Clinical trial NCT03288610: Prediction of Inflammatory Response and Hypotensive Syndrome After Cardiac Surgery by Preoperative Copeptin Level
Official title: Prognostic Value of Copeptin Level Before Cardiac Surgery and Involvement in Systemic Inflammatory Response Syndrome After Cardiopulmonary Bypass
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Systemic Inflammatory Response Syndrome (SIRS)
Postoperative Vasodilation Syndrome
Stress Response
Cardiac Surgery Prognosis
Tissue Oxygenation and Post-ischemic Response
Keywords: Copeptin
Vasopressin
Microcirculation
Inflammation
Vasodilation
Cardiopulmonary bypass
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
Collaborators: name: Thermo Fisher Scientific, Inc
First posted: 2017-09-20
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 81
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients hospitalized and scheduled for cardiac surgery

Brief summary: The purpose of this study is to find a preoperative biomarker before cardiac surgery with cardiopulmonary bypass related to severe postoperative inflammatory response and circulatory complications. The investigators hypothesize that an increase of the preoperative stimulation of vasopressinergic system (in response to acute or chronic conditions) could lead to a microcirculatory dysfunction and favor the occurrence of vasodilatation during and after CPB and increase the symptoms of an inflammatory response after CPB. By defining a high risk population, a targeted strategy of monitoring and early or preventive treatment could improve postoperative prognosis.

Detailed description: The occurrence of a severe systemic inflammatory response syndrome (SIRS) after elective cardiac surgery with cardiopulmonary bypass (CPB) is estimated at about 20% of cases and is characterized by hemodynamic changes (tachycardia, hypotension, hypovolemia). It is also responsible for vasodilation with impaired microcirculation involving increased morbidity and mortality associated with organ dysfunction and the risk of bacterial translocation. However, the participation of vasopressinergic system in the functional impairment of microcirculation is unclear.

Copeptin is considered a marker of vasopressin secretion, deriving from the same precursor, being more stable and easy to dose. In a previous study of 64 patients with CPB, the investigators have shown that high copeptin preoperative levels are associated with the occurrence of vasodilatation syndrome after cardiac surgery (incidence 15%) with a relative deficiency of postoperative vasopressin.

Microcirculatory alterations can be explored through the study of tissue oxygenation by NIRS (StO2) at rest and in response to a hypoxic challenge (provided by brief vascular occlusion). In septic shock, altered recovery slopes of tissue oxygenation are associated with poor prognosis. The investigators could find similar impact on prognosis in cardiogenic shock if first hours of care did not improve this recovery slope.

The investigators hypothesize that an increase of the preoperative stimulation of vasopressinergic system (in response to acute or chronic conditions) could favor the occurrence of vasodilatation during and after CPB and increase the symptoms of an inflammatory response after CPB. The involvement of vasopressin in microcirculatory dysfunction is unknown.

This is a validation study of a predictive test for pathophysiology and prognosis. This study will be monocentric, prospective and observational in routine care.

The main end point of the study is to predict the onset of severe SIRS or postoperative vasodilation syndrome after CPB by the preoperative plasma copeptin level in a cardiac surgery population.

The secondary objectives are to assess the incidences of microcirculatory dysfunction, shock and organs failure after CPB, to determine the postoperative copeptin kinetics for patients with severe SIRS, to evaluate the prognosis with the ICU length of stay and D28 mortality.

Data are recorded prospectively on a paper case report form by ICU physicians in charge of the patients on the basis of clinical observation and electronic medical records. Quality assurance, monitoring and auditing are provided by the study promotor. Data will be checked by the main investigator to assess the accuracy and completeness of entered data into the CRF.

Patients are recruited during the preoperative period after screening of inclusion and exclusion criteria, delivering information and obtaining written consent.

Considering an expected sensitivity for predicting SIRS by preoperative copeptin on the order of 80%, the number of cases (subjects with severe SIRS) to be included for obtaining an estimate of the sensitivity with a lower limit of 95% to 55% is placed in 42 cases. Considering an incidence of severe SIRS at 20%, the total number of patients to be included in the study is 200. In our center the investigators perform 700 CPB / year, 70% met the criteria for inclusion.

For the primary objective, the predictive performance of preoperative copeptin for the occurrence of post-CPB severe SIRS will be evaluated by the construction of a ROC curve with finding an optimal threshold maximizing sensitivity and specificity (calculation of the Youden index) to be then estimated with their 95% confidence interval.

Regarding the secondary objectives, copeptin levels will be compared according to the presence of postoperative microcirculatory dysfunction, hemodynamic failure, organ dysfunction and preoperative factors using a reduced gap test. Univariate and multivariate analysis using linear regressions will be carried out to find the preoperative factors associated significantly and independently to high copeptin level. The postoperative kinetics of copeptin will be modeled using mixed linear regressions with an intercept +/- a random slope and taking into account the intra-individual correlation of the assays. The prognostic value of preoperative copeptin and postoperative StO2 recovery slope on D28 mortality will be analyzed using the ROC curve, determination of an optimal threshold using the Youden index and then calculating Sensitivity and specificity with their 95% confidence interval.

Eligibility criteria: Inclusion Criteria:

* Elective surgery
* Scheduled time of at least 24 hours
* Cardiopulmonary bypass

Exclusion Criteria:

* Urgent surgery within 24 hours of hospital admission
* Chronic renal failure with preoperative glomerular filtration rate below 45 ml/min
* Ongoing sepsis (ie uncontrolled endocarditis)
* Immunosuppressive therapy (solid organ transplant recipient)
* Previously included in this study

Primary outcomes:
measure: Preoperative copeptin level
timeFrame: Preoperative 24 hours
Secondary outcomes:
measure: Postoperative microcirculatory impairment
timeFrame: Within 2h of admission in intensive care unit, before weaning of sedation and mechanical ventilation
measure: Occurrence of SIRS using classical definition
timeFrame: First postoperative 24 hours
measure: Postoperative hemodynamical impairment
timeFrame: First postoperative 24 hours
measure: Perioperative copeptin kinetics
timeFrame: 24 hours before the operation until admission intensive care unit
measure: Perioperative copeptin kinetics
timeFrame: postoperative day
measure: Global organs dysfunction
timeFrame: First postoperative 24 hours
measure: Lengh of mechanical ventilation
timeFrame: Up to 28 days
measure: Acute kidney injury
timeFrame: Up to 28 days
measure: Renal replacement therapy
timeFrame: Up to 28 days
measure: Intensive Care Unit stay
timeFrame: through study completion, an average of 3 month
measure: Hospital stay
timeFrame: through study completion, an average of 3 month
measure: Intensive Care Unit mortality rate
timeFrame: Up to 28 days
measure: Day 28 mortality rate
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: Montpellier
country: France
facility: Department of critical care, Arnaud de Villeneuve Hospital
Study officials:
affiliation: Montpellier University Hospital
name: Philippe Gaudard, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: MacCallum NS, Finney SJ, Gordon SE, Quinlan GJ, Evans TW. Modified criteria for the systemic inflammatory response syndrome improves their utility following cardiac surgery. Chest. 2014 Jun;145(6):1197-1203. doi: 10.1378/chest.13-1023.
citation: Colson PH, Bernard C, Struck J, Morgenthaler NG, Albat B, Guillon G. Post cardiac surgery vasoplegia is associated with high preoperative copeptin plasma concentration. Crit Care. 2011;15(5):R255. doi: 10.1186/cc10516. Epub 2011 Oct 25.