrolled hemorrhagic shock in rats. Anesthesiology. 2012;116:1288Y1298. 7. Li T, Zhu Y, Tian K, Xue M, Peng X, Lan D, Liu L. Ideal resuscitation pressure for uncontrolled hemorrhagic shock in different ages and sexes of rats. Crit Care. 2013;17:R194. 8. Li T, Zhu Y, Hu Y, Li L, Diao Y, Tang J, Liu L. Ideal permissive hypotension to resuscitate uncontrolled hemorrhagic shock and the tolerance time in rats. Anesthesiology. 2011;114:111Y119. 9. Ertmer C, Kampmeier T, Rehberg S, Lange M. Fluid resuscitation in multiple trauma patients. Curr Opin Anaesthesiol. 2011;24:202Y208. 10. Lee CC, Lee MT, Chang SS, Lee SH, Huang YC, Yo CH, Lee SH, Chen SC. A comparison of vasopressin, terlipressin, and lactated ringers for resuscitation of uncontrolled hemorrhagic shock in an animal model. PLoS One. 2014;9:e95821. 11. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Ferna´ndez-Monde´jar E, Filipescu D, Hunt BJ, Komadina R, Nardi G, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17:R76. 12. Yang GM, Li T, Xu J, Liu LM. PKC plays an important mediated effect in arginine vasopressin induced restoration of vascular responsiveness and calcium sensitization following hemorrhagic shock in rats. Eur J Pharmacol. 2010;628:148Y154. 13. Yang GM, Liu LM, Xu J, Li T. Effect of arginine vasopressin on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relationship to Rho-kinase. J Trauma. 2006;61:1336Y1342. 14. Liu L, Tian K, Xue M, Zhu Y, Lan D, Peng X, Wu Y, Li T. Small doses of arginine vasopressin in combination with norepinephrine ‘‘buy’’ time for definitive treatment for uncontrolled hemorrhagic shock in rats. Shock. 2013;40:398Y406. 15. Li T, Fang Y, Zhu Y, Fan X, Liao Z, Chen F, Liu L. A small dose of arginine vasopressin in combination with norepinephrine is a good early treatment for uncontrolled hemorrhagic shock after hemostasis. J Surg Res. 2011;169:76Y84.
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16. Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council. Guide for the Care and Use of Laboratory Animals (Eighth Edition). Washington (DC): National Academy Press; 2011. 17. Liu L, Tian K, Zhu Y, Ding X, Li T. C opioid receptor antagonist, ICI 174,864, is suitable for the early treatment of uncontrolled hemorrhagic shock in rats. Anesthesiology. 2013;119:379Y388. 18. Yang GM, Li T, Xu J, Peng XY, Liu LM. Mitogen-activated protein kinases regulate vascular reactivity after hemorrhagic shock through myosin light chain phosphorylation pathway. J Trauma Acute Care Surg. 2013;74: 1033Y1043. 19. Bockenstedt TL, Baker SN, Weant KA, Mason MA. Review of vasopressor therapy in the setting of vasodilatory shock. Adv Emerg Nurs J. 2012;34:16Y23. 20. Russell JA, Walley KR, Singer J, Gordon AC, He´bert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al; and VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877Y887. 21. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al; and Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580Y637. 22. Du¨nser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk W, Friesenecker B, Hasibeder WR. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003;107: 2313Y2319. 23. Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D’Alessandro D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122Y1125. 24. Indrambarya T, Boyd JH, Wang Y, McConechy M, Walley KR. Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice. Crit Care. 2009;13:R98. 25. Simon F, Giudici R, Scheuerle A, Gro¨ger M, Asfar P, Vogt JA, Wachter U, Ploner F, Georgieff M, Mo¨ller P, et al. Comparison of cardiac, hepatic, and renal effects of arginine vasopressin and noradrenaline during porcine fecal peritonitis: a randomized controlled trial. Crit Care. 2009;13:R113. 26. Wenzel V, Kern KB, Hilwig RW, Berg RA, Schwarzacher S, Butman SM, Lindner KH, Ewy GA. Effects of intravenous arginine vasopressin on epicardial coronary artery cross sectional area in a swine resuscitation model. Resuscitation. 2005;64:219Y226. 27. Bragadottir G, Redfors B, Nygren A, Sellgren J, Ricksten SE. Low-dose vasopressin increases glomerular filtration rate, but impairs renal oxygenation in post-cardiac surgery patients. Acta Anaesthesiol Scand. 2009;53: 1052Y1059. 28. Biban P, Gaffuri M. Vasopressin and terlipressin in neonates and children with refractory septic shock. Curr Drug Metab. 2013;14:186Y192.
