A prospective observational study of early changes in plasma renin concentrations and associations with complications following cardiac surgery

A prospective observational study of early changes in plasma renin concentrations and associations with complications following cardiac surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A prospective observational study of early changes in plasma renin concentrations and associations with complications following cardiac surgery Wajid Khan, Suzanne Weightman, Anders Aneman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8066253/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background. Increased plasma renin concentrations have been reported in patients following cardiac surgery while correlations to clinical outcomes have varied. More evidence is needed to support the potential clinical utility of plasma renin as a biomarker guiding postoperative management, including the need for alternative pharmacotherapy when standard catecholaminergic cardiovascular support is insufficient Methods. Plasma concentrations were determined by direct renin immunoassay (milli-International Units per litre, mIU.l − 1 ) on admission to ICU and then six and 24 hours later. Postoperative complications were assessed by the composite and separate incidence of acute kidney injury, acute myocardial infarction, shock, acute respiratory failure, new onset atrial flutter/fibrillation and cerebrovascular accident. Pharmacological support required to treat postoperative haemodynamic instability was quantified using the vasoactive-inotropic score. Results. 104 patients were studied and 54 (52%) met at least one diagnostic criterion for postoperative complications. Renin concentrations on admission (130 [34–445] mIU.l − 1 ) and six (119 [35–447] mIU.l − 1 ) and 24 hours later (184 [54–513] mIU.l − 1 ) were not significantly different with substantial inter-individual variation. Cumulative renin concentrations over 24 hours were higher in haemodynamically unstable patients (median difference 1296 [54-2943] mIU.l − 1 , p = 0.04) and in patients with any postoperative complication (median difference 1887 [908–6177] mIU.l − 1 , p = 0.04). Plasma renin increased by 11 mIU.l − 1 for each unit increase in the vasoactive-inotropic score. A statistical model using all renin measurements predicted haemodynamic instability (AUC 0.77 [0.55–0.95], p = 0.04) and shock (AUC 0.95 [0.83-1.0], p = < 0.001), but not the composite or separate incidence of the other complications. Conclusions. Haemodynamic compromise in postoperative cardiac patients could be predicted using serial plasma renin concentrations measured during the first 24 hours of ICU admission, supporting the potential role of renin as a biomarker for targeted haemodynamic management. Additional prospective studies are warranted to elucidate the relationship between renin dynamics, postoperative complications, and to establish evidence-based criteria for escalating vasopressor therapy. Trial registration: ClinicalTrials.gov NCT043303455 (registered 8 March 2020) plasma renin cardiac surgery postoperative complications Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Cardiac surgery using cardiopulmonary bypass is associated with postoperative complications [ 1 ] that relate to patient level factors, surgical trauma and the physiological disturbances inherent to extracorporeal circulation. While the impact of changes in oxygen delivery [ 2 ], microcirculatory alterations [ 3 ] and impaired vasomotor control [ 4 ] are recognised contributors to postoperative organ dysfunction, it remains challenging to translate these aetiologies into specific management strategies in ICU for individual patients. Cardiovascular support following cardiac surgery is based on optimising the intravascular volume and using mainly catecholaminergic inotropes and vasopressors. The non-catecholaminergic vasoconstrictors vasopressin, methylene blue, hydroxycobalamine, and angiotensin II are increasingly being used in severe vasoplegic states [ 4 ]. Administration of angiotensin II may be of particular interest since plasma levels of renin, the initial proteolytic enzyme in the pathway to generate angiotensin II, can be measured by standard hospital laboratory techniques within a clinically relevant timeframe. Monitoring of renin-angiotensin activity could potentially be used to guide treatment with exogenous angiotensin II administration. Renin is secreted by the juxtaglomerular cells in response to afferent arteriolar hypotension, sympathetic nerve stimulation, decreased sodium delivery to the distal tubules, hypoxia, increased nitric oxide production and low levels of angiotensin II [ 5 – 7 ]. Many pathophysiological events in the postoperative cardiac surgery patient may thus associate with increased release of renin. Previous studies have reported increased plasma renin concentrations [ 8 – 10 ] or increased plasma renin activity [ 11 ] in patients following cardiac surgery. In these studies, plasma renin assays were performed at variable points in time: before cardiopulmonary bypass, immediately after or during the admission to ICU spanning a period of hours up to days. Changes in plasma renin concentrations were reported using continuous or categorical data. Furthermore, reports on the associations between plasma renin concentrations and postoperative complications have been inconsistent, influenced by sample size and differing definitions. More evidence relating plasma renin kinetics after cardiac surgery to postoperative complications is needed to establish the potential clinical utility of this biomarker to inform the ICU management of cardiac surgical patients. This study aimed to analyse changes in plasma renin concentrations up to 24 hours after admission to ICU following cardiac surgery on cardiopulmonary bypass and any associations with postoperative complications. It was hypothesised that patients with elevated and sustained plasma levels of renin, compared to those with lower or decreasing renin levels, would have an increased risk of adverse postoperative outcomes. Methods This observational prospective cohort study was conducted at the ICU of Liverpool Hospital, Sydney, Australia, between March 2020 and March 2021. The study was approved by the South Western Sydney Local Health District Research and Ethics Office as a low/negligible-risk study with delayed consent obtained from the patient or person responsible (2019/ETH13696). The study was registered on ClinicalTrials (NCT043303455, 8th of March 2020) and is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [ 21 ] (Additional File 1, Table S1). The study inclusion criteria were adult patients admitted to ICU after cardiac surgery using cardiopulmonary bypass. The study exclusion criteria were known pregnancy, severe chronic kidney disease (estimated glomerular filtration rate < 20 ml.min − 1 ) or renal failure requiring renal replacement therapy, liver cirrhosis Child-Pugh B or greater, treatment with systemic mineralocorticosteroids and any patient not expected to survive beyond 24 hours after admission. Usual medications were continued until the day before surgery. The intra- and postoperative management were at the discretion of the clinical teams according to institutional guidelines with the only modification being the positioning of extubated patients on the first postoperative day at time of blood sampling. Exogenous angiotensin II was not used in any patient. Beta-blockers and renin-angiotensin system inhibitors were withheld the first postoperative morning in patients with systolic blood pressure < 90 mmHg, ongoing intravenous cardiovascular therapy or evidence of acute kidney injury. Blood sampling and plasma renin assay Patients were in a flat supine position for one hour before blood samples were collected using ethylenediaminetetraacetic acid (EDTA) tubes on admission to ICU and at six hours and 24 hours after admission. Blood samples were immediately transported to the hospital laboratory for processing. The concentration of renin enzyme in blood plasma was measured using the Diasorin Liaison XL Direct Renin immunoassay (Diasorin Australia Pty Ltd, Macquarie Park, New South Wales, Australia) and reported as milli-International Units per litre (mIU.l − 1 ) with a normal range of 3–40 mIU.l − 1 . The assay was calibrated fortnightly with four quality controls (Biorad Hypertension Markers Control) spanning a clinical range with a relative measurement uncertainty of 5.2–7.4%. Study variables The primary study variable of interest was plasma renin concentration. The primary outcome measure as per the study registration was postoperative morbidity up to 30 days including any of the complications acute kidney injury, acute myocardial infarction, shock, acute respiratory failure, new onset atrial flutter/fibrillation and cerebrovascular accident. There was only one patient diagnosed with ischaemic stroke late in the follow up period and the study outcome was revised to include postoperative complications during the ICU admission. Acute kidney injury was diagnosed according to the Kidney Disease Improving Global Outcomes (KDIGO) definition using both creatinine and urine output criteria [ 12 ], myocardial infarction as an increase in cardiac troponin > 10 times the upper reference limit of 14 nanogram.l − 1 with consistent ECG or imaging changes [ 13 ], shock as a persistent haemodynamic instability with ≥ two inotropic medications required beyond 24 hours of admission [ 14 ] or a vasoplegic state requiring vasopressor to avoid organ hypoperfusion [ 15 ], acute respiratory failure as P a O 2 45 mmHg requiring ventilatory support, and cerebrovascular accident defined as acute clinical symptoms consistent with neuroimaging findings. The secondary outcome measure was haemodynamic stabilisation within the day of ICU admission. Unsuccessful haemodynamic stabilisation despite ongoing support was defined by three criteria comparing variables on admission and six hours later: a) cardiac index not improving and remains 3 mmol.l − 1 , c) mixed venous oxygen saturation (S v O 2 ) not improving and remains at < 60%. Stabilisation was defined as failed if all three criteria were present, partially failed if any one criterion was present, and successful if none present. Routine haemodynamic and biochemical variables were obtained each time blood samples were collected for renin analyses. Pharmacologic cardiovascular support was assessed by the vasoactive-inotropic score (VIS) [ 16 ]. Statistical analyses An indicative sample size calculation was performed for this observational study considering the renin concentrations measured at three time points with adjustment made for one patient severity characteristic. A cohort of 100 patients was deemed sufficient to achieve ten events per variable in regression analyses with an estimated composite postoperative morbidity of 40% based on earlier studies of postoperative cardiac patients in Liverpool ICU [ 17 – 19 ]. Data are presented as medians and interquartile ranges given their non-normal distribution as assessed by the Shapiro–Wilk test and inspection of the Q-Q plots. Continuous variables were compared on group level using the Mann–Whitney U-test and proportions were compared using Fisher’s exact test. A Gaussian Mixture Model using Box-Cox transformed data was used to distinguish any clusters of plasma renin concentrations that could identify patients with complications and is reported with threshold criteria and corresponding frequencies of complications. The cumulative response in plasma renin concentrations was assessed by calculating the area under the curve over the three measurements using the trapezoidal method. Changes in haemodynamic and biochemical variables over time were analysed by a two-factor repeated measures ANOVA with time set as within-subjects factor and presence of postoperative complications set as between-subjects factor. A generalised additive mixed model was used to evaluate plasma renin concentration as a response variable with the VIS, cardiac index, S v O 2 , lactate and creatinine concentrations, and the ratio of P a O 2 to fraction inspired oxygen as predictors to allow for repeated