Early propranolol treatment induces lung heme-oxygenase-1, attenuates metabolic dysfunction, and improves survival following experimental sepsis.

INTRODUCTION: Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis. METHODS: Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics. RESULTS: Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged. CONCLUSIONS: These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.

Pharmacologically dosed oral glutamine reduces myocardial injury in patients undergoing cardiac surgery: a randomized pilot feasibility trial.

BACKGROUND AND OBJECTIVE: Glutamine (GLN) has been shown to protect against in vitro and in vivo myocardial injury. In humans, perioperative ischemia/reperfusion (I/R) injury during cardiac surgery is associated with higher morbidity and mortality. The objective of this safety and feasibility pilot trial was to determine if pharmacologically dosed, preoperative oral GLN attenuates myocardial injury in cardiac surgery patients. METHODS: Patients undergoing elective cardiac surgery, requiring cardiopulmonary bypass, were enrolled in a randomized, double-blind pilot trial to receive 25 g twice of oral alanyl-glutamine (GLN; n = 7) or maltodextrin (CONT; n = 7) daily for 3 days preoperatively. Serum troponin (TROP I), creatine kinase (CK-MB), and myoglobin (MG) were measured at multiple perioperative time points. Clinical outcomes were also recorded and assessed. RESULTS: GLN therapy significantly decreased TROP I levels at 24, 48, and 72 hours postoperatively (all P < .05) vs CONT. GLN also reduced CK-MB at 24 and 48 hours (P < .05, P < .001) vs CONT. MG was reduced at 24 hours vs control (P = .0397). GLN also significantly reduced pooled clinical complications vs CONT (P = .03). CONCLUSION: This pilot study showed that pharmacologically dosed oral GLN therapy prior to cardiac surgery was safe, well tolerated, and feasible. GLN therapy reduced myocardial injury and clinical complications in this small randomized, blinded feasibility trial. These data indicate that a larger trial of preoperative GLN therapy in patients undergoing cardiac surgery is needed to confirm clinical benefit.

Relationship of vitamin D deficiency to clinical outcomes in critically ill patients.

BACKGROUND: Despite the numerous disease conditions associated with vitamin D deficiency in the general population, the relationship of this deficiency to outcome in critically ill patients remains unclear. The objective of this study is to determine the burden of vitamin D deficiency in intensive care unit (ICU) patients and determine if it is associated with poor patient outcomes. METHODS: The authors conducted an analysis of samples collected from a prospective study of 196 patients admitted to a medical/surgical ICU in a tertiary care hospital. They measured serum 25-hydroxyvitamin D at admission and up to 10 days following admission and followed patients prospectively for 28-day outcomes. RESULTS: Of analyzable patients, 50 (26%) were deficient (≤30 nmol/L) and 109 (56%) were insufficient (>30 and ≤60 nmol/L). Baseline 25(OH)D levels decreased significantly in all patients after 3 days in the ICU and remained significantly lower through 10 days (P < .001). 25(OH)D status was not significantly associated with 28-day all-cause mortality (hazard ratio [HR], 0.89; 95% confidence interval, [CI] 0.37-2.24). Higher levels of 25(OH)D were associated with a shorter time-to-alive ICU discharge (HR, 2.11; 95% CI, 1.27-3.51). 25(OH)D-deficient patients showed a nonstatistically significant trend toward a higher infection rate (odds ratio [OR], 3.20; 95% CI, 0.784-13.07; P = .11) compared with patients with sufficient levels of 25(OH)D. CONCLUSIONS: This study demonstrates significant decreases in vitamin D status over the duration of the patient's ICU stay. Low levels of vitamin D are associated with longer time to ICU discharge alive and a trend toward increased risk of ICU-acquired infection.

Standard subcutaneous dosing of unfractionated heparin for venous thromboembolism prophylaxis in surgical ICU patients leads to subtherapeutic factor Xa inhibition.

PURPOSE: To assess coagulation status and factor Xa inhibition in surgical intensive care unit (ICU) patients administered prophylactic unfractionated heparin for venous thromboembolism (VTE) prophylaxis. METHODS: We conducted a randomized, single-blind study at a tertiary academic medical center. Included were patients 18 years and older admitted to the surgical ICU directly after major abdominal surgery. Exclusion criteria included significant bleeding risk, preoperative anticoagulation, or history of heparin-induced thrombocytopenia. Patients were randomized to two regimens for VTE prophylaxis: standard of care unfractionated heparin, 5,000 units subcutaneously three times daily (SQH) versus unfractionated heparin via intravenous infusion, titrated to an activated partial thromboplastin time of 40-45 s (IVH). Blood samples were taken prior to surgical incision on day 0 and daily for 5 days after surgery. Samples were analyzed for factor Xa inhibition and viscoelastic whole blood clotting parameters (Sonoclot analyzer). RESULTS: A total of 50 patients were randomized to either SQH or IVH. The majority of patients had cancer. Patients in the SQH group had no detectable peak anti-factor Xa (aFXa) activity for 5 days after surgery, while patients in the IVH group had statistically elevated levels compared to the SQH group on days 3-5. SQH patients demonstrated a hypercoagulable profile on Sonoclot, while IVH patients displayed a normal profile. CONCLUSIONS: Standard of care subcutaneous dosing of unfractionated heparin for VTE prophylaxis in surgical ICU patients leads to subtherapeutic levels of factor Xa inhibition.

Discovery and verification of protein differences between Er positive/Her2/neu negative breast tumor tissue and matched adjacent normal breast tissue.

This study was designed to quantify and identify differences in protein levels between tumor and adjacent normal breast tissue from the same breast in 18 women with stage I/II ER positive/Her2/neu negative invasive breast cancer. Eighteen separate difference gel electrophoresis (DIGE) gels were run (1 gel per patient). Relative quantification was based on DIGE analysis. After excision and tryptic digestion, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and peptide mass mapping were used to identify protein spots. Two hundred and forty-three spots were differentially abundant between normal and cancer tissues. Fifty spots were identified: 41 were over abundant and nine were less abundant in cancers than in normal breast tissue. Western blotting provided independent confirmation for three of the most biologically and statistically interesting proteins. All 18 gels were replicated by another technician and 32% of the differentially abundant proteins were verified by the duplicate analysis. Follow-up studies are now examining these proteins as biomarkers in blood.