Reply to: very early creatinine changes and 30-day mortality after cardiac surgery

University of Groningen

Reply to

Bernardi, Martin H.; Ristl, Robin; Hiesmayr, Michael; Lassnigg, Andrea

European Journal of Anaesthesiology DOI:

10.1097/EJA.0000000000001457

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Bernardi, M. H., Ristl, R., Hiesmayr, M., & Lassnigg, A. (2021). Reply to: very early creatinine changes and 30-day mortality after cardiac surgery. European Journal of Anaesthesiology, 38(6), 665-667.

https://doi.org/10.1097/EJA.0000000000001457

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Very early creatinine changes and 30-day

mortality after cardiac surgery

Hjalmar R. Bouma, Hubert E. Mungroop, Thomas W.L. Scheeren and Anne H. Epema

From the Departments of Clinical Pharmacy and Pharmacology, Internal Medicine and Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (HRB, HEM, TWLS, AHE)

Correspondence to Hjalmar R. Bouma, MD, PhD, Departments of Clinical Pharmacy and Pharmacology and Internal Medicine, University Medical Center Groningen, P.O. Box 30.001 (EB70), 9700 RB Groningen, The Netherlands Tel: +31 50 361 7870; e-mail: h.r.bouma@umcg.nl

Editor,

With interest we have read ‘Very early changes in serum creatinine are associated with 30-day mortality after cardiac surgery’ by Bernardi et al.1In their observational cohort study among 7651 patients undergoing elective cardiac surgery [40% coronary artery bypass grafting (CABG), 6% off-pump CABG, 34% valve surgery and 20% combined procedures] they demonstrated an asso-ciation between a rise in serum creatinine and postopera-tive 30-day mortality, which persisted after adjusting for fluid balance. The incidence of acute kidney injury (AKI) was 10, 2 and 6% (AKI stage 1, 2 and 3, respectively), and AKI necessitating renal replacement therapy (RRT) occurred in 5% of the patients. The authors demonstrated that very early and minimal changes in serum creatinine (0 to <26.5 mmol l1, measured within 120 min after cardiac surgery), were relevant to outcome. The authors suggested that: ‘Clinicians paying attention to such early increases in serum creatinine (SCrea) at least 26.5 mmol l1 may avoid the evolution of complications and further renal damage’. We agree with the authors that small changes in serum creatinine are relevant to out-come, which is in line with the results from our earlier studies based on first week serum creatinine changes after cardiac operations.2 In addition, we demonstrated that the currently used AKI classification underestimates long-term mortality risk after cardiac valve operations. We revealed that a peri-operative rise in serum creatinine of more than 26.5 mmol l1 or 50% as compared with baseline (KDIGO AKI criteria: AKI 1) was associated with long-term (up to 17 years follow-up) all-cause mor-tality (hazard ratio 2.27, P less than 0.05 for valve; hazard ratio 1.65, P < 0.05 for valveþ CABG; hazard ratio 1.56, P < 0.05 for CABG). Moreover, after valve operations, even a small rise in serum creatinine of at least 10–25% (i.e. below the threshold for AKI) was also strongly associated with long-term mortality (hazard ratio 1.39,

P < 0.05), which was not the case after CABG operations. Although Bernardi et al. included the type of surgery as covariate in their regression analysis model, it is unclear whether the association between peri-operative changes in serum creatinine and mortality were similar or diverg-ing for different types of cardiac operations, for example, CABG, valve or combined operations. In our work, we proposed to use a cut-off of serum creatinine increases of 10% to identify patients at risk of long-term mortality after valve surgery. How should the increased mortality among patients with a rise in serum creatinine of less than 26.5 mmol l1 be used in clinical practice? Finally, the authors discussed several factors (i.e. fluid changes, cre-atinine production and clearance) affecting serum creati-nine level and concluded that patients in the group with the largest rise (>26.5 mmol l1) upon ICU admission had AKI per definition. If serum creatinine production is not significantly affected by surgery, would adjusting the perioperative rise in serum creatinine for the time between both measurements allow even more precise identification of patients at risk of mortality?

Acknowledgements relating to this article

Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none.

References

1 Bernardi MH, Ristl R, Neugebauer T, et al. Very early changes in serum creatinine are associated with 30-day mortality after cardiac surgery: a cohort study. Eur J Anaesthesiol 2020; 37:898–907.

2 Bouma HR, Mungroop HE, de Geus AF, et al. Acute kidney injury classification underestimates long-term mortality after cardiac valve operations. Ann Thorac Surg 2018; 106:92–98.

DOI:10.1097/EJA.0000000000001436

Reply to: very early creatinine changes and

30-day mortality after cardiac surgery

Martin H. Bernardi, Robin Ristl, Michael Hiesmayr and Andrea Lassnigg

From the Division of Cardiac Thoracic Vascular Anaesthesia and Intensive Care Medicine (MHB, MH, AL) and Centre for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria (RR)

Correspondence to Martin H. Bernardi, MD, Division of Cardiac Thoracic Vascular Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria

Tel: +43 1 40400 41090; fax: +43 1 40400 64040; e-mail: martin.bernardi@meduniwien.ac.at

Editor,

We thank Bouma et al. for their comments1 about our recently published article on very early creatinine changes and impact on mortality after cardiac surgery.2We have read with interest the comments and remarks they made.

