Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation. METHODS AND ANALYSIS: The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage. ETHICS AND DISSEMINATION: The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research. TRIAL REGISTRATION NUMBER: NCT04647396.

The Association Between Angiotensin II and Renin Kinetics in Patients After Cardiac Surgery.

BACKGROUND: Hyperreninemia after cardiac surgery is associated with cardiovascular instability. Angiotensin II (AT-II) could potentially attenuate hyperreninemia while maintaining target blood pressure. This study assesses the association between AT-II usage and renin levels in cardiac surgery patients with postoperative hyperreninemia and vasoplegia. METHODS: Between September 2020 and March 2021, we retrospectively identified 40 cardiac surgery patients with high Δ-renin levels (4 hours after cardiopulmonary bypass [CPB] minus preoperative levels) (defined as higher than 3.7 µU/mL) and vasopressor use who received a vasopressor therapy with either AT-II or continued norepinephrine alone. The primary outcome was the renin plasma level at 12 hours after surgery, adjusted by the renin plasma level at 4 hours after surgery. RESULTS: Overall, the median renin plasma concentration increased from a baseline with median of 44.3 µU/mL (Q1-Q3, 14.6-155.5) to 188.6 µU/mL (Q1-Q3, 29.8-379.0) 4 hours after CPB. High Δ-renin (difference between postoperation and preoperation) patients (higher than 3.7 µU/mL) were then treated with norepinephrine alone (median dose of 3.25 mg [Q1-Q3, 1.00-4.75]) or with additional AT-II (norepinephrine dose: 1.33 mg [Q1-Q3, 0.78-2.04]; AT-II dose: 0.34 mg [Q1-Q3, 0.29-0.78]). At 12 hours after surgery, AT-II patients had lower renin levels than standard of care patients (71.7 µU/mL [Q1-Q3, 21.9-211.4] vs 130.6 µU/mL [Q1-Q3, 62.9-317.0]; P = .034 adjusting for the renin plasma level at 4 hours after surgery). CONCLUSIONS: In cardiac surgery patients with hypotonia and postoperative high Δ-renin levels, AT-II was associated with reduced renin plasma levels for at 12 hours and significantly decreased norepinephrine use, while norepinephrine alone was associated with increased renin levels. Further studies of AT-II in cardiac surgery appear justified.

Perioperative renal protection.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is a common but underestimated syndrome in the perioperative setting. AKI can be induced by different causes and is associated with increased morbidity and mortality. Unfortunately, no specific treatment options are available at the moment. RECENT FINDINGS: AKI is now understood as being a continuum ranging from normal kidney function over AKI and acute kidney disease to ultimately chronic kidney disease. The KDIGO organization recommend in 2012 implementation of preventive bundles in patients at high risk for AKI. In the perioperative setting, relevant measures include hemodynamic optimization, with careful consideration of blood pressure targets, adequate fluid therapy to maintain organ perfusion and avoidance of hyperglycaemia. These measures are most effective if patients at risk are identified as soon as possible and measures are implemented accordingly. Although current point of care functional biomarkers can detect patients at risk earlier than the established damage biomarkers, some components of the preventive bundle are still under investigation. SUMMARY: Good evidence exists for the use of biomarkers to identify individual patients at risk for AKI and for the implementation of haemodynamic optimization, abdication of nephrotoxins, adequate fluid administration using balanced crystalloid solutions and glycaemic control. The data for using colloids or the degree of nephrotoxicity of contrast media still remain inconclusive.

Impact of opioid-free anaesthesia on postoperative nausea, vomiting and pain after gynaecological laparoscopy - A randomised controlled trial.

STUDY OBJECTIVE: Opioid-free anaesthesia may enhance postoperative recovery by reducing opioid-related side effects such as nausea, hyperalgesia or tolerance. The objective was to investigate the impact of multimodal opioid-free general anaesthesia on postoperative nausea, vomiting, pain and morphine consumption compared to the traditional opioid-based approach. DESIGN: This study was conducted as a prospective parallel-group randomised controlled trial. SETTING: Perioperative Care. PATIENTS: 152 adult women undergoing elective inpatient gynaecological laparoscopy. INTERVENTIONS: Patients were randomly assigned for opioid-free anaesthesia (Group OF) with dexmedetomidine, esketamine and sevoflurane or to have opioid-based anaesthesia (Group C) with sufentanil and sevoflurane. MEASUREMENTS: Primary outcome was the occurrence of nausea within 24 h after surgery. Patients were assessed for the incidence and severity of PONV, postoperative pain and morphine consumption and recovery characteristics. MAIN RESULTS: Patients in both groups had comparable clinical and surgical data. 69.7% of patients in the control group and 68.4% of patients in the opioid-free group met the primary endpoint (OR 1.06, 95% Confidence Interval (CI) (0.53; 2.12) p = 0.86). The incidence of clinically important PONV defined by the PONV impact scale was 8.1% (Group C) vs 10.5% (OF); p = 0.57). Antiemetic requirements, pain scores and morphine consumption were equivalent in both groups. Postoperative sedation was significantly increased in group OF (p < 0.001), and the median length of stay at the post-anaesthesia care unit was 69.0 min (46.5-113.0) vs 50.0 (35.3-77.0) minutes in the control group (p < 0.001). CONCLUSIONS: Opioid-free multimodal general anaesthesia is feasible but did not decrease the incidence of PONV, or reduce pain scores and morphine consumption compared to an opioid-containing anaesthetic regimen.

