Macrophage cyclooxygenase expression, immunosuppression, and cardiopulmonary dysfunction after blunt chest trauma.

BACKGROUND: Two series of experiments were performed in swine who received severe blunt chest trauma. The goals were to determine the time course of constitutive and inducible cyclooxygenase (COX) isozyme expression in pulmonary macrophages (Mphis), and to determine whether COX expression and cardiopulmonary dysfunction were altered when neutrophils (PMNs) were pharmacologically depleted with cyclophosphamide (CYC). METHODS: In series 1 (n = 17), anesthetized, mechanically ventilated swine were subjected to right chest trauma via captive bolt gun, hemorrhage, and a 60-minute shock period. In series 2 (n = 41), CYC (50 mg/kg intravenously) was administered 4 days before trauma, and the shock period was shortened to 30 minutes. In both series, hemodynamic support and supplemental oxygen were provided for an additional 60 to 90 minutes after shock. Mphis were isolated from serial bilateral bronchoalveolar lavages (BALs) and COX protein expression was measured with Western blots. RESULTS: In series 1, death occurred in 11 of 17. In survivors, Mphi COX-1 peaked at > 100 times baseline in both right BAL and left BAL by 60 minutes (before resuscitation). Changes in Mphi COX-2 were minimal. In series 2, before trauma, CYC (n = 16) reduced circulating and BAL PMNs by > 90% relative to control (n = 25, both p < 0.05) with no complicating side effects. After trauma, death occurred in 11 of 25 controls versus 9 of 16 with CYC. In survivors, PaO2/FIO2 was < 250 and PaCO2 was 25% higher on constant minute ventilation, indicating mismatched ventilation/perfusion; both changes were reduced with CYC (p < 0.05). In controls, bilateral histologic damage included edema, alveolar hemorrhage, and interstitial infiltrates. These changes were reduced by one third with CYC (p = 0.08). Trauma-induced changes in BAL protein, BAL elastase, or Mphi COX expression were not lessened by CYC. CONCLUSION: After unilateral chest trauma, Mphi COX-1, not COX-2, is induced bilaterally and before fluid resuscitation; CYC prevented PMN infiltration and attenuated structural and functional changes after resuscitation, which suggests that PMNs have a role in the pathogenic mechanism of secondary lung injury; Mphi COX expression and other injury markers were not altered by CYC; and since Mphis continued to express proinflammatory COX protein even after pretreatment with a powerful nonspecific immunosuppressant, and since there is residual alveolar capillary damage even in the absence of PMNs, it is logical to conclude that no single cell type or mediator is a practical therapeutic target and that novel resuscitation strategies must address multiple elements in the inflammatory cascade.

Endogenous adenosine and secondary injury after chest trauma.

BACKGROUND: No previous studies have examined actions of adenosine or related compounds after blunt chest trauma, but we have shown that the prototype adenosine-regulating agent, acadesine (aminoimidazole carboxamide ribonucleotide [AICAR]), has multiple favorable anti-inflammatory actions after other forms of trauma, ischemia, hemorrhage, and sepsis; and that a progressive inflammatory response in the contralateral (uninjured) lung after unilateral blunt chest trauma is caused (in part) by activation and sequestration of circulating leukocytes (white blood cells [WBCs]). Thus, we hypothesized that AICAR would ameliorate WBC-dependent, secondary pathophysiologic changes after blunt chest trauma. METHODS: Mongrel pigs (28+/-1 kg, n = 21) were anesthetized, mechanically ventilated, and injured on the right chest (pulmonary contusion) with a captive bolt gun. Either AICAR (1 mg/kg + 0.2 mg/kg/min) or its saline vehicle were administered for a 12-hour period, beginning 15 minutes before injury. RESULTS: Injury caused a three- to fourfold increase in bronchoalveolar lavage (BAL) WBC counts, 10- to 20-fold increases in BAL protein, and 200% increases in lung edema as measured by wet-dry ratio (all p < 0.05), in both the injured (right) and the noninjured (left) lungs. With AICAR versus saline, BAL WBC counts, lung myeloperoxidase levels, and systemic hemodynamics were similar. However, the increases in BAL protein were attenuated by 30% to 50% (p < 0.14, NS) and edema was reduced (p < 0.05) in both lungs. Furthermore, oxygenation, hypercapnia, acidosis (all p < 0.05), and survival were improved (9 of 10 vs. 4 of 11, p < 0.04). CONCLUSION: Pretreatment with AICAR before experimental pulmonary contusion ameliorates the trauma-induced destruction of the alveolar capillary membrane, and attenuates the delayed secondary injury in the contralateral uninjured lung, by a mechanism that may be independent of leukocytes. Endogenous adenosine could have a role in the pathophysiologic response after blunt chest injury, with potential sites of action including the endothelium and alveolar macrophage. Adenosine-regulating agents may have therapeutic potential after blunt chest injury, but further studies are needed in clinically relevant models, with administration begun at the time of resuscitation.

