Correspondence REGIONAL AND SYSTEMIC OXYGEN DELIVERY/UPTAKE RELATIONS AND LACTATE FLUX
To the Editor: I am interested to read that the increase in lactate in severe sepsis
may, in some cases, be related to the inhibition of pyruvate dehydrogenase (PDH) and that this may be prevented by dichloroacetate (1). An alternative approach to increasing PDH activity should perhaps be explored, namely the use of the coenzyme for the PDH enzyme complex, thiamine pyrophosphate (TPP) the active form of thiamine or vitamin B1. It is possible that the decreased activity of PDH and lactate accumulation in sepsis may, in part, be related to thiamine deficiency or impaired phosphorylation of thiamine to form TPP. Evidence for this possibility includes the known association of thiamine deficiencywith lactic acidosis (2),the increased requirements for thiamine in sepsis (3), and the reports of thiamine deficiency mimicking septic shock (4). The role of thiamine deficiency in the critically ill deserves further consideration especially as thiamine deficiency following trauma may be common (5) and because thiamine deficiencyis associated with an increased mortality in critically ill patients (6). It is also of interest to note that thiamine administration delays the onset of shock and prolongs survival after hemorrhage in the absence of any other resuscitative measures (7). It is possible that the reported effect of dichloroacetate in sepsis (1) may merely reflect the relative deficiency of the required coenzyme for PDH, namely TPP the active form of thiamine. I. MCCONACHIE, EEA.R.C.S. Consultant Anaesthetist The Royal Oldham Hospital Oldham, United Kingdom 1. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake relations and lactate flux in hyperdynamic, endotoxin-treated dogs. Am Rev Respir Dis 1992; 145:348-54. 2. Campbell CH. The severe lactic acidosis of thiamine deficiency. Lancet 1984; 1:446-9. 3. Beisel WR. Metabolic effects of infection. Progress in Food and Nutrition Science 1984; 8:43-75. 4. Anderson SH, Charles TJ, Nichol AD. Thiamine deficiency at a district general hospital: report of five cases. Q J Med 1984; 55:15-32. 5. McConachie I, Haskew A. Thiamine status after major trauma. Intensive Care Med 1988; 14:628-31. 6. Cruikshank AM, Telfer ABM, Shenkin A. Thiamine deficiency in the critically ill. Intensive Care Med 1988; 14:384-7. 7. Govier WM, Greer CM. Studies on shock induced by hemorrhage 1: Effect of thiamine on survival time. J Pharmacol Exp Ther1941; 73:317-20.
From the Authors: We appreciate the interest of Dr. McConachie in our paper (1) and welcome the opportunity to comment. The thrust of our article was that lactic acidosis in acutely endotoxic, hyperdynamic dogs appeared more related to pyruvate dehydrogenase (PDH) activity than to tissue hypoxia. The mechanism of PDH inactivation in endotoxicosis was clearly not the subject of this study. Dr. McConachie raises the question of whether the ability of dichloroacetate (DCA) to decrease lactate in our animals was related to a relative deficiency of thiamine pyrophosphate (TPP). We are neither biochemists nor experts in PDH, but the work of others does suggest an answer to his query. The PDH enzyme complex exists as a balance between active and inactive forms, depending upon the relative activities of a kinase and a phosphatase. The activity of the kinase, which inactivates PDH by phosphorylation, is increased in sepsis, probably secondary to increasedacetyl-CoA/CoA ratio (2). DCA indirectly activates PDH by inhibiting the activity of this kinase, as reviewed
by Stacpoole (3). Although TPP is an essential component of the PDH complex, it is not relevant to the above mechanisms. Also, there is no reason why our well-nourished animals should be thiamine deficient, nor do we know of any data showing that DCA can activate PDH lacking TPP. Certainly, one can speculate that patients with sepsis or trauma may have decreased levels of TPP and decreased PDH activity on that basis. SCOTT E. CURTIS, M.D. STEPHEN M. CAIN, PH.D. University of Alabama at Birmingham Birmingham, Alabama 1. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake relations and lactate flux in hyperdynamic, endotoxin-treated dogs. Am Rev Respir Dis 1992; 145:348-54. 2. 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-E40. 3. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989; 38:1124-44. REPORTING THE REPRODUCIBILITY OF SPIROMETRY RESULTS
