Septic shock is characterized by hypotension, myocardial dysfunction, and disturbances in tissue perfusion, all of which compromise the balance between oxygen supply and demand, eventually contributing to the development of multiple organ failure.1
One of the key recommendations for the treatment of severe sepsis is early goal-directed therapy,2 a strategy based on optimization of cardiac preload, afterload, and contractility.3 This strategy aims at reestablishing the balance between oxygen supply and demand. It advocates fluid resuscitation to restore filling pressures and keep central venous oxygen saturation (ScvO2) ≥70%; persistent hypotension is treated with vasopressors and persistent hypoperfusion, as evidenced by ScvO2 <70%, is treated with inotropes.
Current evidence supports the use of either norepinephrine or dopamine as the vasopressor, and dobutamine as the inotrope of choice during sepsis.4,5 Norepinephrine consistently increases mean arterial blood pressure in septic patients,4–6 whereas dobutamine increases cardiac index and systemic oxygen delivery.7 In addition, β-stimulation can improve hepatosplanchnic perfusion8 and the combination norepinephrine-dobutamine results in lower lactate levels and less anatomic organ injury in animal models of septic shock.9
Based on experimental evidence of disturbed calcium homeostasis and β-adrenergic receptor dysfunction during severe sepsis and shock,10–12 the calcium sensitizer levosimendan has been used with some promising results in a few limited trials and case series.13,14 However, the use of potent inodilators in this clinical setting is still a matter of debate because of the potential risks of excessive vasodilation and hypotension.15 In Part 116 of this series of experiments, we investigated the effects of levosimendan without vasopressor support given to moderately volume-resuscitated endotoxemic pigs: mean arterial blood pressure decreased and neither systemic nor regional perfusion was improved.
Adequate arterial blood pressure is considered essential for the preservation of tissue perfusion in severe sepsis.2 We therefore hypothesized that in judiciously volume-resuscitated endotoxemic pigs, given vasopressor support when needed to maintain adequate mean arterial blood pressure, levosimendan would be as effective as dobutamine for the preservation of systemic and hepatosplanchnic perfusion.
The local ethics committee for animal research at Lund University approved the study, and the animals received care in accordance with the Swedish National Guidelines for the Care and Use of Animals in Research. Twenty pigs (26.8 ± 0.5 kg) fasted overnight with free access to water. After premedication (azaperon 10 mg/kg and atropin 0.03 mg/kg), an ear vein was cannulated. After administration of IV thiopental (5 mg/kg) and ketamine (4 mg/kg), the pigs were orally intubated and their lungs mechanically ventilated as previously reported,16 with the exception of tidal volume, which was set at 8 mL/kg. Anesthesia was maintained by an IV infusion of fentanyl (15 μg · kg−1 · h−1) and propofol (6 mg · kg−1 · h−1). All animals received 10 mL · kg−1 · h−1 Ringer's acetate solution and 5 mL · kg−1 · h−1 of glucose 5%. Oxygen consumption (VO2) was monitored by indirect calorimetry with a metabolic computer (Deltatrac™, Datex, Helsinki, Finland). Vascular accesses and blood flow monitoring for assessment of systemic and regional perfusion, as well as monitoring of anesthesia depth, were performed as in Part 1.16 To avoid shivering, dislodging of the catheters, and to facilitate surgery, an infusion of vecuronium (0.35 mg · kg−1 · h−1) was started before laparotomy. A splenectomy was performed to avoid autotransfusion during shock.
