Biomedical subjects

Frank Hildebrand

Publications and source records attributed to Frank Hildebrand.

At least 19 recordsLinked to original sources

PubMed2007

Effects of 17beta-estradiol and flutamide on splenic macrophages and splenocytes after trauma-hemorrhage.

Since splenic immune functions are depressed in metestrus females following trauma-hemorrhage, we hypothesized that administration of the androgen receptor antagonist flutamide at the onset of resuscitation will maintain the immune function of the spleen following trauma-hemorrhage. Female C57BL6/J mice (metestrus state, 8-12 weeks old), underwent laparotomy and hemorrhagic shock (35.0+/-5.0 mm Hg for 90 min) and received 17beta-estradiol (50 microg/25 g), flutamide (625 microg/25 g) or 17beta-estradiol+flutamide. Four hours after resuscitation, the in vitro productive capacity of different cytokines (TNF-alpha, IL-6, IL-10, and IFN-gamma) by splenic MPhi and splenocytes were determined by flow cytometry. A significantly decreased cytokine production by both splenocytes and splenic MPhi was observed following trauma-hemorrhage compared to shams. Administration of 17beta-estradiol, flutamide and 17beta-estradiol+flutamide following trauma-hemorrhage resulted in a significant increase in the in vitro IL-6 release by splenic MPhi. The TNF-alpha productive capacity, however, was only restored by 17beta-estradiol and 17beta-estradiol+flutamide administration following trauma-hemorrhage. No significant effect of either treatment was observed with regard to the suppressed splenic MPhi IL-10 release. Anti-CD3 stimulation, administration of 17beta-estradiol and 17beta-estradiol+flutamide, but not the administration of flutamide alone resulted in a significant increased release of TNF-alpha, IL-6 and IFN-gamma compared to vehicle-treated animals. No significant effect of either treatment was found on IL-10 productive capacity. These results collectively suggest that flutamide administration following trauma-hemorrhage in females has beneficial effects on splenic immune function. However, flutamide administration in combination with estrogen does not provide any significant, additional effects over 17beta-estradiol administration alone.

Animals↗

PubMed2007

The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage.

Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP approximately 35 mm Hg for 90 min), and resuscitation. Kupffer cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-alpha, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-alpha, MCP-1, and KC production by Kupffer cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-alpha and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-alpha and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage.

Animals↗

PubMed2007

Influence of sex and age on mods and cytokines after multiple injuries.

Although salutary effects of female sex steroids have been demonstrated not only in proestrus females but also in male animals treated with estradiol in different models of trauma, it remains unknown whether sex hormones influence post-traumatic immune response in humans. We therefore investigated the effect of sex and age on organ dysfunction and clinical course in patients with multiple injuries. Polytraumatized patients (injury severity score>16) between 16 and 65 years old admitted to the Hannover Medical School Level 1 trauma center between January 1997 and December 2001 were included. Marshall Score for multiple organ dysfunction syndrome (MODS) was calculated for at least 14 days. The length of stay in intensive care unit and the ventilator days were recorded in addition to the number of transfusions the patient received. A total of 106 males and 37 females were included in the study. Patients with MODS had increased plasma levels of IL-6, IL-8, and IL-10. Furthermore, patients with organ dysfunction had more frequent sepsis and higher mortality rates. In addition, MODS was associated with extended length of stay in the intensive care unit and increased ventilator days. Females not older than 50 years with an injury severity score greater than 25 suffered significantly less MODS and sepsis compared with age-matched males. Moreover, they had significantly lower plasma cytokines. Thus, in this prospective study, sex difference was confirmed in MODS and sepsis, with a benefit observed in females. Although the levels of sex steroids were not measured, it seems that the protective effects may be due to estrogen effects on plasma cytokines. This suggestion is based on the fact that such salutary effects were apparent predominantly in premenopausal females.

Adolescent↗

PubMed2006

Effects of 17beta-estradiol and flutamide on inflammatory response and distant organ damage following trauma-hemorrhage in metestrus females.

