- Email: [email protected]
Reply to: Hypotension in preterm infants
16 0
Editorial correspondence
The Journal of Pediatrics January 1995
of suppression sufficient? In these situations, investigators have increased the dosage in the hope that more drug wilt be absorbed, or have altered dose frequency to every 3 weeks, although there are no data to substantiate the efficacy of either strategy. Despite the occasional injection reactions, the convenience and excellent clinical and biochemical suppression promptly attained in 95% of cases make this the drug of choice for CPP. Depot leuprolide, for whatever mix of medical and marketing reasons, has now captured virtually all of the U.S. market for treatment of CPP (a small market in comparison with that for prostate cancer). Leuprolide is the only GnRH analog in depot and daily forms in the United States, whereas other analogs are available only as daily injections (histrelin, deslorelin) or nasal spray (nafarelin). These are excellent alternatives when local reactions are persistent and efficacy is diminished. The approach to managing CPP with depot leuprolide described by Tonini and colleagues, and seemingly prevalent in Europe, diverges in potentially problematic ways from that in the United States. Standard practice here is to use at least 7.5 mg at the start of therapy, but at least some European and Japanese practitioners are using the lower dose of 3.75 mg. Although there is evidence that doses less than 7.5 mg can be effective after therapy is initiated,3 such a reduced dose certainly mandates scrupulous monitoring of hormone levels. Because depot GnRH analog therapy is not completely suppressive in 100% of cases, we hope that clinicians in both the United States and Europe will continue to survey gonadotropin levels during therapy, particularly in patients with a history of injection reactions.
E. Kirk Neely, MD Darrell M. Wilson, MD Department of Pediatrics Stanford University Stanford CA 94305 9/35/60557 REFERENCES 1. Neely EK, Hintz RL, Parker B, et al. Two-year results of treatment with depot leuprolide acetate for central precocious puberty. J PEDIATR 1992;121:634-40. 2. Neely EK, Wilson DM, Hintz RL. Local reactions to depot leuprolide acetate for central precocious puberty [Letter reply]. J PEDIATR 1993;123:335. 3. Parker KL, Baens-Bailon RG, Lee PA. Depot leuprolide acetate dosage for sexual precocity. J Clin Endocrinol Metab 1991;73:50-2.
Hypotension in preterm infants
pressure and the pulse pressure. 2 In addition, it may affect the responses to the two agents if there are relatively different effects on the systemic and pulmonary vascular resistances, as noted in the discussion. Second, was there prenatal and/or postnatal exposure to prostaglandin synthase inhibition? Finally, was there prenatal and/or postnatal exposure to corticosteroids, which are known to enhance vascular responses to noradrenaline? 3 This may be particularly important at higher doses of dopamine. I have a pet peeve about solely reporting the blood pressure in terms of mean arterial blood pressure. Multiple different pulsatile pressure waveforms can yield the same mean arterial blood pressure. The analog signal of the blood pressure has tremendous information content. For example, the area under the systolic portion of the analog signal is proportional to the stroke volume. 4 In addition, the rate of diastolic pressure decay is a function of both vascular resistance and compliance, but for most vascular beds, resistance is the major determinant.5 Such information may provide some insight regarding the derangements responsible for the hypotension, which, in turn, may be predictive of the responses to inotropic and vasoactive agents or to volume expansion. Therefore I encourage inspection of the analog signal as opposed to the mean arterial blood pressure alone, because of the information content.
Jay M. Milstein, MD Division of Neonatology Research Laboratory- TB 193 University of California Davis, CA 95616-8646 9/35/60560 REFERENCES 1. Klarr JM, Faix RG, Pryce CJE, Bhatt-Mehta V. Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. J PEDIATR 1994;125:117-22. 2. Milstein JM, Riemenschneider TA, Goetzman BW, George L, Wennberg RP. Assessment of patent ductus arteriosus shunting using diastolic pressure analysis. J PEDIATR 1979;94:122-6. 3. Walker BR, Connacher AA, Webb D J, Edwards RW. Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of ~,ascular tone in man. Clin Sci 19.92;83:171-8. 4. Bourgeois MF, Gilbert BK, Bernuth GV, Wood EH. Continuous determination of beat-to-beat stroke volume from aortic pressure pulses in the dog. Circulation Res 1976;39:15-24. 5. Milstein JM, Juris AL. Aortic diastolic pressure decay in congenital arteriovenous malformations. Pediatr Cardiol 1993; 14:204-7.
