Biomedical subjects

Z F Ba

Publications and source records attributed to Z F Ba.

At least 55 records · Page 3Linked to original sources

PubMed1994

Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation.

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.

Acetylcholine↗

PubMed1994

Measurement of circulating blood volume in vivo after trauma-hemorrhage and hemodilution.

Although cardiac output (CO) and other hemodynamic variables are used to assess the adequacy of fluid resuscitation after hemorrhage, it is not known whether there is any correlation between restoration of CO and circulating blood volume (CBV). 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 mmHg until 40% of maximum bleedout volume was returned in the form of Ringer lactate (RL). The animals were then resuscitated with four or five times the volume of maximum bleedout in the form of RL. CO and hepatocellular function were measured using an in vivo hemoreflectometer. CBV was monitored by using in vivo indocyanine green clearance. A good correlation between the values of blood volume obtained by this method and the 125I-albumin method indicates that the indocyanine green method is also a reliable technique for measuring CBV. Results indicate that resuscitation after hemorrhage improved the decreased CBV but did not restore it to control levels despite the fact that CO was restored and central venous pressure was more than doubled. A good correlation between depressed CBV and hepatocellular dysfunction was also observed under such conditions. Thus measurement of CBV appears to be useful for evaluating the adequacy of fluid resuscitation after trauma-hemorrhage and hemodilution.

Animals↗

PubMed1993

Endothelial cell dysfunction occurs after hemorrhage in nonheparinized but not in preheparinized models.

Although hemorrhage produces alterations in hemodynamics and cellular functions, it is not known whether endothelial cell function is depressed under such conditions and, if so, whether preheparinization has any protective effect on this function. To study this, rats (with or without heparinization prior to hemorrhage, 1 U/g body wt) were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximal bleedout volume was returned in the form of lactated Ringer's solution (LR). The rats were then resuscitated with four times the volume of maximal bleedout in the form of LR. At 1.5 hr postresuscitation, the thoracic aorta was removed, cut into approximately 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, were determined. Hypoxia-induced contraction (an endothelium-dependent process) was also carried out using 95% N2:5% CO2. The results indicate that endothelium-dependent relaxation and contraction were markedly depressed following hemorrhage and resuscitation in nonheparinized, but not in preheparinized models. However, there was no significant difference in the relaxation induced by an endothelium-independent vasodilator, nitroglycerin, irrespective of heparinization. Thus, endothelial cell dysfunction (i.e., the depressed capacity of aortic endothelium to maximally release endothelium-derived relaxing and contracting factors) occurs after hemorrhage in nonheparinized, but not in preheparinized animals. Since trauma victims are not heparinized before the injury and since preheparinization protects endothelial cell function, pharmacologic agents to restore the depressed cellular function should be tested only in nonheparinized models of hemorrhage and resuscitation.

Acetylcholine↗

PubMed1993

Tumor necrosis factor-alpha produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation.

Although plasma levels of tumor necrosis factor (TNF) are elevated and hepatocellular dysfunction occurs even in the early hyperdynamic stage of sepsis, the precise mechanism responsible for this dysfunction remains unknown. Although TNF at high doses produces circulatory failure, it is not known whether the dose of TNF that does not adversely affect hemodynamics alters hepatocellular function. To study this, recombinant murine TNF-alpha was infused intravenously (0.05 or 0.25 mg/kg) over 30 min in normal rats. At 1 and 4 h after infusion of TNF-alpha or an equivalent volume of saline, hepatocellular function [i.e., maximum velocity (Vmax) and Michaelis constant (Km)] was assessed using in vivo indocyanine green clearance without blood sampling. Additional parameters measured were as follows: cardiac output by dye dilution, hepatic microcirculation by laser Doppler flowmetry and colloidal carbon infusion, plasma TNF and interleukin-6 (IL-6) by cytokine-dependent cellular assays, and plasma glucose enzymatically. The results indicate that although infusion of 0.05 mg/kg TNF-alpha did not affect Vmax and Km, its infusion at 0.25 mg/kg produced a significant depression of hepatocellular function and markedly increased the synthesis and/or release of IL-6. TNF-alpha-induced hepatocellular dysfunction was not associated with any significant changes in hepatic microcirculation, plasma glucose, cardiac output, and other measured hemodynamic parameters. Thus hepatocellular dysfunction observed after TNF infusion may be due to the direct effect of this cytokine alone or in combination with IL-6.

