Lactate/pyruvate ratio as a marker of tissue hypoxia in circulatory and septic shock.
The aims of our study were to use the L/P ratio to assess the contribution of hypoxic and nonhypoxic causes to hyperlactataemia in patients with different shock states and to evaluate the evolution of lactate and the L/P ratio over time in patients with circulatory shock.
PATIENTS AND METHODS
The study was approved by the Ethics Committee of Erasme University Hospital. Informed consent was obtained from the relatives. During a four-month period, we prospectively included consecutive adult patients within four hours of the onset of shock, defined as initiation of catecholamine therapy. Septic shock was defined as sepsis-induced hypotension, persisting despite adequate fluid resuscitation, with the presence of hypoperfusion abnormalities or organ dysfunction. Cardiogenic shock was defined as acute myocardial disease requiring the use of vasoactive drug therapy for a systolic arterial pressure less than 90 mmHg and/or a cardiac index less than 2.5 l/minute/[m.sup.2], in the presence of a pulmonary artery occlusion pressure greater than 15 mmHg with resultant inadequate oxygen supply. Patients with diabetic and hepatic disorders and with a history of acute alcohol intake were excluded. Haemodynamic variables, arterial and mixed-venous blood gases, and arterial lactate and pyruvate concentrations were measured within the first four hours of shock and at four-hour intervals for 24 hours.
A control group of 10 patients without shock (normal lactate levels, mean arterial pressure >75 mmHg without vasopressor agents) and without infection, who were expected to spend more than 24 hours in the intensive care unit (ICU), were also enrolled. In these patients, lactate, pyruvate and the lactate/pyruvate ratio (L/P) were obtained only once, four to six hours after ICU admission.
To measure lactate and pyruvate concentrations, arterial blood samples (2 ml) were immediately deproteinised by the addition of iced perchloric acid (1 mmol/l) and the supernatants were frozen to -80[degrees]C. The samples were analysed within 48 hours of storage using the enzymatic method (GEM 1[degrees] 4000, mixed-model was used to evaluate the evolution of lactate and the L/P ratio over time. Lactate levels and the L/P ratio were analysed using receiver operating characteristic curves to evaluate their Instrumentation Laboratory, Lexington, MA, USA) and a spectrophotometer (UVIKON 930, Kontron CA067, Rotkreuz, Switzerland) with a fixed wavelength (340 nm). A quality control (standard pyruvate in distilled water) was performed for each measurement.
Data were analysed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA). Descriptive statistics were computed for all variables. A Kolmogorov-Smirnov test was used, and histograms and normal-quartile plots were examined to verify the normality of distribution of continuous variables. Continuous variables are expressed as mean [+ or -] SD or median [25th to 75th percentiles]. Differences between ICU survivors and non-survivors were assessed using Student's t-test and Mann-Whitney U test as appropriate. The analysis of repeated measurements with a sensitivity and specificity to predict mortality. For this purpose, an abnormal L/P ratio greater than 16 (the average of upper limit of normal values in other studies with non-shocked ICU patients (9,10)) was used. A P value less than 0.05 was considered significant.
Thirty-nine patients with shock were included during the study period; 26 had septic shock and 13 had cardiogenic shock (Table 1). The principal haemodynamic and biologic data on admission are shown in Table 2. In the control group, lactate concentration ranged from 0.6 to 1.1 mmol/l (mean 0.8 [+ or -] 0.2 mmol/l), pyruvate concentration from 0.06 to 0.16 mmol/l (mean 0.10 [+ or -] 0.02 mmol/l), and the L/P ratio from 6 to 10 (mean 8 [+ or -] 1).
At the onset of shock, 77% of patients had hyperlactataemia; this proportion decreased slowly over time, reaching 56% at 12 hours and 40% at 24 hours. Of these episodes of hyperlactataemia, 73% were associated with an increased L/P ratio at the onset of shock; this proportion remained relatively constant up to eight hours and then progressively decreased to 50% at 24 hours (Table 3).
