Transvisceral Lactate Fluxes During Early Endotoxemia

Transvisceral Lactate Fluxes During Early Endotoxemia* Rinaldo Bellorrw, MD, FCCP; John A. Kellum, MD, FCCP; and Michael R. Pinsky, MD, FCCP

The pathogenesis of hyperlacticemia during sepsis is poorly understood. We investigated the role of lung, kidney, gut, liver, and muscle in endogenous lactate uptake and release during early endotoxemia in an intact, pentobarbital-anesthetized dog model (n= 14). Ultrasonic flow probes were placed around the portal vein and hepatic, renal, and femoral arteries. After splenectomy, catheters were inserted into the pulmonary artery, aorta, and hepatic, left renal, and femoral veins. Whole blood lactate and blood gases from all catheters, organ flows, and cardiac output were measured before and 30 to 45 min after a bolus infusion of Escherichia coli endotoxin (I mglkg). After endotoxin infusion, mean arterial blood lactate level increased from 0.92::!::0.11 to 1.60::!::0.15 mmoVL (p
Hyperlacticemia is a common finding in patients with sepsis and portends a poor prognosis. 1-3 Clinically, it is often used as indirect evidence of inadequate :issue ~erfusion as mani~ested by a~aerobic metabohsm. 1•4 - Although there IS no question that profoundly hypoxic tissue produces lactate, 8·9 there is little direct evidence that this mechanism occurs in patients with sepsis. Indeed, there is a growing body of evidence to suggest otherwise. 10-13 However, the belief that anaerobic glycolysis is largely responsible for hyperlacticemia persists in the clinical literature despite evidence that serum lactate levels correlate poorly with systemic oxygen delivery (Do2) 10 and findings in experimental models of sepsis that muscle either takes up lactate or is neutral to lactate flux. 11 More importantly, it is unclear if increased production or decreased *From the Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh MedicafCenter. Supported by a grant from the Veteran's Administration Medical Center and a research award from the Department of Anesthesiology and Critical Care Medicine. Manuscript received December 22, 1995; revision accepted March 14, 1996. 198

clearance of lactate is responsible for sepsis-associated hyperlacticemia and which organs, if any, are responsible for the increased lactate production. Accordingly, we sought to determine the anatomic location of either increased production or decreased clearance oflactate before and after the induction of acute endotoxemia in the dog. MATERIALS AND METHODS

Surgical Preparation

This study was approved by the Animal Care and Use Committee of the University ofPittsburgh Medical Center. After a 24-h fast, 14 male mongrel dogs (weight range, 18.2 to 21.6 kg) were anesthetized with pentobarbital sodium (30 mglkg IV). Each animal was intubated with a 9F cuffed endotracheal tube and ventilated (Siemens-Servo 900B; Selna, Sweden) at a tidal volume of 12 mUkg and a frequency sufficient to maintain an arterial Pco2 between 38 and 42 mm Hg. This was monitored continually by end-tidal C02 measures (Hewlett-Packard; Palo Alto, Calif). Arterial blood gases were periodically sampled, and arterial pH was maintained between 7.37 and 7.42 by IV infusion of NaHC03 as necessary. A 7F balloon-tipped pulmonary artery thermodilution catheter with a 15-cm proximal port (American Edwards model 93A-095; Irvine, Calif) was advanced into the pulmonary artery through the right Laboratory and Animal Investigations

