Abstract:
Administration of stroma-free crosslinked hemoglobin during standard cardiac pulmonary resuscitation procedures enhances return of spontaneous circulation following electrical defibrillation. The difficulty in restoring spontaneous circulation directly correlates with a generally poor prognosis in cases of cardiac arrest. The therapeutic effect of hemoglobin as an adjunct to conventional treatment may thereby improve survival.

Description:
BACKGROUND OF THE INVENTION 
     Cardiac arrest is a desperate clinical event in which the heart ceases its normal pumping action and devolves into ventricular fibrillation. Unless spontaneous circulation is restored, death from anoxia is rapid. The treatment for cardiac arrest is now standardized in the Handbook for Adult and Pediatric Providers, &#34;Advanced Cardiac Life Support: Algorithms and Drugs&#34;, American Heart Association, reproduced from JAMA, 268: 2199 (1992), which sets out in detail the recommended procedures for administration of drugs and physical intervention in cardiopulmonary resuscitation (CPR). 
     These procedures call for opening an adequate airway to the patient, providing positive-pressure ventilation, giving chest compressions, and inducing defibrillation. These procedures are supported by administration of appropriate drugs. The Handbook referred to above lists the drugs and provides detailed instructions for their respective indications and recommended dosages. In addition there have been many experimental studies in which various drugs have been evaluated. For example, Capparelli, et al., Crit. Care Med., 20: 1140 (1992) describes improved resuscitation in dogs undergoing cardiac arrest upon treatment with diltiazem. Similarly, administration of lidocaine dramatically improved arterial pressure, left ventricular pressure and carotid blood flow in the dog model during cardiopulmonary resuscitation (See Chow, et al., J. Pharm. and Exper. Ther., 224: 531 (1983). 
     One of the consequences of cardiac arrest followed by CPR is venous acidosis. Bleske, et al., Am. J. Emerg. Med., 10: 525 (1992) describes the administration of sodium bicarbonate during CPR to control acidosis. Because of the high incidence of mortality during cardiac arrest, even when the current CPR algorithms are adhered to, strategies for combination therapies are needed to improve patient survival. 
     SUMMARY OF THE INVENTION 
     The present invention provides a method of treatment for improving return of spontaneous circulation during CPR attending cardiac arrest. Return of spontaneous circulation, or alternatively termed, successful resuscitation, is defined as an organized rhythm with an unassisted systolic blood pressure of greater than 60 mm Hg for a period equal to or greater than 2 minutes. 
     In the present method of resuscitating a mammal undergoing cardiac arrest, stroma-free chemically crosslinked, conjugated, or polymerized hemoglobin is administered during ventricular fibrillation in a dose ranging from 50 to 2500 mg per kg of body weight, while simultaneously performing standard cardiopulmonary resuscitation (CPR) procedures, and then defibrillating electrically to effect return of spontaneous circulation. CPR includes, specifically, chest compression which is a procedure for mechanically compressing the thoracic walls to contract and expand the blood volume contained in the heart. This normal working of the heart valves prevents backflow of blood which is expelled during the compression step, thereby simulating blood circulation while the heart is unable to sustain regulated contractions on its own. 
     It is also desirable to reduce or eliminate acidosis occurring during CPR. Coadministration of sodium bicarbonate solutions in a dose range of 0.01 to 1.0 meg per kg of body weight per minute during CPR is efficacious for this purpose. Other drugs such as epinephrine, lidocaine or atropine may also be simultaneously administered in accordance with the Advanced Cardiac Life Support guidelines, supra. 
    
    
     BRIEF DESCRIPTION OF THE DRAWING 
     FIG. 1 is a diagram illustrating the experimental protocol set forth in the Example. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     In the present method, the administration of hemoglobin by infusion (intravenous or intraarterial infusion or cannulation) is intended to augment rather than contravene the standard CPR measures established by the American Heart Association in its Advanced Cardiac Life Support Handbook, supra. The same indications prompted by clinical observation should be adhered to as are recommended in the Handbook. Infusion of hemoglobin should be instituted immediately upon determination of cardiac arrest. As a practical matter, at least several minutes may lapse before a correct diagnosis is made. Since the hemoglobin is understood to act at least in part by increasing tissue perfusion, it is important that contact between the blood-borne hemoglobin and important tissues of the heart and brain be made quickly. The other mechanical and pharmaceutical interventions of CPR are carried out simultaneously. 
