The oxygen supply dependency phenomenon is associated with increased blood lactate levels

CLINICAL

COMMENTARY

The Oxygen Supply Dependency Phenomenon Is Associated With Increased Blood Lactate Levels Jan Bakker and Jean-Louis

U

NDER PHYSIOLOGIC conditions, an organism is capable of maintaining oxygen consumption (VO,) even when oxygen delivery (DO,) to the tissues is decreased. This is accomplished by an increase in the VO, to DO, ratio, ie, oxygen extraction (0,ER). On the other hand, an increase in oxygen demand of the tissues can be met by a combined increase in DO, and 0,ER in physiologic conditions.’ In patients with limited cardiac pump function, the increase in VO, during exercise is met chiefly by an increase in 0,ER.’ Whenever the metabolic demand of the cells exceeds their oxygen availability, aerobic metabolism is jeopardized and anaerobic metabolism occurs, resulting in an increase in blood lactate levels.2~3Hence, an imbalance between oxygen demand and supply is characterized by the oxygen uptake/supply dependency phenomenon and by the development of lactic acidosis. The following analysis of both experimental and clinical studies supports this logical concept. EXPERIMENTAL

STUDIES

Various experimental studies have indicated that VO, could be maintained when DO, is acutely decreased. However, when DO, decreases below a critical value (DO,-crit), the increase in 0,ER becomes surpassed so that a further reduction in DO, will result in a reduction in VO,. In 1965, this oxygen uptake/supply dependency phenomenon was described by Cain4 during acute reductions in DO, induced by severe hypoxemia or anemia. Other investigators observed similar findings when cardiac output was acutely reduced.5,6 The DO,-crit has

From the Depatiment of Intensive Care, Erasme Hospital, Brussels, Belgium. Received April 27, 1991; accepted May 7, 1991. Address reprint requests to Jean-Louis fincent, Department of Intensive Care, Erasme University Route de Lennik 808, B-1070, Brussels, Belgium. Copyright o 1991 by W.B. Saunders Company 0883-9441 I91 /0603-0007$05.00/O 152

University

MD, PhD, Hospital

Vincent

been found to be similar, with severe hypoxemia, anemia, or reduced cardiac output.‘,* A fundamental observation in all of these studies4-l2 is that the blood lactate levels start to rise as soon as the DO,-crit has been reached, illustrating the development of anaerobic metabolism associated with tissue hypoxia. The effects of sepsis were studied specifically by Nelson and colleagues on a dog model of progressive hemorrhage.6.9,‘3 These investigators demonstrated a greater susceptibility of these animals to the reduction in DO, after the administration of either live Pseudomonas aeruginosa6 or endotoxin,y.‘3 as indicated by a significantly higher DO,-crit. At this DO,-crit level, the 0,ER was also significantly lower than in the control experiments. Again, the blood lactate levels started to rise as soon as the DO,-crit was reached. In several studies using a low-resistance dog model of endotoxic shock characterized by lactic acidosis, we observed that the increase in DO, following the administration of intravenous fluids and various vasoactive agents is associated with an increase in V0,.14-‘8 Thus, in experimental studies on various types of acute circulatory failure, the VO,/DO, dependency phenomenon is associated with elevated lactate levels. CLINICAL

STUDIES

The procedures described above are rarely performed in critically ill patients. In particular, an acute decrease in DO, is difficult and often unethical in these patients. In patients undergoing cardiac surgery, Shibutani, Komatsu, and colleagues’9~20lowered DO, by progressively decreasing the bypass pump flow, and observed that a reduction of DO, below 330 mL/min/m’ was associated with a fall in VO, and a simultaneous rise in blood lactate. In patients with low cardiac output, an elevation in blood lactate levels can be related to the reduction in D0,.2’ Rashkin et al’* reported that in critically ill patients, an increase in blood lactate levels JournalofCriticalCare,

