Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre.

BACKGROUND: The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. AIM: To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF. METHOD: A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved. RESULTS: 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics. CONCLUSION: Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.

Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis.

OBJECTIVES: Staphylococcus aureus osteomyelitis often develops to chronicity despite antimicrobial treatments that have been found to be susceptible in in vitro tests. The complex infection strategies of S. aureus, including host cell invasion and intracellular persistence via the formation of dynamic small colony variant (SCV) phenotypes, could be responsible for therapy-refractory infection courses. METHODS: To analyse the efficacy of antibiotics in the acute and chronic stage of bone infections, we established long-term in vitro and in vivo osteomyelitis models. Antibiotics that were tested include ß-lactams, fluoroquinolones, vancomycin, linezolid, daptomycin, fosfomycin, gentamicin, rifampicin and clindamycin. RESULTS: Cell culture infection experiments revealed that all tested antibiotics reduced bacterial numbers within infected osteoblasts when treatment was started immediately, whereas some antibiotics lost their activity against intracellular persisting bacteria. Only rifampicin almost cleared infected osteoblasts in the acute and chronic stages. Furthermore, we detected that low concentrations of gentamicin, moxifloxacin and clindamycin enhanced the formation of SCVs, and these could promote chronic infections. Next, we treated a murine osteomyelitis model in the acute and chronic stages. Only rifampicin significantly reduced the bacterial load of bones in the acute phase, whereas cefuroxime and gentamicin were less effective and gentamicin strongly induced SCV formation. During chronicity none of the antimicrobial compounds tested showed a beneficial effect on bone deformation or reduced the numbers of persisting bacteria. CONCLUSIONS: In all infection models rifampicin was most effective at reducing bacterial loads. In the chronic stage, particularly in the in vivo model, many tested compounds lost activity against persisting bacteria and some antibiotics even induced SCV formation.

Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: results of a randomized, long-term extension trial (RESTORE2).

BACKGROUND: Continuous maintenance therapy with infliximab 5 mg kg(-1) every 8 weeks is effective for moderate-to-severe plaque-type psoriasis. OBJECTIVES: To evaluate the efficacy and safety of continuous vs. intermittent infliximab maintenance therapy. METHODS: RESTORE2 was a long-term extension of RESTORE1. At baseline of RESTORE2, eligible patients who had received infliximab for 26 weeks and achieved Psoriasis Area and Severity Index (PASI) 75 in RESTORE1 were rerandomized 1 : 1 to continuous therapy (infliximab 5 mg kg(-1) every 8 weeks) or intermittent therapy (no infliximab until > 50% loss of PASI improvement). Safety and efficacy assessments occurred throughout the study. RESULTS: In total, 222 patients were randomized to receive continuous therapy, and 219 to intermittent therapy. More serious infusion-related reactions occurred with intermittent therapy (8/219 patients, 4%) than with continuous therapy (1/222 patients, < 1%), leading the sponsor to terminate the study. The mean duration of exposure to infliximab was 40·12 weeks (SD 27·55) with a mean of 5·8 infusions (range 0-16) for continuous therapy and 22·78 weeks (SD 22·98) with a mean of 3·4 infusions (range 0-16) for intermittent therapy. Although no formal efficacy analyses were conducted, continuous therapy led to greater PASI 75 at week 52 in the continuous group (81/101, 80%) than in the intermittent group (39/83, 47%); several other efficacy measures demonstrated similar patterns. CONCLUSIONS: For patients with moderate-to-severe plaque-type psoriasis, continuous therapy with infliximab may be more effective than intermittent therapy. The incidence of serious infusion-related reactions in the intermittent group suggests that clinicians should avoid intermittent therapy in this population.

Analysis of regional hemodynamic regulation in response to scald injury.

Ultrasonic probes were placed around dog femoral arteries to record blood flow. Hind paw scalding with boiling water (5 s) caused a marked increase in ipsilateral femoral blood flow that persisted for the 2-h observation period. Contralateral femoral blood flow and systemic and pulmonary vascular resistances were unchanged. Compared to scald only animals, methysergide pretreatment diminished and shortened the femoral vasodilator response to scald (109 +/- 14 vs 243 +/- 27 ml/min at 5 min; 59 +/- 14 vs 191 +/- 31 ml/min at 2 h). Pretreatment with ritanserin, BW A1433U83, atropine, ICI 118551, diphenhydramine, ranitidine, meclofenamate, L-nitro-arginine methyl ester, 3-amino-1,2,4-triazine, and U 37883A had no effect on the increased femoral blood flow response to scald, suggesting this vasodilator response is not dependent upon activation of serotonergic2, adenosineA1, muscarinic, beta 2-adrenergic, histaminergic1 or histaminergic2 receptors, on cyclooxygenase products, endothelium-derived relaxing factor derived from nitric oxide (NO) synthase III, NO derived from NO synthase II, or KATP channels, respectively. Methysergide given after burn immediately reduced the augmented femoral blood flow to preburn levels, suggesting the vasodilator response to scald is mediated through continual activation of local serotonergic1-like receptors, which may be target site(s) for therapeutic interventions to influence burn-induced hemodynamic alterations.

Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.

BACKGROUND: The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. METHODS AND RESULTS: After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 microgram/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5+/-0.8 mm(3)/mm vessel (range 0.6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r=-0.61, P=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31+/-23 IU/min; ex-smokers, 50+/-33 IU/min; nonsmokers 202+/-73 IU/min; P<0.05). CONCLUSIONS: We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Reduced responsiveness to endothelin-1 in peripheral resistance vessels of patients with syndrome X.

OBJECTIVES: This study sought to assess the contribution and action of nitric oxide and endothelin-1 in peripheral resistance vessels of patients with syndrome X. BACKGROUND: Patients with syndrome X may have a generalized disorder of vascular and endothelial function, promoting vasospasm. METHODS: Changes in blood flow responses to intrabrachial infusion of the endothelium-dependent vasodilators substance P and acetylcholine, the endothelium-independent nitric oxide donor sodium nitroprusside and the endothelin type A (ET(A)) receptor antagonist BQ-123 were assessed using venous occlusion plethysmography in 10 patients with syndrome X and 10 matched control subjects. Vasoconstrictor responses to the nitric oxide synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA) and endothelin-1 were also determined. RESULTS: There were no significant differences in the responses to acetylcholine, substance P, sodium nitroprusside or BQ-123 between patients and control subjects. However, despite similar degrees of vasoconstriction in response to L-NMMA in both groups, endothelin-1 caused a reduction in forearm blood flow of only 20 +/- 2% in patients with syndrome X compared with 35 +/- 3% in matched control subjects at 90 min (p < 0.001). Although plasma endothelin-1 concentrations were not significantly higher in patients with syndrome X (4.8 vs. 4.0 pg/ml, p = 0.17), the vasoconstriction caused by endothelin-1 infusion correlated inversely with plasma endothelin-1 concentrations (r = -0.51, p = 0.04). CONCLUSIONS: Patients with syndrome X had normal basal and stimulated nitric oxide activity and basal endogenous ET(A) receptor-mediated vascular tone. However, despite otherwise normal vascular function, there was reduced responsiveness to exogenous endothelin-1, possibly reflecting overactivity of this system and ET(A) receptor downregulation.

Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression.

Incorporation of a central polypurine tract (cPPT) and a posttranscriptional regulatory element (PRE) into lentivirus vectors provides increased transduction efficiency and transgene expression. We compared the effects of these elements individually and together on transduction efficiency and gene expression, using lentivirus vectors pseudotyped with vesicular stomatitis virus G protein (VSV-G) and encoding enhanced green fluorescent protein (GFP) and rat erythropoietin (EPO). The transduction efficiency was greater than 2-fold higher in the vector containing the PRE element, 3-fold higher in vector encoding the cPPT element, and 5-fold increased in the GFP virus containing both cPPT and PRE elements relative to the parent virus. In comparison with parent vector the mean fluorescence intensity (MFI) of GFP expression was 7-fold higher in cells transduced with virus containing PRE, 6-fold increased in cells transduced with virus containing cPPT, and 42-fold increased in GFP-virus containing both cPPT and PRE elements. EPO-virus containing a PRE element showed a nearly 5-fold increase in EPO secretion over the parent vector, and the vector encoding both PRE and cPPT showed a 65-fold increase. Thus, lentivirus vectors incorporating both PRE and cPPT showed expression levels significantly increased over the sum of the components alone, suggesting a synergistic effect.

Management of necrotizing tracheostomy infections.

