Arthur E. Baue

Cellular Alterations With Shock and Ischemia

From the Department of Surgery, Washington University School of Medicine, and The Jewish Hospital of St. Louis, St. Louis, Missouri 63110. Presented at the nineteenth annual meeting of the American College of Angiology, San Juan, Puerto Rico, January 21-25, 1973. Supported by Army contract DADA-17-69-9165 and U.S. Public Health Service Grant 2 RO 1 HL 12278-04. Ultimately, an inadequate circulation will adversely affect the functions of cell populations of various organs. Such changes could be important factors in the problems of unresponsive shock, prolonged extracorporeal circulation, ischemia and preservation of organs by perfusion techniques for transplantation. Haldane once said that anoxia not only stops the machine, but also wrecks the machinery. In order to evaluate such changes and to try to determine how the

Effect of pulsatile cardiopulmonary bypass on cerebral metabolism

Abstract The effects of pulsatile normothermic highflow cardiopulmonary bypass on cerebral metabolism in the dog were studied with and without the addition of carbon dioxide to the ventilating gas by measuring the pH, P O 2 , and P Co 2 , and the levels of lactate and pyruvate in the arterial blood and CSF. The findings were also compared with those in a similar group of dogs subjected to nonpulsatile cardiopulmonary bypass under identical conditions. The present results do not indicate the development of selective cerebral hypoxia or anaerobiosis at any time, even in the presence of moderately severe respiratory alkalosis. Lactate accumulation in the blood was less than with nonpulsatile perfusion, and P CSF O 2 was higher with pulsatile bypass, but alveolar-arterial oxygen gradients increased markedly after pulsatile perfusion with the Army artificial heart pump. Comparison with nonpulsatile bypass points out the lack of definitive evidence that pulsatile perfusion is more beneficial to cerebral metabolism.

(Na+ + K+)-ATPase Activity in the Liver with Hemorrhagic Shock

Summary (Na+ + K+)-ATPase activity was measured in the liver of rats subjected to an early stage of hemorrhagic shock (25% of shed blood taken back spontaneously) and a late stage (50-70% of shed blood taken back). In unbled control animals the activity was 10.6 ± 1.04 (mean ± SEM) nmoles H+/(mg protein X min). An approximately twofold increase in activity in early shock and a threefold increase in late shock was found. When animals were treated by return of the shed blood plus 5-6 ml of Ringers lactate solution in the early and late stages of shock and allowed 1 hr for recovery, the (Na+ + K+)-ATPase activity decreased to near control levels. These results also indicate that the increased liver (Na+ + K+)-ATPase activity in shock is reversible with treatment.

The Effect of Low ATP on Glucose Uptake in Soleus Muscle During Hemorrhagic Shock

Summary Subclavian arteries of rats were cannulated and the animals were bled rapidly to a pressure of 40 mm Hg and maintained at that level for 2 hr. Glucose uptake by isolated soleus muscles from normal rats and rats which were subjected to severe hemorrhagic shock (“shock muscles”) was the same although ATP levels were significantly lowered in muscles of the latter rats. Whereas shock muscles did not show increased glucose uptake, these muscles still responded to the in vitro effect of anoxia by showing increased glucose uptake, further depletion of ATP and increased lactic acid production. The present experiments indicate that: (a) during severe hemorrhagic shock, there is no cause-effect relationship between glucose uptake and ATP depletion and (b) whatever the mechanism of action of anoxia in promoting glucose uptake in vitro might be, it is quite different from that of in vivo. The studies described in this paper were largely inspired by experiments undertaken by I. H. Chaudry, during the course of his PhD. For this the authors thank Dr. M. K. Gould of Monash University, Australia. We are also thankful to Mr. G. J. Planer for technical assistance and for her skill and assistance in typing of this manuscript, we thank Ms. Gail Perry. This investigation was supported by U.S. Public Health Service Grant 2 RO1 HL 12278-04 and Army Contract DADA-17-69-9165.

Value of the cerebrospinal fluid as an indicator of cerebral metabolic changes

Abstract Ventilation with a gas mixture containing 8% O2 produces cerebral hypoxia in the dog and a shift to anaerobic metabolism and increases the release of lactate by the brain, which is evident immediately in the CSF. These changes were detected within 10 minutes and would indicate that the CSF is an adequate and sensitive indicator of cerebral metabolism. The CSF parameters, therefore, seem to be a true reflection of cerebral metabolic status and confirm the reliability of the use of CSF to study alterations in brain metabolism.

