Neuroendocrine responses mediate macrophage function after trauma

BACKGROUND: Clearly understanding the interactions between macrophage (M phi)-generated inflammatory mediators and the neuroendocrine system in regulating immune function after traumatic injury may aid in reversing trauma-mediated immune dysfunction and diminish the incidence and severity of infection in the traumatized patient. METHODS: Trauma consisted of an open femur fracture and 40% retro-orbital hemorrhage (Trauma) or anesthesia alone (Control). Female Balb/C mice (6-8 weeks) with intact adrenal glands (Intact) or a bilateral adrenalectomy (ADX) were used. For glucocorticoid studies, corticosterone or a vehicle was administered via intraperitoneal (ip) injection 2 hours before the trauma. Splenic M phis were harvested and prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) production, and mRNA, cyclooxygenase-2 (COX-2) protein, and nuclear factor kappa B (NF-kappa B) activity were measured. RESULTS: M phi, PGE(2) and IL-6 production in Trauma+Intact mice was significantly increased compared with Control+Intact mice. Adrenalectomy decreased these levels to Control levels. Similar changes were observed for COX-2 and IL-6 expression. M phi nuclear NF-kappa B levels were increased in Trauma+Intact mice compared with controls. Adrenalectomy abrogated this increase. Treating Trauma+Intact mice with RU-486 did not restore PGE(2) and IL-6 production or COX-2 and IL-6 messenger RNA to control levels. Administering exogenous glucocorticoid to Intact mice did not increase PGE(2) and IL-6 production or COX-2 and IL-6 mRNA to Trauma levels. CONCLUSIONS: The neuroendocrine system upregulates certain M phi inflammatory mediators, including PGE(2), IL-6, and NF-kappa B, after trauma. This upregulation does not seem to be mediated via glucocorticoids and possibly may be mediated via catecholamines. Elucidation of the interactions between the neuroendocrine system, the immune system, and inflammatory mediator secretion might provide novel therapeutic strategies for the injured patient.     

Effect of enhanced macrophage function on early wound healing

Although the macrophage is important to wound healing, research has focused on its relationship to fibroblast and collagen synthesis. This study was designed to assess effects of enhanced macrophage function on early wound healing, before established collagen synthesis. Sprague-Dawley rats had dorsal incisions after one of three treatment regimens: (1) saline solution, 0.5 ml administered intravenously, (2) intravenous glucan, a macrophage stimulant, 20 mg; (3) topical glucan, 20 mg. Intravenous therapy was administered 24 hours before and after incision. Breaking strength was significantly increased (p less than 0.01) by both intravenous glucan (49.8 +/- 5.5 gm) and topical glucan (59.7 +/- 5.6 gm) on the fourth day after incision, compared with controls (22.0 +/- 2.6 gm). Similar results occurred on the seventh day after incision. Although formalin fixation significantly enhanced breaking strength in fresh control wounds (22.0 +/- 2.6 vs 39.5 +/- 2.2 gm), no increase occurred in wounds treated with intravenous glucan (49.8 +/- 5.0 vs 55.3 +/- 6.4 gm), indicating maximal cross-linking of collagen. Collagen synthesis, reflected by tritiated proline uptake, was no different in control versus glucan groups. Supernatants from control or glucan-activated macrophages were injected intraperitoneally or applied topically in the rat model. Activated supernatant, both intraperitoneal and topical, resulted in increased breaking strength on the fourth day after incision. Formalin fixation did not increase breaking strength in the activated supernatant groups. We conclude that enhanced macrophage function increases early wound breaking strength. This effect appears unrelated to collagen synthesis but may be related to increased cross-linking of collagen. Similar effects are seen with activated macrophage secretory products administered intraperitoneally or topically.     

Variation in trauma resuscitation and its effect on patient outcome.

There were significant differences in the time taken to resuscitate 257 trauma patients from four internationally recognized trauma centres. The fastest unit completed resuscitation in 15 min while the slowest took 105 min. This variation was not explained by differences in the type of patient dealt with, seniority of the team leader, or the number of personnel in the trauma team. Although there were significant differences between the units with regard to these parameters, they did not account for the resuscitation time variations. The average post-qualification time of the team leader at the fastest unit was 2 years. Although the slowest unit had the smallest trauma team (two people), larger numbers of personnel did not shorten resuscitation times. The time taken to carry out the ABC of the primary survey was significantly correlated with patient's physiological change in the resuscitation room (R = -0.63, P less than 0.0001 with systolic blood pressure; R = -0.68, P less than 0.01 with the revised trauma score). A multiple regression with survival as the dependent variable revealed that this time was also a predictor of the patient's eventual outcome (t = 3.18, P less than 0.005).     

