Septic shock is characterized by vasodilation, increased microvascular permeability, and capillary leakage resulting in decreased blood volume and facilitating the development of multiple organ failure (1). Adequate fluid resuscitation is essential for restoration and maintenance of intravascular volume and organ perfusion. However, the optimal type and amount of intravenous fluid in this setting remain controversial (2). Hypertonic solutions appear attractive, with their hypertonicity potentially limiting fluid accumulation and interstitial edema.
Administration of hypertonic saline (HTS) in sepsis has been associated with rapid hemodynamic stabilization (3), less capillary leakage (4), reduced edema formation (5), and modulation of the immune response and inflammation (6–8). However, the non-metabolized chloride anions may be associated with renal vasoconstriction and an increased risk of acute renal injury (9). Hence, use of metabolized anions, such as lactate, may be preferable. Moreover, lactate may serve as an energetic substrate for the brain and heart (10–14). In sepsis, raised serum lactate concentrations are associated with worse outcomes (15, 16), but this does not imply that lactate is toxic. Indeed, lactate may protect cardiac function, as illustrated by Levy et al. (10) who showed that systemic lactate deprivation was detrimental to myocardial energetics, cardiovascular performance, and outcome in a lethal endotoxic shock rat model. Lactate has been shown to egress chloride from endothelial cells thereby reducing swelling and improving barrier function (17), and to reduce the inflammatory response and endothelial activation (18). In a pig endotoxemia model (3), resuscitation with hypertonic sodium lactate (HTL) was associated with better maintained arterial pressure, cardiac index, and microvascular reactivity compared with 0.9% saline and hypertonic sodium bicarbonate solutions. These positive effects on vascular filling and cellular feeding (19) raise the question whether HTL could be associated with improved outcomes in sepsis (20).
We, therefore, studied administration of HTL and HTS as supplemental fluids in a sheep peritonitis model. Our hypothesis was that, compared with HTS, 0.9% (“normal”) saline (NS) or Ringer's lactate (RL) with equivalent isosmotic doses of sodium (to separate the effects of hypertonicity), HTL would be associated with improved cardiac function, attenuated microvascular alterations, preserved brain and renal metabolism, and prolonged survival.
MATERIALS AND METHODS
The Ethics committee of the Free University of Brussels, Brussels, Belgium, approved the study and care and handling of the animals was in accordance with National Institute of Health Guidelines. We studied 28 adult female Texel sheep (aged 6–8 months, weight 25–35 kg). The animals were fasted for 12 h prior to the start of the experiment with free access to water.
On the day of the experiment, animals were premedicated with a combination of intramuscular midazolam (0.25 mg/kg, Dormicum, Roche SA, Brussels, Belgium) and ketamine hydrochloride (20 mg/kg, Imalgine, Merial, Lyon, France) and placed in the supine position. The cephalic vein was cannulated with a peripheral venous 18-gauge catheter (Surflo IV Catheter, Terumo Medical Company, Leuven, Belgium). An intravenous bolus of 30 μg/kg fentanyl citrate (Janssen, Beerse, Belgium) and 0.1 mg/kg rocuronium (Esmeron, Organon, Oss, The Netherlands) was given before endotracheal intubation (8-mm endotracheal tube, Hi-Contour, Mallinckrodt Medical, Athlone, Ireland). All sheep were then sedated with a continuous intravenous infusion of midazolam (0.2 mg/kg/h), ketamine hydrochloride (0.5 mg/kg/h), and morphine (0.2 mg/kg/h). Muscle relaxation was achieved by a continuous infusion of rocuronium at 10 μg/kg/h throughout the experiment.
Mechanical ventilation (Servo 300 ventilator; Siemens-Elema, Solna, Sweden) was started with the following settings: tidal volume of 10 mL/kg, respiratory rate of 12 to 16 breaths/min, positive end-expiratory pressure of 5 cmH2O, an inspired oxygen fraction (FIO2) of 30%, and an inspiratory time to expiratory time ratio of 1:2. Respiratory rate was adjusted to maintain end-tidal carbon dioxide (etCO2, 47210 A Capnometer; Hewlett Packard GmbH, Boehlingen, Germany) between 35 mm Hg and 40 mm Hg throughout the experiment. No other intervention was made to correct metabolic alkalosis or acidosis. Blood glucose levels were kept >40 mg/dL.