Hemodynamic Measurements and Calculations
Heart rate, body temperature, and all pressures were recorded through a Spacelabs monitor (ref 90309, Medical, Redmond, WA). Cardiac output (mean value of three injections with <5% variation) and pulmonary artery occlusion pressure (PAOP) were measured every 30 min. Stroke volume and systemic and pulmonary vascular resistances were calculated using standard formulas. Gut vascular resistance and regional flow ratios (%) were calculated as in Part 1.16
Gas Exchange and Lactate Concentrations
Blood gases, glucose and lactate concentrations in arterial, mixed, portal, and hepatic samples were analyzed every 30 min by a Radiometer ABL 700-series blood gas analyzer (Radiometer Medical A/S, Copenhagen, Denmark). Standard formulas were used to calculate systemic and regional oxygen contents, oxygen deliveries, and extraction ratios. Regional oxygen consumptions, gut lactate production, and hepatic lactate uptake were calculated using the Fick principle as described in Part 1.16
The experimental protocol is outlined in Figure 1. Two of the 20 pigs were excluded because of surgically related complications. Starting after baseline (t = 0 min, 60 min after surgery), 18 pigs received 2 μg · kg−1 · h−1 of endotoxin (Escherichia coli serotype 0111:B4, Sigma-Aldrich, St Louis, MI) for 300 min. At t = 60 min, the animals received hapten-dextran (0.3 mL/kg) followed by 20 mL/kg Dextran 70 (60 mg/mL). Afterward, if PAOP decreased, a volume challenge was performed (100–200 mL of Ringer's acetate solution) and volume infusion adjusted to keep PAOP ≥baseline. At t = 120 min, the animals were randomized into three groups of six animals each: levosimendan (25 μg · kg−1 · h−1, Simdax®, Orion Pharma, Espoo, Finland), dobutamine (10 μg · kg−1 · min−1), and control (1 mL · kg−1 · h−1 of 5% glucose, i.e., the vehicle of levosimendan dilution). The end-points of vasopressor and inotropic therapy were 1) to maintain mean arterial blood pressure ≥65 mm Hg, and 2) to increase cardiac output by 15%. During the following measurements, if cardiac output had not increased by 15%, levosimendan and/or dobutamine infusions were doubled to 50 μg · kg−1 · h−1 and 20 μg · kg−1 · min−1, respectively. Additionally, from t = 120 min, norepinephrine (0.5 μg · kg−1 · min−1) was added to levosimendan and/or dobutamine infusions whenever mean arterial blood pressure ≤65 mm Hg, and this infusion could be doubled every 10 min up to a maximum of 2.0 μg · kg−1 · min−1. The control group received no adrenergic drugs. At the end of the study, the animals were killed by an IV injection of potassium chloride.
Statistical analysis was performed using the Sigma Stat v3.5 software (Systat Software GmbH, Ekrath, Germany). Based on pilot studies, death was prospectively defined as systemic VO2 <50 mL/min or cardiac output below 1 L/min, and data from dying animals excluded. To evaluate the effects of endotoxemia and fluid resuscitation (0–120 min), all data were pooled into one group and analyzed at 30-min intervals by analysis of variance (ANOVA) for repeated measurements (RM ANOVA, stage versus baseline). At t = 120 min, we tested for differences between groups by ANOVA. Within-group effects of treatment (120–300 min) were analyzed by RM ANOVA (stage versus 120 min). To compare the effects of treatment and eliminate those of interaction because of group allocation, we built the arithmetic differences between stages t = 300 and t = 120 min for every variable in each group (=overall treatment effect) and then analyzed data using ANOVA. Except for the use of mean ± sd for weight, drugs, and fluid volumes, all results are expressed as median (upper-lower quartile). P < 0.05 was considered statistically significant.
There were two deaths, both in the control group (at 240 and 270 min). PAOP was maintained ≥baseline, and average fluid administration was similar in all groups (21 ± 0.5 mL · kg−1 · h−1). There were no significant differences among groups before the start of treatment (t = 120 min) with the exception of lower portal vein flow (P < 0.05) in the dobutamine group.
