Importance of acid-base strategy in reducing myocardial and whole body oxygen consumption during perfusion hypothermia.

During induced hypothermia with cardiopulmonary bypass, acid-base management usually follows one of two strategies: the so-called ectothermic or alpha-stat strategy, in which the pH of the arterial blood increases 0.015 pH units for every degree Celsius decrease in body temperature, or the pH-stat strategy, in which pH remains 7.4 at all temperatures. It has been assumed that oxygen consumption decreases approximately equally during hypothermia with either strategy, although there are biochemical reasons to hypothesize that oxygen consumption would be better maintained with the alpha-stat strategy. We also hypothesized that venous oxygen tension would be lower with the more alkaline alpha-stat strategy than with the pH-stat acid-base strategy, because of the Bohr effect. We tested these hypotheses by placing 10 anesthetized immature domestic pigs on cardiopulmonary bypass. We measured whole body oxygen consumption and myocardial oxygen consumption. Control measurements were made at 37 degrees C. Then the animals were cooled to 27 degrees C and the measurements were repeated. The alpha-stat strategy (pH 7.554 +/- 0.020 at 27 degrees C) was used in five animals and five animals received pH-stat management (pH 7.409 +/- 0.012 at 27 degrees C). Whole body and myocardial oxygen consumption rate decreased in both groups, but more so in the alpha-stat animals than in the pH-stat animals. The unexpectedly high oxygen consumption in the pH-stat animals also resulted in a lower than expected venous oxygen tension. Thus the effect of hypothermia in reducing oxygen consumption was less pronounced with pH-stat acid-base management.

Ventilation-perfusion relationships during induced normovolemic polycythemia in dogs.

Previous studies on normal subjects and patients with polycythemia have given conflicting results of the effect of polycythemia on pulmonary gas exchange. We studied acutely induced normovolemic polycythemia in the dog and measured arterial blood gases and ventilation-perfusion (VA/Q) relationships using the multiple inert gas elimination technique. The mean base-line hematocrit of 43 +/- 5% was increased to 57 +/- 4 and 68 +/- 8%, respectively, after two exchange transfusions of packed erythrocytes. Subsequent plasma exchange transfusions returned the mean hematocrit to 44 +/- 4%. Polycythemia caused no significant arterial hypoxemia; indeed there was a slight improvement in the alveolar-arterial PO2 difference. The multiple inert gas elimination measurements showed no increase in VA/Q inhomogeneity with no increase in log SD ventilation (V) or log SD blood flow (Q). There was a shift of mean V and mean Q to high VA/Q areas because of a decrease in cardiac output, presumably caused by increased blood viscosity. This study showed no deleterious effects on pulmonary gas exchange within the hematocrit range of 36-76%.

Pulmonary capillaries are more resistant to stress failure in dogs than in rabbits.

We previously showed that stress failure of pulmonary capillaries occurs at transmural pressures of approximately 50 cmH2O (40 mmHg) and above in rabbit lung. In this study, we examined whether pulmonary capillaries are more resistant to failure in dogs than in rabbits. This might be expected because of the greater athletic ability of dogs and therefore their presumably greater tolerance to large cardiac outputs and higher pulmonary vascular pressures. The lungs of 12 anesthetized mongrel dogs [22.1 +/- 5.2 (SD) kg] were perfused in situ with autologous blood and then with saline-dextran (5 min) and glutaraldehyde solution (10 min), all three perfusions at the same preset transmural pressure of 32.5, 72.5, 92.5, or 112.5 cmH2O. In dogs, the stress failure curves relating break number per millimeter of epithelium and endothelium were right shifted by approximately 40 cmH2O compared with rabbits. Blood-gas barrier thickness was significantly greater than in rabbits at 32.5 cmH2O, and unlike in rabbits, neither total nor interstitial thickness increased significantly with increasing pressure. These results indicate that pulmonary capillaries are more resistant to stress failure in dogs than rabbits.

Increased plasma O2 solubility improves O2 uptake of in situ dog muscle working maximally.