external jugular vein. Placement of the proximal port in the right atrium was verified by waveform analysis of the pressure tracing, and placement of the tip in a pulmonary artery was verified by fluoroscopy. A 7F polyethylene catheter was advanced from the right external jugular vein into the left hepatic vein to a distance of approximately 3 em beyond the inferior vena cava under fluoroscopic guidance. A SF catheter with multiple side holes was inserted into the right femoral artery for measurement of arterial pressure. A 7F polyvinyl chloride catheter was inserted into the right femoral vein for continuous infusion of pentobarbital at 2 to 4 mglkg!h and measurement of lactate and blood gases from the lower limb. A splenectomy was performed after maximal splenic contraction to O.S mL of topical epinephrine (1:10,000). The splenic vein was cannulated with aSF polyethylene catheter that was passed into the portal vein to the level of the porta hepatis. The portal vein and the common hepatic artery distal to the takeoff of the gastroduodenal artery were isolated and ultrasonic flow probes (Transonic Systems; Ithaca, NY) were placed around each vessel. Care was taken to minimize dissection of the common hepatic artery to avoid disrupting the nervous sheath. The left renal artery was isolated, and an ultrasonic flow probe was placed around it. All flow probes were cemented into place using an agar gel mixture that minimized movement artifact and improved the acoustic signal. A SF polyethylene catheter was advanced through the left external jugular vein into the left renal vein at the level of the renal pelvis. The infrahepatic vena cava was isolated, and a hydraulic vascular occluder was placed around it for use in a parallel study. In six dogs, an ultrasonic flow probe was also inserted around the left femoral artery. The abdomen was loosely closed with interrupted sutures. All animals were fluid resuscitated with normal saline solution as necessary to maintain the right atrial pressure between 2 and S mm Hg. The conditions of the animals were allowed to stabilize. St11bility was defined as constant heart rate, arterial pressure, end-tidal C0 2, and organ flow signals for at least 30 min.

Experimental Protocol Before the administration of endotoxin and with the animal in a steady state, blood was collected from all catheters in heparinized syringes for the determination of blood gases, 0 2 content, hematocrit, and lactate. Apneic flows to organs were measured and recorded in real time on a strip-chart recorder (Gould Inc; Cleveland). Cardiac output was also measured. After obtaining control measurements, Escherichia coli endotoxin (L-2880 lipopolysaccharide; Sigma; St. Louis) (1 mglkg) was infused overS min via the right atrial port, and the hemodynamic response of the animal was monitored. Acute resuscitative efforts were avoided unless strictly needed. If necessary, a 4S-min bolus infusion of normal saline solution was administered and respiratory rate varied (1 animal only). Administration of NaHC03 was avoided. Thirty to 4S min after endotoxin administration with the dog in a hemodynamic steady state, repeated measurements of flows, cardiac output, blood gases, 02 content, plasma lactate, and hematocrit were made as during control conditions. In two dogs, malfunction of the pulmonary artery catheter thermistor did not allow for measurement of cardiac output. In two dogs, malpositioning of the portal vein catheter did not permit analysis of portal vein blood.

Measurements and Calculations Blood Oz saturation, Oz content, and hemoglobin concentration were measured using a co-oximeter calibrated for dog blood (Instrumentation Laboratories model282; Lexington, Mass). Blood gases and pH were analyzed using a blood gas analyzer (Radiometer ABL-30; Copenhagen, Denmark). Cardiac output was measured using the thermodilution technique and averaging measurements from S bolus injections of S mL of iced saline solution

administered at random intervals in the respiratory cycle as calculated using a cardiac output computer (American Edwards 9S20 A). Organ flow data were obtained from ultrasonic flowmeters calibrated ex vivo using a standard perfusion circuit as recommended by the manufacturer (Transonic Systems). Hematocrit was measured in duplicate, and whole blood lactate was measured by the enzymatic method (YSI 2300 stat plus; Yellow Springs, Ohio). The following formulas were used to calculate lactate fluxes: Lung:

