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Surfactant

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Outline

The history of surfactant
Surfactant composition and function
Surfactant Administration: InSurE
Surfactant Administration: LISA
Surfactant Administration: SALSA
Special Considerations: Pulmonary Hemorrhage
Special Considerations: Meconium Aspiration Syndrome
Summary

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Content prepared by

�Dr. Benjamin Courchia MD

&

Dr. Daphna Yasova Barbeau MD

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The history of surfactant

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The fascinating story of surfactant Henry L Halliday Journal of Paediatrics and Child Health 2017

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The story of surfactant probably began in 1929 when Kurt von Neergaard, a German-born Physiologist working in Switzerland filled a porcine lung with an isotonic gum solution ‘to eliminate surface tension of the air tissue interfaces’
After expanding the lung with air and liquid, he concluded that ‘a lower surface tension would be useful for the respiratory mechanism’ and that ‘Surface tension as a force counteracting the first breath of the newly born should be investigated further’
It would take another 18 years, for someone to follow up on this recommendation, it was Peter Gruenwald, a Pathologist working in New York who 18 years later repeated these experiments with the lungs of stillborn infants.
Gruenwald stated ‘The resistance to aeration is due to surface tension which counteracts the entrance of air’ and he showed that surface active substances reduced the pressure needed for aeration.
Gruenwald would go on to become one of Mary Ellen Avery's teacher, a future giant of the field of neonatology and a key individual in the quest for surfactant therapy.

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AVERY, M. E. & MEAD, J. Surface Properties in Relation to Atelectasis and Hyaline Membrane Disease. M J Dis Child 97, 517–523 (1959).

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Mary Ellen Avery MD

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Enhörning, G. & Robertson, B. LUNG EXPANSION IN THE PREMATURE RABBIT FETUS AFTER TRACHEAL DEPOSITION OF SURFACTANT. Pediatrics 50, 58–66 (1972).

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Fujiwara, T. et al. ARTIFICIAL SURFACTANT THERAPY IN HYALINE-MEMBRANE DISEASE. Lancet 315, 55–59 (1980).

Mary Ellen Avery and Tetsuro Fujiwara

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The fascinating story of surfactant Henry L Halliday Journal of Paediatrics and Child Health 2017

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Group, C. E. M. S. Surfactant Replacement Therapy for Severe Neonatal Respiratory Distress Syndrome: An International Randomized Clinical Trial. Pediatrics 82, 683–691 (1988).

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Surfactant composition and function

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Bordsky & Martin. Neonatology Review 3^rd edition

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BioNinja

Surfactant is made in the alveolar epithelial cells, or the pneumocytes and there are two types of pneumocytes. Type 1 pneumocytes are thin, flat alveolar cells.
And so this makes sense- the long, flat, Type 1 pneumocytes make up the majority of the surface of the alveoli and they are responsible for the gas exchange between alveoli and capillaries.
It's interesting to note that there are actually fewer type 1 pneumocytes than type 2 pneumocytes, even though they make up the majority of the surface area, but that's because they are big and flat. Now, Type 2 pneumocytes are chunky, cuboidal alveolar cells that are responsible for the secretion of pulmonary surfactants that reduce surface tension in the alveoli.
Now, the interesting thing is actually that Type 2 pneumocytes actually differentiate into Type 1 pneumocytes.

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BioNinja

Surfactant is made in the alveolar epithelial cells, or the pneumocytes and there are two types of pneumocytes. Type 1 pneumocytes are thin, flat alveolar cells.
And so this makes sense- the long, flat, Type 1 pneumocytes make up the majority of the surface of the alveoli and they are responsible for the gas exchange between alveoli and capillaries.
It's interesting to note that there are actually fewer type 1 pneumocytes than type 2 pneumocytes, even though they make up the majority of the surface area, but that's because they are big and flat. Now, Type 2 pneumocytes are chunky, cuboidal alveolar cells that are responsible for the secretion of pulmonary surfactants that reduce surface tension in the alveoli.
Now, the interesting thing is actually that Type 2 pneumocytes actually differentiate into Type 1 pneumocytes.

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Thébaud, B. et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers 5, 78 (2019).