Lactate levels (6.1 [3.7 to 7.8] vs 3.4 [1.2 to 4.4] mmol/l, P=0.02) and L/P ratios (24 [17 to 34]) vs 15 [10 to 19], P=0.01) at diagnosis of shock were significantly higher in non-survivors than in survivors (Figure 1). Evolution over time also differed between survivors and non-survivors (P <0.02), with lactate levels and L/P ratios rapidly decreasing in the survivors but remaining high in the non-survivors. The lactate level (6.8 [5 to 13] vs 5.3 [2.6 to 6.7] mmol/l) and the L/P ratio (33 [26 to 35] vs 22 [13 to 29]) were higher in the 7 (18%) patients who died during the first 24 hours of shock than in the 12 (30%) patients who died later in the ICU, but these differences were not statistically significant. Receiver operating characteristic curve analysis confirmed the association of elevated lactate levels and L/P ratio with a poor outcome, with AUCs of 0.72 and 0.73, respectively (Figure 2).
Differences between septic and cardiogenic shock
Individual lactate values and L/P ratios at onset of shock and after 24 hours are presented in Figure 3. All patients with cardiogenic shock had hyperlactataemia at the onset of shock; this proportion decreased to 82% at 12 hours and 50% at 24 hours (Table 3). Of these episodes, 9 (69%) were associated with a high L/P ratio at the onset of the shock; this percentage remained stable up to 12 hours and then decreased to 2 (40%) at 24 hours. In contrast, only 65% of patients with septic shock had hyperlactataemia at the onset of shock; this proportion decreased to 48% at 12 hours and then 35% at 24 hours. Of these episodes of hyperlactataemia in septic shock patients, 76% were associated with a high L/P ratio at the onset of the shock; this proportion remained stable up to 8 hours and then decreased to close to 50% at 12 and 24 hours.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
We observed that the L/P ratio was increased in many but not in all patients with septic and cardiogenic shock and that an elevated L/P ratio was associated with a poor prognosis. These observations suggest that hypoxia contributes to hyperlactataemia, especially in the early phases of shock, and that some patients may, therefore, benefit from further resuscitation efforts.
The L/P ratio is considered to be one of the most reliable indexes of hypoxia in critically ill patients911, but it has never been extensively used because of technical difficulties with measuring the L/P ratio. In patients with septic shock, Levy et al (10) reported that the L/P ratio was elevated but these results were somewhat driven by the large proportion (25%) of patients with refractory shock who died within 24 hours of admission. These results are in contrast with those of a study in children with septic shock, in which the L/P ratio was rarely increased and trends showed considerable variability, not related to patient outcome (12). Another study evaluating the L/P ratio (9), included 100 consecutive admissions to the ICU; hyperlactataemia was present in 50% of the patients on the first ICU day, but of the eight patients with septic shock only two (25%) had a high L/P ratio. Differences between studies may be, at least in part, related to the severity of disease on admission. The patients we studied were severely ill with seven patients dying within 24 hours of admission (15% of the septic shock patients and 25% of the cardiogenic shock patients).
[FIGURE 3 OMITTED]
In our cohort, 65% of septic shock patients had hyperlactataemia at shock onset and 76% of these simultaneously had high L/P ratios, suggesting a non-hypoxic cause for the hyperlactataemia in some patients, which could be explained by several mechanisms: First, Gore et [al.sup.6] demonstrated that pyruvate production increased in a sepsis-associated inflammatory state; second, muscle lactate production increases over time as the Na+K+ ATPase pump is activated in septic shock (8), and finally the pyruvate dehydrogenase complex is inhibited by endotoxin, thus inhibiting the movement of pyruvate into the Krebs cycle5. Therefore, although the incidence of hyperlactataemia decreased over time, the contribution of non-hypoxic causes will have increased, resulting in a decrease in the proportion of patients with a raised L/P ratio over time.