Influx=cardiac outputxmixed venous [lactate] Efflux=cardiac outputxsystemic arterial [lactate] Kidney: Influx=2xleft renal artery flowxsystemic arterial [lactate] Efflux=2xrenal artery flowxrenal vein [lactate] Gut: Influx=portal flowxsystemic arterial [lactate] Efflux=portal flowxportal vein [lactate] Liver: Influx=(portal flowxportal vein [lactate])+(hepatic artery flowxsystemic arterial [lactate]) Efflux=hepatic vein [lactate]x(portal vein flow+hepatic artery flow) Transvascular visceral lactate flux for any organ represents the difference between influx and efflux. Organ Doz, 02 consumption (Vo2), and Oz extraction (Eoz) were calculated using organ inflows and outflows and 0 2 content as in the following example: Liver DOz= (hepatic artery flowxarterial 02 content)+(portal vein flowxportal vein Oz content) Liver Vo2 = Liver Doz-(hepatic vein Oz contentxsum of portal vein and hepatic artery flows) Liver EOz= Voz/Doz (expressed as percentage of Do2 ) Because we measured whole blood lactate, changes in hemoconcentration could potentially confound the results. To account for this, we further adjusted the flux calculation by using the hemoglobin (Hb) concentration to standardize the lactate content in each blood sample. This was done as follows: Adjusted lactate gradient= (arterial [lactate]-venous [lactate])(arterial [Hb]-venous [Hb]) . ) xartenal [lactate] arterial [Hb] ( Statistical comparisons were carried out using analysis of variance and correlations were tested for using Spearman's correlation test. A p
Systemic Do2 decreased from control conditions (485±52 mUmin to 309±31 mUmin; p<0.001), due to a reduction in cardiac output. Systemic Vo2 remained unchanged between conditions (143 ± 13 mU min to 134± 15 mUmi.n; NS), thus resulting in an increase in systemic Eo2 (31.5±3% to 46.8±5%; p<0.001), and the mean arterial pressure fell from 110.3±8.2 to 60.5±5.3 mm Hg (p<0.0001). Arterial lactate levels increased during acute endotoxemia (0.94±0.12 to 1.6±0.15 mmoVL; p<0.01) with a median change of0.64 mmoVL (range, 0.06 to 0.975). The inverse correlation between systemic Do2 and arterial lactate concentration found during control (p
199

0

rz- 0.67 0

2.5 1.5

0

Arterial [lactate] (mmol I L)

0

Arterial [lactate] (mmol I L)

0

2

0

0

0

l.S

0

o.s

0

0

c 0

P<0.001

os+-------r------.------.-----~

§

OXYGEN DELIVERY (ml I min)

OXYGEN DELIVERY (ml I min)

FIGURE l. Relation between systemic Doz and arterial blood lactate concentration before (left) and after (right) endotoxin infusion. There is a significant inverse correlation between Doz and arterial blood lactate before but not after endotoxin.

(p
uptake during control; however, a strong correlation between mesenteric Voz and lactate uptake was demonstrated after the infusion of endotoxin (Fig 3). There was no measurable uptake or release of lactate in the liver during either control or endotoxemia despite an endotoxin-induced decrease in hepatic Do2 and increase in both hepatic Voz and Eoz. Furthermore, no correlation was found between hepatic lactate flux and hepatic Do 2 , Vo2, or Eoz. Lactate fluxes in the hind limb were studied in six animals. Endotoxin infusion was associated with a decrease in limb Do2 and an increase in limb Eo2. Trans muscular lactate flux, however, remained neutral

rz- 0.591

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2.5 l.S

0

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0 0

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Arterial [lactate) (mmol I L)

0

Arterial [lactate) (mmoll L)

0

o.s

0

0

0

0

I.S

0 0

0

o+------,-------.------r------i

'"

OXYGEN CONSUMPTION (ml I min)

OXYGEN CONSUMPTION (ml I min)

2. Relation between systemic Vo2 and arterial blood lactate levels during control conditions (left) and during endotoxemia (righ~)- There is a strong positive correlation between increasing blood lactate concentration and increasing Vo2 during endotoxemia, but none dming control (p<0.002). FIGURE

