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Surfactant use in premature neonates less than 37 weeks gestation: Experience and outcome at a tertiary care hospital.

Byline: Ejaz Ahmed Khan and Ibrar Hashmey

Abstract

Objectives: To assess a single-centre experience and outcome of premature neonates who received surfactant therapy.

Methods: The prospective cohort study was done at Shifa International Hospital, Islamabad, from December 2005 to May 2007 and comprised premature neonates (less than 37 weeks gestation) who had clinical and radiologic evidence of respiratory distress syndrome and had received surfactant therapy. SPSS 21 was used for statistical analysis. Results: A total of 52 premature neonates received surfactant. Mean gestational age was 292.8 weeks and mean birth weight was 1273487gms. Only 16(31%) mothers had received antenatal dexamethasone. Surfactant was used as single dose in 41(78%) neonates at 6.16.6hours of life or two doses in 11(22%). Chest X-ray and respiratory distress syndrome category showed an overall improvement in 29 (56%) neonates. Complications were seen in 17(33%) neonates, and 21(40%) died. Mortality was significantly associated with gestation (pless than 0.000) and weight (pless than 0.008).

Conclusions: Surfactant administration is an option for respiratory distress syndrome in Pakistan.

Keywords: Surfactant, Prematurity, Respiratory distress syndrome, Continuous positive airway pressure. (JPMA 65: 486; 2015)

Introduction

Respiratory distress syndrome (RDS) contributes to morbidity and mortality in preterm neonates mostly in developing countries.1-3 Mortality is 90% in extreme preterm neonates compared to those in the developed countries. Surfactant administration improves respiratory status of premature neonates, decreases ventilatory requirements, hospitalisation rates and overall outcome. The advent of surfactant therapy has decreased the morbidity and mortality rate from RDS by approximately 50%.4-8 The current study was planned to assess and share our experience of surfactant use in premature neonates in order to add to the very limited information from developing countries like Pakistan.

Patients and Methods

The prospective cross-sectional study with non- probability convenient sampling was conducted at Shifa International Hospital, Islamabad, from December 2005 to May 2007 at Level IV neonate intensive care unit (NICU). All premature neonates (less than 37 weeks gestation) presenting within 12 hours of birth with clinical and radiologic evidence of RDS who received surfactant therapy were included. Excluded from the study were those with dysmorphology, suspected congenital heart disease or surgical conditions, or if there was no parental consent for use of surfactant. The institutional review committee approved the study.

Demographic, clinical, laboratory, radiological and other relevant information were recorded. These included total NICU admissions, premature neonates, age (hours), gender, birth place, birth weight, gestational age (weeks), maternal antenatal dexamethasone use (intramuscular [IM] dexamethasone given as 2 doses of 12mg 12 hours apart), ventilatory parameters before and after surfactant over 24 hours (6, 12, 24 hours), arterial blood gases (ABGs) before and after surfactant, duration of ventilation, extubation rate within 48 hours, overall oxygen requirement after 7 days and RDS category (radiological changes) before and after 24 hours.

RDS categories were defined as: Category 1) reduced lung volume with a diffuse reticulogranular pattern, air bronchograms mild or absent; Category 2) reticulogranular pattern more prominent and uniform, lungs hypoaerated with increased air bronchograms; Category 3) progressive opacification of the anterior portions of the lungs with mild obscuration of cardiac silhouette; and Category 4) (lungs appear opaque and display prominent air bronchograms, with total obscuration of cardiomediastinal silhouette.9

Surfactant (Survanta,(R) Abbott Laboratory, Chicago, IL) used in the study was given by intratracheal route, 100mg of beractant phospholipids/kg birth weight/dose (4mL/kg/dose), as per manufacturer's instructions and standard protocol. Possible side effects and complications due to use of surfactant and mechanical ventilation (pulmonary haemorrhage, endotracheal tube blockage, intraventricular haemorrhage, pneumothorax and bronchopulmonary dysplasia) were recorded.

