Coagulation disorders following severe trauma: surgeon's role in prevention

INTRODUCTION: Severe trauma must be considered a "systemic disease" that could lead to severe systemic complications. PHYSIOPATHOLOGIC IMPLICATIONS: Coagulation disorders are present in most trauma patients as hemorrhagic disorder, thrombosis, or like in DIC, with both coexistent phenomenon. Trauma determine the activations of intrinsic and extrinsic coagulation pathways, and of platelets. Intrinsic pathway activation induce a pro-coagulant function and the activation of fibrinolytic system. Both system activation explain low incidence of deep venous thrombosis. Post-traumatic activation of extrinsic coagulation lead to thrombin and fibrin production. In trauma patients platelets activation is related to endothelial damage, exposition of collagen, interaction with PAF and presence of microorganisms. Post-traumatic DIC is characterized by procoagulant factors activation, with intravascular deposit of fibrin and thrombosis, and by hemorrhagic disorders due to consumption of platelet and procoagulant factors. Lower levels of antithrombin III, in trauma patients, are strictly related to severity of damage and shock. Coagulation disorders related to sepsis, that often complicate trauma, are added to those determined by trauma, with a negative synergic effect. Medical treatment with massive infusion of colloid and crystalloid solution, and fluid, and massive transfusion of plasma and red blood cells can determine dilutional thrombocytopenia, reduced activity of coagulation factors and reduced haemostatic activity of RBC due to excessive haemodilution--Hct <20%. PREVENTION STRATEGY: To avoid post-traumatic coagulation disorders is important to prevent sepsis, thrombocytopenia and reduced activity of coagulation factors and of RBC, as well as prevent and immediately treat shock. The early use of high dose antithrombin concentrate, is important to prevent DIC and MOFS, and administer subcutaneous or intravenous heparin, in absence of hemorrhagic disorders that contraindicate its use.     

Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming

Epidemiological studies in many distinct human populations have associated low weight or thinness at birth with a substantially increased risk of cardiovascular and metabolic disorders, including hypertension and insulin resistance/type 2 diabetes, in adult life. The concept of fetal "programming" has been advanced to explain this phenomenon. Prenatal glucocorticoid therapy reduces birthweight, and steroids are known to exert long-term organizational effects during specific "windows" of development. Therefore, we hypothesized that fetal overexposure to endogenous glucocorticoids might underpin the link between early life events and later disease. In rats, birthweight is reduced following prenatal exposure to the synthetic glucocorticoid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental "barrier" to endogenous glucocorticoids. Although the offspring regain the weight deficit by weaning, as adults they exhibit permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis activity. Moreover, physiological variations in placental 11beta-HSD2 activity near term correlate directly with fetal weight. In humans, 11beta-HSD2 gene mutations produce a low birthweight, and some studies show reduced placental 11beta-HSD2 activity in association with intrauterine growth retardation. Moreover, low birthweight babies have higher plasma cortisol levels throughout adult life, indicating that hypothalamic-pituitary-adrenal axis programming also occurs in humans. The molecular mechanisms of glucocorticoid programming are beginning to be unraveled and involve permanent and tissue-specific changes in the expression of key genes, notably of the glucocorticoid receptor itself. Thus, glucocorticoid programming may explain, in part, the association between fetal events and subsequent disorders in adult life.     

Bilateral post-traumatic adrenal hemorrhage. Report of a case with acute adrenal insufficiency

Bilateral adrenal haemorrhage of traumatic origin is rarely observed or possibly missed in severely multi-traumatised patients. It can lead to a potentially fatal adrenal shock. Its emergency diagnosis is made by imaging techniques, usually by CT-scan. Early substitution therapy has to be done. This complication emphasizes the importance of an immediate abdominal morphological exploration in multi-traumatized patients when this is feasible.     

