Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment?

BACKGROUND: We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. METHODS AND RESULTS: This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL(-1)/48 h(-1)); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL(-1)); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL(-1)); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL(-1) (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO(2):FiO(2) ratios 255 (195, 323) versus 263 (210, 308) were similar. CONCLUSIONS: In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. Clinical Trial Registration-URL: http://www.ukcrn.org.uk. Unique identifier: 4659.

Mechanisms of the anti-inflammatory effects of hydroxyethyl starch demonstrated in a flow-based model of neutrophil recruitment by endothelial cells.

OBJECTIVE: To determine whether plasma volume expander hydroxyethyl starch (HES) may protect against reperfusion injury through an ability to reduce neutrophil recruitment. DESIGN: An in vitro study using paired comparisons of adhesion of flowing neutrophils. SETTING: A collaboration between clinical and basic science departments in a university hospital. SUBJECTS: Neutrophils and cultured human umbilical vein endothelial cells (HUVEC). INTERVENTIONS: Treatment with HES (average molecular weight of 200 kd and substitution of 0.62) at clinically relevant concentrations or with gelatin solution (average molecular weight of 30 kDa) of comparable viscosity. MEASUREMENTS AND MAIN RESULTS: Glass capillaries were coated internally with either purified adhesion molecules or HUVEC, which were treated with tumor necrosis factor-alpha in the presence or absence of HES. Neutrophils were perfused over these surfaces (with or without HES) and their recruitment quantified by video microscopy. Expression of adhesion molecules and of the chemokine interleukin-8 by HUVEC were analyzed by enzyme-linked immunosorbent assay and quantitation of messenger RNA. HES over a wide range of concentrations had no effect on selectin- or integrin-mediated adhesion of neutrophils. However, when HUVEC were cultured with 1.5% wt/vol HES, neutrophil capture induced by low-dose (1 unit/mL) tumor necrosis factor-alpha and transendothelial migration induced by high-dose (100 units/mL) tumor necrosis factor-alpha were significantly inhibited (p < .05, in each case). The effects were linked with reductions in expression of E-selectin and interleukin-8 by HUVEC at these respective tumor necrosis factor-alpha concentrations (p < .05, in each case). Gelatin (2% wt/vol) had no significant effect in assays with HUVEC. CONCLUSIONS: Application of HES to HUVEC exerts an inhibitory effect on different stages of neutrophil recruitment, depending on the level of the inflammatory stimulus. These effects are associated with reduced adhesion molecule expression and chemokine production. In vivo, comparable effects might protect against complications associated with reperfusion injury.

Microalbuminuria in the intensive care unit: Clinical correlates and association with outcomes in 431 patients.

OBJECTIVE: Comparison of urine albumin within 6 hrs of intensive care unit (ICU) admission with demography, clinical classification, outcome, inotrope/vasopressor requirement, clinical assessment of mortality risk, and Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores. DESIGN: Urine albumin-creatinine ratio (ACR) was measured on ICU admission (ACR 1) and after 4-6 hrs (ACR 2). SETTING: A 17-bed general ICU in a university teaching hospital. PATIENTS: Unselected medical (206) and surgical (225) patients recruited prospectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Bedside urine ACR was measured by nurses using a Bayer DCA 2000 analyzer and expressed in mg/mmol (reference range <2.3). ACR 1 in medical and surgical patients was 15.5 (12.4-19.5) and 8.2 (5.9-11.1) mg/mmol, respectively (p = .0002), and ACR 2 was 9.0 (5.8-12.5) and 4.6 (3.6-5.3), respectively (p < .0001). For all patients, median (95% confidence interval) ACR fell from 11.2 (8.7-13.2) to 5.4 (4.7-6.8) mg/mmol 4-6 hrs after ICU admission (p < .0001). ACR 1 for nonsurvivors (n = 90) and survivors (n = 341) was 16.1 (11.2-21.3) and 8.8 (6.9-11.9), respectively (p = .0002) and ACR 2, 12.4 (8.2-18.9) and 4.8 (3.9-5.4), respectively (p < .0001). In both medical and surgical patients who died on the ICU, median ACR failed to decrease significantly following admission. ACR1 and ACR 2 were higher in patients who required inotropic or vasopressor support and correlated with duration of therapy. ACR 1 and 2 were inversely correlated with mean Po2/Fio2 ratio 48 hrs after ICU admission and positively correlated with duration of mechanical ventilation and ACR 1 with ICU stay. ACR 2 predicted mortality and ACR 1 inotrope requirement independent of clinical mortality risk assessment and APACHE II and SOFA scores. CONCLUSIONS: Urine albumin changes rapidly within the first 6 hrs following ICU admission and predicts ICU mortality and inotrope requirement as well as or better than APACHE II and SOFA scores. Serial urine albumin measurement may provide a means of monitoring the microvascular effects of systemic inflammation.

