Samir S. Awad

Chlorhexidine–Alcohol versus Povidone–Iodine for Surgical-Site Antisepsis

BACKGROUND Since the patients skin is a major source of pathogens that cause surgical-site infection, optimization of preoperative skin antisepsis may decrease postoperative infections. We hypothesized that preoperative skin cleansing with chlorhexidine-alcohol is more protective against infection than is povidone-iodine. METHODS We randomly assigned adults undergoing clean-contaminated surgery in six hospitals to preoperative skin preparation with either chlorhexidine-alcohol scrub or povidone-iodine scrub and paint. The primary outcome was any surgical-site infection within 30 days after surgery. Secondary outcomes included individual types of surgical-site infections. RESULTS A total of 849 subjects (409 in the chlorhexidine-alcohol group and 440 in the povidone-iodine group) qualified for the intention-to-treat analysis. The overall rate of surgical-site infection was significantly lower in the chlorhexidine-alcohol group than in the povidone-iodine group (9.5% vs. 16.1%; P=0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine-alcohol was significantly more protective than povidone-iodine against both superficial incisional infections (4.2% vs. 8.6%, P=0.008) and deep incisional infections (1% vs. 3%, P=0.05) but not against organ-space infections (4.4% vs. 4.5%). Similar results were observed in the per-protocol analysis of the 813 patients who remained in the study during the 30-day follow-up period. Adverse events were similar in the two study groups. CONCLUSIONS Preoperative cleansing of the patients skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery. (ClinicalTrials.gov number, NCT00290290.)

Aging Reduces Proliferative Capacities of Liver by Switching Pathways of C/EBPα Growth Arrest

The liver is capable of completely regenerating itself in response to injury and after partial hepatectomy. In liver of old animals, the proliferative response is dramatically reduced, the mechanism for which is unknown. The liver specific protein, C/EBPalpha, normally arrests proliferation of hepatocytes through inhibiting cyclin dependent kinases (cdks). We present evidence that aging switches the liver-specific pathway of C/EBPalpha growth arrest to repression of E2F transcription. We identified an age-specific C/EBPalpha-Rb-E2F4 complex that binds to E2F-dependent promoters and represses these genes. The C/EBPalpha-Rb-E2F4 complex occupies the c-myc promoter and blocks induction of c-myc in livers of old animals after partial hepatectomy. Our results show that the age-dependent switch from cdk inhibition to repression of E2F transcription causes a loss of proliferative response in the liver because of an inability to induce E2F target genes after partial hepatectomy providing a possible mechanism for the age-dependent loss of liver regenerative capacity.

Extracorporeal life support in pulmonary failure after trauma

OBJECTIVE To present a series of 30 adult trauma patients who received extracorporeal life support (ECLS) for pulmonary failure and to retrospectively review variables related to their outcome. METHODS In a Level I trauma center between 1989 and 1997, ECLS with continuous heparin anticoagulation was instituted in 30 injured patients older than 15 years. Indication was for an estimated mortality risk greater than 80%, defined by a PaO2: FIO2 ratio less than 100 on 100% FIO2, despite pressure-mode inverse ratio ventilation, optimal positive end-expiratory pressure, reasonable diuresis, transfusion, and prone positioning. Retrospective analysis included demographic information (age, gender, Injury Severity Score, injury mechanism), pulmonary physiologic and gas-exchange values (pre-ECLS ventilator days [VENT days], PaO2:FIO2 ratio, mixed venous oxygen saturation [SvO2], and blood gas), pre-ECLS cardiopulmonary resuscitation, complications of ECLS (bleeding, circuit problems, leukopenia, infection, pneumothorax, acute renal failure, and pressors on ECLS), and survival. RESULTS The subjects were 26.3+/-2.1 years old (range, 15-59 years), 50% male, and had blunt injury in 83.3%. Pulmonary recovery sufficient to wean the patient from ECLS occurred in 17 patients (56.7%), and 50% survived to discharge. Fewer VENT days and more normal SvO2 were associated with survival. The presence of acute renal failure and the need for venoarterial support (venoarterial bypass) were more common in the patients who died. Bleeding complications (requiring intervention or additional transfusion) occurred in 58.6% of patients and were not associated with mortality. Early use of ECLS (VENT days < or = 5) was associated with an odds ratio of 7.2 for survival. Fewer VENT days was independently associated with survival in a logistic regression model (p = 0.029). Age, Injury Severity Score, and PaO2:FIO2 ratio were not related to outcome. CONCLUSION ECLS has been safely used in adult trauma patients with multiple injuries and severe pulmonary failure. In our series, early implementation of ECLS was associated with improved survival. Although this may represent selection bias for less intractable forms of acute respiratory distress syndrome, it is our experience that early institution of ECLS may lead to improved oxygen delivery, diminished ventilator-induced lung injury, and improved survival.