A perfluorocarbon emulsion [formulation containing 90% wt/vol perflubron (perfluorooctylbromide); Alliance Pharmaceutical] was used to increase O2 solubility in the plasma compartment during hyperoxic low hemoglobin concentration ([Hb]) perfusion of a maximally working dog muscle in situ. Our hypothesis was that the increased plasma O2 solubility would increase the muscle O2 diffusing capacity (DO2) by augmenting the capillary surface area in contact with high [O2]. Oxygen uptake (VO2) was measured in isolated in situ canine gastrocnemius (n = 4) while working for 6 min at a maximal stimulation rate of 1 Hz (isometric tetanic contractions) on three to four separate occasions for each muscle. On each occasion, the last 4 min of the 6-min work period was split into 2 min of a control treatment (only emulsifying agent mixed into blood) and 2 min of perflubron treatment (6 g/kg body wt), reversing the order for each subsequent work bout. Before contractions, the [Hb] of the dog was decreased to 8-9 g/100 ml and arterial PO2 was increased to 500-600 Torr by having the dog breathe 100% O2 to maximize the effect of the perflubron. Muscle blood flow was held constant between the two experimental conditions. Plasma O2 solubility was almost doubled to 0.005 ml O2 x 100 ml blood-1 x Torr-1 by the addition of the perflubron. Muscle O2 delivery and maximal VO2 were significantly improved (at the same blood flow and [Hb]) by 11 and 12.6%, respectively (P < 0.05), during the perflubron treatment compared with the control. O2 extraction by the muscle remained the same between the two treatments, as did the estimate of DO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary flow distribution and dynamics during continuous and pulsatile extracorporeal circulation in the pig.

Four extracorporeal perfusion conditions (continuous beating, continuous fibrillating, pulsatile beating, and pulsatile fibrillating) were tested for 15 minutes each in pigs. Coronary flow, endocardial-epicardial flow ratio, phasic coronary flow, myocardial oxygen consumption, and myocardial lactate extraction were measured. No significant differences in any of these variables were found between pulsatile and continuous flow states in either fibrillating or beating hearts (p greater than 0.05). In both fibrillating conditions, significant elevations of myocardial oxygen consumption and decreases in endocardial-epicardial flow ratios were found (p less than 0.05). Lactate extraction occurred in all conditions, and phasic coronary flows were similar in both beating conditions. These data suggest caution in the expectation that pulsatile perfusion will reverse the coronary flow and myocardial oxygen consumption changes seen with fibrillation.

Modest effect of temperature on the porcine oxygen dissociation curve.

It has been generally assumed that normally endothermic mammals have hemoglobins with greater temperature sensitivity than ectotherms or hibernating mammals. We found the pig to be an exception to this rule. We measured 101 dissociation curves using biotonometry on fresh heparinized blood from 9 pigs at 4 temperatures. The partial pressures of O2 at 50% saturation (P50 +/- SE) were 27.8 +/- 1.2, 30.0 +/- 1.3, 35.7 +/- 0.6 and 41.6 +/- 1.8 mm Hg at 30, 33, 37, and 41 degrees C, respectively. The temperature coefficient d log P50/dT was 0.016 +/- 0.002, about two-thirds that of human and dog blood. It was also saturation dependent, being significantly greater at lower saturations than at high saturations. This saturation dependence causes an increase in heme-heme cooperativity in binding oxygen at higher temperatures. The fixed acid Bohr coefficient was -0.441 +/- 0.005 at 37 degrees C and was not temperature sensitive. We conclude that the effect of temperature on the porcine dissociation curve is significantly lower than that reported for other endotherms, and is similar to that previously reported for hibernating mammals and some ectotherms.

Theoretical analysis of oxygen transport during hypothermia.