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Hypotensive resuscitation in combination with arginine vasopressin may prolong the hypotensive resuscitation time in uncontrolled hemorrhagic shock rats Guangming Yang, MD, Yi Hu, MD, Xiaoyong Peng, MS, Yu Zhu, MS, Jiatao Zang, MS, Tao Li, MD, and Liangming Liu, MD, PhD, Chongqing, China
BACKGROUND: The optimal resuscitation strategy for traumatic hemorrhagic shock is not completely determined. The objective of the present study was to investigate whether hypotensive resuscitation in combination with arginine vasopressin (AVP) can prolong the hypotensive resuscitation time by minimizing blood loss and stabilizing hemodynamics for uncontrolled hemorrhagic shock. METHODS: With an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions. RESULTS: Hypotensive resuscitation in combination with AVP maintenance for 3 hours significantly reduced total blood loss and fluid requirement during hypotensive resuscitation period and significantly improved the survival of shock rats as compared with hypotensive resuscitation alone. Among the four concentrations of AVP, 5 10j4 U/mL had the best effect: it significantly improved hemodynamics and increased cardiac function, oxygen delivery, as well as hepatic blood flow and hepatic function in the shock rats. However, renal blood flow in the hypotensive resuscitation + AVP group was lower than that in the hypotensive resuscitation alone group. CONCLUSION: Hypotensive resuscitation in combination with early application of AVP could prolong the tolerance time of hypotensive resuscitation and ‘‘buy’’ longer safe prehospital transport time by reducing blood loss and stabilizing hemodynamics. This strategy may be a promising strategy for the early management of trauma patients with active bleeding. (J Trauma Acute Care Surg. 2015;78: 760Y766. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved.) KEY WORDS: Uncontrolled hemorrhagic shock; hypotensive resuscitation; arginine vasopressin; rats.
T
rauma is the leading cause of death for the population younger than 40 years; it has become a global health problem, with more than 10,000 deaths per day worldwide.1,2 Hemorrhage and subsequently hemorrhagic shock remain the major cause of mortality after trauma. Fluid resuscitation is the ‘‘cornerstone’’ of the therapy of hemorrhagic shock during the last decades.1,3 However, uncontrolled bleeding is often seen in trauma patients (known as uncontrolled hemorrhagic shock), and the ‘‘classic’’ fluid resuscitation (aggressive resuscitation) is deleterious for this condition3,4 because large volume of fluid infusion before bleeding is controlled can induce further blood loss and severe hemodilution. So, hypotensive resuscitation or limited fluid resuscitation emerged and was advocated. Animal studies and clinic trials showed that hypotensive resuscitation resulted in better outcomes than did large-volume fluid resuscitation.4Y7 However, hypotensive resuscitation cannot provide a stable hemodynamics for a long time. Our previous studies suggested that for uncontrolled hemorrhagic shock, 90 minutes Submitted: September 28, 2014, Revised: November 23, 2014, Accepted: November 26, 2014, Published online: March 4, 2015. From the State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China. Address for reprints: Tao Li, PhD, and Liangming Liu, MD, PhD, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Daping, Chongqing 400042, China; email: [email protected], [email protected]. DOI: 10.1097/TA.0000000000000564
of hypotensive resuscitation was the maximal tolerance limit for the body; more than 90 minutes of hypotensive resuscitation caused severe organ damage and worse outcome.8 Unfortunately, the time required for prehospital transport may often be more than 90 minutes in some remote regions or in some disaster situations.9 So, an effective strategy that can prolong the tolerance time for hypotensive resuscitation is urgently needed. Arginine vasopressin (AVP) is an endogenous hormone, which has only a minor effect on blood pressure under physiologic condition. However, under shock state, AVP shows a potent vasoconstriction and vasopressor effect, both in vasodilatory septic shock and hemorrhagic shock patients. A recent study with a rat model of uncontrolled hemorrhagic shock by an 80% tail amputation showed improved