measurements and potential non-linear relationships. A spline smooth term was used for time and the renin concentration was log transformed given its left skewed distribution. A Gaussian distribution with identity link function was used in the model. Random intercepts were included for each patient to account for repeated measurements. Estimates are reported using back-transformed data. The associations between changes in renin levels and postoperative haemodynamic stabilisation or complications were evaluated by a mixed-model ANOVA with time set as fixed effect and individual patients set as random effect. The model was adjusted for EuroScore II, cardiopulmonary bypass time and use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers as potential confounders. Correction for multiple testing was performed using Tukey’s method. The predictive performance of renin concentrations against postoperative complications was evaluated in a heterogeneous ensemble model stacking logistic regression, random forest and gradient boosting analyses. This machine learning technique uses the base model predictions combined in a meta-model to improve the accuracy and robustness. A training set containing 80% of the data was used with 20% used for validation. A two-sided p value of < 0.05 was considered statistically significant. All statistical analyses were performed using R 4.3.3 (R Core Team, 2024, including the packages mclust, lme4, lmerTest, mgcv, caret, randomForest, xgboost). Results The study cohort comprised 104 patients and 54 (52%) met at least one diagnostic criterion for postoperative complications (Table 1 ). Acute kidney injury developed in 40 (38%) (stage 1, n = 35; stage 2, n = 5), acute myocardial infarction in 1 (1%), shock in 9 (9%), atrial flutter/fibrillation in 37 (36%), acute respiratory failure in 28 (27%) and cerebrovascular accident in 1 (1%) patient. The single event outcomes were not explored further beyond the composite of postoperative complications. Patients who developed any postoperative complication were older, more often diagnosed with diabetes and had a greater EuroScore II, but there were no differences in preoperative medications. The collected cardiorespiratory variables and biochemistry results varied over time, but these changes were not statistically significantly different between patients with or without postoperative complications (Table 2 ). Postoperative haemodynamic stabilisation was successful by all three criteria in 78 (75%) patients. Stabilisation partially failed in 25 (24%) patients, most commonly by persistent low cardiac index, and one patient (1%) failed stabilisation by all criteria. Table 1 Characteristics of all study patients and split by the incidence of any postoperative complication. Values are mean (SD), median [IQR] or count (%). Variable All (n = 104) No complication (n = 50) Complication (n = 54) p value Age, years 64 (11) 61 (11) 66 (10) 0.02 BMI, kg.m − 2 29 (6.5) 28 (5.1) 29 (7.0) 0.35 Comorbidities, n (%) Diabetes 46 (44) 16 (32) 30 (56) 0.02 Hypertension 77 (74) 36 (72) 41 (76) 0.66 Chronic kidney disease 11 (11) 2 (4) 9 (17) 0.05 Medications, n (%) Beta blocker 56 (54) 30 (60) 26 (48) 0.24 ACEI 23 (22) 9 (18) 14 (26) 0.36 ARB 38 (37) 18 (36) 20 (37) > 0.99 Procedure, n (%) CABG 72 (69) 39 (78) 33 (61) 0.09 Valve 17 (16) 7 (14) 10 (19) 0.60 CABG + valve 11 (11) 4 (8) 7 (13) 0.53 Thoracic aorta 4 (4) 0 (0) 4 (7) NA EuroScore II (%) 1.95 [1.07–3.18] 1.35 [0.82–2.31] 2.40 [1.41–4.31] < 0.001 APACHE III 26 [13–38] 28 [19–39] 22 [10–38] 0.13 Cross clamp time, min 83 [64–104] 89 [65–110] 82 [59–102] 0.55 Cardiopulmonary bypass time, min 100 [81–133] 100 [81–135] 100 [78–132] 0.94 ICU length of stay, days 2.9 [2.0-5.2] 2.6 [2.0-4.7] 3.7 [2.1–5.7] 0.83 Hospital length of stay, days 13 [9.9–20] 12 [9.0–20] 14 [ 10 – 20 ] 0.85 BMI = body mass index; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CABG = coronary artery bypass grafting; APACHE = acute physiology and chronic health evaluation Table 2 Haemodynamic variables and biochemistry results on admission to ICU and six and 24 hours later. Values are median [IQR]. P values refer to statistical difference (ANOVA for repeated measurements) over time and between patients with and without any postoperative complication. Variable Admission 6 hours 24 hours p_value time p value time * complication HR (bpm) 84 [75–91] 80 [75–90] 83 [76–90] 0.34 0.52 SBP (mmHg) 112 [100–125] 108 [100–118] 120 [113–134] 0.003 0.30 MAP (mmHg) 77 [68–84] 71 [67–75] 77 [72–83] 0.04 0.53 DBP (mmHg) 60 [54–66] 55 [51–61] 57 [53–62] 0.02 0.83 CVP (mmHg) 13 [ 10 – 16 ] 12 [ 10 – 15 ] 14 [ 10 – 17 ] 0.36 0.51 CI (L.min.m − 2 ) 2.4 [1.9–3.0] 2.7 [2.3–3.1] 3.0 [2.6–3.8] 0.03 0.98 SVRI (dyn.s.cm − 5 .m 2 ) 2075 [1603–2481] 1773 [1403–2039] 1687 [1295–1929] 0.02 0.12 S v O 2 (%) 0.72 [0.66–0.78] 0.69 [0.65–0.75] 0.66 [0.61–0.70] 0.78 0.29 Lactate (mmol.l − 1 ) 1.2 [1.0–1.8] 1.4 [1.1–1.9] 1.3 [1.0–1.7] 0.13 0.63 RR (bpm) 12 [ 12 – 14 ] 15 [ 12 – 16 ] 17 [ 14 – 20 ] 0.02 0.10 P a O 2 (mmHg) 127 [96–194] 110 [92–133] 88 [77–101] 0.01 0.40 P a CO 2 (mmHg) 42 [38–46] 40 [37–44] 40 [37–43] 0.04 0.17 P a O 2 /F i O 2 ratio 251 [178–358] 313 [249–383] 265 [212–324] 0.003 0.78 pH 7.36 [7.32–7.40] 7.36 [7.32–7.40] 7.39 [7.35–7.41] 0.03 0.69 HCO 3 − (mmol.l − 1 ) 22 [ 20 – 23 ] 21 [ 19 – 22 ] 22 [ 20 – 24 ] 0.06 0.86 Creatinine (µmol.l − 1 ) 87 [70–104] 91 [76–109] 89 [73–109] 0.65 0.16 HS Troponin T (ng.l − 1 ) 387 [190–714] 622 [154–3313] 753 [234–2345] 0.04 0.59 Hb (g.l − 1 ) 108 [100–119] 101 [92–110] 97 [88–109] 0.01 0.76 HR = heart rate; SBP = systolic blood pressure; MAP = mean arterial pressure; DBP = diastolic blood pressure; CVP = central venous pressure; CI = cardiac index; SVRI = systemic vascular resistance index; S v O 2 = mixed venous oxygen saturation; RR = respiratory rate; P a O 2 = arterial partial pressure of oxygen; P a CO 2 = arterial partial pressure of carbon dioxide; P a O 2 / F i O 2 ratio = ratio of arterial partial pressure of oxygen over inspired fraction oxygen; HCO 3 − = arterial concentration of bicarbonate ; HS Troponin = high sensitivity troponin; Hb = haemoglobin The plasma renin concentrations on admission to ICU (130 [34–445] mIU.l − 1 ) and six (119 [35–447] mIU.l − 1 ) and 24 hours later (184 [54–513] mIU.l − 1 ) are shown in Fig. 1 (top) including the changes over time in individual patients (bottom). There were no statistically significant differences in plasma renin concentrations across sampling times, with substantial inter-individual variation evident at each time point. Plasma renin concentrations were greater in patients treated with angiotensin receptor blocking drugs whereas no differences were observed for beta-blocking agents and angiotensin converting enzyme inhibitors (Additional File 1, Tables S2-S4). Two distinct clusters were identified at each sampling time but only the threshold of 103 mIU.l − 1 at six hours following admission distinguished patients with or without any postoperative complication (Fig. 2 ). The cumulative plasma renin concentration was greater in patients with partially failed postoperative haemodynamic stabilisation (3036 [1442–12963] mIU.l − 1 ) compared to successfully stabilised patients (1740 [833–4328] mIU.l − 1 ) with a median difference of 1296 [54-2943] mIU.l − 1 , p = 0.04. The cumulative plasma renin concentration was also greater in patients with any postoperative complication (1887 [908–6177] mIU.l − 1 ) compared to patients without any complication (1260 [747–2481] mIU.l − 1 ) with a median difference of 627 [33-1671] mIU.l − 1 , p = 0.04. Both VIS and creatinine were significant predictors of changes in plasma renin concentrations in the generalised additive mixed model (Table 3 and Fig. 3 ). Each unit increase in VIS was associated with an increase in plasma renin concentration by approximately 11 mIU.l − 1 . The effect was smaller for creatinine with each unit increase associated with an increase in renin by approximately 3 mIU.l − 1 . The mixed model ANOVA for changes in plasma renin concentrations against postoperative complications was only significant for shock at 24 hours after admission (Table 4 ). The heterogeneous ensemble model predicted non-successful haemodynamic stabilisation (AUC 0.77, 95% CI 0.55–0.95, p = 0.04) and shock as a postoperative complication (AUC 0.95, 95% CI 0.83-1.0, p < 0.001), but did not attain statistical significance for acute kidney injury (AUC 0.61, 95% CI 0.43–0.83, p = 0.15), atrial flutter/fibrillation (AUC 0.61, 95% CI 0.45–0.81, p = 0.13), acute respiratory failure (AUC 0.62, 95% CI 0.46–0.82, p = 0.10), or the composite of any postoperative complications (AUC 0.60, 95% CI 0.42–0.81, p = 0.17) (Fig. 4 ). Table 3 Results from the generalised additive mixed model (GAMM). Predictor Estimate Standard error p value CI -57.3 62.1 0.36 SvO2 4.49 4.81 0.35 Lactate 64.2 43.6 0.14 VIS 10.9 3.31 0.001 P a O 2 /F i O 2 ratio 0.082 0.44 0.85 Creatinine 2.85 1.70 0.04 CI = cardiac index; S v O 2 = mixed venous oxygen saturation; VIS = vasoactive inotropic score; P a O 2 /F i O 2 = ratio of arterial partial pressure of oxygen over inspired fraction oxygen Table 4 Plasma renin concentrations analysed by mixed-effect ANOVA over time and split by postoperative complications. Values are milli-International Units per litre (mIU.l − 1 ) including the 95% CI. AKI p Shock p AF p ARF p Stabilisation * p Complication p Admission No 493 [229 = 757] 538 [321–754] 527 [243–810] 449 [209–690] 266 [155–687] 554 [346–762] Yes 656 [321–990] 0.45 745 [42-1448] 0.58 500 [217–784] 0.77 844 [447–1240] 0.10 654 [416–893] 0.25 717 [528–963] 0.79 495 [209–992] 0.86 6 hours No 416 [151–680] 508 [292–724] 582 [298–865] 419 [178–660] 234 [187–655] 518 [269–768] Yes 623 [288–957] 0.34 810 [341–1065] 0.69 589 [283–895] 0.96 703 [306–1100] 0.23 578 [339–816] 0.34 474 [237–718] 0.75 608 [496–712] 0.21 24 hours No 567 [303–832] 567 [351–784] 489 [183–796] 534 [293–774] 291 [130–712] 577 [328–827] Yes 720 [386–1055] 0.48 1445 [941–1948] 0.04 678 [372–984] 0.65 877 [481–1274] 0.14 725 [487–963] 0.62 671 [428–915] 0.49 966 [607–1201] 0.18 AKI = acute kidney injury; AF = new onset atrial flutter/fibrillation; ARF = acute respiratory failure * Stabilisation refers to postoperative haemodynamic stabilisation within six hours of admission to ICU with the p-value indicating the difference to successful stabilisation, first row Discussion This observational study of patients undergoing cardiac surgery with the use of cardiopulmonary bypass investigated plasma renin concentrations measured on admission to ICU and six and 24 hours later in relation to postoperative complications and haemodynamic support in ICU. Plasma renin levels were not significantly different overall between sampling times related to substantial inter-individual variation. A data driven threshold for renin concentration distinguished patients with or without any postoperative complication at six hours after admission but not at the other time points. The cumulative plasma renin response over 24 hours was increased in patients with signs of cardiovascular compromise persisting after early haemodynamic stabilisation and in patients who developed postoperative complications. Changes in plasma renin concentrations were associated with the vasoactive-inotropic score and postoperative circulatory shock. While changes in plasma renin over 24 hours were also to a lesser degree associated with postoperative increases in creatinine, no significant association with acute kidney injury was found. There are several reasons for the perioperative increase in plasma renin concentrations observed in this study, apart from intraoperative episodes of hypotension. The use of cardiopulmonary bypass excludes the pulmonary circulation and hence the site predominantly expressing angiotensin converting enzyme [ 20 ]. The inflammatory response induced by exposing blood to the extracorporeal circuit and endothelial damage may further suppress the expression of angiotensin converting enzyme [ 21 , 22 ]. Both lead to low levels of angiotensin II that increase renin secretion by feedback mechanisms [ 5 , 7 ]. The feedback mechanism to release renin is also operative in patients on preoperative drugs inhibiting the