Effects of Endotoxin and Fluid Resuscitation in All Animals (0–120 min)
General Hemodynamics and Regional Blood Flows
Results are summarized in Figures 2A and 3A–C, and in Table 1. Endotoxin increased vascular resistances and decreased blood flows, but intravascular volume resuscitation induced a hyperdynamic state with high cardiac output and increased regional blood flows. Mean arterial blood pressure remained low, despite increased PAOP. Systemic and gut vascular resistance (13.2 [9.8–15.0] to 7.2 [6.9–9.7] × 103 dyn · s · cm−5) decreased (P < 0.001). Superior mesenteric artery flow ratio increased (7.3 [4.8–7.9] to 8.9 [6.6–12.7]%, P = 0.009), and hepatic artery flow ratio tended to increase (1.5 [0.7–2.6] to 3.0 [1.2–4.7]%, P = 0.060). Portal vein flow ratio decreased (18.5 [14.8–24.9] to 16.2 [12.7–18.8]%, P < 0.05) at 60 min, recovering to (20.3 [19.0–23.4]% at 120 min. There was a twofold increase in mean pulmonary arterial blood pressure (17.5 [15.0–19.0] to 36.0 [32.0–40.0] mm Hg) and in pulmonary vascular resistance (P < 0.001).
Oxygenation and Lactate
Results are summarized in Figs. 2B–D and 4A–D, and in Table 1. Systemic and regional oxygen deliveries and venous saturations decreased with endotoxin, returning to values ≥baseline after intravascular volume resuscitation. Systemic and gut VO2 remained unchanged but hepatic VO2 progressively decreased along with a 50% decrease in hepatic extraction ratio (P < 0.05). The hemoglobin concentration decreased from (109 [104–113] to 89 [84–95] g/L, P < 0.05). Hepatic lactate uptake decreased (9.6 [1.8–16.6] to 7.8 [0.0–13.8] mmol/h, P < 0.05) and gut lactate production transiently decreased at 60 min (3.8 [2.9–7.0] to 1.9 [0–4.8] mmol/h, P < 0.05). Arterial, portal, and hepatic vein lactate concentrations increased. Arterial pH decreased (7.49 [7.48–7.50] to 7.38 [7.34–7.402], P < 0.05).
Effects of Inotropic Treatment (120–300 min)
Two animals in the dobutamine group and three in the levosimendan group required maximal inotropic doses. There were no significant differences (P = 0.312) between the mean norepinephrine doses in the levosimendan (n = 4, 1.41 ± 0.26 μg · kg−1 · min−1) and in the dobutamine groups (n = 3, 0.88 ± 0.43 μg · kg−1 · min−1).
General Hemodynamics and Regional Blood Flows
Results are summarized in Figs. 2A and 3A–C, and in Table 1. The control group progressively developed hypodynamic shock. Dobutamine increased cardiac output and maintained stroke volume throughout the study, whereas levosimendan only transiently increased cardiac output. Mean arterial blood pressure was maintained in both groups, but systemic vascular resistance decreased with dobutamine and remained unchanged with levosimendan. Mean pulmonary artery pressure remained high in all groups, whereas pulmonary vascular resistance further increased in the control group. Gut vascular resistance remained unchanged in all groups. Although regional flows gradually decreased in all groups, dobutamine maintained portal vein flow, which was thus higher in this group at t = 300 min. With time, blood flow ratios remained unchanged in the control group but significantly decreased in the treatment groups. The superior mesenteric artery flow ratio decreased with levosimendan (11.4 [8.3–12.7] to 4.5 [4.4–6.5]%, P < 0.001) and with dobutamine (7.7 [5.4–11.4] to 2.8 [2.1–4.0]%, P < 0.05). Hepatic artery flow ratio decreased from 4.1 (1.2–5.3)% to 1.3 (0.5–2.1)%, and from 3.3 (2.1–4.7)% to 0.6 (0.5–0.9)% with levosimendan and dobutamine, respectively (P < 0.001). The portal vein flow ratio decreased in the levosimendan group (20.3 [14.2–22.7] to 12.5 [10.4–14.6]%, P < 0.05) and showed a significant decrease in the dobutamine group at 240 min (19.3 [19.0–22.5] to 14.1 [12.5–20.2]%, P < 0.042).