All relevant data was recorded using a proforma and data was analysed using SPSS 21. Chi square test was used to compare significant difference in categorical variables in cluding radiological findings, death in different gender, gestational age, exposure to steroids etc. before and after surfactant receipt, and to test associations among variables. Besides, Wilcoxon Sign Rank Test was used to compare the mean values for ventilatory settings and ABG analysis before and after surfactant administration and in different groups. The significance level was set at less than 0.05.

Results

There were a total of 450 admissions, including 126 (28%) premature neonates, during the study period. Of them, 52 (41%) were given surfactant. The mean age of these neonates at admission was 48 minutes (0.81.7 hours; Range: 0-6 hours) (Table-1). The mean Apgar score at 1and 5minutes was 5.72 and 7.61.7 respectively. Only16(31%) mothers had antenatal dexamethasone.

Table-1: Demographic and clinical characteristics.

###N###%

Total admissions###450###100

Total Premature###126###28

Clinical RDS###49###39

Surfactant recipients###52###100

Surfactant given as single dose###41###78

Age at time of surfactant###6.1 (6.6SD)

Males###37###71

Inborn###43###83

Antenatal dexamethasone###16###31

Single dose of antenatal dexamethasone###7###44

Timing of antenatal dexamethasone###23 hours (20)

Mean age at admission###48 minutes (1.7 hours)

Mean gestational age###29 weeks (2.8)

###less than 28 weeks###18###34.5

###28-33 weeks###32###61.5

###34-37 weeks###2###3.8

Mean birth weight###1273 grams (487)

###less than 750 grams###5###9.6

###750-1000 grams###14###26.9

###1000-1250 grams###11###21.2

###greater than 1250 grams###22###42.3

Table-2: Ventilatory parameters over 24 hours, ABG parameters and RDS severity category premature neonates before and after surfactant therapy.

Ventilator###Before###After Surfactant###p####

value+

parameters###surfactant###6 hours###12 hours###24 hours

RATE###3111###319.5###309.7###268###0.04

FiO2###82.717###6921.7###58.823###5320###0.00

PIP###18.82###19.22.6###19.52.7###191.9###0.48

PEEP###40.3###4.10.33###4.85.3###40.3###0.01

ABG parameters

###Before surfactant After surfactant p#value++

pH###7.260.2###7.30.1###1

PaO2###7669###10773###0.29

HCO3###9.9814###21.36###0.18

PaCO2###4719###4826###0.59

Severity of RDS on CXR

###Before Surfactant N (%) After surfactant N (%)

RDS category9 N (%)

Normal###11 (21.2)###12 (23.1)

Grade 1###2 (3.8)###18 (34.6)

Grade II###9 (17.3)###13 (25)

Grade III###16 (30.8)###7 (13.5)

Grade IV###14 (26.9)###2 (3.8)

Overall improvement###29 (56%)###less than 0.005

However, the timing of the administration of dexamethasone varied with a mean of 2320 hours (range: 1-48 hours) before delivery and 7(44%) were given single dose only.

Besides, 49 (94%) neonates had clinical RDS. Radiological features showed moderate to severe RDS (Category 3 or 4) in 30(58%). Surfactant was used as single dose in 41(78%) neonates at 6.16hours of life, or two doses in 11(22%). There was significant difference between ventilatory rate before and after 24 hours of surfactant administration (pless than 0.05), Fraction of Inspiratory O2 (FiO2) concentration administered before and at 6 hours, 12 hours, and 24 hours respectively (pless than 0.0001), and Positive End- Expiratory Pressure (PEEP)before and at 24 hours (pless than 0.05) (Table-2). However, this difference was not evident statistically for ventilatory rate at 6 and 12 hours, Peak Inspiratory Pressure (PIP) at 6 hours, 12 hours and 24 hours, and PEEP at 6 hours and 12 hours.

ABG analysis showed an improved trend before and after surfactant administration, but was not statistically

Table-3: Association of death after surfactant therapy with demographic and clinical features.

