CLINICAL COMMENTARY

The Oxygen Supply Dependency Phenomenon Is Associated With Increased Blood Lactate Levels

Jan Bakker and Jean-Louis Vincent

U NDER PHYSIOLOGIC conditions, an or- ganism is capable of maintaining oxygen

consumption (VO,) even when oxygen delivery (DO,) to the tissues is decreased. This is accom- plished 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 metab- olism is jeopardized and anaerobic metabolism occurs, resulting in an increase in blood lactate levels.2~3 Hence, an imbalance between oxygen demand and supply is characterized by the oxygen uptake/supply dependency phenome- non 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, de- creases below a critical value (DO,-crit), the increase in 0,ER becomes surpassed so that a further reduction in DO, will result in a reduc- tion 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 investiga- tors observed similar findings when cardiac output was acutely reduced.5,6 The DO,-crit has

From the Depatiment of Intensive Care, Erasme University Hospital, Brussels, Belgium.

Received April 27, 1991; accepted May 7, 1991. Address reprint requests to Jean-Louis fincent, MD, PhD,

Department of Intensive Care, Erasme University Hospital 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

been found to be similar, with severe hypox- emia, 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 metab- olism associated with tissue hypoxia. The effects of sepsis were studied specifically by Nelson and colleagues on a dog model of progressive hemor- rhage.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 endo- toxin,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-resis- tance dog model of endotoxic shock character- ized 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, depen- dency 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 undergo- ing cardiac surgery, Shibutani, Komatsu, and colleagues’9~20 lowered DO, by progressively de- creasing 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 simulta- neous 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

correlated with a fall of DO2 below 8 mL/kg/ min.

Few of the reported clinical studies investigat- ing the relationship between DO, and VOz documented patient blood lactate levels. How- ever, those that did report these levels could usually correlate the VOJDO, dependency with increased blood lactate levels. The strongest element relating the VOJDO, dependency phe- nomenon 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 adminis- tration 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 in- crease 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, in- creased 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/

153

min/m’ in patients without lactic acidosis. Gilbert et al attributed these constant observa- tions 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 dobu- tamine (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 dobu- tamine at a dose of 5 kg/kg/min did not increase VO, in stable, pneumectomized pa- tients. Fenwick et al” studied the effects of blood transfusion in patients with adult respira- tory distress syndrome (ARDS), and also ob- served 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 con- cur that the VOJDO, dependency is observed in patients with, but not in those without, lactic acidosis.

Table 1. Relationship Between Oxygen Uptake and Oxygen Supply in the Clinical Studies Including Measurements of Blood Lactate Levels

No. of QPPb SUPPlY SOUrCe Patients Diagnosis Change in DO, Blood Lactate Dependency Blood Lactate Dependency

Shibutani et all9 58 CABG Pump-flow Increased Yes Normal NO Kaufman et a? 13 Hypovolemic shock Fluids increased Yes

(n = 5)

Septic shock (n = 8) Fluids Increased Yes Haupt et aF3 20 Septic shock Fluids Increased (n = 8) Yes Normal (n = 6) No

Gilbert et al” 54 Septic shock Fluids Increased (n = 14) Yes Normal (n = 6) No Blood transfusion Increased (n = 10) Yes Normal In = 7) No

Adrenergic agents Increased (n = 7) Yes Normal (n = 10) Yes Annat et al” a ARDS PEEP Normal No Astiz et a14’ 10 Septic shock Fluids Increased Yes Mohsenifar et a13’ 8 Chronic CHF Nitroglycerin Normal Yes Komatsu et aPO 66 CABG Fluids, inotropes Increased (n = 22) Yes Normal In = 44) No, above

DO,-crit Vincent et alzs 73 Heartfailure (n = 36) Dobutamine Increased (n = 8) Yes Normal (n = 28) No

Sepsis (n = 37) Dobutamine Increased (n = 16) Yes Normal (n = 21) No Kruse et aP* 58 ARDS Fluids, PEEP Increased (n = 32) Yes Normal In = 26) No Vincent et alG9 ia Septic shock Dobutamine Increased Yes

Fenwick et al” 24 ARDS Blood transfusion Increased (n ~13) Yes Normal (n = 11) No Bollaert et al6’ 13 Septic shock Epinephrine Increased Yes

Abbreviations: CAEG, coronan/ artery bypass grafting; ARDS, adult respiratory distress syndrome; CHF, congestive heart failure; DO,-crit, critical DO, below which supply dependency occurs; PEEP, positive end-expiratory pressure.

