The findings of our monocentric observational study suggest that an NT-proBNP cut-off of 450 pg/ml can be used to estimate postoperative morbidity risk after major non-cardiac surgery with intermediate or high surgical risk in patients older than 65 years. Therefore, the calculated and clinically adjusted cut-off value, derived from point-of-care testing, is a parameter that detects patients at high risk for postoperative morbidity, which could be used in further trials to trigger distinct treatment interventions. Although postoperative mortality was comparable among the groups in our study, which is likely due to the limited sample size, short-term observation period, and the exclusion of non-elective surgeries, an overall broad study population was included. Our study showed that morbidity measures should also be considered when perioperative risk is assessed by NT-proBNP measurement, because we found a large burden of AKI, ADHF, and infections in patients with preoperative NT-proBNP > 450 pg/ml which resulted in overall prolonged ICU and hospital length of stays. Interestingly, the majority of the observed CME events occurred during the first 3 days after non-cardiac surgery.

Based on our results, it could be hypothesized that a relevant fraction of patients older than 65 years undergoing non-cardiac surgery with intermediate or high surgical risk might suffer from undiagnosed chronic HF and congestion, which could be detected with preoperative biomarker screening. However, NT-proBNP levels are known to interfere with other factors, such as weight, sex, and renal function. In general, NT-proBNP is a sensitive and specific parameter when patients are evaluated for chronic HF. Therefore, according to the current ESC guidelines for the diagnosis and treatment of acute and chronic HF, and besides the preoperative setting, chronic HF is unlikely in patients younger than 50 years with NT-proBNP < 125 pg/ml [1]. However, it must be noted that the rule-in cut-offs for chronic HF are adjusted by age, and chronic HF is likely for NT-proBNP levels ≥ 250 pg/ml in patients aged 50 to 75 years and ≥ 500 pg/ml in patients older than 75 years [21]. Although availability of preoperative echocardiography was limited in our analysis, the differences in the evaluated parameters suggest a higher prevalence of pathological findings in patients with NT-proBNP > 450 pg/ml. Furthermore, a new condition termed ‘heart stress’ has recently been introduced for patients with cardiovascular risk factors and elevated natriuretic peptides, who do not present with clinical symptoms of HF [21].

The results of our study are in line with the findings of Gualandro et al., who reported a 51% rate of de novo HF in patients with postoperative ADHF. In our cohort, more than 75% of patients with an NT-proBNP level above the calculated threshold had no prior history of HF that could be detected at the preoperative anaesthesiologic visit [14].

Interestingly, although differences in various clinical baseline characteristics were detected, NT-proBNP outweighed other parameters and risk indices, such as the ASA classification and revised cardiac risk index, in the multivariable Cox regression model. Therefore, the evaluation of preoperative NT-proBNP might enhance the predictive value of the preoperative anaesthesiologic visit. To date, established risk scores and predictive models considering surgical risk in the current guidelines have foremost focused on major adverse cardiovascular events, like cardiac death and myocardial injury or infarction [6, 12, 22]. Therefore, it is plausible why established risk estimation measures, such as the ASA classification and the revised cardiac risk index, could not predict postoperative morbidity in the multivariable model when compared to the NT-proBNP cut-off. Consequently, biomarkers like NT-proBNP could cover a wider range of outcome measures compared with clinical risk scores, which have been validated for certain specific endpoints. Nonetheless, none of the established risk scores include preoperative biomarker measurements, and no clinically applicable combination of modified risk scores, including biomarkers, is available [6]. However, evidence has emerged that biomarkers can enhance predictive models based on clinical risk scores [11, 23]. Predictive models for major adverse cardiovascular events and myocardial injury or infarction improve with the addition of NT-proBNP or high-sensitivity cardiac troponin to the revised cardiac risk score in patients undergoing major non-cardiac surgery [24, 25]. The calculated sensitivity of NT-proBNP in predicting the CME was relatively low in our study, while specificity was considerably greater when the cut-off of 450 pg/ml was chosen. Therefore, clinical risk scores with high sensitivity could prompt preoperative biomarker testing with high specificity, resulting in an overall increased predictivity of postoperative morbidity compared to either biomarker testing or a clinical risk score alone. NT-proBNP might be particularly suitable, as a high negative predictive value was observed when used as a ‘rule-out’ test [25].

It is striking that most of the events that occurred during the postoperative hospital stay occurred within the first PODs in our cohort, as most patients were still receiving comprehensive hospital care during that period. Because other studies reported similar observations, it appears that the current standard of postoperative surgical care may not fully address potential HF-related postoperative complications [11, 14, 26]. In addition, the timing of postoperative adverse events suggests that future optimised perioperative treatment protocols should begin in the preoperative setting. However, limited single preoperative interventions without dedicated peri- and postoperative adapted management strategies did not improve outcomes in previous studies. Routine preoperative echocardiography, cardiopulmonary exercise testing, or the perioperative administration of increased fractions of inspired oxygen did not improve patient outcomes [27,28,29]. Therefore, future efforts should focus on combining preoperative biomarker screening with peri- and postoperative treatment optimisation. In our study, patients with elevated NT-proBNP had lower Hb compared with patients with NT-proBNP below the cut-off value, suggesting that preoperative anaemia treatment should be expanded according to the current guidelines. However, despite the association between preoperative anaemia and postoperative ADHF, it could not predict our combined endpoint in the Cox regression model, which could be due to the limited sample size or selection of endpoint events [14]. Furthermore, it may be more effective to diagnose and subsequently treat preoperatively diagnosed de novo HF or optimise medications in patients with chronic congestion. Therefore, in patients with abnormalities in preoperative cardiac biomarkers, systematic cardiological evaluation, including echocardiographic assessment, should be performed in accordance with the current guidelines for the diagnosis and treatment of acute and chronic HF [1]. Herein, HF with preserved ejection fraction (HFpEF) may require particular attention, because the echocardiographic findings of our study and others suggest that HFpEF is the dominant phenotype of HF first diagnosed during the perioperative period [14].