One hundred percent of our patients with cardiogenic shock had hyperlactataemia at shock onset and 69% of these had raised L/P ratios at shock onset. In cardiogenic shock, increased blood lactate concentration is mainly related to increased production, whereas lactate clearance is preserved13. The presence of inflammatory mediators may, in part, be responsible for this stimulation in lactate production14. We demonstrated that not only was the L/P ratio high at the onset of shock, but this ratio remained elevated during the first 12 hours of treatment compared to septic patients, in whom it decreased more rapidly. This observation may be explained by blood flow redistribution in the septic patients in whom hepatic blood flow declines rapidly and reduces the capacity of the liver to use lactate (14). Moreover, all our patients required administration of high doses of adrenergic agents, which can exert considerable metabolic effects, enhancing glycolysis and glycogenolysis and potentially influencing lactate and pyruvate levels.
Several authors (11,15,16) have reported that increased admission lactate levels and persistence of hyperlactataemia are associated with a poor outcome. There is less data on the prognostic value of the L/P ratio. The present study shows that patients with circulatory shock and increased lactate levels often have an elevated L/P ratio and that raised L/P ratios were associated with a poor outcome. The L/P ratio decreased over time and normalised in the majority of patients, especially in the survivors, although lactate levels remained elevated for a longer period of time in the same patients. Nevertheless, at 24 hours, the L/P ratio was still raised in almost 50% of the patients with circulatory shock and hyperlactataemia. However, use of a ratio of concentrations for two molecules that may have different metabolic properties during dynamic physiological states may complicate interpretation.
The study is limited to some degree by the small number of patients, but they were prospectively included and monitored. Measurement of the L/P ratio can be technically demanding. In the present study, we used a method of measurement that has been described previously (12). The samples were immediately put in ice and deproteinised; supernatants were then analysed by a spectophotometer after the different enzymatic reactions. Analyses were completed within a period of 30 minutes. A quality control was performed for each measurement and the L/P ratios we obtained in the control group (10 patients) were similar to those reported previously (9,10); therefore we believe our measurements were reliable.
The increased L/P ratio confirmed that hyperlactataemia is frequently due to hypoxia in patients with shock, especially at the onset. Nevertheless, there was considerable heterogeneity in the results, particularly in patients with septic shock, suggesting that hyperlactataemia was not just due to tissue hypoxia. Increased lactate levels and high L/P ratios were both associated with poor outcome.
(1.) Antonelli M, Levy M, Andrews PJD, Chastre J, Hudson LD, Manthous C et al. Hemodynamic monitoring in shock and implications for management. International Consensus Conference, Paris, France, 27-28 April 2006. Intensive Care Med 2007; 33:575-590.
(2.) zhang H, Rogiers P, De Backer D, Spapen H, Manikis P, Schmartz D et al. Regional arteriovenous differences in PCO2 and pH can reflect critical organ oxygen delivery during endotoxemia. Shock 1996; 5:349-359.
(3.) Eldridge F. Blood lactate and pyruvate in pulmonary insufficiency. N Engl J Med 1966; 274:878-883.
(4.) Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M et al. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med 1998; 157:1021-1026.
(5.) Vary TC, Siegel JH, Nakatani T, Sato T, Aoyama H. Effect of sepsis on activity of pyruvate dehydrogenase complex in skeletal muscle and liver. Am J Physiol 1986; 250:E634-640.
(6.) Gore DC, Jahoor F, Hibbert JM, DeMaria EJ. Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability. Ann Surg 1996; 224:97-102.
(7.) James JH, Fang CH, Schrantz SJ, Hasselgren PO, Paul RJ, Fischer JE. Linkage of aerobic glycolysis to sodium-potassium transport in rat skeletal muscle. Implications for increased muscle lactate production in sepsis. J Clin Invest 1996; 98:2388-2397.
(8.) Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet 2005; 365:871-875.
