Enhancement of the intrathoracic vacuum during

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1 Critical Care and Trauma Section Editor: Jukka Takala Intrathoracic Pressure Regulation Improves 24-Hour Survival in a Porcine Model of Hypovolemic Shock Demetris Yannopoulos, MD* Scott McKnite, BSc Anja Metzger, PhD Keith G. Lurie, MD BACKGROUND: The intrathoracic pressure regulator (ITPR) plus positive pressure ventilation (PPV) has been shown to improve coronary and cerebral perfusion pressures during hypovolemia by improving mean arterial blood pressure and by decreasing right atrial and intracranial pressures. We hypothesized that application of intermittent negative intrathoracic pressure in a pig model of severe hypovolemic hypotension would increase 24-h neurological intact survival rates. METHODS: Eighteen isoflurane-anesthetized pigs were bled 55% of their estimated blood volume and were then prospectively randomized to either ITPR treatment with 8 mm Hg endotracheal pressure plus PPV or only PPV alone for 90 min. All survivors were reinfused with their own blood. Arterial blood gases, end-tidal CO 2, and aortic pressures were monitored for the 90 min and neurological evaluation was performed at 12 and 24 h after reinfusion. RESULTS: ITPR plus PPV treatment for 90 min prevented the progression of metabolic acidosis and significantly improved mean arterial blood pressure (mean over 90 min, 55 3vs mm Hg, P 0.001) when compared with controls. Twenty-four hour survival significantly improved with use of the ITPR when compared with untreated controls: 9/9 (100%) vs 1/9 (11%), P CONCLUSIONS: Use of the ITPR plus PPV for 90 min significantly increased arterial blood pressure and 24 h neurologically intact survival rates compared with controls treated with PPV alone. (Anesth Analg 2007;104:157 62) Enhancement of the intrathoracic vacuum during spontaneous inspiration has been recently shown to improve hemodynamics in states of hypovolemic hypotension in spontaneously breathing animals and humans (1 7). With inspiration against a low level of resistance, an intrathoracic vacuum is created that enhances venous blood flow back to the heart and decreases intracranial pressures (6,7). A similar physiological approach has demonstrated to improve survival rates in cardiac arrest with an inspiratory From the *Department of Cardiology, University of Minnesota; Minnesota Medical Research Foundation, Hennepin County Medical Center, Minneapolis, Minnesota; Advanced Circulatory Systems, Inc., Eden Prairie, Minnesota; Cardiac Arrhythmia Center at the University of Minnesota; Department of Emergency Medicine, Hennepin County Medical Center; and Minneapolis Medical Research Foundation, Minneapolis, Minnesota. Accepted for publication September 25, Supported by American Heart Association Postdoctoral Fellowship Grant Z, National Institute of Health SBIR Grant R44 HL , and the Dwight Opperman Foundation. Disclosures: Dr. Keith Lurie is a co-inventor of the intrathoracic pressure regulator used in this study and founded a company, Advanced Circulatory Systems Incorporated (ACSI) to develop and commercialize this technology. Dr. Anja Metzger is employed by Advanced Circulatory Systems. Address correspondence and reprint requests to Keith G. Lurie, MD, Minneapolis Medical Research Foundation, 914 South 8th St., 3rd Floor, Minneapolis, MN Address to klurie@ advancedcirculatory.com. Copyright 2006 International Anesthesia Research Society DOI: /01.ane a impedance threshold device (ITD). The ITD impedes the influx of respiratory gases during the chest wall recoil phase of cardiopulmonary resuscitation, thereby enhancing venous return and vital organ circulation (6 13). In an effort to use a similar strategy to intermittently decrease intrathoracic pressures to enhance venous blood flow back to the heart and to decrease intracranial pressures in patients requiring assisted ventilation, an intrathoracic pressure regulator (ITPR) was developed (14). This new device has been recently shown to increase survival rates in pigs in cardiac arrest and to improve hemodynamics in apneic animals during hypovolemic hypotension (14,15). In the hypotensive pigs, there was a dose effect: intermittent application of an intrathoracic vacuum generated a greater hemodynamic benefit down to approximately 10 mm Hg, and the largest benefit was observed in the most hypotensive animals (50% blood loss) (14). Building on the basic physiological principles discovered in these earlier studies, the purpose of the current investigation was to evaluate the effectiveness of the ITPR, designed to regulate intrathoracic pressures in nonbreathing animals during severe hypovolemic hypotension. We hypothesized that application of the ITPR in a porcine model of severe but controlled blood loss would result in improved mean arterial blood pressure (MAP) and neurologically intact survival rates compared with untreated controls. The Vol. 104, No. 1, January

