[An analysis of related factors in thrombocytopenia combined with cirrhosis: a cross-sectional study of 2 517 cases].

Objective: To explore the related factors of thrombocytopenia (TCP) occurrence in patients with cirrhosis. Methods: A cross-sectional study was conducted. Inpatients with an initial diagnosis of cirrhosis at Peking University First Hospital from January 1, 2010 to December 31, 2020 were included. Clinical data such as demographic characteristics, etiology of cirrhosis, complications of cirrhosis, laboratory indicators, Child-Pugh grade, invasive procedures, and mortality during hospitalization were collected. A logistic regression model was used to explore the related factors of TCP occurrence in patients with cirrhosis. Categorical variables were compared by the χ(2) test. The inter-group comparison was performed using continuous variables, a t-test, one-way analysis of variance (ANOVA), or a nonparametric test. Results: There were a total of 2 592 cases of cirrhosis. 75 cases with incomplete clinical data were excluded. 2 517 cases were included for analysis. The median age was 58 (50, 67) years. Males accounted for 64%. 1 435 cases (57.0%) developed TCP, and 434 cases (17.2%) had grade 3-4 TCP. Gender, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and concomitant esophagogastric varices (EGV) were the major factors associated with TCP. Females were more prone to combine with TCP (OR=1.32, 95%CI: 1.12-1.56, P=0.001). Patients combined with EGV (OR=3.09, 95%CI: 2.63-3.65, P<0.001) were more prone to develop TCP, which was associated with the increased incidence of hypersplenism (P<0.001). Patients with PBC (OR=0.64, 95%CI: 0.50-0.82, P<0.001) and PSC (OR=0.23, 95%CI: 0.06-0.65, P=0.010) were less prone to develop TCP, which was due to the shorter prothrombin time and better coagulation function of PBC patients (P<0.001), and the lower proportion of hypersplenism in combined PSC patients (P=0.004). Patients with TCP and grade 3-4 TCP had a higher rate of hemostatic procedures (P<0.05), but a lower rate of liver biopsy (P<0.05). Patients with grade 3-4 TCP had a higher nosocomial mortality rate compared to those without (P=0.004). Conclusion: TCP is common in patients with cirrhosis. However, TCP occurrence is higher in female patients with EGV and lower in patients combined with PBC and PSC. TCP affects invasive procedures and is associated with adverse outcomes.

Search for Spin-Dependent Gravitational Interactions at Earth Range.

Among the four fundamental forces, only gravity does not couple to particle spins according to the general theory of relativity. We test this principle by searching for an anomalous scalar coupling between the neutron spin and the Earth's gravity on the ground. We develop an atomic gas comagnetometer to measure the ratio of nuclear spin-precession frequencies between ^{129}Xe and ^{131}Xe, and search for a change of this ratio to the precision of 10^{-9} as the sensor is flipped in Earth's gravitational field. The null results of this search set an upper limit on the coupling energy between the neutron spin and the gravity on the ground at 5.3×10^{-22} eV (95% confidence level), resulting in a 17-fold improvement over the previous limit. The results can also be used to constrain several other anomalous interactions. In particular, the limit on the coupling strength of axion-mediated monopole-dipole interactions at the range of Earth's radius is improved by a factor of 17.

[HbA1c comparison and diagnostic efficacy analysis of multi center different glycosylated hemoglobin detection systems].