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in this resting muscular bed and did not correlate with limb Do2, Vo2, or Eo2 during control or after endotoxin infusion. The selective contributions of the observed viscera and muscular beds to circulating endogenous lactate during control and endotoxemia conditions are summarized in Figure 4. Lactate influx and efflux in the lungs were similar during control; however, during endotoxemia, lung lactate efflux exceeded influx (p<0.05) at a net mean lactate release of 10.87:±:4.81 mmol!h. These results were consistent among animals; 10 of 14 (71%) either increased lactate release or decreased uptake across the lung following administration of endotoxin. Five animals actually switched from uptake of lactate (12.9 mmol/h) to release (16.6 mmol!h). The details of transpulmonary release of lactate are shown in Table 2. DISCUSSION The results of our study suggest that the lung is an important source of lactate during early endotoxemia in the dog. The transpulmonary contribution to circulating lactate is on the order of 10 mmol!h within the first hour after induction of endotoxemia. This contribution is sufficient by itself to account for the observed increase in blood lactate level, if one assumes a lactate volume of distribution of approximately 8 Lin a 20-kg dog.14 Our finding of a positive transpulmonals lactate gradient is consistent with reports by others 5 •16 and with recent preliminary evidence of a transpulmonary increase in lactate concentration in humans with ARDSPJS These data, however, are inconsistent with the concept that the hyperlacticemia of sepsis is caused by an inadequate tissue perfusion-induced oxygen debt and anaerobic glycolysis. 4·7 In fact, it appears unlikely that pulmonary endothelium would be experiencing significant anaerobic stress because alveolar Pa02 was greater than 150 mm Hg and mixed venous oxygen saturation was greater than 30% at all times. Endothelial cell injury could potentially result in cellular, structural, and functional damage and histotoxic hypoxia. The ability of endotoxin to induce destruction and denudation of arterial endothelium has been documented previously. 19·20 To our knowledge, however, no data are available on the structural changes that may develop in the pulmonary vasculature during early endotoxemia. 16-21 In vitro studies indicate that cell dysfunction occurs within minutes of exposure to endotoxin and that a major functional derangement involves the inhibition of pyruvate dehydrogenase activity.22·23 This inhibition would lead to pyruvate and lactate accumulation in the cell, deranged oxidative phosphorylation, and the spillage of excess lactate into the circulation. That this mechanism may be operating and important in vivo is supported by

s,-------------------------------; 0

4

Gut lactate uptake 2 (mmol I h)

o

Gut oxygen consumption (ml /min)

3. Relation between Vo2 in the gut _during control (circles) and during endotoxemia. Increased gut Vo2 is associated with increased lactate uptake by the gut (p
human and experimental data 11 •24·25 on the effect of dichloroacetate (a pyruvate dehydrogenase activator) in sepsis. If this is indeed the major mechanism responsible for hyperlacticemia during sepsis, then the more severe the cell dysfunction, the higher the serum lactate level will be and the worse the prognosis, independent of either global or regional Do2. According to this scenario, hyperlacticemia would be a marker of illness severity but not necessarily of inadequate tissue perfusion. Interestingly, our data support an even more complex view of the pathogenesis of endotoxin-induced hyperlacticemia (Fig 4). Lactate is taken up by both canine gut and kidney during control and during acute endotoxemia. This occurs despite a significant decrease in regional Do2 and blood flow to these organs during endotoxemia. This lactate uptake is insufficient

E

0 E E

Lung

Kidney

Gut

Liver

Muscle

Frcu~E 4. Histogram showing lactate fluxes across lung, kidney, gut, liver, and muscle during control conditions (hatched bars) and during endotoxemia (solid bars). The value for muscle is an estimate of total body muscle contribution (hind limb flux x5).

CHEST /110/1/ JULY, 1996

201

Table 1---0rgan Do2, Vo2, Eo2, and Lactate Fluxes During Control and Endotoxic Conditions* Kidney Control Do2,

mUmin \ 7o2,

mUmin Eoz, % Organ flow, mUmin Lactate gradient, mmol!L Lactate flux, mmollh

Gut

Endotoxin

41.2::'::7.3

33.3::'::7.3 NS

6.9::'::1.7 9.3::'::2.5 p <0.001 15.4::'::2 27.6::'::4 p<0.005 91::+::20 141 ::'::44 NS -0.14::+::0.03 -0.26::'::0.05 NS -2.7::+::1.2 -3.18::':: 1.8 NS

