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Objectives: Using a new fluorescence-quenching optode which, unlike earlier oximeters, neither consumes oxygen nor generates heat, we sought to determine the effects of hemorrhage and resuscitation on subcutaneous PO2. Additionally, we compared the effects of resuscitation with diaspirin crosslinked hemoglobin, an oxygen-carrying solution, on subcutaneous PO2 to that of traditional resuscitative fluids. We also compared mean arterial pressure and central venous oxygen saturation, indirect indices of perfusion, to subcutaneous PO2, a direct index of perfusion., Design: Prospective trial, randomized for selection of treatment regimen., Setting: Shock-trauma laboratory of a medical university., Subjects: Male Sprague-Dawley rats, weighing 260 to 380 g., Interventions: Rats were bled 22 mL/kg and resuscitated, 1 min later, with either 66 mL/kg of lactated Ringer's solution, 22 mL/kg of human serum albumin, 22 mL/kg of blood, or 22 mL/kg of diaspirin crosslinked hemoglobin. A fifth group of animals was not resuscitated after hemorrhage. Subcutaneous PO2 and mean arterial pressure were monitored continuously throughout the experiment, while central venous oxygen saturation was measured intermittently., Measurements and Main Results: Subcutaneous PO2 decreased in response to hemorrhage and, although it did increase after resuscitation with each fluid, no treatment was able to restore subcutaneous PO2 to baseline within 2 hrs postresuscitation. Subcutaneous PO2 continued to decrease after hemorrhage in the unresuscitated animals. In contrast, mean arterial pressure was restored to baseline values in only blood- and diaspirin crosslinked hemoglobin-treated animals, although this effect was lost within 30 mins in the blood-treated group. Only blood restored the central venous oxygen saturation to baseline values in the early postresuscitation period., Conclusions: The fluorescence-quenching optode consistently followed changes in subcutaneous PO2 during hemorrhage and after resuscitation. Diaspirin crosslinked hemoglobin performed as well as blood in restoring peripheral perfusion, as measured by subcutaneous PO2, while both of these fluids were superior to either lactated Ringer's solution or albumin. Both whole blood and diaspirin crosslinked hemoglobin restored mean arterial pressure to baseline, although the effect of the latter was of a longer duration. The pressor effect of the crosslinked hemoglobin did not affect peripheral perfusion, as reflected by the values for subcutaneous PO2. Subcutaneous PO2 is a useful adjunct in assessment of the adequacy of peripheral perfusion and may help redefine targets for resuscitation.

The purpose of this study was to assess the importance of the hyperglycemic response in defense of plasma volume during hemorrhagic shock. Normal well-fed white rats were divided into four groups of 10 each. Two shock models were used each containing rats fasted for 24 hr and control rats maintained on a standard diet. All rats had free access to water. Hemorrhage was produced either by bleeding to a constant mean arterial blood pressure of 40 mm Hg or by removing a fixed per cent of blood volume at 30-min intervals. All control animals withstood a larger volume of blood loss and survived longer than fasted animals, regardless of which shock model was used. They also manifested a significantly greater mean maximum per cent rise in blood glucose and decline in hematocrit during hypovolemia. A change in blood glucose was correlated with change in hematocrit, and to the extent that the latter is a reflection of plasma refill, fed animals demonstrated a greater ability to refill lost plasma volume. The strong correlation between glucose levels and hematocrit during all phases of hypovolemic shock indicates that blood glucose may be an important determinant of plasma refill. The mechanisms whereby glucose exerts these effects may involve its role as an osmotic agent and as a substrate for energy metabolism.

