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March 18, 1992, Vol 267, No. 11 >
ARTICLE | March 18, 1992

Reevaluation of the Role of Cellular Hypoxia and Bioenergetic Failure in Sepsis FREE

Richard S. Hotchkiss, MD; Irene E. Karl, PhD
[+] Author Affiliations

Reprint requests to Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave, Box 8054, St Louis, MO 63110 (Dr Hotchkiss).


JAMA. 1992;267(11):1503-1510. doi:10.1001/jama.1992.03480110079038
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References

Sepsis is frequently characterized by a number of metabolic abnormalities: increased plasma lactate concentration, metabolic acidosis, increased glycolysis, and an abnormal "delivery-dependent" oxygen consumption. Two hypotheses have been advanced to explain these metabolic abnormalities: (1) cellular hypoxia resulting from abnormal microcirculatory blood flow or (2) defect(s) in energy-producing metabolic pathways of cells. Results of our studies on rat muscle, liver, heart, brain, and plasma suggest that there is no evidence of bioenergetic failure in these septic tissues and that the increase in lactate production is not necessarily due to cellular hypoxia. The adequacy of cellular oxygenation and bioenergetics was verified using in vivo phosphorus 31 nuclear magnetic resonance spectroscopy, [18F]fluoromisonidazole, and microfluorometric enzymatic techniques. Findings from these studies as well as results from several clinical investigations indicate that neither hypothesis can adequately account for the metabolic features typical of sepsis and that the pathophysiology of sepsis awaits further clarification. These studies and important clinical implications are discussed.

(JAMA. 1992;267:1503-1510)