Alanine Transaminase↗

PubMed1993

Trauma-hemorrhage and resuscitation in the mouse: effects on cardiac output and organ blood flow.

Although mice are widely used for the study of immune consequences of hemorrhage, the changes of cardiac output (CO) and blood flow (BF) in response to trauma and hemorrhage in this species have not been well defined. To study this, nonheparinized C3H/HeN mice (n = 6 per group) underwent laparotomy (i.e., trauma induced), were bled to a mean arterial pressure of 35 mmHg, and maintained for 90 min by withdrawing more blood or returning Ringer lactate. The animals were then resuscitated with four times the volume of maximal bleedout in the form of Ringer lactate over 60 min. Sham-operated mice underwent the same procedure but were neither bled nor resuscitated. At the end of hemorrhage, 60 min postresuscitation, or corresponding time after sham operation, CO and BF were determined by radioactive microspheres. Results indicate that CO and BF decreased significantly at the end of hemorrhage. Resuscitation, however, restored CO and BF in various organs except the brain and skeletal muscle. Despite this, 9 of 16 mice died within 6 days postresuscitation, whereas none of sham mice died (n = 16 per group in this additional study). Therefore, we have developed a nonheparinized model of trauma-hemorrhage and resuscitation in mice that is associated with late mortality. Furthermore, the microsphere technique provides a reliable method for assessing CO and BF in mice. Thus it may be possible to study the correlation between cardiovascular and immunologic alterations under such conditions.

Animals↗

PubMed1993

Endothelial cell dysfunction occurs very early following trauma-hemorrhage and persists despite fluid resuscitation.

Although hemorrhage produces alterations in hemodynamics and cellular functions, it remains unknown if endothelial cell function is depressed in a nonheparinized model of trauma-hemorrhage and resuscitation. To study this, rats underwent a 5-cm midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleed-out volume was returned in the form of Ringer lactate (RL). They were then resuscitated with four times the volume of the shed blood with RL over 60 min. At the time of maximal bleed out (approximately 50 min from the onset of hemorrhage), 1.5, and 4 h after the completion of resuscitation, aortic rings (approximately 2.5 mm in length) were isolated and mounted in organ chambers. Dose responses for an endothelium-dependent vasodilator (acetylcholine) and endothelium-independent vasodilator (nitroglycerin) were determined. The results indicate that endothelium-dependent relaxation was depressed at the time of maximal bleed out and persisted even after resuscitation. However, there was no significant difference in nitroglycerin-induced relaxation at any point during the study period. In addition, hypoxia-induced contraction, a process mediated by endothelium-derived contracting factor, decreased significantly following hemorrhage and resuscitation. Thus endothelial cell dysfunction (i.e., reduced release of endothelium-derived relaxing and contracting factors) occurs very early after trauma-hemorrhage and persists despite fluid resuscitation.

Acetylcholine↗

PubMed1993

Pentoxifylline restores cardiac output and tissue perfusion after trauma-hemorrhage and decreases susceptibility to sepsis.

BACKGROUND: Although pentoxifylline produces various beneficial effects in a preheparinized model of hemorrhagic shock, it was unknown whether this agent restores the depressed cardiac output (CO) and tissue perfusion in a nonheparinized model of trauma-hemorrhage and resuscitation and, if so, whether it decreases the susceptibility to sepsis after hemorrhage. METHODS: After laparotomy (i.e., induction of trauma), rats 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. The animals were then resuscitated with Ringer's lactate, four times the volume of shed blood. Pentoxifylline (50 mg/kg body weight) or normal saline solution was infused intravenously more than 95 minutes during and after resuscitation. At 1.5 and 4 hours after resuscitation, CO, tissue perfusion, and plasma liver enzyme levels were determined. Sepsis was induced by cecal ligation and puncture at 20 hours after hemorrhage, and the necrotic cecum was excised 10 hours thereafter. RESULTS: CO and tissue perfusion in the liver, kidney, spleen, and small intestine decreased significantly after hemorrhage and resuscitation. Pentoxifylline treatment, however, restored the depressed CO and tissue perfusion. The elevated liver enzyme levels were also significantly reduced by pentoxifylline treatment. Moreover, pentoxifylline prevented the increased mortality of posthemorrhaged rats subjected to sepsis. CONCLUSIONS: Because pentoxifylline restored the depressed CO and tissue perfusion and decreased the susceptibility to sepsis, this agent appears to be a useful adjunct to crystalloid resuscitation after trauma and hemorrhage, even in the absence of blood resuscitation.