We hypothesized that administration of androgen receptors antagonist flutamide following trauma-hemorrhage (T-H) in metestrus females will maintain immune function and reduce remote organ damage under those conditions. Female B57BL/J6 mice (metestrus state, 8-12 weeks old) underwent laparotomy and hemorrhagic shock (35.0+/-5.0 mmHg for 90 min) and then received 17beta-estradiol (E2; 50 microg/25 g), flutamide (625 microg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF-alpha, IL-6, IL-10, IFN-gamma, and MCP-1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (M Phi) were determined by flow cytometry. Organ damage was assessed by edema formation (wet-to-dry weight ratio) and neutrophil infiltration [myeloperoxidase (MPO) activity]. Administration of E2, flutamide, or E2 + flutamide following T-H resulted in a significant decrease in systemic TNF-alpha, IL-6, and MCP-1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF-alpha release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar M Phi, however, was reduced significantly only by the addition of E2 or E2 + flutamide but not by the addition of flutamide. A significant decrease in pulmonary and hepatic edema formation as well as neutrophil infiltration in the lung was observed after E2, flutamide and E2 + flutamide administration. In contrast, hepatic neutrophil infiltration was only significantly reduced following E2 and E2 + flutamide administration. Thus, although flutamide does not produce synergistic, salutary effects with E2, its administration in females following T-H also produces salutary effects on the immune and organ function, similar to E2 administration under those conditions.

Animals↗

PubMed2006

Are the protective effects of 17beta-estradiol on splenic macrophages and splenocytes after trauma-hemorrhage mediated via estrogen-receptor (ER)-alpha or ER-beta?

The depression in cell-mediated immune function following trauma-hemorrhage is shown to be restored by 17beta-estradiol (E2) administration. However, it remains unknown which of the two estrogen-receptors, (ER)-alpha or ER-beta, plays the predominant role in mediating the beneficial effects of E2. Female B57BL/J6 ER-beta(-/-) transgenic mice [knockout (KO)] and corresponding ovariectomized wild-type (WT) mice were subjected to laparotomy and hemorrhagic shock (35.0+/-5.0 mmHg for 90 min) and treated with E2 (50 microg/25 g) or ER-alpha agonist propyl pyrazole triol (PPT; 50 microg/25 g) following trauma-hemorrhage. Four hours after resuscitation, systemic cytokine concentrations and cytokine release by splenocytes and splenic macrophages were determined by cytometric bead array. Trauma-hemorrhage resulted in a significant increase in plasma tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and IL-10. In contrast, the release of these cytokines by splenic macrophages was decreased significantly in WT and KO animals. Administration of E2 or PPT following trauma-hemorrhage produced a significant reduction in systemic TNF-alpha and IL-6 concentrations in WT and KO mice. Although the suppression in the productive capacity of these cytokines following trauma-hemorrhage by macrophages and splenocyte was also prevented in E2- and PPT-treated WT mice, the release of cytokines by macrophages and splenocytes in E2- and PPT-treated KO mice was not restored to the levels observed in sham animals. These findings collectively suggest that both receptors appear to play a significant role in mediating the immunoprotective effects of E2 in different tissue compartments following trauma-hemorrhage.

Animals↗

PubMed2006

Experimental background--review of animal studies.

UNLABELLED: Most of the research on the physiological effects of intramedullary nailing is technically difficult or ethically impossible to perform in humans. A substantial range of factors apply in clinical cases, which means that the data obtained from this source may lack the control needed to reveal the basic mechanisms of pathophysiology associated with this surgical procedure. Consequently, animal studies have been relied upon to provide answers that would otherwise be unavailable. This review manuscript summarizes the available literature on animal studies dealing with the local and systemic effects of intramedullary nailing. It focuses on whether these studies have contributed to our clinical knowledge of the procedure's impact on perfusion and fracture healing, as well as the medical relevance of coincident systemic effects. DATA SOURCES: Medline, personal library of the first author and of the Department of Trauma Surgery, University of Pittsburgh Medical Center. STUDY SELECTION: All animal studies on intramedullary stabilization published in English, German, and French. CONCLUSIONS: The relevance of animal studies investigating the impact of a surgical procedure and its influence on concomitant injuries depends on the design and the type of the animal model. If this fact is considered, and if a model is selected that simulates a systemic impact comparable with the clinical situation, then animal studies may provide a valuable source of otherwise unobtainable information. Such an example is the study of fat embolization associated with intramedullary nailing. Animal subjects enable assessment of the intervention's additive surgical impact, measurement of side effects that may have adverse results, and influence of cofactors (eg, thoracic trauma, severe shock, polytrauma) that predispose the individual to postoperative complications.