Oxygenation and Lactate
Results are summarized in Figs. 2B–D and 4A–D, and in Table 1. In the dobutamine group, systemic VO2 transitorily increased, oxygen delivery increased, and extraction ratio decreased by 30% (P < 0.05). Whereas systemic oxygen delivery briefly increased with levosimendan, VO2 showed an upward trend (P = 0.054) and extraction ratio remained unchanged. In the control group, systemic VO2 became delivery-dependent: as oxygen delivery decreased, extraction ratio increased 51% (P = 0.004), and VO2 ultimately decreased. Only dobutamine maintained gut and hepatic oxygen deliveries and all venous oxygen saturations; gut oxygen delivery and hepatic vein oxygen saturation were thus significantly higher in this group at 300 min. In contrast, the decreased regional oxygen deliveries in the two other groups were compensated by increased hepatic oxygen extraction ratios (in the levosimendan group by 340%, P = 0.017; in the control group by 180%, P = 0.02) and increased gut oxygen extraction ratio in the control group (by 140%, P < 0.05); consequently, hepatic and gut VO2 remained unchanged in all groups. There were no significant changes in hepatic lactate uptake in any of the groups. Gut lactate production transiently decreased in the control group at 240 min (4.2 [4.1–4.3] to −0.3 [−2.7 to 2.0] mmol/h, P = 0.023). Nevertheless, all lactate concentrations increased in the levosimendan group. Arterial pH decreased to 7.19 (7.15–7.22), 7.32 (7.27–7.35), and 7.25 (7.23–7.26) in the levosimendan, dobutamine, and control groups, respectively (P < 0.001).
We observed that both levosimendan-norepinephrine and dobutamine-norepinephrine treatment sustained a hyperdynamic circulation during the earliest phase of endotoxemia. However, only dobutamine-norepinephrine consistently increased cardiac output, maintained portal vein flow, and preserved systemic and regional oxygen deliveries, which resulted in improved perfusion indexes.
Oxygen homeostasis is severely deranged during sepsis and optimal oxygen supply is difficult to estimate. Whereas targeting inotropes to reach supranormal levels of oxygen delivery in critically ill patients can be harmful,17 the early administration of these drugs to treat sepsis-related hypoperfusion increases survival rates.3 Clearly, titration of inotropic drugs is not straightforward. We restricted maximal levosimendan dose to 50 μg · kg−1 · h−1, which effectively increases contractility in nonseptic pigs18 and, in endotoxemic pigs,15 results in a mean plasma concentration similar to the clinically recommended range.19
In our study, levosimendan maintained cardiac output, but not splanchnic blood flow, which is in contrast to other studies with higher doses given either before or together with endotoxin.20,21 Shorter observation time (120 min) in the experiment of Dubin et al.21 may explain some of the conflicting findings (in our study, gut blood flow decreased first at 240 min). Moreover, levosimendan is a KATP channel opener22 and some of its protective effects are thought to derive from its vasoactive properties.23 The effect of a drug on the splanchnic circulation is, however, dependent on the preexisting vascular tonus.24 Thus, we can only speculate that as intravascular volume resuscitation alone so effectively triggered gut vasodilation in our study, no further protection was obtained from levosimendan given during the hyperdynamic phase.
Interestingly, levosimendan improved cardiac index and mucosal blood flow in septic patients not responding to low-dose dobutamine.14 However, dobutamine-treated patients received less fluids, and 5 μg · kg−1 · min−1 might be an inadequately low dose because of β-adrenoreceptor down-regulation in sepsis.10 Optimal dobutamine dosage during sepsis varies from 2 to 28 μg · kg−1 · min−1,25 and higher doses cause a linear increase in cardiac output.26,27 In endotoxemic pigs, dobutamine improves mucosal blood flow,28 and when combined with norepinephrine, it increases superior mesenteric artery flow and flow ratio in septic sheep.9 In contrast, although it increases cardiac index in septic pigs, it also redistributes flow away from the superior mesenteric artery.29 However, splanchnic blood flow is heterogeneously distributed during endotoxemia,30 and efficacy of hemodynamic therapy should be assessed by a combination of perfusion variables.31 Despite decreased superior mesenteric artery flow, we found that portal vein flow, gut and hepatic oxygen deliveries, portal and hepatic vein oxygen saturations, and lactate concentrations were maintained with dobutamine. Moreover, portal vein flow was higher than what would be expected from the decrease in superior mesenteric artery flow, suggesting that dobutamine favorably redistributed blood within the splanchnic circulation, thereby improving overall gut perfusion.