Objective: Compare and analyze the results of the domestic Lanyi AH600 glycated hemoglobin analyzer and other different detection systems to understand the comparability of the detection results of different detectors, and establish the best cut point of Lanyi AH600 determination of haemoglobin A1c (HbA1c) in the diagnosis of diabetes. Methods: Multi center cohort study was adopted. The clinical laboratory departments of 18 medical institutions independently collected test samples from their respective hospitals from March to April 2022, and independently completed comparative analysis of the evaluated instrument (Lanyi AH600) and the reference instrument HbA1c. The reference instruments include four different brands of glycosylated hemoglobin meters, including Arkray, Bio-Rad, DOSOH, and Huizhong. Scatter plot was used to calculate the correlation between the results of different detection systems, and the regression equation was calculated. The consistency analysis between the results of different detection systems was evaluated by Bland Altman method. Consistency judgment principles: (1) When the 95% limits of agreement (95% LoA) of the measurement difference was within 0.4% HbA1c and the measurement score was≥80 points, the comparison consistency was good; (2) When the measurement difference of 95% LoA exceeded 0.4% HbA1c, and the measurement score was≥80 points, the comparison consistency was relatively good; (3) The measurement score was less than 80 points, the comparison consistency was poor. The difference between the results of different detection systems was tested by paired sample T test or Wilcoxon paired sign rank sum test; The best cut-off point of diabetes was analyzed by receiver operating characteristic curve (ROC). Results: The correlation coefficient R2 of results between Lanyi AH600 and the reference instrument in 16 hospitals is≥0.99; The Bland Altman consistency analysis showed that the difference of 95% LoA in Nanjing Maternity and Child Health Care Hospital in Jiangsu Province (reference instrument: Arkray HA8180) was -0.486%-0.325%, and the measurement score was 94.6 points (473/500); The difference of 95% LoA in the Tibetan Traditional Medical Hospital of TAR (reference instrument: Bio-Rad Variant II) was -0.727%-0.612%, and the measurement score was 89.8 points; The difference of 95% LoA in the People's Hospital of Chongqing Liang Jiang New Area (reference instrument: Huizhong MQ-2000PT) was -0.231%-0.461%, and the measurement score was 96.6 points; The difference of 95% LoA in the Taihe Hospital of traditional Chinese Medicine in Anhui Province (reference instrument: Huizhong MQ-2000PT) was -0.469%-0.479%, and the measurement score was 91.9 points. The other 14 hospitals, Lanyi AH600, were compared with 4 reference instrument brands, the difference of 95% LoA was less than 0.4% HbA1c, and the scores were all greater than 95 points. The results of paired sample T test or Wilcoxon paired sign rank sum test showed that there was no statistically significant difference between Lanyi AH600 and the reference instrument Arkray HA8180 (Z=1.665,P=0.096), with no statistical difference. The mean difference between the measured values of the two instruments was 0.004%. The comparison data of Lanyi AH600 and the reference instrument of all other institutions had significant differences (all P<0.001), however, it was necessary to consider whether it was within the clinical acceptable range in combination with the results of the Bland-Altman consistency analysis. The ROC curve of HbA1c detected by Lanyi AH600 in 985 patients with diabetes and 3 423 patients with non-diabetes was analyzed, the area under curve (AUC) was 0.877, the standard error was 0.007, and the 95% confidence interval 95%CI was (0.864, 0.891), which was statistically significant (P<0.001). The maximum value of Youden index was 0.634, and the corresponding HbA1c cut point was 6.235%. The sensitivity and specificity of diabetes diagnosis were 76.2% and 87.2%, respectively. Conclusion: Among the hospitals and instruments currently included in this study, among these four hospitals included Nanjing Maternity and Child Health Care Hospital in Jiangsu Province (reference instrument: Arkray HA8180), Tibetan Traditional Medical Hospital of TAR (reference instrument: Bio-Rad Variant Ⅱ), the People's Hospital of Chongqing Liang Jiang New Area (reference instrument: Huizhong MQ-2000PT), and the Taihe Hospital of traditional Chinese Medicine in Anhui Province (reference instrument: Huizhong MQ-2000PT), the comparison between Lanyi AH600 and the reference instruments showed relatively good consistency, while the other 14 hospitals involved four different brands of reference instruments: Arkray, Bio-Rad, DOSOH, and Huizhong, Lanyi AH600 had good consistency with its comparison. The best cut point of the domestic Lanyi AH600 for detecting HbA1c in the diagnosis of diabetes is 6.235%.

Cohort effects in dynamic models and their impact on vaccination programmes: an example from hepatitis A.

BACKGROUND: Infection rates for many infectious diseases have declined over the past century. This has created a cohort effect, whereby older individuals experienced a higher infection rate in their past than younger individuals do now. As a result, age-stratified seroprevalence profiles often differ from what would be expected from constant infection rates. METHODS: Here, we account for the cohort effect by fitting an age-structured compartmental model with declining transmission rates to Hepatitis A seroprevalence data for Canadian-born individuals. We compare the predicted impact of universal vaccination with and without including the cohort effect in the dynamic model. RESULTS: We find that Hepatitis A transmissibility has declined by a factor of 2.8 since the early twentieth century. When the cohort effect is not included in the model, incidence and mortality both with and without vaccination are significantly over-predicted. Incidence (respectively mortality) over a 20 year period of universal vaccination is 34% (respectively 90%) higher than if the cohort effect is included. The percentage reduction in incidence and mortality due to vaccination are also over-predicted when the cohort effect is not included. Similar effects are likely for many other infectious diseases where infection rates have declined significantly over past decades and where immunity is lifelong. CONCLUSION: Failure to account for cohort effects has implications for interpreting seroprevalence data and predicting the impact of vaccination programmes with dynamic models. Cohort effects should be included in dynamic modelling studies whenever applicable.