I think when we study surfactant, it's important to discuss the stages of lung development because it helps us understand why the premature infant has decreasing surfactant production by decreasing gestational age. The canalicular stage of lung development is between 16 to 26 weeks, and this is when the earliest, most primitive areas of gas exchange of the peripheral lung is formed along with the differentiation of the respiratory epithelium. During week 20, lamellar bodies, which store surfactant, begin to appear in the cytoplasm of the cuboidal type II pneumocytes lining the distal epithelium. Surfactant production begins at approximately 24 weeks, but it's not until about 32 weeks when you have enough surfactant to prevent atelectasis. The sacular stage is next, and this is where the alveoli sac really begin to develop begins between 25-27 weeks GA. It is in this stage that the surface for gas-exchange in the lung really increases in size, however these alveoli are still very immature.

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Brodsky & Martin. Neonatology Review 3^rd edition

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Brodsky & Martin. Neonatology Review 3^rd edition

We also have to discuss the make up of surfactant.
Pulmonary surfactant is a complex mixture of phospholipids (PL) and surfactant proteins (SP) that are labelled A, B C and D that reduce surface tension at the air-liquid interface of the alveolus.
It is made up of about 70% to 80% PL, mainly dipalmitoylphosphatidylcholine (DPPC), 10% SP, and 10% neutral lipids, mainly cholesterol.

Of note, there are other clinical situations that inhibit the production or metabolism of surfactant or inactive the readily available surfactant. These include meconium aspiration, pulmonary hemorrhage and pneumonia. Phospholipase-A2, (PLA₂) present in meconium, has been found to inhibit the activity of surfactant in vitro in a dose-dependent manner, through the competitive displacement of surfactant from the alveolar film. PLA₂ is also known to induce hydrolysis of DPPC.
In PH, Neutrophils are released following endothelial damage and they, in turn, express proteases, oxygen free-radicals and cytokines. These free oxygen molecules damage the Type II cells that produce SPs, thus inhibiting production of surfactant. Elastase, one of these proteases that are released, damages and degrades SP-A, thereby inhibiting SP-A mediated surfactant lipid aggregation and adsorption in vitro.

ARDS, which can be seen after sepsis or pneumonia, is identified by acute pulmonary inflammation leads to Damage to the alveolar Type I cells , which in turn leads to an influx of protein-rich edema into the alveoli, as well as decreased fluid clearance from the alveolar space. Neutrophils are attracted into the airways by host bacterial and chemotactic factors and express enzymes and cytokines which further damage the alveolar epithelial cells. Type II epithelial cell injury leads to a decrease in surfactant production, with resultant alveolar collapse.

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Surfactant Administration: InSurE

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Verder, H. et al. Surfactant Therapy and Nasal Continuous Positive Airway Pressure for Newborns with Respiratory Distress Syndrome. New Engl J Medicine 331, 1051–1055 (1994).

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The first method of surfactant administration is probably the most known and is none other than INSURE. INSURE stands for intubation-surfactant-extubation.
I was trying to trace back the origins of the technique and I believe the paper that described this technique was published in NEJM on October 20th 1994. This study was titled Surfactant Therapy and Nasal Continuous Positive Airway Pressure for Newborns with Respiratory Distress Syndrome by Verder and colleague from the Danish-Swedish Multicenter Study Group.
This study randomized 68 infants with RDS to either surfactant therapy w nCPAP or nCPAP alone. This was not a blinded trial, and the outcome of interest was the percentage of patients requiring mechanical ventilation.
The description of how INSURE was done is quite interesting, let me read you its description:

Infants randomly assigned to treatment with surfactant were treated with morphine and atropine before intubation. Treatment with naloxone before extubation was optional. Surfactant was given in two bolus doses a few minutes apart. After each dose, the infants underwent manual ventilation, usually for two to five minutes. As soon as respiration was judged satisfactory, the infants were extubated. Treatment was considered to have failed in infants who were not extubated within one hour or who were reintubated for ventilator therapy within five days.

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Verder, H. et al. Surfactant Therapy and Nasal Continuous Positive Airway Pressure for Newborns with Respiratory Distress Syndrome. New Engl J Medicine 331, 1051–1055 (1994).

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This study randomized 68 infants with RDS to either surfactant therapy w nCPAP or nCPAP alone. This was not a blinded trial, and the outcome of interest was the percentage of patients requiring mechanical ventilation.
The description of how INSURE was done is quite interesting, let me read you its description:

Infants randomly assigned to treatment with surfactant were treated with morphine and atropine before intubation. Treatment with naloxone before extubation was optional. Surfactant was given in two bolus doses a few minutes apart. After each dose, the infants underwent manual ventilation, usually for two to five minutes. As soon as respiration was judged satisfactory, the infants were extubated. Treatment was considered to have failed in infants who were not extubated within one hour or who were reintubated for ventilator therapy within five days.