Vol6,

No 3 (September),

1991: pp 152-159

OXYGEN

SUPPLY

DEPENDENCY

AND

BLOOD

LACTATE

153

correlated with a fall of DO2 below 8 mL/kg/ min. Few of the reported clinical studies investigating the relationship between DO, and VOz documented patient blood lactate levels. However, those that did report these levels could usually correlate the VOJDO, dependency with increased blood lactate levels. The strongest element relating the VOJDO, dependency phenomenon to an elevation in blood lactate levels stems from studies evaluating the effects of an increase in DO, separately in patients with and without lactic acidosis (Table 1). Specifically, Haupt et al’” studied the effects of fluid administration and observed that elevated blood lactate levels predicted an increase in VO, in response to the increase in Doz. In addition, in septic patients, Gilbert et alz4 observed that an increase in DOZ, induced by fluid loading or blood transfusion, increased VO, significantly only in patients with lactic acidosis. These reporters also studied the effects of catecholamines in 17 patients treated with various doses of dopamine and dobutamine and observed that VO, increased in all patients. However, it increased from 133 +- 32 mllminlm to 165 -+ 37 mL/ min/m” in patients with lactic acidosis and only from 126 2 35 mL/min/m2 to 134 + 45 mL/ Table

1. Relationship

No. of Patients

SOUrCe

Shibutani

et all9

58

Kaufman

et a?

13

Between

Haupt

et aF3

20

Septic Septic

shock shock

Gilbert

et al”

54

Septic

shock

a

Annat et al” Astiz et a14’

Change in DO,

Yes

increased

Yes

(n = 8)

Fluids Fluids

Increased Increased

(n = 8)

Yes Yes

Normal

(n = 6)

No

Fluids Blood

Increased Increased

(n = 14) (n = 10)

Yes Yes

Normal Normal

(n = 6) In = 7)

No No

Increased

(n = 7)

Yes

Normal Normal

(n = 10)

Yes No

ARDS

73

Heartfailure

Kruse et aP* Vincent et alG9

58

Sepsis (n = 37) ARDS Septic shock

Fenwick Bollaert

24

Abbreviations: DO,-crit, critical

CAEG, coronan/ DO, below which

Fluids,

shock artery supply

agents

Increased

(n = 36)

inotropes

NO

Yes

Nitroglycerin

CABG

ARDS Septic

transfusion

Adrenergic PEEP Fluids

Normal

SUPPlY Dependency

Increased

Vincent

13

Blood Lactate

Fluids

Septic shock Chronic CHF

ia

QPPb Dependency

Including

Pump-flow

10 8 66

et al” et al6’

Blood Lactate

Studies

shock

Mohsenifar et a13’ Komatsu et aPO et alzs

Oxygen Uptake and Oxygen Supply in the Clinical Measurements of Blood Lactate Levels

Diagnosis

CABG Hypovolemic (n = 5)

min/m’ in patients without lactic acidosis. Gilbert et al attributed these constant observations to an increase in oxygen demand induced by the stimulating effect of catecholamines on cellular metabolism. Vincent et al”” evaluated the effects of a limited but fixed dose of dobutamine (5 Fg/kg/min) in 73 patients with either heart failure or sepsis. In the two subgroups of patients, they observed an increase in VOz only in those patients with elevated blood lactate levels associated with signs of acute circulatory failure. Mathru et a12”also observed that dobutamine at a dose of 5 kg/kg/min did not increase VO, in stable, pneumectomized patients. Fenwick et al” studied the effects of blood transfusion in patients with adult respiratory distress syndrome (ARDS), and also observed an increase in VO, only in patients with elevated blood lactate levels. Recently, Kruse et al’” reported similar findings when DO: was altered by fluid infusion, blood transfusion, or appiication of positive end-expiratory pressure. On the other hand, Annat et all9 observed that VO, was independent of DO? in ARDS patients without lactic acidosis. These studies thus concur that the VOJDO, dependency is observed in patients with, but not in those without, lactic acidosis.

Normal

Yes

Increased

(n = 22)

Yes

Normal

In = 44)

Dobutamine

Increased

(n = 8)

Yes

Normal

(n = 28)

No, above DO,-crit No

Dobutamine Fluids, PEEP Dobutamine Blood transfusion

Increased Increased Increased Increased

(n = 16) (n = 32)

Yes Yes Yes

Normal Normal

(n = 21) In = 26)

No No

(n ~13)

(n = 11)

No

Increased

Yes Yes

Normal

Epinephrine

bypass grafting; ARDS, adult respiratory distress dependency occurs; PEEP, positive end-expiratory

syndrome; pressure.

