January 2007 Vol 7 correct A.indd ABSTRACT Objective: to study the effect of the postnatal administration of Ambroxol in the prevention of respiratory distress syndrome in preterm neonates at risk and on the severity of the disease in those neonates already suffering from it. Methods: the study was a randomized clinical trial performed on 20 preterm neonates admitted to the neonatal unit of the Suez Canal University Hospital, Egypt, with gestational age of 28 to 34 weeks. It was performed in the period from September 200 through March 2003. Half of the enrolled neonates received intravenous ambroxol (20 mg/kg/d), while the control group received the routine management of prematurity and a placebo. Results: Ambroxol decreased the incidence of Respiratory Distress Syndrome (RDS), improved the gas exchange, and decreased Continious Positive Airway pressure (CPAP) pressure, the length of mechanical ventilation and also the mortality rate. Conclusion: the study concluded that Ambroxol reduced the incidence of this disease in preterm neonates at risk of developing it, and improved the clinical course of RDS. Key Words: Respiratory Distress Syndrome (RDS), Prematurity, Ambroxol. Evaluation of the Role of Postnatal Ambroxol in the Prevention and Treatment of Respiratory Distress Syndrome in Preterm Neonates Hesham F Elsayed1, Muhammed I Elkhaiouby1 Sunia M Elsharkawey1, *Muna A Elnemr2 SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL DECEMBER 2006 VOL 6, NO. 2 SULTAN QABOOS UNIVERSITY© 1The institution where the research was performed: Neonatal Intensive Care Unit, Pediatric Department, Suez Canal University Hospital, EGYPT, 2Faculty of Medicine, University of Science and Technology, Sanaa, Yemen *To whom correspondence should be addressed. Email: munaabdo@hotmail.com O R I G I N A L S T U D Y الضائقة وعالج متالزمة منع في الوالدة بعد دور االمبروكسول تقييم اخلدج عند املواليد التنفسية املواليد اخلدج ــيَّة عند سِ التَّنَفُّ ةِ ائِقَ الضَّ ــةُ تَالَزِمَ ملنع حصول مُ الوالدة ــد بع ــرة مباش املعطى ــول االمبروكس عقار ــة فعالية امللخص: الهدف: دراس 120خديجا دراسة السريرية العشوائية الدراسة هذه في الطريقة: مت . هؤالء املواليد املصابني بها من عند املرض شدة وتقليل ، بها لألصابة املعرضني من سبتمبر استغرقت الدراسة . الوالدة عند 28 – 34 اسبوعا بني أعمارهم تراوحت (مصر) السويس قناة جامعة مبستشفى اخلدج وحدة في أدخلوا 20 ملجم/كجم/يوم) (بجرعة ــول االمبروكس عقار االولى اموعة ، واعطاء مجموعتني الى ــوائيا عش اخلدج ــيم تقس 2003 . مت مارس 2001 الى اخلاصة باخلدج. الرعاية الى اضافة (كاذبا) ال فْ غُ ــارا عق الضابطة) (العينة الثانية اموعة أعطيت بينما ، متوالية أيام ــة خمس وملدة الوريدي ــن باحلق فترة تقليص أدى الى مما ، ــرض للم املصاحبة االعراض تخفيف الى وأدى ، ة ــيَّ سِ ةِ التَّنَفُّ ائِقَ الضَّ ةُ مبُتَالَزِمَ االصابة حدوث ــول االمبروكس ألنتائــج: قلل من يقلل للخدج الوالدة املعطى بعد ــول عقار االمبروكس أن التجربة هذه اخلالصة: اثبتت . الوفيات بينهم معدل وكذلك قلل االصطناعية التنفس . بها املصابني عند لها املصاحبة االعراض حدة من يخفف و ، يَّة سِ ةِ التَّنَفُّ ائِقَ ةُ الضَّ االصابة مبُتَالَزِمَ أمبروكسول. ، اخلداجة ، التنفسية الضائقة املفردات املفتاحية: متالزمة Respiratory distress syndrome (RDS) is the most common respiratory malfunction oc-curring in preterm newborns.1 It is one of the most important factors determining neonatal morbid- ity and mortality.2 In Egypt, RDS was reported to be the most common cause of morbidity (42.5%) among preterm neonates admitted to the Neonatal Intensive Care Unit (NICU) of Cairo University Hospital and is responsible for 70% of the neonatal mortality.3 There are an estimated 40,000 cases of RDS annually in the United States, representing about 14% of all low-birth weight infants.4 The role of endogenous pulmonary surfactant in the maintenance of alveolar stability has been reported since 1950.4 The deficiency of surfactant in newborns was attributed to pulmonary atelectasis and hyaline membrane disease, the condition now known as respi- ratory distress syndrome.5 H E S H A M F E L S AY E D , M U H A M M E D I E L K H A I O U B Y, S U N I A M E L S H A R K AW E Y, M U N A A E L N E M R 42 Although exogenous surfactant therapy has dra- matically improved survival in clinical RDS, chronic lung disease continues to cause significant mortality and morbidity, thus there is an increasing interest in the potential role of newer therapies that may fur- ther decrease lung injury in susceptible premature newborns6,7 and even prevent its occurrence. Although glucocorticoids are effective in the pre- vention of RDS and in the treatment of chronic lung disease,8 their action depends on the repetition of the dose every seven