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Surfactant for bacterial pneumonia in late preterm and term infants

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Authors

Kenneth Tan1, Nai Ming Lai2, Ajay Sharma3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Monash Newborn, Monash Medical Centre/Monash University, Clayton, Australia [top]
2Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Sunway Campus, Bandar Sunway, Malaysia [top]
3Newborn Services, Monash Medical Centre/Monash University, Clayton, Australia [top]

Citation example: Tan K, Lai NM, Sharma A. Surfactant for bacterial pneumonia in late preterm and term infants. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD008155. DOI: 10.1002/14651858.CD008155.pub2.

Contact person

Kenneth Tan

Monash Newborn
Monash Medical Centre/Monash University
246 Clayton Road
Clayton
Victoria
3168
Australia

E-mail: kenneth.tan@southernhealth.org.au

Dates

Assessed as Up-to-date: 14 September 2011
Date of Search: 29 June 2011
Next Stage Expected: 14 September 2013
Protocol First Published: Issue 4, 2009
Review First Published: Issue 2, 2012
Last Citation Issue: Issue 2, 2012

Abstract

Background

Pulmonary surfactant is an important part of the host defence against respiratory infections. Bacterial pneumonia in late preterm or term newborn infants often leads to surfactant deficiency or dysfunction, as surfactant is either inactivated or peroxidated. Studies of animal models of pneumonia and clinical case reports suggest that exogenous surfactant might be beneficial to infants with bacterial pneumonia.

Objectives

To assess the effect of exogenous surfactant treatment on mortality and pulmonary complications in infants with bacterial pneumonia.

Search methods

We used standard Cochrane Collaboration methodology to conduct our search of databases. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 6); MEDLINE (accessed via Ovid SP June 2011); EMBASE (via Ovid SP 1980 to June 2011); and CINAHL Plus (accessed via EBSCOHost June 2011).

Selection criteria

We limited our search to randomised and quasi-randomised trials of surfactant replacement therapy in infants > 35 weeks gestation with bacterial pneumonia in the first 28 days of life. The primary outcome measures were death, time to resolution of pneumonia, incidence of chronic lung disease, pneumothoraces and pulmonary haemorrhage.

Data collection and analysis

We assessed all studies with predefined criteria as to whether they were eligible for inclusion. We extracted data using RevMan 5 (RevMan 2011). We used the standard Cochrane Collaboration methodology for data collection and analysis to assess risk of bias, heterogeneity, treatment effect, missing data and reporting bias where appropriate.

Results

We did not identify any studies that met our inclusion criteria.

Authors' conclusions

There is no evidence from randomised controlled trials (RCTs) to support or refute the efficacy of surfactant in near-term and term infants with proven or suspected bacterial pneumonia. RCTs are still required to answer this question.

Plain language summary

Surfactant for bacterial pneumonia in term and late preterm infants

Bacterial pneumonia in preterm and term newborn babies can cause problems with the functioning of pulmonary surfactant, a complex combination of fats and proteins that lines the lung and causes the lung to work effectively. Disrupting surfactant function makes breathing very difficult for these infants. In this review, we did not find any suitable clinical trials to assess the benefits or harms of surfactant treatment in addition to standard intensive care in the treatment of babies with bacterial pneumonia. More research is needed to answer the question of whether surfactant treatment is beneficial for near-term and term infants with bacterial pneumonia.

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Background

Description of the condition

Bacterial pneumonia in the neonatal period can be divided into three groups based on the time of onset: congenital (present as a result of primary intrauterine infection), early onset (less than/or equal to 48 hours of age) and late onset (> 48 hours of age) (Dear 2005). True congenital pneumonia is rare (Campbell 1996). Early onset pneumonia may represent infection from bacteria acquired from the birth canal. Late onset pneumonia usually represents either nosocomial or community-acquired infection. Some authors have used seven days as the cut-off limit for distinguishing early onset pneumonia from late onset pneumonia (Duke 2005).

Determination of the true incidence of pneumonia in newborn infants can be difficult, as respiratory problems from non-infectious causes are common in this age group. In a study of infants admitted to a neonatal unit, the incidence of pneumonia was 1.8 per 1000 live births (Webber 1990). Among ventilated infants, much higher incidences of around 12% to over 20% have been reported (Apisarnthanarak 2003; Yuan 2007).

