Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function

Abstract

Introduction: The objective of this study was to evaluate the effects of two different mean arterial blood pressure (MAP) targets on needs for resuscitation, organ dysfunction, mitochondrial respiration and inflammatory response in a long-term model of fecal peritonitis.

Methods: Twenty-four anesthetized and mechanically ventilated pigs were randomly assigned (n = 8/group) to a septic control group (septic-CG) without resuscitation until death or one of two groups with resuscitation performed after 12 hours of untreated sepsis for 48 hours, targeting MAP 50-60 mmHg (low-MAP) or 75-85 mmHg (high-MAP).

Results: MAP at the end of resuscitation was 56 ± 13 mmHg (mean ± SD) and 76 ± 17 mmHg respectively, for low-MAP and high-MAP groups. One animal each in high- and low-MAP groups, and all animals in septic-CG died (median survival time: 21.8 hours, inter-quartile range: 16.3-27.5 hours). Norepinephrine was administered to all animals of the high-MAP group (0.38 (0.21-0.56) mcg/kg/min), and to three animals of the low-MAP group (0.00 (0.00-0.25) mcg/kg/min; P = 0.009). The high-MAP group had a more positive fluid balance (3.3 ± 1.0 mL/kg/h vs. 2.3 ± 0.7 mL/kg/h; P = 0.001). Inflammatory markers, skeletal muscle ATP content and hemodynamics other than MAP did not differ between low- and high-MAP groups. The incidence of acute kidney injury (AKI) after 12 hours of untreated sepsis was, respectively for low- and high-MAP groups, 50% (4/8) and 38% (3/8), and in the end of the study 57% (4/7) and 0% (P = 0.026). In septic-CG, maximal isolated skeletal muscle mitochondrial Complex I, State 3 respiration increased from 1357 ± 149 pmol/s/mg to 1822 ± 385 pmol/s/mg, (P = 0.020). In high- and low-MAP groups, permeabilized skeletal muscle fibers Complex IV-state 3 respiration increased during resuscitation (P = 0.003).

Conclusions: The MAP targets during resuscitation did not alter the inflammatory response, nor affected skeletal muscle ATP content and mitochondrial respiration. While targeting a lower MAP was associated with increased incidence of AKI, targeting a higher MAP resulted in increased net positive fluid balance and vasopressor load during resuscitation. The long-term effects of different MAP targets need to be evaluated in further studies.

Figures

Figure 1

Study design for the low and high mean arterial pressure (MAP) groups. Black circles, samples from the right quadriceps muscle to assess mitochondrial function and quantification of skeletal muscle ATP content; black triangle, first dose of intravenous antibiotic (piperacillin/tazobactam, 2.25 g, 8-hourly); black square, additional tissue samples from the liver for mitochondrial function analysis at the end of the experiment (66 h or before death, if earlier). Animals allocated to the septic control group (Septic-CG) were followed without resuscitation after induction of peritonitis until death. BL, baseline; PI, peritonitis induction; EOP, end of observation period (before starting resuscitation); End, end of the experiment (at 48 hours of resuscitation or before death if earlier.

Figure 2

Kaplan-Meyer survival curve. MAP, mean arterial pressure; Septic-CG, septic control group.

Figure 3

Isolated skeletal muscle mitochondrial respiration during unresuscitated sepsis. Complex I-, II- and IV-isolated skeletal muscle mitochondrial respiration in septic control animals from baseline to end (represented by connecting lines for each pig, n = 8). State 3 and State 4 oxygen consumption is expressed as pmol/second/mg protein. State 3, active respiration after addition of ADP; State 4, respiration after consumption of ADP. The ratio between State 3 and State 4 was calculated as the respiratory control ratio (RCR; state 3/state 4). *P = 0.02, paired t-test.

Figure 4

Isolated liver mitochondrial respiration. Comparison of isolated liver mitochondrial respiration in septic control animals and septic animals resuscitated to low-mean arterial pressure (MAP) and high-MAP targets (n = 8). State 3 and 4 oxygen consumption is expressed as pmol/second/mg protein. No significant differences were found between the groups (P >0.05, one-way analysis of variance). Horizontal lines represent mean values. Filled circles represent animals that died early. State 3, active respiration after addition of ADP; State 4, respiration after consumption of ADP; RCR, respiratory control ratio (oxygen consumption of State 3/State 4).

Figure 5

Skeletal muscle tissue ATP concentrations in septic controls and animals resuscitated to low-mean arterial pressure (MAP) and high-MAP targets. The black horizontal bars represent the mean values. Filled circles represent animals that died early. P >0.05 for all comparisons. BL, baseline; EOP, end of observation period; END, end of the experiment (at 48 h of resuscitation, or before death if earlier).