(9.) Suistomaa M, Ruokonen E, Kari A, Takala J. Time-pattern of lactate and lactate to pyruvate ratio in the first 24 hours of intensive care emergency admissions. Shock 2000; 14:8-12.
(10.) Levy B, Sadoune LO, Gelot AM, Bollaert PE, Nabet P, Larcan A. Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock. Crit Care Med 2000; 28:114-119.
(11.) Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 1970; 41:989-1001.
(12.) Dugas MA, Proulx F, de Jaeger A, Lacroix J, Lambert M. Markers of tissue hypoperfusion in pediatric septic shock. Intensive Care Med 2000; 26:75-83.
(13.) Revelly JP, Tappy L, Martinez A, Bollmann M, Cayeux MC, Berger MM et al. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med 2005; 33:2235-2240.
(14.) Chiolero RL, Revelly JP, Leverve X, Gersbach P, Cayeux MC, Berger MM et al. Effects of cardiogenic shock on lactate and glucose metabolism after heart surgery. Crit Care Med 2000; 28:3784-3791.
(15.) Trzeciak S, Dellinger RP, Chansky ME, Arnold RC, Schorr C, Milcarek B et al. Serum lactate as a predictor of mortality in patients with infection. Intensive Care Med 2007; 33:970-977.
(16.) Soliman HM, Vincent J-L. Prognostic value of admission serum lactate concentrations in intensive care unit patients. Acta Clin Belg 2010; 65:176-181.
R. RIMACHI *, F. BRUZZI DE CARVAHLO ([dagger]), C. ORELLANO-JIMENEZ ([dagger]), F. COTTON ([double dagger]), J. L. VINCENT ([section]), D. DE BACKER **
Department of Intensive Care, Erasme University Hospital, Universite Libre de Bruxelles, Brussels, Belgium
* MD, Fellow.
([dagger]) MD, Staff Member.
[double dagger] MD, Staff Member, Department of Clinical Chemistry.
([section]) MD, PhD, Head of Department.
** MD, PhD, Clinical Director.
Address for correspondence: Dr J.-L. Vincent, Department of Intensive Care, Erasme Hospital, Universite Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium. Email: firstname.lastname@example.org
Accepted for publication on February 6, 2012.
Table 1 Main characteristics of the study population Control, n = 10 Septic shock, n = 26 Age 55 [+ or -] 21 58 [+ or -] 19 Male, n (%) 6 (60) 17 (65) Main diagnosis/origin Cranial bleeding Lung 13 (50) of cardiogenic shock/ 10 (100) source of sepsis, n (%) Abdomen 7 (27) Urinary tract 5 (19) Other 1 (3) APACHE II score 12 [+ or -] 4 21 [+ or -] 8 SOFA score 6 [+ or -] 1 10 [+ or -] 3 ICU mortality, n (%) 1 (10) 15 (58) Cardiogenic shock, n = 13 Age 63 [+ or -] 21 Male, n (%) 6 (46) Main diagnosis/origin AMI 6 (46) of cardiogenic shock/ source of sepsis, n (%) Post-CPB 4 (31) Post heart transplantation 2 (15) Cardiomyopathy 1 APACHE II score 23 [+ or -] 4 SOFA score 12 [+ or -] 3 ICU mortality, n (%) 5 (38) AMI = acute myocardial infarction, post-CPB=post-cardiopulmonary bypass, APACHE = Acute Physiology and Chronic Health Evaluation, SOFA = sequential organ failure assessment, ICU = intensive care unit. Table 2 Principal haemodynamic and