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Cardiovascular and pulmonary effects of morphine (1 mg/kg bolus iv) were investigated in conscious chronically instrumented pigs, a species exhibiting an excitable response. Control animals received an equivalent volume (less than 2 ml) of normal saline. Morphine induced an immediate but small increase in cardiac output and substantial increases in heart rate, mean systemic and pulmonary arterial pressure, left and right ventricular work, hematocrit, and hemoglobin concentration, but did not change stroke volume or systemic vascular resistance. Morphine administration also led to a gradual increase in ventilatory rate and rapid increases in tidal volume, expired and alveolar ventilation, ventilation-perfusion ratio, and shunt fraction. In addition, morphine administration produced substantial decrements in arterial and mixed venous PO2, hemoglobin saturation and mixed venous O2 content; no change in arterial O2 content; and a widening of the arteriovenous O2 difference. Arterial O2 transport was increased slightly. Finally, it produced substantial increments in arterial and mixed venous PCO2 and substantial decrements in arterial and mixed venous pH. It was concluded that arterial O2 delivery did not adequately rise to meet tissue O2 demand, in part because an appropriate increase in cardiac output was attenuated by morphine, and in part because morphine impaired pulmonary gas exchange.

The neuroendocrine responses to resuscitation with 7.5% hypertonic saline/6% Dextran-70 (HSD) following hemorrhagic hypotension were evaluated in conscious swine. Following hemorrhage (37.5 ml/kg/60 min) animals received 4 ml/kg of HSD (n = 6) or 0.9% saline (n = 8). Administration of normal saline did not alter cardiovascular function nor attenuate an increase in hormones. HSD rapidly improved cardiovascular function and acutely decreased ACTH, plasma renin activity (PRA), cortisol, norepinephrine (NE), epinephrine (E), aldosterone, and lysine vasopressin levels (LVP). The initial decreased in ACTH, cortisol, and aldosterone levels was due primarily to hemodilution associated with the expansion of plasma volume. The reductions in NE, E, LVP, and PRA were greater than those attributed to hemodilution alone. Values for LVP, NE, and E remained at values below those at the end of hemorrhage, but greater than basal levels, while PRA returned to values similar to these at the end of hemorrhage. The decrease in LVP, NE, and E following HSD resuscitation for the treatment of hemorrhagic hypotension may result from and contribute to the rectification of cardiovascular and metabolic function.

Effects of a modest dose of morphine sulfate (1 mg/kg) on total body energy metabolism, body thermal status, and the plasma concentrations of certain electrolytes and metabolites were investigated in conscious chronically instrumented pigs (n = 8). Control pigs (n = 8) received an equivalent volume of normal saline. Intravenous morphine injection led to an excitatory state associated with significant (P less than or equal to 0.05) immediate increases in O2 consumption. CO2 production, respiratory exchange ratio, and plasma concentrations of lactate, glucose, potassium, phosphate, epinephrine, and norepinephrine. Significant more gradual increases were observed in rectal and skin temperatures, body heat content, and the plasma concentrations of adrenocorticotropic hormone, cortisol, and phosphate. The hypermetabolic state persisted for approximately 1 h. Thereafter, most functional variables regressed toward, but did not reach, control levels. Increased muscle activity appeared to be the major factor underlying the rise in energy metabolism. Body heat storage after morphine injection appeared to be attributable to increased heat production coupled with an inadequate rise in heat loss.

Conscious, chronically instrumented pigs were subjected to a progressive, fixed-volume hemorrhage (37.5 ml/kg over 1 h) and subsequent resuscitation with 7.5% hemorrhage (37.5 ml/kg over 1 h) and subsequent resuscitation with 7.5% NaCl/6% Dextran 70 (4 ml/kg). Hemorrhage led to increases in arterial PO2, HbO2, plasma lactate, base deficit, and mixed venous PCO2. It led to decreases in arterial PCO2, plasma bicarbonate, and buffer base, as well as mixed venous PO2, HbO2, and pH. These effects were attributable to reduced O2 delivery, lactacidemia, hyperventilation, and hemodilution. Resuscitation with hypertonic saline/dextran produced a transient increase in arterial PCO2 and base deficit and a transient decrease in pH, effects that were attributable to a transfer of venous blood attributes to the arterial circulation. Resuscitation also produced an immediate decrease in arterial buffer base, an effect attributable to hemodilution. Subsequently, over 4 h, most cardiopulmonary and metabolic variables gradually reverted toward control levels, thereby ameliorating the deleterious blood gas and acid-base disturbances produced by severe hemorrhage.

We compared the effectiveness of intravenously administering hypertonic saline/dextran (HSD; 7.5% NaCl in 6% Dextran-70, n = 6) to hypertonic saline (HS) alone (7.5% NaCl, n = 8) in rectifying detrimental effects of hemorrhage on cardiovascular function. Chronically instrumented conscious swine were hemorrhaged 37.5 ml/kg over 60 min. If untreated, this model is 100% lethal within 60 min. Swine received HSD or HS at 4 ml/kg. Functional variables were measured before and at 5, 15, and 30 min following treatment. HSD produced a significantly greater plasma volume expansion than HS alone (13.6 compared to 9.9 ml/kg). Over 30 min expansion was sustained in pigs receiving HSD but pigs receiving HS regressed. Cardiac index (CI) increased for both treatments, being greater with HSD, 104 ml/kg/min, compared to HS alone, 46 ml/kg/min. Neither group fully sustained these elevated values post-treatment, but remained consistently greater than values after hemorrhage; however, the difference in CI between treatments was maintained. Oxygen delivery showed a trend similar to that of CI. We conclude that resuscitation with HSD is superior to HS in improving cardiovascular function over the first 30 min after hemorrhage.