How new biomarkers aid the anesthetist to detect and prevent perioperative acute kidney injury.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is underestimated but common in the perioperative setting. Although the association of this syndrome with an increased morbidity and mortality has been well established, little progress has been made in the diagnosis or prevention of AKI in recent years. This is partly due to the late detection of AKI by conventional criteria based of functional biomarkers, serum creatinine, and urine output. In addition, conceptually AKI is now recognized as being part of a continuum, in which preventive intervention is time critical. This review will summarize the current best available evidence and explain why timely perioperative management does have impact on the development of AKI and overall outcomes for patients. RECENT FINDINGS: Damage biomarkers can reliably identify AKI earlier than conventional functional biomarkers, facilitating more timely preventive intervention. Although the interventions published in the Kidney Disease: Improving Global Outcomes guideline are all important, the most relevant preventive options perioperatively include maintenance of adequate volume status and perfusion pressure, and the focus on balanced crystalloid solutions as maintenance fluid. SUMMARY: AKI is a time critical syndrome that requires timely detection and damage biomarkers can help to adjust the perioperative management to prevent further injury.

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI): study protocol for a multicentre, observational trial.

INTRODUCTION: More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. METHODS AND ANALYSIS: EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. ETHICS AND DISSEMINATION: EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. TRIAL REGISTRATION NUMBER: NCT04165369.

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Rationale: The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI).Objectives: To investigate whether renin concentrations are associated with hypotension and AKI.Methods: This is a single-center, prospective, observational study among patients undergoing cardiac surgery.Measurements and Main Results: The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 µU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 µU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 µU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%; P < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793; P = 0.007).Conclusions: Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.

Perioperative Renoprotection: Clinical Implications.

Acute kidney injury (AKI) remains a common complication in the perioperative setting affecting patients' short- and long-term outcome. Because therapeutic options are restricted to the use of renal replacement therapy, preventive strategies have become increasingly important. Several substances have been investigated for preventing AKI with limited to no effects. The lacking effectiveness of all these therapies might be caused by the fact that the therapy was started too late. In all the studies, therapy was initiated once a reduced kidney function occurred. In contrast to the classical functional biomarkers, new renal biomarkers allow to identify kidney damage without a loss of function thus enabling the implementation of preventive measures at the stage of renal stress. The most promising preventive strategy to date seems to implement a bundle of supportive measures in patients at high risk for AKI as recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) group. This strategy includes the avoidance of nephrotoxic drugs and contrast agents, avoidance of hyperglycemia, optimization of perfusion pressure and hemodynamics with consideration of a functional hemodynamic monitoring, and close monitoring of renal function in patients at high risk for AKI. This review discusses new renal biomarkers for identifying kidney damage, the background of why the different measures of the KDIGO bundle might positively affect renal function and prevent the development of AKI, and presents the current literature of biomarker-based approaches in AKI.

Dynamic changes in clot formation determined using thromboelastometry after reinfusion of unwashed anticoagulated cell-salvaged whole blood in total hip arthroplasty.