CHF, congestive

heart failure;

154

BAKKER

Table

2. Changes

in VO, Associated

With

an Increase in DO, Secondary to the Administration Patients Without Suspected Oxygen Debt

No. of Source Chappel

Gore and Sloan” Brent et aP2

Pulmonary Hypertension Heart failure

Hydralazine, Nitroprusside,

? 6 8

Heartfailure COPD

Milrinone Hydralazine

No change No change Increases

Heart failure ARDS Pulmonary Hypertension

Nitroglycerin Prostacyclin

Increases No change*

14 11

Richard et al% Radermacher et aF

6 9

Abbreviations:

COPD,

Calcium channel ACE inhibitor Prostacyclin

Heartfailure ARDS

chronic

obstructive

patients

with

suspected

pulmonary oxygen

disease;

nifedipine hydralazine,

ARDS,

adult

in

Effect on ‘JO,

26 9

Mohsenifar et aP” Bihari et a14’ Mohsenifar et aP1

converting enzyme. *VO, increased in other

Vasodilators

Drug Administered

Diagnosis

et aP’

of Intravenous

AND VINCENT

No change minoxidil

antagonists

Increases No change* No change

respiratory

distress

syndrome;

ACE,

angiotensin

debt.

It could be argued that the VOJDO, dependency phenomenon has been observed also in relatively stable patients with congestive heart failure,3o pulmonary hypertension3’ chronic obstructive pulmonary disease,32 or sleep apnea syndrome, 33in whom blood lactate levels were expected to be normal. Four general comments could be made. First, the blood lactate levels were not determined in all of these patients, so this issue cannot be completely resolved. Only in one study were the blood lactate levels measured. Second, methods of evaluation can be subjected to scrutiny, as some investigators argued that the VO,/DO, dependency phenomenon could be due to mathematic coupling of data but was otherwise not observed in stable individuals.34,35 Third, the time interval in some studies has been quite variable and sometimes prolonged to 24 hours36.37or simply undefined.3x Peak values of cardiac index over several measurements also have been used.3o All of these factors enhance the chance of repeating measurements when the patient’s condition and thus the oxygen demand has changed. Serial determinations of DO, and VO, could indicate an apparent VO,/DO, dependency in normal or stable individuals, because changes in oxygen demand are normally associated with concurrent changes in oxygen s~pply.~~ Fourth, and perhaps most important, the method used to increase DO, could increase the cellular oxygen demand by sympathic activation. This could be the case with passive leg raising32,4oand especially with drugs having vasodilating properties. Table 2 presents the clinical studies in which

such vasodilating agents were used in patients without suspected oxygen debt. In these patients, an increase in VO, was observed in some studies29”1but not in others.36,37,41-43 These discrepant findings were not clearly related to differences in patient populations. UNIFYING

HYPOTHESIS

The VO,/DO, dependency phenomenon does not seem to be related to a particular disease state, but is rather a hallmark of acute circulatory failure. These elements, schematized in Fig 1, can serve as a basis to account for all abnormalities associated with acute circulatory failure (shock). Hypovolemic, cardiogenic, and obstructive types of shock are characterized by an acute reduction in DO,, while the extraction capabilities of the tissues are maintained. In

L-~---

---__-

______.

02 DELIVERY Fig 1. The oxygen uptake/supply dependency phenomenon characterizes all types of acute circulatory failure (shock). In cardiogenic, hypovolemlc, and obstructive types of shock, 0, delivery is markedly reduced, but the 0, extraction capabilities are maintained. Septic shock is characterized by an increase in OJ demand, a reduction in the Oz extraction capabilities, and a reduction in myocardial performance.

OXYGEN

SUPPLY

DEPENDENCY

AND

BLOOD

LACTATE

contrast, septic shock is characterized by three major alterations. First, the oxygen demand is higher than normal, so that the oxygen availability should also be supranormal. Second, the oxygen extraction capabilities are altered by the microvascular and, perhaps in the later stages, by the cellular alterations related to sepsis.@ Finally, the myocardial depression that is present early during severe sepsis45.4hcan limit DO, despite the apparently normal or increased cardiac output. These observations can account for the VO,/DOZ dependency phenomenon observed in patients with septic shock even when cardiac output is normal or elevated.25~47-49 PROGNOSTIC