Cardiopulmonary function after pulmonary contusion and partial liquid ventilation.

PURPOSE: To compare the effects of mechanical ventilation with either positive end-expiratory pressure (PEEP) or partial liquid ventilation (PLV) on cardiopulmonary function after severe pulmonary contusion. METHODS: Mongrel pigs (32 +/- 1 kg) were anesthetized, paralyzed, and mechanically ventilated (8-10 mL/kg tidal volume; 12 breaths/min; FiO2 = 0.5). Systemic hemodynamics and pulmonary function were measured for 7 hours after a captive bolt gun delivered a blunt injury to the right chest. After 5 hours, FiO2 was increased to 1.0 and either PEEP (n = 7) in titrated increments to 25 cm H2O or PLV with perflubron (LiquiVent, 30 mL/kg, endotracheal) and no PEEP (n = 7) was administered for 2 hours. Two control groups received injury without treatment (n = 6) or no injury with PLV (n = 3). Fluids were liberalized with PEEP versus PLV (27 +/- 3 vs. 18 +/- 2 mL.kg-1.h-1) to maintain cardiac filling pressures. RESULTS: Before treatment at 5 hours after injury, physiologic dead space fraction (30 +/- 4%), pulmonary vascular resistance (224 +/- 20% of baseline), and airway resistance (437 +/- 110% of baseline) were all increased (p < 0.05). In addition, PaO2/FiO2 had decreased to 112 +/- 18 mm Hg, compliance was depressed to 11 +/- 1 mL/cm H2O (36 +/- 3% of baseline), and shunt fraction was increased to 22 +/- 4% (all p < 0.05). Blood pressure and cardiac index remained stable relative to baseline, but stroke index and systemic oxygen delivery were depressed by 15 to 30% (both p < 0.05). After 2 hours of treatment with PEEP versus PLV, PO2/FiO2 was higher (427 +/- 20 vs. 263 +/- 37) and dead space ventilation was lower (4 +/- 3 vs. 28 +/- 7%) (both p < 0.05), whereas compliance tended to be higher (26 +/- 2 vs. 20 +/- 2) and shunt fraction tended to be lower (0 +/- 0 vs. 7 +/- 4). With PEEP versus PLV, however, cardiac index, stroke index, and systemic oxygen delivery were 30 to 60% lower (all p < 0.05). Furthermore, although contused lungs showed similar damage with either treatment, the secondary injury in the contralateral lung (as manifested by intra-alveolar hemorrhage) was more severe with PEEP than with PLV. CONCLUSIONS: Both PEEP and PLV improved pulmonary function after severe unilateral pulmonary contusion, but negative hemodynamic and histologic changes were associated with PEEP and not with PLV. These data suggest that PLV is a promising novel ventilatory strategy for unilateral pulmonary contusion that might ameliorate secondary injury in the contralateral uninjured lung.

Dehydroepiandrosterone, an endogenous immune modulator, after traumatic shock.

Dehydroepiandrosterone (DHEA), an endogenous immune modulator, reduces mortality after endotoxin (lipopolysaccharide (LPS)) administration in rodents. However, there have been no studies in clinically relevant large-animal models. A unique experimental model is used to study the effects of DHEA in resuscitated trauma and to evaluate the protective effect of DHEA on the systemic inflammatory response induced by a delayed LPS challenge. Anesthetized, ventilated pigs were instrumented and then subjected to local hind-limb trauma and 35% hemorrhage. After 1 h, animals were resuscitated with shed blood, supplemental Ringers solution, and in a randomized, blinded fashion, 4 mg/kg of DHEA or vehicle. Two additional groups received 10 mg/kg or 20 mg/kg of DHEA. Animals were dosed again at 24, 48, and 72 h. After 75 h, Escherichia coli LPS was administered. LPS caused a fall in DHEA levels (0.23 +/- .05 ng/mL (60 min post-LPS) versus .94 +/- 35 ng/mL (72 h), p = .01). DHEA levels 60 min post-LPS were significantly higher in treated animals (p < .002). After LPS, all groups manifested progressive septic symptoms with a hyperdynamic state and pulmonary failure. These symptoms were not blunted by the administration of DHEA. DHEA levels are suppressed by LPS in this two-stage model of trauma and delayed sepsis; however, exogenous DHEA administration fails to blunt the associated systemic inflammatory response and pulmonary failure.

A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications.