Parameters###Death###P value

###Yes###No

Gender

Male###17###19

Female###4###11###0.22

Gestational age

less than 28 weeks###20###12

28-33 weeks###1###14

34-37 weeks###0###4###0

Birth weight###12###6

500-1000 grams###8###14

1001-1500 grams###1###10###0.008

reater than 1500 grams

Maternal dexamethasone

Yes###4###11

No###17###19###0.22

Birth Place

Inborn###18###24

Outborn###3###6###0.3

Blood culture

Positive###3###3

Negative###18###28###0.68

Significant. The mean duration of ventilation was 6959 hours, and 23(44%) neonates were extubated within 48 hours. Oxygen was required for 156261 hours (or 6.511 days) in these neonates. Only 8(15%) neonates required oxygen beyond 1 week. The concentration of oxygen given (30-80%) and documented oxygen saturation of the babies (85-100%) varied. Compared to initial chest X-ray, a follow-up chest X-ray within 24 hours showed an overall improvement in 29(56%), worsening in 5(10%) or remained the same in 5(10%). RDS category showed significant overall improvement (pless than 0.005) and was significantly improved in males vs females (p=0.003), in- hospital birth vs outborn (pless than 0.000) and lack of receipt of maternal dexamethasone (pless than 0.000).

Complications were seen in 25(48%) neonates and included apnoea and bradycardia 17(32%), endotracheal tube blockage 7(13.5%), pulmonary haemorrhage 3(5.8%), intraventricular haemorrhage 3(5.8%), pneumothorax 2(3.8%), infection 3(5.8%), (including pneumonia, sepsis, necrotising enterocolitis) and bronchopulmonary dysplasia 2(3.8%) within 2 weeks. Six (11.5%) neonates had positive blood cultures (3(5.8%) each of acinetobacter spp and enterobacter spp).

The mean duration of hospitalisation was 19.515 days with 2(3.8%) requiring re-admission within 7 days of discharge. Overall, 21(40%) neonates died. Of them, 20(95%) were less than 28 weeks of gestation (Table 4). Ten(48%) died within 48 hours and 8(38%) after 168 hours of receipt of surfactant. Mortality was significantly associated with gestation (pless than 0.000) and weight (pless than 0.008) but not with gender (p=0.22), receipt of antenatal maternal dexamethasone (p=0.22), birthplace (p=0.30) or bacteraemia (p=0.68). Among the 31 survivors, 13(42%) had more than 6 months follow-up and 2(18%) had recurrent viral illness or wheezing during the first year of life.

Discussion

According to World Health Organisation ( WHO), an estimated 1.1 million preterm babies die every year.1 In the poorest countries, approximately 12% of babies are born prematurely with Pakistan among the top 10 countries. It has one of the highest rates of preterm births (15.8/100 births or 748 100 preterm births per year).1

The incidence of RDS from Pakistani studies has been well documented. One study reported RDS in 10% consecutive admissions to the NICU over a 6-year period.2,10 Among these, 79% required assisted ventilation, had overall mortality 39% and mortality in preterms less than 1,000 gram was 68%. Another study reported a higher rate of RDS 1.7% of all live births, 37.3% of preterm and 0.11% of term neonates and mortality of 43.6%.3 A recent study estimated incidence of RDS among preterm neonates to be 35.5% with a mortality of 14%.11 This may reflect improved overall neonatal care.