Alanine Transaminase↗

PubMed1993

Alterations in circulating blood volume during polymicrobial sepsis.

Although a great deal is known concerning the pathophysiology of sepsis, it is not clear whether circulating blood volume (CBV) is altered under such conditions. To study, this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Immediately after CLP or sham operation, the animals received 3 ml/100 g body weight normal saline subcutaneously. CBV was determined by using in vivo indocyanine green (ICG) clearance at 2, 5, 10, or 20 hr after CLP or sham operation. This technique does not require any blood sampling. Serum glutamic pyruvic transaminase (SGPT) and glutamic oxaloacetic transaminase (SGOT) were assayed enzymatically as indicators of hepatocyte damage. Hepatic microcirculation was assessed at a selected time point (10 hr post-CLP) by using laser Doppler flowmetry and colloidal carbon infusion techniques. The results indicate that CBV, as determined by ICG clearance, remained unchanged up to 10 hr following the onset of sepsis (i.e., early sepsis) but decreased significantly at 20 hr after CLP (late sepsis). However, systemic hematocrit increased significantly at 5, 10, and 20 hr after CLP, indicating that plasma volume decreased at those time points. This suggests that there may be limitations in accurately assessing CBV at 5 and 10 hr after CLP, i.e., during the hyperdynamic circulatory state of sepsis, using the ICG clearance method. Moreover, SGPT and SGOT levels increased significantly at 10 hr, and the levels increased further at 20 hr post-CLP. In contrast, microvascular blood flow and carbon-perfused areas in the liver were significantly increased at 10 hr post-CLP.

Alanine Transaminase↗

PubMed1992

Mechanism of the beneficial effects of ATP-MgCl2 following trauma-hemorrhage and resuscitation: downregulation of inflammatory cytokine (TNF, IL-6) release.

Although ATP-MgCl2 improves hepatocellular function in a nonheparinized model of trauma-hemorrhage and crystalloid resuscitation, it remains unknown whether the beneficial effects of this agent are due to downregulation of the release of the inflammatory cytokines, tumor necrosis factor (TNF), and interleukin-6 (IL-6) under those conditions. To study this, rats underwent a 5-cm laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum bleedout 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 over 60 min. ATP-MgCl2 (50 mumoles/kg body weight each) or an equivalent volume of normal saline was infused intravenously for 95 min. This infusion was started during the last 15 min of RL resuscitation. Plasma levels of TNF and IL-6 were measured at 1.5 hr after the completion of resuscitation by cytokine-dependent cellular assays. Hepatic blood flow was determined by in vivo indocyanine green clearance (corrected by hepatic extraction ratio for indocyanine green), radioactive microspheres, and [3H]-galactose clearance techniques. The results indicate that the levels of circulating TNF and IL-6 increased significantly in the hemorrhaged-resuscitated animals. ATP-MgCl2 treatment, however, markedly decreased the synthesis and/or release of these cytokines to levels similar to the sham group. The markedly decreased hepatic blood flow (as determined by three different methods) and hepatic extraction ratio for indocyanine green were also restored by ATP-MgCl2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1992

Hepatocellular dysfunction persists during early sepsis despite increased volume of crystalloid resuscitation.

