Adequate crystalloid resuscitation restores but fails to maintain the active hepatocellular function following hemorrhagic shock

Studies have shown that active hepatocellular function is depressed early after trauma-hemorrhage and persists despite resuscitation with two or three times (x) the volume of maximum bleedout (MB) with lactated Ringer's solution (LR). However, it is not known if a larger volume of fluid resuscitation corrects this dysfunction. To study this, rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the MB volume was returned in the form of LR, and then resuscitated with 4x or 5x the volume of MB with LR. Three doses of indocyanine green (ICG) were given intravenously and [ICG] measured in vivo using an in-vivo hemoreflectometer. The initial velocity of the clearance of ICG was calculated. Maximal velocity of the clearance (Vmax: the number of functional ICG receptors) and kinetic constant (Km: the efficiency of the active transport) were determined from the Lineweaver-Burk plot. Vmax decreased during hemorrhage, was restored to control levels at 0-4 hours after resuscitation, but decreased at 4-8 hours after resuscitation despite restoration of cardiac output following resuscitation with 5x LR. This could be the result of increased TNF release. The Km also decreased during hemorrhage, but increased at 0-1.5 hours and remained at control levels even 4-8 hours after resuscitation. Thus the failure of Vmax to remain at control levels following adequate fluid resuscitation may form the basis of cellular dysfunction and multiple organ failure after severe hemorrhagic shock.     

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.     

Cardiac function during hemorrhagic shock and crystalloid resuscitation

It is concluded that (1) myocardial failure develops during hypovolemic shock; (2) inadequate coronary perfusion contributes to the decrease in myocardial function; (3) inadequate resuscitation prolongs myocardial dysfunction and decreased coronary blood flow and may lead to terminal arrhythmias; (4) crystalloid resuscitation relieves heart failure and corrects myocardial ischemia; and (5) no evidence exists for cardiac overload with use of large volumes of crystalloid.     

ATP-MgCl2 restores the depressed hepatocellular function and hepatic blood flow following hemorrhage and resuscitation

Although ATP-MgCl2 produces a myriad of beneficial effects following organ ischemia and simple hemorrhagic shock in animal models which involved heparinization and/or blood resuscitation, it is not known whether ATP-MgCl2 has any salutary effect on the depressed active hepatocellular function (AHF) and hepatic microvascular blood flow (HMBF) in a nonheparinized model of trauma and severe hemorrhage in the absence of blood resuscitation. To determine this, rats underwent a midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum shed blood volume was returned in the form of Ringer's lactate (RL). The animals were then resuscitated with four times the volume of shed blood with RL. ATP-MgCl2, 50 mumoles/kg body weight (BW) each or an equivalent volume of normal saline, was infused intravenously for 95 min during and following crystalloid resuscitation. At 1.5 and 4 hr after resuscitation, AHF (Vmax, maximal velocity of indocyanine green clearance; Km, efficiency of the active transport process) was determined without blood sampling by using an in vivo indocyanine green clearance technique. HMBF was measured with laser Doppler flowmetry. Results indicate that Vmax, Km, and HMBF decreased significantly at 1.5-4 hr after hemorrhage and resuscitation. ATP-MgCl2 infusion restored the depressed Vmax, Km, and HMBF and prevented the occurrence of hepatic edema. The restoration of AHF with ATP-MgCl2 treatment may be due to its direct salutary effect on the active indocyanine green transport process and/or due to improvement in hepatic microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pentoxifylline restores intestinal microvascular blood flow during resuscitated hemorrhagic shock

We studied the intestinal microvascular blood flow responses to hemorrhage and resuscitation with pentoxifylline by in vivo video microscopy. Male Sprague-Dawley rats were hemorrhaged to 50% of baseline mean arterial pressure for 45 minutes and then blindly randomized to receive pentoxifylline (25 mg/kg bolus + 0.2 mg/kg/minute) or an equivalent volume of saline plus return of shed blood and an additional bled volume of Ringer's lactate solution. Hemorrhage caused intestinal microvascular blood flow to decrease to 10% to 15% of baseline values. In the control group, resuscitation restored cardiac output and mean arterial pressure to baseline values, but intestinal microvascular blood flow remained at 30% of baseline values. In contrast, addition of pentoxifylline to the resuscitation regimen resulted in an immediate hyperemic response with an increase in intestinal microvascular blood flow to significantly greater than baseline values followed by return to baseline. Arteriolar dilation was not responsible for the improvement in flow implicating improved flow dynamics between erythrocytes, granulocytes, and vascular endothelia within the microcirculation. We conclude that addition of pentoxifylline to resuscitation from hemorrhagic shock restores intestinal microvascular blood flow.     

