Hydralazine-enhanced Selective Heating of Transmissible Venereal Tumor Implants in Dogs

This study was designed to test the hypothesis that vasodilator drugs can enhance selective heating of solid tumors by producing a favorable redistribution of blood flow between tumor and normal tissues. Subcutaneous transmissible venereal tumor implants were heated by inductive diathermy using Helmholtz coils in 8 dogs. The temperature rise in tumor and adjacent muscle was measured before and after giving hydralazine (0.5 mg/kg i.v.). Blood flow to the tumors and underlying muscle was measured with radioactive tracer microspheres. Before hydralazine treatment mean muscle blood flow was about one-third tumor blood flow (0.11 0.02 vs. 0.28 0.09 ml/min/g), and tumor and normal muscle temperatures were not significantly different (40.0 0.6 vs. 39.7 0.l oC). After hydralazine tumor blood flow decreased and muscle blood flow increased in every dog, and selective heating of the tumors became possible. Muscle blood flow averaged 0.67 0.13 ml/min/g, 17 times greater than tumor blood flow, which decreased to 0.04 0.02 ml/min/g. Core tumor temperature was 48.0 0.9 vs. 38.5 0.5 oC for underlying muscle. Blood pressure was maintained at 80 5.7 mmHg. These results demonstrate that adjuvant treatment with vasodilators is a promising technique to increase the temperature difference between tumors and surrounding normal tissues during local heat therapy

Intrapulmonary Epinephrine During Prolonged Cardipulmonary Resuscitation: Improved Regional Blood Flow and Resuscitation in Dogs

Blood flow to vital organs was measured at five-minute intervals during 20 minutes of cardiopulmonary resuscitation (CPR) and ventricular fibrillation in two groups of anesthetized dogs (n = 15 per group). The relationship between organ blood flow and restoration of circulation after 20 minutes was assessed with no additional treatment in Group I and with intrapulmonary epinephrine in Group II. Cardiac output and organ blood flow did not vary significantly in Group I. In Group II, intrapulmonary epinephrine significantly improved blood flow to the myocardium, the brain, and the adrenal glands. A mean myocardial blood flow of less than 0.13 mL/min/g resulted in no survival, while a flow of greater than 0.16 mL/min/g resulted in survival. These studies show that a critical level of myocardial blood flow is required to restore ability of the heart to function as a pump after prolonged CPR, and that a drug that increases flow improves resuscitation efforts

Improved Oxygen Delivery During Cardiopulmonary Resuscitation with Interposed Abdominal Compressions

The ability of a new modification of cardiopulmonary resuscitation (CPR) to deliver oxygen to tissues was evaluated. The method utilizes standard CPR techniques with the addition of manual abdominal compressions (100 mm Hg) interposed between chest compressions, and is termed interposed abdominal compression-CPR (IAC-CPR). Oxygen delivery was measured by a spirometer in a closed circuit designed to permit positive-pressure ventilation synchronized with mechanical chest compression. Ventricular fibrillation was induced electrically in 10 anesthetized dogs. In each dog, trials of IAC-CPR and standard CPR were alternated every five minutes during a 30-minute period. Arterial and central venous blood pressures, oxygen consumption, and Fick cardiac output were monitored. The addition of interposed abdominal compression significantly (P \u3c 0.01) increased each of these hemodynamic indicators. Oxygen delivery increased from 4.12 0.39 ml O2/kg/min during standard CPR to 6.37 0.35 ml O2/kg/min during IAC-CPR. Arterial systolic blood pressure increased from 67 5 mm Hg to 90 5 mm Hg, while diastolic arterial blood pressure rose from 15 2 mm Hg to 33 3 mm Hg. Cardiac output increased from 19.9 2.6 ml/min/kg to 37.5 2.7 ml/min/kg

Methylene Blue as an Inhibitor of Superoxide Generation by Xanthene Oxidase: A Potential New Drug for the Attenuation of Ischemia/Reperfusion Injury

