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Effect of low-dose dopamine therapy on catecholamine values in cerebrospinal fluid in preterm neonates
Volume 105 Number 3
7. Reichelderfer TE: Acute disulfiram Poisoning in a child. J Studies Alcohol 30:724, 1969. 8. Hotson JR, Langston JW: Disulfiram-inducedencephalopathy. Arch NeuroI 33:141, 1976. 9. Rainey JM Jr: Disulfiram toxicity and carbon disulfide poisoning. Am J Psychiatry 134:371, 1977.
Clinical and laboratory observations
48 9
10. Brien JF, Loomis CW: Disposition and pharmacokinetics of disulfiram and calcium carbimide. Drug Metab Rev 14:113, 1983.
Effect of low-dose dopamine therapy on catecholamine values in cerebrospinal fluid in preterm neonates I. Seri, M.D., T. Tulassay, M.D., J. Kiszel, M.D., E. Sulyok, M.D., T. Ertl, M.D., J. B6dis, M.D., and S. Csiim~ir, M.D. Budapest and Pbcs, Hungary
ALTHOUGH SOME DATA ARE AVAILABLE on the effect of dopamine on neonatal cardiovascular and renal functions, ~-6its exact mechanism of action is far from clear and no information on its effect on the central nervous system monoamine metabolism and on the dopamine-mediated endocrine system can be found. Because monoamines are intimately involved in the regulation of brain growth and functions in human neonates, 7 it seemed important to investigate whether intravenously administered dopamine crosses the blood-brain barrier in preterm sick neonates, and if itdoes, whether it causes any alterations in CNS monoamine metabolism. The importance of this question is stressed by the observations that in preterm infants given dopamine for systemic hypotension5 or oliguria,6 there is marked reduction in apneic episodes (unpublished data), and decreased urinary catecholamine excretion has been reported in premature neonates with apnea) Our study was conducted to determine the effect of low-dose dopamine infusion on the dopamine and noradrenaline levels in cerebrospinal flhid in preterm infants with perinatal infections.
METHODS Patients undergoing repeat lumbar puncture were enrolled in the study. Babies with symptoms of severe C N S lesions, postasphyxia, or hemorrhage were excluded. AI~i From the 1st Department of Gynecology and Obstetrics, Neonatal Intensive Care Unit, Semmelweis University Medical School; and Clinic of Gynecology and Obstetrics, University of Pbcs. Submitted for publication Aug. 5, 1983; accepted Feb. 17, 1984. Reprint requests." lstvhn Seri, M.D., Ist Department of Gynecology and Obstetrics, Neonatal Intensive Care Unit, Semmelweis University Medical School, H-I088 Budapest, Baross U 27, Hungary.
infants studied had perinatal infections. The reason for repeated spinal taps was to reveal CNS involvement (i.e., meningitis). In patients in whom the first lumbar puncture did not verify meningitis, but with clinical symptoms suspect of CNS involvement, repeat spinal tap was performed. Three infants were found to have meningitis at the first spinal tap, and two at the second lumbar puncture. These five infants were excluded from the study, and only neonates with repeatedly negative CSF samples were finally enrolled. Among them, l0 babies had not been given dopamine before the first lumbar puncture, but DA NA
Dopamine Noradrenaline
]
