Opiate receptors and endorphins in the pathophysiology of hemorrhagic shock

We investigated the hypothesis that endorphins released by stress act on opiate receptors to depress cardiovascular function during hemorrhagic shock. Anesthetized adult mongrel dogs were bled into a heparinized reservoir to achieve a mean arterial pressure (MAP) of 45 mm Hg. The reservoir was adjusted to maintain MAP for 1 hour and then clamped for 1 hour, at the end of which time the shed blood was reinfused. While the reservoir was clamped we treated the animals with an intravenous bolus followed by 3-hour infusion of either 0.9% NaCl (as control) or the specific opiate receptor antagonist naloxone at three dose regimens (0.5, 1, or 2 mg/kg plus 0.5, 1, or 2 mg/kg . hr). Naloxone produced dose-dependent increases in MAP, cardiac output, stroke volume, and left ventricular contractility. Survival at 72 hours was related to the dose of naloxone used. None of six dogs treated at 0 mg/kg . hr survived, one of six survived at 0.5 mg/kg . hr, four of five at 1 mg/kg . hr, and five of five at 2 mg/kg . hr. Since naloxone has minimal effect on cardiovascular function in nonshocked dogs, these results implicate opiate receptors and perhaps endorphins in the cardiovascular pathophysiology of hemorrhagic shock.     

Hemodynamic response to naloxone during live Escherichia coli sepsis in splenectomized dogs.

This study was designed to investigate the concept that endogenous opioids are involved in the pathogenesis of septic shock. Infusion of live Escherichia coli (1.0-1.6 X 10(10) organisms/kg) in splenectomized dogs induced profound hypotension (p less than 0.001), peripheral vasodilatation (p less than 0.001), and metabolic acidosis (p less than 0.05) with maintenance of cardiac index as compared to control splenectomized dogs. Treatment with naloxone (3 mg/kg bolus and 2 mg/kg/hr infusion for 2.5 hours), a specific opiate antagonist, during septic shock attenuated the hypotension (p less than 0.002) and systemic acidosis (p less than 0.02) without altering cardiac index or total peripheral resistance. These experimental results indicate that naloxone may be of therapeutic value in the management of the early vasodilatory stage of septicemia.     

The interaction of corticosteroids and naloxone in canine hemorrhagic shock

β-Endorphin is released concomitantly with adrenocorticotropin from the pituitary following stress and, during hemorrhagic shock, can alter cardiovascular hemodynamics. In 41 anesthetized dogs, we assessed the combined effects of pituitary suppression with dexamethasone (D) or methylprednisolone (M) and opiate receptor blockade with naloxone (N) during hemorrhagic shock. We found that N alone was the most effective treatment in improving arterial pressure, cardiac output, and left ventricular contractility and resulted in the best survival. D and M alone were little better than saline. When combined with N, D and M were better than saline but not as good as N alone. This attenuation of the N effect may be due to corticosteroid: suppression of β-endorphin and ACTH release from the pituitary; alterations in opiate metabolism; or changes in opiate receptor availability.     

Naloxone requires circulating catecholamines to attenuate the cardiovascular suppression of endotoxic shock

The opiate antagonist naloxone (NAL) improves cardiovascular performance in canine hemorrhagic and endotoxic shock. If the release of neural and adrenal catecholamines is attenuated, NAL does not produce the expected improvement in cardiovascular function in canine hemorrhagic shock. This study tests the hypothesis that an endorphin-catecholamine interaction at the heart is responsible for a part of the cardiovascular depression of endotoxic shock. Two groups of five dogs were instrumented to measure mean arterial pressure (MAP), the first derivative of left ventricular pressure over time (LV dP/dt max), cardiac output, and heart rate (HR); they were then subjected to bilateral adrenalectomy and given chlorisondamine to produce ganglionic blockade. At t = 0 min the dogs were given Escherichia coli endotoxin at 1 mg/kg (LD80). Group I animals received NAL at 2 mg/kg + 2 mg/kg.hr iv from t = 30 to t = 60. At t = 45 these animals were treated with epinephrine (EPI) at 20 micrograms/kg.hr iv until t = 60. Group II animals got EPI from t = 30 to t = 60 and NAL from t = 45 to t = 60 at the same doses as Group I. In Group I, NAL alone had no effect on MAP, LV dP/dt max, or HR. EPI significantly increased (P less than 0.002) cardiovascular parameters with MAP increasing from 52 +/- 7 to 159 +/- 14 mm Hg. In Group II, EPI produced a significant increase in all parameters, and the addition of NAL produced a further significant increase; MAP increased from 37 +/- 3 to 126 +/- 16 mm Hg with EPI and then to 175 +/- 11 mm Hg with NAL. These data support the above hypothesis and indicate that circulating catecholamines need to be present to allow naloxone to reverse the cardiovascular depression in endotoxic shock.     

