Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2–5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.

Background The efficacy of intravenous acetaminophen compared to its oral formulation for postoperative analgesia is unknown. We hypothesized that the addition of acetaminophen to a multimodal analgesia regimen would provide improved pain management in patients following total knee arthroplasty (TKA) and that the effect of acetaminophen would be variable based upon route of delivery. Methods The study was a single center, randomized, double-blinded, placebo-controlled clinical trial on the efficacy of intravenous versus oral acetaminophen in patients undergoing unilateral TKA. One hundred and seventy-four subjects were randomized to one of three groups: intravenous acetaminophen group (IV Group, n=57) received 1-gram intravenous acetaminophen and oral placebo prior to post-anesthesia care unit (PACU) admission; oral acetaminophen group (PO Group, n=58) received 1-gram oral acetaminophen and volume-matched intravenous normal saline; placebo group (Placebo Group, n=59) received oral placebo and volume-matched intravenous normal saline. Pain scores were obtained every 15 minutes during PACU stay. Average pain scores, maximum pain score, and pain scores before physical therapy were compared among the three groups. Secondary outcomes included total opiate consumption, time to PACU discharge, time to rescue analgesia, and time to breakthrough pain. Results The average PACU pain score was similar in the IV Group (0.56 ±0.99 [mean ±SD]) compared to the PO Group (0.67 ±1.20) (P=0.84) and Placebo Group (0.58 ±0.99) (P=0.71). Total opiate consumption at 6 hours (0.47mg hydromorphone equivalents ±0.56 vs 0.54 ±0.53 vs 0.54 ±0.61; P=0.69) and 24 hours (1.25 ±1.30 vs 1.49 ±1.34 vs 1.36 ±1.31; P=0.46) were also similar between the IV, PO, and Placebo Groups. No significant differences were found between all groups for any other outcome. Conclusion Neither intravenous nor oral acetaminophen provides additional analgesia in the immediate postoperative period when administered as an adjunct to multimodal analgesia in patients undergoing TKA in the setting of a spinal anesthetic.

Background Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood–brain barrier modifies these associations. Methods In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood–brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. Results Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). Conclusions Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood–brain barrier disruption. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Objective: Tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factorbinding protein 7 (IGFBP7) are postoperative urinary biomarkers of renal stress and AKI. We conducted this study to test the hypothesis that intraoperative concentrations of urinary [TIMP-2]•[IGFBP7] are associated with postoperative AKI. Methods: We measured urinary [TIMP-2]•[IGFBP7] at eight perioperative timepoints in 400 patients who participated in a RCT of statins for AKI in cardiac surgery. We compared [TIMP-2]•[IGFBP7] between subjects who did and did not develop KDIGO stage 2-3 AKI within 48 hours of surgery, adjusted for AKI risk factors. Results: Fourteen patients (3.5%) met the primary endpoint of stage 2-3 AKI within 48 hours of surgery, and an additional 77 patients (19.3%) developed stage 1 AKI. Patients who developed stage 2-3 AKI displayed bimodal elevations of [TIMP-2]•[IGFBP7], with a first elevation (median 0.45 [ng/mL] 2 /1000) intraoperatively and the second peak (1.45 [ng/mL] 2 /1000) six hours postoperatively. Patients who did not develop AKI did not have any elevations in [TIMP-2]•[IGFBP7]. Each 10-fold increase in intraoperative [TIMP-2]•[IGFBP7] was independently associated with a 290% increase in the odds of stage 2-3 AKI (P=0.01), and each 10-fold increase in six hours postoperative [TIMP-2]•[IGFBP7] a 650% increase (P<0.001). The maximum [TIMP-2]•[IGFBP7] between these two timepoints provided an AUROC of 0.82 (95% CI: 0.73-0.90), 100% sensitivity, and 100% negative predictive value using the >0.3 cutoff to predict stage 2-3 AKI.

Delirium after cardiac surgery is a major problem. The exact mechanisms behind delirium are not understood. Potential pathways of delirium include neurotransmitter interference, global cognitive disorder, and neuroinflammation. Several predisposing and precipitating risk factors have been identified for postoperative delirium. The development of delirium following cardiac surgery is associated with worse outcomes in the perioperative period. Multiple interventions are being explored for the prevention and treatment of delirium. Studies investigating the potential roles of biomarkers in delirium as well as pharmacological interventions to reduce the incidence and duration of delirium are necessary to mitigate this negative outcome.