hemodynamics and outcome after treatment with AVP or terlipressin (an analog of AVP).10 This study observed only a shorter ‘‘hypotension’’ time (40 minutes) before the active bleeding was controlled, and a bolus injection of AVP was given, which rapidly increased the mean arterial pressure (MAP) up to 120 mm Hg. However, the rapid elevation of blood pressure during uncontrolled hemorrhage is contradictory to the concept of the hypotensive resuscitation according to European trauma guidelines.11 Our previous studies revealed that AVP could significantly strengthen vasoconstriction following shock. Early application of AVP plus norepinephrine (NE) could maintain MAP at 55 mm Hg for 3 hours and win ‘‘time’’ to bring about definitive treatment for uncontrolled hemorrhagic shock.12Y15 In this study, we wanted to know if hypotensive resuscitation in combination with early J Trauma Acute Care Surg Volume 78, Number 4
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application of AVP can prolong tolerance time of hypotensive resuscitation and improve resuscitative effects, by minimizing blood loss and maintaining hemodynamics. It is aimed to search for an effective treatment strategy for traumatic hemorrhagic shock at prehospital stage. To elucidate this issue, with an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain the blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions.
MATERIALS AND METHODS Ethical Approval This study was approved by the Research Council and Animal Care and Use Committee of Research Institute of Surgery, Daping Hospital, Third Military Medical University. The investigation conformed to the Guide for the Care and Use of Laboratory Animals (8th ed. Washington, DC: National Academies Press; 2011).16
Animal Preparation Two hundred sixteen Sprague-Dawley rats (220Y260 g, both male and female) were anesthetized with sodium pentobarbital and Jingsongling (xylidinothiazole) using an established protocol.12,13 The right femoral arteries and veins were catheterized for monitoring the MAP and administration, respectively. The left ventricle of the heart was catheterized via the right carotid artery for monitoring hemodynamics. Uncontrolled hemorrhagic shock model was induced by transection of the splenic parenchyma and one of the branches of the splenic artery and vein as previously described.17 Briefly, after laparotomy, a crosstransection was made in splenic parenchyma between the two major branches of the splenic artery. Simultaneously, one of the major branches of the splenic artery and vein was also transected. Blood was allowed to freely flow into the abdominal cavity. When the MAP decreased to 40 mm Hg, uncontrolled hemorrhagic shock modelwas established for the following experiments. At the end of all the experiments, all animals were euthanatized with a pentobarbital-based euthanasia solution (Sleepaway, 2 mL, intravenously administered).18
Experimental Protocol Experimental Phases and Management Experiments were divided into four phases. Phase I was the uncontrolled hemorrhagic shock period (shock model stage), in which blood was allowed to freely flow into the abdominal cavity. This period was maintained for 20 minutes to 30 minutes. Phase II was the hypotensive resuscitation + AVP application period, in which the MAP was maintained at 50 mm Hg for 3 hours (target MAP) by continuous infusion of different concentrations of AVP along with the lactated Ringer’s solution plus 6% hydroxyethyl starch 130, at a ratio of 1:2 (LR + HES). The concentrations of AVP in LR + HES were 1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL. In this phase, the amount of fluid requirement and AVP administered were dependent on the maintenance of the target MAP; the control group was solely hypotensive resuscitation group. At the end of this phase, the bleeding was controlled by ligation of the spleen and vessels. Phase III was the definitive treatment period, in which rats received two volumes of blood loss of LR + whole blood (1:1), to maintain MAP at 80 mm Hg for 2 hours. Phase IV was the observation period. The hemodynamics, the cardiac function, the blood flow of liver/kidney, and their function were observed, and the time was 2 hours. In addition, the animal survival time and survival rate were also observed, and the time was 24 hours from the beginning of Phase IV (Fig. 1).
