SHOCK, Vol. 30, No. 6, pp.

675Y679, 2008

MECHANICAL CARDIAC ASSISTANCE IMPROVES OUTCOME AFTER PROLONGED HEMORRHAGIC SHOCK

Branislav Radovancevic, Murat Sargin, Egemen Tuzun, Dong Liu, Vijay S. Patel, Gil Costas, Denise Byler, Dan Tamez, and O. H. Frazier
Cardiovascular Surgical Research Laboratories, Texas Heart Institute at St Lukes Episcopal Hospital, Houston, Texas
Received 26 Sept 2007; first review completed 10 Oct 2007; accepted in final form 24 Feb 2008 ABSTRACTTo examine the use of mechanical cardiac assist devices in prolonged hemorrhagic shock lasting up to 120 min. We induced hemorrhagic shock in anesthetized calves that were then treated 30 or 120 min later with either conventional fluid and blood resuscitation methods or the implantation of a mechanical assist device in addition to conventional fluid resuscitation. We measured hemodynamic and hematologic variables, inflammatory mediators, endorgan function via biochemical parameters, and survival time. Although cardiac output and blood flow in the left anterior descending artery decreased significantly in all calves at the end of the hemorrhage period, the drop was significantly less severe in calves who received mechanical assistance in addition to fluids. Furthermore, the biochemical profile, indicating liver and kidney function, and survival time were better after hemorrhage in device-treated calves than in conventionally treated calves. Levels of inflammatory mediators, which contribute to cell and organ dysfunction, were increased after hemorrhage, but calves with mechanical devices had less of an increase than did calves treated only with fluids. Our results indicate that the use of a mechanical cardiac assist device in combination with conventional fluid and blood resuscitation methods improves survival and end-organ recovery and decreases the myocardial inflammatory response after prolonged hemorrhagic shock when compared with the sole use of conventional fluid resuscitation techniques. KEYWORDSShock, hemorrhagic, heart-assist devices, systemic inflamatory response syndrome

INTRODUCTION The leading cause of hemorrhagic shock is traumatic injury. About 40% of injured patients with shock die before being hospitalized (1Y3). On the battlefield, about half of all deaths result from wound-associated shock (1, 2, 4). Motor vehicle accidents leading to hemorrhagic shock are the most common cause of death in persons between the ages of 1 and 44 years. Accordingly, trauma-related health care costs and mortality rates are comparable to those seen with pervasive diseases such as cancer and heart disease (1Y5). Successful treatment of hemorrhagic shock involves controlling the bleeding and restoring adequate tissue perfusion to provide cells with sufficient oxygen to resume aerobic metabolism. Life-threatening conditions such as severe acidosis and multiple organ failure can develop in patients with prolonged hypotension and severe blood loss (6). Furthermore, tissue hypoperfusion in uncontrolled hemorrhagic shock can lead to ischemia (7), and severe tissue trauma in hemorrhagic shock may activate an excessive inflammatory response, which can contribute to cell and organ dysfunction. Levels of inflammatory mediators correlate with clinical severity and prognosis in animal and human studies of hemorrhagic shock (8Y11). Mechanical cardiac assist devices (MCADs) have been used as a bridge to transplantation or a bridge to myocardial recovery in patients with cardiogenic shock caused by postcardiotomy failure, myocardial infarction, and end-stage heart failure (12). Moreover, MCADs are the only alternative
Address reprint requests to Egemen Tuzun, MD, Texas Heart Institute at St Luke_s Episcopal Hospital, Cardiovascular Surgery Laboratories, 6770 Bertner Ave MC 1-268 Houston, TX 77030. E-mail: etuzun@heart.thi.tmc.edu. DOI: 10.1097/SHK.0b013e31816f22bf Copyright 2008 by the Shock Society

