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Comparative pathology of open-chest versus closed-chest cardiopulmonary resuscitation in dogs
Abstracts from the Sixth Purdue Conference CPR and Defibrillation
Effects of Epinephrine Administration During CPR on Patient Survival and Cerebral Recovery. Norman S. Abramson, Kim Sutton, Peter Safar, Katherine Detre, Brain Resuscitation Clinical Trial I Study Group. Resuscitation Research Center, University of Pittsburgh, Pittsburgh, PA 15260. Epinephrine is a standard drug used in the treatment of cardiac arrest. Although its alpha-effects are of proven benefit for the fibrillating heart, recent evidence suggests that its beta-effects are detrimental. This paper analyzes the effects of epinephrine administration during cardiac arrest on mortality and neurological recovery of CPR survivors. Data from a study of 262 initially comatose cardiac arrest survivors who made no purposeful response to pain after restoration of spontaneous circulation (ROSC) were analyzed. Outcome was evaluated during the one-year followup using Cerebral Performance Categories (CPC) and Overall Performance Categories (OPC), our modification of the Glasgow outcome categories. Effects of epinephrine administration during CPR on mortality and cerebral recovery were investigated, using univariate (Chi-square) and multivariate (Cox regression) analyses. Epinephrine was administered during CPR to 191 (73%) of study patients. The mean dose was 2.24 mg (range 1-25 mg). The presenting electrocardiographic (ECG) rhythm in the epinephrine group versus the no-epinephrine group was ventricular tachycardialventricular fibrillation in 51% versus 68% (P = ns); asystole in 38% versus 8% (P < 0.01); and electromechanical dissociation in 9% versus 10% respectively. The epinephrine group had statistically significantly longer mean CPR times (22 minutes versus 14 minutes) (P < 0.04) and mean arrest times (5.8 minutes versus 4.7 minutes) (P < 0.04). Immediate post-resuscitation hypotension occurred in 36% of the epinephrine group patients versus 21% of the patients in the no-epinephrine group (P < 0.05). Mean duration of this hypotension however, was the same in both groups. Other characteristics of the two groups, including age, past history of myocardial infarction or congestive heart failure, pre-arrest cardiac functional status, cause of arrest, and cause of death, were similar. Univariate analyses revealed that mortality after initially successful ROSC in the epinephrine group was significantly higher than in the noepinephrine group (85% versus 62%) (P < 0.001) and that the percentage of patients recovering good cerebral function in the epi group was significantly lower than in the no-epi group (25% versus 58%) (P < 0.001). However, multivariate analyses, which controlled for all known variables related to outcome, showed that epinephrine administration was independently predictive of mortality (P < 0.05) but not of neurological recovery. On the basis of this study, it is concluded that epinephrine administration during CPR does not have an independent effect on neurological outcome. Its apparent relationship to 414
on
increased mortality may be related to epinephrine-induced myocardial necrosis. Evidence of Preventable Lipid Peroxidation in Brain and Heart Four Hours after Cardiac Arrest and Reperfusion in Rats. Charles F. Babbs, Sandra H. Ralston, Stephen F. Badylak, Maxine Nichols, Frances A. Cull, Melissa J. Gale. Purdue University, West Lafayette, IN 47907. To test the hypothesis that vital organ damage after cardiac arrest involves lipid peroxidation during reperfusion, the authors examined brains and hearts of rats after 7 minutes of KCL-induced total circulatory arrest, followed by CPR and return of spontaneous circulation for four hours. Excised brains and hearts were immediately frozen in liquid nitrogen and subsequently analyzed by ultraviolet spectroscopy of lipid extracts at 234 nm for conjugated diene (CD) markers, indicating lipid peroxidation. Five groups of nine rats each were studied, for which the following CD concentrations