Cogo et al., 2009
Upcoming SlideShare
Loading in...5
×
 

Cogo et al., 2009

on

  • 213 views

 

Statistics

Views

Total Views
213
Views on SlideShare
213
Embed Views
0

Actions

Likes
0
Downloads
3
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Cogo et al., 2009 Cogo et al., 2009 Document Transcript

  • Dosing of Porcine Surfactant: Effect on Kinetics and Gas Exchange in Respiratory Distress Syndrome Paola Elisa Cogo, Maddalena Facco, Manuela Simonato, Giovanna Verlato, Clementina Rondina, Aldo Baritussio, Gianna Maria Toffolo and Virgilio Paolo Carnielli Pediatrics 2009;124;e950-e957; originally published online Oct 12, 2009; DOI: 10.1542/peds.2009-0126 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/124/5/e950 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009
  • Dosing of Porcine Surfactant: Effect on Kinetics and Gas Exchange in Respiratory Distress Syndrome WHAT’S KNOWN ON THIS SUBJECT: Multiple surfactant doses versus a single dose and porcine surfactant doses of 200 versus 100 mg/kg seem to be more effective in infants with RDS. Little is known regarding surfactant pharmacokinetics in human patients with RDS. WHAT THIS STUDY ADDS: We report exogenous surfactant DSPC pharmacokinetics in 61 infants who received 100 or 200 mg/kg porcine surfactant as treatment for RDS. The dose of 200 mg/kg was associated with a longer DSPC half-life, fewer retreatments, and better oxygenation index values. abstract OBJECTIVE: The goal was to study exogenous surfactant disaturated phosphatidylcholine (DSPC) kinetics in preterm infants with respiratory distress syndrome (RDS) who were treated with 100 or 200 mg/kg porcine surfactant. METHODS: Sixty-one preterm infants with RDS undergoing mechanical ventilation received, within 24 hours after birth, 100 mg/kg (N ϭ 40) or 200 mg/kg (N ϭ 21) porcine surfactant mixed with [U-13C]dipalmitoylphosphatidylcholine. Clinical and respiratory parameters were recorded, and DSPC half-life and pool size and endogenous DSPC synthesis rate were calculated. RESULTS: Clinical characteristics and short-term outcomes did not differ between groups. In the 100 mg/kg group, 28 infants (70%) received a second dose after 25 Ϯ 11 hours and 9 (22.5%) a third dose after 41 Ϯ 11 hours; in the 200 mg/kg group, 6 infants (28.6%) received a second dose after 33 Ϯ 8 hours and 1 a third dose. The DSPC half-life was longer in the 200 mg/kg group (first dose: 32 Ϯ 19 vs 15 Ϯ 15 hours [P ϭ .002]; second dose: 43 Ϯ 32 vs 21 Ϯ 13 hours [P ϭ .025]). DSPC synthesis rates and pool sizes before the first and second doses did not differ between the groups. The 200 mg/kg group exhibited a greater reduction in the oxygenation index than did the 100 mg/kg group after the first (P ϭ .009) and second (P ϭ .018) doses. AUTHORS: Paola Elisa Cogo, MD, PhD,a Maddalena Facco, MD,a Manuela Simonato, PhD,a Giovanna Verlato, MD, PhD,a Clementina Rondina, MD,b Aldo Baritussio, MD,c Gianna Maria Toffolo, PhD,d and Virgilio Paolo Carnielli, MD, PhDb Departments of aPediatrics, cMedical and Surgical Sciences, and dInformation Engineering, University of Padua, Padua, Italy; and bNeonatal Division, Institute of Maternal-Infantile Sciences, Polytechnic University of Marche and University Hospital of Ancona, Ancona, Italy KEY WORDS pulmonary surfactant, isotopes, low birth weight infants, respiratory distress syndrome ABBREVIATIONS DSPC— disaturated phosphatidylcholine RDS—respiratory distress syndrome DPPC— dipalmitoylphosphatidylcholine FIO2—fraction of inspired oxygen MAP—mean airway pressure TTR—tracer/tracee ratio www.pediatrics.org/cgi/doi/10.1542/peds.2009-0126 doi:10.1542/peds.2009-0126 Accepted for publication Jun 5, 2009 Address correspondence to Paola Elisa Cogo, MD, PhD, Department of Pediatrics, University of Padua, Via Giustiniani 3, Padua 35128, Italy. E-mail: cogo@pediatria.unipd.it PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2009 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Carnielli received a fee for speaking at an educational event sponsored by Dey Laboratories (Napa, CA) and received funds for research from Chiesi Pharmaceuticals (Parma, Italy). CONCLUSIONS: Porcine surfactant given to preterm infants with RDS at a dose of 200 mg/kg resulted in a longer DSPC half-life, fewer retreatments, and better oxygenation index values. Pediatrics 2009;124: e950–e957 e950 COGO et al Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009