Animal Survival, Blood Loss, and Fluid Requirement Eighty Sprague-Dawley rats were randomly divided into five groups (n = 16 per group): hypotensive resuscitation control group and hypotensive resuscitation with AVP (1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL) groups. The experimental phase and fluid infusion procedures were the same as those discussed in the Experimental Phases and Management section. At the end of Phase II, blood loss during Phases I and II was recorded. The amounts of fluid infusion during Phases II and III were also noted. At the end of Phase III, the catheters were removed, the incisions were closed, and the animal survival time was observed to 24 hours after the onset of Phase IV.
Hemodynamics Another forty Sprague-Dawley rats were also randomly divided into five groups and treated identically as described
Figure 1. Experimental protocol (schematic). Phase I, establishment of a model of uncontrolled hemorrhagic shock. Phase II, continuous infusion of AVP along with LR + HES to maintain MAP at 50 mm Hg for 3 hours. Phase III, control of bleeding and maintenance of MAP at 80 mm Hg for 2 hours. Phase IV, observation period. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
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earlier (n = 8 per group). Hemodynamic parameters including MAP, left intraventricular systolic pressure (LVSP), and the maximal change rate of left intraventricular pressure (Tdp/dtmax) were determined at baseline; at the end of Phases I, II, and III; and at 2 hours in Phase IV, with a polygraph physiologic recorder (SP844, AD Instruments, Castle Hill, Australia).
Cardiac Function, Oxygen Delivery, and Oxygen Use
According to the results mentioned earlier, 5 10j4 U/mL AVP showed a better effect among the four doses of AVP, so, this dose of AVP was used in further experiments. Sixteen rats in this experiment were divided into two groups (n = 8 per group): hypotensive resuscitation control group and hypotensive resuscitation + AVP (5 10j4 U/mL) group. The experimental phase and procedures were the same as those discussed in the Experimental Phases and Management section. Cardiac output (CO), cardiac index (CI), oxygen delivery (DO2), and oxygen use (VO2) were observed at baseline; at the end of Phases I, II, and III; and at 2 hours in Phase IV. CO was measured by a Cardiomax-III machine (Columbus Instruments, Columbus, OH). The values of CI, DO2, and VO2 were calculated based on CO and arterial and venous blood gases as described in our previous work.8 Blood gases were measured with a blood gas analyzer (Phox plus L, Nova Biomedical, Waltham, MA). The formulas of DO2 and VO2 were as follows: DO2 = CI 13.4 hemoglobin SaO2 and VO2 = CI 13.4 hemoglobin (SaO2 j SvO2) (where SaO2 is the oxygen saturation of the artery and SvO2 is the oxygen saturation of the vein).
Blood Flow of Liver and Kidney and Their Functions Including Mitochondrial Function An additional eighty Sprague-Dawley rats were also divided into two groups (n = 8 for each group at each time point): hypotensive resuscitation control group and hypotensive resuscitation + AVP (5 10j4 U/mL) group. In this experiment, at each time point (at baseline; at the end of Phases I, II, and III; and at 2 hours in Phase IV), a laparotomy was performed for the measurement of blood flow in the liver and kidney with a laser Doppler blood flowmeter (Feriflux system 5000, Perimed, Stockholm, Sweden). The blood sample was withdrawn for the determination of liver and kidney function (including aspartate aminotransferase [AST], alanine aminotransferase [ALT], blood urea nitrogen [BUN], and serum creatinine [Scr]) by a biochemical analyzer (Beckman, Fullerton, CA). Thereafter, the rats were killed by a pentobarbital-based euthanasia solution (Sleepaway, 2 mL, intravenously administered) to remove the liver and kidney for the measurement of their mitochondrial function by a mitochondrial function analyzer (MT 200, Strathkelvin, Lanarkshire, Scotland). The mitochondrial function was reflected by the respiration control rate (consumed oxygen rate with and without adenosine diphosphate), which was determined as described in our previous work.7
Statistical Analysis Data are presented as mean (SD). The difference between the experimental groups was analyzed by one- or two-factor analyses of variance using SPSS 13.0 software, followed by post hoc Tukey tests. p G 0.05 was considered significant. 762
RESULTS Animal Survival, Blood Loss, and Fluid Requirement Survival The 24-hour survival rate for shock rats in the hypotensive resuscitation control group was 1 (6%) of 16, and the survival time was 2.8 (3.3) hours. AVP (5 10j4 U/mL) in combination with hypotensive resuscitation significantly increased the survival time (13.7 [7.9] hours) and 24-hour survival rate (7 of 16, 44%) for uncontrolled hemorrhagic shock rats as compared with the hypotensive resuscitation control rats. The other three doses of AVP only slightly increased the survival time and 24-hour survival rate, which were 4.3 (3.9) hours and 3 (19%) of 16; 9.0 (8.4) hours and 4 (25%) of 16; and 8.0 (6.6) hours and 2 (13%) of 16 in AVP 1 10j4, 1 10j3, and 5 10j3 U/mL groups, respectively (Fig. 2A and B).