REFERENCES

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Dantzker D.  Oxygen delivery and utilization in sepsis. Crit Care Clin . 1989;;5:81-98.
7 +
Wolf YG, Cotev S, Perel A, Manny J.  Dependence of oxygen consumption on cardiac output in sepsis. Crit Care Med . 1987;;15:198-203.
8 +
Astiz M, Rackow EC, Weil MH, Schumer W.  Early impairment of oxidative metabolism and energy production in severe sepsis. Circ Shock . 1988;;26:311-320.
9 +
Mizock B.  Septic shock: a metabolic perspective. Arch Intern Med . 1984;;144:579-585.
10 +
Kreisberg RA.  Pathogenesis and management of lactic acidosis. Annu Rev Med . 1984;;35:181-193.
11 +
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Gilbert EM, Haupt MT, Mandanas RY, Huaringa AJ, Carlson RW.  The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis . 1986;;134:873-878.
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Vary TC.  Increased pyruvate dehydrogenase kinase activity. Am J Physiol . 1991;;260:E669-E674.
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Hotchkiss RS, Song SK, Ling CS, Ackerman JJ, Karl IE.  Sepsis does not alter red blood cell glucose metabolism or Na+ concentration: a 2H23Na-NMR study. Am J Physiol . 1990;;258:R21-R31.
34 +
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Zeller WP, The SM, Sweet M, et al.  Altered glucose transporter mRNA abundance in a rat model of endotoxic shock. Biochem Biophys Res Commun . 1991;;176:535-540.
37 +
Wichterman KA, Baue AE, Chaudry IH.  Sepsis and septic shock: a review of laboratory models and a proposal. J Surg Res . 1980;;29:189-201.
38 +
Hotchkiss RS, Rust RS, Dence CS, et al.  Evaluation of the role of cellular hypoxia in sepsis by the hypoxic maker [18F] fluoromisonidazole. Am J Physiol . 1991;;261:R965-R972.
39 +
Song SK, Hotchkiss RS, Karl IE, Ackerman JJH.  Concurrent quantification of tissue metabolism and blood flow via 2H/31P NMR in vivo, III: alterations of muscle blood flow and metabolism during sepsis. Magn Reson Med . In press.
40 +
Jepson MM, Cox M, Bates PC, et al.  Regional blood flow and skeletal muscle energy status in endotoxemic rats. Am J Physiol . 1987;;252:E581-E587.
41 +
Jacobs DO, Maris J, Fried R, et al.  In vivo phosphorus 31 magnetic resonance spectroscopy of rat hind limb skeletal muscle during sepsis. Arch Surg . 1988;;123:1425-1428.
42 +
Jacobs DO, Kobayashi, T, Imagire J, et al.  Sepsis alters skeletal muscle energetics and membrane function. Surgery . 1991;;110:318-326.
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Mela L. Pathophysiology of Shock, Anoxia, and Ischemia . Baltimore, Md: Williams & Wilkins; 1982;:90.
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Sprung CL, Peduzzi PN, Shatney CH, et al.  Impact of encephalopathy on mortality in the sepsis syndrome. Crit Care Med . 1990;;18:801-806.
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Hotchkiss RS, Long RC, Hall JR, et al.  An in vivo examination of rat brain during sepsis with 31P-NMR spectroscopy. Am J Physiol . 1989;; 257:C1055-C1061.
46 +
Parrillo JE.  The cardiovascular pathophysiology of sepsis. Annu Rev Med . 1989;;40:469-485.
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Abel FL.  Myocardial function in sepsis and endotoxin shock. Am J Physiol . 1989;;257:R1265-R1281.
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Hotchkiss RS, Song SK, Neil JJ, et al.  Sepsis does not impair tricarboxylic acid cycle in the heart. Am J Physiol . 1991;;260:C50-C57.
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Burns AH, Giaimo ME, Summer WR.  Dichloroacetic acid improves in vitro myocardial function following in vivo endotoxin administration. J Crit Care . 1986;;1:11-17.
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McDonough KH, Henry JJ, Lang CH, Spitzer JJ.  Substrate utilization and high energy phosphate levels of hearts from hyperdynamic septic rats. Circ Shock . 1986;;18:161-170.
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Laughlin MH, Smyk-Randall EM, Novotny MJ, Brown OR, Adams HR.  Coronary blood flow and cardiac adenine nucleotides in E. coli endotoxemia in dogs: effects of oxygen radical scavengers. Circ Shock . 1988;;25:173-185.
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Mori E, Hasebe M, Kobayashi K, Lijima N.  Alterations in metabolite levels in carbohydrate and energy metabolism of rat in hemorrhagic shock and sepsis. Metabolism . 1987;;36:14-20.