To the Editor: Sincewereported the short-term reproducibility of spirometry results from the Lung Health Study (1), we have been asked to state the number of persons excluded from the study due to poor reproducibility (2), and to report the coefficients of repeatability, a "superior statistic" (3). Furthermore, we found that we had overstated our coefficients of variation by a factor of 1.414 in tables 8 and 10. Only 52 men and 26 women were excluded from the study only because they had poor spirometry reproducibility during the second screening visit (FEVts or FVCs did not match within 5OJo). An additional 188men and 101 women had poor spirometry reproducibility during this visit but were excluded because they did not have borderline to moderate airways obstruction. The following table replaces table 8 of our paper. The coefficients of variation were calculated according to Connett and coworkers (4) and the coefficients of repeatability were calculated according to Bland (5) and also given as percentages of the mean values (6):
FEV t FVC FEV6 PEFR PEFT
Coeff Variation
Coefficient of Repeatability
Women
Women
4.1% 4.0% 3.5070 8.6% 18.5%
Men
4.1% 0.24 L (11.5%) 3.7% 0.36 L (11.0%) 3.3% 0.29 L (9.7%) 9.2% 1.31 L/s (22.9%) 19.7% 43.7 sec (62.6%)
Men 0.33 L (11.1%) 0.47 L (10.1%) 0.39 L (9.1%) 2.23 L/s (23.8%) 36.6 sec (70.7%)
The coefficient of repeatability for FEVt may be interpreted as showing that 95% of the differences between the FEVts measured at the two visits (a mean of 25 days apart) were within 240 mL for women and 330 mL for men. PAUL ENRIGHT, M.D. Honalei, HI 1. Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS. Spirometry in the Lung Health Study. Am Rev Respir Dis 1991; 143:1215-23. 2. Crapo RO. Spirometry: Quality control and reproducibility criteria (editorial). Am Rev Respir Dis 1991; 143:1212-13. 3. Spencer D. Letter to the Editor. Am Rev Respir Dis 1992; 145:236. 4. Connett IE, Lee WW. Estimation of the coefficient of variation from 1367
To the Editor: I am interested to read that the increase in lactate in severe sepsis
may, in some cases, be related to the inhibition of pyruvate dehydrogenase (PDH) and that this may be prevented by dichloroacetate (1). An alternative approach to increasing PDH activity should perhaps be explored, namely the use of the coenzyme for the PDH enzyme complex, thiamine pyrophosphate (TPP) the active form of thiamine or vitamin B1. It is possible that the decreased activity of PDH and lactate accumulation in sepsis may, in part, be related to thiamine deficiency or impaired phosphorylation of thiamine to form TPP. Evidence for this possibility includes the known association of thiamine deficiencywith lactic acidosis (2),the increased requirements for thiamine in sepsis (3), and the reports of thiamine deficiency mimicking septic shock (4). The role of thiamine deficiency in the critically ill deserves further consideration especially as thiamine deficiency following trauma may be common (5) and because thiamine deficiencyis associated with an increased mortality in critically ill patients (6). It is also of interest to note that thiamine administration delays the onset of shock and prolongs survival after hemorrhage in the absence of any other resuscitative measures (7). It is possible that the reported effect of dichloroacetate in sepsis (1) may merely reflect the relative deficiency of the required coenzyme for PDH, namely TPP the active form of thiamine. I. MCCONACHIE, EEA.R.C.S. Consultant Anaesthetist The Royal Oldham Hospital Oldham, United Kingdom 1. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake relations and lactate flux in hyperdynamic, endotoxin-treated dogs. Am Rev Respir Dis 1992; 145:348-54. 2. Campbell CH. The severe lactic acidosis of thiamine deficiency. Lancet 1984; 1:446-9. 3. Beisel WR. Metabolic effects of infection. Progress in Food and Nutrition Science 1984; 8:43-75. 4. Anderson SH, Charles TJ, Nichol AD. Thiamine deficiency at a district general hospital: report of five cases. Q J Med 1984; 55:15-32. 5. McConachie I, Haskew A. Thiamine status after major trauma. Intensive Care Med 1988; 14:628-31. 6. Cruikshank AM, Telfer ABM, Shenkin A. Thiamine deficiency in the critically ill. Intensive Care Med 1988; 14:384-7. 7. Govier WM, Greer CM. Studies on shock induced by hemorrhage 1: Effect of thiamine on survival time. J Pharmacol Exp Ther1941; 73:317-20.