2 results have potential implications for the treatment of intraoperative hypotension and traumatic injury. METHODS The Institutional Animal Care Committee of the Minneapolis Medical Research Foundation at Hennepin County Medical Center approved the studies. All animals received treatment and care in compliance with the 1996 Guide for the Care and Use of Laboratory Animals by the National Research Council in accord with the USDA Animal Welfare Act, PHS Policy, and the American Association for Accreditation of Laboratory Animal Care. The study protocol can be summarized as follows. After an acute 55% blood loss and 5 min of stabilization, 18 pigs were prospectively randomized to either the ITPR intervention group, with the ITPR set to maintain intrathoracic pressures of 8 mmhgbetween positive pressure ventilations (PPV), or the control group treated only with PPV. After 90 min, surviving animals received IV fluid (blood) resuscitation and were followed for 24-h to evaluate survival and neurological outcomes. Preparatory Phase All animals received the same initial preparation: initial sedation was achieved with 7 ml (100 mg/ml) of IM ketamine HCl (Ketaset, Fort Dodge Animal Health, Fort Dodge, IA) followed by an IV bolus of propofol (PropoFlo, Abbott Laboratories, North Chicago, IL), (2.3 mg/kg), via the lateral ear vein. The animal s trachea was intubated with a 7.5-mm cuffed endotracheal tube inflated to prevent side air leaks. During the preparatory phase, positive pressure, room air, volume controlled ventilation with a tidal volume of 12 ml/kg were delivered with a NarkoMed 2A (North American Drager) ventilator. Respiratory rate was adjusted (average 12 2 bpm) to keep end-tidal carbon dioxide (ETco 2 ) between mm Hg. Oxygen saturation was 96%. Neither supplemental oxygen nor positive end-expiratory pressure was used. A 4F femoral artery sheath was placed under aseptic conditions. A Millar catheter was used to continuously measure central aortic pressure. Arterial blood gases were collected from the sheath. Surface electrocardiogram was also monitored continuously. All data were digitized using a computerized data analysis program (Superscope II vl.295, GW Instruments, Somerville, MA) and a Power Macintosh G3 computer (Apple Computer, Inc., Cupertino, CA). ETco 2, tidal volume, and arterial oxygen saturation were recorded with a CO 2 SMO Plus, (Novametrix Medical Systems, Wallingford, CT). MAP was electronically calculated from the electronic waveforms in the recording system. Device Description To generate controlled negative endotracheal pressure (ETP), we used an ITPR (Advanced Circulatory Systems, Inc., Minneapolis, MN), a pressure regulator that combines a continuous vacuum source, a regulator valve system, a means to provide intermittent PPV, and an inspiratory ITD. The device has been described previously (14,15). Protocol Eighteen animals were prospectively assigned to either ITPR treatment or control. Isoflurane inhaled anesthesia at a 0.8% 1.2% inspired concentration was used for the study. Once the animals were stable for 10 min (stable MAP, heart rate, ETco 2 and adequate level of anesthesia based on hoof pinching, and canthal reflex checks), they were bled 55% of their calculated circulating blood volume at a rate of 60 ml/min (17). After the bleed, baseline measurements were obtained within 2 min. The animals were then connected to the ITPR. On the basis of computer-generated randomization list, they were assigned at that time to either control (0 mm Hg ETP) or active treatment ( 8 mm Hg ETP). Aortic pressure was recorded continuously. Ventilation was delivered with the same ventilator used for the preparatory phase. The tidal volume was 12 ml/kg, and respiratory rate was 8 breaths/min, with 35% Fio 2.A respiratory rate of 8 breaths/min was chosen because it has been shown that higher rates compromise venous return and MAP in a similar model (18). Samples for arterial blood gases were collected at baseline, at the end of the bleed, every subsequent 15 min for an hour and then at 90 min. There was no intravascular fluid resuscitation during the 90 min of the study. After 90 min, animals were reinfused with their own blood that was maintained in blood donor collection bags at room temperature. After reinfusion and surgical closure of the arterial site with vascular repair, anesthesia was stopped. The animals were extubated on average within 20 min after the end of vascular repair. Only