The University of Rochester, Department of Surgery, in response to an experimental community-wide limit on hospital budgets, studied high-cost general surgical patients as a potential source of leverage for containment of hospital costs. It was found that a small number of patients impact significantly on hospital costs. In 1980, 3935 patients at Strong Memorial Hospital (SMH) had at least one contact with a general surgical patient care or intensive care unit; 261 patients (6.6%) had total 1980 charges of more than $20,000 each. They contributed 32% of the total of both general surgical charges and patient days. A subset of 2021 patients was selected to represent more precisely the general surgical patient. The 85 high-cost patients (4.2%) of this subset were chosen for intensive study. These patients generated a significant and disproportionate per cent of total (2021) general surgical charges (26.8%) and hospital days (27.6%). Average total charges were more than 8 times those of the complementary general surgical subset (1936). Nineteen of the 85 patients (22.3%) died in the hospital and 42 patients (49.4%) were dead within 2 1/2 years. Forty patients (of the 85) were then further identified as "complex", based on multiple, usually unrelated, illnesses and multiple annual admissions. Tending to be elderly with poor prognoses, 60% of them had died by April 1983. The major criterion of complexity was the lack of a well-focused medical problem; the cure for one problem simply relinquished primacy to another. A parallel study of hospital ancillary procedures disclosed a similar high-cost pattern. Of approximately 4000 ancillary procedures, 100 (2.5%) had annual charges of $100,000 or over, accounting for two-thirds of total 1980 ancillary charges. Roughly 20% of a single patient's ordered procedures accounted for 80% of the patient's ancillary charges, thus allowing concentrated study of a relatively small number of charges. Means for cost containment may be applied logically to the high-cost patient and particularly toward the complex patient. The complex patient is especially suited for consideration, since it is postulated that these patients are endemic to all general hospitals and to all clinical services. Strategies to be developed should include: 1) a managerial system in which physicians have an incentive to contain costs, 2) an online data system, 3) an accurate, efficient way to identify prospective high-cost and complex patients and, 4) awareness by physicians, patients, and society that less expensive modes of diagnosis and therapy are an appropriate response to rationed health resources.

Moderate or major hemorrhage leads to diminished cardiac output and to increased total peripheral resistance. These cannot be corrected fully until blood volume is restored, which, in the absence of therapy, requires the movement of fluid and of protein from the interstitium into the capillaries. This movement appears mediated entirely by changes in the Starling forces, dominated in the first phase by a fall in capillary hydrostatic pressure, which promotes a rapid shift of protein-free fluid from the interstitium into the capillaries. The second phase, temporally overlapping the initial phase, involves the return of protein to support plasma oncotic pressure. Interstitial albumin probably constitutes the source of the immediate restoration of plasma protein. The driving force for return of the protein depends on interstitial volume and pressure, which in turn appear to depend on movement of fluid from cells to the interstitium, mediated by an increase in solute bathing the cells, especially glucose. It is suggested that this solute is delivered to peripheral cells from the splanchnic bed, where it appears to be formed under the action of hormones whose secretion is stimulated by hemorrhage and injury.

Normal rats subjected to hypovolemic shock (Wiggers model) exhibited the characteristic rise in blood glucose as well as the initial fall in hematocrit indicative of plasma refill. Concurrently there was a rise in osmolality. Late in shock these animals became hypoglycemic and the hematocrit rose despite a persisting hyperosmolality. Rats which had been deprived of food for 24 hours in order to deplete the liver glycogen did not become hyperglycemic after hemorrhage and had a less marked fall in hematocrit. The plasma osmolality rose to the same high level as that of the fed rats but the rise was slower. From this we conclude that glucose may be largely responsibile for the rise in osmolality early in shock in fed animals but it is not responsible for the continuing hyperosmolality in fed or fasted animals. Nor is it responsible for the initial rise in fasted animals. Hyperosmolality may delay but does not prevent fluid loss from the capillaries late in shock.