  • ARTICLES The alveolar pool of surfactant in newborns with respiratory distress syndrome (RDS) does not differ much from the alveolar pool in adults without respiratory disease.1 Without surfactant supplementation, however, newborns with RDS develop severe respiratory failure, possibly through a combination of mechanisms including altered surfactant composition, lung structural immaturity, and increased surfactant inactivation.2 Dosages and modes of administration of exogenous surfactant have been studied mostly in animal models.3–5 For example, in premature lambs treated with natural sheep surfactant at doses of 19, 53, 64, or 173 mg/kg, pressurevolume curves improved progressively up to a dose of 64 mg/kg but no further gain was observed with the administration of 173 mg/kg.3 Information on the effect of exogenous surfactant dosing in human subjects is limited. In a study by Halliday et al,6 cumulative doses of exogenous surfactant up to 600 mg/kg were no better than 300 mg/kg. Other studies with newborn infants compared different doses of surfactant in the range of 50 to 200 mg/ kg.7–12 Four studies compared beractant (Survanta [Abbott Laboratories, Abbott Park, IL]) administered at 100 mg/kg and poractant ␣ (Curosurf [Chiesi Pharmaceuticals, Parma, Italy]) administered at either 100 or 200 mg/kg to infants with moderate/severe RDS.8,11,13,14 Poractant ␣ was found to have a more-rapid onset of action and was associated with lower neonatal mortality rates. However, the reduction in mortality rates was not statistically significant when poractant ␣ and beractant at the initial dose of 100 mg/kg were compared, which suggests that the most significant effects on mortality rates were seen when 200 mg/kg poractant ␣ was compared with 100 mg/kg beractant or poractant TABLE 1 Clinical Characteristics of Study Infants 200 mg/kg (N ϭ 21) Birth weight, mean Ϯ SD, g Gestational age, mean Ϯ SD, wk Prenatal steroid treatment, n (%) Full steroid treatment, n (%) Delivery through cesarean section, % Patent ductus arteriosus, % Age at study start, mean Ϯ SD, h FIO2 before first surfactant dose, mean Ϯ SD MAP before first surfactant dose, mean Ϯ SD, cmH2O Oxygenation index before first surfactant dose, mean Ϯ SD ␣.15 Data suggest that, for infants with moderate/severe RDS, a porcine surfactant dose of 200 mg/kg may be more effective than 100 mg/kg.8,11,13,14 After the first surfactant dose, irrespective of the amount administered, some neonates respond to treatment only transiently and require further surfactant administration. A recent meta-analysis comparing single versus multiple surfactant doses for preterm infants with established RDS showed greater improvements in oxygenation and ventilatory requirements, a decreased risk of pneumothorax, and a trend toward improved survival rates for infants who received multiple surfactant doses.16 When the retreatment should be performed is still unclear. In clinical practice, some neonatologists prefer to retreat their patients after a fixed time, whereas others choose to retreat them if their respiratory function deteriorates.17 It is likely that better knowledge of the pharmacokinetic features of exogenous surfactant in RDS could help to optimize the treatment of preterm infants. Few studies, with small numbers of infants, have been published.18–20 In this study, we administered to newborns with RDS 100 or 200 mg/kg porcine surfactant mixed with 13C-labeled dipalmitoylphosphatidylcholine (DPPC), and we measured exogenous surfactant kinetics by analyzing the isotopic enrichment of disaturated phosphatidylcholine (DSPC) isolated from tra- 100 mg/kg (N ϭ 40) P 1058 Ϯ 413 28.4 Ϯ 2.6 17 (80.9) 10 (47.6) 61.9 73.7 3.7 Ϯ 2.9 0.50 Ϯ 0.20 8.5 Ϯ 2.5 9.2 Ϯ 7.0 1110 Ϯ 429 28.9 Ϯ 2.7 27 (67.5) 19 (47.5) 72.5 75.0 6.0 Ϯ 5.8 0.54 Ϯ 0.20 8.2 Ϯ 2.1 9.5 Ϯ 6.6 .65 .46 .45 .93 .40 .36 .09 .45 .58 .86 cheal aspirates.16–18 Apart from their safety,21 stable isotopes have the advantage that their enrichment is not affected by sample dilution. From the enrichment curves, we derived the surfactant pool size at the time of dosing, the rate of endogenous surfactant synthesis, and the half-life of administered exogenous surfactant. METHODS Patients and Study Design We studied 61 newborn infants with RDS who were admitted to the NICU of the Department of Pediatrics, University of Padua, or the Division of Neonatology of the Polytechnic University of Marche (Ancona, Italy). Infants were recruited if they required synchronized intermittent mandatory ventilation and received exogenous surfactant within the first 24 hours of life. The study protocol was approved by the ethics committees of both institutions, and written informed consent was obtained from both parents. The study lasted from 2000 to 2004. Newborns with congenital malformations, sepsis, or renal or liver failure were excluded from the study. The diagnosis of RDS was based on clinical data and on chest radiograms,22 after exclusion of infections. All infants, whose clinical characteristics are reported in Table 1, received either 100 or 200 mg/kg porcine surfactant (Curosurf [Chiesi]) as rescue treatment for RDS. Administered surfactant PEDIATRICS Volume 124, Number 5, November 2009 Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009 e951