Rehabilitation of the trauma patient.

Many rehabilitation methods are directed at prevention during the acute management of the trauma patient. Their success is measured by the absence of secondary disabilities. Their cost in relation to health care can be estimated. Figures from 1972 showing cost estimates for treatment of common complications are as follows: Decubitus ulcers $7,000, Urinary tract infection 5,000, Kidney stones 5,000, Thrombophlebitis with pulmonary embolism 4,000, Pneumonia 3,000, Contractual deformities 2,000. Current inflation would revise the above costs at least 25%. It is also important to note that the cost of such complications to the individual is immeasurable in time and energy and quality of life.     

Hand infections in the trauma patient.

Infections are a frequent, unfortunate complication seen in orthopedic trauma patients. The specific anatomy of the upper extremity makes it an easy target for opportunistic organisms, especially after an acute traumatic event. In addition, pathogenic factors and host factors can contribute to the severity of the infection. Meticulous wound management, identification of the offending organism(s), and tailoring of care to the special needs of the very sick trauma patient limit complications.     

Protective effect of glucan-enhanced macrophage function in experimental pancreatitis

In an effort to assess the impact of enhanced macrophage function in acute pancreatitis, mice were subjected to a choline-deficient diet supplemented by ethionine to induce necrotizing pancreatitis. Treatment with the macrophage stimulant glucan resulted in improved survival rates (58 percent versus 14 percent) and maintenance of pancreatic architecture. Glucan treatment also resulted in decreased plasma and peritoneal trypsin activity, as well as increased trypsin-binding activity in the blood and peritoneal cavity. Plasma interleukin-1, as well as macrophage production of interleukin-1, were increased in the glucan-treated mice, which indicated enhanced macrophage function. These composite findings suggest that by enhancing diverse aspects of reticuloendothelial function, clinical use of immunomodulators may have significant impact on the pathogenesis of acute pancreatitis.     

Hypothermia and the trauma patient.

Hypothermia has profound effects on every system in the body, causing an overall slowing of enzymatic reactions and reduced metabolic requirements. Hypothermic, acutely injured patients with multisystem trauma have adverse outcomes when compared with normothermic control patients. Trauma patients are inherently predisposed to hypothermia from a variety of intrinsic and iatrogenic causes. Coagulation and cardiac sequelae are the most pertinent physiological concerns. Hypothermia and coagulopathy often mandate a simplified approach to complex surgical problems. A modification of traditional classification systems of hypothermia, applicable to trauma patients is suggested. There are few controlled investigations, but clinical opinion strongly supports the active prevention of hypothermia in the acutely traumatized patient. Preventive measures are simple and inexpensive, but the active reversal of hypothermia in much more complicated, often invasive and controversial. The ideal method of rewarming is unclear but must be individualized to the patient and institution specific. An algorithm reflecting newer approaches to traumatic injury and technical advances in equipment and techniques is suggested. Conversely, hypothermia has selected clinical benefits when appropriately used in cases of trauma. Severe hypothermia has allowed remarkable survivals in the course of accidental circulatory arrest. The selective application of mild hypothermia in severe traumatic brain injury is an area with promise. Deliberate circulatory arrest with hypothermic cerebral protection has also been used for seemingly unrepairable injuries and is the focus of ongoing research.     

Trauma faculty and trauma team activation: impact on trauma system function and patient outcome.