154 BAKKER AND VINCENT

Table 2. Changes in VO, Associated With an Increase in DO, Secondary to the Administration of Intravenous Vasodilators in Patients Without Suspected Oxygen Debt

Source

Chappel et aP’

Gore and Sloan” Brent et aP2

Mohsenifar et aP” Bihari et a14’ Mohsenifar et aP1

Richard et al% Radermacher et aF

No. of

26 Pulmonary Hypertension 9 Heart failure

? Heartfailure 6 COPD 8 Heart failure

14 ARDS 11 Pulmonary Hypertension

6 Heartfailure 9 ARDS

Diagnosis Drug

Administered

Hydralazine, nifedipine Nitroprusside, hydralazine, minoxidil

Milrinone Hydralazine

Nitroglycerin Prostacyclin

Calcium channel antagonists ACE inhibitor Prostacyclin

Effect on ‘JO,

No change

No change No change Increases

Increases No change*

Increases No change*

No change

Abbreviations: COPD, chronic obstructive pulmonary disease; ARDS, adult respiratory distress syndrome; ACE, angiotensin

converting enzyme. *VO, increased in other patients with suspected oxygen debt.

It could be argued that the VOJDO, depen- dency phenomenon has been observed also in relatively stable patients with congestive heart failure,3o pulmonary hypertension3’ chronic ob- structive pulmonary disease,32 or sleep apnea syndrome, 33 in 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 phenom- enon 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 hours36.37 or simply undefined.3x Peak values of cardiac index over several mea- surements also have been used.3o All of these factors enhance the chance of repeating mea- surements 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 concur- rent 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 raising32,4o and espe- cially 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 pa- tients, an increase in VO, was observed in some studies29”1 but not in others.36,37,41-43 These discrep- ant findings were not clearly related to differ- ences 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 circula- tory 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 phenome- non 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 capabil- ities 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 155

contrast, septic shock is characterized by three major alterations. First, the oxygen demand is higher than normal, so that the oxygen availabil- ity 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 sepsis45.4h can limit DO, despite the apparently normal or increased cardiac output. These observations can account for the VO,/DOZ dependency phenomenon ob- served 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 survi- vors 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 de- pendency. 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 rela- tively 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 produc- tion and a reduced elimination. Their changes with time are thus relatively slow. This can represent both an inconvenience and an advan- tage. Indeed, changes in mixed venous oxygen saturation (SvO?) can be very rapid, so they do not convey much information about the dura- tion and extent of the recent tissue hypoxia. In contrast, elevated blood lactate levels can still reflect the recent tissue hypoxia. The disadvan- tage is that in view of these slow changes in lactate levels, particularly in patients with al-

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 partic- ular, in surgical patients, Shoemaker et al repeat- edly observed that survivors had higher DO2 and V02 values than nonsurvivors.‘1.54 Russell et a15’ and Cryer et a156 made similar observations in patients with ARDS. Patients with septic shock might behave differently, as their oxygen demand can vary considerably. Indeed, we re- cently observed similar DO, and VO, values in survivors and nonsurvivors from septic shock. However, the blood lactate levels were signifi- cantly higher in nonsurvivors.” Initial blood lactate levels have been shown to have a prognos- tic 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, unpub- lished observations). Repeated measurements of blood lactate levels can reflect the degree of tissue hypoxia and constitute a useful prognos- tic indicator.