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Tanaka J, Sato T, Kamiyama Y, Jones RT, Cowley RA, Trump BF.  Bacteremic shock: aspects of high-energy metabolism of rat liver following Escherichia coli injection. J Surg Res . 1982;;33:49-57.
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Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Bone RC.  Sepsis, the sepsis syndrome, multiorgan failure: a plea for comparable definitions. Ann Intern Med . 1991;;114:332-333.
2 +
Parrillo JE, Parker MM, Natanson C, et al.  Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med . 1990;;113:227-242.
3 +
Cerra FB.  Hypermetabolism, organ failure, and metabolic support. Surgery . 1987;;101:1-14.
4 +
Rackow EC, Astiz ME, Weil MH.  Cellular oxygen metabolism during sepsis and shock: the relationship of oxygen consumption to oxygen delivery. JAMA . 1988;;259:1989-1993.
5 +
Hargrove DM, Bagby GJ, Lang CH, Spitzer JJ.  Adrenergic blockage does not abolish elevated glucose turnover during bacterial infection. Am J Physiol . 1988;;254:E16-E22.
6 +
Dantzker D.  Oxygen delivery and utilization in sepsis. Crit Care Clin . 1989;;5:81-98.
7 +
Wolf YG, Cotev S, Perel A, Manny J.  Dependence of oxygen consumption on cardiac output in sepsis. Crit Care Med . 1987;;15:198-203.
8 +
Astiz M, Rackow EC, Weil MH, Schumer W.  Early impairment of oxidative metabolism and energy production in severe sepsis. Circ Shock . 1988;;26:311-320.
9 +
Mizock B.  Septic shock: a metabolic perspective. Arch Intern Med . 1984;;144:579-585.
10 +
Kreisberg RA.  Pathogenesis and management of lactic acidosis. Annu Rev Med . 1984;;35:181-193.
11 +
Trunkey DD, Illner H, Wagner IY, Shires GT.  The effect of septic shock on skeletal muscle action potentials in the primate. Surgery . 1979;;85:638-643.
12 +
Zilva JF.  The origin of the acidosis in hyperlactataemia. Ann Clin Biochem . 1978;;15:40-43.
13 +
Mizock BA.  Controversies in lactic acidosis: implications in critically ill patients. JAMA . 1987;;258:497-501.
14 +
Krebs HA, Woods HF, Alberti KGMM.  Hyperlactataemia and lactic acidosis. Essays Med Biochem . 1970;;1:81-103.
15 +
Brooks GA.  Lactate production under fully aerobic conditions: the lactate shuttle during rest and exercise. Fed Proc . 1986;;45:2924-2929.
16 +
Gilbert EM, Haupt MT, Mandanas RY, Huaringa AJ, Carlson RW.  The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis . 1986;;134:873-878.
17 +
Vincent JL, Dufaye P, Berre J, Leeman M, Degaute JP, Kahn RJ.  Serial lactate determinations during circulatory shock. Crit Care Med . 1983;;11:449-451.
18 +
Mink RB, Pollack MM.  Effect of blood transfusion on oxygen consumption in pediatric septic shock. Crit Care Med . 1990;;18:1087-1091.
19 +
Fenwick JC, Dodek PM, Ronco JJ, Phang PT, Wiggs B, Russell JA.  Increased concentrations of plasma lactate predict pathologic dependence of oxygen consumption on oxygen delivery in patients with adult respiratory distress syndrome. J Crit Care . 1990;;2:81-86.
20 +
Burns HJG, Cowan BN, Ledingham I.  Metabolic acidosis in the critically ill. Ciba Found Symp . 1982;;87:293-306.
21 +
Archie JP.  Anatomic arterial-venous shunting in endotoxic and septic dogs. Ann Surg . 1977;; 186:171-176.
22 +
Carroll GC, Snyder JV.  Hyperdynamic severe intravascular sepsis depends on fluid administration in cynomolgus monkey. Am J Physiol. 1982;; 243:R131-R141.
23 +
Schumacker PT, Wood LD.  Limitations of aerobic metabolism in critical illness. Chest . 1984;;85:453-454.
24 +
Blair E.  Acid-base balance in bacteremic shock. Ann Intern Med . 1971;;127:731-739.
25 +
Astiz ME, Rackow EC, Kaufman B, Falk JL, Weil MH.  Relationship of oxygen delivery and mixed venous oxygenation to lactic acidosis in patients with sepsis and acute myocardial infarction. Crit Care Med . 1988;;16:655-658.
26 +
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-E640.
27 +
Vary TC.  Increased pyruvate dehydrogenase kinase activity. Am J Physiol . 1991;;260:E669-E674.
28 +
Vary TC, Siegel JH, Fall BD, Morris JH.  Metabolic effects of partial reversal of pyruvate dehydrogenase activity by dichloroacetate in sepsis. Circ Shock . 1988;;24:3-18.
29 +
Jahoor F, Shangraw RE, Miyoshi H, Wallfish H, Herndon DN, Wolfe RR.  Role of insulin and glucose oxidation in mediating the protein catabolism of burns and sepsis. Am J Physiol . 1989;;257:E323-E331.
30 +
Wolfe RR, Jahoor F, Herndon DN, Miyoshi H.  Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion. Surgery . 1991;;110:54-67.
31 +
Garber AJ, Karl IE, Kipnis DM.  Alanine and glutamine synthesis and release from skeletal muscle. J Biol Chem . 1976;;251:836-843.
32 +