dopamine infusion (1 to 4 #g/kg/min) was later initiated for oliguria or systemic hypotension; the second CSF sample was obtained during dopamine treatment. The control group consisted of seven preterm neonates who did not receive dopamine infusion either before or after the first spinal tap. The average time between the two lumbar punctures in the treated and control groups was 18 and 17.7 hours, respectively. The CSF samples were frozen immediately and stored at - 2 5 ~ C until analyzed. DA and NA concentrations were determined by the spectrofluorimetric aluminum oxide adsorption procedure as modified by Hahn, 9 as follows. A high-pressure centrifugal filtration device, constructed from a disposable syringe, was used for solid-liquid separation, and facilitated considerably the aluminum oxide adsorption method of catecholamine determination: practically 100% recovery from the adsorbent in as little as 100 tzl eluent was achieved, and the total amount of catecholamines was transferred into the microcuvette of a fluorimeter. This resulted in a significant increase of sensitivity: the detection limit for both DA and NA was 0.1 ng/ml; the
490
Clinical and laboratory observations
The Journal of Pediatrics September 1984
Table. Dopamine and noradrenaline values
Spinal tap l Patient
CSF-DA (ng/ml)
Infants given dopamine 1 12.0 2 15.5 3 15.8 4 10.4 5 13.2 6 9.2 7 7.4 8 11.0 9 25.0 10 8.8 Mean 12.83 _+SD 5.08 Control infants 1 10.1 2 6.6 3 2.6 4 15.1 5 15.5 6 8.2 7 9.6 Mean 9.67:~ +SD 4.57
Spinal tap 2
CSF-NA (ng/ml)
CSF-DA (ng/ml)
CSF-NA (ng/ml)
0.8 1.3 2.0 1.6 0.8 0.2 1.0 3.5 6.6 1.6 1.94 1.86
20.4 30.0 36.0 14.6 19.8 14.0 9.0 27.0 38.0 9.6 21.84"t 10.48
1.9 3,0 3.0 3.0 2.2 1.6 0.9 5.2 10.0 3.0 3.38:~w 2.61
7.1 10.1 3.5 14.2 16.1 8.1 8.9 9.7 4.29
0.5 1.5 0.5 0.7 4.0 2.9 1.2 1.59 1.34
0.6 0.8 0.3 0.9 5.6 2.5 0.9 1.6511 1.87
*P < 0.005 vs pretreatment values in the treated group. t P < 0.025 vs CSF-DA values obtained in the control group at the second spinal tap. :~P < 0.05 vs CSF-NA values obtained in the control group at the second spinaT tap. w < 0.001 vs pretreatment values in the treated group. IINot significant vs pretreatment values in the treated group.
intra-assay coefficient of variation was no more than 10%. The Student paired t test was used for statistical analysis. The infants studied were born to healthy mothers after premature rupture of the membranes. None of the mothers had received antihypertensive, #-sympathomimetic, parasympatholytic, or sedative drugs known to influence catecholamine metabolism. '~ In the infants given dopamine, mean birth weight was 1722 _+ 480 gm and mean gestational age 32 _+ 2.7 weeks, and in the control group was 1557 _+ 463 gm and 30.3 + 2.6 weeks, respectively. There were no significant differences between the groups with respect to birth weight, gestational age, and postnatal age at the time of spinal tap. The infants in the control group had only moderate signs of cardiovascular or renal dysfunction compared with the neonates in the treated group, and did not require dopamine therapy. From this point of view the control group might not be considered ideal, but were the only infants clinically available. Eight of the 10 infants in the treated
group and five of the seven in the control group survived. The study was carried out with the approval of the institutional scientific review committee, and informed parental consent was obtained. RESULTS Dopamine administration resulted in a statistically significant increase in CSF-DA, from a mean value of 12.8 _+ 5.08 mg/ml to 21.8 +__ 10.48 ng/ml (P < 0.005) (Table). This increase was detected in each infant, irrespective of the initial values and the dose and duration of drug administration. Similarly, CSF-NA responded to dopamine infusion with a significant elevation, from a mean value of 1.94 _ 1.86 ng/ml to 3.38 + 2.61 ng/ml (P 0.001). The response pattern was essentially the same in all but one