Traumatic hemorrhagic shock is often seen in civilian and military situations. It is a major cause of early death of injured soldiers, accounting for ≈50% of deaths of battle personnel (1). Reports have shown that ≈40% of trauma-induced deaths occur at 5 to 30 min after trauma (2). Thus, early emergency care for severe trauma or war wounds is very important. Besides hemorrhage control, fluid resuscitation is the important step for the early treatment of traumatic or hemorrhagic shock, but regular and large volumes of fluid infusion at the early stage after trauma (especially after a major disaster) or war wound are not possible. An effective antishock agent is needed in this situation. A good strategy is independent (or slightly dependent) on fluid resuscitation and can win time for the definitive treatment of traumatic shock. Such a situation is badly needed.
Arginine vasopressin (AVP) is a nonpeptide hormone synthesized in the paraventricular and superior optic nucleus and stored in the posterior pituitary gland. Many research showed that AVP and its synthetic long-acting analog terlipressin are the potent alternative vasoconstrictors in the treatment of septic patients with catecholamine-refractive vasodilatory shock and septic shock (3–5). Hypotension after shock is a powerful stimulus for the new synthesis of vasopressin; indeed, vasopressin synthesis increases within ≈10 min after onset of hypotension (6). After the initial release of vasopressin, vasopressin levels decline rapidly because of depletion of stored vasopressin (7–9). Several clinical studies of vasopressin infusion in septic shock have shown that vasopressin infusion increases blood pressure, decreases the requirements for norepinephrine (NE), and improves renal function. But only a few studies investigated the application of AVP on hypovolemic or traumatic hemorrhagic shock, which showed that early application of vasopressin can “buy” time for subsequent definitive treatment, but that the time obtained is very limited. For example, Stadlbauer et al. (10) observed the beneficial effect of the early application of vasopressin on mesentery incision–induced uncontrolled hemorrhagic shock in pigs. In that study, when the mean arterial pressure (MAP) was less than 20 mmHg, vasopressin (0.4 IU/kg) was injected followed by continuous infusion of 0.08 IU/kg min over 30 min, and then bleeding was controlled by surgical intervention: the results demonstrated that this strategy can only obtain 30 min for definitive treatment (surgical operation) (10). Whether vasopressin plus NE can win longer time by maintaining and stabilizing hemodynamic parameters for the following definitive treatment after severe traumatic shock is not known. Based on our previous study that AVP + NE applied after active hemorrhage has been stopped can improve the hemodynamic parameters and tissue blood perfusion for hemorrhagic shock (11), we hypothesized that AVP plus NE applied before the active bleeding has been controlled can win enough time for the following definitive treatment (stopping bleeding and full resuscitation) of severe traumatic shock by maintaining and stabilizing hemodynamic parameters.
To elucidate this issue, using uncontrolled hemorrhagic shock rats (obtained by transection of the splenic parenchyma plus a major branch of the splenic artery and vein), the effects of early application of AVP, NE, and combined use with or without a small volume of fluid infusion on the duration of maintaining stable hemodynamics and subsequent effects were observed.
MATERIALS AND METHODS
Ethical approval of the study protocol
This study was approved by the Research Council and Animal Care and Use Committee of the Research Institute of Surgery, Daping Hospital, Third Military Medical University (Chongqing, People’s Republic of China) and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication, 8th ed., 2011). None of the authors are members of this committee.