Intraperitoneal resuscitation improves intestinal blood flow following hemorrhagic shock

OBJECTIVE: To study the effects of peritoneal resuscitation from hemorrhagic shock. SUMMARY BACKGROUND DATA: Methods for conventional resuscitation (CR) from hemorrhagic shock (HS) often fail to restore adequate intestinal blood flow, and intestinal ischemia has been implicated in the activation of the inflammatory response. There is clinical evidence that intestinal hypoperfusion is a major factor in progressive organ failure following HS. This study presents a novel technique of peritoneal resuscitation (PR) that improves visceral perfusion. METHODS: Male Sprague-Dawley rats were bled to 50% of baseline mean arterial pressure (MAP) and resuscitated with shed blood plus 2 equal volumes of saline (CR). Groups were 1) sham, 2) HS + CR, and 3) HS + CR + PR with a hyperosmolar dextrose-based solution (Delflex 2.5%). Groups 1 and 2 had normal saline PR. In vivo videomicroscopy and Doppler velocimetry were used to assess terminal ileal microvascular blood flow. Endothelial cell function was assessed by the endothelium-dependent vasodilator acetylcholine. RESULTS: Despite restored heart rate and MAP to baseline values, CR animals developed a progressive intestinal vasoconstriction and tissue hypoperfusion compared to baseline flow. PR induced an immediate and sustained vasodilation compared to baseline and a marked increase in average intestinal blood flow during the entire 2-hour post-resuscitation period. Endothelial-dependent dilator function was preserved with PR. CONCLUSIONS: Despite the restoration of MAP with blood and saline infusions, progressive vasoconstriction and compromised intestinal blood flow occurs following HS/CR. Hyperosmolar PR during CR maintains intestinal blood flow and endothelial function. This is thought to be a direct effect of hyperosmolar solutions on the visceral microvessels. The addition of PR to a CR protocol prevents the splanchnic ischemia that initiates systemic inflammation.     

Neutrophil regulation of splanchnic blood flow after hemorrhagic shock.

OBJECTIVE: This study examines the hypothesis that neutrophils impair splanchnic blood flow during resuscitation from hemorrhage by inhibiting the release of the compensatory vasodilator PGI2 from the bowel. SUMMARY BACKGROUND DATA: Resuscitation from hemorrhagic shock is associated with neutrophil infiltration into the intestine, reduced splanchnic perfusion, and reduced release of PGI2 from the intestine. METHODS: Sprague-Dawley rats received either vinblastine (VIN) to deplete circulating neutrophils or normal saline (NS). These animals then underwent either hemorrhage and resuscitation (SK + R) or sham operation (SHAM). Superior mesenteric artery flow and splanchnic 6-keto PGF1a (metabolite of PGI2) release were measured. RESULTS: Superior mesenteric artery blood flow was significantly greater in VIN-treated animals sustaining SK + R than in those treated with NS (p < 0.05). Neutrophil depletion preserved 6-keto PGF1a release after SK + R, whereas 6-keto PGF1a release in the NS-treated, SK + R group was significantly reduced (p < 0.05). CONCLUSION: These data are compatible with the hypothesis that neutrophils may influence splanchnic perfusion after SK + R by inhibiting splanchnic PGI2 release.     

Trans-sodium crocetinate restores blood pressure, heart rate, and plasma lactate after hemorrhagic shock.

BACKGROUND: Trans-sodium crocetinate (TSC) has been shown to increase oxygen consumption during hemorrhagic shock. The current study was done to determine the effect of TSC on other parameters such as blood pressure, heart rate, blood pH, and lactate. METHODS: A rat model of hemorrhagic shock was used, in which a constant volume of blood is removed. RESULTS: TSC increased mean arterial blood pressure from a value (immediately after hemorrhage) of 35 mm Hg to a value of 75 mm Hg, and all treated animals survived. In contrast, blood pressure in control animals decreased, with most dying soon after the hemorrhage. TSC also lessened the tachycardia which resulted from the hemorrhage. Blood pH did not decrease as much when TSC was given, and plasma lactate levels were greatly reduced. CONCLUSION: It would appear that TSC is a promising initial treatment for hemorrhagic shock.     

Hypertonic/hyperoncotic fluid resuscitation after hemorrhagic shock in dogs.