infant, in whom there was no change in CSF-NA level. No elevations occurred in the mean values of CSF-DA and CSF-NA in the infants who did not receive dopamine. There were no significant differences between the groups with respect to the baseline values of CSF-DA and CSF-NA, whereas the values of these monoamines obtained during dopamine treatment showed a statistically significant difference (P < 0.025 and P < 0.05, respectively) compared with the values of the second CSF samples in the control group. DISCUSSION Our data provide convincing evidence that in sick preterm infants systemic administration of dopamine results in a significant elevation in CSF-DA and CSF-NA. These changes are not related to the specific illness, to the age of the infants, or to the lumbar puncture, because no elevations occurred in the CSF monoamine levels in the neonates not given dopamine. Our findings suggest that under such clinical conditions DA crosses the blood-brain barrier and induces marked changes in cerebral monoamine metabolism, as reflected by the fact that elevations occurred not only in CSF-DA :Out also in CSF-NA, which is converted from DA by the dopamine #-hydroxylase enzyme. The permeability of the blood-brain barrier is greatly increased, even in ;the healthy term neonate, for various substances. In adults, dopamine administered intravenously does not alter CSF monoamine levels, 1~ but our results indicate the opposite in sick preterm infants. According to our preliminary observations, plasma DA concentrations in preterm infants during dopamine administration in a dose of 2 /~g/kg/min are extremely high, with an average value of 440 nM. This excessive elevation probably reflects the decrea'sed metabolic clearance rate, which results from the increased plasma half-life, as~eompared with that
Volume 105 Number 3
in adults: 4 to 5 minutes versus 2 minutes (unpublished data). Data on C S F monoamines in neonates are few. In a recent study by B6dis et al., 12 a striking depression of C S F - N A was demonstrated in newborn infants born to mothers receiving long-term methyldopa therapy. The same authors reported that, in response to perinatal asphyxia, C S F - N A increased in full-term infants, whereas it significantly decreased in preterm neonates? 3 Moreover, premature infants with apneic episodes excrete considerably less catecholamine in urine than neonates of the same gestational age without apnea? M o r e recent studies did not confirm these observations, TM ~s but the role of a less developed central monoaminergic System cannot be ruled out. ~5 It is reasonable to assume that neonatal dopamine administration and thereby altered cerebral monoamine metabolism may result in neurohormonal changes; the altered cerebral monoamine system may contribute to alterations of endocrine functions under dopaminergic control. Characterization of these changes requires further investigation.
Clinical and laboratory observations
5.
6.
7. 8.
9.
10. 11.
12.
REFERENCES 1. Drummond WH, Gregory GA, Heymann MA, Phibbs RA: The independent effects of hyperventilation, tolazoline and dopamine on infants with persistent pulmonary hypertension. J PEDIATR98:603, 1981. 2. Fiddler G 1, Chatrach R, Williams G J, Walker DR, Scott O: Dopamine infusion for the treatment of myocardial dysfunction associated with a persistent transitional circulation. Arch Dis Child 55:194, 1980. 3. Hegyi T, Hiatt IM: Tolazoline and dopamine therapy in neonatal hypoxia and pulmonary vasospasm. Acta Paediatr Scand 69:101, 1980. 4. DiSess a TG, Leitner M, Ti CC, Gluck L, Coen R, Friedman
13.
14.
15.
