Dehydroepiandrosterone (DHEA): a steroid with multiple effects. Is there any possible option in the treatment of critical illness?

DHEA is the major circulating steroid in human blood and it is a central intermediate in the metabolic pathway of sex steroid hormone formation. Although the specific effect of DHEA is still unclear it was demonstrated that DHEA modulates several physiologic processes including metabolism and cardiovascular function. Furthermore, a profound immunomodulatory effect of DHEA was reported. Several data demonstrate the beneficial effect of DHEA in situations of critical illness including trauma hemorrhage and sepsis. Accordingly DHEA improved the survival rate and clinical situation in several animal models of trauma hemorrhage and systemic inflammation. This effect was paralleled by profound changes of immunologic parameters, organ function, and heat shock protein production. Therefore, it was claimed that DHEA may be a new alternative/additive in the treatment of trauma and sepsis. In line, DHEA is a frequently used drug in the field of anti-aging medicine, it is an over-the-counter drug in several countries, and it was reported that DHEA medication is free of major side effects. Therefore, DHEA could easily be used in a clinical trial investigating its effects in critical ill patients. This article reviews the reported effects of DHEA on the base of the literature with the specific focus on trauma and sepsis/critical illness including its clinical perspectives.

[Impact of hypothermia on the severely injured patient]. / Bedeutung der Hypothermie in der Traumatologie.

Accidental hypothermia is a common complication in severely injured patients. Risk factors include environmental exposure of the patient at the accident site or in the clinic, infusion of cold fluids, hemorrhagic shock and anesthetics which influence thermoregulation. In contrast to animal studies, human studies and clinical experiences have identified accidental hypothermia of the severely injured patient to be associated with increased complication and mortality rates. As a consequence, hypothermia together with acidosis and coagulopathy, have been coined the lethal triad in severely injured patients. On a cellular level hypothermia reduces cellular activity and metabolism resulting in reduced oxygen consumption, which is therapeutically used in patients following cardiac arrest. However, the activity of important enzymes, such as those of the coagulation pathway, is simultaneously down regulated. Hypothermia-induced coagulopathy, which is refractory to substitution of coagulation factors, is a major complication of hypothermia in traumatized patients. Therefore, hypothermic trauma patients with hemodynamic instability require aggressive rewarming.

[Bite injuries of the hand]. / Bissverletzungen der Hand.

Bite injuries of the hand have a clearly increased risk for infection compared with other regions. Surgical treatment of the wound is indicated, and the debridement must be done thoroughly and with consideration of the wound closure. Antibiotic therapy may be indicated in addition to the surgery if signs of infection exist. Antibiotics alone are not a suitable treatment. Common complications in cases of deficient primary therapy are flexor tenosynovitis, purulent arthritis, and phlegmons of the dorsal hand. These are emergencies and need immediate surgical intervention.

[Damage control orthopaedics in polytraumatised patients with lower leg injuries]. / Verletzungsadaptiertes Vorgehen bei Unterschenkelverletzungen des Schwerverletzten.

In polytraumatised patients, fracture management depends on the overall injury severity. For decision making, patients are grouped in one of four categories (STABILE, BORDERLINE, INSTABLE and IN EXTREMIS). STABILE patients should and BORDERLINE patients may undergo primary definitive fracture stabilisation; in contrast, this is not recommended for INSTABLE or IN EXTREMIS patients. The marginal soft tissue envelope of the tibia predisposes for open fractures, compartment syndrome, and wound infections. Therefore the management of lower leg injuries is demanding, especially in polytraumatised patients. Bilateral tibia fractures and ipsilateral tibia and femur fractures represent a special entity. For these injuries special algorithms, which consider the soft tissue status of the tibia and the overall injury severity, have been developed. The indication for fasciotomy covers a wide field and may be performed prophylactically. The decision for amputation is based on the patient's general condition and the soft-tissue and neurovascular status. Scoring systems are useful for decision making, however individual decisions should be made.

[Treatment strategies for gunshot wounds of the extremities]. / Versorgungsstrategien bei Schussverletzungen der Extremität.