Many mechanisms, including alterations in muscle metabolism, cellular damage, decreased blood volume, and hepatic disfunction, are influential in producing the observed progressive rise in the concentration of amino acids in arterial and venous blood during persisting hypovolemic shock. The rapid rise of venous and arterial concentrations of amino acids and the increase in venoarterial concentration difference suggest that hypovolemia causes a net release from muscle of a potential substrate for energy metabolism. The blood flow through peripheral tissues, however, is reduced to such an extent during hypovolemic shock that the net rate of release of amino acids is not greater than preshock release and may be less. Therefore, the homeostatic advantages served by the alteration in protein metabolism during the more chronic stresses of starvation or after injury may not obtain during acute hypovolemia.

Previous investigations have demonstrated reduction of postischemic organ injury with improved flow rates following administration of superoxide dismutase (SOD) and catalase (CAT) just before reperfusion. Presumably these oxygen-free radical scavengers provide protection against oxygen-free radicals produced during reoxygenation, but the site of action remains unclear. The present study was designed to determine the effect of SOD/CAT on hepatic function following global ischemia independent of flow. Livers obtained from Sprague-Dawley rats fasted 24 hours were perfused with Krebs-Henseleit buffer containing 5 mM lactate for 130 minutes. Following a 30-minute control period, livers were subjected to 55 minutes of warm, global ischemia. The control group (N = 12) was reperfused under oxygenated conditions for an additional 45 minutes. Two other groups (N = 9; N = 4) were reperfused under identical conditions with administration of 150,000 U/L or 450,000 U/L of SOD/CAT 3 minutes before reperfusion. Hepatic flow returned to normal levels following ischemia, but gluconeogenic activity and bile production remained significantly depressed. No significant recovery of gluconeogenic activity or bile production was noted when SOD/CAT was administered before reperfusion. These results demonstrate that in the absence of flow augmentation SOD/CAT do not provide protection from oxygen-free radicals following global ischemia in the isolated rat liver. This implies that previously reported reductions of postischemic reperfusion injury, where blood flow improved as well, may be due to oxygen-free radical scavenging within the vascular network resulting in enhanced organ perfusion and, therefore, improved organ function.

Reduction of liver ATP in proportion to the severity of shock and hypoxia is well known. We have studied the interrelationships among arterial oxygenation, arterial pH, and liver ATP in experimental hypoxia and in hemorrhagic shock in rats. No significant correlation was found between liver ATP and arterial pH in both hemorrhagic shock and hypoxia and between liver ATP and arterial PO2 in hypoxia. Induction of experimental observations suggest that in this form of hemorrhagic shock, arterial pH may be a sensitive indicator of decreased hepatic perfusion and impaired liver ATP production.

Previous studies performed in our laboratory with a constant-pressure model of hemorrhagic shock in the anesthetized rat have failed to find any significant effect of shock on the glycogen or high-energy phosphate content of the soleus muscle that would be consistent with inadequate oxygen supply. The present study examined the extracellular-intracellular lactate concentration gradients under conditions identical to those of our previous studies to determine whether skeletal muscle lactate accumulation might occur under these conditions. Twenty-seven pentobarbital-anesthetized rats were bled to a mean arterial blood pressure of 40 mm Hg during a 10-minute period and maintained at that level by withdrawal or reinfusion of shed blood. Arterial blood samples were taken and soleus muscles rapidly frozen during four defined phases of hemorrhagic shock: the early compensatory (phase I), maximal compensatory (phase II), early decompensatory (phase III), and late decompensatory (phase IV) phases. The results showed that although the plasma lactate and intracellular lactate concentrations change in parallel during all phases of shock, the extracellular--intracellular concentration gradient for lactate was always positive, ranging from 0.64 +/- 0.61 mmol/L in phase I to 6.41 +/- 0.93 mmol/L in phase III. These findings, together with the previous failure to find significant high-energy phosphate or glycogen changes in the soleus muscle, suggest that this skeletal muscle is not metabolizing anaerobically and does not contribute to the observed lactic acidemia in this model of hemorrhagic shock.