Blood Loss At the end of Phase II, blood loss in the hypotensive resuscitation control group was 19.8 (5.2) mL. Hypotensive resuscitation + AVP (1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL) significantly decreased blood loss as compared with the hypotensive resuscitation control group; they were 13.2 (3.3) mL, 14.4 (2.7) mL, 14.1 (4.0) mL, and 13.2 (3.9) mL, respectively (p G 0.05) (Fig. 2C).
Fluid Requirement The fluid requirement in the hypotensive resuscitation control group during Phase II (hypotensive resuscitation period, maintenance of MAP at 50 mm Hg for 3 hours) and Phase III (definitive treatment period, maintenance of MAP at 80 mm Hg for 2 hours) was 22.9 (3.3) mL and 26.5 (4.3) mL, respectively. Application of AVP significantly reduced the fluid requirement
Figure 2. Effects of hypotensive resuscitation + AVP on animal survival, blood loss, and fluid requirement in uncontrolled hemorrhagic shock rats. Data are presented as mean (SD) (n = 16 per group). A and B, Survival number and survival time. C, Blood loss during Phase I plus Phase II. D, Fluid requirement during Phases II and III. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
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as compared with the control group ( p G 0.05 È 0.01). In the hypotensive resuscitation + AVP 1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL groups, the fluid requirement during Phase II was 11.4 (3.2) mL, 10.4 (2.2) mL, 10.7 (4.0) mL, and 10.3 (3.0) mL, respectively, and it was 16.2 (6.3) mL, 16.5 (2.4) mL, 17.3 (4.9) mL, and 16.2 (5.0) mL during Phase III, respectively (Fig. 2D).
resuscitation control group were slightly increased during Phase III and then gradually decreased during Phase IV, while they were significantly increased and maintained at a higher level in hypotensive resuscitation + AVP groups. Among the AVP groups, 5 10j4 U/mL AVP had the best effect (Table 1).
Hemodynamics MAP
At the end of Phase I, the CO and CI were significantly decreased in all groups. They were only slightly increased in the hypotensive resuscitation group during Phases II, III, and IV, while they were significantly increased in the hypotensive resuscitation + AVP group and were significantly higher than those in the hypotensive resuscitation control group ( p G 0.01) (Fig. 3A and B).
Cardiac Function, DO2, and VO2 CO and CI
During Phase II and Phase III, the MAP in all groups was maintained at the target pressure (50 mm Hg and 80 mm Hg, respectively). After Phase III, the MAP could not be maintained in the hypotensive resuscitation control group and gradually decreased to 66 mm Hg at 2 hours during Phase IV. The MAP in the hypotensive resuscitation + AVP groups maintained a stable and higher level during Phase IV. Among all groups, the hypotensive resuscitation + AVP at the concentration of 5 10j4 U/mL had the best effect for improving the MAP, which was close to the normal MAP level during Phase IV.
DO2 and VO2 DO2 and VO2 were also decreased after shock. At the end of Phases II, III and IV, hypotensive resuscitation + AVP infusion significantly restored the DO2 and VO2, which were significantly higher than those in the hypotensive resuscitation control group ( p G 0.01) (Fig. 3C and D).
