Doraid Jarrar

Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals.

ObjectiveTo determine whether female sex steroids have any salutary effects on the depressed cardiovascular and hepatocellular functions following trauma and hemorrhage in male animals. Summary Background DataStudies indicate that gender difference exists in the immune and cardiovascular responses to trauma-hemorrhage, and that male sex steroids appear to be responsible for producing immune and organ dysfunction, but it remains unknown if female sex steroids produce any salutary effects on the depressed cellular and organ functions in males following trauma and hemorrhage. MethodAdult male Sprague-Dawley rats underwent a midline laparotomy (i.e., trauma induction), and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximum bleed-out volume was returned in the form of Ringer’s lactate (RL). Animals were then resuscitated with RL at 4 times the shed blood over 60 minutes. 17&bgr;-Estradiol (50 &mgr;g/kg) or an equal volume of vehicle was injected subcutaneously 15 minutes before the end of resuscitation. The maximal rate of ventricular pressure increase or decrease (±dP/dtmax), cardiac output, and hepatocellular function (i.e., maximal velocity and overall efficiency of in vivo indocyanine green clearance) were assessed at 24 hours after hemorrhage and resuscitation. Plasma levels of interleukin (IL)-6 were also measured. ResultsLeft ventricular performance, cardiac output, and hepatocellular function decreased significantly at 24 hours after trauma-hemorrhage and resuscitation. Plasma levels of IL-6 were elevated. Administration of 17&bgr;-estradiol significantly improved cardiac performance, cardiac output, and hepatocellular function, and attenuated the increase in plasma IL-6 levels. ConclusionAdministration of estrogen appears to be a useful adjunct for restoring cardiovascular and hepatocellular functions after trauma-hemorrhage in male rats.

Critical role of oxygen radicals in the initiation of hepatic depression after trauma hemorrhage.

BACKGROUND Although depression in hepatocellular function occurs early after trauma and severe hemorrhage and persists despite fluid resuscitation, it remains unknown whether reactive oxygen species (ROS) play any role in the initiation of hepatocellular depression and damage under those conditions. We hypothesized that administration of a ROS scavenger at the beginning of resuscitation will attenuate organ injury after severe shock. METHODS Male Sprague-Dawley rats (275-325 g) underwent laparotomy (i.e., induction of soft tissue trauma) and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringers lactate. The animals were then resuscitated with four times the volume of maximal bleed-out with RL over 60 minutes. The ROS scavenger 2-mercaptopropionyl glycine (30 mg/kg) or vehicle was administered intravenously as a bolus at the beginning of resuscitation. At 2 hours after the completion of crystalloid resuscitation or the equivalent interval after sham-operation, cardiac index was measured by a dye dilution technique. Hepatocellular function, i.e., the maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the active transport (Km), was determined using an in vivo hemoreflectometer. Serum levels of tumor necrosis factor (TNF)-alpha and alanine aminotransferase were determined with ELISA and colorimetrically, respectively. RESULTS The results indicate that at 2 hours after trauma hemorrhage and resuscitation, cardiac index and hepatocellular function were markedly depressed with concomitantly increased serum levels of TNF-alpha and alanine aminotransferase (p < 0.05). Administration of 2-mercaptopropionyl glycine, however, restored the depressed cardiac and hepatic function and markedly attenuated liver enzyme release and serum levels of TNF-alpha (p < 0.05). CONCLUSION Our data suggest that ROS play a role in producing the depression in organ functions after severe hemorrhagic shock. Thus, adjuncts that attenuate the detrimental effects of ROS may be useful for improving the depressed cardiac and hepatocellular functions after trauma hemorrhage and resuscitation.