Correspondence 665

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(SCr) after cardiac surgery are relevant to outcome. The impact of even minimal increases (or profound decreases) of SCr after cardiac surgery on mortality has been shown several years ago in 2004 and 2008 by our group.3,4A small decrease in SCr after cardiac surgery is an expected reac-tion due to haemodilureac-tion and blood loss. Moreover, in the current study we showed a very early impact on mortality even 2 h after surgery (hazard ratio 1.98, 95% confidence interval [CI] 1.54 to 2.55, P < 0.001) when a change in SCr is less than 26.5 mmol l1compared with baseline.1 There-fore, the currently used acute kidney injury classification underestimates mortality after cardiac surgery. But, is estimating the risk of mortality after cardiac surgery the goal of acute kidney injury classifications?

However, in contrast to the study by Bouma et al.5, we did not find an influence of valve operations on either short-term mortality2or on long-term mortality (hazard ratio 1.08, 95% CI 0.98 to 1.19, P¼ 0.11; data not published) compared with coronary artery bypass grafts. Only com-bined procedures significantly affected long-term mortal-ity (hazard ratio 1.23, 95% CI 1.12 to 1.36, P < 0.001; data not published), but not the 30-day mortality. Moreover, in a previous study4we did not find any impact of valve procedures on short-term mortality.

Nevertheless, the comparison of the Kaplan –Meier curves of the study by Bouma5et al. and our published long-term data2shows a clear change in the slope after the early postoperative period and an approximately constant slope later on. This indicates that the early phase impacts the survival. Moreover, the prognosis of our patients is defined in this very early postoperative period,2 – 4 but long-term outcome is influenced by pre-existing comor-bidities and not peri-operative alterations in SCr.3 Another work of our group6published in 2015 on influenc-ing risk indicators on mortality after cardiac surgery showed that, beside pre-operative SCr, a few comorbidities and mainly surgical circumstances determine the risk of short-term mortality (e.g. congestive heart failure, hazard ratio 1.42, P < 0.001; urgent operation, hazard ratio 1.55, P < 0.001; early revision, hazard ratio 1.49, P < 0.001; re-operation, hazard ratio 1.47, P < 0.001). However, for long-term mortality, mainly pre-operative comorbidities were decisive (e.g. reduced ejection fraction, hazard ratio 1.65, P < 0.001; atrial fibrillation, hazard ratio 1.52, P < 0.001; chronic obstructive pulmonary disease, hazard ratio 1.40, P < 0.001). Again, the kind of operation did not impact the short-term or the long-term mortality in the multivariate model. Several peri-operative risk factors that are more frequent in valve patients may confound the association between type of surgery and outcome.

To us it would be interesting how the reported impacts on long-term mortality by Bouma et al.5would change when the proportional hazard assumption is split into short-term and long-term outcome. Moreover, we are interested why

no long-term survival influencing risk indicators were included in their multivariate Cox regression analysis. We think that in our analysis a much larger set of intra-operative risk indicators that are also associated with com-plexity of surgery may have removed the confounding effect between valve surgery and 30-day mortality. Moreover, using more intra-operative risk indicators would remove the effect of valve surgery into clinical characteristics. Of course, studies dealing with large databases are always limited by bias owing to omitted or unobserved con-founding risk indicators that are included in the multi-variate analysis. In our studies, the chosen analyses and model selections avoided potential problems with multi-collinearity problems of overfitting. In addition, the slightly different exclusion criteria and thus the higher proportion of patients excluded from the analysis in the Bouma study4may allow for small differences to be found in multivariate models.

Lastly, we do not think that adjusting the peri-operative rise in SCr for the time between both measurements allows an even more precise identification of patients at risk. If the increase in SCr would be linear, an adjustment for time would be reasonable. However, taking a close look at the various intra-operative risk indicators reveals that patients with a more complicated course have an increased risk (e.g. urgent operation, hazard ratio 1.5, P¼ 0.01; transfusion, hazard ratio 1.1, P ¼ 0.01; early revision, hazard ratio 1.6, P¼ 0.01; unplanned assist device, hazard ratio 2.3, P < 0.001). Obviously, these risk indicators not only increase the procedure time, but also the potential renal damage.7

Therefore, we think that the present findings help in very early identification of patients at risk after surgery. Once identified, alteration and increased specific focus on postoperative management with respect to further renal damage (e.g. close haemodynamic management, avoid-ance of nephrotoxic agents, etc.) may reduce the complex pathophysiological causes and progression of acute kidney injury.

Acknowledgements relating to this article

Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none.

References

1 Bernardi MH, Ristl R, Neugebauer T, Hiesmayr MJ, Druml W, Lassnigg A. Very early changes in serum creatinine are associated with 30-day mortality after cardiac surgery: A cohort study. Eur J Anaesthesiol 2020; 37:898– 907.

2 Bouma HR, Mungroop HE, Scheeren TWL, Epema AH. Very early creatinine changes and 30-day mortality after cardiac surgery. Eur J Anaesthesiol 2021; 38:665.

