Rightward shifts of the O2 dissociation curve (ODC) were experimentally obtained in lysed and resealed erythrocytes following encapsulation of inositol hexaphosphate (IHP). This continuous lysing and resealing procedure led to in vitro P50 (Po2 at 50% hemoglobin saturation) increases up to 80 Torr (pH, 7.40; Pco2, 40 Torr; temp, 37 degrees C) for both human and pig erythrocytes. The Hill number of the transformed blood decreased when IHP was fixed on the hemoglobin, but the sigmoid shape of the ODC was maintained. The O2 hemoglobin binding capacity and the mean corpuscular hemoglobin content were found unchanged by the experimental procedure in human and pig erythrocytes. Isovolumic exchange transfusion of high-P50 erythrocytes in anesthetized and ambient air-ventilated piglets (n = 6) led to substantial in vivo P50 increases (range, 8-19 Torr). The rightward shift of the ODC was concomitant with an increase of the arterial Po2 and of the arteriovenous O2 content difference, 19 and 59% respectively above their control values. The mixed-venous Po2 (PVO2) remained unchanged. The cardiac output was shown to be inversely related to the P50 value. In spite of the O2-transport reduction (37%), O2 consumption was maintained due to enhanced O2 extraction.

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We describe a method for perfusion of a working isolated rat heart with washed erythrocytes suspended in a Krebs-Henseleit bicarbonate buffer containing bovine albumin (fraction V). With washed pig red cells, as hematocrit was varied between 0 and 40%, coronary flow (CF), aortic flow (AF), external work (W), and myocardial oxygen consumption (MVO2) were measured. Hemodynamic data at a hematocrit of 30% (CF = 5.4 +/- 0.7 ml/min per g, AF = 75 +/- 8 ml/min per g) were identical with those reported for the intact animal. Coronary sinus PO2 was highest with a red cell-free perfusate suggesting that coronary flow is partially shunted. Human red cells obtained from banked blood, were tried also with success. With careful filtration, the preparation is stable for 2 h and well suited for study of the dynamics of myocardial oxygen delivery.

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The Haemodynamic response to dopamine infusion has been assessed in 30 patients in septic shock with myocardial dysfunction. Dopamine infusion resulted in a haemodynamic improvement as indicated by significant increases in cardiac output of 38.4% (p less than .001), stroke volume 18.7% (p less than .001), and mean arterial pressure of 33% (p less than .001). Despite the inotropic effect, left ventricular filling pressure did not change in 20 cases and increased in 10 cases. Mean peripheral resistance remained unchanged with a scatter of individual responses depending upon factors such as dopamine dose and initial vascular resistance. Dopamine increased intrapulmonary shunting by 48% (p less than .001), insignificantly decreased PaO2, increased mixed venous oxygen saturation by 16% (p less than .02) and decreased pulmonary vascular resistance by 15% (p less than .02). Both isoprenaline and dopamine improve stroke volume by an inotropic action, with an increase in venous return in the case of the latter and a reduction in afterload in the former. It is concluded that the usefulness of dopamine in septic shock may be limited in patients with previous myocardial disease because of the risk of increasing preload and in hypoxaemic patients because of the risk of increasing intrapulmonary shunting.

A continuous lysing and resealing procedure with erythrocytes permitted incorporation in these cells of inositol hexaphosphate (InsP6), a strong allosteric effector of Hb. This leads to significant rightward shifts of the HbO2 dissociation curves with in vitro P50 (partial pressure of 02 at 50% Hb saturation), values increasing from 32.2 ± 1.8 torr for control erythrocytes to 86 ± 60 torr (pH 7.40; Pco2 40 torr at 370C; 1 torr = 1.333 x 10W Pa). The shape of the dissociation curve was still sigmoidal, although the Hill coefficient was decreased. The life span of InsP6-loaded erythrocytes equaled that of control erythrocytes. The long-term physiological effects of the InsP6-loaded erythrocytes on piglets were increased 02 release and reduced cardiac output. The reduced 02 affinity of the InsP6-loaded erythrocytes was still effective 20 days after transfusion in awake piglets. The electrolyte concentration appeared stable over the 5-day observation period except for a transient, but significant, hyperkalemia immediately after transfusion. The reductions in the 02 affinity of Hb reported here are large compared with previously reported values. Introduction of InsP6 into viable erythrocytes improves tissue oxygenation when, for any reason, normal blood flow is impaired.A conformational modification of intracellular Hb may considerably change its affinity for 02, which, in turn, may have physiological implications whenever a limitation of blood flow or reduction of Hb concentration impairs systemic oxygenation (1). When 02 uptake by erythrocytes was maintained, an in vivo decrease in 02 affinity was observed to enhance tissue 02 delivery (1). However, the consequence of a substantial increase of the in vivo P50 (02 partial pressure at 50% Hb saturation) is not well documented due to the difficulty in obtaining substantial and long-term low 02 affinity. Few methods have been reported to raise P50 in vivo, and the induced P50 increases were always modest and/or sustained for only a short time. We previously reported a method for increasing P50 in anesthetized piglets using inositol hexaphosphate (InsP6) (2). Because InsP6, the most effective Hb allosteric effector (3), cannot diffuse through the erythrocytic membrane, InsP6 was incorporated into erythrocytes by using a reversed osmotic-lysis process (4-6).The aim of this study was to sustain a marked decrease in Hb affinity for several days in piglets after exchange transfusion with InsP §-enriched homologous erythrocytes. Physiological properties and life span of lysed-resealed InsP6-loaded erythrocytes (InsP6-erythrocytes) were studied before exchange transfusion. The time courses of P50 variation and electrolyte concentrations were measured in piglets after massive exchange transfusion with InsP6-erythrocytes suspended in porcine plasma. MATERIALS AND METHODSHigh-Pso Erythrocyte Preparation. Human or porcine blood, collected on acid-citrate-dextrose solution, was stored at 4°C no longer than 5 days. After centrifugation ofone blood unit (1000 x g for 10 min)...