for patients with acute cardiogenic shock unresponsive to inotropic support. Because of the success of MCADs in patients with cardiogenic shock, we previously studied the use of mechanical assistance in a large animal model of controlled hemorrhagic shock lasting up to 30 min; we found that MCAD support improved perfusion and end-organ (i.e., kidney and liver) function (13). In the present study, we evaluated the use of MCAD support and its effect on survival time, hemodynamic and hematologic variables, inflammatory mediators, and end-organ function during prolonged periods of hemorrhagic shock of up to 120 min of duration. MATERIALS AND METHODS
Animal model and study design
We randomly divided 18 female Corriente crossbred calves weighing between 92 and 130 kg (mean, 105 T 7 kg) into four experimental groups. Group 1 (n = 5) is comprised of calves resuscitated by administration of fluid and blood 30 min after induction of hemorrhagic shock. Group 2 (n = 4) calves were resuscitated with fluid and blood and placed on MCAD support 30 min after hemorrhagic shock. In group 3 (n = 4), calves were resuscitated by administration of fluid and blood 120 min after induction of shock, whereas group 4 (n = 5) received both fluid and blood and MCAD support 120 min after induction of shock. The study lasted 24 h after initiation of resuscitative treatment. All calves received humane care in compliance with the Principles of Laboratory Animal Care (National Society of Medical Research) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication no. 85-23, revised 1996). Our protocol was approved by our Institutional Animal Care and Use committee.

Hemorrhage and resuscitation

Each calf was premedicated with intramuscular injections of glycopyrrolate (0.02 mg/kg) and xylazine (0.2Y0.7 mg/kg). A 12F triple-lumen venous catheter was inserted percutaneously into the right external jugular vein for fluid replacement. Anesthesia was induced with intravenous ketamine (10Y20 mg/kg), and general anesthesia was maintained with isoflurane (1%Y1.5%). Urine output was monitored via a urinary catheter. We used a warming blanket to maintain body temperature between 35-C and 37-C throughout the study. 675

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FIG. 1. Cardiac output was significantly higher at 2 and 6 h after resuscitation and at study termination in group 2 (MCAD-supported) calves than in any other group. At termination of the study, CO returned to baseline levels only in group 2. *P G 0.05 vs. other groups.

All animals underwent splenectomy (via a left subcostal approach) to avoid variable degrees of autotransfusion, which can reduce the reliability of mortality estimates and measurements of blood volume (14). To induce hemorrhagic shock, we inserted an 8F catheter into the left carotid artery and withdrew arterial blood until the mean aortic pressure dropped to 40 mmHg. The blood was collected in citrated blood bags and used later for autologous blood transfusion during resuscitation. Hemoglobin levels lower than 7 g/dL were considered an indication for blood transfusion. If the calf_s autologous blood supply was depleted, additional blood was obtained from healthy donor cows. For fluid resuscitation, we administered physiologic lactate saline and hydroxyethyl starch solution either 30 or 120 min after achieving a mean aortic pressure of 40 mmHg (shock condition). The ratio of replacement fluids to blood loss during fluid resuscitation (60% of total given amount as lactate saline and 40% as hydroxyethyl starch solution) was similar in all four study groups: 2 mL of fluid for every 1 mL of blood loss.

(SUN), lactic acid, and creatinine levels in all calves. Blood samples were collected before (baseline) and after the induction of hemorrhage, at the beginning of fluid resuscitation, and every 6 h until study termination. Myocardial tissue levels of IL-1, IL-6, TNF-!, and C-reactive protein (CRP) were measured only in groups 1 and 2 at baseline, after hemorrhage, and 6 h after the initiation of resuscitation. MCAD implantation The MCAD was implanted via a left thoracotomy at the fifth intercostal space. In all calves, the pericardium was opened from the apex to the pulmonary artery, and the heart was suspended in a pericardial cradle. In groups 2 and 4, the descending thoracic aorta was exposed and dissected for insertion of the outflow cannula. Heparin was administered to maintain an activated clotting time longer than 300 s in all animals, including groups 1 and 3. A 21F Medtronic EOPA 77722 wire-reinforced outflow cannula was advanced with the use of the Seldinger technique into the descending aorta and secured with previously placed double purse-string sutures. An incision was made in the left ventricular apex. A 32F Edwards Life Sciences model no. TFM032L inflow cannula was inserted and secured with a previously placed 2-0 interrupted pledgeted purse-string suture. The MCAD (Levitronix Centrimag magnetically levitated centrifugal assist device, Waltham, Mass) and tubing lines were primed with a sterile heparin/ NaCl solution and connected to the inflow and outflow cannulas. The pump was initiated at 4,500 rpm, and the impeller was adjusted to maximum speed, allowing partial left ventricular unloading and maintenance of the aortic valve opening for the duration of the study. After the aortic valve opening, an aortic notch was observed in the aortic pressure waveform. The animals were supported for 24 h and then killed. The chest was sealed from room air with a povidone-iodineYimpregnated drape throughout the study. Groups 1 and 3 underwent sham operations without implantation of the MCAD.