Potential Relationships of Changes in Cell Transport and Metabolism in Shock

Circulatory failure or shock is known to produce metabolic changes, including anaerobiosis with increased lactate production, a reduction in ATP stores, and an increase in inorganic phosphate. These changes indicate only a lack of availability of oxygen with depression of the Kreb’s cycle and electron transport system which should be reversible if blood flow or oxygen supply is restored. Ultimately, however, there must be not only a depression of cell function with shock but alterations and aberrations which may limit or destroy the cell’s capabilities even if its environment is improved. Early studies of mitochondrial metabolism in shock were reviewed by Levinson et al. in 1961,8 and they concluded that no significant changes in these cell systems had been found. Hift and Strawitz6 found normal P/O ratios in liver mitochondria of dogs subjected to severe hemorrhagic shock, although oxygen uptake was found to be higher than normal. DePalma et al.4 also demonstrated a lack of alteration of the P/O ratio of liver mitochondria with severe hemorrhagic shock using succinate as a substrate.

Bilateral carotid nerve stimulation in the treatment of angina pectoris.

Presented at the Nineteenth Annual Meeting of the American College of Angiology, San Juan, Puerto Rico, January 21-25, 1973. From the Departments of Surgery and Medicine, Washington University School of Medicine, and the Divisions of Thoracic and Cardiovascular Surgery, and Cardiology, The Jewish Hospital of St. Louis, St. Louis, Missouri 63110. Supported in part by Research Grant #5RO1-HL 13088 from the National Heart and Lung Institute, National Institutes of Health, U.S. Department of Health, Education and Welfare. Angina pectoris is believed to be the result of an imbalance between myocardial oxygen requirements and the availability of oxygen to the myocardium. A variety of surgical approaches to ischemic heart disease aiming at increasing the blood supply to the ischemic myocardium have been introduced in the past, often with considerable enthusiasm, only to meet with frustrating and frequently tragic results. Skeptics readily recall the disappointments following attempts to restore blood flow by implanting systemic vessels into the left ventricular myocardium, or to expand the lumen of damaged coronary vessels using patch grafts. However, there is little doubt that coronary bypass surgery, which utilizes a segment of saphenous vein or a systemic artery to link the aorta and the affected coronary vessel, can accomplish what the other approaches could not, namely immediate perfusion of the region of ischemic myocardium by establishing flow from a source above the obstruction to a relatively healthy portion of the artery beyond it.l5 This approach seems to be a sound one physiologically, and following introduction of saphenous vein bypass surgery for the management of chronic ischemia about five years ago, experience at a number

Failure of nicotinamide in the treatment of hemorrhagic shock

Abstract Hemorrhagic shock in rats was produced by bleeding the animals to a mean arterial pressure of 40 mm Hg which was maintained for 1.5 hr. ATP, ADP, and NAD (nicotinamide adenine dinucleotide) levels decreased and NADH (reduced pyridine nucleotide) levels increased significantly in liver and kidney of such animals. Infusion of NAD, nicotinamide, or nicotinic acid following shock increased the tissue NAD and decreased the NADH levels. Under ideal conditions, the oxidation of NADH to NAD should result in phosphorylation of ADP. Thus more ATP would be expected to be present. However, infusion of the above compounds failed to affect the tissue ATP levels after shock. Failure of animals to survive shock despite increases in tissue NAD levels following NAD, nicotinamide, or nicotinic acid infusion suggests that these infusions have no salutary effect in hemorrhagic shock.

Effect of hydrocortisone and dexamethasone on xylose uptake by isolated rat soleus muscle.

To determine the effects of glucocorticoids on sugar uptake, xylose uptake by isolated rat soleus muscle of bilaterally adrenalectomized animals was studied. The results indicate that in vitro addition of 10-4 M hydrocortisone, dexamethasone or hydrocortisone sodium succinate had no inhibitory effect on basal xylose uptake. In the presence of both low and high medium insulin, the above steroids failed to inhibit insulin-stimulated uptake. When the concentration of hydrocortisone sodium succinate was increased to 10-2 M, insulinstimulated uptake was decreased. The results thus indicate that glucocorticoids at concentrations observed under physiological or pathological conditions do not inhibit basal or insulin-stimulated sugar uptake.

Nicotinamide Adenine Dinucleotide (NAD) Content of Liver with Hemorrhagic Shock

Summary Nicotinamide adenine dinucleotides were determined in the liver of rats subjected to three stages of hemorrhagic shock and treatment. Total nucleotide content was decreased in all stages. The oxidized form, NAD+, appeared to decrease more rapidly than the reduced form, NADH; however this was likely the result of a shift from oxidized to reduced state due to decreased tissue perfusion. Increased enzymic degradation of NAD did not appear to be the mechanism whereby NAD content was lowered; NADase activity of shock liver was not different from that of control liver. These results also indicate that the decreased NAD content in shock is restored to normal by nonspecific treatment by replenishment of circulatory volume. The authors are grateful for the technical assistance of Betty Henton and the clerical assistance of Gail Perry.