A 60-cm plastic tube (inner-diameter 1.8 cm) was inserted via the esophagus into the stomach to drain its content and to prevent rumen distension. A 14F Foley catheter (Beiersdorf AG, Hamburg, Germany) was placed in the bladder to record urinary output throughout the experiment. The right femoral artery and vein were surgically exposed. A 6F arterial catheter (PiCCO, Pulsion, Feldkirchen, Germany) was inserted into the femoral artery connected to a pressure transducer (Edwards Lifesciences, Irvine, Calif) and zeroed at mid-chest level. An introducer was inserted through the femoral vein, through which a 7F pulmonary artery catheter (Swan-Ganz catheter, Edwards Lifesciences) was inserted. A midline laparotomy was then performed. After cecotomy, 1.5 g/kg body weight of feces was collected. The cecum was then closed and the area around the cut disinfected with iodine solution. A purse-string suture was performed to prevent contamination and the cecum was returned to the abdominal cavity. A large plastic tube was inserted through the abdominal wall for later injection of feces. An ultrasonic flow probe (Transonic, Ithaca, NY) was positioned around a main branch of the mesenteric artery. The abdomen was then closed in two layers. After abdominal surgery, the animals were turned to the prone position. The left renal artery was surgically exposed and a second flow probe was positioned around it.
A microdialysis catheter (CMA 20, CMA Microdialysis AB, Kista, Sweden) was introduced into the left kidney cortex. It was connected to a CMA 402 microdialysis syringe pump (CMA 402, CMA Microdialysis AB) infusing T1 peripheral liquid (CMA Microdialysis AB; Na+ 147 mEq/L, K+ 4 mEq/L, Ca2+ 2.3 mEq/L, Cl− 156 mEq/L, osmolality 290 mOsm/kg) at a rate of 0.3 μL/min. The right scalp (1 × 1 cm) was exposed. Three holes (diameter 1 mm) were drilled in the skull. A microdialysis membrane catheter (CMA 20, CMA Microdialysis AB) was connected to a CMA 402 syringe pump (CMA 402, CMA Microdialysis AB), infusing CNS liquid (CMA Microdialysis AB; 148 mEq/L NaCl, 2.7 mEq/L KCl, 1.2 mEq/L CaCl2 and 0.85 mEq/L MgCl2; osmolality 305 mOsm/kg; pH 6) at a rate of 0.3 μL/min. A laser Doppler flowmetry probe (OXYFLO 2000 microvascular perfusion monitor, Oxford Optronix, Abingdon, UK) and a tissue oxygen pressure sensor (Licox CMP, Integra NeuroScience, Plainsboro, NJ) were inserted into the brain cortex at 1-cm depth.
At the end of surgery, the animals were allowed to stabilize for 1 h, after which baseline measurements were taken (T = 0). The withdrawn feces (1.5 g/kg body weight) were then injected intraperitoneally into the right lower quadrant, followed by 120 mL air to empty the plastic tube and encourage feces spread around the abdomen. Throughout the experiment, a 1:1 mixture of RL (Hartman, Baxter International, Deerfield, Ill) and 6% hydroxyethyl starch (HES; Voluven, Fresenius Kabi, Bad Homburg, Germany) solutions was infused to maintain the pulmonary artery occlusion pressure (PAOP) at baseline levels.
Animals were randomized to HTL, HTS, NS, or RL groups (n = 7 each) using sealed, opaque envelopes. Two hours after feces injection, the HTL and HTS groups received equivalent osmotic charges of 0.5 M HTL (PT. Finusolprima Farma International, Bekasi, Indonesia) or 3% HTS (B Braun, Melsungen, Germany), both infused intravenously as a 3 mL/kg bolus over 15 min followed by 1 mL/kg/h infusion for 2 h. The HTL dose was chosen based on a recent pilot study by Nalos et al. (21) in which cardiac function was improved in patients with heart failure who received this dose of HTL. In the other two groups, a bolus of NS (10.8 mL/kg) or RL (10.8 mL/kg) was given over 15 min, followed by 3.6 mL/kg/h for 2 h (the characteristics of the different fluids are shown in Table 1). In each group, the same fluid regimen was repeated at 6 and 10 h after induction of sepsis (Fig. 1). Animals were observed until their spontaneous death.