The incidence of gunshot wounds is increasing also in Europe and surgeons in urban trauma centers are more frequently confronted with this type of injury. Since there is no established treatment algorithm for gunshot injuries to the extremities, the surgeon should rely on established soft tissue injury and fracture protocols. Gunshot fractures with minor soft tissue destruction should be treated as closed fractures. The treatment of choice for unstable fractures is early internal stabilization, whereas stable fractures may be treated by functional bracing. The administration of an antibiotic prophylaxis for fractures with minor soft tissue injury is controversial. Gunshot fractures with major soft tissue injury should be treated as open fractures. Debridement of nonviable tissue and external fixation are recommended. Prophylactic intravenous antibiotics are mandatory and prophylactic fasciotomy is often required. Upon definitive internal stabilization, bone grafting should be considered since gunshot fractures are usually associated with a high degree of comminution. Articular gunshot injuries are treated as open joint injuries and require irrigation, debridement, foreign body removal and antibiotic prophylaxis.

Weakened [corrected] taste-LPS association during endotoxin tolerance.

In naive individuals, the administration of bacterial lipopolysaccharide (LPS) provokes a rapid systemic increase in pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, inducing an acute phase response including sickness behavior. Strong associative learning occurs when relevant gustatory/olfactory stimuli precede the activation of the immune system, affecting long-term individual food selection and nutritional strategies. Repeated LPS administration results in the development of an endotoxin tolerance status, characterized by a drastic reduction in the LPS-induced cytokine response. Here we investigated how the postprandial categorization of a relevant taste (0.2% saccharin) changed after administration of a high dose of LPS (0.5 mg/kg i.p.) in LPS-tolerant animals. Determination of the consummatory fluid intake revealed that, in contrast to LPS-naive rats, taste-LPS association did not occur during endotoxin tolerance. Ninety minutes after the single association trial, the plasma responses of TNF-alpha, IL-1beta and IL-6 were completely blunted in LPS-tolerant animals, which also resulted in low LPS-adipsogenic and LPS-anorexic effects. These findings indicate that an identical immune challenge can result in completely different neuro-behavioral consequences depending on the immune history of the individual, thus revealing part of the complex interconnection between the immune and neuro-endocrine systems in regulating food selection and consumption during the infectious process.

The emergency room transfusion score (ETS): prediction of blood transfusion requirement in initial resuscitation after severe trauma.

The presented study was initiated to develop a scoring system for the prediction of red blood cell transfusion requirement in the early care of trauma patients. All trauma patients admitted to our institution who needed trauma team activation were evaluated during a 4-year period. A set of nine parameters with possible predictive value for the need of blood transfusion was recorded. All relevant data can be acquired during the first 10 min in the emergency room (ER). The data underwent multivariate logistic regression analysis for correlation and the calculation of predictive power. To transform the model into a practical score, we rounded all coefficients. The predictive power of the score was evaluated based on a linear regression equation. Of the 1103 patients (Injury Severity Score [ISS] 21 +/- 16) included in the study, 116 (10.5%; ISS 39 +/- 18) received blood in the ER. Early transfusion need was significantly correlated with systolic blood pressure (SBP) <90 mmHg (coefficient 2.5), SBP 90-120 mmHg (1.5), free fluid in abdominal ultrasound (2.0), clinically unstable pelvic ring fracture (1.5), age 20-60 years (0.5), age >60 years (1.5), admission from scene (1.0), traffic accident (1.0) and fall from >3 m (1.0). The probability for transfusion exponentially increased with the sum of points in the ER transfusion score, i.e. from 0.7% at one point to 5% at three points and 97% at 9.5 points maximum. To establish a practical cutoff point (risk <5%) a low-risk group was defined at

Metoclopramide and cellular immune functions during polymicrobial sepsis.