Tissue oxidases, especially xanthine oxidase, have been proposed as primary sources of toxic oxygen radicals in many experimental models of disease states. Among these, ischemia-reperfusion injury may be of the greatest clinical interest. In this paper we propose the use of methylene blue as a means of suppressing the production of superoxide radicals, O2, by acting as an alternative electron acceptor for xanthine oxidase. Previous work has indicated that methylene blue accepts electrons from xanthine oxidase at the iron-sulfur center. Initial experiments in our laboratory demonstrated that (1) pairs of electrons from each enzymatic oxidation are transferred to methylene blue, (2) the reduction of methylene blue can be achieved by model iron-sulfur centers, similar to the iron-sulfur center of xanthine oxidase, (3) reduced methylene blue auto-oxidizes to produce H2O2 directly, rather than O2, and (4) methylene blue is effective at non-toxic levels (2-5 mg/kg) in preventing free radical damage to liver and kidney tissues in an in vitro model of ischemia and reoxygenation. Accordingly, we propose that methylene blue may represent a new class of antioxidant drugs that competitively inhibit reduction of molecular oxygen to superoxide by acting as alternative electron acceptors for tissue oxidases. We have termed these agents “parasitic” electron acceptors

Regional Blood Flow during Cardiopulmonary Resuscitation with Abdominal Counterpulsation in Dogs

The addition of abdominal counterpulsation to standard cardiopulmonary resuscitation (IAC-CPR) during ventricular fibrillation has been shown to improve cardiac output, oxygen uptake, and central arterial blood pressure in dogs. The present study was performed to determine the effect of IAC-CPR on regional blood flow. Regional blood flow was measured with radioactively labeled microspheres during sinus rhythm and during alternate periods of IAC-CPR and standard CPR (STD-CPR) in nine dogs anesthetized with pentobarbital. Blood pressures and oxygen uptake were measured continuously. As in previous studies, diastolic arterial pressure was higher (30.8%) during IAC-CPR than during STD-CPR, as were cardiac output (24.5%) and oxygen uptake (37.5%). Whole brain and myocardial blood flow increased 12.0% and 22.7%, respectively, during IAC-CPR. Blood flow to abdominal organs was not changed appreciably in response to abdominal compression, and postmortem examination revealed no gross trauma to the abdominal viscera. The IAC-CPR technique is simple and is easily added to present basic life support procedures. In light of the improvements observed in myocardial and cerebral blood flow, IAC-CPR could significantly improve the outcome of CPR attempts

Electroventilation

Electroventilation is a term used to describe the production of inspiration by applying rhythmic bursts of short duration stimuli to extrathoracic electrodes to stimulate motor nerves to the inspiratory muscles. In the dog, the optimum site for the electrodes was found to be on the upper chest wall, bilaterally. The inspired volume increased with increasing current intensity. The maximum tidal volume attainable was about four times resting tidal volume. The ability of electroventilation to maintain arterial blood oxygen saturation without the production of cardiac arrhythmias was demonstrated in pentobarbital-anesthetized dogs. The technique has several potential applications and offers promise in emergency and critical-care medicine

Use of Combined Systemic Hypothermia and Local Heat Treatment to Enhance Temperature Differences Between Tumor and Normal Tissues

The feasibility of combining local heat treatment with wholebody hypothermia in an effort to improve therapeutic gain was assessed. Superficial, non perfused phantom tumors were fashioned in eight anesthetized mongrel dogs by transplantation of the spleen from the abdomen to a subcutaneous site on the hind limb. After pretreatment of the animal with the vasodilator hydralazine (0.5 mg/kg, IV) to enhance normal tissue perfusion, the spleen implant was heated with a 2450-MHz microwave diathermy apparatus, first with the animal\u27s core body temperature in the normal range (39°C) and then after the animal had been packed in ice to reduce core temperature to 30°C. Applied power density and temperatures in both the phantom tumor and underlying muscle tissue were recorded during brief interruptions of diathermy until steady-state temperatures had been achieved. Under normothermic conditions with time-averaged applied power of 0.038 W/ml to phantom tumor and 0.014 W/ml to underlying muscle, tumor temperature rose to 45.9 ± l.8°C, while muscle temperature remained at 40.5 ± 0.7°C. During whole-body hypothermia applied power could be increased to 0.114 W/ml in phantom tumor and to 0.025 W/ml in muscle. Muscle temperature rose only to 33.8 ± l.6°C, while that of the nonperfused phantom tumor rose to 53.6 ± 4.3°C with systemic hypothermia. These results are in agreement with predictions based on the bioheat transfer equation, i.e., heat extraction from well-perfused normal tissues is greatly augmented by cooling of the arterial blood, allowing greater power input to the tumor-bearing region, higher tumor temperatures, and enhanced therapeutic gain during local heat treatments of poorly perfused tumor nodules