Heart rate (HR), mean arterial pressure (MAP), right atrial pressure (RAP), PAOP and mean pulmonary artery pressure (MPAP) (Sirecust 404, Siemens, Erlangen, Germany), cardiac output (CO), core temperature (Vigilance monitor, Edwards Lifesciences), and ventilator parameters were monitored continuously. Cardiac index (CI), stroke volume index (SVI), systemic and pulmonary vascular resistance index (SVRI, PVRI), left ventricular stroke work index (LVSWI), oxygen delivery index (DO2I), oxygen consumption index (VO2I), and oxygen extraction index (O2EI) were calculated using standard formulas. Arterial and mixed-venous blood gases, hemoglobin concentration, blood lactate, and electrolyte concentrations (ABL725 and OSM3, Radiometer Medical A/S, Brønshøj, Denmark) were measured hourly; urine output and infused volume were all recorded hourly. The cumulative fluid balance was estimated as the difference between infusion volume and urine output. When the animal died, the wet/dry weight ratio of the central lobe of the right lung was used as an estimate of pulmonary edema severity. The wet weight was determined after blood removal and the dry weight was measured after the lobe had been dehydrated for 24 h in an oven at 200°C.
Microdialysis samples were collected every hour and processed immediately in an ISCUS clinical microdialysis analyzer (ISCUSflex, microdialysis analyzer, CMA Microdialysis AB) to measure lactate, pyruvate and glucose concentrations. The lactate/pyruvate ratio (LPR) was calculated as: [lactate/ pyruvate] × 1,000.
Left kidney artery and mesenteric artery blood flow data (T208 flowmeter, Transonic), were collected hourly. Microcirculation video-microscopy recordings were performed every 6 h using a sidestream dark field (SDF) imaging device (Microvision Medical BV, Amsterdam, The Netherlands), with a probe on the sublingual area and the left kidney cortex surface. At each time point, five different videos of at least 10 s were recorded from different probe positions. All the videos were put into a randomization table for subsequent blinded analysis. A semiquantitative analysis of the sublingual microcirculation was performed as previously reported (22) to calculate the proportion of perfused vessels (PPV). For the kidney cortex microcirculation analysis, one diagonal line was drawn and the PPV was calculated as previously reported (22).
The effect of the treatment was analyzed using a mixed-effects models analysis with treatment group, time, and subjects nested in-group as factors. If the group × time factor was significant, each time point difference among groups was compared with a t test and Bonferroni correction (the median survival time was used as the last comparison point for each group; missing data were processed by carrying forward the previous value). A one-way ANOVA with least significance difference post hoc multiple comparisons was used to compare baseline characteristics and lung wet/dry ratios. Kaplan–Meier survival curves were constructed and analyzed by the log-rank test with correction for multiple comparisons. Data were analyzed using JMP (SAS, Cary, NC). All reported P values are two-sided and a P <0.05 was considered statistically significant.
A total of 200 mEq to 253 mEq of sodium was infused in the different groups; 200 mEq of lactate was administered in the HTL group and 44 mEq in the RL group (Table 1). The total fluid intakes in the HTL, HTS, RL, and NS groups were 5.1 ± 0.1 L, 7.1 ± 0.8 L, 7.5 ± 0.3 L, and 8.4 ± 0.7 L, respectively.
Baseline characteristics, blood electrolyte data, and systemic hemodynamics
There were no differences in baseline characteristics among groups (Table 2). After induction of peritonitis, all sheep developed fever (core temperature >39.5°C), tachycardia (HR > 100/min), and progressive hypotension (MAP < 60 mm Hg), associated with an increase in CI, and a decrease in SVRI (Table 3). From 12 h, the MAP was statistically significantly lower in the HTL than in the HTS and RL groups, the CI was significantly lower in the HTL than in the HTS group, and the RBF and SvO2 significantly lower in the HTL than in the other three groups (Table 3).