  • doses were labeled with 2.5 mg/kg [U-13C-palmitic acid]DPPC (Martek Biosciences, Columbia, MD) per dose as tracer. [U-13C-palmitic acid]DPPC was suspended in normal saline solution23 and was mixed with the exogenous surfactant during surfactant preparation. The choice of surfactant dosing was at the discretion of the attending neonatologists, who were blinded to laboratory and kinetic results. The indications for surfactant treatment were a fraction of inspired oxygen (FIO2) of Ͼ0.40 and a mean airway pressure (MAP) of Ͼ7.5 cm H2O. Surfactant was administered as a bolus through a small catheter inserted through the endotracheal tube. After the procedure, the neonates were reconnected to the mechanical ventilator at pretreatment settings. The mode of ventilation at the beginning of the study period was standardized, with an inspiratory time of 0.3 to 0.5 seconds, an initial respiratory rate of 50 to 65 breaths per minute, and a positive end expiratory pressure of 3 to 4 cm H2O. Peak inspiratory pressure and FIO2 were adjusted so that PaO2 was between 50 and 70 mm Hg, oxygen saturation was Ͼ88% but Ͻ96%, and PaCO2 was between 40 and 50 mm Hg. Ventilatory parameters were recorded before the start of the study and then every 6 hours. The oxygenation index was calculated as follows: oxygenation index ϭ [(MAP ϫ FIO2)/PaO2] ϫ 100. Tracheal aspirations were performed as described previously,20 and samples were collected before administration of the first dose of surfactant (time 0), every 6 hours until 72 hours, and then every 12 hours until extubation. Patients received additional surfactant doses if FIO2 returned to Ͼ0.35 and MAP was Ն7.5 cm H2O. On the basis of our previous work20 and the policy of the 2 participating neonatal units, retreatment was not given earlier than 18 hours after the previous dose une952 less there was a high index of suspicion regarding surfactant maldistribution, on the basis of clinical evidence or radiologic findings.24 Analytical Methods Lipids from tracheal aspirates and from exogenous surfactant were extracted according to the method described by Bligh and Dyer,25 after addition of the internal standard heptadecanoylphosphatidylcholine. One third of the extract was oxidized with osmium tetroxide.26 DSPC was isolated from the lipid extract through thin-layer chromatography, after oxidation with osmium tetroxide.26 DSPC fatty acids were derivatized27 as pentafluorobenzyl derivatives, extracted with hexane, and stored at Ϫ20°C. A half-spot of exogenous surfactant DSPC was derivatized as the methyl ester,28 and the amount of DSPC was measured through gas chromatography, as described previously.20 Tracheal aspirates with visible blood were discarded. The enrichment of [U-13C-palmitic acid] DPPC from the tracheal aspirates was measured through gas chromatographymass spectrometry in negative ionization mode, and results were expressed in mole percent excess.20 The mole percent excess represents the increase in the mole percentage of [U-13C]palmitic acid above the baseline value obtained at time 0 of the study. Calculations Data were analyzed under the following assumptions: (1) exogenous surfactant DSPC is distributed in the alveolar pool and subsequently internalized and recycled by the type II cells; (2) endogenous DSPC is synthesized by lung parenchyma, secreted in the alveoli, and recycled before degradation; (3) exogenous surfactant DSPC is distributed homogeneously in the lungs, and the system is at steady state; and (4) DSPC kinetics are linear. Under these assumptions, DSPC kinetics can be modeled conveniently on the basis of the tracer/tracee ratio (TTR), that is, the ratio of exogenous (tracer) to endogenous (tracee) DSPC.29,30 This variable is different from enrichment, which measures the ratio of the labeled component of exogenous surfactant to unlabeled DSPC, originating from both exogenous and endogenous sources. Therefore, enrichment (E) measured at time t was converted to TTR by using the following formula (derived in the Appendix): TTR(t) ϭ E(t)[(EI ϩ 1)/[EI Ϫ E(t)]], where EI is the percentage of [U-13C-palmitic acid]DPPC with respect to unlabeled DSPC in the administered surfactant dose, equal to 7 Ϯ 