Although all procedures were elective in our study, not every intervention, such as oncological and trauma surgery, could be postponed until newly diagnosed HF workup was complete. Therefore, optimisation strategies should include the intraoperative period. Our data suggest that routine intraoperative anaesthesiologic management of patients with elevated NT-proBNP requires the administration of higher cumulative doses of norepinephrine to maintain a sufficient mean arterial pressure to effectively prevent perioperative hypotension. Therefore, the higher incidence of AKI in patients with elevated NT-proBNP above the defined threshold could not be attributed to perioperative hypotension, although AKI is generally associated with intraoperative hypotension [30]. Potential mechanisms leading to the high incidence of AKI in our study are the well-known as complex interactions of cardiac function and renal function, which are also expressed by the higher prevalence of chronic kidney disease in patients with NT-proBNP > 450 pg/ml [31].

Fluid administration was comparable between the groups in our study. This leads us to the question whether pre-existing fluid overload - which was most likely present preoperatively, as indicated by elevated NT-proBNP as a marker of cardiac filling pressure - was further aggravated by “liberal” fluid administration. Despite these established implications in HF patients, there is an association between high fluid volumes administered during surgeries and prolonged hospital stays and an increased incidence of postoperative ileus following rectal and colon surgery [32]. Therefore, goal-directed intraoperative haemodynamic therapy, where fluid boluses are guided by haemodynamic parameters, might be beneficial in patients with elevated preoperative NT-proBNP. Goal-directed therapy algorithms guarantee that intraoperative fluid therapy is guided by cardiac stroke volume or dynamic preload parameters, such as pulse pressure variation and stroke volume variation, which predict fluid responsiveness [33]. In general, previous studies have provided evidence that goal-directed therapy can reduce the incidence of postoperative complications after major surgery [34].

Furthermore, because most events occurred in-hospital during the postoperative period, structured complication monitoring should be established during this period. Screening for signs of postoperative complications on surgical wards could reduce postoperative HF complications. HF screening can be effectively performed by specialised HF nurses, a practice that has been shown to reduce HF-related mortality and rehospitalisation in outpatient settings [35].

In summary, preoperative patient evaluation including the use of natriuretic peptide screening has the potential to identify patients at risk of multiple complications. Because single interventions have not yet convincingly demonstrated a clinical benefit in at-risk patients, a novel comprehensive interdisciplinary perioperative medical team approach, including anaesthesiologists, specialist surgeons, and cardiologists, guiding optimal treatment of the patient throughout the hospital stay, should be evaluated in future studies [6, 14].

The following limitations of our study must be acknowledged. First, the sample size was limited to 200 consecutive and elective patients undergoing surgery in general anaesthesia. Therefore, further large-scale studies with independent patient datasets are needed to validate the suggested NT-proBNP cut-off of 450 pg/ml. However, the cut-off may be suitable for use in randomised interventional trials as it can discriminate high CME event rates. Preoperative differences in echocardiographic findings between the two groups must be interpreted with caution as the overall availability of echocardiographic parameters was limited. Second, no interventions or specific perioperative protocol regulating laboratory testing at distinct time points were used due to the observational nature of the study. Therefore, clinical events may have been underestimated when clinical parameters were not measured at the same time points; in contrast, more frequent testing in one group may lead to increased detection of clinically silent events, such as first-degree AKI. There is no evidence that the latter occurred in our study because postoperative treatment was left entirely to the surgeons’ discretion, and they were unaware of the prospective biomarker study. Third, the surgical risk stratification (according to the current guidelines) we used as inclusion criteria might have been insufficient, because this risk stratification only relates to the risk of cardiovascular death, myocardial infarction, and stroke [6]. Moreover, other types of surgery that were not classified as intermediate or high risk may be relevant but were not addressed in this study. Finally, the definition of ADHF used in our study was derived from clinical parameters. Because of the observational nature of our study, patients suffering from postoperative ADHF did not undergo standardized echocardiography at this time. Therefore, left ventricular dysfunction with elevated filling pressures could not be proven, and other reasons for the occurrence of the clinical endpoint ADHF, such as hyperhydration, hypertensive pulmonary oedema, cessation of HF medication, or new-onset atrial fibrillation with tachyarrhythmia, might have also been relevant. Finally, it is possible that elevated NT-proBNP was not only a sign of cardiac dysfunction in our study but also selected pre-existing multimorbid patients within the elevated NT-proBNP cohort who were generally at a special risk for postoperative morbidity measures, such as AKI and infection.