Evolution Of An Immune Suppressive Macrophage Phenotype As A Product Of P38 Mapk Activation In Polymicrobial Sepsis

Studies indicate that polymicrobial sepsis in humans and animals is characterized by a biphasic response, which is dominated early by proinflammation, but over time develops into a state of generalized anti-inflammation (depressed Th1 cell response and decreased macrophage (M0) capacity to release proinflammatory cytokines). However, with respect to the macrophage, it remains unknown what mechanism(s) controls this change. In this regard it is well documented that the p38 mitogen activated protein kinase pathway (MAPK) plays a central role in the regulation of Mphi functions. However, the contribution of p38 MAPK activation to the loss of these Mphi functions in polymicrobial septic animals remains unknown. To determine this we induced polymicrobial sepsis in C3H/HeN male mice using cecal ligation and puncture (CLP). Twenty-four hours post-CLP, during the late, immune-suppressed stage of sepsis, splenic and peritoneal Mphi were harvested, stimulated with lipopolysaccharide (LPS), and the activation of p38 MAPK assessed. In Mphi from CLP mice, p38 MAPK activity was markedly increased. To determine the extent that these changes in p38 MAPK had an impact on Mphi immune function, cells were pretreated with 10 microM of the p38 MAPK inhibitor, SB203580, or with DMSO vehicle, and subsequently stimulated with LPS. IL-10, IL-6, IL-12, and nitric oxide release was determined. Our results indicate that with LPS stimulation alone, there was a marked increase in the release of the anti-inflammatory mediator, IL-10 after CLP. Alternatively, proinflammatory IL-12 and IL-6 release was suppressed. Treatment with SB203580 suppressed the increase in IL-10 release seen after CLP, while partially restoring IL-12 secretion. IL-6 release was partially restored only in splenic macrophages treated with SB203580. To the extent that these in vitro findings could be translated to an in vivo setting, we assessed the in vivo effects of p38 MAPK inhibition on survival. Mice were given 100 mg of SB203580/kg body weight or saline vehicle (intraperitoneal) either immediately post-CLP or 12 h post-CLP. Delayed administration of SB203580 significantly improved survival, while also preventing the increased NO and IL-10 release and improving IL-12 release by macrophages. These results suggest that p38 MAPK pathway plays a critical role in the induction of an immune-suppressive macrophage phenotype, and that inhibition of p38 MAPK markedly improves survival following polymicrobial sepsis.

Inhibition of Tyrosine Kinase Signaling After Trauma-hemorrhage: A Novel Approach for Improving Organ Function and Decreasing Susceptibility to Subsequent Sepsis

OBJECTIVE To determine whether administration of a tyrosine kinase inhibitor after trauma-hemorrhage has any beneficial effects on cardiovascular parameters and hepatocellular function and on survival rate after subsequent sepsis. BACKGROUND Increased inflammatory cytokine release and concomitant activation of intracellular signaling pathways contributes to multiple organ dysfunction and increased susceptibility to subsequent sepsis after severe hemorrhagic shock. METHODS Male Sprague-Dawley rats underwent a midline laparotomy (i.e., soft-tissue trauma induced) and were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringers lactate. The rats were then resuscitated with four times the shed blood volume in the form of Ringers lactate during a 60-minute period. A tyrosine kinase inhibitor, AG 556 (7.5 mg/kg), or vehicle was administered intraperitoneally at the middle of resuscitation. At 24 hours after resuscitation, various in vivo parameters such as heart performance, cardiac index, and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined. Phosphorylation state of the mitogen-activated protein kinases p44/42 and p38 in the liver was assessed by Western blot analysis. In additional groups of rats, sepsis was induced by cecal ligation and puncture at 20 hours after hemorrhage. The necrotic cecum was excised 10 hours thereafter, and the survival rate was monitored for a period of 10 days. RESULTS AG 556 treatment restored the depressed cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation, which was associated with reduced phosphorylation of mitogen-activated protein kinases p44/42 and p38. Moreover, treatment with AG 556 significantly increased the survival rate of rats after trauma-hemorrhage and induction of subsequent sepsis compared with vehicle-treated rats. CONCLUSION Inhibition of tyrosine kinase signaling after trauma-hemorrhage may represent a novel therapeutic approach for improving organ functions and decreasing the death rate from subsequent sepsis under such conditions.

DHEA: a novel adjunct for the treatment of male trauma patients.