in p,mol/g (mean * SE) are reported: normal, non-ischemic controls, brain, 1.2 2 0.2; heart, 1.1. k 0.2; arrested but not reperfused controls, brain, 1.9 t 0.4; heart, 1.8 -+ 0.4. In animals that experienced arrest and were reperfused for 4 hours, values were: brain, 2.6 * 0.2; heart 4.7 * 0.7. Two groups received post-resuscitative therapy within 5 minutes after return of spontaneous circulation. The tissue CD concentrations in animals treated with allopurinol (10 mg/kg IV) were: brain, 1.5 ‘_ 0.2; heart, 2.7 2 0.7. Values for animals treated with deferoxamine (50 mgikg, i.v.) were: brain, 1.3 + 0. I ; heart, 1.6 + 0.3. Brain and heart CD levels in non-treated, “arrested,” and reperfused animals at 4 hours were significantly greater than CD levels in the control or treated groups (Scheffe multiple comparison test, F > 20, P < 0.01). The authors conclude that abnormal lipids, detectable as conjugated dienes, are present in brain and heart after ischemia and 4 hours of reperfusion but not after ischemia alone, confirming the concept of reperfusion injury. Allopurinol or deferoxamine, administered at the onset of reperfusion, blocks early formation of abnormal conjugated dienes in the rat circulatory arrest model. Comparative Pathology of Open-chest versus Closed-chest Cardiopulmonary Resuscitation in Dogs. Stephen F. Badylak, Karl B. Kern, Willis A. Ibcker, Gordon A. Ewy, Wolfgang Janas, Alice Carter. Purdue University, West Lafayette, IN 47907. The pathological changes following open-chest cardiopulmonary resuscitation (OCCPR) were compared with those following closed-chest cardiopulmonary resuscitation (CCCPR) in 28 healthy mongrel dogs subjected to experimentally induced ventricular fibrillation (VF). Ventricular fibrillation was induced in 29 dogs. No treatment was given for 3 minutes, followed by 12 minutes of mechanical
A6STRACTSFAOMPERDUECONFERENCEONCPA
CCCPR. External defibrillation (80 joules) was then attempted twice. One dog was resuscitated. The remaining 28 dogs were divided into two groups of 14 each. Group A received continued CCCPR and group B received OCCPR. All dogs received advanced cardiac life support and were followed until resuscitated or dead. All dogs were autopsied, and gross pathology scores and histopathology scores were determined for each animal, and for each of 19 separate tissues within each animal. The mean gross pathology scores for the following tissues were significantly greater for dogs that received OCCPR than for those that received CCCPR: skin (3.4 versus 1.2; P < O.OOl), subcutaneous tissue (3.7 versus 0.6; P < O.OOl), chest wall muscle (3.7 versus 0.5; P < O.OOl), and pleura (1.9 versus 0.1; P < 0.001). The mean total gross pathology score was also greater in dogs that received OCCPR than in those that received CCCPR (17.2 versus 7.7; P < 0.001). The mean histopathology scores for the following tissues were statistically significantly greater for dogs that received OCCPR than for those that received CCCPR: skin (2.5 versus 0.0; P < O.OOl), subcutaneous tissue (2.2 versus 0.1; P < O.OOl), chest wall muscle (2.3 versus 0.1; P < O.OOl), pleura (1.6 versus 0.0; P < O.OOl), pericardium (1.4 versus 0.2; P < O.Ol), epicardium (2.5 versus 0.2; P < O.OOl), myocardium (2.5versus 0.3; P < O.OOl), and endocardium (1.9 versus 0.5; P < 0.01). The mean total histopathology score was also greater in dogs that received OCCPR than in those that received CCCPR (20.1 versus 7.4; P < 0.001). The histopathology score for brain tissue was greater for the CCCPR group than for the OCCPR group (1.9 versus 0.4; P < 0.05). This study showed that OCCPR in dogs following VF caused more severe pathological changes than CCCPR. These changes were attributed to thoracotomy-induced chest wall injury and to internal defibrillation-induced myocardial injury. Furthermore, OCCPR caused less severe microscopic brain lesions than CCCPR. Protection from Reperfusion Injury in the Isolated Rat Heart. Stephen E Badylak, Abby Simmons, Charles F. Babbs. Purdue University, West Lafayette, IN 47907. The Langendorff isolated rat heart preparation