Fluid balance was significantly less positive from 4 to 12 h in the HTL and HTS groups compared with the other groups (Table 3). Blood sodium concentrations were significantly higher in the HTL and HTS groups than in the RL and NS groups from 4 h (Fig. 2). Blood chloride concentrations increased in all groups but more markedly in the HTS and NS groups than in the HTL and RL groups (Fig. 2). Metabolic alkalosis developed in the HTL group after the first bolus, and all groups developed hyperlactatemia (>2.0 mEq/L) after 10 to 12 h (Fig. 2).
PaCO2 increased in the HTL group after 12 h but remained constant in the other groups (Fig. 2). PaO2/FiO2 decreased sooner in the HTL and NS groups than in the HTS and RL groups (Table 3). The pulmonary wet/dry ratio was higher, although this was not statistically significant, in the HTL group than in the other groups (7.1 ± 0.2 vs. 6.5 ± 0.1 [HTS], 6.5 ± 0.2 [RL], and 6.6 ± 0.3 [NS], P = 0.14).
In the sublingual area, the PPV progressively decreased in all groups, but the microcirculatory alterations were significantly more severe in the HTL than in the other groups (Fig. 3), particularly at 12 h.
Brain perfusion and metabolism
Brain cortical perfusion and oxygenation decreased sooner in the HTL than in the other groups (Fig. 4). Although cortical glucose decreased similarly in all groups, the LPR increased earlier in the HTL than in the other groups (Fig. 4).
Kidney perfusion and metabolism
Renal blood flow and interstitial glucose were similar during the first 8 h in all groups, but then decreased more quickly in the HTL and NS groups than in the other two groups (Fig. 5). During the first 12 h, the renal cortex L/P ratio increased similarly in all groups, but thereafter increased more in the HTL group than in the other groups. In the kidney cortical microcirculation, PPV decreased more markedly in the HTL than in the HTS and RL groups (Fig. 5).
Mesenteric blood flow was significantly higher in the HTS group than in the other groups from 4 h and in the HTL group than in the NS and RL groups at 12 h (Table 3).
The median survival times in the HTL, HTS, RL, and NS groups were 17, 22, 20, and 16.5 h, respectively. The survival time was significantly shorter in the HTL and NS groups than in the HTS or RL groups (Fig. 6).
In this hyperdynamic septic shock model, infusion of hypertonic solutions was associated with a less positive fluid balance than infusion of NS or RL. HTL infusion resulted in early metabolic alkalosis and later in hypercapnia. In contrast with our hypothesis, HTL infusion, even in relatively small amounts (less than 10% of the total infused volume), had more harmful than beneficial effects, resulting in: more rapid hemodynamic alterations; early impairment of renal and sublingual microcirculation and of renal and cerebral perfusion; and a shorter survival (similar to NS).
HTS administration was, compared with the other fluids, associated with higher MAP, higher CI, and improved organ perfusion and tissue oxygenation as reflected by higher renal blood flow and brain and renal cortex perfusion. HTS administration also prolonged survival. These results agree with earlier findings by Shih et al. (4) showing improved organ function and decreased mortality with HTS fluid resuscitation in a rat peritonitis model. There are several possible mechanisms behind the effects of HTS in sepsis, including decreased hydraulic permeability after endothelial activation and, thereafter, decreased microvascular fluid loss from capillary leakage (23); improved rheology and reduced endothelial edema (24) thereby improving the microcirculation (25); improved myocardial function through increased preload, combined with reduced afterload and improved cardiac contractility (26); and stimulated vasopressin secretion (27) resulting in higher blood pressure and improved microcirculatory perfusion. Moreover, HTS may have anti-inflammatory and anti-oxidant roles in sepsis (28, 29), which could help to decrease gut permeability (30) and attenuate lung injury (4, 7). The effects of HTS infusion contrast with the poor outcomes observed in the NS group.