3%, on average. TTR data were fitted to either a monoexponential or biexponential decay model (Fig 1), and DSPC kinetic parameters were calculated as follows. In the monoexponential model, that is, TTR(t) ϭ AeϪKt, the DSPC halflife (in hours) is ln(2)/k, the DSPC pool size (in milligrams per kilogram) is dose/A, and the DSPC synthesis rate (in milligrams per day per kilogram) is (DSPC pool size ϫ k ϫ 24) ϭ [dose/(A/ k) ϫ 24]. In the biexponential model, that is, TTR(t) ϭ A1eϪk1t ϩ A2eϪk2t, the DSPC half-life (in hours) is ln(2)/k2, the DSPC pool size (in milligrams per kilogram) is dose/(A1 ϩ A2), and the DSPC synthesis rate (in milligrams per day per kilogram) is [dose/[A1/k1 ϩ A2/k2]] ϫ 24. Dose (in milligrams per kilogram) is the administered surfactant DSPC dose, t is time (in hours), and, for the biexponential model, k2 indicates the rate constant of the slower component, responsible for the late portion of TTR decay. When data collected after administration of the second dose were analyzed, equations were modified to account for the contribution of the first dose. For example, for the monoexponential model, DSPC pool size is dose/(A Ϫ COGO et al Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009
  • ARTICLES A 3 2 First dose Second dose ln, TTR 1 0 0 24 48 72 96 120 144 168 -1 y = -0.0388x + 2.2823 R2 = 0.989 -2 -3 -4 B Time, h 3 2 Second dose First dose ln, TTR 1 0 0 24 48 72 96 y = -0.0706x + 3.0278 R2 = 0.8891 -1 120 144 168 y = -0.0525x + 6.1915 R2 = 0.9767 -2 -3 C Time, h 2 1 ln, TTR 0 -1 y = 2.9e-0.07x + 1.2e -0.02x- - 0.8 -2 -3 -4 -5 0 24 48 72 96 120 144 168 Time, h FIGURE 1 Three typical surfactant DSPC kinetic patterns (semilogarithmic plots). A, The half-life of the first dose was not computable (Ͻ3 samples available before the second dose). B, DSPC disappeared from the airways monoexponentially after 2 surfactant doses but with different slopes. C, DSPC disappeared from the airways according to a biexponential decay. TTRpre), where TTRpre is the TTR value immediately before administration of the second dose. The derived DSPC pool size is an estimate of the amount of tracee (ie, endogenous DSPC) present in the air- ways during each surfactant administration and is designated as the DSPC pool. DSPC kinetic parameters were PEDIATRICS Volume 124, Number 5, November 2009 Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009 e953
  • missing when DSPC decay curves had Ͻ3 enrichment points, that is, too few points for calculation of DSPC kinetics (Fig 1A). Data were expressed as mean Ϯ SD or median and interquartile range, according to variable distribution, and they were compared with independent t tests or Mann-Whitney U tests for continuous variables and ␹2 tests for binary data. Statistical analyses were performed with SPSS for Windows XP 15.00 (SPSS, Chicago, IL). RESULTS Surfactant DSPC pharmacokinetics could be calculated reliably after 74 surfactant administrations to 61 infants who received Ն1 dose of exogenous surfactant. Forty infants were treated with 100 mg/kg surfactant (100 mg/kg group) and 21 with 200 mg/kg surfactant (200 mg/kg group), at the discretion of the attending neonatologist. All first doses were administered within 24 hours after birth. The 2 groups were similar with regard to all recorded clinical variables (Table 1). The study was conducted in 2 neonatal units, and the proportions of 200 mg/kg doses were 35% and 27% (not significant). The average ventilator settings, including inspiratory time, did not differ between the 2 units or between infants receiving 100 versus 200 mg/kg doses of exogenous surfactant. In the 100 mg/kg group, a second surfactant dose was administered to 28 infants (70.0%) after 25 Ϯ 11 hours, and a third dose was administered to 9 infants (22.5%) 41 Ϯ 11 hours after the second dose. In the 200 mg/kg group, 6 infants (28.6%) received a second dose after 33 Ϯ 8 hours, and only 1 received a third dose. The interval between the first and second doses tended to be longer in the 200 mg/kg group than in the 100 mg/kg group, but the difference did not reach statistical significance (Table 1). After the first and second doses, infants ase954 TABLE 2 Surfactant Dose Effects on Oxygenation and Outcome Parameters 200 mg/kg (N ϭ 21) .59 .44 .81 Ͻ.01 .02 Ͻ.01 6.0 Ϯ 2.6 .02 33 Ϯ 8 DSPC enrichment could be measured in all tracheal aspirates, but decay curves with Ͼ2 enrichment points were obtained for 74 of the 99 surfactant doses. In most cases, decay curves were monoexponential (Fig 1). Biexponential decay was more frequent in the 200 mg/kg group, without reaching statistical significance (43% vs 29% after the first