Severe hypoxemia in the absence of blood loss depresses hepatocellular function and up-regulates IL-6 and PGE2.

Although hepatocellular function is depressed early after trauma and hemorrhage (which are associated with low flow conditions and tissue hypoxemia), it remains unknown whether hypoxemia without blood loss, produces hepatocellular dysfunction and, if so, whether IL-6 and PGE2 are associated with this dysfunction. To study this, rats were placed in a plastic box which was flushed with a gas mixture containing 6.3% O2:93.7% N2 or room air for 60 min, followed by their return to room air. At 0 and 4 h after hypoxemia, hepatocellular function (i.e., maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the transport (Km)) was measured using an in vivo hemoreflectometer. Cardiac output was assessed by dye dilution technique. Tissue microvascular blood flow was determined by laser Doppler flowmetry. Plasma IL-6 and PGE2 were measured by bioassay and radioimmunoassay, respectively. The results indicate that hypoxemia produced a depression in hepatocellular function (i.e., decreased Vmax by 44-50% and Km by 55-68%) despite stable cardiac output and hepatic microcirculation at 0 and 4 h after hypoxemia. Moreover, hypoxemia resulted in a significant increase in plasma IL-6 (by 372%-389%) as well as PGE2 (by 38% at 0 h post-hypoxemia). Thus, hypoxemia observed after trauma and hemorrhagic shock appears to be responsible for producing hepatocellular dysfunction possibly through the up-regulation of IL-6 and PGE2. In view of this, long-lasting hypoxemia in trauma victims should be avoided, perhaps by early intubation and ventilation so that the potential additional proinflammatory cytokine and PGE2 release can be prevented.

Upregulation of Kupffer cell beta-adrenoceptors and cAMP levels during the late stage of sepsis.

Although a burst of immunoresponsiveness may occur during the early stage of sepsis, late sepsis is characterized by severe immunodepression. In addition, although studies have shown that stimulation of macrophage beta-adrenoceptors results in an increase in cAMP and an associated reduction in macrophage phagocytic activity, it remains unknown whether Kupffer cell beta-adrenoceptor characteristics and cAMP levels are altered during polymicrobial sepsis. To study this, Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h (i.e., the early stage of sepsis) or 20 h (late sepsis) after CLP or sham operation, the liver was perfused with collagenase solution and Kupffer cells were isolated. beta-Adrenoceptor characteristics of the isolated Kupffer cells were determined using [125I]iodopindolol, and basal levels of cAMP were measured by radioimmunoassay. The results indicate that while maximum binding capacity (Bmax) of Kupffer cell beta-adrenoceptors was not altered at 5 h, it increased significantly at 20 h after CLP. Similarly, basal levels of cAMP in Kupffer cells did not change at 5 h but increased markedly at 20 h after the onset of sepsis. In contrast, the dissociation constant (Kd, 1/affinity) of Kupffer cell beta-adrenoceptors was not significantly affected by sepsis at both 5 h and 20 h after CLP. Thus, upregulation of beta-adrenoceptors and increase in cAMP levels in Kupffer cells occur during the late stage of polymicrobial sepsis, and this may contribute to the depression of macrophage phagocytic function under such conditions.

Hepatocellular dysfunction occurs earlier than the onset of hyperdynamic circulation during sepsis.

Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using an in vivo indocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2 and PGI2 were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2 levels were not altered, plasma PGI2 increased significantly at 2 h after CLP. The elevated circulating PGI2 levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines.

Differential alterations in cyclic nucleotide levels in Kupffer cells and hepatocytes following trauma-hemorrhage and resuscitation.

Although cyclic nucleotides play an important role in regulating the control of metabolism, it is not known whether there are any differential alterations in cyclic nucleotides in Kupffer cells and hepatocytes after trauma-hemorrhage and resuscitation. To study this, rats underwent laparotomy (i.e., trauma-induced) and were rapidly 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's lactate. The animals were then resuscitated with Ringer's lactate, equivalent to four times the volume of shed blood. At the time of maximum bleedout or at 1.5 h postresuscitation, a portion of the liver was removed, and the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by radioimmunoassay. Moreover, Kupffer cells and hepatocytes were isolated in additional groups of animals and cAMP and cGMP levels were measured. The results indicate that hepatic cAMP decreased, whereas hepatic cGMP increased significantly at the time of maximum bleedout. Although resuscitation normalized hepatic cyclic nucleotide levels, the levels of cAMP and cGMP in Kupffer cells increased significantly at 1.5 h after resuscitation. In contrast, cAMP and cGMP levels in hepatocytes were not significantly different from shams under such conditions. Thus, differential alterations in cyclic nucleotide levels in different liver cell populations occur following trauma-hemorrhage and resuscitation.