generation or action of angiotensin II. There was no difference in plasma renin concentrations comparing patients who did or did not receive beta-blockers preoperatively, in line with previous reports [ 23 ]. The plasma renin concentrations on admission were increased in patients prescribed angiotensin receptor blockers, similar to a previous study [ 8 ] but not observed in another [ 10 ]. No statistically significant increase was observed in patients receiving angiotensin converting enzyme inhibitors, contrary to earlier studies [ 8 , 10 ]. Importantly, the changes in renin levels were not affected by those preoperative medications similar to previous reports [ 8 – 10 ] and more than ten-fold increases were observed in patients without any preoperative medications affecting the renin-angiotensin axis. The renin levels and the degree of interindividual dispersion were similar to previous reports in cardiac surgical patients [ 8 – 10 ], patients with sepsis [ 24 , 25 ] and in a heterogenous cohort of critically ill patients [ 23 ]. Increases in perioperative plasma concentrations of renin among patients undergoing cardiac surgery with cardiopulmonary bypass have been associated with hypotension and vasoplegia [ 9 – 11 ]. In this study, escalating vasopressor-inotropic support summarised by VIS was independently associated with increasing renin levels. Furthermore, an incremental renin concentration was independently predictive of both early persistent haemodynamic compromise and in particular postoperative shock. A recent review identified renin as a promising candidate biomarker for vasoplegia [ 26 ]. Increasing plasma renin concentration has been suggested to identify patients with low endogenous angiotensin II levels or activity, inherent to their feedback dependency, and hence with the greatest potential benefit from exogenous angiotensin administration [ 9 , 10 ]. A change in pre- to postoperative renin concentration of more than 3.7 microunits per millilitre has been used to identify responders to vasopressor support by exogenous angiotensin [ 8 , 9 ]. Fifty-one out of 104 (49%) patients in the present study met this criterion by the change in renin levels from admission to six hours postoperatively. The PORTHOS study protocol [ 27 ] comparing angiotensin with noradrenaline to reduce hospital length of stay after cardiac surgery includes a subgroup of patients with renin levels above 150 microunits per millilitre as the group most at risk for prolonged hospital stay and acute kidney injury. This cutoff was met by 46/104 (44%) patients in the present study. A data driven threshold value of 103 mIU.l − 1 at six hours after admission to ICU in this study distinguished patients that did develop postoperative complications if their plasma renin concentration was higher (76% of this subgroup). No renin threshold value could be associated with complications on admission to ICU or 24 hours, suggesting that the prognostic value of plasma renin responses changes over time. Taken together, the results of this study indicate that these criteria to identify potential responders to exogenous angiotensin II are applicable to a substantial group of postoperative cardiac patients. A multidisciplinary expert panel recently suggested using renin measurements to manage cardiac associated vasoplegia while no numerical thresholds were specified [ 28 ]. The timing and precision of measuring plasma renin as a biomarker for using exogenous angiotensin require further study. In a third of the patients in this study, the renin concentration was increasing in both the early admission to six hours interval as well as in the late six hours to 24 hours postoperative interval. In half of the study cohort, however, the early and late changes in renin concentrations moved in opposite directions. Whether the presence of early hyperreninaemia, a delayed increase or an early increase followed by decreasing renin levels carry the same clinical implications remains to be established. Furthermore, the magnitude of changes and associated cutoff criteria focus on the precision of the renin assay. While this study as well as most published studies in postoperative cardiac patients have used the Diasorin platform, heterogeneity in analytical methods has been identified as a concern [ 29 , 30 ] that could limit data interpretation and translation between reports. Perioperative increase in renin predicted cardiac surgery associated acute acute kidney injury in one study of 197 patients [ 8 ] but could not be demonstrated in a smaller study of 60 patients [ 10 ]. In this study including 104 patients, while creatinine was statistically associated with increased renin levels, this effect was relatively minor and plasma renin did not independently predict AKI in the ensemble model. However, the changes in creatinine over time in the whole study cohort were not significant, no difference in urine output was observed between patients with or without any postoperative complication, and only three patients required postoperative dialysis (data not shown). The study was therefore likely underpowered to detect moderate postoperative changes in renal function defined by KDIGO stage 1, and further limited by the low event rate for stage 2 and above. As might be expected from the association between VIS and increasing renin levels, the performance of the prediction model was significant for residual haemodynamic compromise with a fair discrimination. All patients with postoperative shock were identified in the model, with a positive predicted rate of 0.95 despite its relatively low prevalence of 9%. In addition to AKI, neither postoperative atrial flutter/fibrillation nor acute respiratory failure were predicted by the model meaning that the precision markedly deteriorated for the composite outcome of any postoperative complication. This study thus provides support for plasma renin as a biomarker of cardiovascular compromise in the postoperative context, but not for organ dysfunction more broadly. A recent scoping review reported an association with adverse outcomes and mortality in critically ill, mainly septic patients, while few studies in cardiac surgery were included [ 30 ]. The strengths of this study include using the second largest sample size published to date and using repeated measurements of plasma renin concentrations within a time frame that could guide early management decisions. Patient characteristics were similar to other reports of renin changes in adult cardiac patients treated in a tertiary care ICU [ 8 , 10 , 11 ]. The plasma renin concentration from repeated measurements was mainly analysed as a continuous variable to retain all information provided by each measurement. Only a categorical analysis of renin concentrations at six hours after admission associated with complications, in line with the change cutoff used in a previous study [ 8 ], and highlights the importance of timing between perioperative comparisons. The study adds external validity to using renin as biomarker of cardiovascular instability. The study also has important limitations. Concentrations of angiotensin II were not measured and hence the feedback mechanism for renin release could not be directly assessed and no other components of the renin-angiotensin-aldosterone system were investigated. Renin levels were not measured beyond 24 hours and extended sampling might reveal persistent patterns [ 11 ] with different implications for the outcomes evaluated in this study. The statistical models employed are complex and were used to maximise the exploratory potential of this study, but a simpler way to evaluate renin changes is needed for its clinical implementation. The prevalence and degree of postoperative complications in this pragmatic study limited its statistical power. The follow up period was revised vis-à-vis the registered protocol while this only affected one out of 104 patients. Conclusions Haemodynamic compromise and the need for pharmacological support in postoperative cardiac patients could be predicted using serial plasma renin concentration measurements obtained during the first 24 hours of ICU admission. These findings support the potential role of renin as an early biomarker for targeted haemodynamic management. Additional prospective studies are warranted to elucidate the relationship between renin dynamics, postoperative complications, and to establish evidence-based criteria for escalating vasopressor therapy, including consideration of exogenous angiotensin administration. Abbreviations AKI Acute Kidney Injury ANOVA Analysis of variance AUC Area under the curve ECG Electrocardiogram KDIGO Kidney Disease Improving Global Outcomes mIU.l -1 milli International Units per litre PaCO2 Arterial partial pressure of carbon dioxide PaO2 Arterial partial pressure of oxygen VIS Vasoactive-inotropic score Declarations Ethics approval and consent to participate. The study was approved by the South Western Sydney Local Health District Research and Ethics Office, as a low/negligible-risk study with delayed consent obtained from the patient or person responsible (2019/ETH13696). Consent for publication. Not applicable. Availability of data and materials. All data generated or analysed during this study are included in this published article and its supplementary information files. The datasets used are available from the corresponding author on reasonable request and as permitted by the local Ethics Governance Board. Competing interests. None of the authors have any competing interests to declare. Funding. The study received local funding only by the Liverpool Hospital Intensive Care Research Fund. Authors contributions. WK was involved in study conceptualisation, data collection, analysis and presentation, and manuscript writing; SW was involved in data collection, and analysis; AA was involved in study conceptualisation, data analysis, modelling and presentation, and manuscript writing. All authors read and approved the final manuscript Acknowledgements. The authors extend their sincere gratitude to the patients and their families who participated in this study. 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Additional Declarations No competing interests reported. Supplementary Files ADDITIONALFILE1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":484878,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplot (median, first and third quartile, with whiskers indicating the minimum and maximum within the 1.5 x interquartile range) of plasma renin concentrations at the three study time points (a). The line plot shows individual patients connected between study time points with the thick red line representing the mean over time (b).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8066253/v1/995acec83ecf3ef4976f199f.png"},{"id":97114850,"identity":"c00a92f5-26a2-44f0-97c3-78a35e47ecfe","added_by":"auto","created_at":"2025-12-01 07:01:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":252062,"visible":true,"origin":"","legend":"\u003cp\u003eGaussian Mixture Model using Box-Cox transformed data identified two clusters on admission to ICU (a), six hours later (b) and 24 hours later (c). The threshold values are shown in the tables below together with the numbers of patients without and with a composite of postoperative complications, as well as the p value from Fisher’s exact test.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8066253/v1/cbbfa631374b63fee20304f9.png"},{"id":97114847,"identity":"166f85b5-a9e3-4784-be5c-3f7e6a99f604","added_by":"auto","created_at":"2025-12-01 07:01:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":290166,"visible":true,"origin":"","legend":"\u003cp\u003eGeneralised additive mixed model showing the plasma renin concentration as a response variable against vasoactive-inotropic score (a) and creatinine (b) as predictors.