3 Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 2004; 15:1597–1605.

666 Correspondence

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 2008; 36:1129–1137.

5 Bouma HR, Mungroop HE, de Geus AF, et al. Acute kidney injury classification underestimates long-term mortality after cardiac valve operations. Ann Thorac Surg 2018; 106:92–98.

6 Bernardi MH, Schmidlin D, Schiferer A, et al. Impact of preoperative serum creatinine on short- and long-term mortality after cardiac surgery: a cohort study. Br J Anaesth 2015; 114:53–62.

7 Wang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. Nat Rev Nephrol 2017; 13:697–711.

DOI:10.1097/EJA.0000000000001457

Remote organ ischaemic preconditioning in

human recipients suppresses systemic

inflammation and prevents glycocalyx

degradation in living-donor liver

transplantation

A randomised controlled trial

Melis Tosun, Meltem Guner Can, Ugur Aksu, Remzi Emiroglu and Fevzi Toraman

From the Department of Anesthesiology and Reanimation, Acibadem Mehmet Ali Aydinlar University School of Medicine (MT, MGC, FT), Department of Biology, Faculty of Science, Istanbul University (UA) and Department of Organ Transplantation, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey (RE)

Correspondence to Melis Tosun, Department of Anesthesiology and Reanimation, Acibadem Mehmet Ali Aydınlar University School of Medicine, Acibadem Altunizade Hospital, Uskudar, Istanbul 34662, Turkey

Tel: +90 216 6494871/þ90 535 6694002; e-mail: melistosun@gmail.com

Editor,

Ischaemia-reperfusion injury during liver transplantation is a leading cause of morbidity and mortality. Although there is no standard strategy to reduce or treat ischaemia-reperfusion injury, ischaemic preconditioning and remote organ ischaemic preconditioning (RIPC) are among the most researched methods. Ischaemic preconditioning is the preparation of an organ or tissue for ischaemic damage by creating short-term and reversible ischaemia via arte-rial clamping or a tourniquet before long-term and irre-versible ischaemia.1 RIPC is short-term and reversible ischaemia is applied to a tissue that is distant from the main ischaemic area.2

The objective of this study was to demonstrate the early effects of RIPC on living-donor liver recipients in terms of systemic inflammation parameters and glycocalyx integrity parameters. The systemic inflammatory param-eters measured in this study include TNF-a, intercellular adhesion molecule-1 (ICAM-1), hypoxia-induced factor-1 (HIF-factor-1) and IL-8. The parameters for glycocalyx integ-rity were syndecan-1 (SDC-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1).

The secondary aims of this study were to evaluate differences between groups in the postoperative mortal-ity and morbidmortal-ity (haemodynamic and respiratory com-plications, biliary and thrombotic complications, infection, rejection, bleeding and postoperative dialysis requirements) measured at the first 6 h and at 30 days, aspartate aminotransaminase (AST) and alanine amino-transaminase (ALT) levels measured pre-operatively, during the neohepatic phase and postoperatively at 6 h, day 3 and day 7, ICU stay and length of stay in the hospital.

Between 5 December 2019 and 17 January 2020, a total of 21 recipients followed-up at the Acibadem Hospital Organ Transplantation Center with an ASA class of III, MELD score more than 12, aged between 25 and 68 years, and planning to undergo elective living-donor liver transplantation surgery participated in this study. The Local Ethics Committee of Acibadem Mehmet Ali Aydinlar University (Decision No: 2018-9/1) approved, and the Department of Anesthesiology and Reanimation of Acibadem Mehmet Ali Aydinlar University Faculty of Medicine conducted this study. Informed consent was obtained from all patients. Trial registration: Clinical-trials.gov identifier: NCT04216407.

The recipients were randomised into two groups: the RIPC group (n¼10) and the control group (n¼11). A tourniquet was tied around the right lower extremity of the RIPC group. A total of 30 to 90 min before the onset of the anhepatic phase, the tourniquet was inflated to 250 mmHg for three periods of 3 min with an interval of 3 min in between. The control group was not subjected to any procedures other than the standard procedure.

To evaluate systemic inflammation and glycocalyx integ-rity parameters, blood samples were collected from patients in both groups immediately after the induction of anaesthesia, during ICU admission and during the 6th hour of ICU follow-up.

There were no significant differences between the groups in terms of demographic and clinical features; transplanta-tion cause distributransplanta-tions; haemodynamic parameters and inotropic drug use; anhepatic phase duration, warm ischae-mia time, surgical time, postoperative fluid balance, ICU or hospital stay; pre-operative, neohepatic, or postoperative 6th hour or third or seventh day ALT and AST levels or the complication and mortality rates in the first postoperative 6 h and 30 days (all P > 0.05). None of the patients had postoperative extremity pain, neuropraxia or deep vein thrombosis due to tourniquet.

The plasma TNF-a level was significantly higher in the control group during the 6th hour in the ICU than in the RIPC group (P¼ 0.002, Fig. 1). The plasma ICAM-1 level was significantly higher in the control group during ICU admission and during the 6th hour in the ICU than

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