Modulation of renal calcium handling by 11 beta-hydroxysteroid dehydrogenase type 2

Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11 beta HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THF+5 alpha THF)/THE as a parameter of 11 beta HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THF+5 alpha THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 +/- 10/7 versus 115/73 +/- 8/6 mmHg; P < 0.001 for systolic; P < 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 +/- 0.05 to 1.18 +/- 0.04 mmol/L (P < 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 +/- 3.6 to 31.9 +/- 3.1 micromol/L GFR (P < 0.01). Fractional calcium excretion increased from 2.4 +/- 0.3 to 2.7 +/- 0.3% (P < 0.01) and was negatively correlated to the fractional sodium excretion during GA (R = -0.35; P < 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R = 0.66; P < 0.0001). Inhibition of 11 beta HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.     

Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol. 11beta-HSD-1 is particularly expressed in adipocytes and liver and appears to be causally linked to the development of type 2 diabetes and the metabolic syndrome. Liver X receptor (LXR)-alpha and -beta are nuclear oxysterol receptors whose key role in lipid metabolic regulation has recently been established. In this study, we show that treatment of adipocytes derived from 3T3-L1 cells and mouse embryonic fibroblasts in vitro with synthetic or natural LXR agonists decreases mRNA expression of 11beta-HSD-1 by approximately 50%, paralleled by a significant decline in 11beta-HSD-1 enzyme activity. Downregulation of 11beta-HSD-1 mRNA by LXRs started after a lag period of 8 h and required ongoing protein synthesis. Moreover, long-term per os treatment with a synthetic LXR agonist downregulated 11beta-HSD-1 mRNA levels by approximately 50% in brown adipose tissue and liver of wild-type but not of LXRalpha(-/-)beta(-/-) mice and was paralleled by downregulation of hepatic PEPCK expression. In conclusion, LXR ligands could mediate beneficial metabolic effects in insulin resistance syndromes including type 2 diabetes by interfering with peripheral glucocorticoid activation.     

Isolated adrenal hemorrhage after blunt trauma: Case report and literature review

Isolated adrenal hemorrhage following blunt abdominal trauma is rare. The wide variation in clinical manifestations and lack of specific biologic markers make its diagnosis difficult. Computed tomography (CT) remains the golden standard for detecting this injury. Although isolated adrenal hemorrhage is usually silent and self-limiting, the presence of adrenal hemorrhage in a patient with trauma is associated with higher injury severity, and coexisting injury to the liver, ribs, kidneys, or spleen is common. Blunt trauma-related acute thoracoabdominal pain and skeletal pain are common problems in the emergency room. Patients should be carefully evaluated according to their trauma mechanism and physical examination. If an unusual complaint is presented (e.g., pain associated with cold seating or pain persisting after general analgesics), the emergency room physician should be aware of adrenal injury, the possibility of associated organ injury, and the potential for adrenal insufficiency. It is also necessary for clinicians to become familiar with common diagnostic tools, treatment options, and trends for noninvasive procedures. Prompt recognition of associated injuries and the potential for mortality with adrenal insufficiency can provide the best guidance for patient treatment and care. In this article, we present the report of a 32-year-old male, who suffered from blunt chest trauma and complained of ill-defined chest pain associated with cold seating. His CT results revealed a left adrenal hemorrhage with a large retroperitoneal hematoma. The patient was treated successfully with conservative observation.     

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 Ringer's 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.     

Role of the 11beta-hydroxysteroid dehydrogenase type 2 in blood pressure regulation

The renal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective mineralocorticoid receptor (MR) from occupation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, but also in human placenta, pancreas, and thyroid. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11betaHSD2 enzyme activity results in overstimulation of the MR by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Recent evidence suggests a role of the 11betaHSD2 in essential hypertension. We found hypertension with no other characteristic signs of AME in the heterozygous father of a child with AME and in a girl with a homozygous gene mutation resulting in a mild deficiency of 11betaHSD2. Moreover, some studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites, suggesting a deficient 11betaHSD2 activity. These abnormalities may be genetically determined. A genetic association of a microsatellite flanking the HSD11B2 gene and hypertension in black patients with end-stage renal disease has been reported. We recently analyzed a CA-repeat allele polymorphism in unselected patients with essential hypertension, but did not find any correlation between this marker and blood pressure. However, we did find an association between this polymorphic CA microsatellite marker and salt sensitivity. Moreover, the activity of the 11betaHSD2, as shown by elevated mean ratios of urinary cortisol to cortisone metabolites, was decreased in salt-sensitive compared with salt-resistant subjects. These findings indicate that variants of the HSD11B2 gene contribute to the enhanced blood pressure response to salt in humans.     

