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.     

Pentoxifylline preserves small-intestine microvascular blood flow during bacteremia.

BACKGROUND. Intestinal mucosal ischemia with subsequent mucosal dysfunction has been implicated in the pathogenesis of ongoing sepsis and multiple systems organ failure. We have previously reported vasoconstriction and hypoperfusion in the intestinal microcirculation during sepsis. Efforts to improve microcirculatory blood flow during sepsis may lead to more effective treatment or prevention of multiple systems organ failure. Pentoxifylline improves survival and visceral organ perfusion in experimental sepsis and hemorrhage. The purpose of this study was to determine whether pentoxifylline would improve microvascular blood flow in the small intestine during bacteremia. METHODS. In vivo videomicroscopy was used to quantitate alterations of the small-intestine microcirculation during Escherichia coli bacteremia in rats pretreated with either intravenous pentoxifylline or saline solution. Systemic hemodynamic and microvascular variables were measured every 15 minutes for 2 hours. RESULTS. Tachycardia and increased cardiac output developed in bacteremic rats while they remained normotensive. Intestinal vasoconstriction and hypoperfusion occurred in bacteremic rats treated with saline solution. Microvessel diameters and blood flow remained within 5% to 10% of baseline in bacteremic rats pretreated with pentoxifylline. Pentoxifylline in nonbacteremic rats resulted in intestinal vasodilation and increased blood flow. CONCLUSIONS. Pentoxifylline prevented small-intestine vasoconstriction and preserved microvascular blood flow during hyperdynamic sepsis. Pentoxifylline in nonbacteremic rats increased 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.     

Pentoxifylline improves tissue oxygenation after hemorrhagic shock

This randomized and blinded study was performed to determine whether pentoxifylline significantly improves tissue oxygenation after hemorrhagic shock. Hepatic surface oxygen tension was measured in anesthetized rats before and after hemorrhage. Rats were then randomly assigned to either a placebo group (n = 21) receiving 1 ml of intravenous saline solution or to a treatment group (n = 23) receiving intravenous 25 mg/kg of pentoxifylline in 1 ml of saline solution. Investigators were blinded as to which solution was injected. Five minutes after injection of pentoxifylline, there was significant increase in hepatic surface oxygen tension; this increase persisted throughout 1 hour of observation and was significantly greater than in placebo-treated animals. Further study of the effects of pentoxifylline on tissue perfusion and oxygenation after hemorrhagic shock is warranted.     

Whole body hyperthermia preserves endothelial function and restores mesenteric blood flow after resuscitated hemorrhage

Endothelial dysfunction has been implicated in regional blood flow deficits after resuscitated shock. Whole body hyperthermia generates heat shock proteins (HSP) that attenuate protein denaturation and preserve cellular function. This study was performed to determine the effect of whole body hyperthermia on endothelial function and mesenteric blood flow after resuscitated hemorrhage. Sprague Dawley rats were hemorrhaged to 30% of blood volume and resuscitated with shed blood and an equal of volume of Ringer’s Lactate (Standard Resuscitation, SR). Intravital microscopy was used to determine first order arteriolar (A1) diameters and blood flow (QA1) in the neurovascularly intact ileum at baseline and 90 minutes post resuscitation (T90). Animals treated with SR and whole body hyperthermia (SR-H) were placed into a ventilated heating chamber following hemorrhage and resuscitation to achieve a temperature of 39.5-40°C for 6 hours. Identical microvascular studies were performed 18 hours later. Endothelial function was quantitated by measuring changes in vessel diameter to topical application of the endothelial dependent dilator acetylcholine (Ach, 10⁻⁵ M). A1 diameter is reported in microns and QA1 as nanoliters per second (+/− SEM). Tissue was taken from the ileum for HSP72 determination via Western analysis. This study demonstrated that whole body hyperthermia applied after resuscitated hemorrhage results in an upregulation of HSP expression that is associated with preserved endothelial function and restoration of mesenteric blood flow. These results suggest that whole body hyperthermia may serve as an adjunct to standard resuscitation in restoring blood flow and attenuating subsequent organ dysfunction.