49 1
WF: The cardiovascular effects of dopamine in the severely asphyxiated neonate. J PEDIATR99:772, 1982. Seri I, Tulassay T, Kiszel J, Machay T, Cs6m6r S: The cardiovascular effects of dopamine in hypotensive preterm neonates with severe hyaline membrane disease. Eur J Pediatr 142:3, 1984. Tulassay T, Seri I, Machay T, Kiszel J, Varga J, Cs6m6r S: Effects of dopamine on renal functions in premature neonates with respiratory distress syndrome. Int J Pediatr Nephrol 4:19, 1983. Johnston MV, Singer HV: Brain neurotransmitters and neuromodulators in pediatrics. Pediatrics 70:57, 1982. Kattwinkel J, Mars H, Fanaroff HH, Klaus MH: Urinary biogenic amines in idiopathic apnea of prematurity. J PED~ATR 88:1003, 1976. Hahn Z: Centrifugal microfiltration: A simple way to enhance the sensitivity of the classical aluminum oxide adsorption method of fluorimetric catecholamine determination. J Biochem Biophys Methods 2:163, 1980. Wood JH: Neurochemical analysis of cerebrospinal fluid. Neurology 30:645, 1980. Kopin IJ: Measuring turnover of neurotransmitters in human brain. In Lipton AM, DiMacio A, Killam KF, editors: Psychopharmacology: A generation of progress. New York, 1978, Raven Press, p 936. B6dis J, Sulyok E, Ertl T, Hartmann G, Varga L, Csaba IF: Methyldopa in pregnancy hypertension and the newborn. Lancet 2:498, 1982. B6dis J, Hartmann G, Ertl T, Csaba ! F , Sulyok E: The noradrenaline contant of the CSF in normal and in asphyxiated preterm and term infants. Acta Paediatr Hung (In press.) Bhat AM, Scanlon JW, Lavenstein B, Chuang L, Karoum F: Cerebrospinal fluid concentration of biogenic amine metabolites in idiopathic apnea of prematurity. Biol Neonate 43:16, 1983. Lagercrantz H, Sj6quist B: Deficient sympathoadrenal activity. A cause of apnea? Urinary excretion of catecholamines and their metabolites in preterm infants. Early Hum Dev 4:405, 1980.
Nephrotoxicity associated with vancomycin-aminoglycoside therapy in four children Carla Odio, M.D., George H. McCracken, Jr., M.D., and John D. Nelson, M.D. Dallas, T e x a s
From the Department of Pediatrics University of Texas Health Science Center, Dallas. Submitted for pubBcation Jan. 3, 1984; accepted Feb. 17, 1984. Reprint requests: George H. MeCraeken, Jr., M.D., Department of Pediatrics, University of Texas Health Science Center, Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235.
WHEN VANCOMYCIN WAS I~TRODUCED into clinical practice, ototoxicity and nephr0toxicity were said to occur commonly, although the exact incidence of these toxic effects was difficult to document. It was postulated that impurities present in earlier formulations of vancomycin, and removed from more recent formulations, were respon-
7. Reichelderfer TE: Acute disulfiram Poisoning in a child. J Studies Alcohol 30:724, 1969. 8. Hotson JR, Langston JW: Disulfiram-inducedencephalopathy. Arch NeuroI 33:141, 1976. 9. Rainey JM Jr: Disulfiram toxicity and carbon disulfide poisoning. Am J Psychiatry 134:371, 1977.
Clinical and laboratory observations
48 9
10. Brien JF, Loomis CW: Disposition and pharmacokinetics of disulfiram and calcium carbimide. Drug Metab Rev 14:113, 1983.
Effect of low-dose dopamine therapy on catecholamine values in cerebrospinal fluid in preterm neonates I. Seri, M.D., T. Tulassay, M.D., J. Kiszel, M.D., E. Sulyok, M.D., T. Ertl, M.D., J. B6dis, M.D., and S. Csiim~ir, M.D. Budapest and Pbcs, Hungary
ALTHOUGH SOME DATA ARE AVAILABLE on the effect of dopamine on neonatal cardiovascular and renal functions, ~-6its exact mechanism of action is far from clear and no information on its effect on the central nervous system monoamine metabolism and on the dopamine-mediated endocrine system can be found. Because monoamines are intimately involved in the regulation of brain growth and functions in human neonates, 7 it seemed important to investigate whether intravenously administered dopamine crosses the blood-brain barrier in preterm sick neonates, and if itdoes, whether it causes any alterations in CNS monoamine metabolism. The importance of this question is stressed by the observations that in preterm infants given dopamine for systemic hypotension5 or oliguria,6 there is marked reduction in apneic episodes (unpublished data), and decreased urinary catecholamine excretion has been reported in premature neonates with apnea) Our study was conducted to determine the effect of low-dose dopamine infusion on the dopamine and noradrenaline levels in cerebrospinal flhid in preterm infants with perinatal infections.