Animals↗

PubMed2006

Kupffer cells and their mediators: the culprits in producing distant organ damage after trauma-hemorrhage.

Posttraumatic activation of macrophages enhances development of systemic inflammation/immunosuppression and organ dysfunction. We hypothesized that Kupffer cells are the main source of monocyte chemoattractant protein-1 (MCP-1) production after trauma-hemorrhage, that administration of 17beta-estradiol (E2) after trauma-hemorrhage modulates MCP-1 release and reduces remote organ damage, and that salutary effects of E2 are mediated via estrogen receptor (ER)-alpha. To test these hypotheses, female B57BL/J6 mice received E2 (50 microg/25 g) or vehicle after trauma-hemorrhage and female 129 Sve ER-beta-/- transgenic mice and ovariectomized wild-type mice received E2 or ER-alpha agonist propyl pyrazole triol (50 microg/25 g) after trauma-hemorrhage. Systemic MCP-1 and interleukin-6 and their release by liver, spleen, and lung macrophages were determined by flow cytometry 4 hours after trauma-hemorrhage. Prior Kupffer cell depletion with gadolinium chloride significantly decreased systemic MCP-1 and interleukin-6 after trauma-hemorrhage and was associated with decreased edema/neutrophil infiltration in lung and liver. Kupffer cells were the only macrophages showing significant MCP-1 release, which was markedly reduced by E2 or propyl pyrazole triol in wild-type and in ER-beta-/- mice. Pretreatment of mice with anti-MCP-1 antiserum prevented an increase in myeloperoxidase and edema in lung and liver. These findings suggest that Kupffer cell-derived MCP-1 plays a major role in remote organ dysfunction after trauma-hemorrhage.

Animals↗

PubMed2005

Effects of hypothermia and re-warming on the inflammatory response in a murine multiple hit model of trauma.

INTRODUCTION: Although, hypothermia is a frequent event after trauma, it is unclear whether its beneficial or detrimental effects are more important. This study aims to quantify the effects of hypothermia and re-warming on the inflammatory response after fracture/hemorrhage and subsequent fracture stabilization with resuscitation. MATERIALS AND METHODS: Eighty-one male C57Bl/6 mice (aged 8-10 weeks, weighing 22.0+/-3.0 g) underwent femoral fracture and hemorrhage followed by resuscitation and splint fixation of the fracture. Animals were sacrificed 3h after induction of hemorrhage and fracture. Besides a sham group (n=6), four experimental groups were created: A: normothermia (n=12), B: hypothermia after trauma (n=21), C: re-warming after resuscitation and before stabilization (n=21), and D: hypothermia before trauma (n=21). Groups B-D were further subdivided into three subgroups according to the degree of hypothermia (subgroup 1: 35-33 degrees C, subgroup 2: 32.9-30.0 degrees C, and subgroup 3: 29.9-27.0 degrees C). Plasma cytokine (TNF-alpha, IL-6, and IL-10) and chemokine (MCP-1) concentrations were determined by ELISA, pulmonary permeability changes were quantified, and histological analysis of lung and liver tissues was performed. RESULTS: Normothermia resulted in a significantly increased early mortality rate. A significantly increased pro-inflammatory and decreased anti-inflammatory responses were also observed in normothermia as compared to hypothermia. The extent of these changes was most pronounced in the severe hypothermic group. Re-warming after mild hypothermia resulted in a pro-inflammatory response comparable to normothermia. CONCLUSION: Hypothermia has a beneficial effect on early survival after trauma, which appears to be independent of the level of hypothermia and re-warming. Re-warming, however, enhanced the pro-inflammatory response. Further studies with a longer posttraumatic observation period are required to investigate the long term effects of the hypothermia and re-warming-induced changes on the pro- and anti-inflammatory responses.

Animals↗

PubMed2005

Secondary effects of femoral instrumentation on pulmonary physiology in a standardised sheep model: what is the effect of lung contusion and reaming?