was used to determine the effect of oxypurinol, a xanthine oxidase inhibitor, and deferoxamine, an iron binding agent, on the extent of myocardial reperfusion injury following 60 minutes of ischemia. Twenty-four rats were divided into three groups of eight rats each, and an isolated heart preparation was made from each rat. The isolated hearts were perfused for 15 minutes with a modified Krebs-Henseleit perfusate solution to permit stabilization of the preparation, Each heart was then subjected to 60 minutes of total ischemia at 37°C followed by 60 minutes of reperfusion with either placebotreated perfusate, oxypurinol-treated perfusate (200 p-g/ml), or deferoxamine-treated perfusate (8 &ml). Reperfusion injury was evaluated by the total amount of creatine phosphokinase (CPK) released into the perfusate, changes in myocardial vascular resistance, and morphological examination. The placebo-treated group released an average of 3,492 * 1,420 SU of CPK into the perfusate, versus 1,073 2 426 SU for the oxypurinol-treated group (t, = 2.61, df = 14, P <
0.05) and 1,108 2 497 SU for the deferoxamine-treated group (t, = 2.31, df = 14, P < 0.05). The myocardial vascular resistance increased an average of 1,006 r 321 peripheral resistance units (PRU) in the placebo-treated group during the reperfusion phase, versus 135 ? 47 PRU for the oxypurinol-treated group (t, = 2.87, df = 14, P < 0.02) and 441 r 193 PRU for the deferoxamine-treated group (t, = 2.15, df = 14, P < 0.05). Ultrastructural examination of a randomly selected heart from each group after 60 minutes of reperfusion showed marked attenuation of mitochondrial and endoplasmic reticulum swelling, increased maintenance of membrane integrity, and diminished separation of myocardial myofilaments in the oxypurinol-treated and deferoxamine-treated hearts. The authors conclude that both OXYpurinol and deferoxamine, given after 60 minutes of ischemia at the onset of reperfusion, can protect the isolated rat heart from reperfusion injury. Effects of Abdominal Compression in Three Modes of CPR. E Bertrand, V. Einagel, Ch. Roussos, S. Magder. Royal Victoria Hospital, Mont&d. Carotid blood flow (Q,) during cardiopulmonary resuscitation (CPR) is improved with the addition of interposed abdominal compressions (IAC-CPR). The authors recently showed that the majority of the improved Q, occurs during the abdominal compression phase of IAC-CPR and occurs because of the direct transmission of intra-abdominal pressure to the chest. Therefore, abdominal compression (AC) alone may result in similar Q, to that achieved with IACCPR, and synchronous chest and abdominal compressions (SCAC) should result in an even higher Q,. The authors studied six anesthetized dogs (mean weight, 29.3 kg) and measured Q, with an in-line electromagnetic flow probe during repeated episodes of ventricular fibrillation. Standardized chest compression was produced with a mechanical thumper and abdominal compression by manually applying an external pressure of 150 mm Hg. The authors randomized the three modes of resuscitation and performed an average of six runs per mode per dog. Peak abdominal aortic pressures (in mm Hg) were statistitally significantly higher for SCAC, but there was no difference between IAC and AC (107.1 + 13.2, 98.5 & 12.1, 95.7 ? 9.4, respectively, P < 0.01). Peak thoracic aortic pressures were also greater for SCAC compared with both IAC and AC. The Q, was statistically significantly greater with SCAC compared with the other two modes, and there was no difference between IAC and AC (28.6 + 17.5%, 17.2 2 14.6%, 19.8 + 14.1%, respectively, P < 0.01). In additional studies, IAC-CPR was compared with conventional CPR. Carotid flows with IAC was similar to those in the present study and much higher than with conventional CPR (22.8 & 13.1% versus 8.7 2 5.8%, P < 0.003). These data support the hypothesis that direct transmission of pressure from the abdomen to the chest is an important mechanism for Q, when abdominal compressions are applied during CPR. Simultaneous chest and abdominal compressions produce better Q, than IAC or AC. Finally, AC is as effective as IAC and thus appears to be better than chest compressions alone. 415