TABLE 1. Selected laboratory tests at baseline and 6 and 24 h after starting resuscitation Group 1 Hemoglobin, g/dL Baseline 6h 24 h SUN, mg/dL Baseline 6h 24 h 12.2 T 3.3 20.7 T 3.1* 29.5 T 2.1* 0.9 T 0.2 1.3 T 0.1 2.5 T 0.1 53.6 T 5.4 65.7 T 1.5* 121.0 T 4.2 14.8 T 1.3 25.7 T 2.3* 35.5 T 2.1* 14.6 T 1.5 29.3 T 1.5* 24.5 T 3.5* 10.2 T 2.2 16.4 T 4.0* 26.0 T 6.7* 0.8 T 0.2 1.1 T 0.2 2.3 T 0.7 49 T 14.2 62.6 T 15.9 82 T 13.4*k 13.6 T 2.1 18.2 T 3.3

Group 2

Group 3

Group 4

11.9 T 1.0 7.3 T 0.3* 7.1

10.6 T 1.4 7.9 T 0.5* 7.2 T 0.7*

10.6 T 1.4 7.3 T 0.3* 7.1* 11.2 T 2.6 36.0 T 2.8* 39.0* 0.9 T 0.2 1.8 T 0.1* 2.6 51.0 T 6.0 113.0 T 5.7* 152.0* 15.6 T 1.7 36.0 T 4.2* 62.0* 14.3 T 1.2
k

12.4 T 1.9 8.0 T 0.3* 9.4 T 0.8* 10.0 T 2.6 25.0 T 3.6*, 26.5 T 0.7*, 0.8 T 0.1 1.3 T 0.1 1.6 T 0.1*, 57.6 T 5.8 83.3 T 5.0 95.0 T 11.3*, 15.4 T .7 24.5 T 2.6 36.0 T 4.2*, 14.7 T 1.7 25.8 T 3.7 21.5 T 2.1

Data collection and instrumentation

Hemodynamic and laboratory data To measure cardiac output (CO), we inserted an oximetric Swan-Ganz thermodilution catheter into the pulmonary artery. A pressure line inserted into the left internal mammary artery was used to monitor arterial pressure and blood gases. We placed a 3-mm flow probe around the left anterior descending (LAD) coronary artery to measure LAD blood flow. A 16-channel computer data acquisition system (Ponemah System version 3.3; Gould Instrument Systems Inc, Valley View, Ohio) continuously recorded hemodynamic data. We measured hemoglobin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum urea nitrogen

Creatinine level, mg/dL Baseline 6h 24 h SGPT, U/L Baseline 6h 24 h SGOT, U/L Baseline 6h 24 h

28.5 T 6.6*,k 14.3 T 0.8 19.6 T 1.3 16.2 T 3.8

Lactic acid, mg/dL Baseline 6h

FIG. 2. Blood flow in the LAD artery was significantly higher at 2 and 6 h after resuscitation and at study termination in group 2 (MCADsupported) calves than in any other group. At termination of the study, LAD blood flow returned to baseline levels only in group 2. *P G 0.05 vs. other groups.