Intramedullary nailing is the treatment of choice for patients with femoral shaft fractures. However, there is an ongoing debate in multiple trauma patients with associated lung contusion when primary or secondary definitive stabilisation of the long bone fracture should be performed, as nailing is thought to play an important role in the pathogenesis of adult respiratory distress syndrome (ARDS). In a standardised sheep model, this study aimed to quantify the development of acute pulmonary endothelial changes, to assess the activation of polymorphonuclear leucocytes (PMNL) and to observe the effects on the coagulation system associated with the reamed nailing procedure. Furthermore, the effect of coexisting lung contusion in an experimental model was evaluated. The animals were randomly assigned to one of four different groups (6 animals/group). In control groups, only a sham operation (thoracotomy) was performed, whereas in study groups, lung contusion was induced prior to femoral stabilisation either by external fixation or reamed femoral nailing. Using bronchoalveolar lavage (BAL) pulmonary permeability changes were quantified and PMNL activation was assessed by chemiluminescence. Additionally PMNL diapedesis and interstitial lung oedema were determined by histological analysis. All animals were sacrificed 4 h after the start of the femoral instrumentation. Without an associated lung injury, instrumentation of the femoral canal with the reamed nailing technique induced a transient increase in pulmonary permeability. In the face of an induced lung contusion, reamed femoral nailing resulted in significant increases in PMNL activation, pulmonary permeability and interstitial lung oedema, compared with external fixation. Without pulmonary contusion, reaming of the femoral canal was associated with a transient increase in pulmonary permeability. This was exacerbated in the presence of lung contusion along with increased PMNL activation. External fixation did not provoke similar changes. The findings of this study support the view that reaming of the femoral canal should be avoided in polytrauma patients with severe chest trauma as it could act as an additional stimulus for adverse outcome. Temporary external fixation appears to be a safe method for fracture stabilisation until inflammatory and coagulatory disturbances after trauma have been normalized.

Animals↗

PubMed2005

Role of adhesion molecule ICAM in the pathogenesis of polymicrobial sepsis.

INTRODUCTION: Intercellular adhesion molecule-1 (ICAM-1) is thought to be involved in polymorphonuclear leukocytes (PMNL) recruitment and secondary organ damage in response to infection and inflammation. The precise role of ICAM-1 in disease progression is unknown and remains a topic of controversy. The aim of this study was to investigate the effect of ICAM-1 on histological changes and cytokine synthesis in a murine model of polymicrobial sepsis. METHODS: Polymicrobial sepsis was induced in experimental animals by caecal ligation and puncture (CLP). A control group was formed using sham laparotomy without CLP. In order to ascertain the role of ICAM-1 in the response, procedures were performed in both ICAM-1 knockout animals (ICAM-1-/-) and in C57BL/6 mice that were not genetically modified (wild type, WT). Clinical response was observed daily, morphological changes occurring in the lung and liver were studied using light microscopy and quantified using a scoring system. Plasma concentrations of various cytokines (TNF-alpha, IL-6, IL-10) were measured via ELISA. RESULTS: In ICAM-1-/- mice a less severe clinical response to induced sepsis was observed with significantly less weight loss and hypothermia. A significantly lower mortality rate was observed in ICAM-1-/- mice (12.5% vs. WT: 45.5%) and no significant histological changes were apparent in pulmonary or hepatic tissue on light microscopy following CLP. In WT animals however, significant evidence of leukocyte infiltration and interstitial thickening in pulmonary tissue was observed. Similarly, hepatic tissue sinusoidal widening and hydropic degeneration was present. In addition, pro- and anti-inflammatory cytokine synthesis in ICAM-1-/- animals was significantly attenuated when compared to WT mice. (ICAM-1-/-: TNF-alpha: 67.7+/-12.1pg/microl; IL-6: 208.9+/-26.7pg/microl; IL-10: 34.6+/-5.8pg/microl; WT: TNF-alpha: 840.7+/-150.2pg/microl; IL-6: 3100.2+/-1052.3 pg/microl; IL-10: 1550.1+/-495.7 pg/microl). DISCUSSION: This study suggests that ICAM-1 has an important pathophysiological role in the response to polymicrobial sepsis. It would appear that absence of this molecule impairs the ability of PMNL to migrate into organ tissues and reduces consequent secondary organ damage resulting in improved clinical status and overall survival. Further investigation into the effectiveness of ICAM-1 modulation in the treatment of sepsis is warranted.