METHODS Patients undergoing repeat lumbar puncture were enrolled in the study. Babies with symptoms of severe C N S lesions, postasphyxia, or hemorrhage were excluded. AI~i From the 1st Department of Gynecology and Obstetrics, Neonatal Intensive Care Unit, Semmelweis University Medical School; and Clinic of Gynecology and Obstetrics, University of Pbcs. Submitted for publication Aug. 5, 1983; accepted Feb. 17, 1984. Reprint requests." lstvhn Seri, M.D., Ist Department of Gynecology and Obstetrics, Neonatal Intensive Care Unit, Semmelweis University Medical School, H-I088 Budapest, Baross U 27, Hungary.
infants studied had perinatal infections. The reason for repeated spinal taps was to reveal CNS involvement (i.e., meningitis). In patients in whom the first lumbar puncture did not verify meningitis, but with clinical symptoms suspect of CNS involvement, repeat spinal tap was performed. Three infants were found to have meningitis at the first spinal tap, and two at the second lumbar puncture. These five infants were excluded from the study, and only neonates with repeatedly negative CSF samples were finally enrolled. Among them, l0 babies had not been given dopamine before the first lumbar puncture, but DA NA
Dopamine Noradrenaline
]
dopamine infusion (1 to 4 #g/kg/min) was later initiated for oliguria or systemic hypotension; the second CSF sample was obtained during dopamine treatment. The control group consisted of seven preterm neonates who did not receive dopamine infusion either before or after the first spinal tap. The average time between the two lumbar punctures in the treated and control groups was 18 and 17.7 hours, respectively. The CSF samples were frozen immediately and stored at - 2 5 ~ C until analyzed. DA and NA concentrations were determined by the spectrofluorimetric aluminum oxide adsorption procedure as modified by Hahn, 9 as follows. A high-pressure centrifugal filtration device, constructed from a disposable syringe, was used for solid-liquid separation, and facilitated considerably the aluminum oxide adsorption method of catecholamine determination: practically 100% recovery from the adsorbent in as little as 100 tzl eluent was achieved, and the total amount of catecholamines was transferred into the microcuvette of a fluorimeter. This resulted in a significant increase of sensitivity: the detection limit for both DA and NA was 0.1 ng/ml; the
490
Clinical and laboratory observations
The Journal of Pediatrics September 1984
Table. Dopamine and noradrenaline values
Spinal tap l Patient
CSF-DA (ng/ml)
Infants given dopamine 1 12.0 2 15.5 3 15.8 4 10.4 5 13.2 6 9.2 7 7.4 8 11.0 9 25.0 10 8.8 Mean 12.83 _+SD 5.08 Control infants 1 10.1 2 6.6 3 2.6 4 15.1 5 15.5 6 8.2 7 9.6 Mean 9.67:~ +SD 4.57
Spinal tap 2
CSF-NA (ng/ml)
CSF-DA (ng/ml)
CSF-NA (ng/ml)
0.8 1.3 2.0 1.6 0.8 0.2 1.0 3.5 6.6 1.6 1.94 1.86
20.4 30.0 36.0 14.6 19.8 14.0 9.0 27.0 38.0 9.6 21.84"t 10.48
1.9 3,0 3.0 3.0 2.2 1.6 0.9 5.2 10.0 3.0 3.38:~w 2.61
7.1 10.1 3.5 14.2 16.1 8.1 8.9 9.7 4.29
0.5 1.5 0.5 0.7 4.0 2.9 1.2 1.59 1.34
0.6 0.8 0.3 0.9 5.6 2.5 0.9 1.6511 1.87
*P < 0.005 vs pretreatment values in the treated group. t P < 0.025 vs CSF-DA values obtained in the control group at the second spinal tap. :~P < 0.05 vs CSF-NA values obtained in the control group at the second spinaT tap. w < 0.001 vs pretreatment values in the treated group. IINot significant vs pretreatment values in the treated group.