Tumor necrosis factor-alpha administration increases Kupffer cell cyclic adenosine monophosphate levels.

Although studies have indicated that both Kupffer cell cyclic adenosine monophosphate (cAMP) and circulating TNF levels increase following trauma-hemorrhage and resuscitation, it remains unknown whether the elevated TNF levels are responsible for the increased Kupffer cell cAMP levels. To determine this, recombinant murine TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (.25 mg/kg body wt) over 30 min in normal rats. At 1 h after TNF-alpha or vehicle infusion, Kupffer cells and hepatocytes were isolated and cAMP levels were determined by radioimmunoassay. The levels of cAMP in the spleen and kidney were also measured. In addition, the maximal binding capacity and affinity of beta-adrenergic receptors were determined in Kupffer cells and hepatocytes by using [125I]iodopindolol. To determine whether there is any correlation between Kupffer cell cAMP and prostaglandin E2 (PGE2) or epinephrine, plasma levels of catecholamines and PGE2 were measured. The results indicated that TNF-alpha infusion significantly increased Kupffer cell cAMP levels while hepatocyte cAMP levels were not altered. Moreover, cAMP levels also increased in the macrophage/lymphocyte-rich spleen but were not altered in the kidney. Kupffer cell beta-receptor binding characteristics were not significantly affected by TNF-alpha infusion. In contrast, TNF-alpha administration markedly increased plasma levels of PGE2 and epinephrine. Thus, the elevated Kupffer cell cAMP levels induced by TNF-alpha are not due to upregulation of beta-adrenergic receptors, but may be associated with the elevated levels of circulating PGE2 and/or epinephrine.

Administration of a matrix metalloproteinase inhibitor after hemorrhage improves cardiovascular and hepatocellular function.

Although matrix metalloproteinase inhibitors prevent the increase in soluble tumor necrosis factor-alpha during endotoxemia, it remains unknown whether a novel matrix metalloproteinase inhibitor, GM6001, improves cardiovascular and hepatocellular function after trauma and hemorrhage. To determine this, rats underwent laparotomy (i.e., trauma-induced), and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal shed volume was returned in the form of Ringer's lactate. The animals were then resuscitated with 3 times the volume of maximal bleedout with Ringer's lactate over 45 min, followed by 2 times Ringer's lactate over 60 min. GM6001, at a dose of 100 mg/kg or an equal volume of normal saline, was administered subcutaneously 15 min before the completion of resuscitation. At 2 and 4 h after resuscitation, cardiac output was measured by indocyanine green (ICG) dilution. Hepatocellular function (i.e., maximum velocity and the efficiency of ICG clearance) was determined by in vivo ICG clearance. Microvascular blood flow in various organs was assessed by laser Doppler flowmetry. The results indicate that cardiac output, hepatocellular function, and tissue microvascular blood flow decreased significantly at 2 and 4 h after resuscitation. GM6001 treatment, however, significantly improved the depressed cardiovascular and hepatocellular function. Since GM6001 improves cardiovascular and hepatocellular function, this agent may be a useful adjunct to fluid resuscitation after trauma and hemorrhagic shock.

Up-regulation of a novel potent vasodilatory peptide adrenomedullin during polymicrobial sepsis.

