Angiotensin-converting enzyme inhibition alters the inflammatory and fibrinolytic response to cardiopulmonary bypass in children*

Fleming, Gregory A.; Billings, Frederic T.; Klein, Tom; Bichell, David P.; Christian, Karla G.; Pretorius, Mias

doi:10.1097/pcc.0b013e3181fe3925

Cited by 17 publications

(15 citation statements)

References 29 publications

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“…Techniques aimed to reduce the inflammatory surge associated with cardiac surgery have also been developed, since acute inflammation has been implicated in the development of postoperative kidney injury in some studies [8,26]. Consistent with these studies, we found that perioperative plasma concentrations of IL-6 and to a lesser extent IL-8 or IL-10 are associated with AKI.…”

Section: Discussionsupporting

confidence: 79%

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery

Billings

Byrne

et al. 2014

Cardiorenal Med

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Background: Intraoperative hemolysis and inflammation are associated with acute kidney injury (AKI) following cardiac surgery. Plasma-free hemoglobin induces heme oxygenase-1 (HO-1) expression. HO-1 degrades heme but increases in experimental models of AKI. This study tested the hypothesis that plasma HO-1 concentrations are associated with intraoperative hemolysis and are increased in patients that develop AKI following cardiac surgery. Methods: We measured plasma HO-1, free hemoglobin, and inflammatory markers in 74 patients undergoing cardiopulmonary bypass (CPB). AKI was defined as anincrease in serum creatinine concentration of 50% or 0.3 mg/dl within 72 h of surgery. Results: Twenty-eight percent of patients developed AKI. HO-1 concentrations increased from 4.2 ± 0.2 ng/ml at baseline to 6.6 ± 0.5 ng/ml on postoperative day (POD) 1 (p < 0.001). POD1 HO-1 concentrations were 3.1 ng/ml higher (95% CI 1.1-5.1) in AKI patients, as was the change in HO-1 from baseline to POD1 (4.4 ± 1.3 ng/ml in AKI patients vs. 1.5 ± 0.3 ng/ml in no-AKI patients, p = 0.006). HO-1 concentrations remained elevated in AKI patients even after controlling for AKI risk factors and preoperative drug therapy. Peak-free hemoglobin concentrations correlated with peak HO-1 concentrations on POD1 in patients that developed AKI (p = 0.02). Duration of CPB and post-CPB IL-6 and IL-10 concentrations were also associated with increased HO-1 on POD1. Conclusion: Plasma HO-1 is increased in patients that develop AKI, and CPB duration, hemolysis, and inflammation are associated with increased HO-1 concentrations following cardiac surgery. Strategies that alter hemolysis and HO-1 expression during cardiac surgery may affect risk for AKI.

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Section: Discussionsupporting

confidence: 79%

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery

Billings

Byrne

et al. 2014

Cardiorenal Med

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“…(31) In two small randomized trials in chronic ACE inhibitor users, postoperative PAI-1 concentrations were lower in patients continued on ACE inhibitor therapy compared to in patients whose ACE inhibitor was stopped prior to cardiac surgery. (13, 32) MR antagonists also reduce inflammatory cytokines and PAI-1 in normotensive or hypertensive subjects. (33, 34) In the present clinical trial, we observed the previously reported association between the inflammatory response to cardiac surgery and postoperative AF.…”

Section: Discussionmentioning

confidence: 99%

“…Fleming and co-workers also recently reported that concentrations of the inflammatory cytokines IL-6 and IL-8 were increased in the first postoperative day in children undergoing cardiac surgery randomized to an ACE inhibitor. (32) Activation of the kallikrein-kinin system contributes to both enhanced fibrinolysis and inflammation following cardiac surgery and, thus, potentiation of the kallikrein-kinin system could account for the increased intraoperative tissue-type plasminogen activator concentrations and increased postoperative inflammation observed in the ramipril group.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery*

Pretorius

Murray

et al. 2012

Critical Care Medicine

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Objective This study tested the hypothesis that interruption of the renin-angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the incidence of atrial fibrillation after cardiac surgery. Design Randomized double-blind placebo-controlled study. Setting University affiliated hospitals. Patients Four-hundred and forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery. Interventions One week to four days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5 mg the first three days followed by 5mg/day, with the dose reduced to 2.5mg/d on the first postoperative day only), or spironolactone (25 mg/day). Measurements The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the incidence of hypotension, length of hospital stay, stroke, and death. Main Results The incidence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (P=0.95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, P=0.006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days versus 5.7±3.2 and 5.8±3.4 days, respectively, P=0.08 for the comparison of placebo versus the active treatment groups using log-rank test). Compared to patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 minutes versus 1091.3±3067.3 minutes, P=0.04). Conclusions Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.

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“…(15) Aminocaproic acid (antifibrinolytic), methylprednisolone and dexmedetomidine (alpha-2 agonist) were given intraoperatively at the discretion of the attending anesthesiologist. Briefly, the circuit was primed with a mixture of albumin and plasmalyte-A.…”

Section: Methodsmentioning

confidence: 99%

Acetaminophen Attenuates Lipid Peroxidation in Children Undergoing Cardiopulmonary Bypass

Simpson

Zaccagni

Bichell

et al. 2014

Pediatric Critical Care Medicine

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Objective Hemolysis, occurring during cardiopulmonary bypass (CPB), is associated with lipid peroxidation and postoperative acute kidney injury (AKI). Acetaminophen (ApAP) inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced AKI. This pilot study tests the hypothesis that ApAP attenuates lipid peroxidation in children undergoing CPB. Design Single center prospective randomized double blinded study. Setting University-affiliated pediatric hospital. Patients Thirty children undergoing elective surgical correction of a congenital heart defect. Interventions Patients were randomized to ApAP (OFIRMEV® (acetaminophen) injection, Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for 4 doses starting before the onset of CPB. Measurement and Main Results Markers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes) and AKI were measured throughout the perioperative period. CPB was associated with a significant increase in free hemoglobin (from a pre-bypass level of 9.8±6.2 mg/dl to a peak of 201.5±42.6 mg/dl post-bypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. ApAP attenuated the increase in plasma isofurans compared to placebo (P=0.02 for effect of study drug). There was no significant effect of ApAP on plasma F2-isoprostanes or urinary makers of lipid peroxidation. ApAP did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin or prevalence of AKI. Conclusion CPB in children is associated with hemolysis and lipid peroxidation. ApAP attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients undergoing CPB.

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Angiotensin-converting enzyme inhibition alters the inflammatory and fibrinolytic response to cardiopulmonary bypass in children*

Cited by 17 publications

References 29 publications

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery

Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery*

Acetaminophen Attenuates Lipid Peroxidation in Children Undergoing Cardiopulmonary Bypass

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