Involvement of endogenous opiates in glucose-stimulated hyperinsulinism of canine endotoxin shock. Inhibition by naloxone

Hyperinsulinism has been associated with infection and endotoxin shock in rodents, dogs, and humans. In dogs with Escherichia coli-induced endotoxin shock, this hyperinsulinism was in response to glucose administration. To determine the role of endogenous opiates in endotoxin-induced glucose-stimulated hyperinsulinism, plasma beta-endorphin, Met-enkephalin, Leu-enkephalin, insulin, and glucose concentrations were measured for 6 h in fasted, anesthetized dogs given LD70 of E. coli endotoxin; endotoxin and glucose; endotoxin, glucose, and naloxone (an opiate antagonist); glucose and naloxone; or glucose alone. Plasma endogenous opiate immunoreactivity was elevated in dogs that received endotoxin, regardless of the presence of glucose or naloxone. The elevation of plasma Met-enkephalin and beta-endorphin preceded the onset of hyperinsulinism, but the elevation of plasma Leu-enkephalin did not. Plasma insulin was elevated 100-fold by 360 min in dogs given endotoxin and glucose. The magnitude of this hyperinsulinism was markedly reduced by naloxone, supporting the hypothesis that endogenous opiates are involved in the development of the glucose-stimulated hyperinsulinism associated with endotoxin shock. Interestingly, naloxone, given in conjunction with glucose, appeared to have a stimulatory effect on insulin secretion.     

Effect of different degrees of hypothermia on myocardium in treatment of hemorrhagic shock

The use of hypothermia in cardiac and neurologic surgery is well established, but its use in treating hemorrhagic shock is controversial. Using a modified Wiggers hemorrhagic shock model, we examined the effects of hypothermia (group 1, 33 degrees C, N = 7; group 2, 28 degrees C, N = 12) after inducing hemorrhagic shock. In group 3, N = 6, dogs were maintained at body temperature in hemorrhagic shock and throughout resuscitation (normothermic shock). Sixty minutes after resuscitation (shed blood and lactated Ringer's solution, 50 ml/kg body wt), all hypothermic dogs were rewarmed and studied for an additional 120 min. Comparison of moderately hypothermic, severely hypothermic, and normothermic dogs showed a lower heart rate (80.6 +/- 3.3, 62.5 +/- 4.1, and 136.7 +/- 4.2 beats/min, P less than 0.05), reduced rate of left ventricular pressure fall (938 +/- 125, 700 +/- 75, and 1550 +/- 275 mm Hg/sec, P less than 0.05), a lower arterial pH (7.15 +/- 0.02, 7.10 +/- 0.03, and 7.24 +/- 0.02, P less than 0.05), a lower respiratory rate (18 +/- 1, 14 +/- 1, and 24 +/- 2 breaths/min, P less than 0.05), and a higher arterial pCO2 (36.6 +/- 1.6, 46.9 +/- 4.6, and 20.3 +/- 2.0 mm Hg, P less than 0.05). Left ventricular end-diastolic pressure was lower in the severely hypothermic dogs while stroke volume was higher in this group. Rewarming ablated all differences in cardiovascular performance and acid-base balance. Our data show that moderate hypothermia during hemorrhagic shock increased coronary perfusion, enhanced cardiac contractile performance, and significantly reduced myocardial oxygen requirements.(ABSTRACT TRUNCATED AT 250 WORDS)     