days, which leads to a rise in cumulative side effects.9 There are now growing con- cerns, based on animal and human data, that repeat- ed antenatal doses could lead to growth retardation, decreased fetal brain size and abnormal neuronal development.10 Ambroxol, is a relatively new promoter of fetal lung maturity, the data on its efficacy are not yet as numer- ous as those of corticosteroids, although an increasing number of studies reported its role in the prevention of RDS, when given antenatally, with no side effects on the newborn.11,12,13,14 The effectiveness of postnatal intravenous Ambroxol in the treatment and the pre- vention of RDS remains an area of concern and needs more research. Therefore, this study was conducted to evaluate the role of post-natal intravenous administra- tion of Ambroxol in the treatment of RDS and its ef- fects on the course and severity of the disease among Egyptian neonates. M E T H O D S The sample size of our study was 120 preterm ne- onates with gestational ages between 28 to 34 weeks, admitted to the Neonatal Unit of Suez Canal Univer- sity Hospital between September 2001 and March 2003. The study Protocol was approved by the ethical committee of researches in the Faculty of Medicine in Suez Canal University in Egypt before the launch of the study and an oral consent was taken from every parent before inclusion in the study in which the goal and the nature of the study was explained. The study was funded by University of Science and Technology, Sanaa Republic of Yemen in 2003. Neonates with major congenital malformations or diseases that could cause respiratory distress in the neonates (e.g. congenital diaphragmatic hernia, con- genital heart disease, congenital pneumonia, congeni- tal emphysema, etc.) were excluded, as well as those neonates with a history of maternal conditions that are associated with increased risk of RDS (e.g. toxemia of pregnancy, diabetes mellitus, placenta previa, etc.). Randomisation was done immediately after inclu- sion. All eligible patients assigned to the study were submitted to an initial assessment regarding gesta- tional age, then a complete clinical examination, with particular attention paid to signs of respiratory dis- tress, chest auscultation and cardiac and radiological examinations. At the time of the study (2003) and, as in many Ar- abic countries, surfactant could not be given as stand- ard treatment (that is given for every case of RDS) be- cause it was and still is very expensive. Therefore, the standard treatment for the control group was only the usual management of preterms. Once RDS appeared, Table 1: Distribution of the enrolled neonates according to their birth weight (gm) Ambroxol Group Control Group Total t - test p value Birth weight (gm) Mean S.D Mean S.D 1547.7 241.3 1590.6 305.1 1.290 >0.05 No % No % No % Chi -2 Test p value 1100 - 1400 26 43.4 23 38.3 49 40.83 0.14 >0.05 >1400 - 2000 34 56.6 37 61.6 71 59.17 Total 60 100.0 60 100.0 120 100.00 Not statistically significant difference at 0.05 level Table 2: Distribution of the enrolled neonates according to Apgar score at 5 minutes APGAR Score Ambroxol Group Control Group Total No % No % No % < 5 2 3.33 0 0.0 2 1.67 ≥ 5 58 96.67 60 100.0 118 98.33 Total 60 100 60 100 120 100 Statistically not significant difference at 0.05 level Fisher exact test (2-tailed) p=0.49 E VA L UAT I O N O F T H E R O L E O F P O S T N ATA L A M B R O XO L I N T H E P R E V E N T I O N A N D TR E AT M E N T O F R E S P I R AT O R Y D I S T R E S S S Y N D R O M E I N P R E T E R M N E O N AT E S 43 respiratory support was given with either continuous positive airway pressure (CPAP) in mild cases or me- chanical ventilation if not responding and according to the mentioned indications in the methods. There- fore surfactant was not used in both the control and intervention groups and from here comes the impor- tance of using a cheaper product to support such cases as long as surfactants are not available, especially in poor communities. The treatment protocol in our study was as follows: 1. Resuscitation and supportive care by giving suf- ficient inflation pressures through CPAP in mild cases, and by endotracheal intubation and me- chanical ventilation in severe cases with hypoxia despite CPAP 2. Blood gas monitoring by taking arterial blood samples. 3. Monitoring of blood pressure and adequate circu- latory support. 