Objective To determine the relationship between the production of cell-free plasma hemoglobin (PHb) and acute kidney injury (AKI) in infants and children undergoing cardiopulmonary bypass (CPB) for cardiac surgery. Design Prospective observational study Setting 12-bed cardiac ICU in a university-affiliated children’s hospital Patients Children were prospectively enrolled during their pre-operative outpatient appointment with the following criteria: >1month to <18 years old, procedures requiring CPB, no preexisting renal dysfunction. Interventions None Measurements and Main Results Plasma and urine were collected at baseline (in a subset), the beginning and end of CPB, and 2h and 24h after CPB in 60 subjects. Levels of PHb increased during CPB and were associated (p<0.01) with CPB duration (R2=0.22), depletion of Hp at end and 24h after CPB (R2=0.12 and 0.15, respectively), LDH levels at end CPB (R2=0.27), and change in creatinine (R2=0.12). 43% of patients developed AKI. There was an association between PHb level and change in creatinine that varied by age (overall [R2=0.12, p<0.01], in age >2yrs [R2=0.22, p<0.01], and in <2yrs [R2=0.03, p=0.42]). Change in PHb and male gender were found to be risk factors for AKI (OR 1.02 and OR 3.78, p<0.05). Conclusions Generation of PHb during CPB and male gender are associated with subsequent renal dysfunction in low risk pediatric patients, especially in those >2yrs of age. Further studies are needed to determine whether specific subgroups of pediatric patients undergoing CPB would benefit from potential treatments for hemolysis and PHb-associated renal dysfunction.

The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10-to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O 2 consumption rates (OCR) and the membrane potential (Δψ m ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects | 7037 JIN et al.

Purpose of the review Lipid peroxidation has long been established as a key player in the pathophysiology of critical care illnesses. Recent developments in oxidative lipidomics have aided in deciphering the molecular mechanisms of lipid oxidation. This review discusses the achievements and recent developments of oxidative lipidomics and its contribution to the understanding of critical illness. Recent findings Most studies involving acute injury focus on identifying the end products of lipid peroxidation. This misses the early events and targets of peroxidation mechanisms. Recent developments in LC-MS based oxidative lipidomics have enabled the identification of a wide variety of enzymatically generated lipid oxidation products both in clinical as well as animal injury models. Such lipid mediators have been found to play an important role in injury, inflammation, and recovery in disease states such as sepsis or head trauma. Summary Oxidative stress produces multiple lipid oxidation products either through enzymatic pathways or through free radical reactions. These products are often biologically active and can contribute to the regulation of cellular signaling. Oxidative lipidomics has contributed to the understanding of lipid peroxidation products, the mechanism of their production, time course of development after injury, and synergistic functioning with other regulatory processes in the body. These advances in knowledge will help guide the future development of interventions in critical illness.

To determine potential risk factors for severe hemolysis during pediatric cardiopulmonary bypass and examine whether supraphysiologic levels of oxygen and cardiopulmonary bypass duration are associated with hemolysis.DESIGN: Prospective observational study. SETTING:Cardiac ICU in a university-affiliated children's hospital. PATIENTS:Greater than 1 month to less than 18 years old patients undergoing cardiopulmonary bypass for cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:Plasma samples from 100 patients to assess cell-free plasma hemoglobin levels were obtained at start cardiopulmonary bypass, at the end of cardiopulmonary bypass, and 2 and 24 hours after reperfusion. Arterial blood gas samples were obtained before and every 30 minutes during cardiopulmonary bypass. Patient demographics and laboratory data were collected from the electronic medical record. Plasma hemoglobin levels peaked at the end of cardiopulmonary bypass and haptoglobin levels continued to fall throughout all time points. There were 44 patients with severe hemolysis (change in cell-free plasma hemoglobin > 50 mg/dL). Younger age (odds ratio/sd 0.45 [95% CI, 0.25-0.81]) and higher mean Pao 2 × cardiopulmonary bypass duration (31.11 [1.46-664.64]) were identified as risk factors for severe hemolysis in multivariable analysis. Severe hemolysis was associated with longer hospital and ICU lengths of stay as well as acute kidney injury. CONCLUSIONS:We observed younger age and the exposure to both oxygen and duration of cardiopulmonary bypass as risk factors for hemolysis. Oxygen delivery through the cardiopulmonary bypass circuit is an easily modifiable risk factor. Its role in the production of reactive oxygen species that could alter the erythrocyte membrane deserves further examination in larger prospective studies.KEY WORDS: cardiopulmonary bypass; cell-free plasma hemoglobin; hemolysis; hyperoxia; pediatrics C ardiopulmonary bypass (CPB) is an integral part of pediatric cardiac surgery that has recognized disadvantages, including hypoperfusion, activation of a pro-inflammatory cascade, ischemia-reperfusion injury, and hemolysis (1). Hemolysis during CPB is caused by multiple factors including mechanical shear stress and contact with synthetic surfaces and leads to the production of cell-free plasma hemoglobin (PHb), which is now widely regarded as problematic when not regulated within an intact RBC (1). Mechanical shear stress, blood-air and blood-nonendothelial surface contact, and positive and negative pressures with longer CPB durations associated with higher PHb levels.

Objective: To determine the production of 9-hydroxyoctadecadienoic acid (9-HODE) and 13hydroxyoctadecadienoic acid (13-HODE) during cardiopulmonary bypass (CPB) in infants and children undergoing cardiac surgery, evaluate their relationship with increase in cell-free plasma hemoglobin (PHb), provide evidence of bioactivity through markers of inflammation and vasoactivity (WBC count, milrinone use, vasoactive inotropic score [VIS]), and examine their association with overall clinical burden (ICU/hospital LOS and mechanical ventilation duration) Design: Prospective observational studySetting: 12-bed cardiac ICU in a university-affiliated children's hospital Patients: Children were prospectively enrolled during their pre-operative clinic appointments with the following criteria: >1month to <18 years old, procedures requiring CPB Interventions: NoneMeasurements and Main Results: Plasma was collected at the start (StartCPB) and end of CPB (EndCPB) in 34 patients. 9-HODE, 13-HODE, PHb, and WBC increased. 9:13-HODE at StartCPB was associated with VIS at 2-24h post-CPB (R 2 =0.25, p<.01), milrinone use (R 2 =0.17, p<.05), and WBC (R 2 =0.12, p<.05). 9:13-HODE at EndCPB was associated with VIS at 2-24h (R 2 =0.17, p<.05) and 24-48h post-CPB (R 2 =0.12, p<.05) and milrinone use (R 2 =0.19, p<.05).