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Brain uptake of meperidine
604
July 1. 1981 Am. J. Obstet. Gynecol.
Correspondence
those born to control mothers are remarkably similar, to say the least. Second, the standard deviations of the mean lengths of gestation in the treated and control groups (1.64 and 1.4 days, respectively) are mathematically impossible in the light of the distributions of weeks of gestation (Table II). The mean 2 one standard deviation should include two thirds of observations; these do not. For example, in the case of the treated group, the mean gestational age was precisely 3 1 weeks, but because 25 (36%) were less than 30 weeks and 29 (41%) were more than 32 weeks it is mathematically impossible for two thirds to have fallen within 1.64 days of 217 days (31 weeks). Similarly, because there is a difference of approximately 1,000 gm in infant weight between 28 and 34 weeks, it strains one’s credulity to find the standard deviations of 53 and 43 gm in the aminophylline and control groups, respectively. Also remarkable are the Apgar scores and their standard deviations. Unless these phenomena can be explained by the authors, the conclusions are in doubt. Edward A. Mortimer, Jr., M.D. Department of Epidemiology and Community Health School of Medicine Case Western Reserve University Cleveland, Ohio 44106 REFERENCE
Hadjigeorgiou, E., Kitsiou, S., Psaroudakis, A., Segos, C., Nicolopoulos, D., and Kaskarelis, D.: Antepartum aminophylline treatment for prevention syndrome in premature infants, 135~257, 1979.
of the respiratory AM. J. OBSTET.
distress GYNECOL.
Reply to Dr. Mortimer To the Editors: The letter by Dr. Mortimer gives us the opportunity to clarify the following: 1. In Table I the C 1.64 and 2 1.4 values are not +- 1 SD but *SE of the mean gestational age. The corresponding values for + 1 SD are ? 13.72 and + 12.36, respectively. 2. The +-SDS for weight of the infants are 253 and *43, respectively, and the values for * 1 SD are 443.4 and 379.7 gm, respectively. 3. All 2 values in our Table I are for standard errors. 4. We must also mention that the distribution of babies of different gestational ages in groups of 28 to 30, 30 to 32, and 32 to 34 weeks was not even: There was a greater number of infants at the lower range (near the twenty-eighth, thirtieth, and thirty-second weeks) in the aminophylline group than in the control group. We think that the misunderstanding of SE for SD
answers the questions of Dr. Mortimer. should have specified this in our table.
Certainly
we
E. Hadjigeorgiou S. Kitsiou ‘4. Psaroudakis D. Nicolopoulm D. Kaskarrlb Neonatal Deplrtment Alexandra Maternity Hospital 80 Vas. Sophia’s Avenue Athens 611, Greece
Brain u@ake of nqeridtne To the Editors: In the recent article, “Brain uptake of meperidine in the fetal lamb” (AM. J. OBSTET. GYNECOL. 138:528, 1980), the authors imply that the fetal brain uptake of meperidine was much less following maternal intramuscular administration when compared to the same dose given intravenously. This interpretation was based on the large disparity observed in mean blood concentrations when the meperidine concentrations were equal in the fetal brachiocephalic artery and the sagittal vein. At this arteriovenous equilibrium the concentrations were 233 it 22.9 rig/ml foilowing the intravenous administration and 68 +- 2.1 rig/ml following the intramuscular administration of meperidine. This conclusion does not take into account that although the arteriovenous difference was smaller, the period of injection to equilibration was much longer following the intramuscular injection. We estimated the value of each data point on the drug concentration decay curves provided as examples for intravenous and intramuscular administration. The authors did not specify if the examples were from the same animal. From the product of the blood flow and the arteriovenous difference we calculated relative uptake rates. We can assume that blood flow was constant during the two administrations: A further assumption is that the amount of brain perfused was approximately equal because of similar catheter placement in the sagittal vein. Since we were without specific values for blood flow, we simply applied the label “unit” to the product. The comparison, however, remains valid. We constructed an uptake curve and determined the relative brain meperidine accumulation by integration. Although the intravenous administration produced a slightly higher uptake, 1,750 U versus 1,660 U, the significance of this difference cannot be evaluated but appears far less than the authors implied. After 60 minutes, the intramuscular example demonstrated some clearing with 1,000 U remaining in the brain following the intramuscular administration compared to 1,300 units in the intravenous example. Unfortunately.