OBJECTIVE: The authors randomized patients to an enteral diet containing glutamine, arginine, omega-3 fatty acids, and nucleotides or to an isonitrogenous, isocaloric diet to investigate the effect of septic outcome. A third group of patients, without enteral access but eligible by severity of injury, served as unfed controls and were studied prospectively to determine the risk of infection. SUMMARY BACKGROUND DATA: Laboratory and clinical studies suggest that diets containing specialty nutrients, such as arginine, glutamine, nucleotides, and omega-3 fatty acids, reduce septic complications. Unfortunately, most clinical trials have not compared these diets versus isonitrogenous, isocaloric controls. This prospective, blinded study randomized 35 severely injured patients with an Abdominal Trauma Index > or = 25 or a Injury Severity Score > or = 21 who had early enteral access to an immune-enhancing diet ([IED] Immun-Aid, McGaw, Inc., Irvine, CA; n = 17) or an isonitrogenous, isocaloric diet (Promote [Ross Laboratories, Columbus, OH] and Casec [Mead-Johnson Nutritionals, Evansville, IN]; n = 18) diet. Patients without early enteral access but eligible by severity of injury served as contemporaneous controls (n = 19). Patients were evaluated for septic complications, antibiotic usage, hospital and intensive care unit (ICU) stay, and hospital costs. RESULTS: Two patients died in the treatment group and were dropped from the study. Significantly fewer major infectious complications (6%) developed in patients randomized to the IED than patients in the isonitrogenous group (41%, p = 0.02) or the control group (58%, p = 0.002). Hospital stay, therapeutic antibiotics, and the development of intra-abdominal abscess was significantly lower in patients receiving the IED than the other two groups. This improved clinical outcome was reflected in reduced hospital costs. CONCLUSIONS: An IED significantly reduces major infectious complications in severely injured patients compared with those receiving isonitrogenous diet or no early enteral nutrition. An IED is the preferred diet for early enteral feeding after severe blunt and penetrating trauma in patients at risk of subsequent septic complications. Unfed patients have the highest complication rate.

Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients.

Combination therapy for nosocomial pneumonia with a beta-lactam and aminoglycoside is widely accepted because of synergy and reduction of resistant bacteria. This prospective study of 109 trauma patients (94 blunt, 15 penetrating) with nosocomial pneumonia was performed in consecutive phases. In phase 1, patients were randomized to an anti-pseudomonal third-generation cephalosporin--cefoperazone or ceftazidime. Gentamicin was added to each regimen in phase 2. The mean age of the patients was 37 years, the mean ISS was 31, and there were no differences among the four treatment groups relative to associated injuries. Patients receiving monotherapy had a 56% cure rate compared with 31% for combination therapy (p < 0.04). Persistence rates were similar in these two groups (15% and 20%), but superinfection was significantly higher in the combination group (49% vs. 28%; p < 0.04). The predominant superinfecting organism was methicillin-resistant Staphylococcus aureus (MRSA). Nine patients died (5% monotherapy, 10% combination), and eight had a superinfection. We conclude that monotherapy had a higher cure rate than combination therapy for empiric therapy of pneumonia in our trauma patients. Combination therapy failed because of superinfection (primarily MRSA). Emergence of MRSA may be from host overgrowth or plasmid-mediated induction of resistance, possibly caused by gentamicin.

A randomized clinical study of cefoperazone and sulbactam versus gentamicin and clindamycin in the treatment of intra-abdominal infections.

This report summarizes the experience of investigators in four medical centres who compared the combination of cefoperazone/sulbactam against gentamicin/clindamycin in the treatment of intra-abdominal infections. One hundred and fifty-two patients were enrolled in the study and all were evaluable for safety and tolerance, 110 were evaluable for efficacy. Of the 76 patients (49 male, 27 female) treated with cefoperazone/sulbactam 66 (86.8%) were cured, five (6.6%) improved and five (6.6%) failed to respond to treatment. Of 34 patients treated with gentamicin/clindamycin, 21 (61.8%) were cured, four (11.8%) improved and nine (26.4%) failed. Cure rates for patients receiving cefoperazone/sulbactam were significantly higher than those of patients receiving gentamicin/clindamycin (P less than 0.006). Failures in both groups were attributable in part to pseudomonal and enterococcal infection and abscess formation. The addition of sulbactam to cefoperazone rendered cefoperazone-resistant organisms susceptible to cefoperazone in 11 of the 76 cases (14.4%) and thus permitted treatment with this agent. The present study confirms the safety and clinical efficacy of cefoperazone/sulbactam and suggests that this combination is a viable alternative to an aminoglycoside plus clindamycin for intra-abdominal infections.

Blunt diaphragm injuries. A five-year experience.