Naloxone and methylprednisolone in the treatment of experimental septic shock

Endogenous opiates have been implicated as being deleterious in the pathophysiology of various shock states. Treatment with opiate antagonists or pharmacological doses of corticosteroids have previously been claimed to improve the situation in septic shock. Using a porcine septic shock model, four treatment regimens were compared: saline (control), naloxone alone, methylprednisolone alone, and a combination of naloxone and methylprednisolone. Although naloxone and methylprednisolone each ameliorated the shock state somewhat when given alone, the combination of both agents seemed to display a synergistically beneficial effect, improving cardiac output, mean arterial pressure, and lactate/pyruvate ratio significantly. A possible explanation for this synergistic effect may, at least in part, lie in the inhibition of endogenous opiates.     

An evaluation of naloxone as a gastric cytoprotective agent during hemorrhagic shock

Administration of naloxone, an opiate antagonist, is known to improve survival from hemorrhagic shock and to reverse the effects of septicemia on gastric mucosal O2 tension and potential difference (PD). We tested these potentially cytoprotective actions in the ex-vivo canine gastric chamber model with acid, bile, and hemorrhagic hypotension. Naloxone (2 mg/kg IV bolus, then 2 mg/kg/hr IV) was given before or during shock. Naloxone did not affect oxygen consumption, the bile-induced drop in PD, or the transmucosal oxygen consumption, the bile-induced drop in PD, or the transmucosal movements of H+, Na+, K+, and fluid. The reduction in average mucosal lesion formation with naloxone pretreatment (5.4 +/- 1.2 vs. 2.8 +/- 0.5%) was not statistically significant (p = 0.07). Similarly, administration of naloxone after the onset of shock also failed to protect the mucosa from stress ulceration. We conclude: 1) naloxone does not inhibit the effects of topical bile on the gastric mucosal barrier; 2) naloxone has no apparent effect on local gastric vascular resistance during hemorrhagic shock; and 3) the therapeutic potential of naloxone as an anti-ulcer drug is questionable. 24GM 23095     

The cardiocirculatory and metabolic effects of endotoxin challenge after canine resuscitated hemorrhagic shock

Although adequate volume resuscitation has decreased mortality from hemorrhagic shock, recovery in many patients is complicated by sepsis. To determine whether a subject debilitated by hemorrhagic shock would exhibit greater cardiocirculatory dysfunction when challenged with sepsis, ten dogs (Group I) were hemorrhaged to a mean arterial blood pressure of 30 mm Hg. After 2 hours of hypotension, shed blood and lactated Ringer's solution (50 ml/kg) were given, and the dogs were observed for 3 to 6 days. Ten dogs were sham hemorrhage and served as controls (Group II). On the experimental day, all cardiovascular and hemodynamic parameters were measured in both groups of animals before endotoxin challenge. There was no significant difference in cardiac output, stroke volume, stroke work, +dP/dt max, myocardial blood flow, myocardial oxygen metabolism, or acid-base balance in the two groups. Compared to sham-hemorrhaged dogs, resuscitated shock dogs had a significantly lower mean arterial blood pressure (127 +/- 7 vs. 110 +/- 6 mm Hg; p less than 0.05), and heart rate was significantly higher (86 +/- 6 vs. 109 +/- 7 beats/minute; p less than 0.05). Furthermore, maximal rate of left ventricular pressure fall (-dP/dT max) was significantly lower in the animals previously hemorrhaged, suggesting a persistent defect in left ventricular relaxation. Blood glucose and insulin levels were significantly elevated in the resuscitated shocked dogs, likely due to increased circulating catecholamine concentrations and enhanced glycogenolysis. Endotoxin shock caused significant hypotension, acidosis, and impaired regional perfusion in all dogs. In addition, cardiac output, stroke volume, dP/dT, and left ventricular end-diastolic pressure fell and hyperglycemia and hyperinsulinemia occurred in all dogs after endotoxin injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effects of dopamine, naloxone, and prostacyclin in the resuscitation of fecal-Escherichia coli peritonitis-induced septic shock in neonatal swine