In view of the well-known fact that the liver is more sensitive to ischemia than skeletal muscle, it was the purpose of the present study to determine the relationship between the hemorrhage-induced changes in plasma glucose and lactate concentrations and the status of the energy reserves of these two tissues. Sprague-Dawley rats were bled to a constant mean arterial blood pressure of 40 mm Hg and held there by removal or reinfusion of blood. The stages of shock defined on the basis of the net blood loss were early compensatory, maximal compensatory, early decompensatory, and late decompensatory phases. The results showed a depletion of hepatic ATP levels which occurred between the early compensatory and maximal compensatory phases of shock, coincident with the most dramatic increases in plasma glucose and lactate seen during the shock protocol. Hepatic ATP levels fell no further through the decompensatory phases of shock while plasma glucose declined to hypoglycemic levels and plasma lactate was maintained at the same high level attained at the maximal compensatory phase. Since hepatic sources of glucose were exhausted by the maximal compensatory phase and hepatic energy stores were depleted to a point which precludes significant gluconeogenesis, the large increase in plasma lactate was probably largely due to loss of the hepatic "sink" for lactate during this phase of shock. In contrast to the liver, soleus muscle showed no change in the levels of glycogen, ATP, CrP, free creatine, or total creatine compared to time-matched controls in any phase of hemorrhagic shock suggesting the absence of significant muscle ischemia. The possibility that red skeletal muscle may act as a "sink" for lactate is considered.

In dogs subjected to hypovolemic shock (modified Wiggers model) severe enough to decrease the arterial flow in an isolated hind limb by two-thirds, a marked hyperglycemia (three times control) and an increase in blood glucose AV difference (ten times control) occur. Despite the decreased arterial flow, glucose uptake by peripheral tissues increased by a factor of three within one-half hour of hemorrhage and remained elevated for several hours. Presumably, the increased glucose uptake reflects the need for more energy substrate during the hypoxic conditions of the decreased peripheral blood flow.

Waning of hyperglycemia has been shown to be closely associated with the deterioration of mechanisms supporting homeostasis during hemorrhagic shock. However, the mechanisms which link plasma glucose levels to maintenance of homeostasis during hemorrhagic shock are not clear. The goal of the present study was to evaluate the importance of glucose to maintenance of compensatory mechanisms. This was undertaken by maintaining plasma glucose levels through infusion of hypertonic glucose (2-3 M) starting at the onset of decompensation during persisting hypovolemia. Administration of glucose at a rate of between 60 and 80 mumoles/min X kg arrested the fall in glucose concentration and significantly slowed or arrested the decompensatory phase. All of the saline infused control animals (n = 6) died within 3 hours after reaching their maximum shed blood volume, averaging 145 +/- 25 minutes, while two of the eight animals in the glucose infusion group died less than 4 hours after reaching the maximum shed blood volume. The remaining six animals were sacrificed between 270 and 397 minutes (average, 340 +/- 22 minutes) after reaching the maximum shed blood volume since decompensation was arrested. Compared to the saline-infused control group, animals receiving glucose infusion exhibited a more moderate acidosis, and the hemoconcentration which normally accompanies decompensation was also prevented. Since the increase in plasma osmolality and the fraction of the total osmolality change accounted for by glucose was less in the glucose-infused animals, these results suggest that the effect is not mediated through a glucose-related maintenance of a transcapillary osmotic gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