LVSP and Tdp/dtmax
Blood Flow and Mitochondrial Function of Liver and Kidney
LVSP and Tdp/dtmax in all groups was significantly reduced after shock. Hypotensive resuscitation alone only had a minor effect on LVSP and Tdp/dtmax during Phase II, while hypotensive resuscitation + AVP significantly increased the LVSP and Tdp/dtmax. LVSP and Tdp/dtmax in the hypotensive
Blood flow in the liver and kidney was significantly reduced at the end of Phase I. Hypotensive resuscitation increased the blood flow both in the liver and kidney to some
TABLE 1. Effects of Hypotensive Resuscitation + AVP on Hemodynamic Parameters After Uncontrolled Hemorrhagic Shock Baseline MAP, mm Hg Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 hypotensive resuscitation control LVSP, mm Hg Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 Hypotensive resuscitation control +dp/dtmax, mm Hg/s Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 Hypotensive resuscitation control -dp/dtmax, mm Hg/s Hypotensive resuscitation + AVP 1 10j4 Hypotensive resuscitation + AVP 5 10j4 Hypotensive resuscitation + AVP 1 10j3 Hypotensive resuscitation + AVP 5 10j3 Hypotensive resuscitation control
Phase I
Phase II
Phase III
Phase IV
121.6 (8.9)
40.5 (2.1)
51.2 (3.3) 50.8 (2.6) 53.3 (3.7) 52.4 (4.5) 51.4 (2.2)
80.8 (4.2) 81.7 (5.1) 83.6 (4.4) 81.8 (3.6) 80.4 (5.3)
98.6 (8.5)* 111.2 (7.1)** 104.6 (7.4)* 78.3 (5.8) 65.7 (6.2)
146.8 (11.6)
78.9 (6.2)
104.2 (8.2)* 107.3 (8.5)** 98.6 (7.8)* 89.1 (7.0) 76.2 (6.0)
136.2 (10.8)* 142.9 (11.3)** 131.6 (10.4)* 121.8 (9.6) 108.2 (8.6)
124.5 (9.8)* 135.2 (10.7)** 131.1 (10.4)* 107.3 (8.5) 92.5 (7.3)
6,687 (1,437)
3,024 (650)
3,486 (749) 4,638 (875)* 4,379 (941) 2,824 (607) 2,906 (624)
4,928 (959) 6,136 (968)* 5,023 (1,079) 3,923 (843) 4,012 (862)
5,102 (696) 5,938 (711)* 4,936 (1,061) 4,008 (861) 4,105 (882)
j5,023 (1,079)
j2,247 (483)
j3,124 (762) j3,982 (971)** j3,108 (758) j2,086 (509) j2,136 (521)
j4,863 (1,186) j5,325 (899)** j4,965 (1,211) j2,786 (680) j3,206 (782)
j4,673 (1,140) j5,089 (741)** j4,896 (894) j3,108 (758) j3,236 (789)
*p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Data are presented as mean (SD) (n = 8 per group). Tdp/dtmax, Maximal change rate in left intraventricular pressure.
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Figure 3. Effects of hypotensive resuscitation + AVP on cardiac function, DO2, and VO2 after uncontrolled hemorrhagic shock in rats. Data are presented as mean (SD) (n = 8 per group). A, CO. B, CI. C, DO2. D, VO2. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control.
extent. Hypotensive resuscitation + AVP infusion significantly improved the hepatic blood flow but did not improve the renal blood flow. At the end of Phases II, III, and IV, the hepatic blood flow in the hypotensive resuscitation + AVP group was significantly higher than that in the hypotensive resuscitation control group ( p G 0.05); however, renal blood flow in the hypotensive resuscitation + AVP group was significantly lower than that in the hypotensive resuscitation control group ( p G 0.05 È 0.01). At the end of Phase I, the mitochondrial function in the liver and kidney was significantly reduced. Hypotensive resuscitation + AVP infusion significantly improved the mitochondrial function in the liver but did not improve the mitochondrial function in the kidney during Phases III and IV (Fig. 4AYD).