OBJECTIVE: To determine the impact of the presence of an attending trauma surgeon during trauma team activation on system function and patient outcome. METHODS: After a retrospective review of medical records and trauma registry, a comparative study between two American College of Surgeons Committee on Trauma Level I trauma centers was performed. One center (Hennepin County Medical Center) required a chief surgical resident, two junior residents, and a board-certified emergency medicine faculty to be present in the emergency department for all trauma team activations. The attending trauma surgeon was notified at the time of trauma team activation and was neither required to be present in the emergency department at time of patient arrival nor in the hospital 24 h/day. The other center (St. Paul Ramsey Medical Center) required a chief surgical resident, two junior residents, a board-certified emergency medicine faculty member, and an attending trauma surgeon to be present in the emergency department for all trauma activations and in hospital 24 hours/day. Over a 21-month period, all major trauma patients (Injury Severity Score > 15 or emergent operation within 4 hours of admission and any Injury Severity Score) that triggered trauma team activation were examined. Resuscitation time, time to incision, probability of survival, and mortality were analyzed. RESULTS: Resuscitation time was shorter at St. Paul Ramsey Medical Center when compared with Hennepin County Medical Center. Analysis by mechanism of injury demonstrates that this was true for blunt trauma (39+/-13 vs. 27+/-12 minutes, p = 0.001) and for penetrating trauma (28+/-14 vs. 24+/-17 minutes, p = 0.01). Subgroup analysis of penetrating trauma victims demonstrated that there was a significant difference in resuscitation times for gunshot wounds but not for stabs. There was no difference in how quickly operations could be initiated for blunt trauma patients. However, in penetrating cases, time to incision was significantly shorter at St. Paul Ramsey Medical Center (50+/-29 vs. 66+/-43 minutes, p = 0.01). There was no significant difference in mortality for any category of Trauma and Injury Severity Score probability of survival in blunt or penetrating trauma. Analysis of "in-house" and "out-house" time intervals demonstrated no difference in survival in any mechanism of injury, nor was there a difference in overall mortality. CONCLUSION: The presence of a trauma surgeon on the trauma team reduced resuscitation time and reduced time to incision for emergent operations, particularly in penetrating trauma. However, it had no measurable impact on mortality based on Trauma and Injury Severity Score probability of survival. Attending trauma surgeon presence on the trauma team improves in-hospital trauma system function without affecting patient outcome.     

Renal trauma in the multiple injured patient.

Immediate radiological evaluation of renal injuries by a large dose or infusion excretory urogram resulted in a definitive diagnosis in 87% of the cases. Further radiological evaluation or exploration was required to make a definitive diagnosis in the remaining 13%. Blunt external trauma was responsible for 94% of the renal injuries. Less morbidity and a sharp reduction in delayed renal operation followed the introduction of immediate surgical management with the more severe types of renal injury. Clamping of the renal vessels prior to opening Gerota's fascia prevents reactivation of hemorrhage and allows for a deliverate operation with conservation of undamaged renal tissue. Associated injuries were present in 73% of the patients, including intra-abdominal injuries in 42%. The over-all nephrectomy rate of 5% in this study compares favorably to the nephrectomy rate in studies reporting the expectant management of renal injuries.     

Cardiac contusion. The effect on operative management of the patient with trauma injuries

Sixty-four patients with cardiac contusion documented by electrocardiographic changes and creatine kinase MB fraction assay following blunt chest injury were reviewed to assess the impact of cardiac contusion on subsequent management. Fifty-eight patients had elevated creatine kinase MB levels; 35 patients had electrocardiographic abnormalities, including ST-segment and T-wave changes (25), premature ventricular contraction (ten), right bundle-branch block (nine), atrioventricular block (three), atrial fibrillation (three), and premature atrial contraction (two). Thirty patients underwent general anesthesia. There were only four perioperative complications: ventricular ectopy, ventricular fibrillation, nodal rhythm, and pulmonary edema. There were no deaths attributable to cardiac contusion. In summary, patients with blunt trauma who have sustained a cardiac contusion can undergo elective operation with a low incidence of complication. In the emergency setting, however, hemodynamic monitoring for early detection of arrhythmias is indicated.     

The effect of patient age upon survival in pediatric trauma

Developmental changes in the anatomy and physiology of growing children are thought to improve the survivability of older children to significant injury. The effect of age upon survival, however, is poorly defined. Data for 4,615 patients less than 15 years old from a statewide trauma center registry were analyzed. Injury and survival were characterized by Abbreviated Injury Scale (AIS, 1985 revision), Injury Severity Score (ISS), Revised Trauma Score (RTS), and probability of survival [P(s)] and Z by TRISS. Patients were separated into age groups of 0 through 4, 5 through 9, and 10 through 14 years. The survival rate for patients with a maximum AIS 3 for any region was significantly higher in the 10-14-year age group. There were no significant differences in survival rates from head, thoracic, and abdominal injuries stratified by AIS among the three age groups. Survival rates for ISS cohorts were consistently lowest in the 0-4-year age group, but differences failed to reach significance. Survival for RTS and P(s) intervals were similar for all ages. The Z statistic reached significance for all children (Z = 4.717, W = 1.049), and for each group (Z = 2.203-3.029). Corresponding values of the W statistic suggest approximately one additional unexpected survivor per 100 admitted children when compared with the Major Trauma Outcome Study. Logistic regression for patients with all data required for TRISS showed no significant effect for any of the three age groups. We conclude that for this patient set, survival after childhood injury is independent of the age groups used in this study, after controlling for injury severity.     