Volume Number
140 5
Correspondence
the authors supplied insufficient data to estimate if consistent findings could be expected.. A lower blood concentration at arteriovenous equilibrium does not preclude greater organ uptake. As the authors mentioned, the actual amount of meperidine distributed to the fetal brain tissue depends on the partition coefficient between blood and brain tissue. Tissue affinities composed of lipid solubilities, tissue binding, and ion trapping can be satisfied for a particular level of free drug. Hence, brain concentration may exceed that of the blood. The longer time to arteriovenous equilibration allowed the similar brain uptake to occur despite lower arteriovenous differe,nces seen following intramuscular administration. In summary, we do not believe that the data supplied support the conclusion that the fetal brain exposure to meperidine was significantly greater following intravenous as compared to intramuscular administration. Roland L. Kennedy, M.D. Hansel deSousa, M.D. Department of Anesthesiology West Virginia University Medical Center Morgantown, West Virginia 26506
Reply to Drs. Kennedy and deSousa To the Editors: Drs. Kennedy and deSousa correctly pointed out that, given adequate data, fetal brain uptake of meperidine may be calculated by the method of Kety and Schmidt’: t = equil. Uptake = Q Cart.*1-C ve,n.t t=O
J
where Q is the rate of blood flow to the brain, C,,, is the concentration of drug in the brachiocephalic artery of drug in the at time t, and Cveln,t is the concentration sagittal vein at time t. The integral term is the total area between the curve for C,fi,t and Cvein,t. While their results calculated from the intramuscular
605
data are reasonable, it should be apparent that substantial errors are involved in calculating the area from the intravenous data. Following an intravenous bolus of meperidine, arterial drug concentrations fall in a rapid exponential manner, and the two data points, at 2 and 5 minutes, do not allow us to extrapolate a line back to t = 0 with any degree of confidence. As even greater drug concentrations might be expected prior to 2 minutes, we cannot place a certain upper bound on the area or, therefore, the brain uptake following intravenous administration. In their calculation of area, it appears that Kennedy and deSousa constructed a line from the t = 2 minute point back to the origin (t = 0, concentration = 0), which would grossly underestimate fetal brain uptake. Accepting the limitations of our data and the errors implicit in the assumptions necessary to execute the required calculations, we have not reported brain meperidine uptake following intravenous administration. We have instead reported the peak concentration of free meperidine in the fetal brain following intravenous and intramuscular administration. For reversibly acting drugs, it is actually more important to focus on the peak drug concentration at the site of action, rather than upon the integrated exposure to the drug over time.2 Our data, therefore, would suggest that the peak intensity of response in the fetus to meperidine is less following intramuscular administration. Hazel H. Szeto, Ph.D., M.D. Department of Pharmacology Cornell University Medical College 1300 York Avenue New York, New York 10021 REFERENCES
1. Kety, S. S., and Schmidt, C. F.: The nitrous oxide method for the quantitative determination of cerebral blood flow in man; Theory, procedure, and normal values, J. Clin. Invest. 27:476, 1948. 2. Levy, G., and Gibaldi, M.: Pharmacokinetics of drug action, Annu. Rev. Pharmacol. 14:85, 1972.
July 1. 1981 Am. J. Obstet. Gynecol.
Correspondence
those born to control mothers are remarkably similar, to say the least. Second, the standard deviations of the mean lengths of gestation in the treated and control groups (1.64 and 1.4 days, respectively) are mathematically impossible in the light of the distributions of weeks of gestation (Table II). The mean 2 one standard deviation should include two thirds of observations; these do not. For example, in the case of the treated group, the mean gestational age was precisely 3 1 weeks, but because 25 (36%) were less than 30 weeks and 29 (41%) were more than 32 weeks it is mathematically impossible for two thirds to have fallen within 1.64 days of 217 days (31 weeks). Similarly, because there is a difference of approximately 1,000 gm in infant weight between 28 and 34 weeks, it strains one’s credulity to find the standard deviations of 53 and 43 gm in the aminophylline and control groups, respectively. Also remarkable are the Apgar scores and their standard deviations. Unless these phenomena can be explained by the authors, the conclusions are in doubt. Edward A. Mortimer, Jr., M.D. Department of Epidemiology and Community Health School of Medicine Case Western Reserve University Cleveland, Ohio 44106 REFERENCE
Hadjigeorgiou, E., Kitsiou, S., Psaroudakis, A., Segos, C., Nicolopoulos, D., and Kaskarelis, D.: Antepartum aminophylline treatment for prevention syndrome in premature infants, 135~257, 1979.
of the respiratory AM. J. OBSTET.
distress GYNECOL.
Reply to Dr. Mortimer To the Editors: The letter by Dr. Mortimer gives us the opportunity to clarify the following: 1. In Table I the C 1.64 and 2 1.4 values are not +- 1 SD but *SE of the mean gestational age. The corresponding values for + 1 SD are ? 13.72 and + 12.36, respectively. 2. The +-SDS for weight of the infants are 253 and *43, respectively, and the values for * 1 SD are 443.4 and 379.7 gm, respectively. 3. All 2 values in our Table I are for standard errors. 4. We must also mention that the distribution of babies of different gestational ages in groups of 28 to 30, 30 to 32, and 32 to 34 weeks was not even: There was a greater number of infants at the lower range (near the twenty-eighth, thirtieth, and thirty-second weeks) in the aminophylline group than in the control group. We think that the misunderstanding of SE for SD
answers the questions of Dr. Mortimer. should have specified this in our table.