intra-assay coefficient of variation was no more than 10%. The Student paired t test was used for statistical analysis. The infants studied were born to healthy mothers after premature rupture of the membranes. None of the mothers had received antihypertensive, #-sympathomimetic, parasympatholytic, or sedative drugs known to influence catecholamine metabolism. '~ In the infants given dopamine, mean birth weight was 1722 _+ 480 gm and mean gestational age 32 _+ 2.7 weeks, and in the control group was 1557 _+ 463 gm and 30.3 + 2.6 weeks, respectively. There were no significant differences between the groups with respect to birth weight, gestational age, and postnatal age at the time of spinal tap. The infants in the control group had only moderate signs of cardiovascular or renal dysfunction compared with the neonates in the treated group, and did not require dopamine therapy. From this point of view the control group might not be considered ideal, but were the only infants clinically available. Eight of the 10 infants in the treated
group and five of the seven in the control group survived. The study was carried out with the approval of the institutional scientific review committee, and informed parental consent was obtained. RESULTS Dopamine administration resulted in a statistically significant increase in CSF-DA, from a mean value of 12.8 _+ 5.08 mg/ml to 21.8 +__ 10.48 ng/ml (P < 0.005) (Table). This increase was detected in each infant, irrespective of the initial values and the dose and duration of drug administration. Similarly, CSF-NA responded to dopamine infusion with a significant elevation, from a mean value of 1.94 _ 1.86 ng/ml to 3.38 + 2.61 ng/ml (P 0.001). The response pattern was essentially the same in all but one infant, in whom there was no change in CSF-NA level. No elevations occurred in the mean values of CSF-DA and CSF-NA in the infants who did not receive dopamine. There were no significant differences between the groups with respect to the baseline values of CSF-DA and CSF-NA, whereas the values of these monoamines obtained during dopamine treatment showed a statistically significant difference (P < 0.025 and P < 0.05, respectively) compared with the values of the second CSF samples in the control group. DISCUSSION Our data provide convincing evidence that in sick preterm infants systemic administration of dopamine results in a significant elevation in CSF-DA and CSF-NA. These changes are not related to the specific illness, to the age of the infants, or to the lumbar puncture, because no elevations occurred in the CSF monoamine levels in the neonates not given dopamine. Our findings suggest that under such clinical conditions DA crosses the blood-brain barrier and induces marked changes in cerebral monoamine metabolism, as reflected by the fact that elevations occurred not only in CSF-DA :Out also in CSF-NA, which is converted from DA by the dopamine #-hydroxylase enzyme. The permeability of the blood-brain barrier is greatly increased, even in ;the healthy term neonate, for various substances. In adults, dopamine administered intravenously does not alter CSF monoamine levels, 1~ but our results indicate the opposite in sick preterm infants. According to our preliminary observations, plasma DA concentrations in preterm infants during dopamine administration in a dose of 2 /~g/kg/min are extremely high, with an average value of 440 nM. This excessive elevation probably reflects the decrea'sed metabolic clearance rate, which results from the increased plasma half-life, as~eompared with that
Volume 105 Number 3
in adults: 4 to 5 minutes versus 2 minutes (unpublished data). Data on C S F monoamines in neonates are few. In a recent study by B6dis et al., 12 a striking depression of C S F - N A was demonstrated in newborn infants born to mothers receiving long-term methyldopa therapy. The same authors reported that, in response to perinatal asphyxia, C S F - N A increased in full-term infants, whereas it significantly decreased in preterm neonates? 3 Moreover, premature infants with apneic episodes excrete considerably less catecholamine in urine than neonates of the same gestational age without apnea? M o r e recent studies did not confirm these observations, TM ~s but the role of a less developed central monoaminergic System cannot be ruled out. ~5 It is reasonable to assume that neonatal dopamine administration and thereby altered cerebral monoamine metabolism may result in neurohormonal changes; the altered cerebral monoamine system may contribute to alterations of endocrine functions under dopaminergic control. Characterization of these changes requires further investigation.