Animals↗

PubMed2005

Management of polytraumatized patients with associated blunt chest trauma: a comparison of two European countries.

BACKGROUND: Blunt chest trauma represents one of the most common injuries in polytrauma patients. Blunt chest injury complicating polytrauma is associated with significant prolongation of intensive care stay. Further, it has a great impact on the timing of fixation of skeletal injuries, possibly contributing to adverse outcome. The purpose of this study is to assess whether there are any differences in the management and outcome of polytrauma patients with blunt chest trauma between trauma units in two different countries. Detailed information about advantages and disadvantages of these two systems might allow optimising the management of blunt chest trauma. PATIENTS AND METHODS: This investigation was performed using the polytrauma database of the German Trauma Society and the British Trauma Audit Research Network. After the definition of the inclusion abbreviated injury scale (AIS(chest) > or = 3) and injury severity score (ISS > 16) and exclusion (AIS(head/neck) > or = 2, referral from outside institutions) criteria, patients were recruited solely from these databases. RESULTS: 188 patients from the German database and 181 patients from the British database were enrolled in this study. Demographic data and injury pattern of the two patient populations did not significantly differ. The volume of initial red blood cell transfusion and length of the intensive care stay were significantly higher in Germany (p < 0.05). Mortality in the UK was 9% higher than in Germany (p = 0.057). Time to death in non-survivors was also significantly longer in Germany (p < 0.05). CONCLUSIONS: The reasons for the differences regarding survival times and survival rates seem to be multiple. German patients received more red blood cells, had a longer hospital stay in intensive care and a better survival rate. The use of kinetic therapy in Germany, not standard in the UK, may contribute to a more favourable outcome.

Abbreviated Injury Scale↗

PubMed2005

Genetic predisposition for a compromised immune system after multiple trauma.

Severe trauma induces sustained changes of the immune response, which are thought to be related to secondary organ dysfunction. Despite a similar injury severity, the extent of the inflammatory response may vary between polytraumatized patients. It is unclear whether inflammatory variability is associated with genetic variations. In this prospective cohort study, patients were included when the following criteria were fulfilled: Injury Severity Score >16, age 18 to 60 years, and a survival >48 h after injury. Four different polymorphisms (TNF-Nco1, IL-1-Taq1, IL-6-174G/C, and IL-8-251A/T) were determined. Patients were separated according to the severity of the systemic inflammatory response syndrome (SIRS; ACCP/SCCM criteria: >2 criteria at 2 consecutive days or at 3 days of the observation period: group +SIRS; <or=2 criteria: group -SIRS). Ninety-seven severely injured patients were included (-SIRS, 56 patients; +SIRS, 41 patients). A significantly higher incidence of the IL-6-174G allele and the IL-6-174G homozygous genotype in +SIRS patients was observed. The IL-6-174G/C polymorphism was associated with the severity of posttraumatic SIRS. This data points toward a genetic predisposition regarding an enhanced inflammatory response after polytrauma that may be associated with adverse outcome.

Adolescent↗

PubMed2005

Reamed femoral nailing in sheep: does irrigation and aspiration of intramedullary contents alter the systemic response?

BACKGROUND: Reaming of the femoral canal has been demonstrated to introduce intramedullary contents into the circulation with subsequent pulmonary embolization. The aim of this study was to investigate whether this effect can be minimized by use of a reamer system that provides simultaneous irrigation and aspiration of intramedullary contents. METHODS: A unilateral lung contusion was created and intramedullary femoral nailing was subsequently performed in eighteen female skeletally mature Merino sheep. The animals were divided into three groups, of six animals each, to receive one of three types of treatment: reamed femoral nailing; reaming, irrigation, and aspiration; and unreamed femoral nailing. Blood samples were obtained and a bronchoalveolar lavage was performed at baseline, immediately after creation of the lung contusion, immediately after intramedullary nailing, and at four hours after surgery. Pulmonary permeability, polymorphonuclear leukocyte activity, and systemic hemostatic response were measured. Lung specimens were obtained for histological evaluation. RESULTS: At baseline and immediately after creation of the lung contusion, endothelial permeability was comparable among the three groups. At four hours postoperatively, pulmonary permeability was significantly higher in the group treated with reamed femoral nailing (urea/protein ratio; 256.7) than in the group treated with reaming, irrigation, and aspiration (urea/protein ratio, 91.5) and the group treated with unreamed femoral nailing (urea/protein, 110.64) (p < 0.05). The stimulatory capacity of the polymorphonuclear leukocytes was significantly decreased (p < 0.05) only in the group treated with reamed femoral nailing; the other two groups had no significant decrease postoperatively (p > 0.05). The D-dimer level at four hours postoperatively was significantly higher in the group treated with reamed femoral nailing than it was in the other two groups (p < 0.05). Histological examination showed that the grades of edema and polymorphonuclear leukocyte diapedesis were also highest in the group treated with reamed femoral nailing. CONCLUSIONS: It appears that, in the presence of a unilateral pulmonary injury, the systemic effects of intramedullary reaming of an intact femur can be minimized with use of a modified reamer design that simultaneously irrigates the canal and removes debris. Additional clinical validation of this reaming system is necessary.

