Key Clinical MessageHyaline membrane disease (HMD) or respiratory distress syndrome (RDS) mainly affects premature neonates due to pulmonary surfactant deficiency. Early exogenous surfactant administration within the first two hours of life is the gold standard treatment, but complications such as post-surfactant slump can occur. We present a case of a 29-week gestational age male with very low birth weight (VLBW) who deteriorated at 21 days of life (DOL) due to late post-surfactant slump and pneumonia. After two additional doses of exogenous surfactant at 22 DOL, the patient showed significant improvements clinically and radiographically within hours of treatment, leading to successful recovery and extubation. This case suggests that late booster doses of surfactant can be effective beyond the typical two-hour window, warranting further research into its therapeutic potential and limitations in late-stage HMD.IntroductionHyaline membrane disease (HMD) occurs primarily in premature neonates and its incidence is inversely related to gestational age and birthweight. A decrease in pulmonary surfactant production or secretion leads to reduced pulmonary compliance, increased surface tension, alveolar instability, collapse of small airways at end-expiration and failure to attain adequate functional residual capacity (FRC) [1]. Nowadays, the administration of exogenous surfactant as early as possible, preferably within the first 2 hours of life, is the gold standard of care. Consequently, this improves oxygenation by matching alveolar ventilation and perfusion, decreasing the need of ventilatory support and improving mortality [2].Pulmonary surfactant is composed approximately of 90% lipids and 10% proteins which are secreted into the alveolar space by type II epithelial cells. The major constituents of it are dipalmitoylphosphatidylcholine (DPPC), phosphatidyl glycerol, and the four surfactant specific proteins (surfactant protein A (SP-A), SP-B, SP-C and SP-D). These proteins are divided into two groups: SP-B and SP-C are two small hydrophobic proteins, while SP-A and SP-D are large hydrophilic proteins. The main function of surfactant is to lower the surface tension at the air/liquid interface within the alveoli of the lung leading to a decrease in the work of breathing and preventing alveolar collapse at end-expiration [3]. Merill et al. reported that infants requiring respiratory support after 1 week of life experienced transient episodes of dysfunctional surfactant associated with a deficiency in alveolar surfactant proteins, mainly SP-B and SP-C. SP-B gene expression is decreased by the inflammatory cytokines and mediators like tumor necrosis factor-α (TNF-α), transforming growth factor- β (TGF-β), IL-1, lipopolysaccharide (LPS), and activators of protein kinase C. Concentrations of SP-B content could also be decreased by accelerated degradation secondary to increased proteolytic activity or phagocytosis by nearby cells [4]. In another study by Keller et al. it was reported that late administration of exogenous surfactant increased SP-B levels and improved outcomes [5]. Interestingly, surfactant inactivation and secondary dysfunction may also occur with other conditions like meconium aspiration syndrome, persistent pulmonary hypertension of the newborn, neonatal pneumonia and pulmonary hemorrhage [6].Preterm neonates, born at <30 weeks of gestational age, mainly require respiratory support for several weeks in addition to exogenous surfactant administration. However, multiple complications may arise such as post surfactant slump (defined as respiratory failure after 6 days of life), pneumonia, intraventricular hemorrhage (IVH), pulmonary hemorrhage, pneumothorax and bronchopulmonary dysplasia (BPD), further exacerbating the disease in a vicious cycle [7]. BPD is a form of chronic lung disease that often develops in severe RDS. It’s mainly a consequence of alveolar collapse, due to surfactant deficiency, together with ventilator induced phasic over distention of the lung and oxygen injury. As a result, respiratory failure and death may occur due to rapid progression of the disease [8]. Recently, clinical trials depicted the crucial role of late surfactant administration in improving respiratory function when given within the first 2 weeks of life in extremely low birth weight (ELBW) neonates (<1000g) [9-10]. In our case report, we demonstrated the potential use of exogenous surfactant beyond 3 weeks (22 DOL) in a very low birth weight (VLWB) neonate (1470g) with HMD. This case opens an exciting new avenue of study to better understand the underlying pathophysiological process of this disease and the therapeutic potential of exogenous surfactant as a standard treatment for HMD later in the disease course.Case History and ExaminationA preterm male neonate born at 29 weeks gestational age (GA) by C-section after maternal pre-eclampsia. He has a VLBW of 1,470g. The mother, 45 years old, G1P0A0, was on antihypertensives and received 4 doses of dexamethasone during the antenatal period. Initially, the baby was intubated and supported by mechanical ventilator with PEEP: 4cmH2O. Following the confirmation of HMD on chest X-ray, he received 2 doses of exogenous surfactant, Survanta (natural bovine pulmonary surfactant) 100mg phospholipids/kg (4ml/kg). He was treated with IV antibiotics for presumed sepsis for 7 days. The baby’s chest x-ray improved, showing clearing of HMD changes. We were able to decrease slowly the ventilator’s parameter at 15 DOL where FiO2 reached 30% with low pressures and these parameters were almost stable till the age of 20 days (Figure 1A). At 21 days, the baby’s condition deteriorated rapidly, requiring FiO2 >90%, PIP: 30cmH2O and PEEP: 7cmH2O. His C-reactive protein (CRP) was 6 mg/L, and his chest X-ray showed worsening extensive bilateral patches of consolidations with air bronchograms (Figure 1B and C).Methods (Differential Diagnosis, Investigation