Clinical and laboratory observations
5.
6.
7. 8.
9.
10. 11.
12.
REFERENCES 1. Drummond WH, Gregory GA, Heymann MA, Phibbs RA: The independent effects of hyperventilation, tolazoline and dopamine on infants with persistent pulmonary hypertension. J PEDIATR98:603, 1981. 2. Fiddler G 1, Chatrach R, Williams G J, Walker DR, Scott O: Dopamine infusion for the treatment of myocardial dysfunction associated with a persistent transitional circulation. Arch Dis Child 55:194, 1980. 3. Hegyi T, Hiatt IM: Tolazoline and dopamine therapy in neonatal hypoxia and pulmonary vasospasm. Acta Paediatr Scand 69:101, 1980. 4. DiSess a TG, Leitner M, Ti CC, Gluck L, Coen R, Friedman
13.
14.
15.
49 1
WF: The cardiovascular effects of dopamine in the severely asphyxiated neonate. J PEDIATR99:772, 1982. Seri I, Tulassay T, Kiszel J, Machay T, Cs6m6r S: The cardiovascular effects of dopamine in hypotensive preterm neonates with severe hyaline membrane disease. Eur J Pediatr 142:3, 1984. Tulassay T, Seri I, Machay T, Kiszel J, Varga J, Cs6m6r S: Effects of dopamine on renal functions in premature neonates with respiratory distress syndrome. Int J Pediatr Nephrol 4:19, 1983. Johnston MV, Singer HV: Brain neurotransmitters and neuromodulators in pediatrics. Pediatrics 70:57, 1982. Kattwinkel J, Mars H, Fanaroff HH, Klaus MH: Urinary biogenic amines in idiopathic apnea of prematurity. J PED~ATR 88:1003, 1976. Hahn Z: Centrifugal microfiltration: A simple way to enhance the sensitivity of the classical aluminum oxide adsorption method of fluorimetric catecholamine determination. J Biochem Biophys Methods 2:163, 1980. Wood JH: Neurochemical analysis of cerebrospinal fluid. Neurology 30:645, 1980. Kopin IJ: Measuring turnover of neurotransmitters in human brain. In Lipton AM, DiMacio A, Killam KF, editors: Psychopharmacology: A generation of progress. New York, 1978, Raven Press, p 936. B6dis J, Sulyok E, Ertl T, Hartmann G, Varga L, Csaba IF: Methyldopa in pregnancy hypertension and the newborn. Lancet 2:498, 1982. B6dis J, Hartmann G, Ertl T, Csaba ! F , Sulyok E: The noradrenaline contant of the CSF in normal and in asphyxiated preterm and term infants. Acta Paediatr Hung (In press.) Bhat AM, Scanlon JW, Lavenstein B, Chuang L, Karoum F: Cerebrospinal fluid concentration of biogenic amine metabolites in idiopathic apnea of prematurity. Biol Neonate 43:16, 1983. Lagercrantz H, Sj6quist B: Deficient sympathoadrenal activity. A cause of apnea? Urinary excretion of catecholamines and their metabolites in preterm infants. Early Hum Dev 4:405, 1980.
Nephrotoxicity associated with vancomycin-aminoglycoside therapy in four children Carla Odio, M.D., George H. McCracken, Jr., M.D., and John D. Nelson, M.D. Dallas, T e x a s
From the Department of Pediatrics University of Texas Health Science Center, Dallas. Submitted for pubBcation Jan. 3, 1984; accepted Feb. 17, 1984. Reprint requests: George H. MeCraeken, Jr., M.D., Department of Pediatrics, University of Texas Health Science Center, Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235.
WHEN VANCOMYCIN WAS I~TRODUCED into clinical practice, ototoxicity and nephr0toxicity were said to occur commonly, although the exact incidence of these toxic effects was difficult to document. It was postulated that impurities present in earlier formulations of vancomycin, and removed from more recent formulations, were respon-