Figure 4. Effects of hypotensive resuscitation + AVP on blood flow in the liver and kidney and their mitochondrial function after uncontrolled hemorrhagic shock in rats. Data are presented as mean (SD) (n = 8 per group). A and B, Blood flow in the liver and kidney. C and D, Mitochondrial function (RCR) in the liver and kidney. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control; RCR, respiratory control rate.
studies attempting to answer this question; unfortunately, the optimal resuscitative strategy has not been determined, and the controversy continues. Current research indicates that permissive hypotension resuscitation can improve the survival outcome for traumatic hemorrhagic shock as compared with the high-volume fluid resuscitation.4Y7 The hypotensive resuscitation strategy, however, is still a subject of debate. It is hard to provide stable hemodynamics for trauma patients with active hemorrhage for a long time by hypotensive resuscitation alone, and a longer prehospital transport time is needed in some remote regions or
Liver and Kidney Function There were no significant changes in liver and kidney function parameters at the end of Phase I in all groups as compared with the baseline level. The liver function parameters (AST and ALT) in the hypotensive resuscitation + AVP group were significantly lower than those in the hypotensive resuscitation control group during Phases II and III ( p G 0.05). However, there were no significant differences for the kidney function parameters (BUN and Scr) between the hypotensive resuscitation + AVP group and the hypotensive resuscitation control group at each time point (Fig. 5AYD).
DISCUSSION The most optimal therapeutic strategy for trauma patients with active bleeding is rapid control of bleeding and moderate fluid resuscitation to restore the efficient circulating blood volume. However, in most military and civilian situations, the definitive control of bleeding immediately after trauma or in the prehospital phase is difficult. So, what is the optimal strategy for these patients before surgical bleeding control? Numerous attempts have been made, with clinical investigation and animal 764
Figure 5. Effects of hypotensive resuscitation + AVP on liver and kidney function after uncontrolled hemorrhagic shock in rats. Data are presented as mean (SD) (n = 8 per group). A, AST. B, ALT. C, BUN. D, Scr. *p G 0.05, **p G 0.01 as compared with the hypotensive resuscitation control group. Ctl, control. * 2015 Wolters Kluwer Health, Inc. All rights reserved.
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special conditions. Vasoactive agents are often used to maintain blood pressure and tissue perfusion, such as NE, dopamine, and anisodamine, but most of these agents play effects depending on large-volume fluid infusion.19 Our present study showed that hypotensive resuscitation in combination with early application of AVP at the ‘‘prehospital stage’’ could prolong the tolerance time to hypotensive resuscitation and get a better resuscitation effect on uncontrolled hemorrhagic shock than hypotensive resuscitation alone. Hypotensive resuscitation + AVP could significantly reduce total blood loss and fluid requirements, improve hemodynamics, and increase DO2. Our previous study found that 90 minutes of hypotensive resuscitation was the maximal tolerance limit of tissues in uncontrolled hemorrhagic shock rats; 120 minutes of hypotensive resuscitation can cause severe organ damage and deleterious outcome.8 In the present study, we found that early application of AVP could significantly prolong the tolerance time of shock rats to hypotensive resuscitation (3 hours). These results suggested that hypotensive resuscitation + AVP may provide a longer safe time for the prehospital transport for trauma patients. This may be a promising strategy for the early treatment of trauma patients with active hemorrhage, especially in some remote areas or some military or disaster situations. Recently, more and more attention has been paid to the remarkable ability of vasoconstriction of AVP and its blood pressureYmaintaining effect under pathologic states. Our previous study found that AVP could improve the vascular hyporeactivity and strengthen the vasoconstriction of NE to play an antishock effect.12Y15 Our present study found that blood loss during Phase II in the hypotensive resuscitation + AVP group was significantly lower than that in the hypotensive resuscitation alone group. This result suggested that early application of AVP could reduce the bleeding from the transected spleen and splenic vessels by its vasoconstriction effect, and through this effect and hemodynamic maintaining effects, AVP in combination with hypotensive resuscitation played the beneficial effect on uncontrolled hemorrhagic shock. What is the optimal dose of AVP for the treatment of traumatic shock? Most studies and the Surviving Sepsis Campaign (2012) recommend