Reply
To the Editor: The article by Klarr et al. 1 on the use of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome during the first 24 hours of life raised several questions. First, what was the incidence of the patent ductus arteriosus (PDA) in the two treatment groups? These data were not reported, but a PDA influences both the mean arterial blood
To the Editor: No hemodynamically significant patent ductus arteriosus was detected by clinical examination (including pulse pressure determination), chest radiography, or echocardiography in either group during the relatively brief duration of the study protocol, although echocardiography was not performed in all patients. After comple-
The Journal of Pediatrics Volume 126, Number 1
Editorial correspondence
tion of the study protocol, 6 of 31 dopamine and 10 of 32 dobutamine recipients (p = 0.39) eventually had a significant patent ductus arteriosus that required indomethacin therapy or surgical ligation before hospital discharge. This information was contained in the original manuscript but was deleted from the revision. No infant in either group was exposed to indomethacin tocolysis or received that drug postnatally before or during the study drug protocol. We have no information about maternal consumption of over-the-counter prostaglandin synthase inhibitors (e.g., aspirin, ibuprofen) before admission to the labor and delivery suite. Antenatal corticosteroid therapy was received by four dopamine and two dobutamine recipients (p = 0.32). As indicated in the Resuits section of the published article, no infant in either group received postnatal dexamethasone (or other glucocorticoid) before or during the study drug infusions. We agree that mean arterial blood pressure is only one indicator of hemodynamic performance and that clinically important supplemental information can be derived from many other sources, including (but not limited to) arterial pressure waveform. Such additional information may be useful for therapeutic decisions. We selected mean arterial blood pressure as the primary end point for our trial because (1) it is an index that can be measured easily and reproducibly in most neonatal intensive care units, (2) it has been used in many other reports addressing the treatment of hypotension in preterm infants (references 1 and 2, for example), and (3) other authors have noted the significant association of low mean arterial blood pressure with adverse neurologic outcomes in preterm infants)
Roger G. Faix, MD Associate Professor of Pediatrics Director of Newborn Services and Neonatal-Perinatal Fellowship Program Division of Neonatology Mott Children's Hospital Ann Arbor, MI 48109-0254 9/35/60559. REFERENCES 1. Roze JC, Tohier C, Maingueneau C, Lefevre M, Mouzard A. Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child 1993;69:59-63. 2. Miall-Allen VM, Whitelaw AG. Response to dopamine and dobutamine in the preterm infant of less than 30 weeks' gestation. Crit Care Med 1989;17:1166-9. 3. Miall-Allen VM, de Vries L, Whitelaw AG. Mean arterial pressure and neonatal cerebral lesions. Arch Dis Child 1987;62:1068-9.
