Abstract
We previously observed young lambs to be more tolerant of hypoxia; compared with older lambs, they accumulate lactate at a slower rate during comparable reduction in cardiac output, and have a greater percent decrease in cardiac output before onset of systemic lactate accumulation. To determine the mechanism of lactic acidosis and the cause for this “tolerance,” we reduced cardiac output progressively in seven chronically catheterized conscious lambs (16.4 + 5.1 d) and measured hepatic and gastrointestinal (GI) blood flow (radioactive microspheres) and delivery, uptake, and extraction of lactate and O2. Hepatic O2 consumption declined proportionately below a critical hepatic O2 delivery (≅2 mL O2/min/kg), corresponding to the systemic O2 delivery associated with the onset of systemic lactate accumulation. As hepatic O2 delivery decreased below the critical value, there was initially net hepatic lactate uptake and then a change to net production when the O2 delivery decreased below ≅1 mL O2/min kg. The GI tract had net lactate production at rest, but surprisingly switched to lactate uptake as cardiac output decreased. The mechanism of lactic acidosis was failure of hepatic lactate uptake to increase despite increased hepatic lactate delivery, as reported in adults subjects. However, in contrast, there was “true” hepatic dysfunction and lactate production only at the lowest levels of cardiac output, after onset of systemic lactate accumulation. Moreover, we speculate that tolerance of young lambs to hypoxia is at least due to two factors: 1) hepatic lactate uptake is maintained beyond the “critical” O2 delivery and fall in hepatic O2 consumption, and 2) there is a switch to lactate uptake by the GI tract serving to buffer the lactate.
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Abbreviations
- GI:
-
gastrointestinal
- Hct:
-
hematocrit
- Hbo2:
-
fractional Hb oxygen saturation
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Acknowledgements
The authors thank Andrea O. Ray, Anthony Battelli, and Vincent Santucci for their expert technical assistance.
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Supported by a Child Health Research Grant from the Charles H. Hood Foundation. D.J.S. was supported by a National Heart, Lung, and Blood Institute, Training Grant HL07272. D.I.E. was supported by National Institutes of Health Grant HD19092. G.L. is an Established Investigator of the American Heart Association.
APPENDIX
APPENDIX
Calculations. Oxygen contents. Aortic (a), pulmonary arterial (mixed venous, v), portal venous (pv), and hepatic venous (hv) blood O2 contents (Cao2, Cvo2, Cpvo2, Chvo2, in mL O2/dL) were calculated from the respective Po2 (mm Hg), Hbo2 (fractional), and Hb (g/dL) as: Equation where 0.003 (mL O2/dL plasma mm Hg) is the Bunsen solubility coefficient for O2 in plasma at 37 °C. x = a, v, pv, hv.
Cardiac output. Qt, in mL/min/kg, was calculated using the Fick equation, from whole body O2 consumption (Vo2 in mL/min kg), Cao2, and Cvo2 as: Equation
Systemic O2 transport. Systemic O2 transport(SOT, in mL O2/min/kg) was calculated from its definition:Equation
Hepatic O2 delivery. Oxygen delivered to the liver (mL O2/min) was calculated as the sum of portal vein and hepatic artery contributions, with blood flows (Qpv, Qha, Qh) in mL/min:Equation
Hepatic O2 consumption. Oxygen consumption by the liver (mL O2/min) was calculated by: Equation where Qh = total liver blood flow = Qpv + Qha.
Hepatic O2 extraction. Hepatic O2 extraction was calculated as the quotient of hepatic O2 consumption and hepatic O2 delivery.
Hepatic lactate delivery. The lactate delivered to the liver(mmol/min) was calculated as for O2 delivery, substituting [L] (plasma lactate concentration, in mmol/L plasma) for O2 content.Equation where PCV = packed cell volume = Hct/100; this assumes that packed cell volume is the same in portal and arterial vessels.
Net hepatic lactate uptake (mmol/min).Equation This equation yields uptake of lactate from plasma and assumes that this is similar to uptake from blood because erythrocyte lactate equilibrates slowly with plasma(27).
Actual hepatic lactate extraction ratio.Equation We noted that the hepatic artery flows are a small percentage of the total liver blood flow (<10%) and the majority of hepatic blood flow at all levels of cardiac output was predominately portal flow (i.e. Qha ≪ Qpv; Qh ≅ Qpv). The formula for hepatic lactate extraction is greatly simplified if Qha is assumed to be zero and Qpv= Qh. Making these substitutions yields:
Estimated hepatic lactate extraction ratio.Equation As seen, all flow terms cancel and the estimation requires only measurement of lactate in the portal and hepatic veins. To examine the validity of this assumption, the estimated hepatic lactate extraction is plotted as a function of the actual hepatic lactate extraction in Figure 6. As seen, the linear regression analysis shows an excellent correlation (r = 0.99) with a slope close to one (0.99) and a SEM of the estimate of 0.036. The estimated lactate extraction is obviously a much easier measure to make, because it requires no measurement of blood flow, but only the ability to sample from the hepatic vein and portal vein. This estimation is accurate in the lamb because portal blood flow accounts for 90% of the total hepatic blood flow. The estimation may be less valid in species who have a larger proportion of the hepatic blood flow supplied by the hepatic artery, for example in man or pigs where the hepatic artery supplies approximately one-third of the hepatic blood flow. In the lamb, this estimation can be useful for assessing lactate extraction during times or studies where flow measurements are not possible or are limited in number.
Estimated hepatic lactate extraction as a function of actual hepatic lactate extraction. The linear regression line (y = 0.99x) is drawn. The correlation coefficient is 0.99 (p< 0.001) and the 95% confidence intervals for the y intercept(-0.014, 0.13) include zero.
Net GI O2 consumption.Equation where GI includes stomach, small bowel, large bowel, and spleen.
Net GI lactate uptake. Equation
GI lactate extraction. Equation
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Fahey, J., Lister, G., Sanfilippo, D. et al. Hepatic and Gastrointestinal Oxygen and Lactate Metabolism during Low Cardiac Output in Lambs. Pediatr Res 41, 842–851 (1997). https://doi.org/10.1203/00006450-199706000-00008
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DOI: https://doi.org/10.1203/00006450-199706000-00008