Kreisberg RA.  Glucose-lactate interrelations in man. N Engl J Med . 1972;;287:132-137.
33 +
Hotchkiss RS, Song SK, Ling CS, Ackerman JJ, Karl IE.  Sepsis does not alter red blood cell glucose metabolism or Na+ concentration: a 2H23Na-NMR study. Am J Physiol . 1990;;258:R21-R31.
34 +
Amaral JF, Shearer JD, Mastrofrancesco B, Gann DS, Caldwell MD.  Can lactate be used as a fuel by wounded tissue? Surgery . 1986;;100:252-261.
35 +
Windell CC, Baldwin SA, Davies A, Martin S, Pasternak CA.  Cellular stress induces a redistribution of the glucose transporter. FASEB J . 1990;;4:1634-1637.
36 +
Zeller WP, The SM, Sweet M, et al.  Altered glucose transporter mRNA abundance in a rat model of endotoxic shock. Biochem Biophys Res Commun . 1991;;176:535-540.
37 +
Wichterman KA, Baue AE, Chaudry IH.  Sepsis and septic shock: a review of laboratory models and a proposal. J Surg Res . 1980;;29:189-201.
38 +
Hotchkiss RS, Rust RS, Dence CS, et al.  Evaluation of the role of cellular hypoxia in sepsis by the hypoxic maker [18F] fluoromisonidazole. Am J Physiol . 1991;;261:R965-R972.
39 +
Song SK, Hotchkiss RS, Karl IE, Ackerman JJH.  Concurrent quantification of tissue metabolism and blood flow via 2H/31P NMR in vivo, III: alterations of muscle blood flow and metabolism during sepsis. Magn Reson Med . In press.
40 +
Jepson MM, Cox M, Bates PC, et al.  Regional blood flow and skeletal muscle energy status in endotoxemic rats. Am J Physiol . 1987;;252:E581-E587.
41 +
Jacobs DO, Maris J, Fried R, et al.  In vivo phosphorus 31 magnetic resonance spectroscopy of rat hind limb skeletal muscle during sepsis. Arch Surg . 1988;;123:1425-1428.
42 +
Jacobs DO, Kobayashi, T, Imagire J, et al.  Sepsis alters skeletal muscle energetics and membrane function. Surgery . 1991;;110:318-326.
43 +
Mela L. Pathophysiology of Shock, Anoxia, and Ischemia . Baltimore, Md: Williams & Wilkins; 1982;:90.
44 +
Sprung CL, Peduzzi PN, Shatney CH, et al.  Impact of encephalopathy on mortality in the sepsis syndrome. Crit Care Med . 1990;;18:801-806.
45 +
Hotchkiss RS, Long RC, Hall JR, et al.  An in vivo examination of rat brain during sepsis with 31P-NMR spectroscopy. Am J Physiol . 1989;; 257:C1055-C1061.
46 +
Parrillo JE.  The cardiovascular pathophysiology of sepsis. Annu Rev Med . 1989;;40:469-485.
47 +
Abel FL.  Myocardial function in sepsis and endotoxin shock. Am J Physiol . 1989;;257:R1265-R1281.
48 +
Hotchkiss RS, Song SK, Neil JJ, et al.  Sepsis does not impair tricarboxylic acid cycle in the heart. Am J Physiol . 1991;;260:C50-C57.
49 +
Burns AH, Giaimo ME, Summer WR.  Dichloroacetic acid improves in vitro myocardial function following in vivo endotoxin administration. J Crit Care . 1986;;1:11-17.
50 +
McDonough KH, Henry JJ, Lang CH, Spitzer JJ.  Substrate utilization and high energy phosphate levels of hearts from hyperdynamic septic rats. Circ Shock . 1986;;18:161-170.
51 +
Laughlin MH, Smyk-Randall EM, Novotny MJ, Brown OR, Adams HR.  Coronary blood flow and cardiac adenine nucleotides in E. coli endotoxemia in dogs: effects of oxygen radical scavengers. Circ Shock . 1988;;25:173-185.
52 +
Mori E, Hasebe M, Kobayashi K, Lijima N.  Alterations in metabolite levels in carbohydrate and energy metabolism of rat in hemorrhagic shock and sepsis. Metabolism . 1987;;36:14-20.
53 +
Tanaka J, Sato T, Kamiyama Y, Jones RT, Cowley RA, Trump BF.  Bacteremic shock: aspects of high-energy metabolism of rat liver following Escherichia coli injection. J Surg Res . 1982;;33:49-57.
54 +
Gutierrez G, Pohil RJ, Andry JM, Strong R, Narayana P.  Bioenergetics of rabbit skeletal muscle during hypoxemia and ischemia. J Appl Physiol . 1988;;65:608-616.
55 +
Prichard JW, Alger JR, Behar KL, Petroff OAC, Shulman RG.  Cerebral metabolic studies in vivo by 31P NMR. Proc Nati Acad Sci U S A . 1983;;80:2748-2751.
56 +
Gibson GE, Pulsinelli W, Blass JP, Duffy TE.  Brain dysfunction in mild to moderate hypoxia. Am J Med . 1981;;70:1247-1254.
57 +
Van Os-Corby DJ, Koch CJ, Chapman JD.  Is misonidazole binding to mouse tissues a measure of cellular pO2? Biochem Pharmacol . 1987;;36:3487-3494.
58 +
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To understand the clinical management of acute heart failure syndromes.
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Compression-Only CPR: Pushing the Science Forward
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AAM 2010;304:1493-1495.
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BMJ 2010;341:c5893-c1494.
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