Steven B. Johnson

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels.

Objective:To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab′)2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. Design:Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting:One hundred fifty-seven intensive care units in the United States and Canada. Patients:Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions:Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. Measurements and Main Results:In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. Conclusions:Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

TRANSESOPHAGEAL ECHOCARDIOGRAPHY IN THE DIAGNOSIS OF TRAUMATIC RUPTURE OF THE AORTA

Background Rupture of the aorta is a major cause of death after motor vehicle accidents. Survival depends on early diagnosis, and emergency aortography is the standard imaging method. Although transesophageal echocardiography is noninvasive and can provide high-resolution images of the aorta, information about its value in patients with trauma is limited. We conducted this study to assess prospectively the value of transesophageal echocardiography in the emergency evaluation of patients at risk for aortic injury. Methods Transesophageal echocardiography of the aorta was attempted in 101 patients admitted to the emergency room with a diagnosis of possible traumatic rupture of the aorta. Echocardiography and aortography personnel were notified simultaneously of the arrival of the patient, and the two tests were performed sequentially by operators who were blinded to the results of the other test. The sensitivity and specificity of transesophageal echocardiography were calculated on the basis of the results ...

A Phase I Evaluation of the Safety and Immunogenicity of Vaccination with Recombinant gp160 in Patients with Early Human Immunodeficiency Virus Infection

BACKGROUND Despite multiple antiviral humoral and cellular immune responses, infection with the human immunodeficiency virus (HIV) results in a progressively debilitating disease. We hypothesized that a more effective immune response could be generated by post-infection vaccination with HIV-specific antigens. METHODS We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein, gp160, in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2. The vaccine was administered either on days 0, 30, and 120 or on days 0, 30, 60, 120, 150, and 180. HIV-specific humoral and cellular immune responses were measured; local and systemic reactions to vaccination, including general measures of immune function, were monitored. RESULTS In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160. Seroconversion to selected envelope epitopes was observed, as were new T-cell proliferative responses to gp160. Response was associated with the CD4 cell count determined before vaccination (13 of 16 subjects [81 percent] with greater than 600 cells per milliliter responded, as compared with 6 of 14 [43 percent] with less than or equal to 600 cells per milliliter; P = 0.07) and with the number of injections administered (87 percent of subjects randomly assigned to receive six injections responded, as compared with 40 percent of those assigned to three injections; P = 0.02). Local reactions at the site of injection were mild. There were no adverse systemic reactions, including diminution of general in vitro or in vivo cellular immune function. After 10 months of follow-up, the mean CD4 count had not decreased in the 19 subjects who responded, but it had decreased by 7.3 percent in the 11 who did not respond. CONCLUSIONS This gp160 vaccine is safe and immunogenic in volunteer patients with early HIV infection. Although it is too early to know whether this approach will be clinically useful, further scientific and therapeutic evaluation of HIV-specific vaccine therapy is warranted. Similar vaccines may prove to be effective for other chronic infections.

Closed versus open endotracheal suctioning: Costs and physiologic consequences

ObjectiveTo examine the physiologic consequences and costs associated with two methods of endotracheal suctioning: closed vs. open. DesignA prospective, randomized, controlled study. SettingAn eight-bed trauma intensive care unit (ICU) in a 460-bed level I trauma center. PatientsThe study included 35 trauma/general surgery patients (16 in the open suction group, 19 in the closed suction group) who were treated with a total of 276 suctioning procedures (127 open, 149 closed). Measurements and Main ResultsPhysiologic data collected after hyperoxygenation, immediately after suctioning, and 30 sees after suctioning, were compared with baseline values. Open endotracheal suctioning resulted in significant increases in mean arterial pressure throughout the suctioning procedure. Both methods resulted in increased mean heart rates. However, 30 sees after the procedure, the open-suction method was associated with a significantly higher mean heart rate than was the closed method. Closed suctioning was associated with significantly fewer dysrhythmias. Arterial oxygen saturation and systemic venous oxygen saturation decreased with open suctioning. In contrast, arterial oxygen saturation and systemic venous oxygen saturation increased with the closed suction method. There was no difference between the two methods in the occurrence of nosocomial pneumonia. Open endotracheal suctioning cost 1.88 more per patient per day and required more nursing time. ConclusionsThe closed suction method resulted in significantly fewer physiologic disturbances. Closed suctioning appears to be an effective and cost-efficient method of endotracheal suctioning that is associated with fewer suction-induced complications. (Crit Care Med 1994; 22:658–666)

Tight glycemic control in critically injured trauma patients.