nonsteroidal antiinflammatory IM injections were allowed for pain management. Animals recovered from anesthesia in order to assess cerebral function. The level of consciousness was assessed 12 and 24 h after the bleeding. Based on the animals level of consciousness, respiratory pattern, motor function, and behavior (standing, walking, eating and response when restrained), neurological function was assessed with the following scoring system: 1 normal 2 slightly disabled, 3 severely disabled but conscious, 4 vegetative state and 5 brain death (19). Animals were allowed to drink and eat freely and were observed for 24 h at 6-h intervals. At the end of the protocol, animals were killed with propofol 100 mg and bolus injection of 10 M potassium chloride. Statistical Analysis Hemodynamic and respiratory variables were analyzed using ANOVA. Survival analysis was performed using Kaplan Meier methods with log-rank (Mantel Cox) comparison of cumulative survival by treatment groups. Data were calculated as the mean sem at each 158 ITPR and Survival in Hypovolemic Shock ANESTHESIA & ANALGESIA

3 Figure 1. Two representative real time tracing from two different animals 20 min after 55% bleeding. ITPR intrathoracic pressure regulator; ETP endotracheal pressure; AoPr aortic pressure; ECG electrocardiogram; arrows indicate positive pressure ventilation. time point. A P value of 0.05 was considered statistically significant. RESULTS The average weight of all animals was kg, and there were no differences in weight or age between groups (approximately wk old). The average blood loss in the control group was ml, and in the ITPR group was ml (P NS). After 55% blood withdrawal, the application of a negative airway pressure of 8 mm Hg resulted in a significant increase in MAP for the entire 90 min of treatment when compared with the control group, P 0.01 (Figs. 1 and 2). MAP returned to normal (83 13 mm Hg) after blood reinfusion at 90 min. Heart rate (sampled every 15 min and averaged) was significantly lower in the ITPR PPV group throughout the study when compared with PPV only group, vs bpm, P Nine animals survived to blood reinfusion at 90 min in the ITPR treatment group, and only two animals survived in the control group. After 24 h all animals were alive in the ITPR group, but only 1/9 Figure 2. Mean sem. After controlled blood loss (55%), the intrathoracic pressure regulator (ITPR), set at 8 mmhg, resulted in a significant decrease in endotracheal pressure (when measured between breaths) (ETP) and a significant increase in mean arterial blood pressure (MAP), compared with controls. BL pre bleed baseline, *P 0.05 between groups. The numbers in parenthesis are the animals alive at the end of the 90 min. Values at 90 min are before transfusion. Vol. 104, No. 1, January International Anesthesia Research Society 159

4 Figure 3. Measured acid base variables. *Statistically significant difference between groups with a P Values at 90 min are before transfusion. ETco 2,Paco 2,Pao 2 in mm Hg; HCO 3 and Base Excess in mmol/l; and x-axis in minutes. BL baseline; 55% bl means values after a 55% bleed. Triangle represents ITPR; rectangles represent controls. (11%) was alive in the control group, P One of the two survivors from the control group was found dead in the cage 16 h later. Eight of nine animals in the ITPR group had normal neurological function after 12 and 24 h, and 1/9 had a Cerebral Performance Score of 3 at 12 h and 4 at 24 h. The sole survivor in the control group had a Cerebral Performance Score of 2 at 12 h and normal neurological function after 24 h. Arterial blood gases showed progressive metabolic acidosis with increasing base deficit in the control group, whereas in the ITPR group, metabolic acidosis was maintained to a level compatible with life (Fig. 3). The only two animals that survived the 90 min period of time in the control group had a less severe metabolic acidosis compared to the rest of the control group animals. There was a significant increase in ETco 2 throughout the 90 min of the ITPR application when compared with the control group (Fig. 3). The difference between Paco 2 and ETco 2 has been consistently lower in the ITPR group as well. Oxygenation was adequate in both groups without significant differences (Fig. 3). DISCUSSION It has been recently shown that use of the ITPR and intermittent PPV in pigs subjected to severe blood loss improves key physiological variables, decreases intracranial pressure and improves vital organ perfusion pressures (14). Building on those findings, this study focused on survival after a severe bleed. The results demonstrate that prolonged application of ITPR and intermittent PPV during hypovolemic hypotension