A large number of studies have been and are being carried out to examine the role of nitric oxide in the hyperdynamic and hypodynamic stages of sepsis. It remains unknown, however, whether adrenomedullin (ADM), a novel potent vasodilatory peptide, is up-regulated during hyperdynamic sepsis and, if so, whether its production is sustained during hypodynamic sepsis. To determine this, rats were subjected to sepsis by cecal ligation and puncture (CLP), followed by administration of 3 mL/100 g body weight normal saline to these and sham-operated animals. Blood samples were taken at 1, 1.5, 2, 5, and 10 h (2-10 h post-CLP represents the hyperdynamic stage of sepsis) or at 20 and 30 h after CLP (i.e., the hypodynamic stage). Plasma levels of ADM were measured by radioimmunoassay. Adrenomedullin gene expression in various tissues was examined at 2, 10, or 20 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that plasma levels of ADM did not increase at 1 and 1.5 h after CLP but increased significantly at 2 h after the onset of sepsis. Moreover, circulating ADM increased progressively at 5-20 h and remained elevated at 30 h after CLP. The increased levels of plasma ADM during sepsis were correlated with up-regulation of ADM mRNA in the small intestine, left ventricle, and thoracic aorta. In contrast, ADM gene expression in renal and hepatic tissues was not significantly altered following the onset of sepsis. The association between the up-regulated ADM and the occurrence of hyperdynamic circulation during the early stage of sepsis (both occur at 2 h after CLP) may indicate a possible cause and effect relationship between the two events. Since we have previously shown that ADM-induced vascular relaxation decreased at 20 h after CLP, it appears that the down-regulation of ADM receptors may be responsible for the transition from the hyperdynamic stage to the hypodynamic stage of sepsis.

Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation.

Although interleukin-6 (IL-6) plays an important role in the pathophysiology of trauma-hemorrhage and resuscitation, the cellular origin of this inflammatory cytokine remains unknown. This study was undertaken to determine whether Kupffer cells (KC) are a major source of IL-6 release following trauma-hemorrhage and resuscitation. KC numbers were significantly (p < .05) reduced in vivo with gadolinium chloride (GdCl3; 10 mg/kg IV). KC-reduced (KC(-)) and KC-normal (saline-treated; KC(+)) rats underwent laparotomy (i.e., trauma-induced), followed by either sham operation or hemorrhage. Hemorrhaged rats were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the shed blood volume was returned as Ringer's lactate, and then resuscitated with Ringer's lactate (four times shed blood volume over 1 h). Results indicate that KC reduction per se had no effect on any measured parameter at any time. At 0.5 and 2.0 h postresuscitation, mean arterial pressure, heart rate, cardiac output, stroke volume, and hematocrit were reduced to a similar extent in both the KC(+) and KC(-) hemorrhage groups. KC reduction did, however, significantly reduce plasma IL-6 concentration (means +/- S.E.; U/ml) at both 0.5 h (KC(+) = 709 +/- 391 vs. KC(-) = 159 +/- 5) and at 2.0 h (KC(+) = 527 +/- 394 vs. KC(-) = 83 +/- 20) postresuscitation. In conclusion, this study demonstrates that KC are a major source of in vivo IL-6 release following trauma-hemorrhage and resuscitation.

Sustained elevation in circulating catecholamine levels during polymicrobial sepsis.

Although studies have indicated that the levels of catecholamines increase during sepsis, it remains unknown whether the elevated levels of epinephrine, norepinephrine, and dopamine observed in early sepsis are sustained during late, hypodynamic stages of sepsis. In this study, rats were subjected to sepsis by cecal ligation and puncture (CLP, i.e., polymicrobial sepsis). Immediately after CLP or sham operation, animals received 3 mL/100 g body weight normal saline subcutaneously. At .5, 2, 10 (i.e., early sepsis), or 20 h (late sepsis) after CLP, blood samples were drawn and the plasma was separated. Plasma levels of epinephrine, norepinephrine, and dopamine were determined using a [3H]-radioenzymatic assay. The results indicate that plasma levels of epinephrine, norepinephrine, and dopamine increased significantly as early as .5 h after CLP. The increase in catecholamine levels persisted throughout the study periods. Thus, circulating levels of catecholamines were elevated in both early and late stages of polymicrobial sepsis. These results suggest that the increased catecholamine levels at .5-10 h after CLP may contribute to the hypermetabolic conditions that occur during early, hyperdynamic sepsis. However, there is a lack of an association between the elevated plasma catecholamine levels and hypometabolic/hypodynamic state in late sepsis.

Chemically modified heparin improves hepatocellular function, cardiac output, and microcirculation after trauma-hemorrhage and resuscitation.