TABLE—ABSTRACT 19.

		Ach	QA1	HSP72
Baseline	SR	85 ± 5	161 ± 15	.124 ± .1
	SR-H	90 ± 5	226 ± 17	.124 ± .1
T90	SR	48 ± 8	31 ± 7	.241 ± .1
	SR-H	88 ± 5∗	157 ± 20∗	.924 ± .2∗

∗

P = <0.05 vs. T90 SR for ACH, QA1 and HSP72 by Student’s t test.

Full-size table

     

Absorptive hyperemia restores intestinal blood flow during Escherichia coli sepsis in the rat

Enteral nutritional support has been found to result in better maintenance of mucosal integrity during stress than parenterally administered nutritional support. In our experiments, we employed in vivo microvascular techniques to examine the effect of mucosally applied glucose on intestinal microvascular blood flow during hyperdynamic live Escherichia coli bacteremia in the rat. We observed a significant decrease in intestinal microvascular blood flow during bacteremia when the mucosa was suffused with a nonglucose solution. Blood flow was rapidly restored to above-baseline values after glucose was added. The restoration of blood flow resulted from dilation of arterioles at all branch orders and was associated with dilation of premucosal arterioles to above-baseline diameters. Our results show that glucose-induced absorptive hyperemia restores intestinal blood flow during live E coli bacteremia. Restoration of intestinal microvascular blood flow may be a contributing factor to the improved maintenance of mucosal integrity associated with enteral feeding.     

Interferon-gamma restores immune competence after hemorrhagic shock

Hemorrhagic shock increases the susceptibility to infection in both clinical and laboratory settings. Hemorrhagic shock also is associated with a decreased production of interferon-gamma (IFN-gamma), a potent modulator of immune function. We investigated the effect of IFN-gamma both alone and in addition to antibiotic prophylaxis upon infection following hemorrhagic shock. Sprague-Dawley rats were bled to a mean arterial pressure of 45 mm Hg for 45 min and then were resuscitated with shed blood and normal saline. Abscess formation was induced 1 hr later by subcutaneous injection of 1 X 10(8) Staphylococcus aureus. Four treatments were investigated: (1) control; (2) recombinant rat IFN-gamma, 7500 units, 30 min after inoculation and daily for 3 days; (3) cefamandole (CEF) nafate, 30 mg/kg, 30 min before and 4 hr after inoculation; and (4) IFN-gamma + CEF as in (2) and (3). Abscess size, weight, and quantitative bacterial counts were measured 7 days after inoculation. Hemorrhagic shock increased mean abscess size from 11.7 +/- 2.8 to 14.1 +/- 1.9 mm (P less than 0.05), in untreated rats. IFN-gamma alone resulted in minor changes in abscess formation in both shocked and unshocked animals. Shock rendered CEF ineffective in reducing abscess size. IFN-gamma + CEF significantly reduced abscess size (14.1 +/- 1.9 to 8.1 +/- 1.8 mm) and weight (771 +/- 214 to 252 +/- 132 mg) and decreased bacterial count after shock to 12% of control (all P less than 0.05). These data demonstrate that hemorrhagic shock impairs antibiotic efficacy; however, the addition of IFN-gamma restores the ability of host defenses to combat bacterial infection.     

Diltiazem administration after crystalloid resuscitation restores active hepatocellular function and hepatic blood flow after severe hemorrhagic shock.