dose [P ϭ .3] and 43% vs 13% after the second dose [P ϭ .15]). In the 200 mg/kg group, DSPC kinetics were calculated for 10 Ϯ 10 82.5 44.1 70.0 192 Ϯ 73 6.9 Ϯ 5.4 3.2 Ϯ 1.5 signed to the 200 mg/kg group showed a better oxygenation index, compared with the 100 mg/kg group (Table 2). The 2 groups were not statistically different with respect to duration of mechanical ventilation, survival rates, rates of bronchopulmonary dysplasia (defined as oxygen dependency at 36 weeks), or rates of the combination of death and bronchopulmonary dysplasia (P ϭ .860) (Table 2). P 12 Ϯ 13 90.0 52.9 28.6 250 Ϯ 89 4.0 Ϯ 1.9 Conventional ventilation, mean Ϯ SD, d Survival, % Bronchopulmonary dysplasia at 36 wk, % Ͼ1 surfactant dose, % Total surfactant dose, mean Ϯ SD, mg/kg Oxygenation index after first surfactant dose, mean Ϯ SD Oxygenation index after second surfactant dose, mean Ϯ SD Interval between first and second doses, mean Ϯ SD, h 100 mg/kg (N ϭ 40) 25 Ϯ 11 .09 15 infants (71.4%) after the first dose and 5 (83.3%) after the second dose. In the 100 mg/kg group, DSPC kinetics were calculated for 31 infants (77.5%) after the first dose and 23 (82.1%) after the second dose. The DSPC pool sizes were similar in the 100 and 200 mg/kg groups during the first and second surfactant administrations (Table 3). The DSPC half-life was significantly longer in the 200 mg/kg group after both the first and second doses, whereas endogenous surfactant DSPC synthesis rates were similar in the 2 groups (Table 3). DSPC kinetic variables did not seem to be influenced by the mode of TTR decay (ie, monoexponential versus biexponential). DISCUSSION Exogenous surfactant therapy is a cornerstone of modern neonatology, be- TABLE 3 DSPC Half-Life, Endogenous DSPC Pool Size, and Synthesis Rate for Preterm Newborns Treated With 200 or 100 mg/kg Porcine Surfactant Extract 200 mg/kg (N ϭ 21) DSPC half-life, mean Ϯ SD, h First dose Second dose Third dose Endogenous DSPC pool size, median (interquartile range), mg/kg First dose Second dose DSPC synthesis, median (interquartile range), mg/kg per d First dose Second dose 100 mg/kg (N ϭ 40) P 32 Ϯ 19 (n ϭ 15) 43 Ϯ 32 (n ϭ 5) 15 Ϯ 15 (n ϭ 31) 21 Ϯ 13 (n ϭ 23) 17 Ϯ 7 (n ϭ 7) Ͻ.01 .02 5.3 (1–12.7) (n ϭ 15) 2.6 (0.7–18.5) (n ϭ 5) 2.5 (0.5–6.8) (n ϭ 31) 4.4 (1.2–16.1) (n ϭ 23) .32 .67 4.8 (0.1–14.4) (n ϭ 15) 2.4 (1.7–5.8) (n ϭ 5) 7.2 (3.8–10.8) (n ϭ 31) 4.8 (2.2–13.4) (n ϭ 23) .80 .35 COGO et al Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009
  • ARTICLES cause it reduces mortality and morbidity rates for neonates with RDS.24 Current treatment schemes are derived from human and animal studies with very high doses of surfactant.3,5,7,8,11–13,17,31 Studies performed with different animal species showed that the amount of surfactant present in the airways at birth is correlated with the severity of RDS and that administered surfactant disappears with a half-life of 4 to 12 hours.32–35 Little is known about surfactant turnover in premature newborns, and studies measuring surfactant pools in this population are limited.18–20 Furthermore, most clinical trials have been performed with intention-to-treat analyses, and the effectiveness of different dosing schemes remains unclear. This report describes pharmacokinetics and clinical outcomes after the administration of 100 or 200 mg/kg poractant ␣ to preterm infants with moderate/severe RDS. Stable-isotope DSPC labeling of the administered surfactant dose allowed us to trace exogenous surfactant DSPC and to calculate the TTR, that is, the exogenous (tracer)/endogenous (tracee) surfactant DSPC ratio. This variable is the most convenient way to express data from experiments with stable isotopes. Pharmacokinetic parameters such as DSPC halflife, pool size (estimation of the alveolar DSPC pool size), and synthesis rate can be estimated easily by fitting a multiexponential model to TTR data and then applying simple formulas to the model parameters. The main clinical findings of this study were that the larger dose had a longer half-life and that newborns receiving it needed fewer additional doses and had better oxygenation index values. There were no differences in durations of mechanical ventilation, mortality rates, or development of bronchopulmonary dysplasia. The cumulative dose of exogenous surfactant was sig- nificantly greater in the 200 mg/kg group, but the 100 mg/kg group required more redosing, in agreement with data by Ramanathan et al.11 In both groups, the alveolar surfactant DSPC level was on the order of 2.5 to 5 mg/kg, which is markedly lower than that found in mature newborns.36 The DSPC pool in preterm newborns with RDS