Control

Liver Endotoxin

38.9::+::8.3 49.4::'::6.5 p<0.05 9.9::':: 1.4 11.4::'::0.7 NS 21.9::'::3 35.3::'::4 p<0.007 243::'::28 197 ::'::33 NS -0.13::'::0.04 -0.22::+::0.06 NS -1.44::+::0.48 -2.46::+::0.6 NS

Control

Hind Limb Endotoxin

60.8::+::11.5 43.2::':: 10.1 p<0.02 11.4::'::2 12.2::'::3.3 NS 21.5::'::3.6 32.1::'::4.9 p<0.02 316::+::42 1 279::'::57 1 NS

Control

Endotoxin

7.4::'::1.2 3.3::'::1.3 p<0.02 3::':: 1.4 2.4::':: l.l NS 39.9::+::18.6 72.6::'::13.6 p<0.02 39::'::3 15::'::1

p
-0.05::'::0.1 NS

0.24::'::0.12

0.06::'::0.12 NS

-0.42::'::0.24

-0.18::'::0.2 NS

No lactate gradient data can be shown for the liver since both hepatic artery and portal vein lactate must be considered along with their flows. Gradient refers to venous concentration-arterial concentration, ie, a positive gradient indicates release. Flux refers to outflow concentrationxoutflow-inflow concentrationxinflow. A negative flux indicates uptake . 1"Liver flow" refers to hepatic vein flow~hepatic artery flow+ portal vein flow. *NS~nonsignificant.

to balance the increased lactate released from the lung. In part, this imbalance is accentuated by the endotoxin-associated decrease in gut and kidney blood flows , minimizing the expected increase in gut and kidney lactate influx that would otherwise occur in the presence of a doubling in serum lactate concentrations. Furthermore, our data demonstrate that both gut and kidney continue to take up lactate when organ Do2 is markedly diminished and that such lactate uptake correlates closely with organ Vo2 in both cases. These data are consistent with the metabolic model that regards lactate as an obligatory substrate of oxidative phosphorylation. Increases in blood lactate levels should then occur not only as a result of pyruvate dehydrogenase inhibition but also as part of the mechanisms by which injured cells improve their bioenergetics at a time of stress. This view is sur£orted by studies in isolated muscle preparations, · -28 which show intracellular lactate accumulation in the absence of 02-limited respiration, with accumulation propor-

tional to Vo2 and the cytosolic redox state. 29 These studies suggest that the aerobic increase in cell lactate and the associated changes in the reduced form of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide (NADHINAD ) can influence mitochondrial NADH/NAD to support oxidative phosphorylation as the dominant source of adenosine triphosphate. This may occur either by the enhanced availability of NAD in the cytosol or by increasing the substrate supply or both. We did not measure redox state in the present study. In another potential mechanism, lactate is a substrate for gluconeogenesis under stress. 30 ·31 In support of this mechanism, lactate oxidation is markedly increased during sepsis, becoming the major substrate supplfng 25 to 50% of the body's oxidative metabolism3 and participating actively in the increased gluconeogenesis of sepsis. 33 Our study design and data do not allow us to differentiate between these two mechanisms. Furthermore, because we examined the

Table 2-Lung Lactate Flux* Condition

Lactate Arterial

Lactate Mixed-Venous

Lactate Gradient

Corrected Lactate Gradient

Control Endotoxemia p value

0.94::+::0.12 1.61::'::0.15 0.002

0.95::'::0.11 1.52::'::0.13 0.003

-0.02::'::0.03 0.09::'::0.05 1 0.067

-0.04::'::0.04 0.09::'::0.05 1 0.041

Condition

Cardiac Output

Lactate Flux (per Hour)

Corrected Lactate Flux (per Hour)

Control Endotoxemia p value

2.46::'::0.24 1.63::'::0.16 0.008

-3.15::'::4.34 10.87::'::4.81 1 0.04

-6.6::'::5.82 8.86::'::4.11 0.04

*Lactate measurements are in mmol!L. The lactate gradient is the difference between arterial and mixed-venous concentrations. The corrected lactate gradient is corrected for the difference in he moconcentration (see text). Hourly, lacate flux is obtained from the gradientxcardiac outputx60. The corrected flux uses the corrected gradient. The p values shown are for the difference between control and endotoxemia conditions (analysis of variance). 1For the gradients and fluxes, this denotes a difference from zero (p <0.05). Cardiac output is expressed in Umin.