Pulmonary and renal function following cardiopulmonary bypass is associated with systemic capillary leak.

OBJECTIVE: The purpose of this study was to compare perioperative capillary permeability during cardiac surgery with subsequent pulmonary and renal function. DESIGN: An observational prospective comparison of capillary permeability (microalbuminuria) during and after cardiopulmonary bypass (CPB), with postoperative pulmonary and renal function. SETTING: A university teaching hospital. PARTICIPANTS: Forty patients, mean (range) age 67.8 (50-85) years, undergoing elective first-time coronary artery bypass grafting (CABG). INTERVENTIONS: Urine albumin concentration (AC) and albumin creatinine ratio (ACR) were compared with PO2 /FIO2 ratio, mechanical ventilation (intermittent positive-pressure ventilation [IPPV]) duration, and renal function. MEASUREMENTS AND MAIN RESULTS: Median (range) AC and ACR increased from 8.3 (1.6-184.2) mg/L and 0.65 (0.1-18.8) mg/mmol preoperatively to 13.6 (1.6-267.2) mg/L and 4.80 (0.3-54.2) mg/mmol 10 minutes postbypass (p = 0.003 for ACR Wilcoxon rank test: not significant for AC). AC 2 hours postbypass was associated with mean PO2 /FIO2 ratio 0 to 2 hours postbypass and AC 4 hours postbypass was associated with mean PO2 /FIO2 ratio 0 to 2 and 2 to 12 hours postbypass (p < 0.05 Spearman). ACR 2 hours postbypass was associated with mean PO2 /FIO2 ratio 0 to 2 and 2 to 12 hours postbypass (p < 0.05 Spearman). AC 10 minutes and 2 hours postbypass and ACR 2 hours postbypass were associated with the duration of IPPV (p < 0.03). Day 1 serum creatinine was associated with pre- and 4 hours postbypass AC and ACR (p < 0.05). Day 2 serum creatinine was associated with 2 and 4 hours postbypass ACR (p < 0.05). CONCLUSIONS: The magnitude of increase in capillary permeability during CABG is associated with later pulmonary and renal function.

Mortality prediction at admission to intensive care: a comparison of microalbuminuria with acute physiology scores after 24 hours.

OBJECTIVE: To compare low level albumin excretion (microalbuminuria), a marker of systemic capillary permeability, with mortality, Acute Physiologic And Chronic Health Evaluation (APACHE II) score, the Simplified Acute Physiologic (SAP II) score, and their derived mortality probabilities in patients admitted to a general intensive care unit. DESIGN: Prospective observational study. SETTING: A 14-bed intensive care unit in a university teaching hospital. PATIENTS: A total of 140 consecutive patients (59 surgical, 48 medical, 22 trauma, and 11 burns). INTERVENTIONS: Urine collection within 15 mins of intensive care unit admission for assessment of microalbuminuria. MEASUREMENTS AND MAIN RESULTS: Microalbuminuria, expressed as the albumin-creatinine ratio (ACR: normal, <2.3 mg/mmol), was compared with mortality, APACHE II and SAP II scores and their derived mortality probabilities after 24 hrs, intensive care unit stay, and markers of organ function and inflammation. Median (95% confidence interval) ACR at admission for survivors (n = 115) and nonsurvivors (n = 25) were 4.2 (3.6-6.5) and 17.8 (8.0-40.8) mg/mmol, respectively (p =.0002 Mann Whitney). For 92 surgical, trauma, and burn patients, of whom 81 survived, ACR of >5.9 mg/mmol gave a sensitivity for death of 100%, specificity of 59%, positive predictive value of 25%, and negative predictive value of 100%. Mortality probability receiver operator characteristic curve areas for ACR, APACHE II, and SAP II were 0.843 (p <.0001), 0.793 (p =.0004), and 0.770 (p =.0017), respectively. ACR was associated with intensive care unit stay (p =.0021) and highest serum C-reactive protein (p =.0002), serum creatinine (p <.0001), and bilirubin (p =.0009). For 48 medical patients, of whom 34 survived, admission ACRs for survivors and nonsurvivors were 8.3 (5.7-10.8) and 10.7 (4.1-48.2) mg/mmol, respectively (p =.32). SAP II, but not APACHE II, score was significantly higher for nonsurvivors. CONCLUSIONS: For surgical, trauma, and burn patients, but not medical patients, microalbuminuria within 15 mins of intensive care unit admission predicted death as well as APACHE II and SAP II scores calculated after 24 hrs, and it shows promise as a predictor of outcome.