The hyperglycemic response to hypovolemia has been regarded as an essential osmotic force for promoting the early phase of the internal restoration of plasma volume. Our previous studies of rats fasted 24 hours revealed that they did not develop the hyperglycemic response to hemorrhage observed in fed animals but they had a similar hyperosmotic response. The solutes responsible for the hyperosmolality in the fasted animals were primarily products of anaerobic glycolysis, rather than glucose which accounted for most of the hyperosmolality in fed animals. Plasma refill as reflected by a fall in the hematocrit (Hct) and survival time was significantly reduced in the fasted animals. This study was undertaken to test the hypothesis that the failure of fasted rats to exhibit a normal restoration of plasma volume after hemorrhage may reflect the detrimental effects of fasting on the state of hydration and on the plasma oncotic pressure of the fasted animals rather than the absence of a hyperglycemic response. Four groups of anesthetized rats (280-380 gm) were bled acutely and maintained at an arterial pressure of 40 mm Hg. Before hemorrhage animals in Group A were well fed, those in Groups B, C, and D were fasted for 24 hours. Rats in Group B were induced to drink by addition of sodium chloride in their water, rats in Group C spontaneously had a normal fluid intake, and rats in Group D had a significant reduction in their 24-hour fluid intake. The results demonstrated that 24 hours of fasting led to a loss of body weight of 7 to 10% and a fall in the concentration of plasma total protein of 12 to 17% in all rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The question addressed in this study was whether exogenous insulin can enhance the rate of assimilation of blood glucose after prolonged hypovolemia when homeostasis is waning. Twenty-three well-fed mongrel dogs were maintained at a mean arterial blood pressure of 50 mm Hg by bleeding. Periodic analyses were made of arterial and venous plasma concentration of glucose, femoral blood flow, arterial plasma concentration of insulin, and hematocrit. At the onset of physiologic deterioration signaled by the need to reinfuse 50 ml of shed blood to maintain 50 mm Hg blood pressure, dogs received either 10 ml saline (control; n=15) or 10 ml saline containing 2 units insulin (treated; n=8). Administration of 2 units of insulin to eight of the dogs caused a significantly faster decline of blood glucose than that observed in saline-treated animals. Despite the more rapid decline in plasma concentration of glucose in animals that received insulin, there was no significant difference in glucose uptake between the two groups of animals. The hemoconcentration reflected by a rising hematocrit that develops when hypovolemia persists was accentuated by the administration of insulin without supplementary fluids. The absence of any effect of insulin on glucose uptake in the hindlimb in the late phase of hypovolemic shock suggests that the accelerated decline in arterial glucose levels may be due to inhibitory effects of insulin on hepatic glucose release. These results are not consistent with the resistance of plasma glucose to insulin in the late phases of hypovolemic shock.

Prior nutrition is known to influence tolerance to hypovolemic shock. This study was undertaken to determine the influence of dietary composition on the response of animals subjected to hypovolemic shock. Particular attention was directed to the role of high and low protein diet content with a proportionate change in carbohydrate content to yield isocaloric diets. Rats were placed on one of three diets and were subsequently subjected to shock either by 1) hemorrhage to a pre-determined mean arterial blood pressure, or by 2) hemorrhage of a pre-determined volume of blood based on per cent of body weight. Serial measurements were made of blood pressure, blood volume removed, survival time,hematocrit, blood glucose, pH and blood gases. The results indicate that a high protein diet does not prolong tolerance to recurrent blood loss but there is a greatly reduced tolerance to hemorrhage shock in rats whose body weight was maintained on a low protein/high carbohydrate diet. The latter animals also exhibited impaired refill of plasma volume and a paradoxical, continuing hyperglycemic response during hypovolemia. This study suggests that although an abundant supply of blood glucose is available as an energy source, glucose uptake in the peripheral tissues is inhibited during hypovolemia by unknown mechanisms and thus homeostasis is curtailed. The protein content of the diet may be a critical factor in carbohydrate use during shock.

This study was done to determine why the plasma insulin remained elevated during shock. Mongrel Female dogs (12-15 kg) were depancreatized and maintained on a constant intraportal infusion of porcine insulin while they were bled to reduce and maintain the mean arterial blood pressure at 50 mm Hg for 165 min. Blood samples were taken for glucose and plasma insulin at 15 min intervals. The data show that there was a progressive rise of plasma insulin during the course of hemorrhagic shock. This occurred despite a constant infusion of insulin, the sole source of insulin available to these depancreatized dogs. Since removal of plasma insulin is largely due to insulin utilization, our findings imply that the rise of plasma insulin in hemorrhagic shock is caused by decreased utilization.