We performed an observational prospective cohort study at “Città della Salute e della Scienza di Torino” University Hospital in Turin, Italy. The local ethical committee “Comitato Etico Interaziendale” in Turin, approved the study protocol on 12th October 2015 (protocol n. 0099127) and the study has been conducted in accordance with the Declaration of Helsinki.
All patients scheduled for cardiac surgery with CPB and admitted to the Cardiac Intensive Care Unit after the intervention were consecutively evaluated for enrolment. Exclusions criteria were age less than 18 years old, off pump surgery, cardiac transplantations, extracorporeal membrane oxygenation (ECMO), dialysis, end stage hepatic disease, endocarditis, sepsis, septic shock, preoperative use of vasoactive or inotropic drugs and lack of consent.
Variables and data measurements
We defined PCVS as the simultaneous occurrence of a mean arterial blood pressure (MAP) < 60 mmHg together with a systemic vascular resistance index (SVRI) < 1,200 dyn*s/cm5*m2, resulting in the need for a NE infusion with dosages ≥ 0.1 µg/kg/ minute for at least 12 hours and within the first 24 hours after cardiac surgery [1, 7].
We collected demographic and clinical data, as following: age, gender, EuroSCORE, SAPS II and SOFA score, type of surgery, CPB and cross clamping time, preoperative left ventricular ejection fraction (LVEF), anti-hypertensive drugs assumed before surgery (if suspended or not), renal failure (AKIN classification). Additionally, we evaluated if patients needed inotropic and/or vasoactive drugs after CPB and dose. Systolic and mean arterial pressure, central venous pressure, left atrial pressure, when available, and systemic vascular resistance index were also collected.
Before surgery (T0), one day (T1) and 7 days after surgery (T2), copeptin and NT-proBNP levels were measured together with routine biochemical analysis, hemodynamic monitoring (MAP, SVRI, CO) and NE infusion were also recorded.
Moreover, at T0, early in the morning, all patients underwent to HPA axis evaluation with a LD, followed by a SD, ACTH stimulation test as follows: after baseline cortisol measurement, i.v. Cortrosyn 1 µg bolus was administrated with collection of venous blood sample for cortisol at 30 minutes and 60 minutes (LD ACTH test); immediately after, i.v. Cortrosyn 250 µg was administrated with collection of venous blood samples for cortisol at 120 minutes (SD ACTH test). A lack of response to both tests was defined for a peak cortisol level < 180 µg/L.
Finally, we evaluated the intensive care unit length of stay (ICU-LOS), expressed as days free from ICU stay, considering 28 days as the maximum length of ICU stay.
Blood from an EDTA-containing tube was centrifugated at 4,000 rpm for 5 minutes and a plasma aliquot was immediately frozen and stored at − 80 °C until analysis. Copeptin concentrations were then determined with the B.R.A.H.A.M.S. KRYPTOR compact PLUS (ThermoFisher Scientific, Hennigsdorf, Germany) automated method. Copeptin is measured using TRACE (Time-Resolved Amplified Cryptate Emission) technique, an immune fluorescent analysis that measures the delayed fluorescent signal transferred from donor molecules when bound in an immunocomplexes. The signal is proportional with the concentration of copeptin in the sample. The limit of detection of the assay is 0.9 pmol/L, while intra-assay coefficients of variation were below 7% and below 12% for inter-assay coefficients.
Blood samples were collected in an EDTA-containing tube and processed on Cobas e602 automated platform (Roche Diagnostics), including centrifugation at 3,500 rpm for 5 minutes and determination by sandwich immunoassay with two monoclonal antibodies directed against N-terminal portion (1–76) of proBNP molecule (Elecsys proBNP II), using electrochemiluminescence detection (ECLIA). The limit of detection of the assay was 5 pg/mL (0.6 pmol/L), with a 5–35,000 (0.6-4,130) dynamic range as well as intra-assay and inter-assay coefficients of variation of less than 5% at three different concentrations (46, 125 and 14,150).
All the remaining routine laboratory measurements on serum, plasma and urine samples were performed with automated biochemical assays in the local laboratory (Baldi & Riberi Laboratory, University Hospital “Città della Salute e della Scienza di Torino”, Turin, Italy).
All continuous variables were expressed as mean and standard deviation (SD) or median and interquartile range (IQR), while categorical variables were expressed as number and percentage (%).
Inter-group comparisons for continuous variables were performed with the T-test or the Wilcoxon-Mann-Whitney test depending on type of distribution. The Chi square test or the Fisher’s exact test were used to analyse categorical variables, when appropriate. The Receiver Operating Curves (ROC) analysis was used to assess copeptin and NT-proBNP cut-offs able to discriminate patients who developed PCVS. Logistic regression models were calculated in order to identify the predictors of PCVS among the preoperative or intraoperative variables. A multiple linear regression model was also calculated to define the best predictor of log-normalized copeptin values at 7 days post-surgery. As outcome variable we evaluated the ICU length of stay (ICU-LOS), with a follow up at 28 days.
Statistical analysis was performed using Stata/IC 14.2, version 29 Jan 2018. Figures were made using GraphPad Prism™, version 8.01.