From the Authors: We appreciate the interest of Dr. McConachie in our paper (1) and welcome the opportunity to comment. The thrust of our article was that lactic acidosis in acutely endotoxic, hyperdynamic dogs appeared more related to pyruvate dehydrogenase (PDH) activity than to tissue hypoxia. The mechanism of PDH inactivation in endotoxicosis was clearly not the subject of this study. Dr. McConachie raises the question of whether the ability of dichloroacetate (DCA) to decrease lactate in our animals was related to a relative deficiency of thiamine pyrophosphate (TPP). We are neither biochemists nor experts in PDH, but the work of others does suggest an answer to his query. The PDH enzyme complex exists as a balance between active and inactive forms, depending upon the relative activities of a kinase and a phosphatase. The activity of the kinase, which inactivates PDH by phosphorylation, is increased in sepsis, probably secondary to increasedacetyl-CoA/CoA ratio (2). DCA indirectly activates PDH by inhibiting the activity of this kinase, as reviewed
by Stacpoole (3). Although TPP is an essential component of the PDH complex, it is not relevant to the above mechanisms. Also, there is no reason why our well-nourished animals should be thiamine deficient, nor do we know of any data showing that DCA can activate PDH lacking TPP. Certainly, one can speculate that patients with sepsis or trauma may have decreased levels of TPP and decreased PDH activity on that basis. SCOTT E. CURTIS, M.D. STEPHEN M. CAIN, PH.D. University of Alabama at Birmingham Birmingham, Alabama 1. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake relations and lactate flux in hyperdynamic, endotoxin-treated dogs. Am Rev Respir Dis 1992; 145:348-54. 2. 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-E40. 3. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989; 38:1124-44. REPORTING THE REPRODUCIBILITY OF SPIROMETRY RESULTS
To the Editor: Sincewereported the short-term reproducibility of spirometry results from the Lung Health Study (1), we have been asked to state the number of persons excluded from the study due to poor reproducibility (2), and to report the coefficients of repeatability, a "superior statistic" (3). Furthermore, we found that we had overstated our coefficients of variation by a factor of 1.414 in tables 8 and 10. Only 52 men and 26 women were excluded from the study only because they had poor spirometry reproducibility during the second screening visit (FEVts or FVCs did not match within 5OJo). An additional 188men and 101 women had poor spirometry reproducibility during this visit but were excluded because they did not have borderline to moderate airways obstruction. The following table replaces table 8 of our paper. The coefficients of variation were calculated according to Connett and coworkers (4) and the coefficients of repeatability were calculated according to Bland (5) and also given as percentages of the mean values (6):
FEV t FVC FEV6 PEFR PEFT
Coeff Variation
Coefficient of Repeatability
Women
Women
4.1% 4.0% 3.5070 8.6% 18.5%
Men
4.1% 0.24 L (11.5%) 3.7% 0.36 L (11.0%) 3.3% 0.29 L (9.7%) 9.2% 1.31 L/s (22.9%) 19.7% 43.7 sec (62.6%)
Men 0.33 L (11.1%) 0.47 L (10.1%) 0.39 L (9.1%) 2.23 L/s (23.8%) 36.6 sec (70.7%)
The coefficient of repeatability for FEVt may be interpreted as showing that 95% of the differences between the FEVts measured at the two visits (a mean of 25 days apart) were within 240 mL for women and 330 mL for men. PAUL ENRIGHT, M.D. Honalei, HI 1. Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS. Spirometry in the Lung Health Study. Am Rev Respir Dis 1991; 143:1215-23. 2. Crapo RO. Spirometry: Quality control and reproducibility criteria (editorial). Am Rev Respir Dis 1991; 143:1212-13. 3. Spencer D. Letter to the Editor. Am Rev Respir Dis 1992; 145:236. 4. Connett IE, Lee WW. Estimation of the coefficient of variation from 1367