The need for subsequent mechanical ventilation was reduced with surfactant therapy (to 43 percent of the surfactant-treated babies, as compared with 85 percent of the controls; P = 0.003)
After 28 days, two of the surfactant-treated babies had died, as compared with five of the control babies.
This study confirmed the merits of the insure techniques, and it would not be long before other invetsigators tried it out.

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1.Bohlin, K., Gudmundsdottir, T., Katz-Salamon, M., Jonsson, B. & Blennow, M. Implementation of surfactant treatment during continuous positive airway pressure. J Perinatol 27, 422–427 (2007).

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1.Bohlin, K., Gudmundsdottir, T., Katz-Salamon, M., Jonsson, B. & Blennow, M. Implementation of surfactant treatment during continuous positive airway pressure. J Perinatol 27, 422–427 (2007).

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Surfactant Administration: LISA

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Kribs, A. et al. Early surfactant in spontaneously breathing with nCPAP in ELBW infants – a single centre four year experience. Acta Paediatr 97, 293–298 (2008).

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Kribs, A. et al. Early surfactant in spontaneously breathing with nCPAP in ELBW infants – a single centre four year experience. Acta Paediatr 97, 293–298 (2008).

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1.Abdel-Latif, M. E., Davis, P. G., Wheeler, K. I., Paoli, A. G. D. & Dargaville, P. A. Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Db Syst Rev 2021, CD011672 (2021).

The goals of the review were to compare surfactant administration via thin catheter with intubation and surfactant administration through an endotracheal tube (ETT); or continuation of non-invasive respiratory support without surfactant administration or intubation.
The review included randomised trials comparing surfactant administration via thin catheter (S-TC) with (1) surfactant administration through an ETT (S-ETT), or (2) continuation of non-invasive respiratory support without surfactant administration or intubation. They also included trials comparing diﬀerent methods/strategies of surfactant administration via thin catheter.
Patients selected were preterm infants (at < 37 weeks' gestation) with or at risk of RDS.

The search yielded a total 16 studies (18 publications; 2164 neonates)

Some of the outcomes they looked at included:

Death or bronchopulmonary dysplasia (BPD): the composite outcome of death or BPD, defined as the need for oxygen or respiratory support at 36 weeks' postmenstrual age (PMA) (Shennan 1988).
Need for intubation within the first 72 hours of life.
Air leak requiring drainage (during first hospitalisation).
Severe intraventricular haemorrhage (IVH), including grades III and IV (Papile 1978).
Death during first hospitalisation (all causes).
BPD (clinical definition) among survivors to 36 weeks' PMA.
Death or survival with neurosensory disability

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Abdel-Latif, M. E., Davis, P. G., Wheeler, K. I., Paoli, A. G. D. & Dargaville, P. A. Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Db Syst Rev 2021, CD011672 (2021).

Looking at these outcomes, the results showed the following:

comparison of Death or BPD between LISA and surf via ETT was reported by 10/16 studies: The meta-analysis of trials showed a significant decrease in the risk of this outcome with S-TC compared to S-ETT (typical RR 0.59, 95% CI 0.48 to 0.73; typical RD -0.11, 95% CI -0.15 to -0.07; NNTB 9, 95% CI 7 to 16); 10 studies, 1324 infants). Heterogeneity among the studies was low (IT = 19%).
Need for intubation within 72 hours was reported by 12/16 studies and the meta-analysis showed a significant decrease in the risk of this outcome with S-TC compared to SETT (typical RR 0.63, 95% CI 0.54 to 0.74; typical RD -0.14, 95% CI -0.18 to -0.09; NNTB 8, 95% CI; 6 to 12; 12 studies, 1422 infants). Heterogeneity among the studies was low (IT = 31%).
Air leak requiring chest tube/needle was reported by 6/16 studies, and the meta-analysis of trials showed no significant diﬀerences in the risk of this outcome between S-TC and S-ETT (typical RR 0.58, 95% CI 0.33 to 1.02; typical RD -0.03, 95% CI -0.05 to 0.00; 6 studies, 1036 infants).
Severe IVH was reported by 5/16 studies and showed a significant decrease in the risk of this outcome with S-TC compared to S-ETT (typical RR 0.63, 95% CI 0.42 to 0.96; typical RD -0.04, 95% CI -0.08 to -0.00; NNTB 22, 95% CI 12 to 193; 5 studies, 857 infants).
Death during hospitalization was reported by 10/16 studies and showed a significant diﬀerence in the risk of this outcome between S-TC and S-ETT (typical RR 0.63, 95% CI 0.47 to 0.84; typical RD -0.02, 95% CI -0.10 to 0.06; NNTB 20, 95% CI 12 to 58; 10 studies, 1424 infants).
BPD was analyzed 11 studies and showed a significant diﬀerence in the risk of this outcome between S-TC and S-ETT (typical RR 0.57, 95% CI 0.45 to 0.74; typical RD -0.08, 95% CI -0.11 to -0.04; NNTB 13, 95% CI 9 to 24; 11 studies, 1567 infants)
Finally, Death or survival with neurosensory disability was not reported by any of the studies.