Metoclopramide (MCP) has been demonstrated to restore the depressed cellular immune function after hemorrhage by increasing the release of the immunomodulatory pituitary hormone prolactin. We investigated the effect of MCP on serum prolactin concentrations, on cellular immune functions (immune cell distribution, splenocyte proliferation, apoptosis and cytokine release) and on the survival 48 h after induction of a polymicrobial sepsis in mice. Administration of MCP increased circulating serum prolactin concentrations and splenocyte apoptosis rate and improved cellular cytokine release, but did not affect mortality of septic mice. We therefore conclude that administration of MCP modulated splenocyte apoptosis and cytokine release in a murine model of sepsis without an impact on the survival. Furthermore, this effect may be mediated by an increased endogenous prolactin release.

[Significance of physical examination and radiography of the pelvis during treatment in the shock emergency room]. / Wertigkeit der körperlichen und radiologischen Basisdiagnostik des Beckens in der Schockraumbehandlung.

AIM: Physical examination and radiography of the pelvis is part of most routine protocols in the emergency room (ER) management of blunt trauma patients. The purpose of this study was to determine the usefulness of these diagnostic tests with respect to diagnostic accuracy, therapeutic consequences, and prognosis in severely injured patients. METHOD: In a prospective study including all trauma patients admitted to the ER, physical examination and clinical management were evaluated. All patients underwent physical examination of the pelvis and were grouped into two categories: patients without (group I) and with (group II) clinical pelvic instability. A comparison between these two groups was made for standard demographic data, indices of shock, diagnostic and therapeutic procedures, and results. RESULTS: During a 45-month period a total of 1160 patients were enrolled: 979 subjects (ISS 21+/-16) with blunt trauma were included in this analysis. Of these, 929 patients had negative (group I) and 51 (group II) positive examination results for clinical stability of the pelvis. When comparing these two groups, group II patients had a higher injury severity score, higher incidence of shock with a lower initial systolic blood pressure, a lower initial hemoglobin, and a higher rate of associated severe chest and abdominal injuries (AIS > or = 3). Among the 51 patients with abnormal pelvis instability, there were 6 type A, 16 type B, and 27 type C fractures, whereas in two cases no pelvic fracture could be found. Of the 928 patients without positive clinical signs, 866 (93%) had no pelvic fracture. There were 40 type A, 19 type B, and 3 type C fractures missed on clinical examination. The physical examination had a sensitivity of 44% and specificity of 99% for detecting pelvic fracture. A comparison between groups I and II showed the patients with positive physical pelvic examination to have greater transfusion requirements and a higher rate of surgical intervention for pelvic stabilization and blood control. CONCLUSION: The clinical diagnosis of pelvic instability should result in an immediate order for blood products, taking surgical intervention into account. Pelvic radiographs in the ER are required for early surgical management. In patients with negative pelvis examination results, a routine pelvic radiograph is recommended because clinical examination cannot reliably rule out surgically significant pelvic fractures (20%) in the severely injured and intubated blunt trauma patient.

Dehydroepiandrosterone decreases mortality rate and improves cellular immune function during polymicrobial sepsis.

OBJECTIVE: Sepsis is associated with a marked depression of cellular immune function. The steroid hormone dehydroepiandrosterone (DHEA) is proposed to have immunoenhancing activities. We, therefore, investigated the effect of DHEA on the mortality rate and cellular immune functions in an experimental model of sepsis. DESIGN: Randomized animal study. SETTING: Level I trauma center, university research laboratory. SUBJECTS: Male NMRI mice. INTERVENTIONS: Mice were subjected to laparotomy (sham) or cecal ligation and puncture (CLP). Mice were treated with (sham/DHEA; CLP/DHEA) or without (sham; CLP) the steroid hormone DHEA (30 mg/kg sc). Animals were killed 48 hrs after the onset of sepsis. MEASUREMENTS AND MAIN RESULTS: The survival rate of septic mice was determined 24 and 48 hrs after onset of sepsis. Forty-eight hours after the septic challenge, a white blood cell count was performed and serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations were monitored using ELISA. Furthermore, the delayed type of hypersensitivity (DTH) reaction was evaluated on the basis of ear pinna swelling after dinitrofluorobenzene (DNFB) administration, and clinical variables (body weight, temperature, heart rate, fluid input/output, food intake) were monitored using metabolic cages. DHEA administration improved the survival rate (87% vs. 53% after 48 hrs; p <.001). This was accompanied by a restoration of the depressed DTH reaction and a reduction in TNF-alpha serum concentrations (20.7 +/- 1.4 pg/mL vs. 32.4 +/- 6.6 pg/mL). CONCLUSIONS: These results demonstrate that DHEA administration leads to an increased survival following a septic challenge. The immunoenhancing effect of DHEA is accompanied by a reduction of TNF-alpha release and an improved activity of T-cellular immunity. DHEA administration may, therefore, be beneficial in systemic inflammation.