Sprague-Dawley rats (220–260 g) were fasted for 12 h but allowed water ad libitum before the experiments. Rats were anesthetized with sodium pentobarbital (30 mg/kg). This agent was then added until the rats had no response to a needle stimulus. The total amount of sodium pentobarbital was 50 mg/kg or less. Rats were breathing spontaneously without mechanical ventilation. The right femoral arteries and veins were catheterized with a polyethylene catheter (outer diameter, 0.965 mm; inner diameter, 0.58 mm) for monitoring the MAP and drug administration, respectively. The left ventricle was catheterized with the polyethylene catheter described above and used for hemodynamic measurement via the right carotid artery. To prevent clot formation, the carotid artery catheter was filled with normal (physiological) saline (0.9%) containing 30 U/mL of heparin. A model of uncontrolled hemorrhagic shock was induced by transection of the splenic parenchyma and one of the branches of the splenic artery and vein, as described previously by our research team (12–14). Briefly, after the completion of catheterization, the abdomen was disinfected, and a laparotomy was performed. The spleen was exposed, and a cross-transection was made in the splenic parenchyma between the two major branches of the splenic artery (the transected spleen was not removed out of abdomen). Meanwhile, 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 mmHg (20–30 min), uncontrolled hemorrhagic shock model was established for the subsequent experiments.
All experiments were conducted in two parts. The first part was aimed to investigate if AVP in combination with NE can buy time for the definitive treatment of uncontrolled hemorrhagic shock by increasing and maintaining the hemodynamics for a longer time before bleeding is controlled. The second part was aimed to investigate the beneficial effects of early application of AVP in combination with NE on subsequently definitive treatment.
First part: effect of AVP in combination with NE on uncontrolled hemorrhagic shock rats
One hundred eighty Sprague-Dawley rats were randomly divided into three groups: one-fourth volume of total blood volume of lactated Ringer’s (LR) infusion group (rats in this group received 17.5 mL/kg of LR infusion; the total blood volume of rat accounts for 70 ml/kg), one-eighth volume of total blood volume of LR infusion group (rats in this group received 8.75 mL/kg of LR infusion), and no additional fluid infusion group (rats in this group received only the solvent [1 mL/kg of LR solution]). Each group was equally divided into six subgroups (n = 10/group): AVP 0.04 or 0.4 U/kg, NE 3 µg/kg, AVP (0.04 or 0.4 U/kg) in combination with NE, and the fluid control group. Experiments were defined as three phases. Phase 1 was the model stage (period of uncontrolled hemorrhage) in which blood was allowed to freely flow into the abdominal cavity. This phase was maintained for 30 min, during which no fluid was given (the MAP decreased about 30–40 mmHg). Phase 2 was the AVP or NE or combined-use period: AVP or NE or in combination was infused along with the LR solution (17.5, 8.75, or 1 mL/kg) within 30 min; after this administration, the rats did not receive any further fluid treatment. Phase 3 was the observation period; MAP, blood loss, and survival time were observed. The blood loss was observed by weighing lap pads at the end of experiment. The animal survival time was observed every 10 min during the observation time. During the entire experiment of this part, the bleeding was not controlled (the transected spleen and splenic artery and vein were not ligated). In this part of the experiment, the abdomen was not closed until the natural bleeding from the transected spleen and transected branches of splenic artery and vein stopped. The time was about 3 h from the beginning of spleen transected. Before the abdomen closed, the abdomen incision was dressed with wet gauze. During the observation of animal survival, when the rats were in articulo mortis, they were killed by overdose of sodium pentobarbital. (Fig. 1).
Second part: beneficial effects of early application of AVP in combination with NE on subsequently definitive treatment
According to the first part of the experiments, AVP 0.4 U/kg in combination with NE with one-eighth total blood volume of LR infusion had the best effects on uncontrolled hemorrhagic shock This part of the experiments was aimed to investigate the beneficial effects of this strategy on subsequently definitive treatment (full resuscitation after bleeding control). The experiment was divided into five groups (n = 16/group): AVP 0.4 U/kg, NE 3 µg/kg, AVP + NE with one-eighth total blood volume of LR solution group, pure one-eighth total blood volume of LR solution group, and permissive hypotensive resuscitation group (MAP was maintained at 50 mmHg with 6% hydroxyethyl starch 130 plus LR solution [at a ratio of 1:2]). Permissive hypotensive resuscitation has been regarded as an “ideal” resuscitation strategy for uncontrolled hemorrhagic shock before bleeding is stopped (8) and was adopted as the control group in the present study.