Adherence to Surgical Care Improvement Project Measures and Post-Operative Surgical Site Infections

BACKGROUND Surgical site infection (SSI) is unequivocally morbid and costly. The estimated 300,000 SSIs annually in the United States represent the second most common infection among surgical patients, prolong hospitalization by 7-10 days, and have an estimated annual incremental cost of

Extracellular ATP activates c‐jun N‐terminal kinase signaling and cell cycle progression in hepatocytes

1 billion. The mortality rate associated with SSI is 3%, with about three quarters of deaths being attributable directly to the infection. Prevention is possible for the most part, and concerted effort has been made to limit these infections, arguably to little effect. METHODS Review of pertinent English-language literature. RESULTS Numerous risk factors for SSI and tactics for prevention have been described, but efforts to bundle these tactics into an effective, comprehensive prevention program have been disappointing. Numerous studies now demonstrate that the Surgical Care Improvement Program (SCIP), which focused on process improvement rather than outcomes, has been ineffective despite governmental support, financial penalties for non-compliance, and consequent widespread implementation. CONCLUSION Required reporting has increased awareness of the problem of SSI, but just as the complexity of SSI risk, pathogenesis, and preventions reflects the complexity of the disease, many other factors must be taken into account, including the skill and knowledge of the surgical team and promulgation of a culture of quality and safety in surgical patient care.

Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy.

Partial hepatectomy leads to an orchestrated regenerative response, activating a cascade of cell signaling events necessary for cell cycle progression and proliferation of hepatocytes. However, the identity of the humoral factors that trigger the activation of these pathways in the concerted regenerative response in hepatocytes remains elusive. In recent years, extracellular ATP has emerged as a rapidly acting signaling molecule that influences a variety of liver functions, but its role in hepatocyte growth and regeneration is unknown. In this study, we sought to determine if purinergic signaling can lead to the activation of c‐jun N‐terminal kinase (JNK), a known central player in hepatocyte proliferation and liver regeneration. Hepatocyte treatment with ATPγS, a nonhydrolyzable ATP analog, recapitulated early signaling events associated with liver regeneration—that is, rapid and transient activation of JNK signaling, induction of immediate early genes c‐fos and c‐jun, and activator protein‐1 (AP‐1) DNA‐binding activity. The rank order of agonist preference, UTP>ATP>ATPγS, suggests that the effects of extracellular ATP is mediated through the activation of P2Y2 receptors in hepatocytes. ATPγS treatment alone and in combination with epidermal growth factor (EGF) substantially increased cyclin D1 and proliferating cell nuclear antigen (PCNA) protein expression and hepatocyte proliferation in vitro. Extracellular ATP as low as 10 nM was sufficient to potentiate EGF‐induced cyclin D1 expression. Infusion of ATP by way of the portal vein directly activated hepatic JNK signaling, while infusion of a P2 purinergic receptor antagonist prior to partial hepatectomy inhibited JNK activation. In conclusion, extracellular ATP is a hepatic mitogen that can activate JNK signaling and hepatocyte proliferation in vitro and initiate JNK signaling in regenerating liver in vivo. These findings have implications for enhancing our understanding of novel factors involved in the initiation of regeneration, liver growth, and development. (HEPATOLOGY 2004;39:393–402.)

A Phase 3 Randomized Double-Blind Comparison of Ceftobiprole Medocaril Versus Ceftazidime Plus Linezolid for the Treatment of Hospital-Acquired Pneumonia

Chronic lithium therapy in patients with affective psychiatric disorders has been implicated as the cause of hypercalcemia and primary hyperparathyroidism. Our objective was to evaluate whether primary hyperparathyroidism was caused by an adenoma or four-gland hyperplasia. The medical records of 15 patients with affective psychiatric disorders who were treated with chronic lithium therapy from 1982 to 1997, all of whom were operated on for primary hyperparathyroidism, were reviewed. Data on age, symptoms, duration of lithium therapy, pre- and postoperative calcium levels, and parathyroid hormone levels were collected. Parathyroid histology for each patient was independently and blindly reviewed. The mean age was 58 ± 10 years, the mean duration of lithium therapy 10.7 ± 6 years, and the mean preoperative calcium level 11.7 ± 0.5 mg/dl. All patients underwent bilateral neck exploration with selective resection of enlarged glands. Of the 15 patients, 14 (92%) had adenomas (11 single, 3 double), and 1 (8%) had four-gland hyperplasia. All patients were rendered eucalcemic, with a postoperative calcium level of 9.2 ± 0.5 mg/dl (p < 0.005). All patients resumed their lithium therapy, with 1 of 15 patients developing recurrent hyperparathyroidism 2 years following the first operation; this patient required reexploration, at which time an adenoma was resected. In our experience hyperparathyroidism in patients who have undergone prolonged therapy with lithium is associated with a high incidence of parathyroid adenomas versus four-gland hyperplasia. This suggests that lithium selectively stimulates growth of parathyroid adenomas in susceptible patients, who are best treated with adenoma excision rather than subtotal parathyroidectomy.

Effect of rate and inspiratory flow on ventilator-induced lung injury.