Certainly
we
E. Hadjigeorgiou S. Kitsiou ‘4. Psaroudakis D. Nicolopoulm D. Kaskarrlb Neonatal Deplrtment Alexandra Maternity Hospital 80 Vas. Sophia’s Avenue Athens 611, Greece
Brain u@ake of nqeridtne To the Editors: In the recent article, “Brain uptake of meperidine in the fetal lamb” (AM. J. OBSTET. GYNECOL. 138:528, 1980), the authors imply that the fetal brain uptake of meperidine was much less following maternal intramuscular administration when compared to the same dose given intravenously. This interpretation was based on the large disparity observed in mean blood concentrations when the meperidine concentrations were equal in the fetal brachiocephalic artery and the sagittal vein. At this arteriovenous equilibrium the concentrations were 233 it 22.9 rig/ml foilowing the intravenous administration and 68 +- 2.1 rig/ml following the intramuscular administration of meperidine. This conclusion does not take into account that although the arteriovenous difference was smaller, the period of injection to equilibration was much longer following the intramuscular injection. We estimated the value of each data point on the drug concentration decay curves provided as examples for intravenous and intramuscular administration. The authors did not specify if the examples were from the same animal. From the product of the blood flow and the arteriovenous difference we calculated relative uptake rates. We can assume that blood flow was constant during the two administrations: A further assumption is that the amount of brain perfused was approximately equal because of similar catheter placement in the sagittal vein. Since we were without specific values for blood flow, we simply applied the label “unit” to the product. The comparison, however, remains valid. We constructed an uptake curve and determined the relative brain meperidine accumulation by integration. Although the intravenous administration produced a slightly higher uptake, 1,750 U versus 1,660 U, the significance of this difference cannot be evaluated but appears far less than the authors implied. After 60 minutes, the intramuscular example demonstrated some clearing with 1,000 U remaining in the brain following the intramuscular administration compared to 1,300 units in the intravenous example. Unfortunately.
Volume Number
140 5
Correspondence
the authors supplied insufficient data to estimate if consistent findings could be expected.. A lower blood concentration at arteriovenous equilibrium does not preclude greater organ uptake. As the authors mentioned, the actual amount of meperidine distributed to the fetal brain tissue depends on the partition coefficient between blood and brain tissue. Tissue affinities composed of lipid solubilities, tissue binding, and ion trapping can be satisfied for a particular level of free drug. Hence, brain concentration may exceed that of the blood. The longer time to arteriovenous equilibration allowed the similar brain uptake to occur despite lower arteriovenous differe,nces seen following intramuscular administration. In summary, we do not believe that the data supplied support the conclusion that the fetal brain exposure to meperidine was significantly greater following intravenous as compared to intramuscular administration. Roland L. Kennedy, M.D. Hansel deSousa, M.D. Department of Anesthesiology West Virginia University Medical Center Morgantown, West Virginia 26506
Reply to Drs. Kennedy and deSousa To the Editors: Drs. Kennedy and deSousa correctly pointed out that, given adequate data, fetal brain uptake of meperidine may be calculated by the method of Kety and Schmidt’: t = equil. Uptake = Q Cart.*1-C ve,n.t t=O
J
where Q is the rate of blood flow to the brain, C,,, is the concentration of drug in the brachiocephalic artery of drug in the at time t, and Cveln,t is the concentration sagittal vein at time t. The integral term is the total area between the curve for C,fi,t and Cvein,t. While their results calculated from the intramuscular
605
data are reasonable, it should be apparent that substantial errors are involved in calculating the area from the intravenous data. Following an intravenous bolus of meperidine, arterial drug concentrations fall in a rapid exponential manner, and the two data points, at 2 and 5 minutes, do not allow us to extrapolate a line back to t = 0 with any degree of confidence. As even greater drug concentrations might be expected prior to 2 minutes, we cannot place a certain upper bound on the area or, therefore, the brain uptake following intravenous administration. In their calculation of area, it appears that Kennedy and deSousa constructed a line from the t = 2 minute point back to the origin (t = 0, concentration = 0), which would grossly underestimate fetal brain uptake. Accepting the limitations of our data and the errors implicit in the assumptions necessary to execute the required calculations, we have not reported brain meperidine uptake following intravenous administration. We have instead reported the peak concentration of free meperidine in the fetal brain following intravenous and intramuscular administration. For reversibly acting drugs, it is actually more important to focus on the peak drug concentration at the site of action, rather than upon the integrated exposure to the drug over time.2 Our data, therefore, would suggest that the peak intensity of response in the fetus to meperidine is less following intramuscular administration. Hazel H. Szeto, Ph.D., M.D. Department of Pharmacology Cornell University Medical College 1300 York Avenue New York, New York 10021 REFERENCES
1. Kety, S. S., and Schmidt, C. F.: The nitrous oxide method for the quantitative determination of cerebral blood flow in man; Theory, procedure, and normal values, J. Clin. Invest. 27:476, 1948. 2. Levy, G., and Gibaldi, M.: Pharmacokinetics of drug action, Annu. Rev. Pharmacol. 14:85, 1972.