34.4 T 6.2* 39.0*

24 h

Data are means T SD. *P G 0.05 vs. baseline; P G 0.05 vs. group 3, 6 h; P G 0.05 vs. group 3. 24 h; P G 0.05 vs. 6 h; kP G 0.05 vs. group 1, 24 h; P G 0.05 vs. group 1, 6 h.

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FIG. 3. IL-1" levels were significantly higher in both groups after hemorrhage and at 6 h after starting resuscitation than at baseline; however, IL-1" levels were significantly higher in group 1 than in group 2 calves at 6 h. *P G 0.05 vs. baseline (for both groups); P G 0.05 for group 1 vs. group 2. TSAYtissue stained amount as percent.

yethyl starch (40%). The amount of the immediate replacement was equal to the total blood loss of each individual animal, and there was no significant difference between study groups. The amount of fluid (as per protocol, 2 mL fluid for every 1 mL blood loss) given during the first 6 h of resuscitation was similar for all calves (mean volume, 2,250 mL T 300 mL; P = not significant). After the sixth hour, the animals received 3 mL/kg per h of fluid until termination of the study. Calves with hemoglobin levels lower than 7 g/dL received a blood transfusion, and the total volume of blood transfused was similar for all groups. The mean hourly volume of urine was significantly lower in group 1 (58 T 25.9 mL/h) than in group 2 (142 T 40.2 mL/h; P G 0.05). Similarly, group 3 had a significantly lower hourly urine output (27 T 8.4 mL/h) than did group 4 (92 T 19.2 mL/h; P G 0.05).
Laboratory data

Statistics
All statistical tests were performed by using Microsoft Excel software. A single-tailed Student t test or ANOVA was used to compare 2 or multiple group variables, respectively. A value of P G 0.05 was considered significant.

RESULTS
Hemorrhage and resuscitation

All calves survived surgery and the subsequent induction of hemorrhage. A mean aortic pressure of 40 mmHg was achieved in all calves after bleeding. The mean arterial bleeding time was 21 T 3 min, and there was no statistical difference between groups. The amount of blood loss required to create shock conditions was similar for all groups (902 T 162 mL; P = not significant). The mean weight of the spleens removed was 1050 T 270 g. Fluid resuscitation was begun 30 min after induction of shock in groups 1 and 2 and 120 min after shock in groups 3 and 4. The MCAD support was initiated concomitantly with fluid resuscitation in groups 2 and 4. According to the study protocol, the immediate fluid replacement consisted of physiologic lactate saline (60%) and hydrox-

Hemodynamic data Cardiac output decreased significantly in all calves to about 35% T 5% of baseline levels at the end of the hemorrhage period (Fig. 1). At 2 h after initiating resuscitation, mean CO was significantly lower than baseline levels in group 1 (2.3 L/min, 38% of baseline; P G 0.01) and group 2 (3.0 L/min, 51% of baseline; P G 0.05). By 6 h after resuscitation, CO was still significantly lower than baseline for calves in group 1 (4.4 L/min, 74% of baseline; P G 0.05); however, CO was not significantly different from baseline measurements by 6 h in MCAD-treated calves (group 2). Furthermore, CO was significantly higher at 2 and 6 h after resuscitation in group 2 calves than in group 1 (P G 0.05); however, CO in both groups 1 and 2 was not significantly different from baseline levels by the end of the study. Cardiac output in group 3 was significantly lower than baseline at 2 h (2.0 L/min, 35% of baseline; P G 0.01) after resuscitation and at 6 h (2.5 L/min, 43% of baseline; P G 0.01). For group 4, the respective values were 2.4 L/min (41% of baseline; P G 0.01) at 2 h and 4.2 L/min (72% of baseline; P G 0.05) at 6 h. Calves in group 4 had significantly higher CO at 6 h than did calves in group 3 (P G 0.05). Cardiac output at the end of the study was 67% of baseline value for group 3 and 84% of baseline value for group 4 (P G 0.05). Cardiac output

FIG. 4. IL-6 levels were significantly higher in both groups after hemorrhage and at 6 h after starting resuscitation than at baseline; however, IL-6 levels were significantly higher in group 1 than in group 2 at 6 h. TSA as percent. *P G 0.05 vs. baseline (for both groups); P G 0.05 for group 1 vs. group 2.

