Release of Lactate by the Lung in Acute Lung Injury

Release of Lactate by the Lung in Acute Lung Injury* John A. Kellum, MD; David]. Kramer, MD; Kang Lee, MD; Sunil Mankad, MD; Rinaldo Bellomo, MD; and Michael R. Pinsky, MD

The pathogenesis of hyperlactatemia during sepsis is poorly understood. We have previously described an increase in lactate concentration across the lung in the dog during early endotoxemia. Accordingly, we sought to determine if the lung releases lactate in humans and what relation this has with lung injury. Methods: We measured lactate concentrations across the lung and lung injury scores (LIS) in two groups of patients. Group 1 consisted of nine patients with acute lung injury (LIS ~2.0) and elevated lactate concentrations (>2.0 mmoi!L). Group 2 contained 12 patients with no acute lung injury (LIS scores Sl.5), with or without increased lactate concentrations. Simultaneous measurements of plasma lactate and blood gases were obtained from indwelling arterial and pulmonary artery catheters. Measurements of cardiac output were also obtained. Lactate measurements were done using a lactate analyzer (YSI; Yellow Springs, Ohio). Results: For each patient with acute lung injury and hyperlactatemia, an arterial-venous lactate gradient existed demonstrating release of lactate by the lung. This gradient persisted after correction for changes in hemoconcentration across the lung. The mean lactate gradient across the lung was 0.4±0.2 mmoi!L for group 1 vs 0.05±0.1 mmoi!L for group 2 (p=0.001). This corresponded to a mean pulmonary lactate flux of 231.3±211.3 vs 5.0±37.2 mmol!h (p=0.001). The lactate flux and the arterial-venous lactate difference correlated with LIS both for the entire sample and for the subgroup with hyperlactatemia (r=0.69, p<0.01). Pulmonary lactate flux was not related to arterial lactate levels (r=0.25). Conclusion: In patients with acute lung injury and hyperlactatemia, the lung is a major source of lactate and lactate flux correlates with LIS. This lactate flux could explain some of the hyperlactatemia seen in sepsis. (CHEST 1997; 111:1301-05) Key words: acidosis; acute lung injury; lactate Abbreviations: ALI=acute lung injury; Hb=hemoglobin; LIS=lung injury score; SIRS=systemic inflammatory response syndrome

The pathogenesis of hyperlactatemia during the systemic inflammatory response syndrome (SIRS) is poorly understood. Yet lactate is often used clinically as a marker of anaerobic metabolism and is thus assumed to represent inadequate tissue perfuFor editorial comment see page 1157 sion. 1 -5 This hypothesis is supported by the high mortality seen in patients with hyperlactatemia 1•2 and by the disordered oxygen transport exhibited by patients with sepsis. 6 ·7 Many clinicians routinely use *From the Depa1tment of Anesthesiology and Critical Care Medicine, University of Pittsburgh Medical Center. Manuscript received April 16, 1996; revision accepted November 4. Reprint requests: Dr. Kellum, Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh Medical Center, 640 Scaife Hall, 3550 Te1Tace Street, Pittsburgh, PA 15213

therapies to improve global oxygen transport on the assumption that such treatment will reverse tissue dysoxia and ameliorate hyperlactatemia.8 •9 The belief that anaerobic glycolysis is primarily responsible for hyperlactatemia in SIRS persists in the clinical literature despite a growing body of evidence to the contrary. For example, direct measurements of cellular hypoxia using 3 1 P-MRI techniques in animal models of sepsis appear to show ample intracellular oxygen. 10 In human studies, tissue Po 2 actually increases with worsening sepsis, further challenging the notion that cellular hypoxia is the major pathophysiologic abnormality in sepsis.l 1 In clinical studies of patients with sepsis , increasing oxygen delivery often fails to decrease the serum lactate concentration8 and may even result in an increase. Moreover, serum lactate levels correlate poorly with systemic oxygen delivery.l 2 From where then, does the hyperlactatemia of CHEST/111 /5/MAY, 1997

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SIRS arise? Although the lung is not commonly considered as a source of lactate even in patients with acute lung injury (ALI) , over the past 25 years there have been reports of a positive lactate gradient across the lung in various disease states, 6 · 13 - 16 while no such gradient exists in normal subjectsJ7·18 We have previously described an increase in lactate concentration across the lung in the dog during early endotoxemia. 13 Accordingly, we sought to determine if the lung is a source of lactate release in humans with hyperlactatemia and to determine the relationship between lung lactate release and lung injury.

