Changes in inflammatory and vasoactive mediator profiles during valvular surgery with or without infective endocarditis: A case control pilot study

Abstract

Background: More than 50% of patients with infective endocarditis (IE) develop an indication for surgery. Despite its benefit, surgery is associated with a high incidence of multiple organ dysfunction syndrome (MODS) and mortality, which may be linked to increased release of inflammatory mediators during cardiopulmonary bypass (CPB). We therefore assessed plasma cytokine profiles in patients undergoing valve surgery with or without IE.

Methods: We performed a prospective case-control pilot study comparing patients undergoing cardiac valve surgery with or without IE. Plasma profiles of inflammatory mediators were measured at 7 defined time points and reported as median (interquartile). The degree of MODS was measured using sequential organ failure assessment (SOFA) score.

Results: Between May and December 2016 we included 40 patients (20 in each group). Both groups showed similar distribution of age and gender. Patients with IE had higher preoperative SOFA (6.9± 2.6 vs 3.8 ± 1.1, p<0.001) and operative risk scores (EuroSCORE II 18.6±17.4 vs. 1.8±1.3, p<0.001). In-hospital mortality was higher in IE patients (35% vs. 5%; p<0.001). Multiple organ failure was the cause of death in all non-survivors. At the end of CPB, median levels of following inflammatory mediators were higher in IE compared to control group: IL-6 (119.73 (226.49) vs. 24.48 (40.09) pg/ml, p = 0.001); IL-18 (104.82 (105.99) vs. 57.30 (49.53) pg/ml, p<0.001); Mid-regional pro-adrenomedullin (MR-proADM) (2.06 (1.58) vs. 1.11 (0.53) nmol/L, p = 0.003); MR- pro-atrial natriuretic peptide (MR-proANP) (479.49 (224.74) vs. 266.55 (308.26) pmol/l, p = 0.028). IL-1β and TNF- α were only detectable in IE patients and first after starting CPB. Plasma levels of IL-6, IL-18, MRproADM, and MRproANP during CPB were significantly lower in survivors than in those who died.

Conclusion: The presence of infective endocarditis during cardiac valve surgery is associated with increased inflammatory response as evident by higher plasma cytokine levels and other inflammatory mediators. Actively reducing inflammatory response appears to be a plausible therapeutic concept.

Trial registration: ClinicalTrials.gov, ID: NCT02727413.

Fig 1. IE: Infective endocarditis; VHD: Valvular heart disease.

Fig 2

A. Boxplots comparing SOFA score of endocarditis patients (bright) to VHD patients (dark). SOFA: Sequential Organ Dysfunction; preop; within 24 h pre-operative; VHD: valvular heart disease. B. SOFA subscores within 24 h pre-operative in IE and VHD patients. on the X-axis SOFA subscores within 24 h pre-operative in IE patients compared to control group. The dark columns represent the proportions of patients having organ failure (subscore ≥3), while the bright columns represent proportions of patients having no or less than sever organ dysfunctions (SOFA<3). SOFA: Sequential Organ Dysfunction; preop; within 24 h pre-operative; VHD: valvular heart disease.

Fig 3. Cumulative doses of norepinephrine in IE and in VHD patients.

The cumulative doses of norepinephrine administered during the 24 hours pre-operative (-24) as well as during the 1st post-operative day (24) and during the 2nd post-operative (48) day in patients with infective endocarditis (bright line) compared to VHD patients. VHD: valvular heart disease (dark line).

Fig 4

Line chart comparing median plasma levels of markers of acute phase regulations between the two study groups. (A) median plasma levels of IL-6 (B) median plasma levels of CRP, (C) median plasma levels of PCT.Bright line: patients with IE; dark line: patients with VHD; 0 on the x-axis represents the beginning of cardiopulmonary bypass (CPB); the shaded area represents the CPB time; *: p<0.05; IE: infective endocarditis; VHD: valvular heart disease; IL: interleukin; CRP: C-reactive protein; PCT: procalcitonin.

Fig 5

Line chart comparing median plasma levels of biomarkers of cardiovascular dysfunction between the two study groups. (A) Line chart comparing median plasma levels of MR-proADM. (B) Line chart comparing median plasma levels of proAVP. (C) Line chart comparing median plasma levels of CT-proET-1. (D) Line chart comparing median plasma levels of MR-proANP. Bright line: IE patients; dark line: VHD patients; 0 on the x-axis represents the beginning of cardiopulmonary bypass (CPB); the shaded area represents the CPB time; *: p<0.05; IE: infective endocarditis; VHD: valvular heart disease; MR-proADM: midregional pro adrenomedullin; proAVP: copeptin pro vasopressin; CTproET-1: C-terminal pro endothelin; MR-proANP: midregional pro atrial natriuretic peptide.

Fig 6

Line chart comparing median plasma levels of markers of inflammasome activation between the two study groups. (A) Line chart comparing median plasma levels ofIL-1β. (B) Line chart comparing median plasma levels of IL-18. Bright line: IE; dark line: VHD; 0 on the x-axis represents the beginning of cardiopulmonary bypass (CPB); the shaded area represents the CPB time; *:p<0.05; IE: infective endocadarditis; VHD: valvular heart disease; IL: interleukin.

Fig 7

Line chart comparing median plasma levels of regulators of the inflammatory response between the two study groups. (A) Line chart comparing median plasma levels of TNF-alpha. (B) Line chart comparing median plasma levels of IL-10. Bright line: IE; dark line: VHD; 0 on the x-axis represents the beginning of cardiopulmonary bypass (CPB); the shaded area represents the CPB time; *:p<0.05; IE: infective endocarditis; VHD: valvular heart disease; TNF: tumour necrosis factor; IL: interleukin.