and Treatment)By 22 days, the baby was still in critical condition with multiple episodes of desaturation despite high ventilator parameters (FiO2 100%, PIP: 45cmH2O and PEEP: 8cmH2O), and CRP increased to 42.7 mg/L. The chest X-ray revealed extensive HMD changes with ground glass appearance and air bronchograms (Figure 1D). The prolonged ventilation, pneumonia and worsening X-ray results suggested an endogenous surfactant deficiency. To note, the baby was receiving IV Colistin (3mg/kg/day) and Amikacin (15mg /kg/dose every 36 hours) due to the presence of MDR Klebsiella pneumonia in the deep tracheal aspirate culture. Following consultation with an infectious disease specialist, Teicoplanin (16 mg/kg loading dose, followed by 8 mg/kg/day) was added to our treatment.Given the rapid deterioration, a decision was made to administer booster doses of exogenous surfactant. Survanta (4 ml/kg) was given via ET tube for 2 doses 7 hours apart. Following the first dose, significant improvement in HMD changes were noted on chest X-ray films after 2 hours (Figure 1E). After the second dose, the baby’s condition substantially improved, particularly in terms of desaturation episodes. Chest X-ray showed significant improvement and clearing of the HMD changes 5 hours after the second dose (Figure 1F). At that night, steroids and diuretics were initiated to complement the surfactant treatment and improve the respiratory function.Outcome and Follow-upThe day after surfactant administration, ventilator support was minimized, and FiO2 was reduced by more than 50% within 5 days. By 24 DOL, chest X-ray showed impressive improvement with the clearance of pulmonary infiltrates and granular opacities (Figure 1G). At 34 DOL, ventilator parameters were weaned, and the patient was placed on alternating mechanical ventilation modes (IMV and CPAP mode) for 2 weeks. At 48 DOL, the patient was extubated and placed in an oxygen hood (10 L/min). By 95 DOL, the patient was clinically stable without any ventilatory support, and X-rays showed complete resolution of lung opacities and HMD changes. The patient was discharged home with no significant complications.DiscussionSince its discovery in the 1950s, surfactant administration has become the first line treatment for HMD in preterm neonates. This has led to substantial decrease in mortality rates and improvement in respiratory outcomes [11]. Nowadays, it is well established that surfactant administration improves oxygenation through increasing lung compliance and matching alveolar ventilation/perfusion [12]. The United States Food and Drug Administration (FDA) recommends the administration of natural exogenous surfactant within the first 48 hours of life for beractant (Survanta)/poractant alfa and 72 hours for calfactant [13]. Subsequently, treatment modalities were subdivided into prophylactic and rescue therapy. With prophylaxis, surfactant is administered within 10-30 mins after birth to infants at high risk of developing RDS, however, rescue therapy is given to infants with established RDS usually within the first 12 hours of life [14]. Compared to rescue therapy, randomized trials have shown that prophylactic treatment with surfactant decreased the risk of developing pneumothorax, pulmonary interstitial emphysema, and neonatal mortality [2]. In addition, when compared to a single dose, more evidence supports the use of multiple doses of rescue surfactant to decrease the risk of pneumothorax and improve survival [15].However, when it comes to the efficacy of surfactant therapy beyond the early neonatal period, studies are scarce. In one study, Bissinger et al. reported 3 cases of late surfactant administrations (range: 12-17 days of life) in extremely preterm (<27 weeks) ELBW (<1000g) neonates. Results showed that improvement in blood gas and ventilatory parameters were short-term and patients deteriorated thereafter [16]. Another retrospective cohort analysis studied the effect of repeat surfactant therapy, after 6 DOL, on postsurfactant slump in ELBW infants. Results also showed only transient improvement for 48 hours [17]. Recently, clinical trials depicted improvement in pulmonary morbidity at 1-year corrected age when late surfactant was given during the second week of life with no remarkable adverse effects [9-10]. Eventually, we considered a late trial of 2 doses of exogenous surfactant (beractant) in a very preterm neonate with a VLBW (1470g) beyond 3 weeks at 22 DOL. Our patient showed substantial improvement clinically and radiographically. He was then weaned off the respirator and discharged home with no significant complications. This report allows us to widen the therapeutic window for late surfactant administration especially beyond 3 weeks of life in VLBW neonates.In HMD, neonates with continuous respiratory support beyond 1 week were found to have abnormal surfactant function due to a deficiency in SP-B and SP-C [4-5]. Notably, dysfunctional surfactant was also noted in other diseases including meconium aspiration syndrome, pneumonia, persistent pulmonary hypertension and pulmonary hemorrhage where rescue surfactant was reported to improve outcomes [6]. More research is warranted here to delineate the mechanisms leading to SP-B deficiency in different disease states with hopes for developing targeted therapies to improve respiratory outcomes.In conclusion, our case report challenges the conventional practice of administering exogenous surfactant primarily within the first 48 hours of life in premature neonates with HMD. By presenting a successful late booster dose of surfactant at 22 days of life in a VLBW neonate, we highlight the potential therapeutic benefits of extending the window for surfactant administration beyond the early neonatal period. This unique case prompts further investigation into the efficacy and limitations of late exogenous surfactant interventions, particularly in the later stages of HMD.