Oxygen transport and delivery to peripheral tissues during hypothermia are analyzed theoretically, taking into consideration various conditions observed both in nature and clinically. With decreasing temperature, P50 (the oxygen tension [PO2] at 50% hemoglobin saturation with oxygen) decreases, thereby leading to low mixed venous oxygen tension (PvO2) and thus low tissue PO2 values. On cooling from 37 degrees C to 25 degrees C at pH 7.4, the P50 decreases from a normal 26.8 mm Hg to 13.2 mm Hg. In the intact animal, as well as in a patient on cardiopulmonary bypass, oxygen consumption (Vo2) and cardiac output (QT, or recommended pump flow rate) decrease. If the ratio of Vo2/QT remains constant, then the arteriovenous O2 content difference, C(a-v)O2, must remain constant. If C(a-v)O2 is 5 ml/dl, we calculate that the PvO2 must decrease from a normal 40 mm Hg to 26.8 mm Hg at 25 degrees C. Clinically induced hypothermia is usually accompanied by hemodilution of the patient's blood to 50% normal hematocrit, which would reduce PvO2 to 13.7 mm Hg. Use of constant relative alkalinity (pH = 7.58 at 25 degrees C) further reduces the P50 to 10.8 mm Hg and the PvO2 to 10.9 mm Hg. Other clinical situations are also discussed. Sensitivity analysis predicts that during hypothermia PvO2 (and thus tissue PO2) is very dependent on P50, hemoglobin concentration, and QT, and less dependent on oxygen solubility and arterial PO2. We conclude that monitoring of mixed venous or tissue PO2 might be advisable, and that blood flow is the component of oxygen transport most amenable to manipulation by the clinician to ensure adequate tissue oxygenation during induced hypothermia.

Theoretical analysis of optimal P50.

A simple expression is derived to describe the partial pressure at 50% hemoglobin saturation with oxygen (P50) that maximizes venous oxygen tension (PO2) for a given arterial PO2 and oxygen consumption. That "optimal P50" also maximizes arteriovenous saturation differences for given arterial and venous PO2 values. The optimal P50 can be expressed as the square root of the product of arterial and venous PO2 values. Alternatively, it can be expressed as a simple function of the arterial PO2 and the arteriovenous saturation difference. Nomograms summarize the relationships between the variables, and published observations that suggest an observational basis for our theoretical analysis are reviewed. We conclude that for normoxia or moderate hypoxia a high P50 is advantageous, whereas for more severe hypoxia or increased metabolic demands, a low P50 is advantageous.

Decreased critical mixed venous oxygen tension and critical oxygen transport during induced hypothermia in pigs.

The effects of hypothermia on oxygen delivery and tolerance to hypoxia were studied in 8 normothermic (36.8 degrees C) and 10 hypothermic (29.3 degrees C) pigs that had been anesthetized and surgically implanted with instruments. Cardiac output (QT), VO2 [oxygen consumption, or QT X C(a-v)O2, where C(a-v)O2 is arteriovenous oxygen content difference], arterial and mixed venous blood gas values, and lactate concentrations were measured as the animals were made progressively hypoxic. Under control, normoxic conditions, mixed venous oxygen tension (PvO2) was 41.4 +/- 2.1 mm Hg (mean +/- SE) in the normothermic animals and 26.1 +/- 1.6 mm Hg in the hypothermic animals; these values are close to those predicted in our previous theoretical analysis. To study tolerance to hypoxia during hypothermia, critical PvO2 and critical total oxygen transport (TOT = QT X CaO2, where CaO2 is oxygen content of arterial blood) were determined by decreasing the inspired oxygen concentration (FIO2) in steps and measuring the point where VO2 and blood lactate levels became PO2 or TOT dependent. Again as predicted, the critical PVO2 was lower in the hypothermic animals (15.5 +/- 1.0 mm Hg at 29.3 degrees C compared with 22.0 +/- 1.4 mm Hg at 36.8 degrees C), but critical venous oxyhemoglobin saturation values were not statistically different at the two temperatures. Critical TOT was also decreased during hypothermia, as was the margin of reserve in both PVO2 and TOT (the difference between the normoxic and the critical values).

Responses of harbor seal and pig heart to progressive and acute hypoxia.