Experiments were defined as four phases. Phase 1 was the model stage, which was identical to the first part of the experiments. Phase 2 was the AVP or NE or combined-use period (2 h). The infusion time for AVP or NE or in combination use was 30 min, no other treatment was given after this time (the main purpose was aimed to know the beneficial effect of early and short-term use of AVP plus NE on subsequently definitive treatment). For hypotensive resuscitation control group, the MAP was targeted at 50 mmHg for 2 h with infusion of 6% hydroxyethyl starch 130 plus LR solution (at a ratio of 1:2). At the end of this phase, the transected spleen and artery and vein were ligated (hemorrhage controlled). Phase 3 was the definitive treatment period: after bleeding was controlled, the rats received definitive resuscitation with LR solution plus whole blood (2:1) to achieve a target MAP of 80 mmHg for 2 h. Phase 4 was the observation period, 2 h for hemodynamic measurements and 20 h for survival observation. After 2-h measurements during this phase, all catheters were removed, and incisions were closed. The animal survival was also observed. During the period of survival observation, if the rats were in articulo mortis or survived over 24 h, they were killed by overdose of sodium pentobarbital.
The MAP; hemodynamic parameters (left intraventricular systolic pressure [LVSP], maximal change rate of left intraventricular pressure [±dp/dtmax]); cardiac output (CO); oxygen delivery (DO2); oxygen utilization (VO2); blood gases; tissue blood flow in the liver, kidney, and brain; and function in the liver and kidney were observed at baseline; at the end of phase 1, phase 2 (before ligation), and phase 3 (maintenance of MAP at 80 mmHg for 2 h); and at the end of phase 4 (2-h observation period).
The hemodynamics was monitored by a Polygraph Physiological Recorder (SP844, Power Laboratory; AD Instruments, Castle Hill, New South Wales, Australia) via the left ventricular catheter of heart. Cardiac output was measured by a Cardiomax-III machine (Columbus Instruments, Columbus, Ohio). The values of DO2 and VO2 in tissue were calculated using the following equations: DO2 = cardiac index (CI) × 13.4 × hemoglobin × SaO2; VO2 = CI × 13.4 × hemoglobin × (SaO2 − SVO2). The blood flows of liver, kidney, and brain were measured by a laser Doppler blood flowmeter (Periflux system 5000; Primed, Stockholm, Sweden) via flowmeter probe (probe 403, ID: 021205). The probes were put on the center of the middle leaf of the liver and parenchyma of the left kidney (as the representative of kidney) to measure the liver and kidney blood flow. For the measurement of brain blood flow, a small hole was made on the parietal bone by the side of sagittal suture. The variables of liver and kidney function were measured by a Biochemical Analyzer (DX800, Biochemical Analyzer; Beckman, Fullerton, Calif). The blood gases were measured by a blood gas analyzer (Phox plus L; Nova Biomedical, Waltham, Mass). The volumes of the blood samples for the blood gases and organ function tests were 0.3 and 0.5 mL, respectively. To avoid the additional blood loss for rats, equal volumes of blood were supplied after each sample was taken (Fig. 1).
Data for fluid requirement, blood loss, MAP, LVSP, ±dp/dtmax, CO, DO2, VO2, partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PCO2), blood pH, tissue blood flow, and the parameters of organ function are presented as the mean ± SD of n observations. Statistical differences were analyzed by repeated-measures one- or two-way analysis of variance followed by the post hoc Tukey test (SPSS version 15.0; SPSS Inc, Chicago, Ill). P < 0.05 was considered significant.
Part 1: Effects of AVP, NE alone, or combined use with or without a small volume of fluid infusion on hemorrhagic shock
Mean arterial pressure
Arginine vasopressin (0.04 and 0.4 U/kg) and NE (3 μg/kg) used alone or in combination significantly increased the MAP during uncontrolled hemorrhagic shock in rats with or without infusion of a small volume of LR solution. The MAP in the control group and in NE or AVP (0.04 U/kg) used-alone group decreased rapidly to a very low level (≈20 mmHg). AVP (0.4 U/kg) plus NE (3 μg/kg) with one-eighth total blood volume of LR infusion could maintain MAP at 55 mmHg for 3 h, whereas AVP (0.4 U/kg) plus NE (3 μg/kg) with one-fourth total blood volume of LR infusion could maintain MAP of 55 mmHg or greater for only 1 h (Fig. 2, A–C).