     In resuscitation of patients undergoing cardiac arrest, there is a necessary correlation between return of spontaneous circulation and successful resuscitation, since restoration of normal pumping action must occur if the heart is to survive. Spontaneous circulation means a correction of ineffectual fibrillation to ventricular contraction effective for displacing blood contained in the heart chamber to the aorta with regular sinus rhythm. Many of the drugs used in connection with cardiac arrest have the properties of helping to establish and maintain this action, and to suppress arrhythmias. The mechanisms by which these drugs act have in some cases been at least partially elucidated. The mechanism of the present invention involving infusion of hemoglobin is unknown, but the administration of hemoglobin during CPR significantly improves return of spontaneous circulation. 
     The hemoglobin utilized in the present invention may be of any type which is stroma-free and modified chemically to prevent subunit dissociation and to increase the oxygen binding affinity to the range of P 50  values between about 20 and 45 mmHg. The modified hemoglobin may be a conjugated hemoglobin, crosslinked hemoglobin, or polymerized hemoglobin. 
     Several examples of hemoglobin modification technology have been described in the scientific literature which may be used to advantage in the practice of the present invention. For example, see the review contained in Winslow, R. M., Hemoglobin-based Red Cell Substitutes, The John Hopkins U. Press (1992). More specifically, the methods of making chemically modified hemoglobin are set forth hereinafter. 
     A conjugated hemoglobin is one to which a non-protein macromolecule is bound covalently to hemoglobin. One example is a hemoglobin chemical modified by poly-alkylene glycol, which is described together with a process for its preparation in PCT application no. 91/07190 (Enzon). An example of a hemoglobin conjugated to poly(alkylene oxide) and a process for its preparation are provided in U.S. Pat. Nos. 4,301,144, 4,412,989 and 4,670,417, and in Japanese Patent Nos. 59-104323 and 61-053223 (Ajinomoto). Hemoglobin may be conjugated to inulin in a process disclosed in U.S. Pat. No. 4,377,512 (Ajinomoto). PCT application no. 91/07190, U.S. Pat. Nos. 4,301,144, 4,670,412, 4,377,512 and Japanese Patent Nos. 59-104323 and 61-053223 are hereby incorporated by reference. 
     A crosslinked hemoglobin contains an intramolecular chemical link. Examples of crosslinked hemoglobins and methods for their preparation are described in U.S. Pat. Nos. 4,001,401 and 4,053,590, which disclose intramolecular crosslinking between an alpha and beta subunit of a hemoglobin tetramer utilizing compounds such as halogenated cycloalkanes, diepoxides, and diazobenzidines. In the present method, a preferred modified hemoglobin is crosslinked with bis(3,5-dibromosalicyl)fumarate to create a fumarate crosslink between the two alpha subunits. This crosslinked hemoglobin is more fully described, together with methods for its preparation, in U.S. Pat. Nos. 4,598,064, 4,600,531, RE 34,271, omitting the chromatography step. It is preferably manufactured under the conditions disclosed in U.S. Pat. No. 5,128,452 (Hai) to prevent crosslinking between β chains. U.S. Pat. Nos. 4,598,064, 4,600,531, RE 34,271 and U.S. Pat. No. 5,128,452 are hereby incorporated by reference. PCT application no. 90/13309 (Staat Der Nederlanden De Minister van Defeuric) discloses a method for crosslinking hemoglobin through a β-β linkage. The preferred diaspirin crosslinked hemoglobin will hereafter be referred to as &#34;DCLHb&#34;. 
     A polymerized hemoglobin is one in which intermolecular cross-linking of hemoglobin tetramers has been used to increase the molecular weight of the modified hemoglobin. An example of a polymerized hemoglobin and a process for its preparation are described in U.S. pending application Ser. No. 08/149,679 (now abandoned), 08/173,882, 08/480,593 (now abandoned) and 08/473,459. U.S. Pat. No. 4,777,244 discloses a method for crosslinking and polymerizing with aliphatic dialdehydes. The foregoing patents are hereby incorporated by reference. 