Theoretical Feasibility of Vasodilator-enhanced Local Tumor Heating

Normal arterioles, in contrast to the abnormal microvasculature of many solid tumors, provide a target for selective drug action that can enhance local heat treatment of the tumors. Measurements of tissue blood flow with radioactive microspheres and estimates of changes in blood flow with thermal clearance methods revealed that vasodilator drugs either decreased or did not alter blood flow in hamster melanoma, rat hepatoma, and canine transmissible venereal tumor, while increasing perfusion in adjacent normal tissues 2 to 4-fold. Solutions of the bio-heat transfer equation, which take into account such selective effects of vasodilators on blood flow in normal tissues, clearly demonstrate improved selective heating for spheroidal tumors over 2 cm in diameter. In the presence of vasodilator drug effect, steady-state center tumor temperatures of 45-50°C can be achieved by increased power input, while surrounding normal tissues remain below 42°C

Myocardial Perfusion Pressure: A Predictor of 24Hour Survival During Prolonged Cardiac Arrest in Dogs

Myocardial perfusion pressure, defined as the aortic diastolic pressure minus the right atria1 diastolic pressure, correlates with coronary blood flow during cardiopulmonary resuscitation (CPR) and predicts initial resuscitation success. Whether this hemodynamic parameter can predict 24-h survival is not known. We examined the relationship between myocardial perfusion pressure and 24-h survival in 60 dogs that underwent prolonged (20 min) ventricular fibrillation and CPR. Forty-two (70%) animals were initially resuscitated and 20 (33%) survived for 24 h. Myocardial perfusion pressure was significantly greater when measured at 5, 10, 15 and 20 min of ventricular fibrillation in the resuscitated animals than in the non-resuscitated animals (P \u3c 0.01). Likewise, the myocardial perfusion pressure was also greater in the animals that survived 24 h than in animals that were resuscitated, but died before 24 h (P \u3c 0.02). Myocardial perfusion pressure measured after 10 min of CPR was 11 2 mmHg in animals never resuscitated, 20 3 mmHg in those resuscitated that died before 24 h and 29 2 mmHg in those that survived 24 h (P \u3c 0.05). A myocardial perfusion pressure at 10 min of CPR of 20 mmHg or less is an excellent predictor of poor survival (negative predictive value = 96%). Myocardial perfusion pressure is a useful index of CPR effectiveness and therefore may be a useful guide in helping to optimize resuscitation efforts

Changes in Expired End-Tidal Carbon Dioxide During Cardiopulmonary Resuscitation in Dogs: A Prognostic Guide for Resuscitation Efforts

Expired end-tidal carbon dioxide (PCO2) measurements made during cardiopulmonary resuscitation have correlated with cardiac output and coronary perfusion pressure when wide ranges of blood flow are included. The utility of such measurements for predicting resuscitation outcome during the low flow state associated with closed chest cardiopulmonary resuscitation remains uncertain. Expired end-tidal PCO2 and coronary perfusion pressures were measured in 15 mongrel dogs undergoing 15 min of closed chest cardiopulmonary resuscitation after a 3 min period of untreated ventricular fibrillation. In six successfully resuscitated dogs, the mean expired end-tidal PCO2 was significantly higher than that in nine nonresuscitated dogs only after 14 min of cardiopulmonary resuscitation (6.2 ± 1.2 versus 3.4 ± 0.8 mmHg; p \u3c 0.05). No differences in expired end-tidal PCO2 values were found at 2, 7 or 12 min of cardiopulmonary resuscitation. A significant decline in end-tidal PCO2 levels during the resuscitation effort was seen in the nonresuscitated group (from 6.3 ± 0.8 to 3.4 ± 0.8 mmHg; p \u3c 0.05); while the successfully resuscitated group had constant PCO2 levels throughout the 15 min of cardiac arrest (ranging from 6.8 ± 1.1 to 6.2 ± 1.2 mmHg). Changes in expired PCO2 levels during cardiopulmonary resuscitation may be a useful noninvasive predictor of successful resuscitation and survival from cardiac arrest