Although hepatocellular dysfunction occurs early in sepsis despite fluid resuscitation, it is unknown if an increased volume of resuscitation protects hepatocellular function. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). These and sham-treated rats then received either 3 or 6 mL/100 g BW normal saline subcutaneously. Studies were performed at 5 hours (i.e., early sepsis) or 20 hours (late sepsis) after CLP. Hepatic blood flow was determined by radioactive microspheres, 3H-galactose clearance technique, and laser Doppler flowmetry in both groups. Active hepatocellular function (i.e., Vmax and Km) was assessed by an in vivo indocyanine green clearance technique. The results indicate that: (1) hepatic blood flow increased markedly in early sepsis; (2) Vmax and Km decreased significantly at 5 hours and 20 hours after CLP; and (3) the increased volume of fluid resuscitation did not improve the depressed active hepatocellular function 5 hours following CLP. Cardiac output and hepatic microcirculation, however, were significantly increased in early sepsis. These results confirm the notion that the depression in hepatocellular function in early sepsis is not the result of any reduction of hepatic perfusion. The dissociation of increased hepatic blood flow from depressed hepatocellular function remains despite the larger volume of resuscitation. The hepatocellular dysfunction that occurs even in early sepsis cannot be corrected simply by increasing the volume of crystalloid resuscitation.

Animals↗

PubMed1992

ATP-MgCl2 restores renal microcirculation following trauma and severe hemorrhage.

Although ATP-MgCl2 enhances the recovery of renal function after ischemia and reperfusion, it is not known whether this agent has any beneficial effects on renal microcirculation and function in a nonheparinized model of trauma and severe hemorrhage. To study this, a midline laparotomy was performed (i.e., trauma induced) and the rats were bled to and maintained at a mean arterial pressure of 40 mmHg (1 mmHg = 133.32 Pa) until 40% of the maximum shed blood volume was returned in the form of Ringer's lactate (RL) solution. Animals were then resuscitated with 4 times the volume of the shed blood in the form of RL. ATP-MgCl2, 50 mumol/kg body weight, or an equivalent volume of saline, was infused intravenously during and following resuscitation. Renal microcirculation was examined by using colloidal carbon infusion and laser Doppler flow-metry. Glomerular filtration rate (GFR) was assessed with [3H]inulin clearance and cardiac output (CO) was determined by dye dilution technique. The results indicate that the depressed renal microcirculation following hemorrhage and resuscitation was restored by ATP-MgCl2 treatment. GFR was significantly higher in ATP-MgCl2-treated than saline-treated rats. ATP-MgCl2 also increased urine output, restored the decreased CO, and prevented the occurrence of renal edema after hemorrhage and resuscitation. Thus, ATP-MgCl2 appears to be a useful adjunct to crystalloid resuscitation following trauma and severe hemorrhagic shock even in the absence of blood resuscitation.

Adenosine Triphosphate↗

PubMed1992

Measurement of hepatic blood flow after severe hemorrhage: lack of restoration despite adequate resuscitation.

Although Ringer lactate (RL) is routinely used for resuscitation, it is not known whether the volume of RL that restores cardiac output after severe hemorrhagic shock also restores the depressed effective hepatic blood flow (EHBF). To study this, a 5-cm midline laparotomy was performed in rats (i.e., trauma induced), and the animals were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximum bleedout volume was returned in the form of RL. Animals were then resuscitated with four or five times the volume of maximum bleedout with RL. EHBF was determined during hemorrhage and at various intervals thereafter by an in vivo indocyanine green (ICG) clearance technique and corrected by the appropriate hepatic extraction ratio for ICG. Cardiac output was determined by ICG dilution, and hepatic microvascular blood flow (HMBF) was measured with laser Doppler flowmetry. In addition, hepatic blood flow was assessed by using radioactive microspheres. Results indicate that resuscitation markedly improved but did not restore the depressed EHBF after trauma and hemorrhagic shock despite the fact that cardiac output was restored. Similar changes in EHBF, HMBF, and hepatic blood flow as determined by microspheres were observed, suggesting that the in vivo ICG clearance is a reliable method to assess effective hepatic perfusion. Thus the lack of restoration of EHBF may be responsible for the subsequent hepatocellular dysfunction after trauma and severe hemorrhage.

Animals↗

PubMed1992

Differential alterations in microvascular perfusion in various organs during early and late sepsis.