THERAPEUTIC IMPLICATIONS

From what precedes, the VO,/DO, depen- dency phenomenon primarily reflects tissue hy- poxia and is thus the hallmark of acute circula- tory 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 circula- tory 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 respira- tory muscleshZ or by the use of morphine’j or antipyretic agents. Unfortunately, this ap- proach, although very valid, is usually insuffi- cient so that oxygen delivery must be simulta- neously increased. Fluid therapy is the basis for treatment of all types of shock, even though it is rapidly limited when heart failure is predomi-

156 BAKKER AND VINCENT

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.45.46,49 This 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 vaso- pressor agents is limited.64-67 The administration of antibodies directed to endotoxin or tumor necrosis factor might represent a more efficient therapeutic option to restore tissue oxygen ex- traction 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 mac- rophageP and increase the secretion and tran- scription of TNF69; this is potentially deleteri- ous. 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. Carbi- carb, an equimolar mixture of sodium bicarbon- ate and sodium carbonate, does not have this problem; however, its superiority over bicarbon- ate has been shown in some studies,76.77 but not in others.78-80 Dichloroacetate is a substance that can effectively reduce blood lactate levels by activating the pyruvate dehydrogenase.*“’ Al- though some positive effects on myocardial metabolism have been sometimes observed,“2’83 the overall hemodynamic effects of dichloroace- tate in circulatory shock have not been impres- sive.84 The results of a multicenter study evaluat- ing the effects of dichloroacetate administration in patients with lactic acidosis are awaited with interest. These observations emphasize that

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 asso- ciated with elevated blood lactate levels re- flecting 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 ab- sence 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 dobu- tamine to rule out the persistence of tissue hypoxia. Finally, the uptake/supply dependency phenomenon is not primarily related to extram- itochondrial oxygen metabolism. Questions have been appropriately raised regarding oxygen me- tabolism by extramitochondrial (non-adenosine triphosphate-producing) processes resulting in the production of toxic oxygen-free radicals. The observation of VO,/DO, dependency phe- nomenon in all patients with sepsis and ARDS would support such a worrisome concept. How- ever, 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 phenom- enon primarily reflects a lack of available oxy- gen within the cell. Therefore, the rapid resolu- tion of a sufficient DO, represents a reasonable therapeutic goal to prevent organ failure, and measurements of blood lactate levels can repre- sent a useful clinical guide for this purpose.

OXYGEN SUPPLY DEPENDENCY AND BLOOD LACTATE 157

REFERENCES 1. Weber KT, Kinasewitz GT, Janicki JS, et al: Oxygen

utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 6.5:1213-1223, 1982

2. Vary TC, Siegel JH, Rivkind A: Clinical and therapeu- tic significance of metabolic patterns of lactic acidosis. Perspect Crit Care 1:8.5-132, 1988

3. Vincent J-L: The value of blood lactate monitoring, in Gutierrez G, Vincent J-L (eds): Tissue Oxygen Utilization; Update in Intensive Care and Emergency Medicine (12). Heidelberg, Germany, Springer Verlag, 1991, pp 260-269

4. Cain SM: Appearance of excess lactate in anesthetized dogs during anemic and hypoxic hypoxia. Am J Physiol 209:604-608. 1965

5. Fahey JT, Lister G: Postnatal changes in critical cardiac output and oxygen transport in conscious lambs. Am J Physiol Heart Circ Physiol22:HlOO-H106, 1987

6. Nelson DP, Beyer C, Samsel RW, et al: Pathological supply dependence of O2 uptake during bacteremia in dogs. J Appl Physiol63:1487-1492, 1987

7. Heusser F, Fahey JT, Lister G: Effect of hemoglobin concentration on critical cardiac output and oxygen trans- port. Am J Physiol253:H527-H532, 1987

8. Moss M, Moreau G, Lister G: Oxygen transport and metabolism in the conscious lamb: The effects of hypox- emia. Pediatr Res 22:177-183, 1987

9. Nelson DP, Samsel RW, Wood LD, et al: Pathological supply dependency of systemic and intestinal 0, uptake during endotoxemia. J Appl Physiol64:2410-2419, 1988