To explain the high neonatal mortality from peritonitis-induced septic shock despite current resuscitation practices, the efficacy of dopamine, naloxone, and prostacyclin was evaluated in an experimental neonatal model. Hemodynamics were monitored and survival was measured in anesthetized neonatal swine, which were subjected to fatal fecal-Escherichia coli peritonitis-induced septic shock. All the animals received fluid resuscitation, antibiotics, and bicarbonate to correct acidosis. Pharmacologic resuscitation began when cardiac output dropped below baseline in the experimental groups. Although significant differences were observed between groups in cardiac output, mean arterial and mean pulmonary arterial pressures, left ventricular stroke work, stroke volume, and pulmonary vascular resistance indices (P less than 0.02), and each animal exhibited favorable hemodynamic responses during the first several hours of dopamine and naloxone infusion, these drugs failed to prolong survival. Also, 5 of the 9 naloxone-treated pigs (56%), died with histologically proven intestinal ischemia (P less than 0.02). Thus, dopamine, naloxone, and prostacyclin (at doses commonly recommended for the treatment of septic shock) fail to positively influence the fatal course of this condition, and the use of naloxone in this model is associated with profound intestinal ischemia.     

Effects of naloxone on stress-induced analgesia after hemorrhagic shock

BACKGROUND AND OBJECTIVES: To investigate whether endogenous opioids might be involved in the mechanisms that underlie hemorrhagic shock-induced analgesia, formalin tests were performed after hemorrhage and reinfusion in naloxone pretreated and untreated rats. METHODS: Twenty-four adult male Sprague-Dawley rats were divided into control (n = 6), saline (n = 6), naloxone 10 mg/kg (n = 6), and naloxone 100 mg/kg (n = 6) groups. The mean blood pressure (mBP) was kept at 50 to 60 mm Hg for 30 minutes by draining arterial blood in the saline group and the naloxone groups. After 15 minutes of returning mBP to normal levels by reinfusion of the drained shed blood, 10% formalin (3.7% formaldehyde solution, 0.1 mL) was injected into the left rear paw. Nociceptive behaviors were observed for 1 hour after the formalin injection. RESULTS: Nociceptive behaviors of the posthemorrhagic shock groups were significantly lower than those of the control group. No significant difference was seen in nociceptive behaviors among the saline and naloxone groups. CONCLUSION: Naloxone did not reverse the hemorrhagic shock-induced analgesia, which suggests that endogenous opioids might not be a major factor that governs stress-induced analgesia (SIA) after hemorrhagic shock.     

Contrasting actions of naloxone in experimental spinal cord trauma and cerebral ischemia: a review

Endorphins have been implicated in the pathophysiology of both spinal cord injury and cerebral ischemia. This review examines the nature of the experimental evidence to support this hypothesis. Present studies suggest that naloxone administration improves neurological function and outcome in the setting of the spinal cord trauma by centrally inhibiting an opiate receptor-mediated diminution of spinal cord flow. In the setting of spinal shock, naloxone administration is associated with improvement in vital sign and cardiovascular parameters as measured by mean arterial pressure, cardiac output, body temperature, and ventilation. Experiments using a variety of animal stroke models similarly support the notion that naloxone improves neurological function in the setting of cerebral ischemia by a stereospecific opiate receptor-mediated effect, but this improvement does not seem to be accompanied by augmentation of blood flow to affected areas of the brain or by any improvement in vital signs or cardiovascular parameters as seen in spinal cord trauma. A variety of mechanisms are discussed to explain these observations. The therapeutic implications of administering opiate agonists and antagonists in the setting of neurological deficits are outlined for the neurosurgeon.     