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]) . l[Hb] artena X

arterial [lactate])

Statistical comparisons were cartied out using Wilcoxon's rank sum test and correlations were tested for using Spearman's correlation test. A p<0.05 was considered statistically significant. All data were expressed as SD.

RESULTS MATERIALS AND METHODS After approval from our institution's biomedical investigational review board, 21 patients were evaluated. Patients were eligible for the study if they were admitted to an ICU, had pulmonary arterial and peripheral arterial catheters in place, and had at least one simultaneous arterial and mixed venous blood sample drawn. In all cases, this was done as part of a hemodynamic profile. In addition, patients were required to have a chest radiograph on the same day as the blood samples. Nine patients were found with clinical evidence of lung injury and arterial lactate levels >2.0 mmoVL. These patients composed the study group (group l ). In addition, 12 other patients without clinical evidence oflung injury but \vith varying atterial lactate levels were studied as a control group (group 2). Simultaneous arterial and mixed venous blood samples were obtained and analyzed for plasma lactate concentrations. These measurements were timed to coincide with cardiac output determinations using thermodilution. For patients in group l, a second arterial lactate measurement was made to determine the direction of the lactate level over time. Laboratory records for these 21 patients were reviewed (including arterial blood gas values, ventilator setting, and total respiratory compliance) and the chest radiographs were examined by investigators who were blinded to the results of the lactate determinations. Using these data, a Murray Lung Injury Scoret9 (LIS) was calculated and recorded for each patient. In group l (ALI), patients had ALI as defined by LIS 2:2.0 and also hyperlactatemia (serum lactate concentrations >2.0 mmoV L). There were nine patients in this group. Group 2 (control) consisted of 12 patients who had no ALI (LIS scores ~ 1.5 ), with or \vithout increased lactate concentrations.

Clinical data for the 21 patients are summarized in Tables l and 2. For each patient with ALI and hyperlactatemia (group l), an arterial-venous lactate gradient existed demonstrating release of lactate by the lung (Fig l). This gradient persisted after correction for changes in hemoconcentration across the lung. Arterial lactate levels were found to be increasing in six of nine patients in this group and stable in three patients. The mean transpulmonary lactate flux differed in each group (231.3 vs 5.0 mmol/h; p=O.OOl). The lactate flux and the arterial-venous lactate difference correlated with LIS both for the entire sample and for the subgroup with hyperlactatemia (r=0.69, p
DISCUSSION

The results of this study suggest that the lung is an important source of lactate during ALI in humans. These data also suggest that lung lactate release is related to the extent of lung injury. In these nine patients with ALI, the transpulmonary contribution to circulating lactate was approximately 200 mmol/h. This value is well in excess of what would be required to produce a significant increase in blood

Measurements and Calculations

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 five bolus injections of 5 mL of room temperature saline solution administered at random intervals in the respiratory cycle as calculated using a cardiac output computer (Siemens; Danvers, Mass ). Hemoglobin and hematocrit were measured, and serum blood lactate level was measured by the enzymatic method (YSI 2300 stat plus; Yellow Springs, Ohio). The transpulmonary lactate gradient was determined as the mixed venous [lactate ]-arterial [lactate]. Lactate flux is defined as the lactate gradient X flow (cardiac output). To avoid the confounding effects of changes in hemoconcentration on serum lactate levels, we further adjusted the calculation by using the 1302

Table !-Summary Data

n Age, yr Arterial lactate, mmoi/L Cardiac output, Umin LIS Lactate gradient, mmoi/L Lactate flux, mmol/h Adjusted lactate flux, mmol/h Survival,%

Group 1

Group 2

p Value

9 59 9.6::'::7.5 10.4::'::4.1 3.0::'::0.5 0.4::'::0.2 273::'::241 231::'::211 11.1

12 62 3.4::'::3.9 5.9::'::1.9 0.8::'::0.6 0.05::'::0.1 21::'::54 5.0::'::37 75.0

NS* 0.006 0.014 < 0.001 0.001 0.001 0.001 <0.001

*NS=not significant. Clinical Investigations in Critical Care

Table 2-Patient Data* Lactate, mmol/L n Group 1 1 2 3 4 .5 6 7 8 9 Group 2 1 2 3 4 5 6 7 8 9 10 11 12