Although cellular dysfunction occurs very early in sepsis, it remains controversial whether this is solely due to a decrease in tissue perfusion. Recent studies have indicated that while active hepatocellular function was depressed, hepatic surface microvascular blood flow (MBF) increased in early sepsis but decreased in late sepsis as produced by cecal ligation and puncture (CLP). However, it is not known whether microvascular hyperperfusion in early sepsis and microvascular hypoperfusion in late sepsis are common events in other organs under such conditions. To study this, rats were subjected to sepsis by CLP, after which these and the corresponding shams received 3 ml/100 g body wt normal saline. Microvascular perfusion and MBF in various tissues were assessed by colloidal carbon infusion and laser-Doppler flowmetry, respectively, at 5 h (i.e., early sepsis) or 20 h (late sepsis) after CLP or sham operation. Carbon-perfused areas were quantitated by an Optomax image analyzer. The results indicate that the carbon-perfused areas and MBF in the liver, renal cortex, spleen, and small intestinal serosa (only MBF) increased significantly 5 h after CLP. In late sepsis, however, the carbon-perfused areas and MBF were found to be significantly decreased. A highly linear relationship was observed between the changes of carbon-perfused areas and MBF during sepsis in the tested organs. Thus the microvascular responses in the fluid-resuscitated sepsis model are characterized by hyperperfusion in the early stage and hypoperfusion in the late stage of sepsis in the tested tissues. The cellular dysfunctions observed during the early stage of sepsis are, therefore, not due to any reduction in tissue perfusion.

Animals↗

PubMed1992

Differential effects of ATP-MgCl2 on portal and hepatic arterial blood flow after hemorrhage and resuscitation.

Although ATP-MgCl2 administration after hemorrhage and resuscitation restores the decreased hepatic blood flow, it is not known whether this is due to the increase in portal blood flow or hepatic arterial blood flow. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal shed blood volume was returned in the form of Ringer lactate (RL). The animals were resuscitated with four times the volume of the shed blood with RL, during and after which ATP-MgCl2 (50 mumol/kg body wt) or an equal volume of normal saline was infused intravenously over 95 min. Cardiac output and organ blood flow were determined by 85Sr-labeled microspheres at 90 min after the completion of resuscitation. The results indicate that portal blood flow and total hepatic blood flow decreased significantly after hemorrhage and resuscitation. ATP-MgCl2 treatment, however, restored these parameters to sham values. In contrast, hepatic arterial blood flow did not change significantly after either hemorrhage and resuscitation or ATP-MgCl2 infusion. Moreover, the depressed cardiac output was normalized and coronary blood flow was higher than shams after ATP-MgCl2 treatment. Unlike small intestinal blood flow, blood flows to the stomach, spleen, pancreas, mesentery, and cecum were not markedly affected with ATP-MgCl2 infusion. Thus the restoration of hepatic blood flow with ATP-MgCl2 treatment under such conditions is due to the increased portal blood flow, i.e., solely due to the increased small intestinal blood flow.

Adenosine Triphosphate↗

PubMed1992

Diltiazem restores cardiac output and improves renal function after hemorrhagic shock and crystalloid resuscitation.

Although calcium antagonists produce salutary effects after shock and ischemia, it is unknown whether such agents restore the depressed cardiac output (CO) and renal function in a nonheparinized model of trauma-hemorrhage and resuscitation. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximum bleedout was returned in the form of Ringer lactate (RL). They were then resuscitated with four times the volume of shed blood with RL over 60 min. Diltiazem (400 micrograms/kg body wt) or an equal volume of saline was infused intravenously over 95 min. This infusion was started during the last 15 min of resuscitation. CO was determined by indocyanine green dilution. Glomerular filtration rate (GFR) was assessed with [3H]inulin clearance, and cortical microcirculation was examined by laser Doppler flowmetry. Results indicate that crystalloid resuscitation alone transiently restored but did not maintain CO after hemorrhage. Diltiazem infusion in conjunction with crystalloid resuscitation, however, restored and maintained CO and cortical microcirculation. Although GFR decreased in both groups, the values in diltiazem-treated animals were significantly higher than those in the sham-operated animals. Furthermore, diltiazem markedly decreased tissue water content. Thus diltiazem appears to be a promising adjunct in the treatment of hemorrhagic shock even in the absence of blood resuscitation.