10. Schlichtig R, Kramer DJ, Pinsky MR: Flow redistribu- tion during progressive hemorrhage is a determinant of critical O? delivery. J Appl Physiol70:169-178, 1991

11. Schlichtig R, Snyder JV, Pinsky RM: Multiple organ oxygen supply-dependent relationships and redistribution, in Gutierrez G, Vincent J-L (eds): Tissue Oxygen Utiliza- tion: Update in Intensive Care and Emergency Medicine (12). Heidelberg, Germany, Springer Verlag, 1991, pp 143-160

12. Van der Linden P, Gilbart E, Engelman E, et al: Effects of anesthetic agents on systemic critical 0, delivery. J Appl Physiol (in press)

13. Samsel RW, Nelson DP, Sanders WM, et al: Effect of endotoxin on systemic and skeletal muscle 0, extraction. J Appl Physiol65:1377-1382, 1988

14. Luypaert P, Vincent J-L, Domb M, et al: Fluid resuscitation with hypertonic saline in endotoxic shock. Circ Shock 20:31 l-320, 1986

IS. Vincent J-L, Van der Linden Ph, Domb M, et al: Dopamine compared with dobutamine in experimental septic shock: Relevance to fluid administration. Anesth Analg 66:565-571, 1987

16. Preiser J-C, Armistead C, Minh Le T, et al: Increase in oxygen supply during experimental septic shock: The eflects of dobutamine versus dopexamine. J Crit Care 4:40-44, 19x9

17. Armistead CW, Vincent J-L, Preiser J-C, et al: Hypertonic saline solution/MHetastarch for fluid resuscita- tion in experimental septic shock. Anesth Analg 69:714-720, 1989

IX. De Boelpaepe C, Vincent J-L, Contempre B, et al:

Combination of norepinephrine and amrinone in the treat- ment of endotoxin shock. J Crit Care 4:202-207, 1989

19. Shibutani K, Komatsu T, Kubai K, et al: Critical level of oxygen delivery in anesthetized man. Crit Care Med 11:640-643, 1983

20. Komatsu T, Shibutani K, Okamoto K, et al: Critical level of oxygen delivery after cardiopulmonary bypass. Crit Care Med 15:194-197, 1987

21. Weber KT, Janicki JS, Maskin CS: Pathophysiology of cardiac failure. Am J Cardiol56:3B-7B, 1985

22. Rashkin M, Boxkin C, Baughman R: Oxygen delivery in critically il l patients. Relationship to blood lactate and survival. Chest 87:580-584, 1985

23. Haupt MT, Gilbert EM, Carlson RW: Fluid loading increases oxygen consumption in septic patients with lactic acidosis. Am Rev Respir Dis 131:912-916, 1985

24. Gilbert EM, Haupt MT, Mandanas RY. et al: The effect of fluid loading, blood transfusion and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis 134:873-878, 1986

25. Vincent J-L, Roman A, DeBacker D, et al: Oxygen uptake/supply dependency: Effects of short-term dobu- tamine infusion. Am Rev Respir Dis 142:2-8, 1990

26. Mathru M, Dries DJ, Kanuri D. et al: Effect of cardiac output on gas exchange in one-lung atelectasis. Chest 97:1121-1124,199O

27. Fenwick JC, Dodek PM, Ronco JJ, et al: Increased concentrations of plasma lactate predict pathological depen- dence of oxygen consumption on oxygen delivery in patients with adult respiratory distress syndrome. J Crit Care 5:8l- 87,199O

28. Kruse JA, Haupt MT, Puri VK, et al: Lactate levels as predictors of the relationship between oxygen delivery and consumption in ARDS. Chest 98:959-962, 1990

29. Annat G, Viale J-P, Percival C, et al: Oxygen delivery and uptake in the adult respiratory distress syndrome. Am Rev Respir Dis 133:999-1001, 1986