Hb, g!dL

Diagnosis

Age, yr

Art

MV

Art

MV

LIS

Outcome

Sepsis Pneumonia Sepsis Sepsis Pneumonia Sepsis Sepsis Pneumonia Sepsis

36 74 51 60 66 69 41 78 .56

12.5 8.8 17.3 7.9 5.1 25.0 5.2 2.1 2.6

12.2 8.3 16.4 7.5 4.7 24.6 4.9 1.8 2.5

10.4 9.7 8.6 10.3 10.8 9.8 7.7 9.4 10.1

10.8 9.6 8.3 10.0 10.6 9.7 8.0 9.2 10.0

3.7.5 3.0 3.67 2.33 3.0 3.33 2.67 2.7.5 2.33

Died Di ed Died Died Died Died Died Survived Died

Sepsis Sepsis CABG CABG CABG Heart Tx CABG Sepsis MI Trauma Trauma UC 1 hlePd

.55 66 64 76 60 .54 62 66 37 64 70 68

2.0 15.4 1.1 1.8 1.9 2.9 4.3 4.3 2.1 1.5 2.1 3. 1

2.1 15.0 1.1 1.8 1.9 2.9 4.4 4.4 1.8 1.5 2.1 3.0

9.9 10.4 10.2 9.6 10.2 12.5 10.0 7.2 10.6 12.3 10.1 10.5

9.8 10.2 10.1 9.7 10.1 12.3 9.9 7.1 10.3 12.4 10.0 10 ..5

1.0 1..5 0 0 1.3 1.0 1.0 0 1.0 1.5 1.25 0.33

Survived Died Survived Survived Survived Survived Survived Survived Smvived Died SUJvived Died

*CABG=coronmy artety bypass graft; Tx=transplant; MI=myocardial inh1rction; UGI =upper GI; Art=mtetial; MV=mixed venou s.

lactate level, assuming a volume of distribution of 20 to 30 L in these patients. 20 Our finding of a positive transpulmonary lactate flux is consistent with reports by others 6 •14 - 16 and with our own animal study using an endotoxemia model. 13 However, these data are inconsistent with the traditional view that hyperlactatemia of critical illness is caused by an inadequate tissue perfusion

..... ~

0 E E

2

Group FIGUHE l. Histograms of the mean transpulmomuy lactate flux per hour for both gro ups (p=O.OOl ).

and anaerobic glycolysis. 2 •3 Still, it is possible that this mechanism may have been impmiant in many of these patients . The etiology of lung lactate release in ALI is unclear. It is unlikely that the lung parenchyma was hypoxic as these patients were closely monitored and only one patient exhibited an arterial Po2 of <60 mm Hg. However, it is possible that some areas of the lung were collapsed and potentially hypoxic. Alternatively, the lungs have the largest vascular endothelial surface in the human body. Injury to the endothelial cells in this vasculature may result in lactate release from either aerobic or anaerobic metabolism or from the inhibition of pyruvate dehydrogenase. This latter mechanism is known to exist in vitro 2 l ·22 and would be expected to lead to pyruvate and lactate accumulation in the cell, deranged oxidative phosphorylation, and the release of lactate into the circulation. Fmihermore, neutrophils are sequestered in the pulmonary circulation in ALI and they may also serve as a source of lactate release and increased lung 0 2 consumption. Interestingly, lung 0 2 consumption (0 2 consumption measured b y espiratory r gas analysis minus 0 2 consumption measured b ythe indirect Fick method) in patients with ALI has only recently been appreciated to be significant. In a dog model of ALI using pneumococcal pneumonia, Light 23 demonstrated CHEST I 111 I 5 I MAY, 1997

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600 500 400

.!: ~ E

300 200 100

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Lung Injury Score FIGURE 2. Relation between mean transpulmona1y lactate flu x and LIS (R= 0.69, p < O.Ol).