increased MAP and survival rates compared with untreated controls. The data support the hypothesis that use of the ITPR may be of benefit to increase survival rates by enhancing perfusion pressures and preventing the development of severe metabolic acidosis in the setting of severe hypotension. This is the first time the ITPR has been shown increase survival rates after severe hemorrhage. The application of the ITPR to generate 8 mmhg ETP resulted in an immediate increase in MAP. An earlier study showed that this device instantaneously decreases intracranial and right atrial pressures, which results in an immediate increase in coronary and cerebral perfusion pressures in pigs with severe hypovolemia (14). It is likely that the improved vital organ perfusion helped, in the current study, to prevent lifethreatening metabolic acidosis in the ITPR-treated group. Higher ETco 2 may also reflect better tissue perfusion and greater CO 2 clearance, whereas a decrease in Paco 2 ETco 2 supports better ventilation/perfusion matching (14). 160 ITPR and Survival in Hypovolemic Shock ANESTHESIA & ANALGESIA

5 The ITPR was set to 8 mm Hg of ETP for the survival study based on an earlier study where 10 mm Hg was used (14) and pilot studies demonstrating that animals tolerated this dose for up to 6 h without changes in oxygenation or acid base balance. The hemodynamic benefits appear to plateau around 8 to 10 mm Hg. To have the maximum effect with the smallest risk for pulmonary complications, an intrathoracic vacuum set to 8 mm Hg was used in this survival study. Although there may be greater benefit using lower pressures, pulmonary complications may be more frequent. This issue requires further characterization and investigation. In the control group, profound acute volume depletion resulting in severe progressive metabolic acidosis was observed simultaneously with the high death rate. The ITPR prevented the downward spiral of metabolic acidosis suggesting that a potential application of the new device could be to buy time in clinical scenarios when immediate intravascular fluid resuscitation is not possible, as long as active bleeding is controlled. Thus, the technology may be helpful in the treatment of traumatic injuries outside of the hospital. In addition, it is possible that the ITPR may be of clinical value in treating intraoperative hypovolemic hypotension in intubated, anesthetized patients, especially when treatment with vasopressors or fluids is relatively contraindicated. Longer duration studies will be required to determine the potential value of the ITPR in these clinical settings before alternative therapies, such as surgery, intravascular fluid resuscitation, or vasopressor drugs, are required. There are limitations in this study. First, we did not measure actual vital organ blood flow. Nonetheless, the effects on perfusion pressures and survival observed in this study with the use of the ITPR suggest that blood flow was significantly higher in the treated group. Second, our model of fixed severe hypovolemic hypotension cannot be generalized to uncontrolled bleeding where the ITPR could potentially worsen the blood loss. Third, we evaluated only one negative ETP: the optimal negative ETP resulting in maximum benefit at minimal risk needs to be better characterized and investigated. Finally, we used the anesthetic isoflurane in this study without measuring exhaled concentrations. Other drugs we have used previously, such as propofol, have known vasodepressor effects and can cause metabolic acidosis, cardiodepression, and neuroprotection with prolonged use (20 25). Isoflurane has the fewer side effects and is among the least cardiodepressive drug among the commonly used anesthetics (26). Thus, although it possible, it is not likely that the anesthetic may have influenced the outcome of this study. Finally, the survival rate in the control group precludes definite neurological comparisons between groups. A larger study is underway. CONCLUSION Use of the ITPR during severe hypovolemic hypotension, resulted in 1) a significant improvement in MAP and ETco 2, 2) stabilization of the metabolic effects of systemic hypoperfusion, and 3) a significant improvement in neurologically intact 24-h survival rates when compared with controls in this porcine model of fixed volume hypovolemic hypotension. REFERENCES 1. Lurie KG, Zielinski TM, McKnite S, et al. Treatment of hypotension in pigs with an inspiratory impedance threshold device: a feasibility study. Crit Care Med 2004;32: Convertino VA, Cooke WH, Lurie KG. Inspiratory resistance as a potential treatment for orthostatic intolerance and hemorrhagic shock. 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