4. Other general supportive measures like tempera- ture control and minimal handling. The intervention group received, in addition to the above mentioned protocol, intravenous Ambroxol (Mucosolvan, Boehringer, Ingelheim am Rhein, Ger- many) in a dose of 10 mg /kg, repeated every 12 hours for a duration of 5 days as infusion over 5 minutes, as early as possible after birth. Ambroxol was available in ampoules containing 15 mg diluted in 2 ml saline. The control group received a placebo, which was avail- able as similar indistinguishable ampoules in dose and duration. Antenatal steroids were given for every woman with threatened premature labour and in our patients it was given prenatally to all cases of both groups (at least one dose of betamethasone was given) O U TC OME ME A SUR E ME N TS The diagnosis of respiratory distress syndrome was based on clinical, radiological and blood gas examina- tions according to Kimya et al., (1995)11 ie. onset of respiratory distress within the first four hours of life, with a duration of more than 24 hours, tachypnea of more than 60 beats/minute, intercostal retractions, grunting on expiration, cyanosis and/or PaO2 less than 60mmHg at room air temperature, reticulogranular pattern and/or air bronchogram on chest x-ray. Table 3: Vital signs of the enrolled neonates at the initial assessment Neonates Characteristics Ambroxol Group Control Group t- Test p value Range Mean ±SD Range Mean ±SD Respiratory rate 45-80 64.17 7.86 50-80 66.77 6.29 1.555 >0.05 Heart rate 110-180 146.33 22.40 120-180 144.50 23.10 0.466 >0.05 Temperature 35.5-37 36.44 0.34 35.5-37 36.52 0.39 1.497 >0.05 SaO2 88-100% 94.83 4.34 66-95% 94.13 3.80 0.944 >0.05 Not significant at 0.05 level SaO2: Oxygen Saturation at room air. Table 4: Result of assessments after 24 hrs of admission Incidence of RDS at 24hrs Ambroxol Group Control Group Chi 2 test p value No % No % Yes 20 33.3 29 48.4 2.21 0.049* No 40 66.7 31 51.6 Mean ±SD Mean ±SD t- Test p value paO2 mmHg 94.03 5.24 76.75 16.72 7.971 0.0007* pCO2 mmHg 35.57 3.58 42.62 8.44 5.933 0.0003* SaO2 % 95.94 3.77 83.25 9.14 9.798 0.008* PH 7.34 0.03 7.31 0.5 0.463 >0.05 *Statistically Significant difference at p< 0.05. H E S H A M F E L S AY E D , M U H A M M E D I E L K H A I O U B Y, S U N I A M E L S H A R K AW E Y, M U N A A E L N E M R 44 The severity of the disease was determined by the fol- lowing indices: 1. The need for continuous positive air way pressure (CPAP), defined as the presence of mild respira- tory distress requiring a fraction of inspired oxy- gen (FIO2) below 0.40 to maintain a pressure of arterial oxygen of 50-80 mmHg. 2. The need for mechanical ventilation was defined as PaO2 ≤ 50 mmHg at oxygen concentration of 70-100% and CPAP 8-10 cmH2O, arterial blood PCO2 of 60mmHg or more or persistent apnea. 3. The main airway pressure (MAP) needed during the ventilation to keep PaO2 at an adequate limit at the initial settings was calculated by the specific formulas as well as the oxygenation index (OI). R E S U L T S The mean gestational age in the intervention group was 30.23 weeks, while in the control group was 30.63 weeks. The mode of delivery was lower segment cesar- ean section in 11.67% of the neonates in the interven- tion group, while 13.33 % of the control group deliv- ered by cesarean section. The distribution of the enrolled neonates accord- ing to their birth weight, APGAR score at 5 minutes, is shown in the Tables 1 and 2 respectively. Fisher Exact Test (2-tailed) P= 0.49 Unfortunately, the cause of preterm delivery was not recorded as part of the research. The result of the initial assessment of the enrolled neonates regarding respiratory rate, heart rate, tem- perature and oxygen saturation percentage are shown in Table 3. It shows no significant differences in the two groups of the neonates. The incidence of RDS was significantly lower in the Ambroxol group (33.3%) compared with the control group (48.4%) as shown in Table 4. This table shows also the blood gas analysis to be significantly better in the Ambroxol group. The main pressure of CPAP needed during the course of the treatment was found to be significantly lower in the Ambroxol group [Table 5]. The need for and the duration of mechanical ven- tilation were lower in the Ambroxol group. The oxy- genation index as an indicator of gas exchange during the mechanical ventilation was lower in the Ambroxol group [Table 6]. Table 5: Results of the analysis of CPAP settings Effect of Ambroxol Ambroxol Control Chi 2 Test p value No % No % Need for CPAP Yes 9 15.00 27 45 11.47 0.0007* No 51 85.00 33 55 Mean ±SD Mean ±SD t-test p value Pressure of CPAP Cm H2O 5.78 1.09 7.71 1.45 8.540 0.0006* *Statistically significant difference at p< 0.05. Table 6: Results of the analysis of the need for mechanical ventilation and