Management of three patients with necrotizing tracheostomy infections resulting in tracheal dissolution was reviewed with respect to presentation, cause, and management. Loss of tracheal substance led to difficulty in ventilation because of a large air leak. The stomal area cavitated in two patients, denuding the right common carotid artery in one. Purulent peristomal drainage was present in all three patients. Common factors of possible etiologic significance included necrotizing polymicrobial gram-negative tracheobronchial infections caused by Pseudomonas, Enterobacter, and Klebsiella species. Also of possible importance were suture fixation of the appliance, history of neurologic injury, and closure of the incision. Immediate therapy consisted of oral intubation for ventilatory purposes and a regimen of hourly application of 1% neomycin dressings. Seven to 21 days were necessary to allow formation of sufficient granulation tissue to support replacement of the tracheostomy appliance for continued mechanical ventilation. Once spontaneous ventilation was possible, a Montgomery T-tube was inserted for long-term tracheal stenting prior to reconstruction. The two patients treated by tracheal stenting are long-term survivors. Avoidance of suture fixation of the appliance, aggressive treatment of bronchopulmonary infection, and adequate stomal toilet may help to avoid this devastating complication.

Preventive antibiotic usage in traumatic thoracic injuries requiring closed tube thoracostomy.

OBJECTIVE: To evaluate the safety and effectiveness of antibiotics in reducing the infectious complications following closed tube thoracostomy for isolated chest trauma. DESIGN: Double-blind, randomized clinical trial. SETTING: Medical school affiliated large urban teaching hospital and trauma center. PATIENTS: One hundred nineteen of 159 patients over 18 years old presenting to the emergency department requiring closed tube thoracostomy for isolated chest injuries (113 penetrating, 6 blunt). INTERVENTION: Patients received either placebo or 1 g cefonicid daily intravenously started at chest tube insertion and stopped within 24 h of removal. MEASUREMENTS AND RESULTS: The development of wound infections, pneumonia (CDC criteria), or empyema; the incidence of adverse events; length of hospitalization. One nonspecific infection was seen in the cefonicid group (1.6 percent) and six respiratory tract infections (10.7 percent) in the placebo group (three empyema, one empyema with pneumonia, two pneumonia) (p = 0.0505; p = 0.0094 [excluding nonspecific infection]). No significant differences with antibiotic use were seen in the duration of chest tube use (p = 0.766), peak WBC counts (p = 0.108), lower peak temperatures (p = 0.063), or length of hospitalization (p = 0.165). Patients who developed infectious complications averaged approximately 8 days longer hospitalization than those without (p < 0.0001). CONCLUSION: This study showed that patients receiving antibiotics had a significantly reduced rate of infection than did patients administered placebo. No significant adverse events were seen in either group.

Arterial injuries with lower extremity fracture.

Review of the records of 41 patients with lower extremity fractures associated with major arterial injuries disclosed that femoral artery injuries were consistently repaired with excellent results and no amputations. Diagnostic delay contributed to an 18% amputation rate following popliteal artery disruption. When arteries distal to the popliteal trifurcation were completely disrupted, a 25% rate of long-term good results was obtained.

Evaluation of ventilatory therapy for acid aspiration.

Aspiration of hydrochloric acid in experimental animals results in severe, progressive hypoxia which is due to intrapulmonary shunting and depressed cardiac output. This preparation is useful therefore in studying the therapy of hypoxia. Mongrel dogs were subjected to acid aspiration and the effects of several ventilatory patterns on intrapulmonary shunt fractions and lung water accumulation observed. The combination of large tidal volumes (30 c.c. per kilogram) with positive end-expiratory pressure was effective in preventing intrapulmonary shunting and other ventilatory patterns were ineffective. Pulmonary edema uniformly followed acid aspiration and was not affected by ventilatory therapy. When ventilatory therapy was delayed for 4 hours, the progression of shunting apparently was limited, but the existing shunt was not reduced.

Intimal disruption of major cerebral vasculature following blunt trauma.

A child with blunt traumatic intimal disruption involving the major vessels responsible for cerebral circulation was treated by operation. The injured vessels included both common carotid arteries, both vertebral arteries, and the left subclavian artery. The carotid injuries were treated by saphenous vein interposition grafts, whereas the left subclavian and vertebral arteries were ligated. The patient sustained no neurological deficit and is now completely well 2 years after treatment. The case reported herein is unique in that total intimal disruption of the four major vessels responsible for cerebral flow was treated by operation, resulting in complete recovery. The successful outcome underscores the importance of complete angiographic evaluation and adequate operative exposure in such cases.

Peritoneal lavage: a useful diagnostic adjunct for peritonitis.