The effects of HTL were far less beneficial than we had hypothesized. Despite similar tonicity to HTS and a comparable effect on fluid balance, HTL was associated with impaired kidney and brain cortex perfusion and worse sublingual microcirculatory alterations. These adverse effects were associated with early signs of tissue hypoxia, more rapid onset of cardiac and pulmonary dysfunction and shorter survival time. As the arterial pressure was similar among groups for at least the first 10 to 12 h, HTL-induced metabolic alkalosis is the most likely reason for the early decrease in perfusion: exogenous lactate enters the cells while exogenous sodium remains in the plasma, inducing an increase in the strong ion difference and in the plasma bicarbonate concentration when lactate is metabolized (31). In the HTL group, arterial pH increased to 7.5 for 8 h, suggesting that alkalosis developed during this period. Both in vitro and in vivo studies on penetrating cerebral arterioles (32, 33) have shown that alkalosis induces vasoconstriction: one study reported a 21.8% increase in vasoconstriction for each 0.1 increase in pH between 7.3 and 7.8 (34). Kidney dysfunction also prevents bicarbonate from being filtered in acute metabolic alkalosis (35). Moreover, compensated hypercapnia following acute metabolic alkalosis may exacerbate the situation, as infusion of alkali in the presence of hypercapnia can reduce cerebral blood flow, as well as cerebral oxygen tension (36). Finally, metabolic alkalosis can shift the oxygen-hemoglobin dissociation curve to the left, impairing gas exchange (37).
Our findings contrast with some studies on the use of HTL in patients with acute heart failure (21), during cardiac surgery (38) and after coronary artery bypass grafting (39). In these studies, HTL was associated with improved cardiac performance (21, 38) and resulted in a negative fluid balance after surgery (39). These studies may have included patients whose lactate utilization was not impaired, as suggested by the decreased rather than increased blood lactate level 12 h (39) or 24 h after the HTL infusion (21). Recently, in a pig endotoxemia model, Duburcq et al. (3) showed that HTL infusion was associated with higher arterial pressure, cardiac output, and PaO2 than infusions of NS or hypertonic bicarbonate. However, an endotoxemia model does not reproduce sepsis well, and may result in better utilization of the exogenous lactate than in our model of peritonitis-induced septic shock. In addition, the study by Duburcq et al. (3) used HTL alone, fixed-dose fluid resuscitation, a hypodynamic rather hyperdynamic state and only 5 h of observation, all of which limit its extrapolation to the clinical context. Indeed, in our study, the successive peaks in blood lactate following each administration of HTL normalized more slowly, suggesting that lactate utilization was increasingly impaired over time. This may be a result of the sepsis process with altered expression and function of mono-carboxyl transporters impairing cellular uptake of lactate (40), decreased pyruvate dehydrogenase complex activity limiting glucose oxidation and promoting the conversion of pyruvate to lactate (41), and mitochondrial dysfunction impairing oxidative phosphorylation of pyruvate (42). Furthermore, sepsis causes abnormal microvascular oxygen transport because the impaired microcirculation cannot compensate for decreased functional capillary density (43). The resulting maldistribution causes a mismatch of oxygen delivery and oxygen demand (44), which further worsens liver oxidative phosphorylation and impairs lactate utilization (45).
Our study has some limitations. First, we used several boluses of HTL, and a continuous infusion may have different effects (21). Also, we cannot exclude the possibility that administration of HTL at different time points, especially when lactate utilization is not impaired, may have had a beneficial effect. Second, the animal model mimics the clinical features of human sepsis, but does not exactly replicate the human situation in which patients have various comorbidities and receive full vasopressor support and antibiotic treatment. Third, even though the observation period was relatively long, we cannot exclude longer term effects of hypertonic solutions. Fourth, the anesthetic regimen used to avoid suffering may have influenced the hemodynamic status, although this would have been the same for all animals so is unlikely to have influenced our results. Finally, we had to use some colloid solution in this model to limit edema formation, but we do not think the HES solutions will have significantly influenced the renal function in this acute setting, and all animals were similarly exposed to HES.
Not all hypertonic fluids are equally beneficial in septic shock. Administration of relatively small amounts of HTL resulted in earlier onset impaired tissue perfusion and a shorter survival time than similar infusions of HTS. The present observations raise concerns about the use of HTL in septic shock.
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