Pentoxifylline but not saralasin restores hepatic blood flow after resuscitation from hemorrhagic shock

After determining that hepatic blood flow remains impaired after resuscitation from hemorrhagic shock, we used the angiotensin II receptor antagonist saralasin and pentoxifylline to investigate their respective effects on hepatic blood flow responses after resuscitation from hemorrhagic shock. Rats were bled to 50% of baseline blood pressure for 60 min and resuscitated with shed blood and an equal volume of lactated Ringer's solution. Saralasin [10 micrograms/kg per min (n = 6)], pentoxifylline [25 mg/kg bolus and 12.5 mg/kg per hr (n = 7)], or saline (n = 11) were started with the onset of resuscitation. Total hepatic blood flow measured by ultrasonic transit time flow meter, effective nutrient hepatic blood flow measured by galactose clearance, mean arterial pressure, and cardiac output were recorded at 15-min intervals for 2 hr after resuscitation. Hemorrhage decreased cardiac output 57% below baseline and decreased total hepatic blood flow 64% below baseline. Resuscitation restored cardiac output to baseline levels in all three groups. Despite restoration of cardiac output, total hepatic and effective hepatic blood flow remained significantly below baseline in the saline control and saralasin groups but was restored to baseline levels in the pentoxifylline group. These data indicate that angiotensin II does not contribute significantly to the hepatic blood flow impairment after resuscitation from hemorrhagic shock. Improvement in flow with pentoxifylline implies that hemorrhage and resuscitation impair hepatic microvascular hemorrheology and that addition of pentoxifylline to standard resuscitation corrects the impairment.     

Ethanol impairs cardiocirculatory function in treated canine hemorrhagic shock

This study examined the hypothesis that ethanol-induced alterations in cardiac function and regional blood flow impair recovery from shock after resuscitation. Blood ethanol levels 45 minutes after ethanol (3 gm/kg) was administered intrajejunally were 276 +/- 30 mg/100 ml (N = 14 dogs). Twelve dogs received saline solution and served as control animals. Elevated blood ethanol levels increased the rate of left ventricular pressure rise (+763 +/- 80 mm Hg X sec) and coronary blood flow (+0.77 +/- 0.18 ml X min X gm), decreased respiration, and caused a significant metabolic acidosis (arterial pH, 7.25 +/- 0.02; arterial lactate, 1.5 +/- 0.07 mmol/L). Two hours of hemorrhagic shock impaired cardiovascular function and regional blood flow to a similar extent in all dogs. Volume replacement (shed blood and lactated Ringer's solution, 50 ml/kg) transiently improved cardiac performance in the ethanol group. Two hours after volume replacement, a lower cardiac output, stroke volume, stroke work, myocardial oxygen efficiency, and persistent acidosis occurred in the intoxicated dogs (p less than 0.05) despite adequate coronary perfusion. Myocardial sensitivity to acidosis after shock may account for the reduced cardiac function in the ethanol group. However, it is possible that shock aggravated ethanol-induced pancreatic ischemia and contributed to impaired cardiocirculatory function in postinfusion shock.     

Inhibition of CD18-dependent neutrophil adherence reduces organ injury after hemorrhagic shock in primates

Neutrophil adherence or aggregation may be important in the development of organ injury after hemorrhagic shock. Monoclonal antibody (MAb) 60.3 prevents both adherence and aggregation. Therefore we investigated MAb 60.3 treatment in prevention of organ injury after hemorrhagic shock in rhesus monkeys (Macaca mulatta). We performed esophagogastroscopy and placed catheters to measure cardiac output, mean arterial pressure, arterial blood gases, and urine output. Blood was removed to decrease CO to 30% of baseline for 90 minutes. Just before resuscitation, MAb 60.3 (2 mg/kg) or saline solution (control) was administered intravenously. Monitoring and fluid resuscitation continued for 24 hours, with lactated Ringer's solution given as a maintenance infusion (4 ml/kg/hr) plus additional lactated Ringer's solution to maintain CO at preshock levels. Esophagogastroscopy was repeated 24 hours after shock. There were two deaths in the control group at about 72 hours and none in the MAb 60.3 group. MAb 60.3-treated animals required less fluid (9.6 +/- 8.8 ml/kg vs 263.8 +/- 225.7 ml/kg), gained less weight (0.08 +/- 0.11 kg vs 0.70 +/- 0.37 kg), and maintained a higher hematocrit level (35.0% +/- 1.0% vs 26.9% +/- 4.9%). All five control animals had gastritis; MAb 60.3-treated animals had none (p less than 0.05; Fisher's exact test). Inhibition of neutrophil adherence or aggregation with MAb 60.3 at the time of resuscitation reduces fluid requirements and gastric injury in monkeys after hemorrhagic shock.     