Despite significant advances in the management of trauma victims, traumatic injury with the ensuing sepsis and multiple organ failure remains the leading cause of death between the ages of 18 and 44 in the USA. Recently, interest in the clinically and experimentally observed gender dimorphic response to traumatic injury has led to the possibility of modulating cell and organ functions following trauma and hemorrhagic shock by the administration of sex steroids. Here, we review the effects of the adrenal steroid dehydroepiandrosterone (DHEA), a precursor of sex steroid synthesis, on organ and immune functions following trauma-hemorrhage, and its potential as a novel therapy for improving the depressed cell and organ functions in trauma patients.

Progesterone administration after trauma and hemorrhagic shock improves cardiovascular responses.

OBJECTIVE Studies have shown that female rats during the proestrus stage have significantly improved cell and organ functions after trauma-hemorrhage compared with male and ovariectomized females. This study investigated the hypothesis that progesterone can improve the depressed cardiovascular function in sex steroid-deficient female rats (i.e., ovariectomized females) after trauma-hemorrhage and resuscitation. DESIGN Prospective study. SETTING University laboratory. SUBJECTS Ovariectomized female Sprague-Dawley rats (weight, 250-300 g). INTERVENTIONS Rats underwent a 5-cm midline laparotomy (i.e., soft-tissue trauma), were bled to a mean arterial pressure of 35 mm Hg for approximately 90 mins, and were then resuscitated using Ringers lactate. A single dose of progesterone (25 mg/kg of body weight) or vehicle was administered subcutaneously during resuscitation. MEASUREMENTS At 20 hrs after trauma-hemorrhage or sham operation, cardiac output and heart performance and the circulating blood volume were assessed using the indocyanine green dilution technique and a left ventricular catheter. Furthermore, the binding activity of progesterone receptors in nuclear extracts of left ventricular tissue was determined. RESULTS Cardiac output, heart performance, and circulating blood volume were significantly decreased in vehicle-treated animals after trauma-hemorrhage. Administration of progesterone significantly improved cardiac output and heart performance and increased the circulating blood volume. This was associated with an increased progesterone receptor activity in the left ventricular nuclear extracts. CONCLUSION Because administration of progesterone after trauma-hemorrhage in sex steroid-deficient females improved cardiovascular responses, this hormone seems to be a useful adjunct for the treatment of cardiovascular depression in postmenopausal and ovariectomized female trauma patients.

Mechanism of immune dysfunction in sepsis: inducible nitric oxide-meditated alterations in p38 MAPK activation.

BACKGROUND After the onset of sepsis, there is a marked dysfunction in cell-mediated immunity that contributes to the morbidity and mortality seen in this condition. Although both nitric oxide (NO) from inducible NO synthase (iNOS) and the activation of p38 mitogen-activated protein kinase (p38 MAPK) appear to contribute to this immune dysfunction, the extent to which NO regulates p38 MAPK activity in sepsis remains unknown. METHODS To examine this, we induced sepsis by cecal ligation and puncture (CLP) in iNOS knockout (iNOS -/-) or C57BL/6 control mice. Twenty-four hours after CLP or sham operation, splenic T cells and macrophages were isolated and then stimulated with monoclonal antibody against the T-cell marker CD3 (anti-CD3) or lipopolysaccharide. At 4 or 24 hours after stimulation, cytokine release was determined by enzyme-linked immunosorbent assay, and p38 MAPK phosphorylation (activation) was determined by immunoblotting with antibody specific to phosphorylated p38 MAPK. RESULTS Splenic T-cell p38 MAPK activation and interleukin (IL)-10 release was increased by CLP, whereas Th1 cytokine (IL-2, interferon-gamma) release was depressed. iNOS gene deficiency inhibited p38 MAPK activation in splenic T cells taken from septic mice, and also suppressed IL-10 release in both sham and septic mice. Interestingly, although deficiency of iNOS restored IL-2 release after CLP, both sham and CLP T cells remained depressed in their ability to release interferon-gamma. Septic insult markedly suppressed C57BL/6 splenic macrophage release of proinflammatory agents tumor necrosis factor, IL-12, and IL-1, while augmenting the release of IL-10. However, although deficiency of iNOS concomitantly restored the ability to produce tumor necrosis factor while suppressing the rise in IL-10 release and p38 MAPK activation, it only partially restored IL-1 release and had no effect on IL-12 production seen after CLP. CONCLUSION These data suggest that NO release from iNOS regulates aspects of sepsis-induced immune dysfunction by the activation of p38 MAPK.