BACKGROUND: Cell salvage is a key part of patient blood management. Different techniques are available for salvaging blood. A new intra-operative autotransfusion filter system became available for reinfusion of unwashed whole blood. Concern exists regarding whether this technique induces coagulation disturbances, offsetting the benefits of the reinfusion of autologous blood. This study was designed to investigate the content of intra-operatively salvaged filtered blood and its impact after reinfusion on clot formation in patients undergoing primary hip arthroplasty. MATERIALS AND METHODS: Twenty-five patients scheduled for primary total hip arthroplasty were enrolled in the study. Cell salvage was performed using a new intra-operative autotransfusion filter system. Before surgery and within 1 hour of reinfusion of 300 mL or more of salvaged whole blood, blood samples were taken to assess clot formation by thromboelastometry and standard laboratory-based coagulation profiling. Cytokine content of the salvaged blood was assessed by enzyme-linked immunosorbent assays. RESULTS: Following reinfusion of 460 mL (median) of salvaged blood, thromboelastometry showed normal clot formation and did not indicate a coagulopathy. Clotting time, clot formation time, maximum firmness and maximum lysis all remained within the normal range. Standard laboratory coagulation tests were also normal in all patients before surgery and after reinfusion. Although monocyte chemoattractant protein-1 levels were higher than normal, all other measured cytokines were either undetectable or within the normal range. No adverse events were seen following cell salvage. DISCUSSION: Reinfusion of unwashed salvaged whole blood did not alter clot formation in our patients. The results add to the knowledge about this approach and contribute to the growing body of evidence regarding the lack of adverse events when reinfusing unwashed shed blood in major orthopaedic procedures.

Sucrose malabsorption and impaired mucosal integrity in enterally fed critically ill patients: a prospective cohort observational study.

OBJECTIVE: Inadequate nutrition is common in critical illness due in part to gastric stasis. However, recent data suggest that altered small intestinal mucosal function may be a contributing factor. The aim of this study was to examine the effects of critical illness on sucrose absorption, permeability, and mucosal morphology. DESIGN: Prospective, observational study. SETTING: Tertiary critical care unit. SUBJECTS: Twenty mechanically ventilated patients (19 men; 52.2 ± 20.5 yr; 9 feed intolerant; Acute Physiology and Chronic Health Evaluation II score 16.2 ± 6.0) and 20 healthy subjects (14 men; 51.6 ± 21.5 yr). INTERVENTIONS: Following a 4-hr fast, a "meal" (100 kcal Ensure, 20-g enriched C-sucrose, 1.1 g rhamnose, 7.5 mL lactulose) was administered into the small intestine. Sucrose absorption was evaluated by analyzing 13CO2 concentration (cumulative percent of administered 13C dose recovered) in expiratory breath samples taken at timed intervals. At 90 minutes, a plasma lactulose/rhamnose concentration was also measured, with lactulose/rhamnose ratio, a marker of small intestinal mucosal permeability. When possible duodenal biopsies were taken in critically ill patients on insertion of the small intestinal feeding catheter and examined for disaccharidase levels and histology. Data are mean ± SD. RESULTS: When compared with healthy subjects, critically ill patients had significantly reduced cumulative CO2 recovery (90 min: 1.78% ± 1.98% vs. 8.04% ± 2.55%; p < 0.001) and increased lactulose/rhamnose ratio (2.77 ± 4.24 vs.1.10 ± 0.98; p = 0.03). The lactulose/rhamnose ratio was greater in feed-intolerant patients (4.06 ± 5.38; p = 0.003). In five patients, duodenal mucosal biopsy showed mild to moderate epithelial injury. Sucrase levels were normal in all patients. CONCLUSIONS: Sucrose absorption is reduced and intestinal permeability increased in critically ill patients, possibly indicating an impairment of small intestinal mucosal function. These results, however, are discordant with duodenal mucosal histology and sucrase levels. This may reflect an inactivation of sucrase in vivo or inadequate nutrient exposure to the brush border due to small intestinal dysmotility.

Intravenous iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum iron deficiency anemia: a randomized trial.

OBJECTIVE: To compare oral iron to intravenous iron administration to women in late pregnancy and/or after labor to correct iron deficiency. METHODS: 271 anemic women (148 pregnant women and 123 women post lower segment caesarean section) with hemoglobin (Hb) levels below 110 g/L were enrolled over a two-year period and randomized to receive either two tablets FGF (ferrous sulfate with folic acid) or 400 mg of intravenous iron sucrose plus folic acid 600 µg. Treatment effectiveness was assessed by measuring Hb and ferritin postpartum on day 1, day 14 and day 42. Transfusions of red blood cells and adverse drug reactions were recorded. RESULTS: Data of 214 women were available for analysis. Both forms of iron replacement therapy led to increased hemoglobin and ferritin levels over the testing period. Ferritin was significantly higher in the i.v. iron treatment group compared to the oral iron treatment group (p = 0.004) two weeks after delivery, while Hb values did not differ between the groups. No serious adverse drug reactions were observed. Red blood cell transfusion rate was low (1.9%), with equal rates observed in both treatment groups. CONCLUSION: Intravenous and oral irons were both effective in correcting peripartum anemia, although intravenous iron restored stores faster than oral iron.