     A hemoglobin that has been modified by a combination of methods is exemplified by the following. Hemoglobins modified by pyridoxal-5&#39;-phosphate to adjust the oxygen affinity and by polyethylene glycol conjugation and processes for its preparation are described in Japanese Patent Nos. 59-089629, 59-103322 and 59-104323 Ajinomoto). U.S. Pat. No. 5,248,766 discloses a crosslinking polymerizing strategy and a process for covalently interconnecting tetrameric units with oxiranes to form polyhemoglobins with molecular weights in excess of 120,000 Daltons. The foregoing patents disclosing polymerized hemoglobins, U.S. Pat. Nos. 5,194,590, 5,248,766, Japanese Patent Nos. 59-103322, 59-089629 and 59-104323, are hereby incorporated by reference. 
     Hemoglobin may be modified by site-directed mutagenesis and expressed in micro-organisms or transgenic animals. Recombinant mutant and artificial hemoglobin and its production in cell cultures or fluids is described in U.S. Pat. No. 5,028,588 (Somatogen). Di-alpha and di-beta globin-like polypeptide(s) used for production of hemoglobin in bacteria and yeast are described in PCT application no. 90/13645 (Somatogen). A non-natural multimeric hemoglobin-like protein is described in PCT application no. 93/09143 (Somatogen). In general any method of crosslinking, polymerizing, encapsulating or genetically modifying, or combination thereof which yields a free tetramer having a P 50  in the operative range of 20 to 45 mmHg will have efficacy in the present method. Conditions may be adjusted for each such crosslinked tetramer or polymer derived therefrom without undue experimentation. 
     The dosage of hemoglobin administered in the present method may vary over a range of 50 to 2500 mg per kg of body weight. Larger doses may be indicated in situations where return to spontaneous circulation is more protracted or difficult, or where restored circulation is unstable. Dosage is also influenced by the type and dose of other drugs administered simultaneously or in sequence post-cardiac arrest. In general, repeat treatment after return of spontaneous circulation is unnecessary, unless another episode of cardiac arrest occurs. 
     Another benefit of hemoglobin therapy is increased perfusion to the brain. One problem in resuscitation from cardiac arrest, is the loss of blood flow to the brain resulting in ischemia and brain damage. It is possible that successful resuscitation will only result in an incurable vegetative state. The use of hemoglobin to enhance perfusion and minimize brain cell damage thus has a secondary advantage. Other advantages will be apparent from the Example which follows. 
     EXAMPLE 
     Ventricular fibrillation (VF) was induced by direct current stimulation to the right ventricle of test pigs. The pigs were paced from the right ventricular apex at a rate of 200 to 235 bpm for eight beats using a current equal to twice the pacing threshold. The intensity of the electrical stimulus was increased in 2 mA increments until VF developed. After the induction of VF, ventilation was stopped for five minutes. Then, cardiopulmonary resuscitation (CPR) was started using a pneumatic chest compression device (Thumper). The thumper was set at 80 compressions per minute with a force sufficient to achieve an aortic blood pressure of 50 to 65 mm HG. After five compressions, diastole was prolonged by 0.5 seconds and the lungs inflated to an inspiratory pressure of approximately 20 cm H 2  O by a synchronized pressure limited ventilator with room air. The CPR was stopped at 15 minutes and followed with external defibrillation which was attempted at 200 J. If needed, the shocks were repeated at 300 J and then at 360 J until sinus rhythm (SR) was restored. If the pigs could not achieve or maintain a blood pressure ≧60 mm Hg with organized sinus rhythm, 100% oxygen was added and epinephrine, lidocaine or atropine were administered according to the American Heart Association (AHA) and Advanced Cardiac Life Support (ACLS) guidelines. Successful resuscitation was defined as return of spontaneous circulation (ROSC) post-defibrillation with a blood pressure ≧60 mm Hg for at least two minutes with or without additional O 2  or drugs (see protocol shown in FIG. 1). 