Studies have shown that active hepatocellular function is depressed after hemorrhagic shock, despite crystalloid resuscitation. It is also known that calcium antagonists produce various beneficial effects on cell and organ function after ischemia and shock. However, it remains unknown whether such agents have any salutary effects on the depressed active hepatocellular function and hepatic blood flow in a nonheparinized model of trauma and hemorrhage. To study this, rats underwent a midline laparotomy (trauma-induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum bleedout was returned in the form of Ringer's lactate. They were then resuscitated with four times the volume of shed blood with Ringer's lactate over 60 minutes, during and after which diltiazem (400 micrograms/kg body weight) was infused intravenously over 95 minutes. Active hepatocellular function (Vmax and Km) was determined with an in vivo indocyanine green clearance technique. Effective hepatic blood flow (EHBF) was determined by Fick principle and corrected by the indocyanine green extraction ratio. Hepatic microvascular blood flow (HMBF) was measured by laser Doppler flowmetry. Results indicate that Vmax, Km, EHBF, and HMBF decreased significantly at 1.5 and 4 hours after resuscitation. Diltiazem infusion restored the depressed Vmax, Km, EHBF, and HMBF and prevented the occurrence of hepatic edema. Thus, diltiazem may be a useful adjunct in the treatment of trauma and severe hemorrhage even in the absence of blood resuscitation.     

Delayed-onset pulmonary insufficiency in primates resuscitated from hemorrhagic shock.

Forty-one unanesthetized cynomolgus monkeys were subjected to 2 hours of hemorrhagic hypotension at various mean arterial pressures (MAP) between 40 and 60 mm Hg. Resuscitation and maintenance of MAP were provided by lactated Ringer's solution and homologous blood. Thirty-eight per cent (57% of those surviving greater than 24 hours) developed a delayed-onset (18 to 24 hours) pulmonary insufficiency in spite of good urinary output, and which did not respond to furosemide. The group in which this caused death (24%) showed significantly decreased PaO2, PaCO2, dynamic compliance, and FECO2, and increased minute volume, Qs/Qt, pulmonary artery pressure, and VD/VT before death. Their lungs were heavier, with abnormal pressure/volume curves and increased minimum surface tension. During the entire post-resuscitation phase, this group remained in a high-output, low-resistance hemodynamic state in contract to survivors and those dying of shock. The implications regarding current practices of monitoring and resuscitating patients with traumatic shock are discussed.     

Sequential changes in cerebral blood flow and distribution of flow within the brain during hemorrhagic shock.

Sequential changes in cerebral blood flow as well as in regional blood flow to the brain (brain stem, cerebellum, hypothalamus, white matter and grey matter) were measured in unanesthetized dogs subjected to gradual prolonged hemorrhage according to a protocol which stimulates the most commonly encountered type of clinical hemorrhagic shock. Microspheres labeled with five different radioactive isotopes were injected into a left atrial catheter at five different times: control, early hypotension (immediately after hemorrhage), late hypotension (just before reinfusion of the shed blood), as well as one and eight hours after reinfusion of the shed blood. Immediately after hemorrhage, the total cerebral blood flow decreased slightly, but increased when calculated as a percent of the cardiac output. In the late hypotensive, hypovolemic stage, there was decreased flow calculated both as percentages of cardiac output and absolute flow as compared with the initial response to hemorrhage. Immediately after reinfusion of the shed blood, there were further reductions of flow. Eight hours subsequently, flow rose to values slightly above control. The patterns of each region was almost identical to that of the total cerebral flow. Since each of the major regions of the brain are approximately equally affected, changes in the level of consciousness and other cerebral functions occurring with hypovolemic shock may reflect circulation of the white matter as well as that of the whole brain.     

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.     

Sepsis, resuscitated hemorrhagic shock and "shock lung:" An experimental correlation.

Dogs were submitted to hermorrhagic shock, resuscitated shock and resuscitated shock plus a pulmonary bacterial insult. Pulmonary familure was absent in dogs submitted only to shock or to shock and its resuscitation. The addition of usually sub-lethal amounts of micro-organisms to the shock-resuscitated lung caused rapid death from pulmonary failure. Pulmonary failure was demonstrated by increased lung weight, hypoxemia, decreased compliance and a hemorrhagic destruction of lung tissue. These findings strongly support recent concepts of an infective genesis of "shock lung" in man.