Hyperreninemic Hypoaldosteronism Syndrome, Plasma Concentrations of Interleukin-6 and Outcome

HYPERRENINEMIC HYPOALDOSTERONISM SYNDROME, PLASMA CONCENTRATIONS OF INTERLEUKIN-6 AND OUTCOME IN CRITICALLY ILL PATIENTS WITH LIVER CIRRHOSIS

Authors : Damien du Cheyron, MD, PhD, Bruno Bouchet, MD; Brigitte Cauquelin, Damien Guillotin, MD; Michel Ramakers, MD; Cédric Daubin, MD; Jean-Jacques Ballet, MD, PhD; Pierre Charbonneau, MD

"Electronic Supplementary Material" METHODS Definitions Sepsis, severe sepsis and septic shock were defined and managed as recommended by the ACCP/SCCM [ESM1]. In patients with shock, dopamine, a tonically inhibitor of aldosterone production, was not used. Organ dysfunction/failure was defined as a SOFA score  3 for any organ system considered [ESM2]. For central nervous system, the Coma Glasgow Scale was considered as normal in patients with sedo-analgesia. Multiple organ failure (MOF) was defined as the simultaneous presence of two or more organ failures at the time of blood sampling, other than cardiovascular. Department protocol for RRT indications followed standard recommendations [ESM3]. Haemofiltration was the technique of choice for haemodynamically unstable patients, whereas intermittent haemodialysis was most frequently used in patients stable enough to tolerate either form of RRT. Finally, all patients were submitted to glycaemic control by insulin protocol that aimed to maintain blood glucose below 150 mg/dL.

Data abstraction Primary diagnosis at admission to ICU was assessed by the presence or absence of sepsis, encephalopathy, acute respiratory failure defined as a PaO2/FiO2 < 200 for acute respiratory distress syndrome (ARDS) or PaO2/FiO2 < 300 for Acute lung injury (ALI), gastrointestinal bleeding, and other causes. The severity of the acute illness was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE) II [ESM4] and the initial Sequential Organ Failure Assessment (SOFA) scores [ESM5]. Volume status was checked on by central venous pressure (CPV) and pulse pressure variation (PPV) measurements.

Analysis We used Receiver Operating Characteristic (ROC) curves to determine the area under the curve (AUC) of the ROC curves constructed with plasma renin and IL-6 values at baseline, and the threshold value of these variables with the highest sensitivity/specificity to predict RRA >2. REFERENCES ESM1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250-1256 ESM2. Moreno R, Vincent JL, Matos R, Mendonca A, Cantraine F, Thijs L, Takala J, Sprung C, Antonelli M, Bruining H, Willatts S (1999) The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med 25:686-696 ESM3. Murray P, Hall J (2000) Renal replacement therapy for acute renal failure. Am J Respir Crit Care Med 162:777-781 ESM4. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818-829 ESM5. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707-710 LEGEND TO FIGURE Figure S1 : Receiver Operating Characteristic (ROC) curves of plasma renin and serum Interleukin (IL)-6 concentrations. The ROC curves were generated by plotting sensitivity against (100-specificity) for each value of variables. The areas under the ROC curves were 0.867, 0.706, respectively. For renin, a threshold value of 240 pg/mL with the highest sensitivity and specificity (73.1% and 95.8%, respectively) was set to predict RRA above 2. For IL-6, a threshold value of 400 pg/mL with the highest sensitivity and specificity (62.5% and 75.0%, respectively) was set to predict RRA above 2. Table S1 : Additional baseline characteristics of the study population, and comparison of patients with RRA below 2 and patients with RRA above 2

Patients with RRA <2 Patients with RRA >2 p value (n=24) (n=26) Diuretics& Antialdosterone agent, n(%) 2 (8) 4 (15) 0.67 Furosemide/Thiazide, n (%) 4 (17) 2 (8) 0.41 Laboratory variables* Blood urea nitrogen, mmol/L 8.36.5 10.97.5 0.21 Creatinine, mg/dL 1.51.1 1.90.9 0.13 Sodium, mmol/L 1348 1337 0.54 Potassium, mmol/L 4.20.9 4.71.0 0.12 Bilirubin, mg/dL 3.92.9 7.97.0 0.01 Albumin, g/L 247 176 0.001 Serum lactate, mmol/L 2.8 [0.7-21.0] 8.7 [0.7-20.0] 0.07 Arterial pH 7.350.21 7.220.19 0.04 Platelet count, G/L 10161 8281 0.34 Leukocyte count, 103 cells/mL 9.97.5 11.29.2 0.62 C-reactive protein, mg/dL 5.9 [0.6-38.0] 4.2 (0.5-35] 0.36 Hemoglobin, g/dL 9.62.1 8.12.8 0.06 Prothrombin time, % 4117 3117 0.05 Fluid loading (mL/kg) 297 429 0.004 CVP*, mmHg 7.94.1 7.33.7 0.32 PPV*, % 8.62.7 11.14.0 0.02

Values are expressed as meanSD, median [range], or number (percent) when appropriate. & Before admission to ICU. * At the time of blood sampling for ACTH test. Abbreviations : RRA, renin over aldosterone ratio; CVP, central venous pressure; PPV, pulse pressure variation. Figure S1