that the lung was responsible for up to 15% of whole body 0 2 consumption, whereas control animals without ALI showed no significant lung 0 2 consumption. Similarly, Myburgh and coworkers 24 showed a mean lung 0 2 consumption of 24 mUmin in 20 critically ill patients (mean APACHE [acute physiology and chronic health evaluation] II score of 29). More recently, Gill et al 25 demonstrated significant lung 0 2 consumption in patients with ALI . Nonspecific lung injury itself does not appear to produce any significant lung lactate release. Lee et aF 6 were unable to show lung lactate release using unilateral hydrochloric acid instillation in the dog. This may have occurred because of the heterogenous injury and the resultant decrease in perfusion to the injured segments. Alternatively, other mechanisms (such as pyruvate dehydrogenase inhibition) may be more important. Another approach has been to examine lung tissue lactate. In one study, lung slices from guinea pigs given endotoxin demonstrated lactate accumulation along with a decrease in lung adenosine triphosphate. 27 Finally, assessing transpulmonary lactate flux is complicated by the presence of the bronchial circulation, part of which drains to the pulmonmy veins, while the rest drains to the bronchial veins. 28 Bronchial circulation increases in ALI, 29 and is also affected by the alveolar pressures. 30 If this part of the bronchial circulation is not taken into consideration, lactate flux derived from arterial-mixed venous differences may underestimate the true amount of lactate release by the lung as a whole. Additionally, the thebesian veins that drain the left side of the heart would be expected to contribute some lactate to the arterial circulation, although the contribution in terms of total blood flow would be minuscule. Indeed, the very notion that a transpulmona1y lactate gradient represents lactate release by the lung is questionable. The lung might, in fact, be neutral to 1304

lactate and the rest of the body might be consuming the lactate and thus lowering the mixed venous concentration relative to arterial concentration. We consider this possibility to be unlikely in these patients because none showed decreasing lactate levels and six of nine showed an increase on repeated measurement. YVith lactate levels increasing, an increase in lactate content across the pulmonary circulation must represent lung release. Lastly, we examined plasma lactate levels and as such cannot exclude the possibility that exchange of lactate betvveen the RBCs and the plasma did not contribute to our findings . However, we are not aware of any mechanism whereby lactate would be expected to move out of the RBC on transit through the lung or why this would be related to the extent of lung injury. Furthermore, this mechanism could not explain the sustained hyperlactatemia observed in these patients. The results of this study should not be interpreted to show the magnitude of lactate release by the lung or as evidence of mechanism. Although the unadjusted lactate flux across the lung was very large in group 1 (43.2 to 864.0 mmol!h), it was based on relatively small arte1ial-venous gradients (0.1 to 0.9 mmol!L). Furthermore, these values were affected to varying degrees by hemoconcentration such that individual lactate gradients were altered by 15 to 67%. Although adjusting for hemoconcentration is theoretically more accurate (and did not affect the primary conclusions in this study), it does introduce further opportunity for error. Furthermore, at our institution, except for some routine corona1y artery bypass graph cases, the inclusion crite1ia for this study select a very ill patient population. Routine arterial and mixed venous blood samples are not obtained as part of our practice. As such, the patients included in this study represent a group of patients who were judged to be at high risk by the clinicians caring for them . Most of the patients in group 1 had arterial lactate levels in excess of 5.0 mmol!L. This factor alone predicts a mortality of > 70% in this population. 2 Accordingly, we are unable to estimate the prevalence of lung lactate release in patients with ALI. In conclusion, our study demonstrates that the pathogenesis of hyperlactatemia in critically ill patients with ALI is complex. In patients with lung injmy and hyperlactatemia, the lung can be a major source of lactate. In patients \vi.th lung injury, lactate release by the lung correlates with increased LISs.

REFERENCES

l Vitek V, Cowley RA. Blood lactate in tb e prognosis of various Forms of shock. Ann Surg 1971; 173:308-13 Clinical Investigations in Critical Care