IMPLICATIONS

Bihari et a14*observed that the VO, response to an acute increase in DO, produced by a prostacyclin infusion could separate the survivors and the nonsurvivors from critical illness. Similarly, Gutierrez and Pohil”’ observed a higher mortality in a subgroup of critically ill patients who showed oxygen uptake/supply dependency. However, it is likely that both the intensity and the duration of the tissue hypoxia must be taken into account. Shoemaker et a15’ observed that the development of organ failure after surgery was directly related to the total oxygen deficit during the surgical procedure. It is likely that a transient tissue hypoxia is relatively common but can be well tolerated. In particular, a transient episode of hypovolemic/ hemorrhagic shock does not usually result in the development of multiple organ failure. To some extent, strenuous exercise above the anaerobic threshold represents a situation in which oxygen demand also exceeds oxygen supply. Blood lactate levels have been sometimes criticized because they reflect both an increased production and a reduced elimination. Their changes with time are thus relatively slow. This can represent both an inconvenience and an advantage. Indeed, changes in mixed venous oxygen saturation (SvO?) can be very rapid, so they do not convey much information about the duration and extent of the recent tissue hypoxia. In contrast, elevated blood lactate levels can still reflect the recent tissue hypoxia. The disadvantage is that in view of these slow changes in lactate levels, particularly in patients with al-

155

tered liver function, the titration of therapy cannot be reliably guided by the blood lactate levels. The severity of tissue hypoxia can be reflected by both the magnitude and duration of lactic acidosis.s’ Several studies have correlated V02 and DO? with mortality in critically ill patients. In particular, in surgical patients, Shoemaker et al repeatedly observed that survivors had higher DO2 and V02 values than nonsurvivors.‘1.54 Russell et a15’ and Cryer et a156made similar observations in patients with ARDS. Patients with septic shock might behave differently, as their oxygen demand can vary considerably. Indeed, we recently observed similar DO, and VO, values in survivors and nonsurvivors from septic shock. However, the blood lactate levels were significantly higher in nonsurvivors.” Initial blood lactate levels have been shown to have a prognostic value in various types of circulatory shock.iX-h” More importantly, the time course of blood lactate levels must be taken into account.i2.57.6’ Persistently elevated blood lactate levels have been also correlated with the development of multiple organ failure (Jan Bakker, unpublished observations). Repeated measurements of blood lactate levels can reflect the degree of tissue hypoxia and constitute a useful prognostic indicator. THERAPEUTIC

IMPLICATIONS

From what precedes, the VO,/DO, dependency phenomenon primarily reflects tissue hypoxia and is thus the hallmark of acute circulatory failure. Its persistence can lead to the development of multiple organ failure and death. An imbalance between oxygen demand and oxygen supply characterizes all types of circulatory shock, so that the correction of the V02/ DO2 dependency phenomenon is ultimately the treatment of shock. A reduction in oxygen demand can sometimes be considered by the use of mechanical ventilation to rest the respiratory muscleshZ or by the use of morphine’j or antipyretic agents. Unfortunately, this approach, although very valid, is usually insufficient so that oxygen delivery must be simultaneously increased. Fluid therapy is the basis for treatment of all types of shock, even though it is rapidly limited when heart failure is predomi-

BAKKER

156

nant. Blood should be transfused to optimize hemoglobin level. Vasopressors can be required in case of profound cardiovascular collapse to restore a minimal tissue perfusion pressure. Inotropic therapy can be indicated not only in the management of cardiogenic shock but also in septic shock, in which myocardial depression can be present.45.46,49This represents a means to increase oxygen transport above its critical value. In severe sepsis, a pharmacologic increase in oxygen extraction would be highly desirable, but is difficult to achieve. In these conditions, the increase in oxygen extraction induced by vasopressor agents is limited.64-67The administration of antibodies directed to endotoxin or tumor necrosis factor might represent a more efficient therapeutic option to restore tissue oxygen extraction in severe sepsis. SHOULD

LACTIC

ACIDOSIS

BE CORRECTED?

Elevated blood lactate levels represent a marker of tissue hypoxia, but are not necessarily harmful per se. However, some recent studies have suggested that lactate can activate macrophageP and increase the secretion and transcription of TNF69; this is potentially deleterious. Although acidosis can reduce myocardial contractility,“-‘* it can also increase 0,ER by the tissues73 and probably protect the cell from anoxic damage.74 Bicarbonate administration has been recently challenged on the basis that it exerts deleterious hemodynamic effects and increases lactate production.75 These effects have been related to the production of carbon dioxide, which rapidly enters the cells. Carbicarb, an equimolar mixture of sodium bicarbonate and sodium carbonate, does not have this problem; however, its superiority over bicarbonate has been shown in some studies,76.77but not in others.78-80Dichloroacetate is a substance that can effectively reduce blood lactate levels by activating the pyruvate dehydrogenase.*“’ Although some positive effects on myocardial metabolism have been sometimes observed,“2’83 the overall hemodynamic effects of dichloroacetate in circulatory shock have not been impressive.84The results of a multicenter study evaluating the effects of dichloroacetate administration in patients with lactic acidosis are awaited with interest. These observations emphasize that