BACKGROUND Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. METHODS This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneumonia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous ceftobiprole 500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was clinical cure at the test-of-cure visit. RESULTS Overall cure rates for ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT], 95% confidence interval [CI] for the difference, -10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI, -10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, -7.3 to 8.8), and 77.8% vs 76.2% (CE, 95% CI, -6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, -26.0 to -1.5) and 37.7% vs 55.9% (CE, 95% CI, -36.4 to 0). Microbiological eradication rates in HAP (excluding VAP) patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, -16.7 to 7.6), and in VAP patients 30.4% vs 50.0% (ME, 95% CI, -38.8 to -0.4). Treatment-related adverse events were comparable for ceftobiprole (24.9%) and ceftazidime/linezolid (25.4%). CONCLUSIONS Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP (excluding VAP). Further investigations are needed before recommending the use of ceftobiprole in VAP patients. Clinical Trials Registration. NCT00210964, NCT00229008.

A prospective comparison of atrio-femoral and femoro-atrial flow in adult venovenous extracorporeal life support

BACKGROUND We examined the effects of decreasing respiratory rate (RR) at variable inspiratory times (It) and reducing inspiratory flow on the development of ventilator-induced lung injury. METHODS Forty sheep weighing 24.6+/-3.2 kg were ventilated for 6 hours with one of five strategies (FIO2 = 1.0, positive end-expiratory pressure = 5 cm H2O): (1) pressure-controlled ventilation (PCV), RR = 15 breaths/min, peak inspiratory pressure (PIP) = 25 cm H2O, n = 8; (2) PCV, RR = 15 breaths/min, PIP = 50 cm H2O, n = 8; (3) PCV, RR = 5 breaths/min, PIP = 50 cm H2O, It = 6 seconds, n = 8; (4) PCV, RR = 5 breaths/min, PIP = 50 cm H2O, It = 2 seconds, n = 8; and (5) limited inspiratory flow volume-controlled ventilation, RR = 5 breaths/min, pressure-limit = 50 cm H2O, flow = 15 L/min, n = 8. RESULTS Decreasing RR at conventional flows did not reduce injury. However, limiting inspiratory flow rate (LIFR) maintained compliance and resulted in lower Qs/Qt (HiPIP = 38+/-18%, LIFR = 19+/-6%, p < 0.001), reduced histologic injury (HiPIP = 14+/-0.9, LIFR = 2.2+/-0.9, p < 0.05), decreased intra-alveolar neutrophils (HiPIP = 90+/-49, LIFR = 7.6+/-3.8,p = 0.001), and reduced wet-dry lung weight (HiPIP = 87.3+/-8.5%, LIFR = 40.8+/-17.4%,p < 0.001). CONCLUSIONS High-pressure ventilation for 6 hours using conventional flow patterns produces severe lung injury, irrespective of RR or It. Reduction of inspiratory flow at similar PIP provides pulmonary protection.

ATP release after partial hepatectomy regulates liver regeneration in the rat

INTRODUCTION In the United States, venovenous extracorporeal life support has traditionally been performed with atrial drainage and femoral reinfusion (atrio-femoral flow). Although flow reversal (femoro-atrial flow) may alter recirculation and extracorporeal flow, no direct comparison of these 2 modes has been undertaken. OBJECTIVE Our goal was to prospectively compare atrio-femoral and femoro-atrial flow in adult venovenous extracorporeal life support for respiratory failure. METHODS A modified bridge enabling conversion between atrio-femoral and femoro-atrial flow was incorporated in the extracorporeal circuit. Bypass was initiated in the direction that provided the highest pulmonary arterial mixed venous oxygen saturation, and the following measurements were taken: (1) maximum extracorporeal flow, (2) highest achievable pulmonary arterial mixed venous oxygen saturation, and (3) flow required to maintain the same pulmonary arterial mixed venous oxygen saturation in both directions. Flow direction was then reversed, and the measurements were repeated. Data were compared with paired t tests and are presented as mean +/- standard deviation. RESULTS Ten patients were studied, and 9 were included in the data analysis. Femoro-atrial bypass provided (1) higher maximal extracorporeal flow (femoro-atrial flow = 55.6 +/- 9.8 mL/kg per minute, atrio-femoral flow = 51.1 +/- 11.1 mL/kg per minute; P = .04) and (2) higher pulmonary arterial mixed venous oxygen saturation (femoroatrial flow = 89.9% +/- 6.6%, atrio-femoral flow = 83.2% +/- 4.2%; P = .006); (3) furthermore, it required less flow to maintain an equivalent pulmonary arterial mixed venous oxygen saturation (femoro-atrial flow = 37.0 +/- 12.2 mL/kg per minute, atrio-femoral flow = 46.4 +/- 8.8 mL/kg per minute; P = .04). CONCLUSIONS During venovenous extracorporeal life support, femoro-atrial bypass provided higher maximal extracorporeal flow, higher pulmonary arterial mixed venous oxygen saturation, and required comparatively less flow to maintain an equivalent mixed venous oxygen saturation than did atrio-femoral bypass.