Effect of superoxide dismutase on mitochondrial function in rats with hemorrhagic shock]

We observed the alterations in mitochondrial function and activity of endogenous SOD, and studied the protective effects of SOD on rats with hemorrhagic shock. It was found that after two hours' shock, RCR in hepatic and kidney mitochondria decreased significantly (liver P less than 0.01, kidney P less than 0.05), the activity of endogenous SOD depressed more or less in samples of blood and mitochondrial fraction (blood P less than 0.01. liver P less than 0.01. kidney P greater than 0.05). Further descent was found in these parameters in the deteriorating process of shock. After the rats were treated with SOD, RCR and activity of endogenous SOD increased considerably. Mere reflow did not affect them remarkably. This results suggest that oxygen-derived free radicals be the important factor impairing mitochondrial function in hemorrhagic shock, and that SOD can effectively ameliorate mitochondrial function.     

The effect of triiodothyronine (T3) and reverse triiodothyronine (rT3) on canine hemorrhagic shock

The euthyroid sick ("low T3") syndrome occurs in circulatory collapse and could influence survival. To evaluate the role of T3 and rT3 in shock, 36 mongrel dogs were subjected to hemorrhagic shock. In 13 dogs 15 micrograms/kg of T3 was given after 60 min of hypotension and 15 micrograms/kg of rT3 was administered IV 30 min before hemorrhage in 10 dogs. An equal volume of saline was injected in 13 dogs for control study. These dogs were bled rapidly into a reservoir to a mean arterial pressure (MAP) of 40 mmHg. After 60 min of hypotension the reservoir line was clamped for 30 min. The shed blood was then reinfused over 30 min. T3 administration caused significant increases during the clamped period in cardiac output, stroke volume, MAP, right and left ventricular stroke work and systemic vascular resistance, with a decrease in pulmonary vascular resistance (PVR). In the group receiving rT3 the only significant hemodynamic-metabolic differences were PVR and mean arterial pH. In the control group, 6 of 13 dogs died, whereas 9 of 10 dogs given rT3 died (p less than 0.03) and only one of 13 T3 dogs died (p less than 0.05). This study strongly suggests that T3 improves survival by acting on cardiovascular receptors or via the hypothalamic-pituitary-thyroid axis and that exogeneous rT3 is detrimental during the stress of shock and may play a biologically causative role in the sick euthyroid syndrome.     

Myocardial utilization of hypertonic glucose during hemorrhagic shock.

Awake pigs were rapidly bled 40% of total blood volume to induce hemorrhagic shock. Immediately after the induction of shock, all pigs received a single intravenous injection of radioactive-labeled glucose-U-14C. Simultaneously with glucose-U-14C injection, ten pigs received single central intravenous injections of unlabeled 50% glucose, four pigs received equiosmolar 25% mannitol, six did not receive either 50% glucose or mannitol, and two received 50% glucose plus insulin. Mean arterial pressure with 50% glucose was 89.9 mm. Hg at 15 minutes of shock and significantly higher than without 50% glucose, 48.3 mm. Hg or after mannitol, 46.7 mm. Hg (P = 0.05). Mean cardiac output at 10 minutes of shock with 50% glucose was 2.24 L. per minute and significantly higher than with mannitol, 1.34 L. per minute, or without 50% glucose, 0.94 L. per minute (P = 0.05.). Evidence for increased anaerobic myocardial utilization of the administered unlabeled 50% glucose was shown by a 12% greater production of unlabeled lactate in the venous coronary sinus blood from unlabeled 50% glucose in contrast to those not given 50% glucose at 10 minutes after shock (P = 0.05). Also, 50% glucose significantly increased mean arterial pressure, cardiac output, and survival over both control groups.     