     Blood samples were collected at baseline, and then at 11 minutes, and 14 minutes post-induction of ventricular fibrillation (corresponding to 6 and 9 minutes of initiation of CPR) from the femoral artery, internal jugular vein, and pulmonary artery for measurement of blood gases (238 pH blood gas analyzer, Ciba Corning, Mass.), lactate concentration (ultraviolet method, Sigma Chemical Co., St. Louis, Mo.), hemoglobin concentration (coulter counter method), and hematocrit (coulter counter method). 
     The colored microspheres were injected into the left ventricle at baseline and during CPR. The blood samples were collected over two minutes for the calculation of total cardiac output. Organ samples were collected at the end of the experiment for measuring of organ blood flow. Aortic, left ventricular, and pulmonary artery pressure were monitored during the study and recorded at 0, 6, 9, 12, 14 minutes of fibrillation (see protocol shown in FIG. 1). 
     One minute after the initiation of CPR (t=6 minutes of ventricular fibrillation), DCLHb or normal saline (control treatment) were infused over a 5 minute time interval in a random and blinded manner. The total dose of DCLHb or normal saline administered in each animal was either 5 ml/kg or 15 ml/kg. All animals also received sodium bicarbonate infusion at 0.1 meg/kg/min at the beginning of CPR to decrease development of acidosis (see protocol shown in FIG. 1). 
     The outcome of the treatment is shown in Table 1. Two pigs in the control group (saline treatment) compared to 6 in the DCLHb group achieved a return of spontaneous circulation (ROSC; p&lt;0.05) at the end of 15 minutes of VF following defibrillation (see FIG. 1). 
     
                       TABLE 1______________________________________Return of Spontaneous Circulation(ROSC) Post-CPRPressure(mm Hg)Pig #LV       A        PA    Drug  # Shock                                    ROSC*______________________________________Control14   132/0    97/59    29/9  YES   1     YES20   66/0     54/10     33/10                        YES   3     YES 3                           YES   3     NO 6                           YES   3     NO 8                           YES   3     NO11                           YES   3     NO12                           YES   3     NO16                           YES   3     NODCLHb 2            94/75          NO    1     YES 5   68/4     74/26     62/12                        YES   2     YES13    88/11   83/59    15/8  YES   2     YES15   90/4     80/48    15/5  YES   3     YES17   92/9     86/71    37/5  NO    1     YES21   80/1     74/21          YES   1     YES 4                           YES   3     NO 9                           YES   3     NO______________________________________ *p &lt; 0.05 (control vs. DCLHb using Chi Square analysis) Abbreviations: LV  left ventricular; PA  pulmonary artery; A  aortic. Drug: either of epinephrine, lidocaine or atropine used during ACLS # Shock: number of DC shocks delivered to achieve defibrillation 
    
     The mean blood gases obtained at arterial (from aorta), venous (from pulmonary artery), and internal jugular venous sites are summarized in Table 2. Significantly better venous pH, venous pCO 2  were observed in the DCLHb treatment group compared to the control group. 
     The mean O 2  content is also summarized as shown in Table 3. Significantly high venous O 2  content were observed in the DCLHb treatment group compared to the control group. 
     The mean blood pressures at different sites are summarized in Table 4. Significantly higher cerebral perfusion pressures (Cepp) were observed in the DCLHb group compared to the control group (p&lt;0.05). Although not statistically significantly different, other mean systolic and diastolic pressures were generally higher in the DCLHb group. A decrease in coronary perfusion pressure (Copp) at 14 minutes compared to 6 minutes (beginning of CPR) were observed in 6 of 8 control animals as compared to 2 of 8 DCLHb treatment animals (p&lt;0.05). 
     The total cardiac output, myocardial blood flow, and cerebral blood flow during normal sinus rhythm (baseline) and CPR in the two groups are shown in Tables 5, 6, and 7. The mean cardiac output during CPR ranged from 17-21% of baseline, whereas the mean cerebral blood flow during CPR ranged 48 to 78% of baseline, indicating a preferential shunting of flow to the brain during CPR. The mean myocardial flow during CPR ranged only 7-10% of baseline, indicating the critical nature of the myocardium during CPR. There was a trend toward higher myocardial flow during CPR in the DCLHb group, however no statistically significant difference was observed for all flow parameters between the 2 groups due to large variability observed in these measured values. 