Surfactant is one of the expensive modalities for treatment of RDS in premature neonates. But it is proven to be the most effective and standard treatment for RDS in preterm infants in developed countries with significant reduction in mortality and morbidity. Randomised clinical trials have shown that surfactant therapy in RDS results in an overall 40% reduction in mortality and a 35-50% reduction in air leaks.12-14 Despite the proven and evidence-based literature about the benefits of surfactant, its use is limited, and only few developing countries have reported, including Kuwait,15 South Africa,16 India17 and Iran.18

Experience with surfactant in Pakistan has not been reported or published.2,3,10,11 Only few large teaching and private hospitals across Pakistan have used surfactant in the past, but there is increasing trend over the last few years. Like many countries in the region, the main reason for limited surfactant use is high cost, lack of equipment and experienced personnel. Our small study has demonstrated that it has potential benefit in treatment of RDS with significant radiological and clinical improvement in respiratory distress, but not in ABG analysis. Specifically, rapid decrease in FiO2 and other ventilator parameters at 24 hours indicate lower barotrauma in these babies. This significance was much more for males, being born within the hospital and those who had not received antenatal dexamethasone (data not shown). This implies that antenatal dexamethasone has a role in our population and should be given to all to those at risk.

The high mortality was possibly related to extreme prematurity (95% in less than 28 weeks), severity of RDS (Category 3 or 4 in 58%) and either complications of surfactant or mechanical ventilation. However, mortality in these surfactant recipient neonates is also high in other less- developed countries (21-80%).16,19

Limitations of our study were small numbers, lack of control group, limited follow-up and possible other confounders that may have biased our observations.

Since the early experience of this study, we are now much more liberal in using surfactant and have another ongoing study to document improved survival. A multi- centre prospective study from many cities across Pakistan has also been initiated to assess surfactant use with or without other modalities such as conventional ventilation, Nasal Continuous Positive. Airway Pressure (nCPAP) and compare it with no-intervention cases. It will likely shed more light on the specific use of this form of treatment in premature neonates with RDS.

The successful management of RDS depends on early diagnosis and initiation of treatment. Management of RDS includes invasive and non-invasive mechanical ventilation such as nCPAP. Additionally, supplemental oxygen, surfactant administration and availability of support systems such as nursing support, appropriate equipment, X-rays and laboratory support is also important. In developing countries these resources are limited and cost prohibits their routine use. In our cohort of patients, RDS was severe (Grade 3 or 4 in 58%) and so surfactant was probably justified. However, new data suggests that using simple and inexpensive treatments may be more or equally effective in reducing these RDS- related deaths in prematurity.

A recent WHO report says that "inexpensive, proven forms of care for premature babies could save at least three quarters of these babies in the developing world."1 These include antenatal steroid, "Kangaroo care," antiseptic cream for cord care and antibiotics for sepsis. Increasing concerns about lung damage has prompted a shift to less intensive respiratory support. Now there is emphasis on use of non-invasive ventilation such as nCPAP alone, or nCPAP following initial mechanical ventilation with or without surfactant as an alternative. This use of nCPAP alone has been proven to be cost-effective with equal results. More importantly, trials from developed countries and a Cochrane review have shown that nCPAP groups required less ventilation days and had significantly lower mortality.20-22 Fewer studies in less developed countries have used this potential cost-effective and life-saving strategy.

Small studies from Fiji, Kuwait, India and South Africa have shown advantage with reduction in need for surfactant, mechanical ventilation and mortality.23-25 It is a simple inexpensive method of "delivering nasal CPAP using nasal prongs to deliver pressurised, humidified, warmed gas (air and/or oxygen) to reduce lung and alveoli collapse". The added advantage is obvious with a fraction of the cost of a conventional ventilator and less technical skills required. These low cost CPAP devices are being developed specifically for low-income countries. The impact of such interventions in premature neonates may be huge with reducing the major killer RDS.1,24 In Pakistan, low-cost nCPAP should be offered in all premature neonates with mild to moderate RDS.

Conclusions

Surfactant administration was associated with decreased ventilatory requirements, improved respiratory status, chest X-ray findings and early extubation, especially in those with severe disease and greater than 28 weeks of gestation. Surfactant therapy is an option for RDS in Pakistan, but high complication, mortality rates and costs in our setup need further study.

Acknowledgement

We are grateful to Mr Danish Hassan Khan for his help in data analysis.

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Publication:Journal of Pakistan Medical Association
Article Type:Clinical report
Geographic Code:9PAKI
Date:May 31, 2015
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