Levels of antibodies to endotoxin and cytokine release in patients with severe trauma: does posttraumatic dysergy contribute to organ failure?

BACKGROUND: We conducted a prospective study in patients with multiple injuries investigating the time course of trauma-related changes of systemic immunologic defense mechanisms. METHODS: Patients with multiple injuries with Injury Severity Scores of more than 20 were included if they survived for more than 4 days after injury. Further inclusion criteria were no local or systemic infection (pneumonia, sepsis, soft-tissue infection, acquired immunodeficiency syndrome, tuberculosis, etc.) at the time of injury and no history of liver disease, bowel disease, or abdominal surgery. Serum endotoxin levels were measured from peripheral venous blood, as were the immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against lipid A and against the core polysaccharide of endotoxin (lipopolysaccharide [LPS]), during the course of intensive care management. Serial central venous levels of interleukin-6 were determined as a marker of the inflammatory response. RESULTS: The patients were grouped according to their survival, with the survivors belonging to group S (48 patients) and the nonsurvivors belonging to group N (16 patients). The time of death for the nonsurvivors was between days 10 and 32 after the initial trauma. Thirteen of these patients (81%) died of multiple organ failure between days 12 and 17, two died of head trauma, and one died of sepsis. In patients who died of multiple organ failure, a significantly lower production of the IgM and IgG antibodies (AB) against lipid A and LPS was found before death (lipid A IgM-AB, day 11: group N, 29 +/- 11 U/mL; group S, 106 +/- 16 U/mL; p = 0.008; lipid A IgG-AB, day 11: group N, 18 +/- 9 U/mL; group S, 57 +/- 18 U/mL; p = 0.007; LPS IgM-AB, day 11: group N, 36 +/- 14 U/mL; group S, 122 +/- 23 U/mL; p = 0.009; LPS IgG-AB, day 11: group N, 17 +/- 12 U/mL; group S, 56 +/- 19 U/mL; p = 0.03). Interleukin-6 levels were significantly increased in the nonsurvivors (day 1: group N, 1,095 +/- 112 pg/mL; group S, 393 +/- 67 U/L; p = 0.008). CONCLUSION: In patients who died of severe trauma and in whom the cause of death was multiple organ failure, a significantly lower production of antiendotoxin antibodies was measured shortly before death. An insufficient immune defense (dysergy) may be involved in the pathomechanisms leading to the development of organ dysfunction.

Effects of beta-adrenoceptor-blockade on stress-induced adrenocorticotrophin release in humans.

We investigated the mechanisms of stress-induced alterations in adrenocorticotrophin (ACTH) release. Tandem parachutists received either a placebo or the beta-adrenoceptor antagonist propranolol prior to a first time parachute jump. Blood samples were drawn 4 h before, immediately after, and 1 h after the jump. Cortisol and catecholamine concentrations displayed a significant stress-induced increase in both groups. The ACTH plasma concentrations significantly increased in the placebo and the propranolol group, with significantly more pronounced changes in the propranolol-treated subjects compared to the placebo group. These data demonstrated a stress-induced increase of ACTH plasma concentrations in humans that was enhanced by beta-blockade.

Endocrine mechanisms of stress-induced DHEA-secretion.