What is the best way to manage the pressure-flow dilemma? The optimal vasopressor dosage in sepsis is difficult to assess because the vascular autoregulation threshold varies among organs.32 Besides, the splanchnic bed is rich in α-receptors24 and administration of 1–2 μg · kg−1 · min−1 of norepinephrine to endotoxemic pigs is associated with regional blood flow redistribution.33 As blood flow ratios decreased, we cannot exclude the possibility that either norepinephrine therapy affected hepatosplanchnic blood flow or that the levosimendan-associated hypotension should be managed in a different manner.
The porcine endotoxin model is characterized by an initial hypodynamic phase that converts to a hyperdynamic one with aggressive intravascular volume resuscitation.34 In this model, cardiac output is often used as a surrogate for myocardial function, but the degree of intrinsic myocardial dysfunction might be better quantified by contractility indices derived from pressure-volume loops. Nevertheless, in the early hours, the endotoxemic model reproduces the physiological changes of the earliest phase of sepsis-related hypoperfusion, when ScvO2 is low, and hemodynamic optimization may improve tissue perfusion and outcome.3 Consistent with these observations, enhanced systemic VO2 has shown a strong correlation with changes in the microcirculation and is associated with improved survival in sepsis.35,36 Whereas both levosimendan and dobutamine maintained VO2, only dobutamine maintained the systemic and regional oxygen balance, as reflected by preserved global and regional venous oxygen saturations and lower lactate concentrations. These findings possibly reflect better microcirculatory blood flow in this group. Conversely, the lower hepatic vein oxygen saturations associated with the decreased gut and hepatic oxygen deliveries in the levosimendan and control groups suggest worsened oxygen balance in the hepatosplanchnic circulation.37
Lactate metabolism during sepsis is quite complex. As a result of hypoxia or secondary to enhanced glycolysis,38 lactate can also be increased because of cellular dysfunction39 or pyruvate dehydrogenase inhibition.40 Regardless of the cause, persistently elevated lactate levels indicate poor prognosis in septic shock.35,41 Despite the fact that the gut might either consume or produce lactate, and that the capacity of the gut and liver to extract higher loads of lactate might be reduced during sepsis,42,43 the hepatosplanchnic circulation is usually not a major source of lactate in sepsis unless the liver is profoundly hypoxic.44 In our study, hepatic oxygen delivery decreased in the levosimendan and control groups, but hepatic VO2 was maintained by increased oxygen extraction, suggesting that critical oxygen delivery was not reached and liver lactate uptake could therefore be maintained. However, our study design does not allow us to exclude the occurrence of either enhanced pyruvate production or reduced hepatosplanchnic capacity to process an increased lactate load. The major source of lactate in the levosimendan group is thus not entirely clear, but there was a step-up in lactate values from the hepatic vein to the arterial blood in this group, indicating that at least some of the lactate originated from either the inferior vena cava (muscle or kidneys) or the heart/lungs.
In conclusion, whereas the control group gradually developed severe hypodynamic shock, both levosimendan-norepinephrine and dobutamine- norepinephrine maintained a high cardiac output and preserved systemic VO2 in adequately volume-resuscitated endotoxemic pigs. Only dobutamine-norepinephrine, however, consistently increased systemic oxygen delivery, and maintained portal vein blood flow and hepatosplanchnic oxygen delivery, thereby preventing deteriorations in the systemic and the hepatosplanchnic indexes of perfusion.
Professor Stig Steen, MD, PhD, and his research team at the Department of Cardiothoracic Surgery, University Hospital of Lund, Sweden; Per-Erik Isberg, Teaching Assistant, Centre for Mathematical Sciences and Statistics of the University of Lund, Sweden.
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