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8066253/v1/9a8930c3e86d1e123de31cea.png"},{"id":97114854,"identity":"a63c4b56-3dbb-4802-94b0-e279165761bf","added_by":"auto","created_at":"2025-12-01 07:01:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":331804,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristics curves showing the false positive rate (x-axis) \u003cem\u003eversus\u003c/em\u003e the true positive rate (y-axis) generated by the heterogenous ensemble model for the predictions of non-successful haemodynamic stabilisation (a), shock (b), atrial flutter/fibrillation (c), acute kidney injury (d), acute respiratory failure (e) and the composite of any postoperative complication (f). The model employed all plasma renin concentrations measured on admission to ICU and six and 24 hours later to predict complications occurring during the stay in ICU.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8066253/v1/75e6ab579069ae43be96d0a9.png"},{"id":97892669,"identity":"c0ce2d38-00ff-4c7c-9741-5bb9f270841f","added_by":"auto","created_at":"2025-12-10 15:17:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1999569,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8066253/v1/3b5f4cb2-2fd2-4503-8b7f-2e8602c1eeaf.pdf"},{"id":97142111,"identity":"db442262-dc0b-4992-90e7-2f86a7aed009","added_by":"auto","created_at":"2025-12-01 10:07:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":777000,"visible":true,"origin":"","legend":"","description":"","filename":"ADDITIONALFILE1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8066253/v1/1618963f4f4ea0b0d1c85d8c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A prospective observational study of early changes in plasma renin concentrations and associations with complications following cardiac surgery","fulltext":[{"header":"Background","content":"\u003cp\u003eCardiac surgery using cardiopulmonary bypass is associated with postoperative complications [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] that relate to patient level factors, surgical trauma and the physiological disturbances inherent to extracorporeal circulation. While the impact of changes in oxygen delivery [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], microcirculatory alterations [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and impaired vasomotor control [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] are recognised contributors to postoperative organ dysfunction, it remains challenging to translate these aetiologies into specific management strategies in ICU for individual patients. Cardiovascular support following cardiac surgery is based on optimising the intravascular volume and using mainly catecholaminergic inotropes and vasopressors. The non-catecholaminergic vasoconstrictors vasopressin, methylene blue, hydroxycobalamine, and angiotensin II are increasingly being used in severe vasoplegic states [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Administration of angiotensin II may be of particular interest since plasma levels of renin, the initial proteolytic enzyme in the pathway to generate angiotensin II, can be measured by standard hospital laboratory techniques within a clinically relevant timeframe. Monitoring of renin-angiotensin activity could potentially be used to guide treatment with exogenous angiotensin II administration. Renin is secreted by the juxtaglomerular cells in response to afferent arteriolar hypotension, sympathetic nerve stimulation, decreased sodium delivery to the distal tubules, hypoxia, increased nitric oxide production and low levels of angiotensin II [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Many pathophysiological events in the postoperative cardiac surgery patient may thus associate with increased release of renin.\u003c/p\u003e\u003cp\u003ePrevious studies have reported increased plasma renin concentrations [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] or increased plasma renin activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] in patients following cardiac surgery. In these studies, plasma renin assays were performed at variable points in time: before cardiopulmonary bypass, immediately after or during the admission to ICU spanning a period of hours up to days. Changes in plasma renin concentrations were reported using continuous or categorical data. Furthermore, reports on the associations between plasma renin concentrations and postoperative complications have been inconsistent, influenced by sample size and differing definitions. More evidence relating plasma renin kinetics after cardiac surgery to postoperative complications is needed to establish the potential clinical utility of this biomarker to inform the ICU management of cardiac surgical patients.\u003c/p\u003e\u003cp\u003eThis study aimed to analyse changes in plasma renin concentrations up to 24 hours after admission to ICU following cardiac surgery on cardiopulmonary bypass and any associations with postoperative complications. It was hypothesised that patients with elevated and sustained plasma levels of renin, compared to those with lower or decreasing renin levels, would have an increased risk of adverse postoperative outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis observational prospective cohort study was conducted at the ICU of Liverpool Hospital, Sydney, Australia, between March 2020 and March 2021. The study was approved by the South Western Sydney Local Health District Research and Ethics Office as a low/negligible-risk study with delayed consent obtained from the patient or person responsible (2019/ETH13696). The study was registered on ClinicalTrials (NCT043303455, 8th of March 2020) and is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] (Additional File 1, Table S1).\u003c/p\u003e\u003cp\u003eThe study inclusion criteria were adult patients admitted to ICU after cardiac surgery using cardiopulmonary bypass. The study exclusion criteria were known pregnancy, severe chronic kidney disease (estimated glomerular filtration rate\u0026thinsp;\u0026lt;\u0026thinsp;20 ml.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) or renal failure requiring renal replacement therapy, liver cirrhosis Child-Pugh B or greater, treatment with systemic mineralocorticosteroids and any patient not expected to survive beyond 24 hours after admission.\u003c/p\u003e\u003cp\u003eUsual medications were continued until the day before surgery. The intra- and postoperative management were at the discretion of the clinical teams according to institutional guidelines with the only modification being the positioning of extubated patients on the first postoperative day at time of blood sampling. Exogenous angiotensin II was not used in any patient. Beta-blockers and renin-angiotensin system inhibitors were withheld the first postoperative morning in patients with systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg, ongoing intravenous cardiovascular therapy or evidence of acute kidney injury.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eBlood sampling and plasma renin assay\u003c/h2\u003e\u003cp\u003ePatients were in a flat supine position for one hour before blood samples were collected using ethylenediaminetetraacetic acid (EDTA) tubes on admission to ICU and at six hours and 24 hours after admission. Blood samples were immediately transported to the hospital laboratory for processing. The concentration of renin enzyme in blood plasma was measured using the Diasorin Liaison XL Direct Renin immunoassay (Diasorin Australia Pty Ltd, Macquarie Park, New South Wales, Australia) and reported as milli-International Units per litre (mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) with a normal range of 3\u0026ndash;40 mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The assay was calibrated fortnightly with four quality controls (Biorad Hypertension Markers Control) spanning a clinical range with a relative measurement uncertainty of 5.2\u0026ndash;7.4%.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy variables\u003c/h3\u003e\n\u003cp\u003eThe primary study variable of interest was plasma renin concentration. The primary outcome measure as per the study registration was postoperative morbidity up to 30 days including any of the complications acute kidney injury, acute myocardial infarction, shock, acute respiratory failure, new onset atrial flutter/fibrillation and cerebrovascular accident. There was only one patient diagnosed with ischaemic stroke late in the follow up period and the study outcome was revised to include postoperative complications during the ICU admission. Acute kidney injury was diagnosed according to the Kidney Disease Improving Global Outcomes (KDIGO) definition using both creatinine and urine output criteria [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], myocardial infarction as an increase in cardiac troponin\u0026thinsp;\u0026gt;\u0026thinsp;10 times the upper reference limit of 14 nanogram.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e with consistent ECG or imaging changes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], shock as a persistent haemodynamic instability with \u0026ge;\u0026thinsp;two inotropic medications required beyond 24 hours of admission [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] or a vasoplegic state requiring vasopressor to avoid organ hypoperfusion [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], acute respiratory failure as P\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e \u0026lt; 60 mmHg and/or P\u003csub\u003ea\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003e \u0026gt;45 mmHg requiring ventilatory support, and cerebrovascular accident defined as acute clinical symptoms consistent with neuroimaging findings. The secondary outcome measure was haemodynamic stabilisation within the day of ICU admission. Unsuccessful haemodynamic stabilisation despite ongoing support was defined by three criteria comparing variables on admission and six hours later: a) cardiac index not improving and remains\u0026thinsp;\u0026lt;\u0026thinsp;2.2 l.min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e, b) lactate not improving and remains\u0026thinsp;\u0026gt;\u0026thinsp;3 mmol.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, c) mixed venous oxygen saturation (S\u003csub\u003ev\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e) not improving and remains at \u0026lt;\u0026thinsp;60%. Stabilisation was defined as failed if all three criteria were present, partially failed if any one criterion was present, and successful if none present. Routine haemodynamic and biochemical variables were obtained each time blood samples were collected for renin analyses. Pharmacologic cardiovascular support was assessed by the vasoactive-inotropic score (VIS) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eAn indicative sample size calculation was performed for this observational study considering the renin concentrations measured at three time points with adjustment made for one patient severity characteristic. A cohort of 100 patients was deemed sufficient to achieve ten events per variable in regression analyses with an estimated composite postoperative morbidity of 40% based on earlier studies of postoperative cardiac patients in Liverpool ICU [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eData are presented as medians and interquartile ranges given their non-normal distribution as assessed by the Shapiro\u0026ndash;Wilk test and inspection of the Q-Q plots. Continuous variables were compared on group level using the Mann\u0026ndash;Whitney U-test and proportions were compared using Fisher\u0026rsquo;s exact test. A Gaussian Mixture Model using Box-Cox transformed data was used to distinguish any clusters of plasma renin concentrations that could identify patients with complications and is reported with threshold criteria and corresponding frequencies of complications. The cumulative response in plasma renin concentrations was assessed by calculating the area under the curve over the three measurements using the trapezoidal method. Changes in haemodynamic and biochemical variables over time were analysed by a two-factor repeated measures ANOVA with time set as within-subjects factor and presence of postoperative complications set as between-subjects factor. A generalised additive mixed model was used to evaluate plasma renin concentration as a response variable with the VIS, cardiac index, S\u003csub\u003ev\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, lactate and creatinine concentrations, and the ratio of P\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e to fraction inspired oxygen as predictors to allow for repeated measurements and potential non-linear relationships. A spline smooth term was used for time and the renin concentration was log transformed given its left skewed distribution. A Gaussian distribution with identity link function was used in the model. Random intercepts were included for each patient to account for repeated measurements. Estimates are reported using back-transformed data. The associations between changes in renin levels and postoperative haemodynamic stabilisation or complications were evaluated by a mixed-model ANOVA with time set as fixed effect and individual patients set as random effect. The model was adjusted for EuroScore II, cardiopulmonary bypass time and use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers as potential confounders. Correction for multiple testing was performed using Tukey\u0026rsquo;s method. The predictive performance of renin concentrations against postoperative complications was evaluated in a heterogeneous ensemble model stacking logistic regression, random forest and gradient boosting analyses. This machine learning technique uses the base model predictions combined in a meta-model to improve the accuracy and robustness. A training set containing 80% of the data was used with 20% used for validation. A two-sided p value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using R 4.3.3 (R Core Team, 2024, including the packages mclust, lme4, lmerTest, mgcv, caret, randomForest, xgboost).