Diagnostic peritoneal lavage (DPL) was used to aid in the rapid diagnosis of peritonitis in 138 patients for whom standard diagnostic criteria were not applicable because the patients had altered sensorium, were elderly, or had multiple medical problems. There were abnormal results in 77 patients, and all but one patient had peritonitis. Sixty-five patients had lesions that could be cured only by operative means; 54% of this group of extremely ill patients survived. Of 61 patients with negative results of DPL, only one had intraperitoneal inflammation (acute cholecystitis), which occurred 4 days after DPL. We believe DPL is a useful procedure for the detection of peritonitis in a critically ill subset of patients for whom the standard diagnostic criteria were not available.

Occult splenic abscess: an unrecognized complication of heroin abuse.

Despite increased recognition of surgical problems related to narcotic addiction, splenic abscess has not been commonly recognized as such a complication. Seven male patients with splenic abscess secondary to heroin abuse have been treated. Six had bacterial endocarditis. Symptoms were nonspecific. Splenomegaly in two patients was the only useful physical finding. Five patients had left pleural effusion, of which three were proven to be empyemas. Staphylococcus aureus was the predominant pathogen of of bacterial endocarditis and splenic abscess. The splenic scan was diagnostic. All patients recovered following curative splenectomy.

Microcirculatory norepinephrine constrictor response in hemorrhagic shock.

Hemorrhagic shock is characterized by a phase of compensation that preserves central blood flow and intravascular pressure through an integrated vasoconstrictor response mediated by catecholamines, particularly norepinephrine (NE). The skeletal muscle microcirculation is important in this response. Decompensation occurs when arteriolar vasodilation occurs despite continued hypovolemia and high circulatory levels of NE. Using an isolated decerebrate rat cremaster muscle, we measured constrictor response to NE (10(-7)M tissue concentration) in compensated and decompensated shock. Our data indicate that larger arterioles (143 to 152 microns) show persistent constrictor response with lowered sensitivity to NE. Smaller arterioles (11 to 22 microns) and all venules dilate late in shock but retain constrictor responses to NE. Dilator responses contribute to decompensation in small arterioles and venules but not because of altered NE constrictor response.

Hepatic cellular hypoxia in murine peritonitis.

Reduced oxygen consumption and lactic acidosis were observed frequently in patients with peritonitis. This study was designed to evaluate whether reduced oxygen consumption is secondary to deficient oxygen delivery or is a function of primary injury to mitochondria. Peritonitis was produced in rats by cecal ligation and perforation. Animals were killed at 2, 4, and 6 hours and agonally. Oxygen utilization was studied polarographically in isolated hepatic mitochondria with glutamate, pyruvate, and succinate substrates. State 3, state 4, respiratory control index (RCI), and ADP:O ratios were determined. Whole tissue and isolated mitochondrial ultrastructure were examined by electron microscopy. Systemic blood pressure and oxygenation were monitored. Hepatic tissue oxygenation was examined using a surface oxygen electrode. Peritonitis resulted in acceleration of state 3 respiratory rates and increased respiratory control indices at all time intervals. Maximal respiratory control was observed at 4 hours with all substrates. Whole tissue mitochondria demonstrated mild swelling and thinning of membranes and matrix. Experimental and control isolates showed similar orthodox-to-condensed conformational changes. Hepatic tissue oxygenation declined to less than 10% of control by 6 hours, while arterial Po2 was unchanged. The conclusions of this study are that lethal peritonitis results in (1) no primary injury to the hepatic mitochondria, (2) increased efficiency of hepatic mitochondrial oxygen utilization, and (3) reduced hepatic tissue oxygenation. The exact mechanisms of defective oxygen delivery require further study.

Evaluation of a novel synthetic material for closure of large abdominal wall defects.

BACKGROUND: This study was undertaken to compare the efficacy of a novel synthetic material (TMS-1) with polytetrafluoroethylene, polypropylene, and primary closure of experimentally fashioned clean and contaminated abdominal wounds. METHODS: One square centimeter full-thickness abdominal wall defects were created in each of the four abdominal quadrants of anesthetized rats (n = 6). Patches of polytetrafluoroethylene, polypropylene, and a polyurethane-polypropylene composite material (TMS-1) were used to repair three of these defects; the fourth was primarily closed. A second group of rats (n = 9) underwent the same operative protocol; however, peritonitis was induced at the time of operation by using the fecal inoculation technique. Animals were killed 2 to 3 weeks later, and surface area and severity of formed adhesions were assessed. RESULTS: By all methods of assessment, primary closure proved significantly superior to all other methods of closure in clean and contaminated conditions. The three synthetic materials were equally matched for surface area involved in adhesion formation. When compared with the other synthetic materials, TMS-1 was associated with significantly milder adhesions in uninfected (p < 0.002) and in infected (p < 0.002) conditions. CONCLUSIONS: The clear superiority of TMS-1 over other nonabsorbable synthetic materials shown in this pilot study warrants further investigation relative to its use to close large abdominal wall defects.