30. Mohsenifar Z, Amin D, Jasper AC, ct al: Depen- dence of oxygen consumption on oxygen delivery in patients with chronic congestive heart failure. Chest 9?:447-450. 1987

31. Mohsenifar Z, Jasper AC, Koerner SK: Relationship between oxygen uptake and oxygen delivery in patients with pulmonary hypertension. Am Rev Respir Dis 13X:69-73. 1988

32. Brent BN, Matthay RA, Mahler DA, et al: Relation- ship between oxygen uptake and oxygen transport in stable patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 129:682-686, 1984

33. Williams AJ, Mohsenifar Z: Oxygen supply depen- dency in patients with obstructive sleep apnea and its reversal after therapy with nasal continuous positive airway pressure. Am Rev Respir Dis 140:1308-1311, 1989

34. Vermey CG, Feenstra BWA, Bruining HA: Oxygen delivery and oxygen uptake in postoperative and septic patients. Chest 98:415-420, 1990

35. Bartlett RH, Dechert RE: Oxygen kinetics: Pittalls in clinical research. J Crit Care 5:77-80. 1990

36. Richard C, Thuillez C, Pezzano M. et al: Kelation-

BAKKER AND VINCENT

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: Indepen- dence 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 RK, Schrijen F, Poincelot F: Oxygen consump- tion and transport in stable patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 134:678-682,1986

41. Gore JM, Sloan K: Use of continuous monitoring of mixed venous saturation in the coronary care unit. Chest 86:757-761,1984

42. Bihari D, Smithies M, Gimson A, et al: The effects of vasodilation with prostacyclin on oxygen delivery and up- take in critically ill patients. N Engl J Med 317:397-403,1987

43. Radermacher P, Santak B, Wust HJ, et al: Prostacy- clin for the treatment of pulmonary hypertension in the adult respiratory distress syndrome: Effects on pulmonary capillary pressure and ventilation-perfusion distributions. Anesthesiology 72:238-244,199O

44. Rackow EC, Astiz ME, Weil MH: Cellular oxygen metabolism during sepsis and shock. The relationship of oxygen consumption to oxygen delivery. JAMA 259:1989- 1993,1988

45. Parker MM, Suffredini AF, Natanson C, et al: Re- sponses of left ventricular function in survivors and nonsur- vivors of septic shock. J Crit Care 4:19-25,1989

46. Vincent J-L, Frank RN, Contempre B, et al: Right ventricular dysfunction in septic shock: Assessment by measurements of right ventricular ejection fraction using the thermodilution technique. Acta Anaesthesiol Stand 33:34-38,1989

47. Astiz ME, Rackow EC, Falk JL: Oxygen delivery and consumption in patients with hyperdynamic septic shock. Crit Care Med 15:26-28,1987

48. Kaufman BS, Rackow EC, Falk JL: The relationship between oxygen delivery and consumption during fluid resuscitation of hypovolemic and septic shock. Chest 85:336- 340,1984

49. Vincent J-L, Roman A, Kahn RJ: Dobutamine admin- istration in septic shock: Addition to a standard protocol. Crit Care Med 18;689-693,199O

50. Gutierrez G, Pohil RJ: Oxygen consumption is lin- early related to 0, supply in critically ill patients. J Crit Care 1:45-53,1986

51. Shoemaker WC, Appel PL, Kram HB: Tissue oxygen debt as a determinant of lethal and nonlethal postoperative organ failure. Crit Care Med 16:1117-1120,1988

52. Vincent J-L, Dufaye Ph, Berre J, et al: Serial lactate determinations during circulatory shock. Crit Care Med 11:449-451, 1983

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

54. Shoemaker WC, Appel PL, Kram HB, et al: Prospec- tive trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 94:1176-1186, 1988

55. Russell JA, Ronco JJ, Lockhat D, et al: Oxygen delivery and consumption and ventricular preload are greater in survivors than in nonsurvivors of the adult respiratory distress syndrome. Am Rev Respir Dis 141:659- 665,1990