Animals↗

PubMed2005

Impact of hypothermia on the immunologic response after trauma and elective surgery.

An Hypothermia is defined as a decrease in core temperature below 35 degrees C. The well-described deleterious effects of accidental hypothermia on outcome in multiple-trauma patients contrast the beneficial effect of controlled hypothermia on organ function during ischemia in elective surgery. Experimental studies have shown that induced hypothermia during hemorrhagic shock might have beneficial effects on outcome. The beneficial effects of induced hypothermia appear to be partly mediated by the prolongation of the "golden hour" with prevention of hypoxic organ dysfunction. However, hypothermia also has been thought to have an impact on the immunologic response after trauma and elective surgery. Induction of hypothermia seems to decrease the release of pro-inflammatory cytokines believed to influence distant organ damage positively, and is mediated by the interaction of polymorphonuclear leucocytes (PMNL) and capillary endothelial cells. Nevertheless, the incidence of posttraumatic infectious complications may be increased after induction of hypothermia due to an overexpression of anti-inflammatory cytokines. Together with this immunosuppressive profile, coagulopathy and bleeding might limit the use of induced hypothermia after multiple trauma and elective surgery. The purpose of this Chapter is to highlight current knowledge regarding the interaction of hypothermia and posttraumatic immune reactivity. A better understanding of these mechanisms would assist the introduction of preventive and therapeutic strategies into clinical practice.

Brain Injuries↗

PubMed2004

Pathophysiologic changes and effects of hypothermia on outcome in elective surgery and trauma patients.

Generally, hypothermia is defined as a core temperature <35 degrees C. In elective surgery, induced hypothermia has beneficial effects. It is recommended to diminish complications attributable to ischemia reperfusion injury. Experimental studies have shown that hypothermia during hemorrhagic shock has beneficial effects on outcome. In contrast, clinical experience with hypothermia in trauma patients has shown accidental hypothermia to be a cause of posttraumatic complications. The different etiology of hypothermia might be one reason for this disparity because induced therapeutic hypothermia, with induction of poikilothermia and shivering prevention, is quite different from accidental hypothermia, which results in physiological stress. Other studies have shown evidence that this contradictory effect is related to the plasma concentration of high-energy phosphates (e.g., adenosine triphosphate [ATP]). Induced hypothermia preserves ATP storage, whereas accidental hypothermia causes depletion. Hypothermia also has an impact on the immunologic response after trauma and elective surgery by decreasing the inflammatory response. This might have a beneficial effect on outcome. Nevertheless, posttraumatic infectious complications may be higher because of an immunosuppressive profile. Further studies are needed to investigate the impact of induced hypothermia on outcome in trauma patients.

Animals↗

PubMed2004

Damage control: extremities.

