Frank LoVecchio

A Randomized Trial of Protocol-Based Care for Early Septic Shock

BACKGROUND In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary. METHODS In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. RESULTS We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. CONCLUSIONS In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

Chest Compression–Only CPR by Lay Rescuers and Survival From Out-of-Hospital Cardiac Arrest

CONTEXT Chest compression-only bystander cardiopulmonary resuscitation (CPR) may be as effective as conventional CPR with rescue breathing for out-of-hospital cardiac arrest. OBJECTIVE To investigate the survival of patients with out-of-hospital cardiac arrest using compression-only CPR (COCPR) compared with conventional CPR. DESIGN, SETTING, AND PATIENTS A 5-year prospective observational cohort study of survival in patients at least 18 years old with out-of-hospital cardiac arrest between January 1, 2005, and December 31, 2009, in Arizona. The relationship between layperson bystander CPR and survival to hospital discharge was evaluated using multivariable logistic regression. MAIN OUTCOME MEASURE Survival to hospital discharge. RESULTS Among 5272 adults with out-of-hospital cardiac arrest of cardiac etiology not observed by responding emergency medical personnel, 779 were excluded because bystander CPR was provided by a health care professional or the arrest occurred in a medical facility. A total of 4415 met all inclusion criteria for analysis, including 2900 who received no bystander CPR, 666 who received conventional CPR, and 849 who received COCPR. Rates of survival to hospital discharge were 5.2% (95% confidence interval [CI], 4.4%-6.0%) for the no bystander CPR group, 7.8% (95% CI, 5.8%-9.8%) for conventional CPR, and 13.3% (95% CI, 11.0%-15.6%) for COCPR. The adjusted odds ratio (AOR) for survival for conventional CPR vs no CPR was 0.99 (95% CI, 0.69-1.43), for COCPR vs no CPR, 1.59 (95% CI, 1.18-2.13), and for COCPR vs conventional CPR, 1.60 (95% CI, 1.08-2.35). From 2005 to 2009, lay rescuer CPR increased from 28.2% (95% CI, 24.6%-31.8%) to 39.9% (95% CI, 36.8%-42.9%; P < .001); the proportion of CPR that was COCPR increased from 19.6% (95% CI, 13.6%-25.7%) to 75.9% (95% CI, 71.7%-80.1%; P < .001). Overall survival increased from 3.7% (95% CI, 2.2%-5.2%) to 9.8% (95% CI, 8.0%-11.6%; P < .001). CONCLUSION Among patients with out-of-hospital cardiac arrest, layperson compression-only CPR was associated with increased survival compared with conventional CPR and no bystander CPR in this setting with public endorsement of chest compression-only CPR.

Trimethoprim–Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess

BACKGROUND U.S. emergency department visits for cutaneous abscess have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). The role of antibiotics for patients with a drained abscess is unclear. METHODS We conducted a randomized trial at five U.S. emergency departments to determine whether trimethoprim-sulfamethoxazole (at doses of 320 mg and 1600 mg, respectively, twice daily, for 7 days) would be superior to placebo in outpatients older than 12 years of age who had an uncomplicated abscess that was being treated with drainage. The primary outcome was clinical cure of the abscess, assessed 7 to 14 days after the end of the treatment period. RESULTS The median age of the participants was 35 years (range, 14 to 73); 45.3% of the participants had wound cultures that were positive for MRSA. In the modified intention-to-treat population, clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005). In the per-protocol population, clinical cure occurred in 487 of 524 participants (92.9%) in the trimethoprim-sulfamethoxazole group versus 457 of 533 participants (85.7%) in the placebo group (difference, 7.2 percentage points; 95% CI, 3.2 to 11.2; P<0.001). Trimethoprim-sulfamethoxazole was superior to placebo with respect to most secondary outcomes in the per-protocol population, resulting in lower rates of subsequent surgical drainage procedures (3.4% vs. 8.6%; difference, -5.2 percentage points; 95% CI, -8.2 to -2.2), skin infections at new sites (3.1% vs. 10.3%; difference, -7.2 percentage points; 95% CI, -10.4 to -4.1), and infections in household members (1.7% vs. 4.1%; difference, -2.4 percentage points; 95% CI, -4.6 to -0.2) 7 to 14 days after the treatment period. Trimethoprim-sulfamethoxazole was associated with slightly more gastrointestinal side effects (mostly mild) than placebo. At 7 to 14 days after the treatment period, invasive infections had developed in 2 of 524 participants (0.4%) in the trimethoprim-sulfamethoxazole group and in 2 of 533 participants (0.4%) in the placebo group; at 42 to 56 days after the treatment period, an invasive infection had developed in 1 participant (0.2%) in the trimethoprim-sulfamethoxazole group. CONCLUSIONS In settings in which MRSA was prevalent, trimethoprim-sulfamethoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00729937.).

Envenomations by rattlesnakes thought to be dead.

To the Editor: Even after suffering potentially fatal injuries, venomous snakes are capable of injuring humans. Klauber performed experiments showing that rattlesnake heads are dangerous for 20 to ...