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study cohort comprised 104 patients and 54 (52%) met at least one diagnostic criterion for postoperative complications (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Acute kidney injury developed in 40 (38%) (stage 1, n\u0026thinsp;=\u0026thinsp;35; stage 2, n\u0026thinsp;=\u0026thinsp;5), acute myocardial infarction in 1 (1%), shock in 9 (9%), atrial flutter/fibrillation in 37 (36%), acute respiratory failure in 28 (27%) and cerebrovascular accident in 1 (1%) patient. The single event outcomes were not explored further beyond the composite of postoperative complications. Patients who developed any postoperative complication were older, more often diagnosed with diabetes and had a greater EuroScore II, but there were no differences in preoperative medications. The collected cardiorespiratory variables and biochemistry results varied over time, but these changes were not statistically significantly different between patients with or without postoperative complications (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Postoperative haemodynamic stabilisation was successful by all three criteria in 78 (75%) patients. Stabilisation partially failed in 25 (24%) patients, most commonly by persistent low cardiac index, and one patient (1%) failed stabilisation by all criteria.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of all study patients and split by the incidence of any postoperative complication. Values are mean (SD), median [IQR] or count (%).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;104)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo complication\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eComplication (n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e61 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e66 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI, kg.m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29 (6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29 (7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComorbidities, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 (74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41 (76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic kidney disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedications, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBeta blocker\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56 (54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 (48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACEI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 (26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eARB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38 (37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 (37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProcedure, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCABG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72 (69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39 (78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33 (61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eValve\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCABG\u0026thinsp;+\u0026thinsp;valve\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThoracic aorta\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEuroScore II (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.95 [1.07\u0026ndash;3.18]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.35 [0.82\u0026ndash;2.31]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.40 [1.41\u0026ndash;4.31]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE III\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 [13\u0026ndash;38]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 [19\u0026ndash;39]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22 [10\u0026ndash;38]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCross clamp time, min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e83 [64\u0026ndash;104]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89 [65\u0026ndash;110]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82 [59\u0026ndash;102]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiopulmonary bypass time, min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100 [81\u0026ndash;133]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100 [81\u0026ndash;135]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100 [78\u0026ndash;132]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.94\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICU length of stay, days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.9 [2.0-5.2]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.6 [2.0-4.7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.7 [2.1\u0026ndash;5.7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospital length of stay, days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 [9.9\u0026ndash;20]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 [9.0\u0026ndash;20]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI\u0026thinsp;=\u0026thinsp;body mass index; ACEI\u0026thinsp;=\u0026thinsp;angiotensin converting enzyme inhibitor; ARB\u0026thinsp;=\u0026thinsp;angiotensin receptor blocker; CABG\u0026thinsp;=\u0026thinsp;coronary artery bypass grafting; APACHE\u0026thinsp;=\u0026thinsp;acute physiology and chronic health evaluation\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHaemodynamic variables and biochemistry results on admission to ICU and six and 24 hours later. Values are median [IQR]. P values refer to statistical difference (ANOVA for repeated measurements) over time and between patients with and without any postoperative complication.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdmission\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 hours\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 hours\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep_value\u003c/p\u003e\u003cp\u003etime\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003cp\u003etime * complication\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHR (bpm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e84 [75\u0026ndash;91]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80 [75\u0026ndash;90]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83 [76\u0026ndash;90]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e112 [100\u0026ndash;125]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e108 [100\u0026ndash;118]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e120 [113\u0026ndash;134]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMAP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 [68\u0026ndash;84]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71 [67\u0026ndash;75]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77 [72\u0026ndash;83]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 [54\u0026ndash;66]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55 [51\u0026ndash;61]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e57 [53\u0026ndash;62]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCVP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCI (L.min.m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.4 [1.9\u0026ndash;3.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.7 [2.3\u0026ndash;3.1]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.0 [2.6\u0026ndash;3.8]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSVRI (dyn.s.cm\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e.m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2075 [1603\u0026ndash;2481]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1773 [1403\u0026ndash;2039]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1687 [1295\u0026ndash;1929]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eS\u003csub\u003ev\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.72 [0.66\u0026ndash;0.78]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.69 [0.65\u0026ndash;0.75]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.66 [0.61\u0026ndash;0.70]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLactate (mmol.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.2 [1.0\u0026ndash;1.8]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.4 [1.1\u0026ndash;1.9]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.3 [1.0\u0026ndash;1.7]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRR (bpm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 [\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eP\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e127 [96\u0026ndash;194]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e110 [92\u0026ndash;133]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e88 [77\u0026ndash;101]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eP\u003csub\u003ea\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003e (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42 [38\u0026ndash;46]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40 [37\u0026ndash;44]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40 [37\u0026ndash;43]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eP\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003ei\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e ratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e251 [178\u0026ndash;358]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e313 [249\u0026ndash;383]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e265 [212\u0026ndash;324]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.36 [7.32\u0026ndash;7.40]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.36 [7.32\u0026ndash;7.40]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.39 [7.35\u0026ndash;7.41]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e (mmol.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 [\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22 [\u003cspan additionalcitationids=\"CR21 CR22 CR23\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine (\u0026micro;mol.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87 [70\u0026ndash;104]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91 [76\u0026ndash;109]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e89 [73\u0026ndash;109]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHS Troponin T (ng.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e387 [190\u0026ndash;714]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e622 [154\u0026ndash;3313]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e753 [234\u0026ndash;2345]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHb (g.