Animals↗

PubMed1992

ATP-MgCl2 restores the depressed cardiac output following trauma and severe hemorrhage even in the absence of blood resuscitation.

A number of beneficial effects of ATP-MgCl2 administration have been demonstrated in preheparinized models of shock and ischemia. However, it is not known whether ATP-MgCl2 restores and maintains the depressed cardiac output in a nonheparinized model of trauma and severe hemorrhage in which resuscitation following shock was provided only with crystalloid. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were then 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). Animals were then resuscitated with 4 times the volume of shed blood with RL (4 X RL) during and following which ATP-MgCl2 (50 mumol/kg body weight each or an equivalent volume of normal saline) was infused intravenously. Cardiac output was determined every 15-30 min for 4.5 hr, using an in vivo hemoreflectometer and indocyanine green dilution technique. Resuscitation with 4 X RL transiently restored but did not maintain cardiac output; however, ATP-MgCl2 treatment restored and maintained cardiac output at control values. ATP-MgCl2 infusion also significantly decreased total peripheral resistance and attenuated tissue water content. Thus, ATP-MgCl2 appears to be a promising adjunct to the treatment of trauma-hemorrhage even in the absence of blood resuscitation.

Adenosine Triphosphate↗

PubMed1992

Mechanism of the beneficial effects of pentoxifylline on hepatocellular function after trauma hemorrhage and resuscitation.

BACKGROUND: The purpose of this study was to determine whether pentoxifylline administration restores the depressed hepatocellular function after trauma hemorrhage and crystalloid resuscitation and, if so, whether this is the result of the down-regulation of inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-6 (IL-6). METHODS: After laparotomy rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum shed blood volume was returned in the form of Ringer's lactate. They were then resuscitated with Ringer's lactate to four times the shed blood volume. Pentoxifylline (50 mg/kg body weight) or saline solution was infused intravenously for 95 minutes during and after resuscitation. One and a half hours and 4 hours after resuscitation, hepatocellular function (maximal velocity [Vmax] and the efficiency of the active transport [Km] of indocyanine green clearance) and plasma. TNF and IL-6 levels were determined with in vivo hemoreflectometer and cellular assays, respectively. RESULTS: Circulating TNF and IL-6 levels increased significantly after hemorrhage and resuscitation. Pentoxifylline treatment, however, markedly decreased the levels of these cytokines, and the values were similar to those of sham rats. The decreased Vmax and Km values were also restored by pentoxifylline treatment. Moreover, there was a significant correlation between Vmax and TNF or IL-6 levels. CONCLUSIONS: The down-regulation of inflammatory cytokines by pentoxifylline may be the mechanism by which this agent restores the depressed hepatocellular function after trauma hemorrhage and resuscitation.

Animals↗

PubMed1991

Hepatic extraction of indocyanine green is depressed early in sepsis despite increased hepatic blood flow and cardiac output.

Although active hepatocellular function is depressed during sepsis, it is not known whether this occurs in the very early stages of sepsis and whether it is due to depressed cardiac output or hepatic blood flow. To study this, rats were subjected to sepsis by cecal ligation and puncture and hepatocellular function was determined at various intervals thereafter by assessing the ability of the liver to clear different doses of indocyanine green. The indocyanine green concentration was continuously measured in vivo with a fiberoptic catheter and an in vivo hemoreflectometer. Maximal velocity and kinetic constant of the clearance of indocyanine green, hepatic blood flow, and cardiac output were determined in experimental and sham-operated rats. The results demonstrate that hepatic blood flow and cardiac output increased 2 to 10 hours after cecal ligation and puncture, while hepatocellular function (maximum velocity and kinetic constant) was decreased even 2 hours following cecal ligation and puncture. No linear correlation between hepatocellular function and hepatic blood flow or cardiac output was found under such conditions. The extremely early depression in active hepatocellular function, despite the increased hepatic blood flow and cardiac output, may form the basis for cellular dysfunctions leading to multiple organ failure during sepsis.

Animals↗