during the first day of life ranged from 1 to 15 mg/kg,20 whereas term infants without RDS have 3 times that value.36 In this study, for both groups of newborns, the pool of DSPC was Ͻ6 mg/kg (median) before the first dose and Ͻ5 mg/kg before the second dose. Therefore, patients who needed a second dose had endogenous surfactant DSPC pool values similar to those found before the first dose, which suggests incomplete retention of the first dose, high catabolic rates, or insufficient endogenous synthesis. Infants who required a second dose had surfactant deficiency and were at risk of mechanical and alveolar instability.31,37 Endogenous DSPC synthesis rates were not different between our study groups. It must be noted that this kinetic parameter represents only the surfactant DSPC synthesized de novo, is not affected by surfactant recycling, and does not reflect other DSPC synthetic pathways. Among our infants, the DSPC synthesis rates ranged between 2.4 and 7.2 mg/kg per day, which suggests that preterm infants with RDS need at least 3 or 4 days to accumulate adequate amounts of surfactant in their airways. These findings are in agreement with previous estimates of DSPC synthesis obtained through intravenous administration of stable-isotope glucose and palmitate. In those studies, the DSPC synthesis rates ranged between 2.7 and 4.8 mg/kg per day among preterm infants with respiratory failure who required no surfactant or Ն1 dose of exogenous surfactant.38,39 Therefore, in RDS, surfactant administration is needed to compensate for slow de novo synthesis and to substitute for surfactant degraded or lost through the conducting airways. Little is known regarding exogenous surfactant turnover in human RDS18–20 and, to the best of our knowledge, this is the first time the half-life of exogenous surfactant has been measured in preterm infants with RDS receiving 100 or 200 mg/kg doses of exogenous surfactant. We found that, after administration of 200 mg/kg, the half-life of administered surfactant was longer. This difference is unlikely to be attributable to heterogeneity of the study groups, because all infants had received a single mode of ventilation (synchronized intermittent mandatory ventilation) from birth and patients with signs of infection, such as increased white blood cell and neutrophil counts, increased C-reactive protein levels, and temperature instability, were excluded prospectively from analyses.40 An interesting finding is that administered surfactant left the airways monoexponentially most of the time and in a biexponential mode only in some cases (Fig 1). This might have happened through several mechanisms. For example, a slow rate of uptake of administered material or a low rate of de novo synthesis might have favored a biexponential mode of decay. On the whole, however, it seems that the kinetic differences between the 100 mg/kg group and the 200 mg/kg group were not attributable to differences in data fitting, because the distributions of decay modes did not differ significantly between the 2 groups. The major limitation of the present study was that patients were not assigned randomly to the treatment groups, because of different orientations regarding surfactant administration among attending neonatologists. However, the 2 groups were well PEDIATRICS Volume 124, Number 5, November 2009 Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009 e955
  • matched with respect to all clinical parameters, respiratory disease severity, and DSPC pool sizes during the first and second doses. Furthermore, to obtain reliable kinetic measurements, we needed to collect tracheal aspirates for at least 18 to 24 hours. Therefore, our design might have favored the selection of preterm infants with intermediate to severe RDS. Studies are needed to analyze DSPC kinetics in infants with less-severe respiratory failure and those receiving different types of ventilatory support. CONCLUSIONS The present study compared the pharmacokinetics of different doses of porcine surfactant (100 or 200 mg/kg) in preterm infants with moderate/severe RDS. We found that, after administration of 200 mg/kg, the half-life of administered surfactant was longer, oxygenation was better, and the need for redosing was reduced. Further studies E͑t͒ ϭ APPENDIX The calculation of TTR from enrichment (E) measurements is described. At any time t, the following equations express TTR and E as functions of [U-13C-palmitic acid]DPPC levels, coming from the surfactant dose (q), unlabeled DSPC levels, also coming from the surfactant dose (Qexo), and endogenous unlabeled DSPC levels (Qendo): q͑t͒ ϩ Q exo͑t͒ TTR͑t͒ ϭ Q endo͑t͒ (2) Dividing the left sides of eqs 1 and 2 by Qexo(t) yields TTR͑t͒ ϭ EI ϩ 1 q͑t͒/Q exo͑t͒ ϩ 1 ϭ Q endo͑t͒/Q exo͑t͒ Q endo͑t͒/Q exo͑t͒ (3) EI 1 ϩ Q endo͑t͒/Q exo͑t͒ (4) In eq 4, the result given in ref 29 was used, namely, that the percentage of [U-13C-palmitic acid]DPPC (q) with respect to exogenous DSPC (Qexo) remains constant in the system and equal to the percentage (EI) of [U-13Cpalmitic acid]DPPC with respect to DSPC in the administered surfactant dose. Solving eq 4 for Qendo(t)/Qexo(t) and substituting into eq 3 yields TTR͑t͒ ϭ E͑t͒ (1) q͑t͒ E͑t͒ ϭ Q exo͑t͒ ϩ Q endo͑t͒ q͑t͒/Q exo͑t͒ 1 ϩ Q endo͑t͒/Q exo͑t͒ ϭ are in progress to explore the possibility that the higher dose also might lead to earlier extubations and/or fewer reintubations. EI ϩ 1 E I Ϫ E͑t͒ (5) which is the desired expression for TTR in terms of E. ACKNOWLEDGMENTS This study was supported by laboratory core funds and by the Department of Pediatrics, University of Padua, for 1 doctoral salary. REFERENCES 1. Rebello CM, Jobe AH, Eisele JW, Ikegami M. Alveolar and tissue surfactant pool sizes in humans. Am J Respir Crit Care Med. 1996;154(3): 625– 628 2. Jobe AH, Ikegami M. Protein permeability abnormalities in the preterm. In: Effros RM, Chang HK, eds. Lung Biology in Health and Disease: Fluid and Solute Transport in the Airspaces of the Lung. New York, NY: Marcel Dekker; 1994:335–355 3. Ikegami M, Adams FH, Towers B, Osher AB. The quantity of natural surfactant necessary to prevent the respiratory distress syndrome in premature lambs. Pediatr Res. 1980;14(9): 1082–1085 4. Pettenazzo A, Jobe AH, Ikegami M, Rider E, Seidner SR, Yamada T. Cumulative effects of repeated surfactant treatments in the rabbit. Exp Lung Res. 1990;16(2):131–143 5. Alvarez FJ, Alfonso LF, Gastiasoro E, LopezHeredia J, Arnaiz A, Valls-i-Soler A. The effects of multiple small doses of exogenous surfactant on experimental respiratory failure induced by lung lavage in rats. Acta Anaesthesiol Scand. 1995;39(7):970 –974 6. Halliday HL, Tarnow-Mordi WO, Corcoran JD, Patterson CC. Multicentre randomised trial comparing high and low dose surfactant reg- e956 imens for the treatment of respiratory distress syndrome (the Curosurf 4 Trial). Arch Dis Child. 1993;69(3 Spec No):276 –280 7. Speer CP, Robertson B, Curstedt T, et al. Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of Curosurf. Pediatrics. 1992; 89(1):13–20 8. Speer CP, Gefeller O, Groneck P, et al. Randomised clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed. 1995;72(1):F8 –F13 9. Walti H, Relier JP, Huon C, et al. Treatment of severe hyaline membrane disease with a single dose of natural exogenous surfactant of porcine origin: a randomized trial: immediate effects and outcome at 28 days of life [in French]. Arch Fr Pediatr. 1990;47(5):329 –334 10. Walti H, Paris-Llado J, Breart G, Couchard M. Porcine surfactant replacement therapy in newborns of 25–31 weeks’ gestation: a randomized, multicentre trial of prophylaxis versus rescue with multiple low doses. Acta Paediatr. 1995;84(8):913–921 11. Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K. A randomized, multi- 12. 13. 14. 15. 16. 17. center masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol. 2004;21(3):109 –119 Dunn MS, Shennan AT, Possmayer F. Singleversus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks’ gestation with respiratory distress syndrome. Pediatrics. 1990;86(4):564 –571 Baroutis G, Kaleyias J, Liarou T, Papathoma E, Hatzistamatiou Z, Costalos C. Comparison of three treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Eur J Pediatr. 2003;162(7– 8): 476 – 480 Malloy CA, Nicoski P, Muraskas JK. A randomized trial comparing beractant and poractant treatment in neonatal respiratory distress syndrome. Acta Paediatr. 2005;94(6):779 –784 Halliday HL. History of surfactant from 1980. Biol Neonate. 2005;87(4):317–322 Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2009; (1):CD000141 Kattwinkel J, Bloom BT, Delmore P, et al. High- COGO et al Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009