a continuous infusion of small doses of AVP (0.01Y0.03 U/min) for septic shock.20,21 High doses of AVP may be associated with the increased adverse effects in advanced vasodilatory shock and septic shock, such as impairment of intestinal microcirculation and hepatic function.22,23 Our previous studies showed that low-dose AVP (an initial bolus of 0.4 U/kg followed by an infusion of 0.04 U/kg/min) could improve the decreased vascular responsiveness following controlled hemorrhagic shock,13 and AVP (0.4 U/kg) + NE was beneficial for uncontrolled hemorrhagic shock.14 The present study observed the effects of four doses of AVP (1 10j4, 5 10j4, 1 10j3, and 5 10j3 U/mL) in combination with hypotensive resuscitation and found that all the four doses of AVP could decrease blood loss and improve hemodynamics. Among these doses, 5 10j4 U/mL had the best effects in improving hemodynamics and survival outcome for the hemorrhagic shock rats. Of course, further studies and clinical trials are needed to further confirm the exact dose of AVP beneficial for traumatic patients. Another ongoing debate was on the effects of AVP on cardiac function and myocardial contractility. Indrambarya
et al.24 reported that AVP infusion reduced left ventricular ejection fraction and increased the 7-day mortality in ischemic/ reperfusion injury mice. A similar result was observed in a porcine model of septic shock.25 In contrast, Wenzel et al.26 reported that AVP significantly increased left anterior descending coronary artery cross-sectional area during ventricular fibrillation with cardiopulmonary resuscitation. Our present study found that hypotensive resuscitation in combination with early application of AVP significantly restored the CO and DO2 in uncontrolled hemorrhagic shock rats. These conflicting findings may be due to the different doses and application time of AVP and the different pathophysiologic state. The results of this study suggested that hypotensive resuscitation + AVP could protect the cardiovascular function for traumatic hemorrhagic shock in rats. Rats receiving AVP in the present study had a significant improvement in the blood flow of the liver and its function including mitochondrial function. However, the blood flow and mitochondrial function in the kidney in rats receiving AVP did not improve. A potential explanation for this finding may be the heterogeneous vasoconstriction of AVP on splanchnic beds. A trial of AVP in postYcardiac surgery patients showed that AVP could induce the renal vasoconstriction and result in a decrease in renal blood flow and an increase in glomerular filtration rate.27 However, another study showed that in neonates and children with septic shock, vasopressin has the potential to improve organ perfusion with preservation of renal blood flow as well as increase urine production and creatinine clearance.28 Further studies are needed to define the roles of AVP on the renal function in shock patients, including effectiveness, safety, and adverse effects. There were some limitations in the present study. First, the animal we used in the present study is a small animal (rat); that this result can be extrapolated to large animals or even humans needs further confirmation. Second, although we hoped for AVP to prolong the tolerance time to hypotensive resuscitation and increase the safe time for prehospital transportation, 3 hours of hypotensive resuscitation used in the present study seems little bit long. The ideal safe time of prehospital transportation needs further investigation. In conclusion, the present study showed that hypotensive resuscitation in combination with early application of AVP can significantly prolong the tolerance time to hypotensive resuscitation and increase the safe time of prehospital transportation. The beneficial effect of this strategy is closely related to AVP reducing blood loss, stabilizing hemodynamics, and improving tissue perfusion and vital organ function. Future studies are needed to define the effectiveness and safety of hypotensive resuscitation + AVP in traumatic shock patients. AUTHORSHIP G.Y. participated in the design of the study, statistical analysis, entire experiment, and preparation of the manuscript. Y.H., XP., Y.Z., and J.Z. participated in the entire experiment as well as data collection and analysis. T.L. and L.L. oversaw all aspects of the study, participated in the design and coordination, and edited the manuscript. All authors read and approved the final manuscript. DISCLOSURE This work was supported by the National Natural Science Foundation of China (81270400 and 30901559), Natural Science Foundation of Chongqing (Cstc2013jcyjA10012), and Foundation of State Key Laboratory of Trauma, Burns and Combined Injury (SKLZZ201020).
* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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* 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