The principles of fracture management in polytrauma patients continue to be of crucial importance. Over the last five decades, various strategies of fracture treatment in the multiply injured patient have evolved. The various new methodologies remain controversial. In the beginning, early surgical fracture treatment of long bone fractures after multiple trauma was not routinely advocated. It was believed that the polytraumatised patient did not have the physiological reserve to withstand prolonged operations. The introduction of standardised, definitive surgical protocols, led to the concept of early total care (ETC) in the 1980s. This concept was subsequently applied universally, in all patient groups, regardless of injury severity and distribution. Later, it became apparent that certain patients did not appear to benefit from ETC. Indeed, extended operative procedures, during the early phase of multiple trauma recovery, were associated with adverse outcome. This applied for patients with significant thoracic, abdominal and head injuries and those with high injury severity scores (ISS). In response, the concept of damage control orthopaedics (DCO) was developed in the 1990s. DCO methodology is characterised by primary, rapid, temporary fracture stabilization. Secondary definitive management follows, once the acute phase of systemic recovery has passed. We explore the processes underlying the systemic biological impact of fracture fixation, the evolution of operative treatment strategies for major fractures in polytrauma and the current trends toward staged management of these patients.

Acute-Phase Reaction↗

PubMed2004

L-selectin shows time and gender dependency in association with MODS.

BACKGROUND: Recent investigations have demonstrated gender related immunologic alterations after trauma. These complications arise due to polymorphonuclear granulocytes (PMN) interacting with endothelium via L-selectin. Therefore, the purpose of this study was to investigate gender related differences in the expression of L-selectin in relation to posttraumatic multiple organ dysfunction syndrome (MODS). METHODS: Multiply injured patients were prospectively entered in the study. MODS was determined using the Denver score. The concentration of L-selectin on the surface of PMN was determined using flow cytometry during a 14 days' period. RESULTS: 48 patients were included in the study. The kinetics of L-selectin were different comparing male and female patients. Male patients with MODS initially showed a rapid decrease of surface L-selectin from 80 to 20 ng/ml. A return to admission levels was related to MODS. Male patients without MODS displayed elevated L-selectin levels up to 140 ng/ml. Female patients, however, all showed an initial rapid decrease of L-selectin to 20 ng/ml. Women who developed posttraumatic MODS had significantly increased levels up to 110 ng/ml before development of MODS developed. CONCLUSIONS: We feel that a gender related dimorphism in the initial L-selectin expression following trauma exists and is associated with MODS. These findings indicate new therapeutic means for the treatment of MODS. Therapies should be timely and gender dependently coordinated.

Adolescent↗

PubMed2003

The importance of systemic cytokines in the pathogenesis of polymicrobial sepsis and dehydroepiandrosterone treatment in a rodent model.

The pathogenesis of sepsis is still undetermined to a large extent. It is an established fact that female gender is associated with a lower mortality and that sex steroid hormones influence the immunologic response. Dehydroepiandrosterone (DHEA) seems to have a protective immunologic effect in sepsis. It is still unknown in which way DHEA influences the pathogenesis of sepsis. Therefore, the effect of DHEA application on cytokine concentrations in tumor necrosis factor (TNF) receptor (TNF-RI(-/-)) and interleukin-6 (IL-6(-/-)) knockout mice was determined. In a model of polymicrobial sepsis induced by coecal ligation and puncture (CLP), the effect of DHEA on survival and cytokine concentrations was examined. For clarification of the role of TNF-RI, CLP was performed in TNF-RI knockout mice (TNF-RI(-/-)). In addition, IL-6 knockout mice (IL-6(-/-)) were used to clarify the role of IL-6. Furthermore, experiments were performed in mice that were not genetically modified (wild type, WT). The protective effect of DHEA could be confirmed in this CLP model. DHEA application was associated with a reduction in mortality in WT animals. Moreover, DHEA-treated animals demonstrated a reduction in systemic inflammatory effects, as determined by proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the antiinflammatory cytokine IL-10. In this work, it was shown that the TNF-RI is essential for survival after CLP. DHEA application was associated with a reduction of mortality of 100% in TNF-RI(-/-) mice after CLP to 50%. This result engages, that the effect of DHEA is TNF-RI independent. However, the application of DHEA had no influence on the mortality in IL-6-/- mice. It can be concluded that the protective effect of DHEA in polymicrobial sepsis is mediated IL-6 dependently. DHEA reduces the systemic inflammation, measurable via the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the antiinflammatory cytokine IL-10. IL-6 might be involved in the DHEA-mediated reduction of postseptic complications. In contrast, DHEA seems to be TNF-RI independent. Consequently, DHEA might be useful as an adjunct therapy for the immune modulation in sepsis.

Adjuvants, Immunologic↗