Effects of Epinephrine Administration During CPR on Patient Survival and Cerebral Recovery. Norman S. Abramson, Kim Sutton, Peter Safar, Katherine Detre, Brain Resuscitation Clinical Trial I Study Group. Resuscitation Research Center, University of Pittsburgh, Pittsburgh, PA 15260. Epinephrine is a standard drug used in the treatment of cardiac arrest. Although its alpha-effects are of proven benefit for the fibrillating heart, recent evidence suggests that its beta-effects are detrimental. This paper analyzes the effects of epinephrine administration during cardiac arrest on mortality and neurological recovery of CPR survivors. Data from a study of 262 initially comatose cardiac arrest survivors who made no purposeful response to pain after restoration of spontaneous circulation (ROSC) were analyzed. Outcome was evaluated during the one-year followup using Cerebral Performance Categories (CPC) and Overall Performance Categories (OPC), our modification of the Glasgow outcome categories. Effects of epinephrine administration during CPR on mortality and cerebral recovery were investigated, using univariate (Chi-square) and multivariate (Cox regression) analyses. Epinephrine was administered during CPR to 191 (73%) of study patients. The mean dose was 2.24 mg (range 1-25 mg). The presenting electrocardiographic (ECG) rhythm in the epinephrine group versus the no-epinephrine group was ventricular tachycardialventricular fibrillation in 51% versus 68% (P = ns); asystole in 38% versus 8% (P < 0.01); and electromechanical dissociation in 9% versus 10% respectively. The epinephrine group had statistically significantly longer mean CPR times (22 minutes versus 14 minutes) (P < 0.04) and mean arrest times (5.8 minutes versus 4.7 minutes) (P < 0.04). Immediate post-resuscitation hypotension occurred in 36% of the epinephrine group patients versus 21% of the patients in the no-epinephrine group (P < 0.05). Mean duration of this hypotension however, was the same in both groups. Other characteristics of the two groups, including age, past history of myocardial infarction or congestive heart failure, pre-arrest cardiac functional status, cause of arrest, and cause of death, were similar. Univariate analyses revealed that mortality after initially successful ROSC in the epinephrine group was significantly higher than in the noepinephrine group (85% versus 62%) (P < 0.001) and that the percentage of patients recovering good cerebral function in the epi group was significantly lower than in the no-epi group (25% versus 58%) (P < 0.001). However, multivariate analyses, which controlled for all known variables related to outcome, showed that epinephrine administration was independently predictive of mortality (P < 0.05) but not of neurological recovery. On the basis of this study, it is concluded that epinephrine administration during CPR does not have an independent effect on neurological outcome. Its apparent relationship to 414
on
increased mortality may be related to epinephrine-induced myocardial necrosis. Evidence of Preventable Lipid Peroxidation in Brain and Heart Four Hours after Cardiac Arrest and Reperfusion in Rats. Charles F. Babbs, Sandra H. Ralston, Stephen F. Badylak, Maxine Nichols, Frances A. Cull, Melissa J. Gale. Purdue University, West Lafayette, IN 47907. To test the hypothesis that vital organ damage after cardiac arrest involves lipid peroxidation during reperfusion, the authors examined brains and hearts of rats after 7 minutes of KCL-induced total circulatory arrest, followed by CPR and return of spontaneous circulation for four hours. Excised brains and hearts were immediately frozen in liquid nitrogen and subsequently analyzed by ultraviolet spectroscopy of lipid extracts at 234 nm for conjugated diene (CD) markers, indicating lipid peroxidation. Five groups of nine rats each were studied, for which the following CD concentrations in p,mol/g (mean * SE) are reported: normal, non-ischemic controls, brain, 1.2 2 0.2; heart, 1.1. k 