The blood losses during the entire experiment among AVP, NE alone, or combined use in the same fluid volume group were not different (Fig. 2, D–F). However, the blood losses in the same drug group between different fluid volume groups had significant differences. For example, blood loss in one-fourth was significantly more than one-eighth and no-fluid groups (P < 0.05). There was no significant difference between one-fourth and one-eighth group (P > 0.05) (Fig. 2, D–F).
Arginine vasopressin (0.4 U/kg) in combination with NE (3 μg/kg) with one-fourth or one-eighth total blood volume of LR infusion significantly improved the survival time of uncontrolled hemorrhagic shock rats as compared with the control fluid group. Among all groups, AVP (0.4 U/kg) + NE with one-eighth total blood volume LR infusion had the best effect on survival time (about 380 min) (Fig. 2, G–I).
Part 2: Effects of AVP + NE with one-eighth total blood volume of LR infusion on the effect of definitive treatment
Early application of AVP (0.4 U/kg) + NE (3 μg/kg) with one-eighth volume of LR infusion significantly improved the beneficial effect of definitive resuscitation for uncontrolled hemorrhagic shock rats. The survival time and 12-h survival rate in the AVP + NE group were 16.2 h and 75%, respectively, which were significantly higher than those in the AVP and NE alone or LR solution and permissive hypotension groups (Fig. 3, A and B).
Blood loss at the end of phase 2 (before ligation) in the AVP, NE, AVP + NE, and LR control groups was 54% to 56% of the estimated total blood volume: there was no significant difference among all groups. In the hypotensive resuscitation group, blood loss was 109.3%, which was significantly higher than that in the AVP, NE, AVP + NE, and LR control groups (Fig. 3C).
Fluid requirement in phases 2 and 3
Fluid infusion in the AVP, NE, AVP + NE, or LR control groups during phase 2 was 8.75 mL/kg, whereas the fluid infusion in the hypotensive resuscitation group (maintenance of MAP at 50 mmHg for 2 h) during phase 2 was 86.95 mL/kg: the difference between the two groups was significant (P < 0.05). During phase 3 (the definitive treatment period after bleeding was controlled), the fluid requirement to maintain MAP at 80 mmHg for 2 h in the AVP, NE, and AVP + NE groups was also lower than that in the hypotensive resuscitation group (Fig. 3D).
At baseline and at the end of phase 1 (model stage, data not shown), the MAP, ±dp/dtmax, and LVSP showed no differences in all groups. At the end of phase 2, the MAP, LVSP, and ±dp/dtmax in the AVP or AVP +NE groups were higher than those in the LR, NE, or hypotensive resuscitation groups. At the end of phase 3 (definitive treatment stage) and phase 4 (2-h observation period), the MAP, LVSP, and ± dp/dtmax in the AVP + NE group were higher than those in the AVP, NE, LR, or hypotensive resuscitation groups (Table 1).
At baseline and at the end of phase 1 (model stage, data not shown), blood pH, base deficit, PaO2, PCO2, and arterial oxygen saturation (SaO2) showed no differences in all groups. At the end of phase 2, blood pH, PaO2, and SaO2 demonstrated a slight decrease, and PCO2 showed a slight increase in all groups, but there were no significant differences among the groups. At the end of phases 3 and 4, the blood gas variables showed some recovery in all groups, among which the AVP + NE group recovered best (Table 2).
Cardiac output, CI, stroke index, and heart rate
At baseline and at the end of phase 1 (model stage, data not shown), CO, stroke index (SI), CI, and heart rate (HR) showed no differences in all groups. At the end of phases 2, 3, and 4, the CO, CI, and SI in the AVP and AVP + NE groups were higher than those in the NE, LR, or 50-mmHg hypotensive resuscitation groups. In the AVP and AVP + NE groups, the AVP + NE group had the better effect (Fig. 4, A–C). There were no significant differences in HRs in all groups (data not shown).