Objectives:Evaluate the impact of a tight glucose control (TGC) protocol during the first week of admission in critically injured trauma patients. Methods:A prospective quasi-experimental interrupted time-series design was used to evaluate the impact of TGC [24-month preintervention phase (no TGC) vs. 24-month postintervention phase]. Patients were stratified by serum glucose level on day 1 to 7 (low, 0–150 mg/dL; medium-high, 151–219 mg/dL; and high, ≥220 mg/dL), age, gender, and injury severity. Patients were further stratified by pattern of glucose control (all low, all medium high, all high, improving, worsening, highly variable). Outcome was measured by ventilator days, infection, hospital (HLOS) and ICU (ILOS) length of stay, and mortality. Results:One thousand twenty-one patients were evaluated in the preintervention phase as compared with 1108 patients in the postintervention phase. There was no significant difference in mechanism of injury (83% vs. 84% blunt), gender (74% vs. 73% male), age (44 vs. 43 years), and Injury Severity Score (ISS) (26 vs. 25). The TGC group was more likely to be in the all low and improving pattern of glucose control (P < 0.001). The incidence of infection significantly decreased (over the first 2 weeks) from 29% to 21% in the TGC group (P < 0.001). Ventilator days (OR = 3.9, 1.8, 8.1), ILOS (OR = 4.3, 2.1, 7.5), and HLOS (OR = 5.5, 2.2, 11) and mortality (OR = 1.4, 1.1, 10) were significantly higher in the non-TGC group when controlled for age, ISS, obesity, and diabetes (P < 0.01). Conclusion:The positive outcomes associated with the implementation of a TGC protocol necessitates further evaluation in a randomized prospective trial.

Percutaneous dilational tracheostomy: Report of 141 cases

Tracheostomy is indicated frequently in the treatment of critically ill patients who require prolonged mechanical ventilation. The purpose of this prospective study was to evaluate our initial experience with 141 cases of percutaneous dilational tracheostomy (PDT) performed over a 2-year period. One hundred twenty PDTs (85%) were placed at the bedside, and 21 (15%) were performed in the operating room in conjunction with other procedures. The procedural complication rate was 11% (16 of 141). Most complications were easily recognized and did not preclude the completion of PDT. One death occurred secondary to severe bronchospasm. The postoperative complication rate was 8% (11 of 141). The most frequent complication was peristomal oozing. The average duration of follow-up after decannulation for patients discharged alive and decannulated was 36 +/- 27 weeks. There were 3 recognized cases of clinically symptomatic tracheal stenosis. We conclude that PDT is comparable with the open method and can be performed rapidly and safely at the patients bedside.

Gene expression profiles differentiate between sterile SIRS and early sepsis.

Introduction:The systemic inflammatory response syndrome (SIRS) occurs frequently in critically ill patients and presents similar clinical appearances despite diverse infectious and noninfectious etiologies. Despite similar phenotypic expression, these diverse SIRS etiologies may induce divergent genotypic expressions. We hypothesized that gene expression differences are present between sepsis and uninfected SIRS prior to the clinical appearance of sepsis. Methods:Critically ill uninfected SIRS patients were followed longitudinally for the development of sepsis. All patients had whole blood collected daily for gene expression analysis by Affymetrix Hg_U133 2.0 Plus microarrays. SIRS patients developing sepsis were compared with those remaining uninfected for differences in gene expression at study entry and daily for 3 days prior to conversion to sepsis. Acceptance criteria for differentially expressed genes required: >1.2 median fold change between groups and significance on univariate and multivariate analysis. Differentially expressed genes were annotated to pathways using DAVID 2.0/EASE analysis. Results:A total of 12,782 (23.4%) gene probes were differentially expressed on univariate analysis 0 to 48 hours before clinical sepsis. 626 (1.1%) probes met acceptance criteria, corresponding to 459 unique genes, 65 (14.2%) down and 395 (85.8%) up expressed. These genes annotated to 10 pathways that functionally categorized to 4 themes involving innate immunity, cytokine receptors, T cell differentiation, and protein synthesis regulation. Conclusions:Sepsis has a unique gene expression profile that is different from uninfected inflammation and becomes apparent prior to expression of the clinical sepsis phenotype.