Hypothermia in the trauma patient

Hypothermia is a common finding in severely injured patients. Historically described as a consequence of wartime casualties where cold exposure was common, this topic has resurfaced in the trauma literature because of the increasing recognition of the morbidity and mortality associated with hypothermia. Hypothermia, along with acidosis and coagulopathy, has been identified as a component of the "lethal triad" in injured patients, and has been shown to contribute to increased mortality in these patients. Decreases in core temperature during the course of initial evaluation and resuscitation are common, and can contribute to poor outcomes in the injured patient. As induced hypothermia has been shown to be beneficial in some clinical situations, recent animal studies have attempted to investigate whether hypothermia in the trauma patient has any beneficial effects. This review examines the incidence and pathophysiology of hypothermia, and discusses mechanisms of heat loss and rewarming techniques that can be utilized in the trauma patient.     

Occult pneumothorax in the mechanically ventilated trauma patient.

The term occult pneumothorax (OP) describes a pneumothorax that is not suspected on the basis of clinical examination or plain radiography but is ultimately detected with thoracoabdominal computed tomography (CT). This situation is increasingly common in trauma care with the increased use of CT. The rate is approximately 5% in injured people presenting to hospital, with CT revealing at least twice as many pneumothoraces as suspected on plain radiography. Whereas pneumothorax is a common and treatable cause of mortality and morbidity, there is substantial disagreement regarding the appropriate treatment of OP. The greatest controversy is in patients in the critical care unit who require positive-pressure ventilation. There is little current evidence to direct the proper management of ventilated trauma patients with OP, and no studies have focussed specifically on these patients. Future randomized trials will need to consider the potential effects of OP on pulmonary mechanics and potential influences on the known risks of ventilator-induced lung injury associated with mechanical ventilation.     

Beneficial effect of inguinal hernioplasty on testicular perfusion and sexual function

Aim  To evaluate the effects of Lichtenstein tension-free inguinal hernioplasty on sexual function and generic quality of life, testicular volume, and perfusion. Patients and methods  In a prospective study, testicular volume, testicular perfusion, sexual function, generic quality of life, chronic inguinal pain, and groin sepsis were investigated before and 3 and 9 months after surgical hernia repair. Results  Forty male patients completed this study. No differences in testicular volume or in peak systolic velocity were observed between the hernia and healthy sides of the body (P > 0.05). Preoperatively, there was a significantly higher end diastolic velocity (P < 0.04) and resistive index (P < 0.001) on the hernia side compared with the normal side; these elevations returned to normal postoperatively. Three months postoperative, the studied sexual function domains, except orgasm domain, and total sexual score presented significant improvement (P _s < 0.05 and 0.001 respectively). By the end of the study, the mean total sexual score and the number of patients with enhanced total score had showed further clinical progress. The total generic quality-of-life score, general health perception and physical function, vitality, and social domains were statistically recovered at 3 months postoperative (P < 0.05), with further improvement in total score at 9 months. Two patients developed superficial groin sepsis, and seven (17.5%) experienced chronic inguinal pain. Conclusion  Inguinal hernia impaired testicular perfusion that improved postoperatively. Lichtenstein tension-free hernioplasty improved sexual function and generic quality of life without adverse mesh effects on testicular volume or perfusion.     

Impaired macrophage function in severe protein-energy malnutrition.

Protein-energy malnutrition induces immunosuppression that predisposes to sepsis, but the mechanisms are unclear. This study examines the role of the macrophage in host defense in the malnourished state. Swiss-Webster mice (N = 300) were randomly allocated to control (24% casein) or low-protein (2.5% casein) diets for 8 weeks. We studied the ability of two populations of macrophages, peritoneal macrophages, and Kupffer cells to produce superoxide anion after in vivo administration of endotoxin or mycobacterium (bacille Calmette-Guérin). Phorbol diester and Candida albicans were used as stimuli. In another group of mice, we evaluated the ability of interferon gamma to up-regulate superoxide anion release and Candida phagocytosis and killing. Mice under protein-energy malnutrition demonstrated decreased mean body weights, serum protein levels, and cell yields. Superoxide anion production in resident and activated (lipopolysaccharide, interferon gamma, bacille Calmette-Guérin infection) peritoneal macrophages was significantly reduced in the malnourished group. Candida phagocytosis and killing were also both depressed in malnourished mice. Kupffer cells failed to generate superoxide anion in all groups. We conclude that severe protein-energy malnutrition significantly impairs macrophage function, which could diminish response to acute and chronic septic challenges. Interferon gamma up regulated peritoneal macrophage and Kupffer cell microbicidal function, which suggests a therapeutic role for this lymphokine in the malnourished septic host.