A comparison of several hypertonic solutions for resuscitation of bled sheep

Small volumes (4 ml/kg) of 2400 mOsm NaCl restore cardiac output and mean arterial pressure to 80% of baseline after hemorrhage (65% of blood volume) in unanesthetized sheep. An equal volume of normal saline is less effective. To identify an optimal hypertonic solution, we screened six 2400 mOsm solutions in 18 randomized experiments in 8 sheep: NaCl, NaHCO3, NaCl/sodium acetate, NaCl/mannitol, NaCl/6% Dextran 70, and glucose. Cardiovascular function, as determined by cardiac output and mean arterial pressure, was restored best with NaCl, NaCl/NaAc, and NaCl/Dex. These three solutions were then evaluated using 18 sheep in 36 experiments. Following a 1-hr baseline period, the sheep were bled to a mean arterial pressure of 50 mm Hg for 2 hr. One of the solutions was then given in a volume of 4 ml/kg over 2 min and the sheep were monitored for 3 hr. Within 3 min of the infusion, cardiac output increased to greater than 100% of baseline for all three solutions. The NaCl-Dex solution sustained a significantly higher cardiac output over the 3-hr observation period than the other solutions. Plasma volume increased for all solutions following infusion. NaCl-Dex maintained plasma volume significantly better than the other solutions. As a further control, an isotonic solution of 6% Dextran 70 in normal saline was studied. It was not as effective as the hypertonic NaCl-Dex in maintaining cardiac output, mean arterial pressure, or plasma volume. Osmolality increased 10% (309 to 326 mOsm/kg H2O), plasma [NA] increased 7% (151 to 161 meq/liter), and plasma [K] decreased from 3.9 to 2.6 meq/liter following the hypertonic infusions. The sheep appeared to tolerate these electrolyte changes well. We conclude that a single bolus infusion of 2400 mOsm NaCl with 6% Dextran 70 best resuscitates sheep that have been subjected to a moderate degree of hemorrhagic shock compared to several other solutions. Its beneficial effects are caused in part by a sustained reestablishment of plasma volume. More studies are needed to document the safety of dextran in the clinical setting of hemorrhagic shock. Small volumes of hypertonic solutions may be valuable in the initial fluid resuscitation of patients in hemorrhagic shock.     

Influence of hemorrhage on propofol pseudo-steady state concentration

BACKGROUND: A small induction dose has been recommended in cases of hemorrhagic shock. However, the influence of hemorrhage on the amplitude of plasma propofol concentration has not yet been fully investigated during continuous propofol infusion. The authors hypothesized that the effect of hemorrhage on plasma propofol concentration is variously influenced by the different stages of shock. METHODS: After 120 min of steady state infusion of propofol at a rate of 2 mg x kg(-1) x h(-1), nine instrumented immature swine were studied using a stepwise increasing hemorrhagic model (200 ml of blood every 30 min until 1 h, then additional stepwise bleeding of 100 ml every 30 min thereafter, to the point of circulatory collapse). Hemodynamic parameters and plasma propofol concentration were recorded at every step. RESULTS: Before total circulatory collapse, it was possible to drain 976 +/- 166 ml (mean +/- SD) of blood. Hemorrhage of less than 600 ml (19 ml/kg) was not accompanied by a significant change in plasma propofol concentration. At individual peak systemic vascular resistance, when cardiac output and mean arterial pressure decreased by 31% and 14%, respectively, plasma propofol concentration increased by 19% of its prehemorrhagic value. At maximum heart rate, when cardiac output and mean arterial pressure decreased by 46% and 28%, respectively, plasma propofol concentration increased by 38%. In uncompensated shock, it increased to 3.75 times its prehemorrhagic value. CONCLUSIONS: During continuous propofol infusion, plasma propofol concentration increased by less than 20% during compensated shock. However, it increased 3.75 times its prehemorrhagic concentration during uncompensated shock.