Terbutaline powder for acute asthma To the Editor: We read with interest the article by Laberge et al., ~who pointed out the necessity of testing the efficacy of a dry powder inhaler in children with acute moderate asthma. We have compared the efficacy of 0.5 mg of terbutaline inhaled either with a Turbuhaler
16 1
Table. Bronchodilator response to terbutaline: Percentage of improvement from baseline (mean + SD)
At 15 rain Specific airway resistance (cm H20/L/sec) Forced expiratory volume in 1 second (ml) Peak expiratory flow rate (L/min) At 30 rain Specific airway resistance (cm H20/L/sec) Forced expiratory volume in 1 second (ml) Peak expiratory flow rate (L/min)
Dry powder inhaler
Metered-dose inhaler with spacer
-51.1 _+ 12.9
-47.7 _+ 10.9
+16.4 + 14.2
+23.2 + 19.1
+26.6 + 20.7
+16.0 _+ 10.8
-52.9 _+ 14.3
-54.2 _+ 7.8
+19.8 _+ 1 3 . 6
+27.0 _+ 13.4
+30.4 _+ 24.2
+26.7 + 24.5
(Astro Draco AB, Sweden) or with a metered-doseinhaler attached to a spacer (Nebuhaler, Astra Draco AB) in 30 5- to 14-year old children with acute wheezing. These children with asthma were included in an open, randomized parallel group study (15 children in each group). Administration of the drug was similar to that in the study by Laberge et al. We measured the following parameters before and 15 and 30 minutes after inhalation: specific airway resistance (in centimeters of water displaced per liter per second; body plethysmograph mode I 2800, Physiosystem, Noisy Le Grand, France), forced expiratory volume in 1 second in milliliters; Pulmonet III, Gould Medical, Runois, France), and peak expiratory flow rate (in liters per minute; mini Wright). Basal obstruction was similar in both groups (dry powder inhaler, 14.2 _+ 3.7 cm HzO/L per second; metered-dose inhaler with a spacer, 14.0 _+ 3.3 cm HzO/L per second). The Table shows that both inhalational techniques improved lung functions compared with baseline (p <0.01). There was no difference between treatments at any time (Mann-Whitney U test). Clinical efficacy and tolerance were excellent. These results2 confirm our preliminary study3 and demonstrate the efficacy of terbutaline powder in chil2: dren older than 5 years of age who have acute moderate asthmL
e. Rufin, MD M. R. Benoist, MD J. de Blic, MD P. Scheinmann, MD Departmen'ts of Pneumonology and Pediatric Allergy Hbpital des Enfants Malades Paris, France 9/35/60736 REFERENCES 1. Laberge S, Spier S, Drblik SP, Turgeon JP. Comparison of inhaled terbutaline administered by either the Turbuhaler dry
Editorial correspondence
The Journal of Pediatrics January 1995
of suppression sufficient? In these situations, investigators have increased the dosage in the hope that more drug wilt be absorbed, or have altered dose frequency to every 3 weeks, although there are no data to substantiate the efficacy of either strategy. Despite the occasional injection reactions, the convenience and excellent clinical and biochemical suppression promptly attained in 95% of cases make this the drug of choice for CPP. Depot leuprolide, for whatever mix of medical and marketing reasons, has now captured virtually all of the U.S. market for treatment of CPP (a small market in comparison with that for prostate cancer). Leuprolide is the only GnRH analog in depot and daily forms in the United States, whereas other analogs are available only as daily injections (histrelin, deslorelin) or nasal spray (nafarelin). These are excellent alternatives when local reactions are persistent and efficacy is diminished. The approach to managing CPP with depot leuprolide described by Tonini and colleagues, and seemingly prevalent in Europe, diverges in potentially problematic ways from that in the United States. Standard practice here is to use at least 7.5 mg at the start of therapy, but at least some European and Japanese practitioners are using the lower dose of 3.75 mg. Although there is evidence that doses less than 7.5 mg can be effective after therapy is initiated,3 such a reduced dose certainly mandates scrupulous monitoring of hormone levels. Because depot GnRH analog therapy is not completely suppressive in 100% of cases, we hope that clinicians in both the United States and Europe will continue to survey gonadotropin levels during therapy, particularly in patients with a history of injection reactions.
E. Kirk Neely, MD Darrell M. Wilson, MD Department of Pediatrics Stanford University Stanford CA 94305 9/35/60557 REFERENCES 1. Neely EK, Hintz RL, Parker B, et al. Two-year results of treatment with depot leuprolide acetate for central precocious puberty. J PEDIATR 1992;121:634-40. 2. Neely EK, Wilson DM, Hintz RL. Local reactions to depot leuprolide acetate for central precocious puberty [Letter reply]. J PEDIATR 1993;123:335. 3. Parker KL, Baens-Bailon RG, Lee PA. Depot leuprolide acetate dosage for sexual precocity. J Clin Endocrinol Metab 1991;73:50-2.