0.2; arrested but not reperfused controls, brain, 1.9 t 0.4; heart, 1.8 -+ 0.4. In animals that experienced arrest and were reperfused for 4 hours, values were: brain, 2.6 * 0.2; heart 4.7 * 0.7. Two groups received post-resuscitative therapy within 5 minutes after return of spontaneous circulation. The tissue CD concentrations in animals treated with allopurinol (10 mg/kg IV) were: brain, 1.5 ‘_ 0.2; heart, 2.7 2 0.7. Values for animals treated with deferoxamine (50 mgikg, i.v.) were: brain, 1.3 + 0. I ; heart, 1.6 + 0.3. Brain and heart CD levels in non-treated, “arrested,” and reperfused animals at 4 hours were significantly greater than CD levels in the control or treated groups (Scheffe multiple comparison test, F > 20, P < 0.01). The authors conclude that abnormal lipids, detectable as conjugated dienes, are present in brain and heart after ischemia and 4 hours of reperfusion but not after ischemia alone, confirming the concept of reperfusion injury. Allopurinol or deferoxamine, administered at the onset of reperfusion, blocks early formation of abnormal conjugated dienes in the rat circulatory arrest model. Comparative Pathology of Open-chest versus Closed-chest Cardiopulmonary Resuscitation in Dogs. Stephen F. Badylak, Karl B. Kern, Willis A. Ibcker, Gordon A. Ewy, Wolfgang Janas, Alice Carter. Purdue University, West Lafayette, IN 47907. The pathological changes following open-chest cardiopulmonary resuscitation (OCCPR) were compared with those following closed-chest cardiopulmonary resuscitation (CCCPR) in 28 healthy mongrel dogs subjected to experimentally induced ventricular fibrillation (VF). Ventricular fibrillation was induced in 29 dogs. No treatment was given for 3 minutes, followed by 12 minutes of mechanical
A6STRACTSFAOMPERDUECONFERENCEONCPA
CCCPR. External defibrillation (80 joules) was then attempted twice. One dog was resuscitated. The remaining 28 dogs were divided into two groups of 14 each. Group A received continued CCCPR and group B received OCCPR. All dogs received advanced cardiac life support and were followed until resuscitated or dead. All dogs were autopsied, and gross pathology scores and histopathology scores were determined for each animal, and for each of 19 separate tissues within each animal. The mean gross pathology scores for the following tissues were significantly greater for dogs that received OCCPR than for those that received CCCPR: skin (3.4 versus 1.2; P < O.OOl), subcutaneous tissue (3.7 versus 0.6; P < O.OOl), chest wall muscle (3.7 versus 0.5; P < O.OOl), and pleura (1.9 versus 0.1; P < 0.001). The mean total gross pathology score was also greater in dogs that received OCCPR than in those that received CCCPR (17.2 versus 7.7; P < 0.001). The mean histopathology scores for the following tissues were statistically significantly greater for dogs that received OCCPR than for those that received CCCPR: skin (2.5 versus 0.0; P < O.OOl), subcutaneous tissue (2.2 versus 0.1; P < O.OOl), chest wall muscle (2.3 versus 0.1; P < O.OOl), pleura (1.6 versus 0.0; P < O.OOl), pericardium (1.4 versus 0.2; P < O.Ol), epicardium (2.5 versus 0.2; P < O.OOl), myocardium (2.5versus 0.3; P < O.OOl), and endocardium (1.9 versus 0.5; P < 0.01). The mean total histopathology score was also greater in dogs that received OCCPR than in those that received CCCPR (20.1 versus 7.4; P < 0.001). The histopathology score for brain tissue was greater for the CCCPR group than for the OCCPR group (1.9 versus 0.4; P < 0.05). This study showed that OCCPR in dogs following VF caused more severe pathological changes than CCCPR. These changes were attributed to thoracotomy-induced chest wall injury and to internal defibrillation-induced myocardial injury. Furthermore, OCCPR caused less severe microscopic brain lesions than CCCPR. Protection from Reperfusion Injury in the Isolated Rat Heart. Stephen E Badylak, Abby Simmons, Charles F. Babbs. Purdue University, West Lafayette, IN 47907. The Langendorff isolated rat heart preparation was used to determine the effect of oxypurinol, a xanthine oxidase inhibitor, and deferoxamine, an iron