Acute psychological stress of a first time parachute jump stimulated DHEA and cortisol secretion in healthy volunteers. A significant shift from cortisol to DHEA occurred during this stress exposure. This effect was more pronounced in subjects receiving the beta-adrenoceptor antagonist propranolol prior to the jump. In contrast, infusion of epinephrine (0.10 microgram/kg/min) or norepinephrine (0.15 microgram/kg/min) for 20 min neither affected DHEA plasma levels nor the DHEA/cortisol ratio. However, pretreatment with propranolol resulted in a significant increase of the DHEA/cortisol ratio upon infusion of the beta-adrenoceptor agonist epinephrine. These data demonstrate that during acute psychological stress stimulation of adrenal steroid release is accompanied by a shift towards DHEA. Augmentation of this effect by beta-adrenoceptor blockade indicates a beta-adrenoceptor-dependent mechanism affecting DHEA release.

Expression and in-vivo modulation of alpha- and beta-adrenoceptors on human natural killer (CD16+) cells.

Expression and in-vivo modulation of beta- and alpha-adrenoceptors on peripheral human natural killer (CD16+) cells was investigated. Ligand binding studies revealed that CD16+ lymphocytes express beta2, alpha1-, alpha2- but not beta1-adrenoceptors. Infusion of adrenaline, but not noradrenaline, significantly decreased beta2- and alpha1-adrenoceptor numbers on NK cells. Both catecholamines did not appreciably alter alpha2-adrenoceptor numbers. Additional analyses showed that adrenaline administration increases alpha2-adrenoceptor numbers on peripheral mononuclear blood cells (PBMC) and T-cell subsets (CD4+, CD8+) in contrast to decreased receptor numbers on CD16+ cells. These data demonstrate a specific effect of increasing levels of circulating catecholamines on beta2-adrenoceptors on NK cells.

Epinephrine or norepinephrine fail to influence pituitary-adrenal secretion in man.

It is unknown whether plasma catecholamines have direct physiologic effects on pituitary-adrenocortical secretion in man. Therefore we investigated the effects of epinephrine and norepinephrine on plasma concentrations of adrenocorticotropin (ACTH), beta-endorphin and cortisol. Nineteen healthy male volunteers received infusions of either NaCl, epinephrine (0.10 micrograms/kg/min) or norepinephrine (0.15 micrograms/kg/min) for 20 minutes. 30 min before to 120 min after the infusion blood was continuously drawn to determine plasma levels of epinephrine, norepinephrine, and cortisol. In addition, ACTH and beta-endorphin plasma concentrations were analyzed at 6 time points before, during and after infusion. Infusion of catecholamines increased epinephrine and norepinephrine concentrations in physiological ranges as observed during intense psychological stress or exhausting physical exercise. However, these increases in catecholamine plasma levels neither affected concentrations of POMC-derived hormones nor plasma levels of cortisol. We conclude that in man, physiologic increases in circulating catecholamines have no influence on pituitary-adrenal hormone concentrations.

Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms.

Increases in catecholamines have been shown to induce changes in migration of lymphocytes, in particular NK cells. To analyze the mechanisms of catecholamine-induced NK cell trafficking, normal healthy male human subjects and splenectomized individuals were infused with either adrenaline (0.10 microgram/kg/min), noradrenaline (0.15 microgram/kg/min), or NaCl i.v. for 20 min. Lymphocyte subsets (CD3+, CD4+, CD8+) transiently increased after administration of both catecholamines, with most pronounced increases (up to 600%) in NK cell numbers (CD16+ or CD56+) after infusion of adrenaline. These changes in NK cell numbers and function were accompanied neither by alterations in expression of adhesion molecules (CD11a), CD11b, CD31, CD43, CD44, CD62L) on NK cells nor by changes in plasma concentrations of soluble (s) adhesion molecules (sVCAM-1, sICAM-1, sE-selectin). Comparable increases in lymphocyte subsets were observed in splenectomized subjects, suggesting lymphocyte recruitment from other sources than the spleen. Furthermore, catecholamine-induced increases in lymphocyte subsets could be inhibited by pretreatment with the nonselective beta-adrenoceptor antagonist propranolol, but not by the beta1-selective antagonist bisoprolol. These data demonstrate that adrenaline and noradrenaline modulate the migratory capacity of human NK cells via spleen-independent beta 2-adrenoceptor mechanism.