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e108 [100\u0026ndash;119]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e101 [92\u0026ndash;110]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97 [88\u0026ndash;109]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eHR\u0026thinsp;=\u0026thinsp;heart rate; SBP\u0026thinsp;=\u0026thinsp;systolic blood pressure; MAP\u0026thinsp;=\u0026thinsp;mean arterial pressure; DBP\u0026thinsp;=\u0026thinsp;diastolic blood pressure; CVP\u0026thinsp;=\u0026thinsp;central venous pressure; CI\u0026thinsp;=\u0026thinsp;cardiac index; SVRI\u0026thinsp;=\u0026thinsp;systemic vascular resistance index; S\u003csub\u003ev\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e = mixed venous oxygen saturation; RR\u0026thinsp;=\u0026thinsp;respiratory rate; P\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e = arterial partial pressure of oxygen; P\u003csub\u003ea\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003e = arterial partial pressure of carbon dioxide; P\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e / F\u003csub\u003ei\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e ratio\u0026thinsp;=\u0026thinsp;ratio of arterial partial pressure of oxygen over inspired fraction oxygen; HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e = arterial concentration of bicarbonate ; HS Troponin\u0026thinsp;=\u0026thinsp;high sensitivity troponin; Hb\u0026thinsp;=\u0026thinsp;haemoglobin\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe plasma renin concentrations on admission to ICU (130 [34\u0026ndash;445] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and six (119 [35\u0026ndash;447] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and 24 hours later (184 [54\u0026ndash;513] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (top) including the changes over time in individual patients (bottom). There were no statistically significant differences in plasma renin concentrations across sampling times, with substantial inter-individual variation evident at each time point. Plasma renin concentrations were greater in patients treated with angiotensin receptor blocking drugs whereas no differences were observed for beta-blocking agents and angiotensin converting enzyme inhibitors (Additional File 1, Tables S2-S4). Two distinct clusters were identified at each sampling time but only the threshold of 103 mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e at six hours following admission distinguished patients with or without any postoperative complication (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The cumulative plasma renin concentration was greater in patients with partially failed postoperative haemodynamic stabilisation (3036 [1442\u0026ndash;12963] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) compared to successfully stabilised patients (1740 [833\u0026ndash;4328] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) with a median difference of 1296 [54-2943] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, p\u0026thinsp;=\u0026thinsp;0.04. The cumulative plasma renin concentration was also greater in patients with any postoperative complication (1887 [908\u0026ndash;6177] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) compared to patients without any complication (1260 [747\u0026ndash;2481] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) with a median difference of 627 [33-1671] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, p\u0026thinsp;=\u0026thinsp;0.04. Both VIS and creatinine were significant predictors of changes in plasma renin concentrations in the generalised additive mixed model (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Each unit increase in VIS was associated with an increase in plasma renin concentration by approximately 11 mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The effect was smaller for creatinine with each unit increase associated with an increase in renin by approximately 3 mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The mixed model ANOVA for changes in plasma renin concentrations against postoperative complications was only significant for shock at 24 hours after admission (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The heterogeneous ensemble model predicted non-successful haemodynamic stabilisation (AUC 0.77, 95% CI 0.55\u0026ndash;0.95, p\u0026thinsp;=\u0026thinsp;0.04) and shock as a postoperative complication (AUC 0.95, 95% CI 0.83-1.0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but did not attain statistical significance for acute kidney injury (AUC 0.61, 95% CI 0.43\u0026ndash;0.83, p\u0026thinsp;=\u0026thinsp;0.15), atrial flutter/fibrillation (AUC 0.61, 95% CI 0.45\u0026ndash;0.81, p\u0026thinsp;=\u0026thinsp;0.13), acute respiratory failure (AUC 0.62, 95% CI 0.46\u0026ndash;0.82, p\u0026thinsp;=\u0026thinsp;0.10), or the composite of any postoperative complications (AUC 0.60, 95% CI 0.42\u0026ndash;0.81, p\u0026thinsp;=\u0026thinsp;0.17) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eResults from the generalised additive mixed model (GAMM).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePredictor\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEstimate\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStandard error\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-57.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e62.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSvO2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLactate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e64.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e43.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVIS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eP\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003ei\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e ratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.082\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eCI\u0026thinsp;=\u0026thinsp;cardiac index; S\u003csub\u003ev\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e = mixed venous oxygen saturation; VIS\u0026thinsp;=\u0026thinsp;vasoactive inotropic score; P\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003ei\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e = ratio of arterial partial pressure of oxygen over inspired fraction oxygen\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePlasma renin concentrations analysed by mixed-effect ANOVA over time and split by postoperative complications. Values are milli-International Units per litre (mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) including the 95% CI.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"13\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAKI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eShock\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eARF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eStabilisation *\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eComplication\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdmission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e493 [229\u0026thinsp;=\u0026thinsp;757]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e538 [321\u0026ndash;754]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e527 [243\u0026ndash;810]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e449 [209\u0026ndash;690]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e266 [155\u0026ndash;687]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e554 [346\u0026ndash;762]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e656 [321\u0026ndash;990]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e745 [42-1448]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e500 [217\u0026ndash;784]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e844 [447\u0026ndash;1240]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e654 [416\u0026ndash;893]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e717 [528\u0026ndash;963]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e0.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e495 [209\u0026ndash;992]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6 hours\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e416 [151\u0026ndash;680]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e508 [292\u0026ndash;724]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e582 [298\u0026ndash;865]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e419 [178\u0026ndash;660]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e234 [187\u0026ndash;655]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e518 [269\u0026ndash;768]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e623 [288\u0026ndash;957]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e810 [341\u0026ndash;1065]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e589 [283\u0026ndash;895]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e703 [306\u0026ndash;1100]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e578 [339\u0026ndash;816]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e474 [237\u0026ndash;718]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e0.75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e608 [496\u0026ndash;712]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24 hours\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e567 [303\u0026ndash;832]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e567 [351\u0026ndash;784]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e489 [183\u0026ndash;796]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e534 [293\u0026ndash;774]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e291 [130\u0026ndash;712]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e577 [328\u0026ndash;827]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e720 [386\u0026ndash;1055]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1445 [941\u0026ndash;1948]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e678 [372\u0026ndash;984]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e877 [481\u0026ndash;1274]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e725 [487\u0026ndash;963]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e671 [428\u0026ndash;915]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e0.49\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e966 [607\u0026ndash;1201]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"13\"\u003eAKI\u0026thinsp;=\u0026thinsp;acute kidney injury; AF\u0026thinsp;=\u0026thinsp;new onset atrial flutter/fibrillation; ARF\u0026thinsp;=\u0026thinsp;acute respiratory failure\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"13\"\u003e* Stabilisation refers to postoperative haemodynamic stabilisation within six hours of admission to ICU with the p-value indicating the difference to successful stabilisation, first row\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis observational study of patients undergoing cardiac surgery with the use of cardiopulmonary bypass investigated plasma renin concentrations measured on admission to ICU and six and 24 hours later in relation to postoperative complications and haemodynamic support in ICU. Plasma renin levels were not significantly different overall between sampling times related to substantial inter-individual variation. A data driven threshold for renin concentration distinguished patients with or without any postoperative complication at six hours after admission but not at the other time points. The cumulative plasma renin response over 24 hours was increased in patients with signs of cardiovascular compromise persisting after early haemodynamic stabilisation and in patients who developed postoperative complications. Changes in plasma renin concentrations were associated with the vasoactive-inotropic score and postoperative circulatory shock. While changes in plasma renin over 24 hours were also to a lesser degree associated with postoperative increases in creatinine, no significant association with acute kidney injury was found.