2 Wei! MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatOty frulure (shock). Circulation 1970; 41:989-1001 3 Vincent JL, Dufaye P, Berre J, et a!. Serial lactate determinations during circulatory shock Crit Care Med 1983; 11: 449-51 4 Madias NE. Lactic acidosis. Kidney lnt 1986; 28:752-74 5 Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992; 20:80-93 6 Sayeed MM. Pulmonary cellular dysfunction in endotoxin shock: metabolic and transport derangements. Circ Shock 1982; 9:335-55 7 Rackow EC, Astiz ME, Wei! MH. Cellular m.:ygen metabolism during sepsis and shock: the relationship of oxygen consumption to oxygen delivery. JAMA 1988; 259:1989-93 8 Vincent JL, Dufaye P, Berre J, eta!. Serial lactate determinations during circulatory shock. Crit Care Med 1983; 11: 449-51 9 Fiddian-Green RG, Haglund U, Gutierrez G, eta!. Goals for the resuscitation of shock. Crit Care Med 1993; 2l:S25-31 10 Hotchkiss RS, Rust RS, Dence CS, et al. Evaluation of the role of cellular hypoxia in sepsis by hypoxic marker [18 F] fluoromisonidazole. Am J Physiol 1991; 26l:R965-72 11 Boekstegers P, Weidenhofer S, Kapsn er T , e tal. Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 1994; 22:640-50 12 Ronco JJ, Fenwick JC, Tweeddale MG, et al. Identification of the critical oxygen d elivery for anaerobic metabolism in critically ill septic and nonseptic humans. JAMA 1993; 270: 1724-30 13 Bellomo R, Kellum JA, Pinsky MR. Visceral lactate fluxes during early endotoxemia in the dog. Chest 1996; 110:198204 14 Strauss B, Caldwell PRB, Fritss HW Jr. Observations on a model of proliferative lung disease: I. Transpulmonary arteriovenous differences of lactate, pyruvate and glucose. J Clin Invest 1970; 49:1305-10 15 Bowles SA, Schlichtig R, Kramer DJ, etal. Arteriovenous pH and partial pressure of C0 2 detect critical m.ygen delivery during progressive hemorrhage in dogs. J Crit Care 1992; 7:95-105 16 Brown SD, Clark C, Gutierrez G. Pulmonary lactate release in patients with sepsis and ARDS. J Crit Care 1996; 11:2-8 17 Mitchel AM , Coumaud A. The fate of circulating lactic acid in

the human lung. J Clin Invest 1955; 34:471-76 18 Harris P, Bailey T, Bateman M, et al. Lactate, pyruvate, glucose and free fatty acid in mixed venous and arterial blood. J Appl Physiol 1963; 18:933-36 19 Murray JF, Matthay MA, Luce JM , et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:720-23 20 Woods HF, Connor H. The role of liver dysfunction in the genesis of lactic acidosis. In: Woods HF, Connor H , eds. Lactate in acute conditions. Basel: Karger, 1979; 102-14 21 Kilpatrick-Smith L, Erecinska M. Cellular effects of endotoxin in vitro: I. Effect of endotoxin on mitochondrial substrate metabolism and intracellular calcium. Circ Shock 1983; 11:85-99 22 Kilpatrick-Smith L, Dears J, Erecinska M, e t al. Cellular effects of endotoxin in t;itro: II. Reversibility of endotoxic damage. Circ Shock 1983; 11:101-11 23 Light RB. Intrapulmonary oxygen consumption in experimental pneumococcal pneumonia. J Appl Physiol 1988; 64: 2490-95 24 Myburgh JA, Webb RK, Worthley LIG. Ventilation/perfusion indices do not correlate with the difference between oxygen consumption measured by the Fick principle and metabolic monitoring systems in critically ill patients. Crit Care Med 1992; 20:479-82 25 Gill RS, Cunningham DC, Sharpe MD. Oxygen consumption in sepsis: contribution of the lung [abstract]. Am J Resp Crit Care Med 1994; 149:A414 26 Lee KH, Rico P, Ondulick BW, et al. Hydrochloric acidinduced lung injury is not associated with a positive lung lactate flux [abstract]. Am J Respir Crit Care Med 1995; 151:A761 27 Sayeed MM, Murthy PNA. Adenine nucleotide and lactate metabolism in the lung in endotoxin shock. Circ Shock 1981 ; 8:657-66 28 Deffebach ME, Charan NB, Lakshminarayan S, et al. The bronchial circulation: small, but a vital attribute of the lung. Am Rev Respir Dis 1987; 135:463-81 29 Deffebach ME, Lakshminarayan S, Kirk W, et al. Bronchial circulation and cyclo-oxygenase products in acute lung injury. J Appl Physiol 1987; 63:1083-88 30 Charan NB, Albert RK, Lakshminarayan S, et al. Factors affecting bronchial blood flow through bronchopulmonary anastomoses in dogs. Am Rev Respir Dis 1986; 134:85-8

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