New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Veno-Arterial Extracorporeal Membrane Oxygenation in the Rat

Abstract

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

Keywords: V-A ECMO; inflammation; intestinal perfusion; sepsis.

Figure 1

Means of the time course of intestinal (A) regional oxygen saturation, (B) relative blood flow, (C) relative hemoglobin concentration, hepatic (D) regional oxygen saturation, (E) relative blood flow, and (F) relative hemoglobin concentration. Rats treated with V-A ECMO showed reduced regional oxygen saturation and relative hemoglobin of the intestine and liver compared to sham animals. Relative blood flow in the intestine and liver did not differ significantly between V-A ECMO therapy and sham procedure. The asterisks denote the degree of statistical significance: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Abbreviations: ECMO = extracorporeal membrane oxygenation; RU = relative units; SO₂ = tissue oxygen saturation; V-A = veno-arterial.

Figure 2

Time course of (A) SAP, (B) MAP, (C) DAP, and (D) heart rate. SAP, DAP, and MAP were measured elevated during low- and high-flow V-A ECMO therapy and septic shock than during sham procedure. Heart rate did not differ significantly between low- and high-flow V-A ECMO therapy and sham therapy. The asterisks denote the degree of statistical significance: ***, p < 0.001. Abbreviations: DAP = diastolic arterial pressure; ECMO = extracorporeal membrane oxygenation; MAP = mean arterial pressure; SAP = systolic arterial pressure; V-A = veno-arterial.

Figure 3

Time course of (A) SV, (B) CO, (C) LVEDV, and (D) LVEDP. While SV, CO, and LVEDV were significantly higher with low- and high-flow V-A ECMO therapy than sham procedure, LVEDP was only significantly higher with high-flow V-A ECMO therapy than sham procedure. The asterisks denote the degree of statistical significance: *, p < 0.05; ***, p < 0.001. Abbreviations: CO = cardiac output; ECMO = extracorporeal membrane oxygenation; LVEDP = left ventricular end-diastolic pressure; LVEDV = left ventricular end-diastolic volume; SV = stroke volume.

Figure 4

Time course of the plasma concentrations of the inflammatory parameters (A) TNF-α, (B) IL-6, (C) IL-10, (D) CXCL2, and (E) CXCL5. While CXCL2 concentrations were significantly higher with high-flow V-A ECMO therapy than sham procedure, TNF-α, IL-6, IL-10, and CXCL5 concentrations did not differ significantly between low- and high-flow V-A ECMO therapy and sham animals. The asterisks denote the degree of statistical significance: **, p < 0.010. Box and whisker plots indicate the median, interquartile range (box), and minimum and maximum (whiskers). Abbreviations: CXCL2 = C-X-C motif ligand 2; CXCL5 = C-X-C motif ligand 5; TNF-α = tumor necrosis factor alpha.

Figure 5

The concentrations of the inflammatory (A) TNF-α, (B) IL-6, (C) IL-10, (D) CXCL2, and (E) CXCL5 in the BAL. While CXCL2 and CXCL5 concentrations were significantly higher during low-flow V-A ECMO than sham therapy, TNF-α, IL-6, and IL-10 concentrations did not differ significantly between low- and high-flow V-A ECMO therapy and sham procedure. The asterisks denote the degree of statistical significance: *, p < 0.05. Box and whisker plots indicate the median, interquartile range (box), and minimum and maximum (whiskers). Abbreviations: CXCL2 = C-X-C motif ligand 2; CXCL5 = C-X-C motif ligand 5; TNF-α = tumor necrosis factor alpha.