     In the present study of 16 immature pigs that suffered 5 minutes of fibrillation arrest followed by 10 minutes of CPR, DCLHb treatment significantly improved resuscitation (great ROSC at the end of CPR) as compared to saline treatment. This improved resuscitation in the DCLHb group is accompanied by significantly better venous O 2  content and less coronary perfusion pressure deterioration. 
     Based upon the results obtained in the present study, DCLHb appeared to improve resuscitation post-cardiac arrest and CPR in this animal model. The beneficial effect of DCLHb may be related to improved oxygen delivery during CPR. 
     
         __________________________________________________________________________  Control group      DCLHb groupParameter  baseline        11 min              14 min baseline                           11 min 14 min__________________________________________________________________________pH(A)   7.41 ± 0.03         7.38 ± 0.14               7.36 ± 0.18                      7.40 ± 0.03                            7.41 ± 0.10                                   7.44 ± 0.10pH(V)   7.37 ± 0.04         7.03 ± 0.31               7.04 ± 0.28*                      7.37 ± 0.04                            7.28 ± 0.07                                   7.27 ± 0.07pH(IJ)  7.37 ± 0.04         7.30 ± 0.18               7.31 ± 0.22                      7.37 ± 0.03                            7.29 ± 0.11                                   7.29 ± 0.10pCO.sub.2 (A)  41.13 ± 2.59        40.00 ± 11.              43.25 ± 14.0                     42.63 ± 2.67                           37.25 ± 10.42                                  36.83 ± 12.12pCO.sub.2 (V)  49.13 ± 3.87        99.71 ± 44.              92.50 ± 34.0                     46.38 ± 3.42                           61.86 ± 20.22                                  57.13 ± 15.83pCO.sub.2 (IJ)  48.63 ± 8.45        68.00 ± 24.              71.14 ± 36.8                     48.63 ± 6.12                           63.00 ± 13.39                                  64.38 ± 17.08O2 sat(A)  96.09 ± 1.93        88.30 ± 7.0              87.08 ± 9.29                     96.49 ± 1.31                           90.89 ± 5.15                                  90.77 ± 4.41O2 sat(V)  77.73 ± 16.2        30.96 ± 14.              31.00 ± 14.5                     87.11 ± 3.52                           46.40 ± 15.23                                  43.60 ± 15.82O2 sat(IJ)  79.51 ± 13.7        47.17 ± 9.8              43.60 ± 10.1                     86.13 ± 13.3                           52.66 ± 21.77                                  50.60 ± 20.43pO.sub.2 (A)  90.13 ± 22.6        60.00 ± 14.              62.38 ± 14.8                     90.63 ± 16.3                           63.00 ± 12.96                                  62.00 ± 17.99pO.sub.2 (V)  47.25 ± 11.6        26.14 ± 4.1              25.50 ± 7.12                     55.75 ± 7.50                           29.00 ± 6.72                                  28.00 ± 6.35pO.sub.2 (IJ)  51.38 ± 15.4        31.75 ± 4.7              30.29 ± 5.22                     55.88 ± 16.4                           34.13 ± 8.32                                  31.63 ± 8.35O2 content(A)  12.80 ± 0.83        11.88 ± 1.9              12.17 ± 1.94                     13.44 ± 0.62                           13.74 ± 1.88                                  13.87 ± 1.91O2 content(V)   9.98 ± 2.72         3.48 ± 2.50               3.68 ± 2.89                     12.05 ± 0.90                            6.99 ± 2.73                                   6.61 ± 2.79O2 content(IJ)  10.76 ± 2.31         5.77 ± 2.81               5.27 ± 2.89                     11.91 ± 1.85                            7.82 ± 3.48                                   7.64 ± 3.41hemoglobin(A)   9.78 ± 0.79         9.83 ± 1.03              10.05 ± 1.01                     10.18 ± 0.54                           11.11 ± 0.98                                  10.96 ± 1.02hematocrit(A)   0.33 ± 0.02         0.32 ± 0.03               0.33 ± 0.02                      