Dopexamine prevents depression of mesenteric blood flow caused by positive end-expiratory pressure in rats.

BACKGROUND: The purpose of this study was to investigate the effects of two vasoactive agents, dopamine and dopexamine, on the depression of mesenteric blood flow caused by positive end-expiratory pressure (PEEP) during mechanical ventilation. METHODS: Sprague-Dawley rats were mechanically ventilated with either no PEEP (control group) or increasing levels of PEEP (PEEP group) up to 20 cm H2O pressure. We evaluated PEEP's effect on blood pressure, cardiac output (CO), and the mesenteric microcirculation with a continuous infusion of 2.5 or 12.5 micrograms/kg/min dopamine or 1, 3, or 5 micrograms/kg/min dopexamine. RESULTS: PEEP caused a 20% to 25% decrease in mean arterial pressure and a 30% decrease in CO at both 15 and 20 cm H2O of PEEP (all p < 0.05 versus baseline). Low dose dopamine partially corrected the decrease in CO to 16% and 21% below baseline at 15 and 20 cm H2O of PEEP, respectively (both p < 0.05 versus PEEP group) and partially ameliorated the depression of mesenteric blood flow associated with the application of PEEP. High dose dopamine did not positively affect either CO or mesenteric blood flow. Dopexamine had little effect on CO compared with dopamine. All three doses of dopexamine blocked the effect of PEEP on mesenteric blood flow (p < 0.05 compared with the PEEP group at all levels of PEEP, p < 0.05 compared with the low dose dopamine group at 15 and 20 cm H2O of PEEP). CONCLUSIONS: Dopexamine is superior to dopamine in protecting mesenteric blood flow in the face of increasing levels of PEEP.

Management of transmediastinal gunshot wounds.

Gunshot wounds that transverse the mediastinum are major management problems for two primary reasons: (1) multiple injuries to vital structures are common and (2) the operative approach to control hemorrhage may not afford the optimum exposure to repair the various injuries encountered. We devised a management plan whereby patients in hemodynamically unstable condition underwent immediate operation and patients in stable condition underwent a rapid work-up to evaluate the organs at risk for injury including angiography, esophagoscopy, esophagography, bronchoscopy, and pericardial exploratory surgery while under local anesthesia. A total of 76 patients were treated. Thirty-three patients in unstable condition underwent immediate thoracotomy for hemorrhage or shock or median sternotomy for cardiac tamponade. Multiple organs were injured (average 2.7) and the mortality rate was high (12 of 33) because of the severity of the injuries. Twenty-seven of 43 patients in stable condition required operation after the systematic evaluation disclosed injuries to the great vessels (11), esophagus (9), trachea and bronchi (6), and heart (6). Three patients died of delayed complications (6.9%). The 16 patients who were in stable conditions and had no demonstrable injury were closely followed without operation with one complication and one death from an associated abdominal injury. A management plan for this difficult subset of patients with penetrating thoracic trauma is detailed.

Bleeding vascular malformations of the intestine.

Thirty-nine patients with bleeding vascular malformations were evaluated. The age range was from 3 to 78 years, with a bimodal age distribution. The younger patients had no associated diseases, while those in the older category invariably had an associated cardiac lesion (aortic stenosis in 12 patients and severe atherosclerotic disease in 11 patients). With experience, colonoscopy has become a valuable adjunct to arteriography with the lesion visualized in 12 patients. Arteriography is the most useful study being diagnostic in 35 of 38 cases. Exploration alone was diagnostic in only one of 39 patients. The most common site of bleeding was the cecum (21 patients) followed by the proximal small intestine (eight patients), terminal ileum (seven patients), and ascending colon (five patients). The lesions in the proximal small bowel were much more common in the younger patients and were believed to be congenital. Resection controlled the bleeding in the majority of patients, although four recurrences have been noted. All have been documented angiographically to have been from a new lesion and two were controlled with reoperation. The key elements to control of these patient's bleeding include: (1) systematic work-up with a team approach emphasizing careful visceral angiography, and (2) the avoidance of a premature laparotomy prior to complete evaluation.