  • ARTICLES 18. 19. 20. 21. 22. 23. 24. 25. versus low-threshold surfactant retreatment for neonatal respiratory distress syndrome. Pediatrics. 2000;106(2):282–288 Hallman M, Merritt TA, Pohjavuori M, Gluck L. Effect of surfactant substitution on lung effluent phospholipids in respiratory distress syndrome: evaluation of surfactant phospholipid turnover, pool size, and the relationship to severity of respiratory failure. Pediatr Res. 1986;20(12):1228 –1235 Griese M, Dietrich P, Reinhardt D. Pharmacokinetics of bovine surfactant in neonatal respiratory distress syndrome. Am J Respir Crit Care Med. 1995;152(3):1050 –1054 Torresin M, Zimmermann LJ, Cogo PE, et al. Exogenous surfactant kinetics in infant respiratory distress syndrome: a novel method with stable isotopes. Am J Respir Crit Care Med. 2000;161(5):1584 –1589 Jones PJ, Leatherdale ST. Stable isotopes in clinical research: safety reaffirmed. Clin Sci (Lond). 1991;80(4):277–280 Thome U, Topfer A, Schaller P, Pohlandt F. Comparison of lung volume measurements by antero-posterior chest X-ray and the SF6 washout technique in mechanically ventilated infants. Pediatr Pulmonol. 1998;26(4):265–272 Ikegami M, Jobe A, Duane G. Liposomes of dipalmitoylphosphatidylcholine associate with natural surfactant. Biochim Biophys Acta. 1985;835(2):352–359 Sweet D, Bevilacqua G, Carnielli V, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome. J Perinat Med. 2007;35(3):175–186 Bligh EG, Dyer WJ. A rapid method of total lipid 26. 27. 28. 29. 30. 31. 32. 33. 34. extraction and purification. Can J Biochem Physiol. 1959;37(8):911–917 Mason RJ, Nellenbogen J, Clements JA. Isolation of disaturated phosphatidylcholine with osmium tetroxide. J Lipid Res. 1976;17(3): 281–284 Christie W. Gas Chromatography and Lipids: A Practical Guide. Ayr, Scotland: Oily Press; 1989: 64 – 84 Carnielli VP, Pederzini F, Vittorangeli R, et al. Plasma and red blood cell fatty acid of very low birth weight infants fed exclusively with expressed preterm human milk. Pediatr Res. 1996;39(4):671– 679 Cobelli C, Toffolo G. Constant specific activity input allows reconstruction of endogenous glucose concentration in non-steady state. Am J Physiol. 1990;258(6):E1037–E1040 Cobelli C, Toffolo G, Foster D. Tracer-to-tracee ratio for analysis of stable isotope tracer data: link with radioactive kinetic formalism. Am J Physiol. 1992;262(6):E968 –E975 Glatz T, Ikegami M, Jobe A. Metabolism of exogenously administered natural surfactant in the newborn lamb. Pediatr Res. 1982;16(9): 711–715 Ikegami M, Jobe A, Yamada T, et al. Surfactant metabolism in surfactant-treated preterm ventilated lambs. J Appl Physiol. 1989;67(1): 429 – 437 Jobe AH, Ikegami M, Seidner SR, Pettenazzo A, Ruffini L. Surfactant phosphatidylcholine metabolism and surfactant function in preterm, ventilated lambs. Am Rev Respir Dis. 1989; 139(2):352–359 Kramer BW, Ikegami M, Jobe AH. Surfactant phospholipid catabolic rate is pool size dependent in mice. Am J Physiol Lung Cell Mol Physiol. 2000;279(5):L842–L848 35. Seidner SR, Jobe AH, Ruffini L, Ikegami M, Pettenazzo A. Recovery of treatment doses of surfactants from the lungs and vascular compartments of mechanically ventilated premature rabbits. Pediatr Res. 1989;25(4): 423– 428 36. Cogo PE, Zimmermann LJ, Meneghini L, et al. Pulmonary surfactant disaturatedphosphatidylcholine (DSPC) turnover and pool size in newborn infants with congenital diaphragmatic hernia (CDH). Pediatr Res. 2003; 54(5):653– 658 37. Jobe AH, Ikegami M, Jacobs HC, Jones SJ. Surfactant pool sizes and severity of respiratory distress syndrome in prematurely delivered lambs. Am Rev Respir Dis. 1983;127(6): 751–755 38. Bunt JE, Carnielli VP, Janssen DJ, et al. Treatment with exogenous surfactant stimulates endogenous surfactant synthesis in premature infants with respiratory distress syndrome. Crit Care Med. 2000;28(10):3383–3388 39. Cavicchioli P, Zimmermann LJ, Cogo PE, et al. Endogenous surfactant turnover in preterm infants with respiratory distress syndrome studied with stable isotope lipids. Am J Respir Crit Care Med. 2001;163(1):55– 60 40. Verlato G, Cogo PE, Pesavento R, et al. Surfactant kinetics in newborn infants with pneumonia and respiratory distress syndrome. Ital J Pediatr. 2003;29(11):414 – 419 PEDIATRICS Volume 124, Number 5, November 2009 Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009 e957
  • Dosing of Porcine Surfactant: Effect on Kinetics and Gas Exchange in Respiratory Distress Syndrome Paola Elisa Cogo, Maddalena Facco, Manuela Simonato, Giovanna Verlato, Clementina Rondina, Aldo Baritussio, Gianna Maria Toffolo and Virgilio Paolo Carnielli Pediatrics 2009;124;e950-e957; originally published online Oct 12, 2009; DOI: 10.1542/peds.2009-0126 Updated Information & Services including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/124/5/e950 References This article cites 37 articles, 12 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/124/5/e950#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Premature & Newborn http://www.pediatrics.org/cgi/collection/premature_and_newborn Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml Downloaded from www.pediatrics.org. Provided by Chiesi Framaceutici S.P.A. on November 2, 2009