DO2 and VO2
At baseline and at the end of phase 1 (model stage), DO2 and VO2 did not show differences in any group (data not shown). At the end of phases 2, 3, and 4, DO2 and VO2 in the AVP and AVP + NE groups were higher than those in the NE, LR, and hypotensive resuscitation groups. In the AVP and AVP + NE groups, the latter had the better effect for improving DO2 and VO2 (Fig. 4, D and E).
Blood flow in the liver, kidney, and brain
There were no significant differences in blood flow in the liver, kidney, and brain at baseline and at the end of phase 1 (model stage) in all groups (data not shown). AVP + NE significantly increased blood flow in the liver and kidney, which were significantly higher than that in the AVP, NE, LR, and hypotensive resuscitation groups at phases 2, 3, and 4. Blood flow in the brain showed no significant differences in all groups at phases 2, 3, and 4 (Fig. 5, A–C).
Liver and kidney function
There were no significant differences in parameters reflecting liver and kidney function such as alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and serum creatinine in all groups at baseline and phases 1 and 2. These parameters in the AVP + NE group in phases 3 and 4 were significantly lower than those in the other groups (data not shown).
Reports from military conflicts as well as traumatic accidents or traffic accidents in the civilian population have shown that greater than 50% of deaths are due to trauma and hemorrhagic shock at the scene of the incident, where medical care is limited. Antishock agents such as dopamine, anisodamine (654-2), calcium-channel blockers, oxygen free-radical scavengers, and cytokine antagonists must be administered along with sufficient fluid infusion to elicit their antishock effects (2). However, at military conflicts and civilian trauma, implementation of large amounts of fluid infusion is not possible. Hence, a strategy that is independent (or slightly dependent) of fluid resuscitation and that can buy time for definitive treatment is very important at the early stage of severe trauma and hemorrhagic shock.
The present study demonstrated that early application of 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth total blood volume of LR solution significantly increased and maintained the MAP and hemodynamic parameters, prolonged the survival time, and bought time for follow-up definitive treatment for severe hemorrhagic shock. This treatment strategy significantly enhanced the beneficial effects of subsequently definitive treatments. It increased the subsequent survival, improved the hemodynamic parameters and cardiac function, and increased the tissue blood flow and DO2 and VO2. It has been suggested that AVP + NE may be a very good strategy for the emergency care of severe traumatic or hemorrhagic shock, which may buy time for subsequently definitive treatment after bleeding stopped. This finding implicates these treatments are suitable for the early treatment of traumatic-hemorrhagic shock.
Our previous study found that AVP plus NE had good beneficial effects on hemorrhagic shock in rats applied after bleeding has been stopped (11). Norepinephrine, despite being a potent vasoactive agent, does not have beneficial effect when used alone. They can play effect only when used in combination with AVP. There may be two reasons for this phenomenon: (i) AVP in combination with NE can have a synergistic effect, i.e., increasing the effect of AVP on vascular tone and the inotropic effect of NE on cardiac function; (ii) our previous studies showed that AVP can improve vascular responsiveness and increase the cardiovascular function of NE (15, 16). Hence, AVP in combination with NE can effectively improve and stabilize hemodynamic parameters and increase tissue perfusion and DO2, as well as increase and improve the early effect for traumatic or hemorrhagic shock.
Interestingly, the MAP in the one-eighth total blood volume of LR solution groups was higher than in the “no fluid” and one-fourth total blood volume of LR solution groups, especially 2 h after AVP and NE administration, whereas the blood loss in the one-fourth total blood volume of LR solution group was more than that in the one-eighth total blood volume of LR solution or no-fluid group. The reason may be that AVP and NE have some vasoconstrictor effects. In the no-fluid group, AVP or NE may prevent and reduce bleeding from the transected spleen and splenic artery and vein by vasoconstriction effects (17). In the greater-volume expansion group (one-fourth volume of LR solution group), the vasoconstriction effect of AVP or NE is still present, but the volume expansion and hemodilution caused by fluid infusion may increase the bleeding of transected spleens and splenic arteries, and then the MAP is decreased. Hence, the MAP in the one-eighth total blood volume of LR solution groups was higher than that in the one-fourth volume of LR solution groups, whereas the blood loss in the one-fourth total blood volume of LR solution group was more than that in the one-eighth volume of LR solution and no-fluid groups.