FIG. 5. TNF-! levels were significantly higher in both groups after hemorrhage and at 6 h after starting resuscitation than at baseline; however, TNF-! levels were significantly higher in group 1 than in group 2 at 6 h. TSA as percent. *P G 0.05 vs. baseline (for both groups); P G 0.05 for group 1 vs. group 2.

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CO or related arrhythmias or both before the end of the study. One calf in group 2 and two in group 4 died of ventricular fibrillation before study termination. DISCUSSION In this study of prolonged hemorrhagic shock in calves, the use of an MCAD in combination with fluid and blood resuscitation techniques improved survival and end-organ function when compared with fluid resuscitation alone. Furthermore, the inflammatory response in the myocardium usually associated with shock was milder in calves treated with MCAD and fluid resuscitation than in those treated with just fluids. Of the calves who received mechanical assistance in addition to fluid replacement, recovery was significantly better for those maintained in shock conditions for 30 min than for those in 120 min of shock. The MCADs improve hemodynamic and metabolic status and increase survival in cardiogenic shock (15Y17). In a comparison study of pulsatile and nonpulsatile pumps in pigs, Drakos et al. (18) showed the effectiveness of a nonpulsatile centrifugal pump in the management of profound cardiogenic shock refractory to conventional treatment. In similar models of cardiogenic shock, percutaneous MCADs decompressed the left ventricle and provided circulatory support similar to that of an intra-aortic balloon pump, thus limiting infarct size and subsequent ventricular remodeling (19, 20). Together, these data indicate a role for MCAD support in the treatment of patients in cardiogenic shock. Based on the success of MCAD support in cardiogenic shock, we previously studied the use of mechanical circulatory support in a porcine model of hemorrhagic shock lasting 30 min; our results showed that MCAD treatment improved perfusion and led to less significant changes in endorgan function (13). In the present study, we evaluated the efficacy of MCAD support in preserving end-organ function for a longer period of hemorrhagic shockVup to 120 min. Our laboratory findings indicate that circulatory assistance via MCAD helps maintain tissue perfusion and preserve organ function during prolonged hemorrhagic shock. Our biochemical measures of liver, cardiac, and renal function indicated the condition of shock in all calves; however, increases in SGOT, SGPT, SUN, and creatinine levels were lower in calves who received mechanical circulatory assistance than in those treated with traditional fluid replacement therapy. Lactic acid levels in blood reflect the metabolic acidosis in tissues that results from inadequate tissue perfusion. The significantly lower levels of lactic acid and the less severe increases in liver and renal markers in MCAD-treated calves indicate improved tissue perfusion in these groups. Furthermore, the higher mean urine output and CO seen in groups 2 and 4 provide further evidence to support our overall hypothesis of improved tissue perfusion and organ function associated with circulatory assistance. Coronary blood flow must be maintained in hemorrhagic shock to preserve the myocardium and ensure patient survival. In a comparative study on the effects of pulsatile versus nonpulsatile extracorporeal circulation on the pattern of coronary artery blood flow during cardiac arrest, Son et al. (21) suggested

FIG. 6. The CRP levels were significantly higher in both groups at 6 h after starting resuscitation than at baseline; however, CRP was significantly higher in group 1 than in group 2 at 6 h. *P G 0.05 vs. baseline (for both groups); P G 0.05 for group 1 vs. group 2.