its settings Ambroxol Control Chi 2 test p value Need for M.V No % No % Yes 4 6.67 20 33.33 11.72 0.0006* No 56 93.33 40 66.66 Mean ±SD Mean ±SD T-Test P-value OI during M.V 10 0.1 12.42 1.85 8.593 0.0001* MAP during M.V 9 0.1 10.24 0.97 9.850 0.0001* Duration of M.V(hrs) 84 12.70 169.60 32.0 2.923 0.004* * Statistically Significant difference at p< 0.05. For Duration of M.V, two-sample Wilcoxon Rank-Sum for equality of medians was used. M.V: Mechanical Ventilation. OI: Oxygenation Index. MAP: Mean Airway Pressure. E VA L UAT I O N O F T H E R O L E O F P O S T N ATA L A M B R O XO L I N T H E P R E V E N T I O N A N D TR E AT M E N T O F R E S P I R AT O R Y D I S T R E S S S Y N D R O M E I N P R E T E R M N E O N AT E S 45 The present study shows also that the mortality rate was significantly lower in the Ambroxol group (18.3%) compared with the control group (35%) [Table 7]. D I S C U S S I O N There are increasing numbers of studies that report the improving effect of Ambroxol on lung maturation and on the course of RDS in preterms.15 It is possible to increase surface active material in the alveolar spac- es either by direct installation of exogenous surfactant or by accelerating endogenous surfactant biosynthesis in the alveolar type 2 cells by Ambroxol.16 In this work, the prevalence of RDS at 24 hours of administration was significantly lower in the group of neonates who received Ambroxol group. This preven- tive effect coincides with the effect reported by Wauer et al.,17 Leurti et al.,18 Laoag et al.17,18,19 Ambroxol gen- erally reduced the severity of RDS among the enrolled neonates. The need for CPAP was used as an index for severity (morbidity of RDS). Ambroxol reduced the need for CPAP and its mean pressure. Moreover Am- broxol reduced the need for the initiation of mechani- cal ventilation during the course of illness and the ini- tial ventilator setting. This coincides with the results of Wauer et al.20 Ambroxol also reduced the oxygenation index (OI) which reflects a better gas exchange, a lower mean air- way pressure (MAP) and a lower fraction of inspired oxygen (FIO2). The MAP was also lower in the group treated with Ambroxol. This reflects a reduced peak inspiratory pressure (PIP) and peak expiratory end pressure (PEEP), as well as reduced inspiratory time. This result goes with those reported by Durisova,21 Sackdy et al.,12 and Schmalisch et al.14 Our study showed the overall death rate to be sig- nificantly lower in the group treated with Ambroxol. This is consistent with the results concluded by Du- resova in 1992.21 Ambroxol efficacy is probably dependent not only on lung pathology, but also on the dose administered and the duration of administration. Our choice of 20mg/kg/day was the minimal dose reported in the literature; larger doses could be used safely. The Ambroxol used in this study was safe and caused no complications. According to literature no significant complications were attributed to this drug during 30 years of research and it has been used in neonates intravenously for pneumonias to improve Table 8: Mortality and cause of death among the two studied groups Ambroxol Group Control Group Chi-2 test P-value No % No % Yes 11 18.33 21 35.0 3.261 0.039* No 49 81.66 39 65.0 Cause of death HMD 4 36.4 8 38.1 0.01 0.993Hypo 1 9.1 2 9.5 Sepsis 6 45.5 11 52.4 Death at day <14 6 54.5 12 57.1 FE** 1.000 ≥14-28 5 45.5 9 42.9 * Statistically Significant at p< 0.05 HMD: Hyaline Membrane Disease. Hypo: Hypotension **FE: Fisher Exact Test (2 tailed) Table 7: Mortality among the two studied groups Death rate Ambroxol Group Control Group Chi-2 test p value No % No % Yes 11 18.33 21 35 3.261 0.039* No 49 81.66 39 65 * Statistically Significant at p< 0.05. HMD: Hyaline Membrane Disease. Hypo: Hypotension. **FE: Fisher Exact Test (2 tailed) 46 thick secretions, so we were looking for simple com- plications such as frothy secretions as well as it is be- ing mucolytic. Moreover, its administration is simple in comparison with surfactant administration and is cheaper. C O N C L U S I O N Finally, we could conclude that Ambroxol administra- tion to preterm neonates at risk of/or suffering from RDS improves gas exchange, and decreases the length of mechanical ventilation, as well as the incidence of RDS and of mortality. Furthermore, Ambroxol thera- py could be considered as a therapeutic option in cas- es of at risk neonates for RDS and for those neonates with established RDS. 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H E S H A M E L S AY E D , M E L K H A I O U B Y, S E L S H A R K AW E Y A N D M E L N E M R