AND VINCENT

therapeutic interventions should aim at the correction of the underlying cellular hypoxia rather than at the correction of lactic acidosis per se. CONCLUSION

Experimental and clinical studies concur to indicate that the VO,/DO, dependency is associated with elevated blood lactate levels reflecting the concurrent cellular hypoxia. The vast majority of studies in which blood lactate levels were determined did not demonstrate the VOJDO, dependency phenomenon in the absence of lactic acidosis. Thus, normal blood lactate levels reasonably exclude the existence of tissue hypoxia. On the other hand, elevated blood lactate levels do not always imply the VO,/DO, dependency phenomenon. As lactate clearance can take some time, the elevated blood lactate levels do not necessarily indicate an ongoing tissue hypoxia, but could only reflect a recent oxygen debt. A trend analysis of blood lactate levels can be useful to confirm the resolution of tissue hypoxia, and thus represents a valuable guide to therapy. Alternatively, a “VO, challenge” test could be performed using a fluid challenge or a limited dose of dobutamine to rule out the persistence of tissue hypoxia. Finally, the uptake/supply dependency phenomenon is not primarily related to extramitochondrial oxygen metabolism. Questions have been appropriately raised regarding oxygen metabolism by extramitochondrial (non-adenosine triphosphate-producing) processes resulting in the production of toxic oxygen-free radicals. The observation of VO,/DO, dependency phenomenon in all patients with sepsis and ARDS would support such a worrisome concept. However, the existence of a plateau in the VOJDO, relationship in patients with sepsis and ARDS but without lactic acidosis plays down such a phenomenon. Although the participation of extramitochondrial metabolic processes cannot be ruled out, the VOJDO, dependency phenomenon primarily reflects a lack of available oxygen within the cell. Therefore, the rapid resolution of a sufficient DO, represents a reasonable therapeutic goal to prevent organ failure, and measurements of blood lactate levels can represent a useful clinical guide for this purpose.

OXYGEN

SUPPLY

DEPENDENCY

AND

BLOOD

LACTATE

157

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BAKKER

ship between mixed venous oxygen saturation and cardiac index in patients with chronic congestive heart failure. Chest 95:1289-1294,1989 37. Chappell TR, Rubin LJ, Markham RV, et al: Independence of oxygen consumption and systemic oxygen transport in patients with either stable pulmonary hypertension or refractory left ventricular failure. Am Rev Respir Dis 128:30-33,1983 38. Dorinsky PM, Costello JL, Gadek JE: Relationships of oxygen uptake and oxygen delivery in respiratory failure not due to the adult respiratory distress syndrome. Chest 93:1013-1019,1988 39. Villar J, Slut&y AS, Hew E, et al: Oxygen transport and oxygen consumption in critically ill patients. Chest 98:687-692,199O 40. Albert

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AND

VINCENT

53. Shoemaker WC, Chang PC, Czer LSC, et al: Cardiorespiratory monitoring in postoperative patients: I. Prediction of outcome and severity of illness. Crit Care Med 7:237-242,1979 54. Shoemaker

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HG, Richardson JD, Longmire-Cook S, et al: Oxygen delivery in patients with adult respiratory distress syndrome who undergo surgery. Arch Surg 124:1378-1385, 1989 57. Bakker J, Coffernils M, Leon M, et al: Blood lactate levels are superior to oxygen derived variables in predicting outcome in human septic shock. Chest (in press) 58. Weil MH, Afifi AA: Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 41:989-1001,197O 59. Henning RJ, Weil MH, Weiner F: Blood lactate as a prognostic indicator of survival in patients with acute myocardial infarction. Circ Shock 9307-315, 1982 60. Azimi G, Vincent J-L: Ultimate survival from septic shock. Resuscitation 14:245-253,1986 61. Bollaert PE, Bauer Ph, Audibert G, et al: Effects of epinephrine on hemodynamics and oxygen metabolism in dopamine resistant shock. Chest 98:949-953,199O 62. Aubier M, Syllie G, Mazes R, et al: Respiratory muscle contributing to lactic acidosis in low cardiac output. Am Rev Respir Dis 126:648-652,1982 63. Rouby JJ, Eurin B, Glaser P, et al: Hemodynamic and metabolic effects of morphine in the critically ill. Circulation 64:53-59,1981 64. Hussain

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OXYGEN

SUPPLY

DEPENDENCY

AND

BLOOD

LACTATE

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