Although the domestic pig is rapidly becoming an animal of choice in certain areas of biomedical research requiring a large animal model, effective utilization of the species is often encumbered by a lack of reference values for common functional variables. To address this problem, normal data for over 100 physiologic or related variables were collected from conscious chronically instrumented animals that were maintained under near basal conditions. Included were measurements of body composition, fluid volumes, blood physical and biochemical characteristics, blood gas and acid-base status, plasma hormone levels, energy metabolism, renal function, hemodynamics and pulmonary function. Most porcine values were similar to those collected under comparable conditions from humans. Compared to adult man, however, pigs had higher values for extracellular space, plasma volume, arterial pH, plasma bicarbonate, cardiac output, arterial pressure, expired ventilation, heat production, and core temperature, and lower values for red cell volume, hemoglobin level, plasma osmotic and oncotic pressure, arterial O2 content, renal blood flow and glomerular filtration rate. Many of these deviations were due to immaturity. Nevertheless, we have found pigs to be an excellent large animal model for a variety of functional studies.

Some of the interrelations of neuroendocrine changes associated with hypovolemia were investigated in a model simulating an arterial hemorrhage. beta-Endorphin, adrenocorticotropin hormone (ACTH), and cortisol levels were measured by radioimmunoassay before, during, and after controlled bleeding of conscious splenectomized pigs. All animals showed significant (P less than 0.05) increases in the three neuroendocrine substances during hemorrhage. beta-Endorphin values initially were 55 +/- 7 pg/ml (+/- SE) and rose to a peak of 386 +/- 44 pg/ml at the nadir of blood pressure (mean arterial pressure = 47.5 mmHg). ACTH showed a similar pattern, increasing from 49 +/- 10 to a peak of 518 +/- 56 pg/ml. Cortisol values reached their peak of 18.2 +/- 2.5 micrograms % during the recovery phase. beta-Endorphin values displayed a close inverse correlation to blood pressure during hemorrhage, but returned to basal levels more rapidly than blood pressure during the recovery period. Plasma ACTH levels rose significantly more slowly than beta-endorphin as the hemorrhage progressed. An equimolar ratio of ACTH and beta-endorphin returned only as levels declined following the hemorrhagic insult. In awake pigs therefore an arterial hemorrhage is accompanied by endorphin release proportional to the decrement in blood pressure, a somewhat retarded buildup of ACTH, and a still later cortisol peak during recovery.

A conscious porcine model was used to investigate the adequacy of O2 delivery relative to O2 demand, initially during a fixed-volume hemorrhage (37.5 ml/kg over 1 hr) and subsequently after resuscitation with 7.5% NaCl/6% Dextran 70 (4 ml/kg). Hemorrhage produced a small increase in O2 consumption, severe lactacidemia, and a doubling of apparent O2 demand. These effects were attributable to a behavioral compensation (periodic bouts of muscle activity) which presumably served to improve venous return. Despite enhanced ventilatory function, arterial O2 delivery was markedly reduced by hemorrhage, an effect that was due entirely to decrements in cardiac output and hemoglobin level. The disparity between O2 delivery and O2 demand was lessened following resuscitation with 7.5% NaCl/6% Dextran 70, primarily by suppression of demand and secondarily by an augmentation of delivery.

When estimated by the dilution of 51Cr-labeled red blood cells under nearly basal conditions, immature splenectomized pigs (n = 20) had a circulating red cell volume of 17.8 +/- 1.64 (SD) ml/kg. At an assumed body-to-large vessel hematocrit (BH:LH) ratio of 0.9, plasma volume was 49.6 +/- 3.12 ml/kg and blood volume 67.3 +/- 3.67 ml/kg. Sham-operated pigs (n = 20) had a circulating red cell volume of 16.2 +/- 1.39 ml/kg, a plasma volume of 51.1 +/- 3.42 ml/kg, and blood volume of 67.2 +/- 4.12 ml/kg. Kinetic analysis of early 51Cr loss from the circulating blood of the sham-operated pigs indicated a splenic red cell sequestration of 4.5 +/- 0.89 ml/kg and a t1/2 of 9.76 +/- 1.93 min for splenic red cell turnover. Epinephrine injection (n = 6) and physical restraint (n = 8) caused rapid mobilization of splenic red blood cells in sham-operated pigs. Volume estimates in splenectomized pigs (n = 7) based on simultaneous dilutions of 51Cr-labeled red blood cells and 125I-labeled bovine albumin gave circulating red cell, plasma, and blood volumes of 18.4 +/- 2.46, 60.7 +/- 4.01, and 79.0 +/- 3.51 ml/kg, respectively, and a BH:LH ratio of 0.756 +/- 0.029. The latter value may have reflected an overestimation of plasma volume by the 125I-labeled albumin procedure.

Efficacy of small-volume resuscitation (4 ml/kg) with 7.5% NaCl in 6% Dextran 70 (HSD), 7.5% NaCl (HS), dextran (D), and 0.9% NaCl (NS) was evaluated in conscious swine bled 37.5 ml/kg over 60 min. Hemorrhage reduced cardiac index (CI), stroke volume (SV), and mean arterial pressure (MAP). Four-hour survival after HSD (67%) was significantly (P less than 0.05) greater than after HS (25%), D (17%), or NS (0%). The superior performance of HSD, and to a lesser extent HS, was associated with rapid plasma volume expansion, improved CI and SV, and decreased heart rate. The acute increases in cardiac index and stroke volume were greater following treatment with HSD and the improvement persisted for 4 hr. HSD also produced a transient increase in MAP. Plasma Na+ concentration and osmolality were increased to a similar extent with HSD and HS, while plasma K+ levels were initially decreased, returning to control levels within 60 min. HSD appears to be a superior small-volume resuscitation solution compared to the other treatments with no detrimental effects.