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Dargaville, P. A. et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome. Jama 326, 2478–2487 (2021).

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Dargaville, P. A. et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome. Jama 326, 2478–2487 (2021).

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Härtel, C. et al. Association of Administration of Surfactant Using Less Invasive Methods With Outcomes in Extremely Preterm Infants Less Than 27 Weeks of Gestation. Jama Netw Open 5, e2225810 (2022).

Preterm Infants Less Than 27 Weeks of Gestation by Hartel et al.

This study analyzed the short-term outcome data from 2534 LISA-exposed infants of 22 to 26 weeks’ GA within the German Neonatal Network (GNN) collaborative.
This was a large dataset from one of the most experienced groups in this field.
They looked at a variety of outcomes. The main outcomes they looked at were rates of LISA use, use of mechanical ventilation within the first 72 hours (considered failure of LISA), and association of LISA with outcomes, including death from all causes, bronchopulmonary dysplasia (BPD), death and BPD combined, pneumothorax, retinopathy of prematurity, intracerebral hemorrhage, and periventricular leukomalacia.
Their study included A total of >6000 infants with a gestational age of 22 to 26 weeks
Interestingly they gave LISA to 2534 infants in what they call a quasi-prophylactic approach during delivery room management.

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Härtel, C. et al. Association of Administration of Surfactant Using Less Invasive Methods With Outcomes in Extremely Preterm Infants Less Than 27 Weeks of Gestation. Jama Netw Open 5, e2225810 (2022).

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Härtel, C. et al. Association of Administration of Surfactant Using Less Invasive Methods With Outcomes in Extremely Preterm Infants Less Than 27 Weeks of Gestation. Jama Netw Open 5, e2225810 (2022).

Due to the success experienced in Germany, LISA now has broad European acceptance and surfactant administration with this method has received an indication throughout European Union countries by the National Authorization Procedure.
Specially designed catheters for the LISA procedure have also received European Conformity approval. In 2019, both the United Kingdom and the European consensus guidelines recommended this mode of surfactant administration because of its minimally invasive nature and potential impact on care.
The beneficial effects of the noninvasive methods have also been noted by the Canadian Pediatric Society as surfactant replacement guidelines updated in 2021 noted that “non-invasive methods of surfactant administration, such as LISA or minimally invasive surfactant therapy, are preferable.” LISA continues to gain acceptance among US neonatologists slowly.

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Surfactant Administration: SALSA

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Guthrie, S. O., Fort, P. & Roberts, K. D. Surfactant Administration Through Laryngeal or Supraglottic Airways. Neoreviews 22, e673–e688 (2021).

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Surfactant Administration: Aerosolized

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Cummings, J. J. et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics 146, e20193967 (2020).

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Cummings, J. J. et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics 146, e20193967 (2020).

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Gaertner, V. D., Thomann, J., Bassler, D. & Rüegger, C. M. Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis. Pediatrics 148, e2021052504 (2021).

These results were quite encouraging and the following year a meta-analysis on this technique was published in pediatrics, the article was authored by Gaertner and colleagues and is called: Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis
This analysis searched for all randomized controlled trials (RCTs) and quasi-RCTs enrolling preterm infants (<37 weeks’ gestation) comparing NEBULIZED SURFACTANT with any control group (ie noninvasive respiratory support, no respiratory support or intratracheal surfactant application)
The primary outcome was intubation rate at 72 hours after birth and there were a number of interesting secondary outcomes.
Nine studies recruiting 1095 infants met inclusion criteria.
Surfactant Nebulization (SN) compared with standard care significantly reduced intubation rate at 72 hours after birth: 40% vs 53.2% risk ratio [RR]: 0.73, 95% confidence interval [CI]: 0.63–0.84; number needed to treat: 8; 95% CI: 5–14
Prespecified subgroup analysis identified important heterogeneity: SN was most effective in infants ≥28 weeks' gestation (RR: 0.70, 95% CI: 0.60–0.82), with a pneumatically driven nebulizer and in infants receiving ≥200 mg/kg and animal-derived surfactant (RR: 0.63, 95% CI: 0.52–0.75).
No differences in neonatal morbidities or mortality were identified.
SN reduced the intubation rate in preterm infants with a higher efficacy for specific subgroups. There was no difference in relevant neonatal morbidities or mortality.
The author did acknowledge that the quality of the evidence was low because of risk of bias and imprecision.