binding agent, on the extent of myocardial reperfusion injury following 60 minutes of ischemia. Twenty-four rats were divided into three groups of eight rats each, and an isolated heart preparation was made from each rat. The isolated hearts were perfused for 15 minutes with a modified Krebs-Henseleit perfusate solution to permit stabilization of the preparation, Each heart was then subjected to 60 minutes of total ischemia at 37°C followed by 60 minutes of reperfusion with either placebotreated perfusate, oxypurinol-treated perfusate (200 p-g/ml), or deferoxamine-treated perfusate (8 &ml). Reperfusion injury was evaluated by the total amount of creatine phosphokinase (CPK) released into the perfusate, changes in myocardial vascular resistance, and morphological examination. The placebo-treated group released an average of 3,492 * 1,420 SU of CPK into the perfusate, versus 1,073 2 426 SU for the oxypurinol-treated group (t, = 2.61, df = 14, P <
0.05) and 1,108 2 497 SU for the deferoxamine-treated group (t, = 2.31, df = 14, P < 0.05). The myocardial vascular resistance increased an average of 1,006 r 321 peripheral resistance units (PRU) in the placebo-treated group during the reperfusion phase, versus 135 ? 47 PRU for the oxypurinol-treated group (t, = 2.87, df = 14, P < 0.02) and 441 r 193 PRU for the deferoxamine-treated group (t, = 2.15, df = 14, P < 0.05). Ultrastructural examination of a randomly selected heart from each group after 60 minutes of reperfusion showed marked attenuation of mitochondrial and endoplasmic reticulum swelling, increased maintenance of membrane integrity, and diminished separation of myocardial myofilaments in the oxypurinol-treated and deferoxamine-treated hearts. The authors conclude that both OXYpurinol and deferoxamine, given after 60 minutes of ischemia at the onset of reperfusion, can protect the isolated rat heart from reperfusion injury. Effects of Abdominal Compression in Three Modes of CPR. E Bertrand, V. Einagel, Ch. Roussos, S. Magder. Royal Victoria Hospital, Mont&d. Carotid blood flow (Q,) during cardiopulmonary resuscitation (CPR) is improved with the addition of interposed abdominal compressions (IAC-CPR). The authors recently showed that the majority of the improved Q, occurs during the abdominal compression phase of IAC-CPR and occurs because of the direct transmission of intra-abdominal pressure to the chest. Therefore, abdominal compression (AC) alone may result in similar Q, to that achieved with IACCPR, and synchronous chest and abdominal compressions (SCAC) should result in an even higher Q,. The authors studied six anesthetized dogs (mean weight, 29.3 kg) and measured Q, with an in-line electromagnetic flow probe during repeated episodes of ventricular fibrillation. Standardized chest compression was produced with a mechanical thumper and abdominal compression by manually applying an external pressure of 150 mm Hg. The authors randomized the three modes of resuscitation and performed an average of six runs per mode per dog. Peak abdominal aortic pressures (in mm Hg) were statistitally significantly higher for SCAC, but there was no difference between IAC and AC (107.1 + 13.2, 98.5 & 12.1, 95.7 ? 9.4, respectively, P < 0.01). Peak thoracic aortic pressures were also greater for SCAC compared with both IAC and AC. The Q, was statistically significantly greater with SCAC compared with the other two modes, and there was no difference between IAC and AC (28.6 + 17.5%, 17.2 2 14.6%, 19.8 + 14.1%, respectively, P < 0.01). In additional studies, IAC-CPR was compared with conventional CPR. Carotid flows with IAC was similar to those in the present study and much higher than with conventional CPR (22.8 & 13.1% versus 8.7 2 5.8%, P < 0.003). These data support the hypothesis that direct transmission of pressure from the abdomen to the chest is an important mechanism for Q, when abdominal compressions are applied during CPR. Simultaneous chest and abdominal compressions produce better Q, than IAC or AC. Finally, AC is as effective as IAC and thus appears to be better than chest compressions alone. 415