0.32 ± 0.02                            0.31 ± 0.03                                   0.32 ± 0.03hematocrit(V)   0.33 ± 0.02         0.33 ± 0.04               0.32 ± 0.04                      0.33 ± 0.03                            0.31 ± 0.04                                   0.31 ± 0.04hematocrit(IJ)   0.34 ± 0.03         0.32 ± 0.06               0.30 ± 0.08                      0.32 ± 0.02                            0.32 ± 0.04                                   0.31 ± 0.04__________________________________________________________________________ *p &lt; 0.05 at same time points, V  at 12 min from start of fibrillation Abbreviations: A  arterial sample from aorta, V  venous sample, IJ  internal jugular vei sample, O.sub.2 content in ml/dl (calculated as  pO.sub.2 × 0.003) ± (1.34 × O.sub.2 sat × hemoglobin)! × 1/100- 
    
     
                       TABLE 3______________________________________O.sub.2 Content (ml/dl)Control             DCLHbpig #0 min   11 min  14 min                      pig #                           0 min 11 min                                       14 min______________________________________ 3   NT      NT      NT     2   13.61 14.18 15.80 6   12.47   12.83   13.47  4   14.55 15.95 14.20 8   13.20   9.59    11.33  5   13.87 16.25 16.3411   NT      NT      NT     9   12.93 11.21 12.1412   13.86   14.99   15.04 13   12.48 13.00 NT14   11.49   10.30   9.73  15   13.40 13.40 NT16   13.29   11.71   10.75 17   13.19 14.56 12.9720   12.48   11.75   12.70 21   13.49 11.35 11.77mean 12.80   11.88   12.17 mean 13.44 13.74 13.87SD   0.83    1.92    1.94  SD   0.62  1.88  1.91V 3   NT      NT      NT     2   12.21 8.74  9.7 6   11.59   3.04    NT    4    13.77 6.24  5.64 8   11.3    NT      NT    5    12.83 11.37 10.7411   NT      NT      NT    9    11.44 3.91  4.5812   11.8    7.09    7.08  13   10.94 8.8   7.9714   4.86    1.22    1.2   15   12.05 5.84  3.7216   8.9     4.78    5.08  17   11.75 7.84  7.420   11.4    1.25    1.35  21   11.41 3.16  3.12mean 9.98    3.48*   3.68  mean 12.05 6.99  6.61SD   2.72    2.60    2.89  SD   0.90  2.73  2.79IJ 3   NT      NT      NT     2   11.03 10.21 12.36 6   9.14    5.60           4   14.06 3.98  5.88 8   12.81   7.46    7.42   5   13.78 10.82 10.5911   NT      NT      NT     9   12.35 5.02  5.8312   11.67   9.30    8.38  13   11.98 11.37 9.4514   6.83    4.05    3.31  15   8.21  4.44  2.6118   12.43   6.89    5.82  17   12.67 11.75 9.9820   11.68   1.31    1.40  21   11.16 4.97  4.46mean 10.76   5.77    5.27  mean 11.91 7.82  7.54SD   2.31    2.81    2.89  SD   1.85  3.48  3.41______________________________________ *p &lt; 0.05 (two groups comparing at same time point) NT; sample not taken (not able to calculate, see Table 2 for calculation) 
    
     
                       TABLE 4______________________________________Mean Blood PressuresParameter   Baseline    11 Min.      14 Min.______________________________________Control Group(LV)s   115.9 ± 17.86               82.38 ± 19.29∇                            74.25 ± 25.94(A)s    96.38 ± 12.42               62.88 ± 13.62∇                            55.38 ± 8.91(PA)s   18.00 ± 11.35               57.50 ± 19.72∇                            54.00 ± 22.48(LV)d    2.63 ± 2.72                6.00 ± 6.05∇                             5.25 ± 4.83(A)d    72.00 ± 14.24               15.25 ± 7.17∇                            13.00 ± 9.18(PA)d    8.50 ± 7.37               12.67 ± 5.47∇                            10.00 ± 2.77CoPP    69.38 ± 13.31                9.25 ± 5.12∇                             7.75 ± 7.63CePP    60.00 ± 10.002                6.33 ± 6.62*∇                             3.40 ± 9.37**DCLHb Group(LV)s   120.0 ± 17.5               79.75 ± 23.48∇                            70.13 ± 25.35(A)s    110.9 ± 16.08               78.14 ± 18.08∇                            64.13 ± 20.19(PA)s   17.43 ± 18.52               61.71 ± 26.23∇                            60.86 ± 25.35(LV)d    3.63 ± 3.66                7.88 ± 3.14∇                             6.38 ± 3.38(A)d    87.00 ± 16.24               23.00 ± 7.48∇                            21.25 ± 8.10(PA)d    8.00 ± 6.37               10.86 ± 5.18∇                            14.00 ± 10.25COPP    83.38 ± 14.74               14.43 ± 8.56∇                            14.50 ± 8.54CePP    84.86 ± 16.27               19.29 ± 11.25∇                            21.29 ± 8.75______________________________________ *p &lt; 0.05 **p &lt; 0.001 (group A vs. group B as same time points, twosample ttest) ∇ at 12 min. from start of fibrillation 
    