Myocardial oxidative and glycolytic reserves were evaluated in four harbor seals, Phoca vitulina richardsi, and six domestic pigs, Sus scrofa (hematocrits: 58 +/- 5 and 34 +/- 1%., respectively). Progressive hypoxia was induced by lowering arterial hemoglobin-oxygen saturation in 10% decrements, each maintained for 10-min periods, until the onset of heart failure. Myocardial oxygen consumption rate (VO2), lactate release/uptake rate (L), and triple product, an index of myocardial energetic demand, were determined at each saturation level. Onset of L began in pigs at Sao2 = 57 +/- 5% and in seals at Sao2 = 35 +/- 4%. Cumulative oxygen consumption (VO2) during hypoxia, determined from the onset of cardiac lactate release, was 435 ml O2/100 g in seals and 172 ml O2/100 g in pigs. Cumulative lactate release during the same period was 14 mM/100 g in seals and 4.6 mM/100 g in pigs. The pigs' left ventricular contractile response (dP/dtmax) was greater than that of seals throughout the time of lactate release. Total myocardial energetic sources were higher in seals than in pigs, and seals were better able to tolerate myocardial hypoxia than were pigs. In a separate experiment, two seals and six pigs were made acutely hypoxic until cessation of cardiac output (seals, 17.5 min; pigs, 7.4 min) and were then reoxygenated. Both seals recovered promptly to control levels of cardiac mechanical function, whereas none of the pigs recovered. Additionally, five pigs were beta-blocked with 0.10 mg/kg of propranolol and were subjected to acute hypoxia. Tolerance to cardiac hypoxia in beta-blocked pigs was significantly increased compared with that of control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature and the oxygen-hemoglobin dissociation curve of the harbor seal, Phoca vitulina.

To determine the effect of temperature and pH on oxygen-hemoglobin affinity of the harbor seal, we measured 61 biotonometric oxygen-hemoglobin dissociation curves on blood from 5 seals at 3 temperatures and a range of pH values. The average (+/- SEM) hemoglobin concentration was 3.44 +/- 0.15 mM, nearly 50% greater than found in normal humans. At pH 7.4 the P50 (partial pressure of O2 at 50% hemoglobin saturation) +/- SEM values were 22.4 +/- 0.6,25.3 +/- 0.5, and 28.5 +/- 0.4 Torr at 33, 37 and 41 degrees C, respectively. The effect of temperature on oxygen-hemoglobin affinity, (delta log P50/delta T) was 0.014 +/- 0.001 at pH 7.4, significantly lower than that observed in human and dog blood. This low temperature sensitivity may facilitate oxygen off-loading from hemoglobin when temperature gradients exist within the animal or as tissue temperature decreases during a dive. Temperature did not significantly affect the Hill coefficient 'n' (shape) of the dissociation curve which averaged 2.43 +/- 0.04 at 37 degrees C. The fixed-acid Bohr coefficient (delta log P50/delta pH) was -0.606 +/- 0.032 at 37 degrees C and increased with temperature. This relatively large value for the Bohr coefficient was similar to those previously reported for the Northern Elephant, Bladdernose, and Weddell Seals, and may facilitate oxygen off-loading as acidosis develops during a dive.

The physiologic effects of oxygen transport by hemoglobin solutions.

Two chronic animal models and one acute animal model were used to evaluate exchange transfusion with stroma-free hemoglobin solutions. A direct comparison was made between stroma-free hemoglobin solutions having differing oxygen offloading characteristics as well as a colloid solution consisting of 7% bovine albumin. These studies involved a partial exchange involving approximately 50% of the animal's blood volume to simulate a clinically more appropriate partial blood replacement situation. We noted a consistent increase in the arterial oxygen content of animals exchanged with the stroma-free hemoglobin solutions and some modest improvement in oxygen dynamics. Our studies examining myocardial contractility, especially those carried out in the right heart bypass swine preparation failed to substantiate any difference between an exchange with albumin or stroma-free hemoglobin solutions. The conscious animal models examined both at rest and at exercise demonstrated marked differences in exercise response. Animals exchanged transfused with stroma-free hemoglobin solutions often had an almost normal exercise response while those animals exchanged with non-oxygen carrying albumin solution frequently failed to exercise on a treadmill. Blood flow measurements using radiolabeled microspheres were performed in chronically instrumented swine. These animals had a normal variation in organ blood flow during exercise which was noted both during the control period as well as following exchange with stroma-free hemoglobin solutions. Animals exchanged transfused with albumin had a marked derangement in organ blood flow apparently reflecting the decreased oxygen availability. Results from these three studies substantiate a significant benefit to animals undergoing a 50% exchange when that exchange is done with an oxygen carrying solution such as stroma-free hemoglobin solutions as opposed to a non-oxygen carrying but oncotically active solution such as albumin solution. These studies seem to offer encouragement to the continued investigation and ultimate clinical utilization of hemoglobin solutions as an appropriate blood substitute.