We compared canine systemic and cerebral hemodynamics after resuscitation from hemorrhagic shock with 4 mL/kg (a volume approximating 12% of shed blood volume) of 7.2% saline (HS; 1233 mEq/L sodium), 20% hydroxyethyl starch (HES) in 0.8% saline, or a combination fluid consisting of 20% hydroxyethyl starch in 7.2% saline (HS/HES). Eighteen endotracheally intubated mongrel dogs (18-24 kg) were ventilated to maintain normocarbia with 0.5% halothane in nitrous oxide and oxygen (60:40). After a 30-min period of hemorrhagic shock (mean arterial blood pressure = 40 mm Hg), extending from time T0 to T30, animals received one of three randomly assigned intravenous resuscitation fluids: HS, HES, or HS/HES. Data were collected at baseline, at the beginning and end of the shock period (T0 and T30), immediately after fluid infusion (T35), and at 60-min intervals for 2 h (T95, T155). After resuscitation, mean arterial blood pressure and cardiac output increased similarly in all groups, but failed to return to baseline. Intracranial pressure decreased during shock and increased slightly, immediately after resuscitation in all groups. During shock, cerebral blood flow (cerebral venous outflow method) declined in all groups. After resuscitation, cerebral blood flow increased, exceeding baseline in the HS and HS/HES groups but remaining low in the HES group (P less than 0.05 HS vs HES at T35). We conclude that small-volume resuscitation (4 mL/kg) with HS, HS/HES, or HES does not effectively restore or sustain systemic hemodynamics in hemorrhaged dogs. In dogs without intracranial pathology, the effects on cerebral hemodynamics are also comparable, except for transiently greater cerebral blood flow in the HS group in comparison with the HES group.     

Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: a pharmacokinetic and pharmacodynamic analysis

BACKGROUND: Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol. METHODS: After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 microg x kg(-1) x min(-1)) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. RESULTS: The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. CONCLUSIONS: Hemorrhagic shock followed by resuscitation with lactated Ringer's solution did not alter the pharmacokinetics but did increase the potency of propofol. These results demonstrate that alterations in propofol pharmacokinetics observed in moderate to severe blood loss can be reversed with resuscitation. These results suggest that a modest reduction in propofol is prudent to achieve a desired drug effect after resuscitation from severe hemorrhagic shock.     

Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass.

After severe hemorrhage, hypertonic saline restores systemic hemodynamics and decreases intracranial pressure (ICP), but its effects on regional cerebral blood flow (rCBF) when used for resuscitation of experimental animals with combined shock and intracranial hypertension have not been reported. We compared rCBF changes (by radiolabeled microsphere technique) after resuscitation from hemorrhage with either 0.8 or 7.2% saline in animals with and without a right hemispheric subdural mass. We studied 24 mongrel dogs anesthetized with 0.5% halothane and 60% nitrous oxide. In group 1 (n = 12), hemorrhage reduced mean arterial pressure (MAP) to 45 mmHg for 30 min. In group 2 (n = 12), ICP was increased and maintained constant at 15 mmHg, whereas hemorrhage reduced MAP to 55 mmHg for 30 min (cerebral perfusion pressure [CPP] approximately 40 mmHg in each group). After the 30-min shock period, 6 animals in each group received one of two randomly assigned resuscitation fluids over a 5-min interval: 1) 7.2% hypertonic saline (HS; sodium 1,232 mEq.l-1, volume 6.0 ml.kg-1); or 2) 0.8% isotonic saline (SAL; sodium 137 mEq.l-1, volume 54 ml.kg-1). Once fluid resuscitation began, ICP was permitted to vary independently in both groups. Data were collected at baseline (before subdural balloon inflation in group 2), midway through the shock interval (T15), immediately after fluid infusion (T35), and 60 and 90 min later (T95, T155). In groups 1 and 2, ICP was significantly less in animals resuscitated with HS compared to those receiving SAL (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of whole blood, crystalloid, and colloid resuscitation of hemorrhagic shock on renal damage in rats: an ultrastructural study

Purpose:

The aim of this study was to determine the effects of whole blood, crystalloid, and colloid treatment on histopathologic damage of kidney induced by hemorrhagic shock in rats.

Methods:

Fifty-six male Sprague Dawley rats were divided into 8 groups. The carotid artery was cannulated, and systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR), and rectal temperature (RT) were observed during the procedure. The jugular vein also was cannulated, and the SAP was decreased by aspiration of 75% of blood through the jugular vein in the control (nonresuscitated) and study (resuscitated) groups, whereas blood was not diminished in the sham group. The hemorrhagic shock was permitted to last 45 minutes; then, the study group rats were resuscitated with heparinized shed autologous whole blood (WB), normal saline (NS), Lactated Ringer’s solution (LR), hydroxyethyl starch 6% (HES6), hydroxyethyl starch 10% (HES10), or dextran 40 (D40). Histopathologic evaluation was performed under light and electron microscope.