Hypotension in preterm infants
pressure and the pulse pressure. 2 In addition, it may affect the responses to the two agents if there are relatively different effects on the systemic and pulmonary vascular resistances, as noted in the discussion. Second, was there prenatal and/or postnatal exposure to prostaglandin synthase inhibition? Finally, was there prenatal and/or postnatal exposure to corticosteroids, which are known to enhance vascular responses to noradrenaline? 3 This may be particularly important at higher doses of dopamine. I have a pet peeve about solely reporting the blood pressure in terms of mean arterial blood pressure. Multiple different pulsatile pressure waveforms can yield the same mean arterial blood pressure. The analog signal of the blood pressure has tremendous information content. For example, the area under the systolic portion of the analog signal is proportional to the stroke volume. 4 In addition, the rate of diastolic pressure decay is a function of both vascular resistance and compliance, but for most vascular beds, resistance is the major determinant.5 Such information may provide some insight regarding the derangements responsible for the hypotension, which, in turn, may be predictive of the responses to inotropic and vasoactive agents or to volume expansion. Therefore I encourage inspection of the analog signal as opposed to the mean arterial blood pressure alone, because of the information content.
Jay M. Milstein, MD Division of Neonatology Research Laboratory- TB 193 University of California Davis, CA 95616-8646 9/35/60560 REFERENCES 1. Klarr JM, Faix RG, Pryce CJE, Bhatt-Mehta V. Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. J PEDIATR 1994;125:117-22. 2. Milstein JM, Riemenschneider TA, Goetzman BW, George L, Wennberg RP. Assessment of patent ductus arteriosus shunting using diastolic pressure analysis. J PEDIATR 1979;94:122-6. 3. Walker BR, Connacher AA, Webb D J, Edwards RW. Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of ~,ascular tone in man. Clin Sci 19.92;83:171-8. 4. Bourgeois MF, Gilbert BK, Bernuth GV, Wood EH. Continuous determination of beat-to-beat stroke volume from aortic pressure pulses in the dog. Circulation Res 1976;39:15-24. 5. Milstein JM, Juris AL. Aortic diastolic pressure decay in congenital arteriovenous malformations. Pediatr Cardiol 1993; 14:204-7.
Reply
To the Editor: The article by Klarr et al. 1 on the use of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome during the first 24 hours of life raised several questions. First, what was the incidence of the patent ductus arteriosus (PDA) in the two treatment groups? These data were not reported, but a PDA influences both the mean arterial blood
To the Editor: No hemodynamically significant patent ductus arteriosus was detected by clinical examination (including pulse pressure determination), chest radiography, or echocardiography in either group during the relatively brief duration of the study protocol, although echocardiography was not performed in all patients. After comple-
The Journal of Pediatrics Volume 126, Number 1
Editorial correspondence
tion of the study protocol, 6 of 31 dopamine and 10 of 32 dobutamine recipients (p = 0.39) eventually had a significant patent ductus arteriosus that required indomethacin therapy or surgical ligation before hospital discharge. This information was contained in the original manuscript but was deleted from the revision. No infant in either group was exposed to indomethacin tocolysis or received that drug postnatally before or during the study drug protocol. We have no information about maternal consumption of over-the-counter prostaglandin synthase inhibitors (e.g., aspirin, ibuprofen) before admission to the labor and delivery suite. Antenatal corticosteroid therapy was received by four dopamine and two dobutamine recipients (p = 0.32). As indicated in the Resuits section of the published article, no infant in either group received postnatal dexamethasone (or other glucocorticoid) before or during the study drug infusions. We agree that mean arterial blood pressure is only one indicator of hemodynamic performance and that clinically important supplemental information can be derived from many other sources, including (but not limited to) arterial pressure waveform. Such additional information may be useful for therapeutic decisions. We selected mean arterial blood pressure as the primary end point for our trial because (1) it is an index that can be measured easily and reproducibly in most neonatal intensive care units, (2) it has been used in many other reports addressing the treatment of hypotension in preterm infants (references 1 and 2, for example), and (3) other authors have noted the significant association of low mean arterial blood pressure with adverse neurologic outcomes in preterm infants)
Roger G. Faix, MD Associate Professor of Pediatrics Director of Newborn Services and Neonatal-Perinatal Fellowship Program Division of Neonatology Mott Children's Hospital Ann Arbor, MI 48109-0254 9/35/60559. REFERENCES 1. Roze JC, Tohier C, Maingueneau C, Lefevre M, Mouzard A. Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child 1993;69:59-63. 2. Miall-Allen VM, Whitelaw AG. Response to dopamine and dobutamine in the preterm infant of less than 30 weeks' gestation. Crit Care Med 1989;17:1166-9. 3. Miall-Allen VM, de Vries L, Whitelaw AG. Mean arterial pressure and neonatal cerebral lesions. Arch Dis Child 1987;62:1068-9.