BACKGROUND: Although heparinization before hemorrhagic shock improves tissue perfusion and organ function, the anticoagulant properties of conventional heparin preclude its clinical use. The purpose of this study was to determine whether chemically modified heparin (CMH), which does not have any significant anticoagulant activity, produces any beneficial effects on hepatocellular and cardiovascular function and microcirculation after trauma-hemorrhage and resuscitation. METHODS: After induction of tissue trauma (that is, laparotomy), rats 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 three times the volume of shed blood with RL over 45 minutes, followed by two times RL and CMH (7 mg/kg body wt; approximately 10% of the anticoagulant activity of conventional heparin), conventional heparin (7 mg/kg), or normal saline solution over 60 minutes. Hepatocellular function, cardiac output, and microvascular blood flow were determined thereafter. RESULTS: The results indicate that hepatocellular function, cardiac output, and microvascular blood flow in the liver, kidney, spleen, and small intestine decreased markedly after trauma-hemorrhage and resuscitation. Infusion of CMH or conventional heparin during resuscitation, however, restored or significantly improved the mentioned parameters. CONCLUSIONS: Because CMH does not have any significant anticoagulant properties and because it restores or significantly improves hepatocellular function, cardiac output, and tissue perfusion, this agent appears to be a useful adjunct in the treatment of trauma and hemorrhagic shock, even in the absence of blood resuscitation.

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.

Pentoxifylline maintains vascular endothelial cell function during hyperdynamic and hypodynamic sepsis.

BACKGROUND: Although pentoxifylline produces various beneficial effects after endotoxemia or sepsis occurs, it is not known whether this agent attenuates the depressed endothelial cell function during sepsis. Therefore the aim of this study was to determine whether pentoxifylline maintains vascular endothelial cell function (i.e., improves the release of endothelium-derived nitric oxide) during hyperdynamic and hypodynamic stages of polymicrobial sepsis. METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP), after which 3 ml/100 gm body wt normal saline solution was injected subcutaneously in these and rats in a sham-operated group. At 1 hour after the onset of sepsis, pentoxifylline (50 mg/kg body wt) or an equal volume of normal saline solution was infused intravenously during a 30 minute period. At 10 and 20 hours after CLP was performed (10-hour CLP, hyperdynamic sepsis; 20-hour CLP, hypodynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) mol/L) was used to achieve near maximal tension. Dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were carried out. The changes in percentage relaxation in the aortic rings by these agonists were then determined. RESULTS: Endothelium-dependent (acetylcholine-induced) vascular relaxation decreased significantly at 10 and 20 hours after CLP. Administration of pentoxifylline, however, maintained acetylcholine-induced vascular relaxation at both time points. In contrast, no significant reduction in nitroglycerine-induced vascular relaxation was seen in rats with sepsis irrespective of pentoxifylline treatment. CONCLUSIONS: Because pentoxifylline prevented endothelial cell dysfunction at 10 and 20 hours after CLP occurred, this agent appears to be a useful agent for maintaining vascular endothelial function during the hyperdynamic and hypodynamic stages of polymicrobial sepsis.

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.

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.

Continuous resuscitation after hemorrhage and acute fluid replacement improves cardiovascular responses.

BACKGROUND: Although acute fluid replacement after trauma and severe hemorrhage remains the cornerstone in the management of trauma victims, it remains unknown whether continuous resuscitation after trauma-hemorrhage and acute fluid replacement produces salutary effects on cardiovascular function and reduces proinflammatory cytokine release. METHODS: Adult male rats underwent laparotomy (ie, soft tissue trauma) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the shed blood volume was returned in the form of Ringer's lactate (RL). The animals were then resuscitated with 4 times the volume of shed blood with RL for 60 minutes, followed by continuous resuscitation with RL at 5 mL/h/kg for 48 hours after the acute fluid replacement. At 48 hours after hemorrhage, mean arterial pressure, cardiac output, and left ventricular contractility parameters, such as the maximal rates of ventricular pressure increase (+dP/dt(max)) and decrease (-dP/dt(max)), were determined. Microvascular blood flow in the intestine and kidney was assessed by laser Doppler flowmetry. In addition, plasma levels of TNF-alpha were assayed by enzyme-linked immunosorbent assay. RESULTS: The mean arterial pressure and cardiac output were decreased by 34% and 18%, respectively, at 48 hours after hemorrhage and acute resuscitation. Continuous resuscitation, however, markedly improved these parameters. Similarly, +dP/dt(max) and -dP/dt(max) decreased significantly after hemorrhage and acute fluid replacement but was restored to sham values after continuous resuscitation. Microvascular blood flow in the gut and kidneys was decreased after hemorrhage and acute resuscitation by 34% and 35%, respectively. However, intestinal and renal perfusion was maintained at the sham levels at 48 hours after continuous resuscitation. In addition, the upregulated TNF-alpha after acute resuscitation alone was reduced after continuous resuscitation. CONCLUSIONS: Continuous resuscitation after acute fluid replacement appears to be a useful approach for restoring and maintaining cardiovascular function and organ perfusion after trauma and severe hemorrhage.