Results:

The RT, SAP, and DAP decreased, and HR increased significantly in the control and study groups during the shock period compared with those of sham group. After volume resuscitation, these parameters changed to preshock levels. Electron and light microscopic examinations of kidneys showed severe proximal tubular degeneration with moderate glomerular damage in the control group; moderate proximal tubular degeneration with mild glomerular damage in the NS, LR, HES6, and HES10 groups; and mild proximal tubular degeneration with no evidence of glomerular damage in the WB and D-40 groups.

Conclusions:

The characteristic ultrastructural features of hemorrhagic shock appear to be severe tubular degeneration and mild to moderate changes in glomeruli. Resuscitation of hemorrhagic shock with whole blood or dextran 40 solution appears to be most favorable therapy in preventing ultrastructural renal damage in rats.     

Diaspirin cross-linked hemoglobin fails to improve left ventricular diastolic function after fluid resuscitation from hemorrhagic shock.

In severe hemorrhagic shock, left ventricular (LV) diastolic dysfunction is an early sign of cardiac failure due to compromised myocardial oxygenation. Immediate fluid replacement or, in particular, administration of a hemoglobin-based oxygen carrier (diaspirin cross-linked hemoglobin; DCLHb) improves myocardial oxygenation; therefore, positive effects on LV diastolic function could be expected. The effects of fluid resuscitation from severe hemorrhagic shock with DCLHb were investigated in 20 anesthetized domestic pigs. After generation of a critical left anterior descending coronary artery stenosis (narrowing of the artery until disappearance of reactive hyperemia after a 10-second complete vessel occlusion), hemorrhagic shock (mean arterial blood pressure 45 mm Hg) was induced within 15 min by controlled blood withdrawal and maintained for 60 min. Fluid resuscitation consisted of replacement of the plasma volume withdrawn during hemorrhage by infusion of either 10% DCLHb (DCLHb group, n = 10) or 8% human serum albumin (HSA) oncotically matched to DCLHb (HSA group, n = 10). After completion of resuscitation, an observation period of 60 min elapsed. Measurements of central hemodynamics, myocardial oxygenation, and LV diastolic function were performed at baseline, after induction of critical coronary artery stenosis, after 60 min of hemorrhagic shock, immediately after resuscitation, and 60 min later. While 5 out of 10 animals treated with HSA died within the first 20 min after fluid resuscitation from acute LV pump failure, all DCLHb-treated animals survived until the end of the protocol (p < 0.05). Despite superior myocardial oxygenation due to augmentation of the arterial O(2) content as well as of coronary perfusion pressure, no beneficial effects on LV diastolic function were observed after infusion of DCLHb. Peak velocity of LV pressure decrease (dp/dt(min)) did not reveal significant differences between the two groups. Immediately after completion of fluid resuscitation with DCLHb, the time constant of LV diastolic relaxation (tau) was prolonged when compared with HSA-treated animals (p < 0.05), indicating retardation of early LV diastolic relaxation. Our data suggest that DCLHb fails to improve LV diastolic function after fluid resuscitation from severe hemorrhagic shock. However, positive effects on myocardial perfusion and oxygenation result in a significant reduction of the mortality of severe hemorrhagic shock.     

Crystalloid is as effective as blood in the resuscitation of hemorrhagic shock.

Recently there has been increasing concern over transfusion-related diseases, especially acquired immune deficiency syndrome (AIDS). The authors therefore investigated the efficacy of lactated Ringer's solution (LRS) alone as compared with blood plus LRS resuscitation on body weight change and mortality rate after severe trauma-hemorrhagic shock. Rats, 250 to 310 g (n = 85), had a midline laparotomy performed (i.e., trauma induced), the incision was closed, and a carotid artery, jugular vein, and femoral artery were cannulated. The unrestrained, nonheparinized rats were allowed to recover from anesthesia and were bled within 10 minutes to a mean arterial pressure (MAP) of 40 mmHg. This MAP was maintained by removing more blood until the animal was unable to compensate (maximal bleedout; MB). The MAP was further maintained at 40 mmHg by returning fluid (LRS) until 50% of the MB volume (MBV) was returned. The rats were then resuscitated: group 1 with LRS 4 times the MBV; group 2 with 5 x LRS; group 3 with the shed blood returned + 2 x LRS. There was no difference between the groups in the initial weights, MAP, or hematocrit (Hct), percentage of blood volume removed, time to MB, or time to end of hemorrhage. The final Hct and MAP were higher in group 3 (p less than 10(-6)) than in either of the other groups. Body weight gain was greater in group 2 compared with either of the other groups (p less than 0.05) on day 1 after hemorrhage because of edema, but no differences were seen on subsequent days. There were no differences in the survival of animals in the different groups. These results suggest that there should perhaps be a higher threshold for blood transfusion in the management of severe trauma-hemorrhagic shock than is currently practiced.