A Randomized Trial of Clindamycin Versus Trimethoprim-sulfamethoxazole for Uncomplicated Wound Infection

BACKGROUND With the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in the United States, visits for skin infections greatly increased. Staphylococci and streptococci are considered predominant causes of wound infections. Clindamycin and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed, but the efficacy of TMP-SMX has been questioned. METHODS We conducted a randomized, double-blind, superiority trial at 5 US emergency departments. Patients >12 years of age with an uncomplicated wound infection received oral clindamycin 300 mg 4 times daily or TMP-SMX 320 mg/1600 mg twice daily, each for 7 days. We compared the primary outcome, wound infection cure at 7-14 days, and secondary outcomes through 6-8 weeks after treatment, in the per-protocol population. RESULTS Subjects had a median age of 40 years (range, 14-76 years); 40.1% of wound specimens grew MRSA, 25.7% methicillin-susceptible S. aureus, and 5.0% streptococci. The wound infection was cured at 7-14 days in 187 of 203 (92.1%) clindamycin-treated and 182 of 198 (91.9%) TMP-SMX-treated subjects (difference, 0.2%; 95% confidence interval [CI], -5.8% to 6.2%; P = not significant). The clindamycin group had a significantly lower rate of recurrence at 7-14 days (1.5% vs 6.6%; difference, -5.1%; 95% CI, -9.4% to -.8%) and through 6-8 weeks following treatment (2.0% vs 7.1%; difference, -5.1%; 95% CI, -9.7% to -.6%). Other secondary outcomes were statistically similar between groups but tended to favor clindamycin. Adverse event rates were similar. CONCLUSIONS In settings where MRSA is prevalent, clindamycin and TMP-SMX produce similar cure and adverse event rates among patients with an uncomplicated wound infection. Further study evaluating differential effects of antibiotics on recurrent infection may be warranted. CLINICAL TRIALS REGISTRATION NCT00729937.

Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial

Importance Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, &bgr;-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity. Objective To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone. Design, Setting, and Participants Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012. Interventions Cephalexin, 500 mg 4 times daily, plus trimethoprim-sulfamethoxazole, 320 mg/1600 mg twice daily, for 7 days (n = 248 participants) or cephalexin plus placebo for 7 days (n = 248 participants). Main Outcomes and Measures The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%. Results Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, −2.0%; 95% CI, −9.7% to 5.7%; P = .50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim–sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, −1.0% to 15.5%; P = .07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly. Conclusions and Relevance Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed. Trial Registration clinicaltrials.gov Identifier: NCT00729937

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection

BACKGROUND The effect of procalcitonin‐guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear. METHODS In 14 U.S. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real‐time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual‐care group. We hypothesized that within 30 days after enrollment the total antibiotic‐days would be lower — and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher — in the procalcitonin group than in the usual‐care group. RESULTS A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual‐care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual‐care group. In both groups, the procalcitonin‐level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual‐care group in antibiotic‐days (mean, 4.2 and 4.3 days, respectively; difference, ‐0.05 day; 95% confidence interval [CI], ‐0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, ‐1.5 percentage points; 95% CI, ‐4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital‐based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986.)

Subgroup Analysis of Antibiotic Treatment for Skin Abscesses

Study objective Two large randomized trials recently demonstrated efficacy of methicillin‐resistant Staphylococcus aureus (MRSA)–active antibiotics for drained skin abscesses. We determine whether outcome advantages observed in one trial exist across lesion sizes and among subgroups with and without guideline‐recommended antibiotic indications. Methods We conducted a planned subgroup analysis of a double‐blind, randomized trial at 5 US emergency departments, demonstrating superiority of trimethoprim‐sulfamethoxazole (320/1,600 mg twice daily for 7 days) compared with placebo for patients older than 12 years with a drained skin abscess. We determined between‐group differences in rates of clinical (no new antibiotics) and composite cure (no new antibiotics or drainage) through 7 to 14 and 42 to 56 days after treatment among subgroups with and without abscess cavity or erythema diameter greater than or equal to 5 cm, history of MRSA, fever, diabetes, and comorbidities. We also evaluated treatment effect by lesion size and culture result. Results Among 1,057 mostly adult participants, median abscess cavity and erythema diameters were 2.5 cm (range 0.1 to 16.0 cm) and 6.5 cm (range 1.0 to 38.5), respectively; 44.3% grew MRSA. Overall, for trimethoprim‐sulfamethoxazole and placebo groups, clinical cure rate at 7 to 14 days was 92.9% and 85.7%; composite cure rate at 7 to 14 days was 86.5% and 74.3%, and at 42 to 56 days, it was 82.4% and 70.2%. For all outcomes, across lesion sizes and among subgroups with and without guideline antibiotic criteria, trimethoprim‐sulfamethoxazole was associated with improved outcomes. Treatment effect was greatest with history of MRSA infection, fever, and positive MRSA culture. Conclusion Treatment with trimethoprim‐sulfamethoxazole was associated with improved outcomes regardless of lesion size or guideline antibiotic criteria.

Houston Consensus Conference on Testing for Helicobacter pylori Infection in the United States

&NA; Despite guidelines for detection and treatment of Helicobacter pylori infection, recommendations to test patients before and after therapy are commonly not followed in the United States. At the Houston Consensus Conference, 11 experts on management of adult and pediatric patients with H pylori, from different geographic regions of the United States, met to discuss key factors in diagnosis of H pylori infection, including identification of appropriate patients for testing, effects of antibiotic susceptibility on testing and treatment, appropriate methods for confirmation of infection and eradication, and relevant health system considerations. The experts divided into groups that used a modified Delphi panel approach to assess appropriate patients for testing, testing for antibiotic susceptibility and treatment, and test methods and confirmation of eradication. The quality of evidence and strength of recommendations were evaluated using the GRADE system. The results of the individual workshops were presented for a final consensus vote by all panel members. After the Expert Consensus Development meeting, the conclusions were validated by a separate panel of gastroenterologists, who assessed their level of agreement with each of the 29 statements developed at the Expert Consensus Development. The final recommendations are provided, on the basis of the best available evidence, and provide consensus statements with supporting literature to implement testing for H pylori infection at health care systems across the United States.