\u003c/p\u003e\u003cp\u003eThere are several reasons for the perioperative increase in plasma renin concentrations observed in this study, apart from intraoperative episodes of hypotension. The use of cardiopulmonary bypass excludes the pulmonary circulation and hence the site predominantly expressing angiotensin converting enzyme [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The inflammatory response induced by exposing blood to the extracorporeal circuit and endothelial damage may further suppress the expression of angiotensin converting enzyme [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Both lead to low levels of angiotensin II that increase renin secretion by feedback mechanisms [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The feedback mechanism to release renin is also operative in patients on preoperative drugs inhibiting the generation or action of angiotensin II. There was no difference in plasma renin concentrations comparing patients who did or did not receive beta-blockers preoperatively, in line with previous reports [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The plasma renin concentrations on admission were increased in patients prescribed angiotensin receptor blockers, similar to a previous study [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] but not observed in another [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. No statistically significant increase was observed in patients receiving angiotensin converting enzyme inhibitors, contrary to earlier studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Importantly, the changes in renin levels were not affected by those preoperative medications similar to previous reports [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and more than ten-fold increases were observed in patients without any preoperative medications affecting the renin-angiotensin axis. The renin levels and the degree of interindividual dispersion were similar to previous reports in cardiac surgical patients [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], patients with sepsis [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and in a heterogenous cohort of critically ill patients [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIncreases in perioperative plasma concentrations of renin among patients undergoing cardiac surgery with cardiopulmonary bypass have been associated with hypotension and vasoplegia [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this study, escalating vasopressor-inotropic support summarised by VIS was independently associated with increasing renin levels. Furthermore, an incremental renin concentration was independently predictive of both early persistent haemodynamic compromise and in particular postoperative shock. A recent review identified renin as a promising candidate biomarker for vasoplegia [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Increasing plasma renin concentration has been suggested to identify patients with low endogenous angiotensin II levels or activity, inherent to their feedback dependency, and hence with the greatest potential benefit from exogenous angiotensin administration [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A change in pre- to postoperative renin concentration of more than 3.7 microunits per millilitre has been used to identify responders to vasopressor support by exogenous angiotensin [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Fifty-one out of 104 (49%) patients in the present study met this criterion by the change in renin levels from admission to six hours postoperatively. The PORTHOS study protocol [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] comparing angiotensin with noradrenaline to reduce hospital length of stay after cardiac surgery includes a subgroup of patients with renin levels above 150 microunits per millilitre as the group most at risk for prolonged hospital stay and acute kidney injury. This cutoff was met by 46/104 (44%) patients in the present study. A data driven threshold value of 103 mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e at six hours after admission to ICU in this study distinguished patients that did develop postoperative complications if their plasma renin concentration was higher (76% of this subgroup). No renin threshold value could be associated with complications on admission to ICU or 24 hours, suggesting that the prognostic value of plasma renin responses changes over time. Taken together, the results of this study indicate that these criteria to identify potential responders to exogenous angiotensin II are applicable to a substantial group of postoperative cardiac patients. A multidisciplinary expert panel recently suggested using renin measurements to manage cardiac associated vasoplegia while no numerical thresholds were specified [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The timing and precision of measuring plasma renin as a biomarker for using exogenous angiotensin require further study. In a third of the patients in this study, the renin concentration was increasing in both the early admission to six hours interval as well as in the late six hours to 24 hours postoperative interval. In half of the study cohort, however, the early and late changes in renin concentrations moved in opposite directions. Whether the presence of early hyperreninaemia, a delayed increase or an early increase followed by decreasing renin levels carry the same clinical implications remains to be established. Furthermore, the magnitude of changes and associated cutoff criteria focus on the precision of the renin assay. While this study as well as most published studies in postoperative cardiac patients have used the Diasorin platform, heterogeneity in analytical methods has been identified as a concern [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] that could limit data interpretation and translation between reports.\u003c/p\u003e\u003cp\u003ePerioperative increase in renin predicted cardiac surgery associated acute acute kidney injury in one study of 197 patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] but could not be demonstrated in a smaller study of 60 patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In this study including 104 patients, while creatinine was statistically associated with increased renin levels, this effect was relatively minor and plasma renin did not independently predict AKI in the ensemble model. However, the changes in creatinine over time in the whole study cohort were not significant, no difference in urine output was observed between patients with or without any postoperative complication, and only three patients required postoperative dialysis (data not shown). The study was therefore likely underpowered to detect moderate postoperative changes in renal function defined by KDIGO stage 1, and further limited by the low event rate for stage 2 and above. As might be expected from the association between VIS and increasing renin levels, the performance of the prediction model was significant for residual haemodynamic compromise with a fair discrimination. All patients with postoperative shock were identified in the model, with a positive predicted rate of 0.95 despite its relatively low prevalence of 9%. In addition to AKI, neither postoperative atrial flutter/fibrillation nor acute respiratory failure were predicted by the model meaning that the precision markedly deteriorated for the composite outcome of any postoperative complication. This study thus provides support for plasma renin as a biomarker of cardiovascular compromise in the postoperative context, but not for organ dysfunction more broadly. A recent scoping review reported an association with adverse outcomes and mortality in critically ill, mainly septic patients, while few studies in cardiac surgery were included [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e The strengths of this study include using the second largest sample size published to date and using repeated measurements of plasma renin concentrations within a time frame that could guide early management decisions. Patient characteristics were similar to other reports of renin changes in adult cardiac patients treated in a tertiary care ICU [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The plasma renin concentration from repeated measurements was mainly analysed as a continuous variable to retain all information provided by each measurement. Only a categorical analysis of renin concentrations at six hours after admission associated with complications, in line with the change cutoff used in a previous study [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and highlights the importance of timing between perioperative comparisons. The study adds external validity to using renin as biomarker of cardiovascular instability. The study also has important limitations. Concentrations of angiotensin II were not measured and hence the feedback mechanism for renin release could not be directly assessed and no other components of the renin-angiotensin-aldosterone system were investigated. Renin levels were not measured beyond 24 hours and extended sampling might reveal persistent patterns [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] with different implications for the outcomes evaluated in this study. The statistical models employed are complex and were used to maximise the exploratory potential of this study, but a simpler way to evaluate renin changes is needed for its clinical implementation. The prevalence and degree of postoperative complications in this pragmatic study limited its statistical power. The follow up period was revised vis-\u0026agrave;-vis the registered protocol while this only affected one out of 104 patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eHaemodynamic compromise and the need for pharmacological support in postoperative cardiac patients could be predicted using serial plasma renin concentration measurements obtained during the first 24 hours of ICU admission. These findings support the potential role of renin as an early biomarker for targeted haemodynamic management. Additional prospective studies are warranted to elucidate the relationship between renin dynamics, postoperative complications, and to establish evidence-based criteria for escalating vasopressor therapy, including consideration of exogenous angiotensin administration.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAKI Acute Kidney Injury\u003c/p\u003e\n\u003cp\u003eANOVA Analysis of variance\u003c/p\u003e\n\u003cp\u003eAUC Area under the curve\u003c/p\u003e\n\u003cp\u003eECG Electrocardiogram\u003c/p\u003e\n\u003cp\u003eKDIGO Kidney Disease Improving Global Outcomes\u003c/p\u003e\n\u003cp\u003emIU.l\u003csup\u003e-1 \u003c/sup\u003emilli International Units per litre\u003c/p\u003e\n\u003cp\u003ePaCO2 Arterial partial pressure of carbon dioxide\u003c/p\u003e\n\u003cp\u003ePaO2 Arterial partial pressure of oxygen\u003c/p\u003e\n\u003cp\u003eVIS Vasoactive-inotropic score\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate.\u0026nbsp;\u003c/strong\u003eThe study was approved by the\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eSouth Western Sydney Local Health District Research and Ethics Office, as a low/negligible-risk study with delayed consent obtained from the patient or person responsible (2019/ETH13696).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication.\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials.\u003c/strong\u003e All data generated or analysed during this study are included in this published article and its supplementary information files. The datasets used are available from the corresponding author on reasonable request and as permitted by the local Ethics Governance Board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests.\u003c/strong\u003e None of the authors have any competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u003c/strong\u003e The study received local funding only by the Liverpool\u0026nbsp;Hospital Intensive Care Research Fund.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions.\u003c/strong\u003e\u0026nbsp; WK was involved in study conceptualisation, data collection, analysis and presentation, and manuscript writing; SW was involved in data collection, and analysis; AA was involved in study conceptualisation, data analysis, modelling and presentation, and manuscript writing. All authors read and approved the final manuscript\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements.\u0026nbsp;\u003c/strong\u003eThe authors extend their sincere gratitude to the patients and their families who participated in this study. We are grateful to the ICU nursing staff for their expert clinical care and support during the study. We acknowledge the valuable discussions of the manuscript with Dr Danielle Austin and Dr Luis Schulz, Liverpool ICU.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKim KM, Arghami A, Habib R, Daneshmand MA, Parsons N, Elhalabi Z, Krohn C, Thourani V, Bowdish ME. The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2022 Update on Outcomes and Research. Ann Thorac Surg. 2023;115(3):566\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDias RD, Borges P, Rance G, Srey R, Kennedy Metz LR, Martinez-Rioux A, Arney D, Paladugu P, Gikandi A, Miccile C et al. Delivery of oxygen during cardiopulmonary bypass and associated clinical outcomes among adult cardiac surgery patients: A systematic review. Perfusion 2025:2676591251380659.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDe Cuyper H, Poelaert J. Microcirculatory Alterations in Cardiac Surgery: A Comprehensive Guide. J Cardiothorac Vasc Anesth. 2024;38(3):829\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePolyak P, Kwak J, Kertai MD, Anton JM, Assaad S, Dacosta ME, Dimitrova G, Gao WD, Henderson RA, Hollon MM, et al. Vasoplegic Syndrome in Cardiac Surgery: A Narrative Review of Etiologic Mechanisms and Therapeutic Options. J Cardiothorac Vasc Anesth. 2025;39(7):1815\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKurtz A. Renin release: sites, mechanisms, and control. Annu Rev Physiol. 2011;73:377\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKong W, Liao Y, Zhao L, Hall N, Zhou H, Liu R, Persson PB, Lai E. Kidney Renin Release under Hypoxia and Its Potential Link with Nitric Oxide: A Narrative Review. Biomedicines 2023, 11(11).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReid IA, Morris BJ, Ganong WF. The renin-angiotensin system. Annu Rev Physiol. 1978;40:377\u0026ndash;410.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKullmar M, Saadat-Gilani K, Weiss R, Massoth C, Lagan A, Cortes MN, Gerss J, Chawla LS, Fliser D, Meersch M, et al. Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients. Am J Respir Crit Care Med. 2021;203(9):1119\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeersch M, Weiss R, Massoth C, Kullmar M, Saadat-Gilani K, Busen M, Chawla L, Landoni G, Bellomo R, Gerss J, et al. The Association Between Angiotensin II and Renin Kinetics in Patients After Cardiac Surgery. Anesth Analg. 2022;134(5):1002\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCoulson TG, Miles LF, Zarbock A, Burrell LM, Patel SK, von Groote T, Pilcher D, Weinberg L, Landoni G, Bellomo R. Renin-angiotensin-aldosterone system dynamics after targeted blood pressure control using angiotensin II or norepinephrine in cardiac surgery: mechanistic randomised controlled trial. Br J Anaesth. 2023;131(4):664\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMontgomery ML, Gross CR, Lin HM, Ouyang Y, Levin MA, Corkill HE, El-Eshmawi A, Adams DH, Weiner MM. Plasma Renin Activity Increases With Cardiopulmonary Bypass and is Associated With Vasoplegia After Cardiac Surgery. J Cardiothorac Vasc Anesth. 2023;37(3):367\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eScurt FG, Bose K, Mertens PR, Chatzikyrkou C, Herzog C. Cardiac Surgery-Associated Acute Kidney Injury. \u003cem\u003eKidney360\u003c/em\u003e 2024, 5(6):909\u0026ndash;926.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD. Executive Group on behalf of the Joint European Society of Cardiology /American College of Cardiology /American Heart Association /World Heart Federation Task Force for the Universal Definition of Myocardial I: Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuncan AE, Kartashov A, Robinson SB, Randall D, Zhang K, Luber J, James RA, Halvorson S, Bokesch P. Risk factors, resource use, and cost of postoperative low cardiac output syndrome. J Thorac Cardiovasc Surg. 2022;163(5):1890\u0026ndash;e18981810.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShaefi S, Mittel A, Klick J, Evans A, Ivascu NS, Gutsche J, Augoustides JGT. Vasoplegia After Cardiovascular Procedures-Pathophysiology and Targeted Therapy. J Cardiothorac Vasc Anesth. 2018;32(2):1013\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBelletti A, Lerose CC, Zangrillo A, Landoni G. Vasoactive-Inotropic Score: Evolution, Clinical Utility, and Pitfalls. J Cardiothorac Vasc Anesth. 2021;35(10):3067\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eButler E, Mahendran S, Nguyen J, Aneman A. Microvascular reactivity, assessed by near-infrared spectroscopy and a vascular occlusion test, is associated with patient outcomes following cardiac surgery: A prospective observational study. Eur J Anaesthesiol. 2018;35(5):356\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChan B, Aneman A. A prospective, observational study of cerebrovascular autoregulation and its association with delirium following cardiac surgery. Anaesthesia. 2019;74(1):33\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNeuman J, Schulz L, Aneman A. Associations between mean systemic filling pressure and acute kidney injury: An observational cohort study following cardiac surgery. Acta Anaesthesiol Scand. 2021;65(3):373\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRyan US, Ryan JW, Whitaker C, Chiu A. Localization of angiotensin converting enzyme (kininase II). II. Immunocytochemistry and immunofluorescence. Tissue Cell. 1976;8(1):125\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang W, Chen X, Huang L, Lu N, Zhou L, Wu G, Chen Y. Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosis. Exp Ther Med. 2014;7(5):1342\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChawla LS, Busse LW, Brasha-Mitchell E, Alotaibi Z. The use of angiotensin II in distributive shock. Crit Care. 2016;20(1):137.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGleeson PJ, Crippa IA, Mongkolpun W, Cavicchi FZ, Van Meerhaeghe T, Brimioulle S, Taccone FS, Vincent JL, Creteur J. Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients. Crit Care Med. 2019;47(2):152\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNguyen M, Denimal D, Dargent A, Guinot PG, Duvillard L, Quenot JP, Bouhemad B. Plasma Renin Concentration is Associated With Hemodynamic Deficiency and Adverse Renal Outcome in Septic Shock. Shock. 2019;52(4):e22\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, Hastbacka J, Khanna AK, Albertson TE, Tumlin J, et al. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial. Am J Respir Crit Care Med. 2020;202(9):1253\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoyer N, Upadhyay P, Hicks MH, Zarbock A, Khanna AK, Forni LG, Creagh-Brown BC. Circulating biomarkers of vasoplegia: a systematic review. Ann Intensive Care. 2025;15(1):150.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCoulson TG, Paul E, Miles LF, Pilcher D, Marasco SF, Frei D, Bellomo R. A Prospective double-blind, randomised controlled trial comparing angiotensin II to norepinephrine to reduce length of hospital stay in cardiac surgery patients (the PORTHOS study protocol). BMJ Open. 2025;15(4):e095099.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZarbock A, Vincent JL, De Backer D, Bellomo R, Legrand M, Khanna AK, Ostermann M, Kotfis K, Filippo A, Wieruszewski PM et al. The Renin-Angiotensin-Aldosterone System in Cardiac Surgery and Angiotensin II Therapy for Vasoplegia. Anesth Analg 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKotani Y, Chappell M, Landoni G, Zarbock A, Bellomo R, Khanna AK. Renin in critically ill patients. Ann Intensive Care. 2024;14(1):79.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKotani Y, Belletti A, Maiucci G, Lodovici M, Fresilli S, Landoni G, Bellomo R, Zarbock A. Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review. Anesth Analg. 2024;138(5):929\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"plasma renin, cardiac surgery, postoperative complications","lastPublishedDoi":"10.21203/rs.3.rs-8066253/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8066253/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e\u003cp\u003eIncreased plasma renin concentrations have been reported in patients following cardiac surgery while correlations to clinical outcomes have varied. More evidence is needed to support the potential clinical utility of plasma renin as a biomarker guiding postoperative management, including the need for alternative pharmacotherapy when standard catecholaminergic cardiovascular support is insufficient\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e\u003cp\u003ePlasma concentrations were determined by direct renin immunoassay (milli-International Units per litre, mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) on admission to ICU and then six and 24 hours later. Postoperative complications were assessed by the composite and separate incidence of acute kidney injury, acute myocardial infarction, shock, acute respiratory failure, new onset atrial flutter/fibrillation and cerebrovascular accident. Pharmacological support required to treat postoperative haemodynamic instability was quantified using the vasoactive-inotropic score.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e\u003cp\u003e104 patients were studied and 54 (52%) met at least one diagnostic criterion for postoperative complications. Renin concentrations on admission (130 [34\u0026ndash;445] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and six (119 [35\u0026ndash;447] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) and 24 hours later (184 [54\u0026ndash;513] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) were not significantly different with substantial inter-individual variation. Cumulative renin concentrations over 24 hours were higher in haemodynamically unstable patients (median difference 1296 [54-2943] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, p\u0026thinsp;=\u0026thinsp;0.04) and in patients with any postoperative complication (median difference 1887 [908\u0026ndash;6177] mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, p\u0026thinsp;=\u0026thinsp;0.04). Plasma renin increased by 11 mIU.l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for each unit increase in the vasoactive-inotropic score. A statistical model using all renin measurements predicted haemodynamic instability (AUC 0.77 [0.55\u0026ndash;0.95], p\u0026thinsp;=\u0026thinsp;0.04) and shock (AUC 0.95 [0.83-1.0], p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but not the composite or separate incidence of the other complications.\u003c/p\u003e\u003ch2\u003eConclusions.\u003c/h2\u003e\u003cp\u003eHaemodynamic compromise in postoperative cardiac patients could be predicted using serial plasma renin concentrations measured during the first 24 hours of ICU admission, supporting the potential role of renin as a biomarker for targeted haemodynamic management. Additional prospective studies are warranted to elucidate the relationship between renin dynamics, postoperative complications, and to establish evidence-based criteria for escalating vasopressor therapy.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eClinicalTrials.gov NCT043303455 (registered 8 March 2020)\u003c/p\u003e","manuscriptTitle":"A prospective observational study of early changes in plasma renin concentrations and associations with complications following cardiac surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 07:01:26","doi":"10.21203/rs.3.rs-8066253/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f886033-8c6a-4091-9b42-d82f127c393e","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-03T07:54:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 07:01:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8066253","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8066253","identity":"rs-8066253","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}