biological data on admission All patients, Survivors, n = 39 n = 21 Age, y 71 [+ or -] 11 57 [+ or -] 23 MAP, mmHg 69 (65-71) 71 (64-78) CI, l/min/[m.sup.2] 2.9 (2.4-4.7) 3.2 (2.4-4.7) APACHE score 26 [+ or -] 2 20 [+ or -] 6 SOFA score 12 [+ or -] 2 9 [+ or -] 2 Arterial pH 7.31 (7.25 [+ or -] 7.30 [+ or -] 0.13 7.40) [P.sub.a] C[O.sub.2], 34 [+ or -] 41 35 [+ or -] 12 mmHg Hb, g/dl 10 [+ or -] 2 10 [+ or -] 2 D[O.sub.2], ml/min/ 381 (289-560) 422 (328-521) [m.sup.2] V[O.sub.2], ml/min/ 120 (117-187) 126 (100-193) [m.sup.2] Dopamine, n (dose, 21 (14 [+ or -] 7) 13 (13 [+ or -] 6) g/Kg/min) Dobutamine, n (dose, 18 (14 [+ or -] 7) 7 (15 [+ or -] 6) g/Kg/min) Noradrenaline, n (dose, 15 (24 [+ or -] 11) 5 (36 [+ or -] 17) g/Kg/min) Lactate, mmol/l 4 (2.4-6.5) 3.4 (1.2-4.4) L/P ratio 19 (12-26) 15 (10-19) Non survivors, n = 18 Age, y 62 [+ or -] 16 MAP, mmHg 69 (69-75) CI, l/min/[m.sup.2] 2.6 (1.8-4.6) APACHE score 23.5 [+ or -] 7.7 SOFA score 12 [+ or -] 3 ** Arterial pH 7.20 [+ or -] 0.17 [P.sub.a] C[O.sub.2], 36 [+ or -] 6 mmHg Hb, g/dl 10 [+ or -] 2 D[O.sub.2], ml/min/ 302 (213-644) [m.sup.2] V[O.sub.2], ml/min/ 102 (85-140) [m.sup.2] Dopamine, n (dose, 8 (15 [+ or -] 8) g/Kg/min) Dobutamine, n (dose, 11 (13 [+ or -] 7) g/Kg/min) Noradrenaline, n (dose, 10 (30 [+ or -] 17) g/Kg/min) Lactate, mmol/l 6.1 (3.7-7.8) * L/P ratio 24 (17-34) ** Data are presented as mean [+ or -] SD or median (percentile 25 to 75). * P <0.05 and ** P <0.01, non survivors versus survivors. MAP = mean arterial pressure, CI = cardiac index, APACHE = Acute Physiology and Chronic Health Evaluation, SOFA = sequential organ failure assessment, Hb = haemoglobin concentration, D[O.sub.2] = oxygen delivery, V[O.sub.2] = oxygen uptake, L/P = lactate/pyruvate. Table 3 Proportion of patients with high lactate levels ([greater than or equal to] 2 mmol/l) and lactate/pyruvate (L/P) ratios ([greater than or equal to] 16) over time All patients 39 38 35 Hyperlactataemia 30 (77) 27 (71) 22 (63) Elevated lactate and L/P 22 (73) 17 (63) 16 (73) ratio Cardiogenic shock 13 13 11 Hyperlactataemia 13 (100) 12 (92) 9 (82) Elevated lactate and L/P 9 (69) 8 (67) 6 (67) ratio Septic shock 26 25 24 Hyperlactataemia 17 (65) 15 (60) 13 (54) Elevated lactate and L/P 13 (76) 9 (60) 10 (77) ratio All patients 34 30 Hyperlactataemia 19 (56) 12 (40) Elevated lactate and L/P 10 (53) 6 (50) ratio Cardiogenic shock 11 10 Hyperlactataemia 8 (82) 5 (50) Elevated lactate and L/P 5 (63) 2 (40) ratio Septic shock 23 20 Hyperlactataemia 11 (48) 7 (35) Elevated lactate and L/P 5 (45) 4 (57) ratio Data are presented as number (%) of patients with abnormal values.
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|Author:||Rimachi, R.; De Carvahlo, F. Bruzzi; Orellano-Jimenez, C.; Cotton, F.; Vincent, J.L.; De Backer, D.|
|Publication:||Anaesthesia and Intensive Care|
|Date:||May 1, 2012|
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