Terbutaline powder for acute asthma To the Editor: We read with interest the article by Laberge et al., ~who pointed out the necessity of testing the efficacy of a dry powder inhaler in children with acute moderate asthma. We have compared the efficacy of 0.5 mg of terbutaline inhaled either with a Turbuhaler
16 1
Table. Bronchodilator response to terbutaline: Percentage of improvement from baseline (mean + SD)
At 15 rain Specific airway resistance (cm H20/L/sec) Forced expiratory volume in 1 second (ml) Peak expiratory flow rate (L/min) At 30 rain Specific airway resistance (cm H20/L/sec) Forced expiratory volume in 1 second (ml) Peak expiratory flow rate (L/min)
Dry powder inhaler
Metered-dose inhaler with spacer
-51.1 _+ 12.9
-47.7 _+ 10.9
+16.4 + 14.2
+23.2 + 19.1
+26.6 + 20.7
+16.0 _+ 10.8
-52.9 _+ 14.3
-54.2 _+ 7.8
+19.8 _+ 1 3 . 6
+27.0 _+ 13.4
+30.4 _+ 24.2
+26.7 + 24.5
(Astro Draco AB, Sweden) or with a metered-doseinhaler attached to a spacer (Nebuhaler, Astra Draco AB) in 30 5- to 14-year old children with acute wheezing. These children with asthma were included in an open, randomized parallel group study (15 children in each group). Administration of the drug was similar to that in the study by Laberge et al. We measured the following parameters before and 15 and 30 minutes after inhalation: specific airway resistance (in centimeters of water displaced per liter per second; body plethysmograph mode I 2800, Physiosystem, Noisy Le Grand, France), forced expiratory volume in 1 second in milliliters; Pulmonet III, Gould Medical, Runois, France), and peak expiratory flow rate (in liters per minute; mini Wright). Basal obstruction was similar in both groups (dry powder inhaler, 14.2 _+ 3.7 cm HzO/L per second; metered-dose inhaler with a spacer, 14.0 _+ 3.3 cm HzO/L per second). The Table shows that both inhalational techniques improved lung functions compared with baseline (p <0.01). There was no difference between treatments at any time (Mann-Whitney U test). Clinical efficacy and tolerance were excellent. These results2 confirm our preliminary study3 and demonstrate the efficacy of terbutaline powder in chil2: dren older than 5 years of age who have acute moderate asthmL
e. Rufin, MD M. R. Benoist, MD J. de Blic, MD P. Scheinmann, MD Departmen'ts of Pneumonology and Pediatric Allergy Hbpital des Enfants Malades Paris, France 9/35/60736 REFERENCES 1. Laberge S, Spier S, Drblik SP, Turgeon JP. Comparison of inhaled terbutaline administered by either the Turbuhaler dry