was significantly higher at 2 and 6 h after resuscitation and at study termination in group 2 than in any other group (P G 0.05 vs. groups 1, 3, and 4). Furthermore, groups 1 and 4 had significantly higher CO values at 6 h and at study termination than group 3 (P G 0.05). Among the survivors, CO returned to baseline levels only in group 2 calves. The trend of changes for LAD flow was similar to the trend seen for CO (Fig. 2). At the end of the hemorrhage period, the mean LAD flow in all groups decreased from 70.7 T 4.3 mL/ min to 38.8 T 2.2 mL/min (P G 0.05). The LAD flow was significantly higher at 2 and 6 h after initiation of resuscitation and at study termination in group 2 than in the other groups (P G 0.05). Groups 1 and 4 had significantly higher LAD flow at 6 h and at study termination than did group 3 (P G 0.05). The LAD flow returned to baseline levels only in group 2 calves. Hematologic data and inflammatory mediators Hematologic data indicated the status of shock in all calves (Table 1). The levels of lactic acid, SGOT, SGPT, SUN, and creatinine, which indicate end-organ damage (cardiac, hepatic, and renal), increased in all groups after induction of shock, but the increase was significantly lower in groups 2 and 4 than in groups 1 and 3. Inflammatory mediators were measured only in groups 1 and 2 (Figs. 3Y6). Levels of IL-1, IL-6, TNF-!, and CRP were similar in groups 1 and 2 at baseline and directly after hemorrhage. However, levels of all inflammatory mediators were significantly higher in both groups at 6 h after resuscitation than at baseline (P G 0.05). Nevertheless, levels of IL-1, IL-6, TNF-!, and CRP were significantly higher at 6 h in group 1 calves than in group 2 calves (P G 0.05).
Survival time

Mean survival time from initiation of resuscitation was shortest in group 3 calves (7.8 T 9.3 h) and longest in group 2 (23.6 T 0.9 h). Despite having a longer period of shock, calves in group 4 (21.4 h T 3.6 h) survived longer than those in group 1 (12.2 T 10.8 h). Survival time of calves in groups 2 and 4 was significantly longer than that of calves in groups 1 and 3. All calves in group 3 and three calves in group 1 died of low

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that pulsatile circulation provides better blood flow and velocity and less resistance to coronary artery than does nonpulsatile circulation. We used a continuous-flow MCAD in our study, and we found that LAD flow was maintained closer to normal levels in MCAD-treated groups and was significantly higher than flow in groups that received only fluid resuscitation. Although hemodynamic status was affected by the shock conditions in all calves, those calves in each time group (30 min and 120 min) that received MCAD support had less drastic changes, and hemodynamic status tended to return to normal levels quicker than their respective fluid-treated counterparts. Moreover, end-organ function and survival time were better in calves who received mechanical assistance. The inflammatory system is activated in response to trauma and shock (22, 23), and death may result from circulatory collapse caused in part by the progression of the inflammatory response and the negative effects of inflammatory cytokines (24). TNF-! contributes to the pathophysiology of multiple organ failure and to the decrease in cardiac function after hemorrhagic shock (25). In addition, IL-6, a cytokine produced by many cell types, mediates organ system dysfunction, and its levels correlate with the severity of trauma (26, 27). Similarly, CRP may contribute to the acute-phase inflammatory response after trauma (28, 29). In our study, the progressive deterioration of cardiac function, despite the restoration of circulating fluid and blood volume after controlled hemorrhage, may have been related to the increased levels of inflammatory markers in the tissue. The lower levels of inflammatory mediators in MCAD-treated calves suggest a downregulation of cardiac inflammation in these animals, which may have contributed to the preservation of cardiac function in mechanically assisted groups. The negative inotropic effects of the inflammatory cascade may be partially ameliorated by mechanical circulatory assistance, as supported by the blood chemistry profile of MCAD-treated calves in our study. In summary, our findings indicate that the use of MCAD, in conjunction with conventional fluid restoration, improves endorgan recovery and survival and reduces the inflammatory response after prolonged hemorrhagic shock when compared with the use of fluid replacement alone. Mechanical assistance offers another therapeutic option that may help preserve organ function and improve outcome in hemorrhagic shock. ACKNOWLEDGMENTS
The authors thank Levitronix Co (Waltham, Mass) for the donation of cardiac assist devices. The authors also thank Rebecca A. Bartow, PhD, of the section of scientific publications at the Texas Heart Institute for editorial assistance.

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