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Laboratory and Animal Investigations

immediate effects of endotoxemia on metabolism, if established sepsis induced more gradual changes in cellular metabolism, they could not be predicted from our results. However, studies on sepsis in the rat suggest that cellular bioenergetics are not primarily altered by time. 34 The liver is considered a major organ responsible for blood lactate clearance. This view is supported by the hyperlacticemia of severe liver disease and by the documentation of arterial to hepatic vein blood lactate gradients. 35 These latter data, however, assume the gut to be lactate neutral, which our study questions. In support of this hypothesis, however, clearance studies using exogenous radiolabeled lactate infusions demonstrate its uptake by the liver. Studies utilizing severe hypoxia9 or phenformin36 have documented lactate release from the gut and decreased uptake by the liver. Our findings do not support the belief that the liver is a major clearing organ at the (low) lactate levels seen in our animals. Our data are consistent with those of others who demonstrated that, over a wide range of hepatic Do2, the liver does not take up lactate.37 We studied muscle lactate fluxes in six dogs. Our findings of no lactate production by the muscle during early endotoxemia are consistent with other studies of muscle metabolism during early endotoxemia or other stress situations in the dog. 38•39 In a previous study, van Lambalgen and colleagues40 were unable to demonstrate lactate release by the lung or lactate uptake by the gut and kidney. They used a larger dose of endotoxin, smaller numbers of animals, and were more likely to experience a type II statistical error. It is important to consider the findings of the current study as representative of a particular experimental model of sepsis. Endotoxin infusion induced a decrease in cardiac output and blood pressure in our animals (hypodynamic model of sepsis). No IV fluids were administered during the 30- to 45-min experiment and endotoxin was infused into the right atrium, and thus immediately reached the pulmonary vascular bed. It is unknown how this model relates to human sepsis. Patients who develop Gram-negative bacteremia are likely to experience similar pathophysiologic derangements before resuscitative efforts. In other patients, especially those with an intra-abdominal focus of sepsis or those who receive immediate and aggressive fluid resuscitation, pathophysiologic changes are likely to be different. Therefore, while consistent with preliminary clinical reports,l1.1 8 clinical extrapolations from our findings must be interpreted with caution. An additional note of caution is required regarding the size of the effect we have seen. While the transpulmonary lactate flux (with or without adjustment for hemoconcentration) is quite large (roughly 10 mmol!h), the actual lactate gradient across the lung is

very small (approximately 0.1 mmoi!L) and approaches the limits of accuracy of the assay. Although theoretically more correct, additional inaccuracy is introduced by adjusting the lactate levels by the change in Hb concentration. For this reason, we have presented the data both with and without adjustment (Table 2). In conclusion, our study demonstrates that the pathogenesis ofhyperlacticemia during early endotoxemia is complex. The lung becomes the primary contributor of lactate to the circulation. The gut and kidney continue to take up lactate but fail to adequately match .their uptake with the near doubling in serum concentration because their blood flows do not increase proportionately. The liver and muscle remain lactate neutral during acute endotoxemia. The lack of correlation between Do2 and organ lactate uptake or release during endotoxemia makes global organ hypoperfusion alone an improbable single explanation for the hyperlacticemia of sepsis. However, the correlation between Vo2 and lactate uptake by the kidney and gut (the two major organs taking up lactate) suggests that lactate may be both an important and useful fuel during cell stress, and a sensitive but nonspecific marker of stress. Globally, these findings challenge a simplistic view and a single theory for the hyperlacticemia of sepsis. ACKNOWLEDGMENTS: Brian Ondulick, BA, gave technical assistance. REFERENCES

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Laboratory and Animal Investigations