Between 1983 and 1988, 33 (21 men, 12 women) patients were treated for blunt diaphragmatic injuries following motor-vehicle (90%) or auto-pedestrian (10%) accidents at the Presley Trauma Center. Thirteen patients (39%) were right sided and 19 (56%) were left sided. One patient sustained bilateral ruptures. The mean Injury Severity Score (ISS) in both those that lived and those that died was not significantly different when right- and left-sided injuries were compared. Admission chest films were abnormal in 28 patients and diagnostic in nine patients (27%). The chest x ray was abnormal in 10 (78%) of those with right-sided injury. Twenty-three patients had diagnostic peritoneal lavage (DPL); 19 were initially positive, two were initially negative but became positive on relavage. There were two false-negative lavages. CT scan (4 patients) and barium enema (1 patient) were nondiagnostic. Diagnosis was delayed in four patients, two were diagnosed by repeat chest x ray and two by repeat lavage. All patients had multiple associated injuries, with 82 per cent having concomitant intra-abdominal injuries. All patients were explored via the transabdominal route. Complications occurred in 55 per cent and there were eight deaths (24%), all unrelated to the diaphragmatic injury. There was no relationship to mortality and hemidiaphragm injured. Chest x ray remains the single most beneficial diagnostic test for diaphragmatic injury. DPL is an insensitive test for isolated diaphragm injuries; however, the combination of CXR and DPL will lead to the diagnosis in the majority of cases. Ancillary radiologic tests are not beneficial. An elevated or obscured right hemidiaphragm should raise suspicion for blunt rupture.(ABSTRACT TRUNCATED AT 250 WORDS)

Sigmoid volvulus. A four-decade experience.

During the 40 years from 1945 to 1984, 159 occurrences of sigmoid volvulus in 140 patients were diagnosed and managed. Treatment modalities gradually evolved from primarily operative decompression in the first 20 years to selective, sigmoidoscopic, nonoperative reduction in the most recent 10-year period. Operative reduction was associated with a 10 per cent mortality, while no deaths were associated with nonoperative reduction. A 60 per cent mortality was noted when gangrenous bowel was present. In the most recent 10-year period, 71 per cent of cases were associated with neuropsychiatric diseases, and one third had a previous episode of sigmoid volvulus. The diagnosis was made on the initial plain abdominal radiograph in 60 per cent, and nonoperative sigmoidoscopic reduction attained in 95 per cent. Following nonoperative reduction, elective resection was performed during the same hospitalization with a 5 per cent mortality. Initial management of sigmoid volvulus should consist of nonoperative attempts at reduction with operative reduction reserved for refractory cases or those with ischemic bowel. Elective resection can be safely performed during the same hospitalization.

Use of fibronectin and somatomedin-C as markers of enteral nutrition support in traumatized patients using a modified amino acid formula.

The purpose of this study was to evaluate the use of serum fibronectin and serum somatomedin-C as nutritional markers during enteral nutrition support (ENS) of critically ill, traumatized patients using an enteral product containing high concentrations of branched-chain amino acids. Twelve critically injured patients received a standard enteral formula with 30 g of a 44% branched-chain amino acid supplement added to each liter of formula. Fibronectin concentration, somatomedin-C concentration, and nitrogen balance were measured on study days 1, 4, 7, 14, 21, 28 or until adequate oral intake began. Both fibronectin and somatomedin-C concentrations increased significantly from baseline by day 7 of ENS. Nitrogen balance increased significantly from baseline by day 4. On days 14 and 21, only somatomedin-C and nitrogen balance increased significantly from baseline. Nitrogen balance was significantly correlated with somatomedin-C concentration (r = 0.53, p less than 0.01), cumulative caloric intake (r = 0.68, p less than 0.01), and cumulative nitrogen intake (r = 0.72, p less than 0.01). The results of this study suggest that serum somatomedin-C is useful and serum fibronectin has potential in monitoring nutrition support response in critically ill, traumatized patients.

Colonic atony in association with sigmoid volvulus: its role in recurrence of obstructive symptoms.

We reviewed a 30-year experience in management of 129 patients with 163 acute obstructions due to sigmoid volvulus. Recurrent obstruction of the colon was observed in 47 (or 45%) of 104 patients who survived their initial obstructive episode: 61% after rectal tube insertion, 45% after detorsion, 33% after sigmoid plication, and 21% despite sigmoid colectomy. Subsequent barium enema or surgical exploration showed true sigmoid volvulus to be the cause of recurrent obstruction in 36 of 47 patients, while atonic bowel, involving the sigmoid alone or more proximal colon as well, was responsible for the other 11 recurrent obstructions. Sigmoid excision was corrective only if bowel atony was limited to that portion of the colon. Only more extensive colectomy, so as to include all flaccid colon, consistently obviated recurrence. Failure to recognize functional obstruction accounted for five of the 25 total deaths.