Does early infusion of red blood cells after trauma and hemorrhage improve organ functions

ObjectiveEarly management of trauma victims includes control of bleeding and rapid restoration of intravascular volume. However, it remains controversial whether infusion of blood products is superior to crystalloids alone. Therefore, it was the aim of the present study to determine whether resuscitation with red blood cells plus lactated Ringer’s solution (RL) is more effective than RL alone in improving the cardiovascular and hepatocellular functions after trauma and severe hemorrhage. DesignProspective study. SettingLaboratory. SubjectsSprague-Dawley rats. Interventions and MeasurementsMale adult rats were anesthetized and underwent a laparotomy to induce tissue trauma before hemorrhage. The animals were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out (MB) volume was returned in the form of RL, and were then resuscitated with either four times the volume of MB with RL or washed red blood cells (RBC) (∼45% the volume of MB) in three times the volume of RL over 60 mins. Various in vivo heart performance variables, cardiac output, and hepatocellular function (ie, the maximum velocity and the overall efficiency of indocyanine green clearance) were determined at 4 hrs after resuscitation. Hemoglobin, systemic oxygen delivery, circulating blood volume, and plasma levels of interleukin-6 were also measured. Main ResultsAt 4 hrs after RL resuscitation, heart performance, cardiac output and hepatocellular function were significantly depressed and plasma levels of interleukin-6 were significantly increased. Although infusion of RBC significantly increased mean arterial pressure, hemoglobin, and oxygen delivery compared with animals resuscitated with RL only, infusion of RBC did not further improve the depressed cardiovascular and hepatocellular functions under such conditions. ConclusionBecause infusion of RBC and RL resuscitation do not improve organ functions compared with RL resuscitation without RBC, it appears that pharmacologic agents in addition to fluid resuscitation are needed to restore cardiovascular and hepatocellular functions after trauma and hemorrhage.

Management of thoracic esophageal perforations

OBJECTIVE To assess our results of a prospective algorithm applied to patients with thoracic esophageal perforation. METHODS A retrospective review of a prospective algorithm. Patients with esophageal perforation underwent an esophagram. If there was a contained esophageal perforation they were admitted, kept nothing by mouth, and restudied in 3-5 days. If the leak was not contained, they underwent operative repair. RESULTS From 1/1998 to 6/2009 there were 81 patients. The gastrograffin swallow showed 56 patients had contained perforations and 25 did not. Twenty-two of the 25 patients with noncontained perforation underwent immediate operative repair (one patient refused surgery, two were not stable enough for the operating room); their morbidity was 68% and there were six (24%) operative mortalities. Median hospital length of stay (LOS) was 11 days (range, 2-120). Of the 56 patients with contained perforations, 26 were managed successfully without surgery. However, 30 of the patients initially treated nonoperatively eventually required operations due to new pleural effusion, mediastinal abscess, or conversion to noncontained perforation. Their morbidity was 41% and there were three operative mortalities (5%). On univariate analysis, these patients were more likely to have undergone previous esophageal procedures (surgical or dilation) (p=0.03), had new or increased pleural effusion (p=0.04), and had greater than 24h between diagnosis and treatment (p=0.02). Only greater than 24h between diagnosis and treatment remained a significant predictor on multivariate analysis. Their median hospital LOS was 21 days (range, 7-77). CONCLUSION Contained thoracic esophageal perforations can usually be safely managed nonoperatively without significant morbidity or mortality. However, careful in-hospital monitoring is needed if surgery is not chosen.

Multimodality Approach to Management of Stage III Non–Small Cell Lung Cancer

Stage III non-small cell lung cancer represents a heterogeneous group of patients who are best managed with a multidisciplinary approach, including evaluation for surgical, radiation, and chemotherapeutic options.