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Special scenarios: Pulmonary Hemorrhage

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Aziz, A. & Ohlsson, A. Surfactant for pulmonary haemorrhage in neonates. Cochrane Db Syst Rev 2020, CD005254 (2020).

The conclusion of that review was that they could not find any randomised or quasi-randomised trials that evaluated the eﬀect of surfactant in PH
Therefore, no conclusions from such trials can be drawn.
They do however mention the outcomes from some observational studies they found.
One retrospective case series of 15 neonates treated with surfactant following PH, Pandit et al (Pandit 1995) noted improvement in the oxygen index following surfactant treatment. One infant died from infection and BPD and an additional four infants developed BPD
Amizuka et al (Amizuka 2003) gave surfactant to 26 of a total of 27 neonates with PH occurring soon after birth. A good response to exogenous surfactant, defined as ventilatory index < 0.047 at one hour after surfactant administration, was seen in 82% of cases. No neonate died or developed BPD.

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Special scenarios: Meconium Aspiration

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Shahed, A. I. E., Dargaville, P. A., Ohlsson, A. & Soll, R. Surfactant for meconium aspiration syndrome in term and late preterm infants. Cochrane Db Syst Rev CD002054 (2014) doi:10.1002/14651858.cd002054.pub3.

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The point of this review was to elucidate whether surfactant could in the case of meconium aspiration syndrome have some effect on the primary outcome of MORTALITY, and a litany of secondary outcomes that included:

Treatment with extracorporeal membrane oxygenation (ECMO);
Pneumothorax;
Pulmonary interstitial emphysema;
Air leaks
Duration of assisted mechanical ventilation (days);
Duration of supplemental oxygen (days);
Need for supplemental oxygen at discharge;
Chronic lung disease (defined as need for oxygen therapy at 28 days or 36 weeks postmenstrual age);
Intraventricular haemorrhage (any grade);
Severe IVH (grade III - IV);
Duration of hospital stay (days).
Death or chronic lung disease at 28 days;
Death or chronic lung disease at 36 weeks postmenstrual age;
Neurodevelopmental follow-up.

They looked for randomised controlled trials comparing surfactant treatment to routine management of late preterm and term infants with MAS.
Four randomised controlled trials met inclusion criteria which included 326 infants

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Shahed, A. I. E., Dargaville, P. A., Ohlsson, A. & Soll, R. Surfactant for meconium aspiration syndrome in term and late preterm infants. Cochrane Db Syst Rev CD002054 (2014) doi:10.1002/14651858.cd002054.pub3.

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The results showed no statistically significant effect on mortality [typical risk ratio (RR) 0.98, 95% confidence interval (CI) 0.41 to 2.39; typical risk diﬀerence (RD) -0.00, 95% CI -0.05 to 0.05].
The risk of requiring extracorporeal membrane oxygenation was significantly reduced in a meta-analysis of two trials (n = 208); [typical RR 0.64, 95% CI 0.46 to 0.91; typical RD -0.17, 95% CI -0.30 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 3 to 25].
One trial (n = 40) reported a statistically significant reduction in the length of hospital stay (mean diﬀerence -8 days, 95% CI -14 to -3 days; test for heterogeneity not applicable).
There were no statistically significant reductions in any other outcomes studied (duration of assisted ventilation, duration of supplemental oxygen, pneumothorax, pulmonary interstitial emphysema, air leaks, chronic lung disease, need for oxygen at discharge or intraventricular haemorrhage).
And so the authors conclude that in infants with MAS, surfactant administration may reduce the severity of respiratory illness and decrease the number of infants with progressive respiratory failure requiring support with ECMO.

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Summary

Surfactant help reduce surface tension at the air-liquid interface of the alveolus.
Surfactant are produced by Type II pneumocytes.
Surfactant are composed mainly of phosphatidylcholine (monosaturated 20%, desaturated 50%)
Surfactant proteins only make up 8% of surfactant
There are many ways surfactant can be administered: via an ET tube, a thin catheter, a supraglottic airway device or aerosolized.
Observational evidence supports the use of surfactant in pulmonary hemorrhage
Surfactant has been shown to reduce the severity of meconium aspiration syndrome

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Thank You

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