Another phenomenon was that in the present study, although we tried to get the target MAP at 80 mmHg in phase 3 in all groups in the second part of the experiment by infusion of LR solution plus whole blood, the target MAP in LR and hypotensive resuscitation control group was difficult to get. The precise reason was not known; the possible reason may be because LR solution and hypotensive resuscitation in phase 2 did not get a good resuscitation effect, so the organ function including cardiovascular function had some content of damage in this phase; hence, the target MAP cannot be easily achieved by simple infusion of LR solution plus whole blood in these two groups in phase 3. The precise reasons need further investigations.
Some studies have shown that AVP used in septic shock or the isolated perfused heart reduces CO because of vasoconstrictor effects (18). Ouattara et al. (19) report that AVP reduced CO and HR in isolated perfused rabbit hearts. Ryckwaert et al. (20) found that an analog of AVP, terlipressin (a more selective V1 receptor agonist), induced coronary vasoconstriction in an animal model, which was associated with a decrease in cardiac contractile function. To ascertain if AVP or AVP + NE has the same adverse effects on CO in hemorrhagic shock rats, we measured the changes of CO, CI, SI, and HR after administration of AVP or AVP + NE. The early application of AVP (0.4 U/kg) or AVP (0.4 U/kg) + NE (3 μg/kg) did not decrease the CO, CI, SI, and HR, but did have some increasing effects (Fig. 4). This result suggested that early application of AVP or AVP + NE may protect cardiovascular function as well as increase and stabilize hemodynamic parameters.
Several studies have suggested that there is considerable regional heterogeneity in the reactivity of blood vessels to vasopressin. Vasopressin produces a marked constriction in cutaneous, splanchnic, and muscle vessels, whereas it produces dilatation or weak constriction in the renal vasculature (21, 22). Nakajima and colleagues (23) found that lipopolysaccharide decreased perfused flow in intestinal villi. Vasopressin increased the MAP and prevented further falls in the flow in perfused intestinal villi. The present study suggested regional heterogeneity of AVP or AVP + NE on regional blood flow. Early application of AVP or AVP + NE increased blood flow in the liver and kidney, but did not increase blood flow in the brain. However, whether AVP or AVP + NE constricts or dilates blood vessels in the liver, kidney, intestine, and brain is not known, so further investigation is needed.
The present study had some limitations. First, some studies have shown that AVP has effects on coagulation and platelet count (24–26). We did not observe these effects of AVP in the present study, so further investigation is needed. Second, only a short-term infusion effect was observed in the present study; how the effect of a longer time infusion (of AVP and NE) is, such as on 24- or 72-h survival, needs further investigation. Third, the certain reason for the result that PO2 was increased, but SaO2 was not simultaneously increased after treatment, needs to be answered in future work.
Our results showed that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can buy time for the definitive treatment of uncontrolled hemorrhagic shock and improve subsequent treatment effects. This effect is mainly through increasing and stabilizing hemodynamics, improving cardiac function, and increasing tissue blood flow and tissue DO2. This finding implicates these treatments may be suitable for the early treatment of traumatic-hemorrhagic shock.
AVP: arginine vasopressin
CO: cardiac output
CI: cardiac index
Do2: oxygen delivery
±dp/dtmax: maximal change rate of left intraventricular pressure
HR: heart rate
LR: lactated Ringer’s
LVSP: left intraventricular systolic pressure
MAP: mean arterial pressure
Pao2: partial pressure of arterial oxygen
Pco2: partial pressure of arterial carbon dioxide
Sao2: arterial oxygen saturation
SI: stroke index
Vo2: oxygen utilization
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