     Abbreviations: A - arterial sample from aorta; V-venous sample from pulmonary artery; (LV)s and (LV)d - left ventricular systolic and diastolic blood pressure; (A)s and (A)d - aortic systolic and diastolic blood pressure; (PA) s and (PA)d - pulmonary artery systolic and diastolic blood pressure; CoPP - coronary perfusion pressure (calculated as aortic diastolic pressure - LV diastolic pressure); CePP - cerebral perfusion pressure (calculated as aortic diastolic pressure - pulmonary artery diastolic pressure). 
     
                       TABLE 5______________________________________Total Cardiac Output (L/min)Pig #    NSR           CPR______________________________________Control 3       3.989         0.553  13.86% 6       NO            NO     NO 8       2.966         0.363  12.24%11       3.176         0.837  26.35%12       2.471         0.342  13.84%14       3.757         1.045  27.81%16       2.646         0.648  24.49%20       2.005         0.583  29.08%Mean     3.001         0.624  21.10%SD       0.705         0.251  7.43%DCLHb 4       4.452         0.412  9.25% 7       4.811         1.116  23.20% 9       3.832         0.312  8.14%13       3.119         0.75   24.05%15       2.478         0.304  12.27%17       2.393         0.53   22.15%19       3.381         0.48   14.20%21       4.273         0.849  19.87%Mean     3.592         0.594  16.64%SD       0.902         0.287  6.44%______________________________________ NSR: during normal sinus rhythm CPR: during cardiopulmonary resuscitation NO: flow not obtained 
    
     
                       TABLE 6______________________________________Myocardial Blood Flow (ml/organ/min)Pig #    NSR           CPR______________________________________Control 3       108.9         1.7    1.56% 6       NO            NO     NO 8       81.3          3.8    4.67%11       115.9         13.3   11.48%12       116.1         1.4    1.21%14       81.4          14.4   17.57%16       101           7.6    7.52%20       74.9          4.5    6.01%Mean     97.07         6.66   7.15%SD       17.60         5.30   5.79%DCLHb 4       134.6         3.1    2.30% 7       148.5         18.4   12.39% 9       99.6          1.6    1.61%13       94.2          14.9   15.82%15       53.3          1.3    2.44%17       126.1         21.1   16.73%19       140           14.1   10.07%21       188.9         36.6   19.38%Mean     123.15        13.89  19.38%SD       40.82         12.04  7.17%______________________________________ NSR: during normal sinus rhythm CPR: during cardiopulmonary resuscitation NO: flow not obtained 
    
     
                       TABLE 7______________________________________Cerebral Blood Flow (ml/organ/min)Pig #    NSR           CPR______________________________________Control 3       34.3          17.6   51.31% 6       NO            NO     NO 8       18.4          6.3    34.24%11       19.5          2D.7   106.15%12       20.7          16.3   78.74%14       25.3          29.4   116.21%16       25.5          15.1   59.22%20       15.2          14.S   97.37%Mean     22.70         17.17  77.61%SD       6.30          6.96   30.57%DCLHb 4       34.7          11     31.70% 7       25.5          12.9   50.59% 9       26.7          8.4    31.4613       27.5          26.1   94.91%15       23.5          3.5    14.89%17       34.6          25.7   74.28%19       23.1          12.7   54.98%21       36.2          12.5   34.53%Mean     28.98         14.10  48.42%SD       5.35          7.92   26.08%______________________________________