Early hyperglycemic control is important in critically injured trauma patients

BACKGROUND Our objectives were to determine whether persistent hyperglycemia when compared with normoglycemia was predictive of outcome in the later stages of hospitalization in critically injured trauma patients. METHODS A prospective study was conducted on 896 consecutive trauma patients admitted to the intensive care unit during a 2-year period. Patients were stratified by serum glucose level on day 1 to day 28 (low = 0-139 mg/dL, medium to high = 140-219 mg/dL, and high = >220 mg/dL), age, gender, race, insulin dependent diabetes, obesity, and Injury Severity Score (ISS). Patients were further stratified by pattern of glucose control (all low, all moderate, all high, improving, worsening, highly variable. Outcome was measured by ventilator days, infection, hospital and intensive care unit length of stay, and mortality. Multiple variable logistic and linear regression models were used to determine level of significance. RESULTS Eighty-three percent were victims of blunt trauma. The majority (74%) were male, with a mean ISS of 26 +/- 12. Hyperglycemia (moderate, worsening, and highly variable) in the first week was associated with significantly greater hospital and intensive care unit length of stay, ventilator time, infection, and mortality when controlling for age, race, gender, ISS, mechanism of injury, obesity, and insulin dependent diabetes (p < 0.03). However, hyperglycemia in later weeks was not associated with infection and only weakly associated with mortality when analyzed by the same model. When controlling for glucose levels in subsequent weeks, patients who were normoglycemic in the first week had a lower infection rate and were less likely to die even when controlling for age, ISS, and obesity (p < 0.05). CONCLUSIONS Early euglycemia is associated with improved outcome and appears to be protective regardless of glucose levels in subsequent weeks. Further studies are warranted to determine the etiology of this protective effect.

Brachial plexus injury : association with subclavian and axillary vascular trauma

Proximal upper extremity (subclavian and axillary) vascular injury (SAVI) and brachial plexus injury (BPI) occur uncommonly. However, BPI may be associated with SAVI and frequently is an important determinant of long-term disability. The medical records of patients with traumatic SAVI, BPI, or both over a 5-year period were reviewed. A total of 31 patients were identified. The group was predominantly male (28 men/3 women) with a mean age of 30.5 +/- 1.8 years (range, 15-63 years). Blunt trauma accounted for 43.5% of SAVI cases and 77.8% of BPI cases. Thirteen patients (41.9%) sustained SAVI alone (group I), 10 patients (32.2%) had combined SAVI and BPI (group II), and 8 patients (25.9%) had BPI alone (group III). Subclavian and axilliary vascular injury occurred in 10 of 18 patients (55.6%) with a BPI. Brachial plexus injury occurred in 10 of 23 patients (43.5%) with a SAVI. Patients with SAVI from blunt trauma were significantly more likely to have an associated complete BPI than patients with penetrating trauma. All patients with a complete BPI (6 patients) had an associated SAVI regardless of mechanism of injury. Only one patient with a partial BPI from blunt trauma had an associated SAVI. The Injury Severity Score was significantly higher for patients in group II. An average of 2.8 and 3.3 associated injuries were observed in patients with SAVI (groups I and II) versus patients without SAVI (group III), respectively. No patient who had a complete BPI showed an improvement in neurologic status during a mean follow-up of 7.2 months. No late vascular sequelae occurred in group-III patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of transesophageal echocardiography in the evaluation of traumatic aortic injury.

Indications for aortography following blunt chest trauma are broad and ill-defined. This study prospectively assessed the role of transesophageal echocardiography (TEE) in the evaluation of suspected aortic injury. We used both TEE and aortography to evaluate 69 patients with suspected thoracic aortic injury. The studies were performed and interpreted by staff radiologists and cardiologists. The mean study time for TEE was 27 minutes, whereas the mean study time for aortography was 76 minutes (p < 0.05). No complications occurred with either procedure. Both TEE and aortography revealed no evidence of aortic injury in 61 patients. There was one false-positive aortogram. TEE identified seven aortic injuries; four were confirmed by aortography. One patient underwent thoracotomy and aortic repair based on TEE findings alone. Aortograms yielded false-negative results for two patients; one injury was confirmed at thoracotomy, the other at autopsy. TEE accurately predicted the presence or absence of aortic injury in each case, for a diagnostic sensitivity and specificity of 100%. TEE can be performed safely and efficiently on the multiple-injury patient. We conclude that TEE is useful in the evaluation of suspected aortic injury.