Increased cortisol metabolites and reduced activity of 11beta-hydroxysteroid dehydrogenase in patients on hemodialysis

BACKGROUND: Patients with renal failure have symptoms assumed to be attributable to the accumulation of toxic endo- or xenobiotics. Most of these molecules, especially those with a molecular weight>300 D, have not been identified. In addition to excretion, the kidney is involved in some defined metabolic processes. In the cortical collecting duct, the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) interconverts cortisol (F) and cortisone (E), and the metabolites of these glucocorticoids, tetrahydrocortisol (THF), 5alpha-tetrahydrocortisol (5alpha-THF) and tetrahydrocortisone (THE), are excreted in urine. We hypothesized that first, these metabolites accumulate and second, their concentration pattern changes in patients on hemodialysis. METHODS: THF, 5alpha-THF, THE, F and E were measured in plasma of 63 patients on dialysis and in 34 healthy controls by gas-chromatography-mass spectrometry (GC/MS). In 11 patients, the metabolite clearance was determined during high flux hemodialysis by using a population pharmacokinetic approach. RESULTS: Mean plasma concentrations of THF, 5alpha-THF and THE were more than five times higher and those of E lower in patients than in controls. The ratios of (THF + 5alpha-THF)/THE and F/E were increased in patients, indicating a reduced activity of 11beta-HSD2. Intradialytic clearances were between 120 and 300 mL/min and not sufficient to normalize the steroid concentrations. CONCLUSION: Patients on hemodialysis exhibit pronounced increases in THF, 5alpha-THF and THE concentrations in plasma with insufficient removal during dialysis. Due to a reduced 11beta-HSD2 activity, an abnormal pattern of the concentrations of these cortisol and cortisone metabolites is observed. Since many signs and symptoms in uremic patients resemble those observed in subjects with glucocorticoid excess, the clinical relevance of the high concentrations of these glucocorticoid metabolites deserves further investigation.     

Brainstem hypoperfusion in severe symptomatic vasospasm following aneurysmal subarachnoid hemorrhage: role of basilar artery vasospasm

Summary Background. The hemodynamic effects of vertebrobasilar vasospasm are ill defined. The purpose of this study was to determine the effects of basilar artery (BA) vasospasm on brainstem (BS) perfusion. Methods. Forty-five patients with delayed ischemic neurological deficits (DIND) following aneurysmal subarachnoid hemorrhage (SAH) underwent cerebral angiography prior to decision-making concerning endovascular treatment. BA diameter was compared with baseline angiogram. Regional brainstem (BS) cerebral blood flow (CBF) was qualitatively estimated by ^99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD-SPECT). Findings. Delayed BS hypoperfusion was found in 22 (48.9%) of 45 patients and BA narrowing of more than 20% was found in 23 (51.1%). Seventeen of 23 (73.9%) patients with BA narrowing of more than 20% experienced BS hypoperfusion compared to 6 of 22 (27.3%) patients with minimal or no narrowing (p = 0.0072). Patients with severe and moderate BS hypoperfusion had higher degree of BA narrowing compared to patients with normal BS perfusion and mild BS hypoperfusion (p < 0.001). The three-month outcome of patients n-22) with BS hypoperfusion was significantly worse compared to patients (n-23) with unimpaired (p = 0.0377, odd ratio for poor outcome 4, 1.15–13.9 95% confidence interval). Interpretation. These findings suggest that the incidence of BA vasospasm in patients with severe symptomatic vasospasm is high and patients with significant BA vasospasm are at higher risk to experience BS ischemia. Further studies should be done to evaluate the effects of endovascular therapy on BS perfusion and the impact of BS ischemia on morbidity and mortality of patients with severe symptomatic vasospasm.