56. Cryer 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 SNA, Ritledge F, Roussos C, et al: Effects of norepinephrine and fluid administration on the selective blood flow distribution in endotoxic shock. J Crit Care 3:32-42.1988

65. Breslow MJ, Miller CF, Parker SD, et al: Effect of vasopressors on organ blood flow during endotoxin shock in pigs. Am J Physiol252:H291-H300,1987

66. Shoemaker WC, Appel PL, Kram HB: Measurement of tissue perfusion by oxygen transport patterns in experi- mental shock and in high-risk surgical patients. Intensive Care Med 16:S135-S144,1990

67. Bakker J, Vincent J-L: Dobutamine and norepine- phrine treatment in relation to oxygen delivery and consump- tion in endotoxin shock. Anesthesiology 73:A313, 1990 (abstr)

68. Paty PB, Banda MJ, Hunt TK: Activation of macro- phages by L-lactic acid. Surg Forum 39:27-28,1988

69. Jensen JC, Buresh C, Norton JA: Lactic acidosis increases tumor necrosis factor secretion and transcription in vitro. J Surg Res 49:350-353, 1990

70. Opie LH, Kadas T, Gevers W: Effect of pH on the function and glucose metabolism of the heart. Lancet 2:551-553, 1963

71. Cingolani HE, Faulkner SL, Mattiazzi AR, et al:

OXYGEN SUPPLY DEPENDENCY AND BLOOD LACTATE

Depression of human myocardial contractility with “respiratory” and “metabolic” acidosis. Surgery 77:427-432, 1975

72. Crie JS, Wildenthal K, Adcock R, et al: Inhibition of inotropic effect of hyperosmotic mannitol by lactate in vitro. Am J Physiol231:1209-1213,1976

73. Cain SM, Adams RP. 0, transport during two forms of stagnant hypoxia following acid and base infusions. J Appl Physiol54:1518-1524, 1983

74. Gores GJ, Nieminen A-L, Wray BE, et al: Intracellu- lar pH during “chemical hypoxia” in cultured rat hepato- cytes. Protection by intracellular acidosis against the onset of cell death. J Clin Invest 83:386-396,1989

75. Graf H, Leach W, Arieff AI: Evidence for a detrimen- tal effect of bicarbonate therapy in hypoxic lactic acidosis. Science 221:754-X6,1985

76. Bersin RM, Arieff AI: Improved hemodynamic func- tion during hypoxia with carbicarb, a new agent for the management of acidosis. Circulation 77:227-233, 1988

77. Sun JH, Filley GF, Hord K, et al: Carbicarb: An effective substitute for NaHC03 for the treatment of acidosis. Surgery 102:835-839,1987

78. Kette F, Weil MH, Von Planta M, et al: Buffer agents

do not reverse intramyocardial acidosis during cardiac resuscitation. Circulation 81:1660-1666, 1990

79. Klepper ID, Kucera RF, Kindig NB, et al: A compar- ative study of sodium bicarbonate and carbicarh in the treatment of metabolic acidosis induced by hemorrhagic shock. J Crit Care 4:256-261, 1988

80. Blecic S, De Backer D, Deleuze M, et al: Correction of metabolic acidosis in experimental CPR: A comparative study of sodium bicarbonate, carbicarb and dextrose. Ann Emerg Med 20:235-238.1991

81. Crabb DW, Yount EA, Harris RA: The metabolic effects of dichloroacetate in dogs. Metabolism 30:1024- 1039,198l

82. Mjos OD, Miller NE, Riemersma RA, et al: Effects of dichloroacetate on myocardial substrate extraction, epicar- dial ST-segment elevation and ventricular blood flow follow- ing coronary occlusion in dogs. Cardiovasc Res 10:427-436, 1976

83. Wargovich TJ, Macdonald RG, Hill JA, et al: Myocar- dial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol61:65-70, 1988

84. Preiser J-C, Moulart D, Vincent J-L: Dichloroacetate administration in the treatment of endotoxin shock. Circ Shock 30:221-228, 1990