The diagnosis of clinical bacterial pneumonia may be made by clinical signs, chest radiographic appearance and other ancillary measurements of infection such as total white cell count including immature neutrophil ratio, inflammatory markers like C-reactive protein (Forest 1986) and procalcitonin (Verboon-Maciolek 2006). The Centers for Diseases Control and Prevention (CDC) criteria for clinical pneumonia ("PNU 1") in infants below the age of one, includes chest x-ray findings (new or persistent infiltrate, consolidation, cavitation or pneumatoceles), clinical symptoms (worsening gas exchange and any three of the following criteria: temperature instability, leukopenia, purulent sputum, apnoea/tachypnoea, wheezing/rales, cough and mechanical ventilation (Horan 2008). Proven pneumonia is categorised by the CDC as "pneumonia with specific laboratory findings" ("PNU 2") where there is positive blood, pleural or bronchoalveolar lavage (BAL) culture or intracellular organisms in BAL cells or microorganisms identified in lung biopsy specimens (Horan 2008). Positive isolates from tracheal aspirates results may not necessary point towards pneumonia and should be interpreted in conjunction with the clinical picture (Cordero 2002). In addition, for the diagnosis of ventilator-associated pneumonia (VAP), the patient is also required to have received at least 48 hours of mechanical ventilation prior to onset of pneumonia (Horan 2008). However, it is very difficult to make the diagnosis of pneumonia in neonates as even the CDC criteria was developed primarily for surveillance or reporting and has not been validated from a microbiological viewpoint (Baltimore 2003).

Description of the intervention

Pulmonary surfactant is a lipoprotein complex secreted by type II pneumocytes (Goerke 1998). The ability of surfactant to lower the surface tension of an air-water interface makes it essential in pulmonary gas exchange by keeping the alveoli open. This ability depends largely on the saturated phosphatidylcholine species and surfactant proteins (SP-B and SP-C) (Jobe 2006). The hydrophilic surfactant proteins (SP-A and SP-D) function as antibody-independent opsonin that binds a range of bacteria and helps macrophage microbial clearance (McCormack 2002). Two general classes of surfactant are available for surfactant replacement therapy: synthetic surfactant and surfactant derived from animal lungs. Synthetic surfactants are either mixtures of phospholipids or mixtures of phospholipids with proteins or peptides. Synthetic lipids-only surfactant is no longer produced for clinical use; having been replaced by a newer generation of synthetic surfactant that contains mixtures of both lipids and peptides. Surfactant obtained from the lungs of animals also contains both phospholipids and surfactant proteins (Jobe 2008).

Exogenous surfactant therapy involves the administration of surfactant (animal derived or synthetic) into the endotracheal tube of an intubated infant. Other modes of surfactant administration, for example via nebulisation, have been described (Fok 1998).The benefits of exogenous surfactant for preterm infants with respiratory distress syndrome are well established. Surfactant therapy reduces pneumothorax and mortality in premature infants at risk of or having respiratory distress syndrome (Soll 2001a). Animal derived surfactant appears to provide greater improvements in survival compared to synthetic lipids-only surfactant (Soll 2001b). However, a newer generation of synthetic surfactant with protein may be as effective as animal derived surfactant (Pfister 2007).

Other major issues to consider in surfactant therapy are dosing (single versus multiple) and the mode of administration (single bolus versus lavage). In neonates with respiratory distress, there is evidence that multiple doses of surfactant compared to a single dose of surfactant lead to a reduced risk of pneumothorax and a trend towards improved survival (Soll 2009a). However, in animal models, more uniform pulmonary distribution of exogenous surfactant treatment has been noted with lavage administration (Balaraman 1998).

Evidence exists to support the use of surfactant in term or late preterm infants with meconium aspiration syndrome (MAS) (El-Shahed 2007) in whom inactivation of type 2 cells and surfactant itself have been proposed as the main mechanism of surfactant deficiency, similar to that postulated in infants with congenital pneumonia (Rudiger 2001). In MAS, surfactant can be delivered as a bolus dose or as a lavage dose (Lejeune 2005; Lo 2008), although reports on the relative effectiveness of these two approaches have not yet been published. The studies of surfactant therapy in MAS have also shown that multiple doses is more efficacious than single dose therapy (Dargaville 2005). Extrapolating from the evidence on the use of surfactant in MAS, dosing and mode of administration appear to be relevant in evaluating the role of surfactant in congenital bacterial pneumonia.

How the intervention might work

In any episode of pneumonia, secondary surfactant deficiency may develop through reduced surfactant production (Taeusch 2000), surfactant dysfunction, inactivation (Rudiger 2001) or peroxidation (Bouhafs 1999; Bouhafs 2004). An autopsy study of neonates who died from Group B Streptococcus sepsis confirmed that most of these infants had surfactant deficiency or dysfunction (Payne 1988). Deficiency or deranged composition of surfactant has also been noted in infants beyond the first few days of life as well as in older children with severe bacterial pneumonia (LeVine 1996). It may be that the surfactant pool in early neonatal life is not as large as later on (for example, after two weeks of age) and this may potentially affect the severity of illness in these infants with pneumonia.

Evidence on the possible role of surfactant in neonatal bacterial pneumonia is provided by animal studies. In animal models of Group B Streptococcus pneumoniae (S. pneumoniae), surfactant is reported to have immunomodulating effects (Talati 2001). The addition of surfactant with or without concurrent administration of immunoglobulin (Herting 1994; Herting 1999) seems to enhance bacterial clearance. In a study investigating the role of specific neutralising antibodies to bacterial pneumonia, the antibodies are effective only when surfactant is added (Gan 2001).

Along with supportive treatment and antibiotics, surfactant therapy may be useful in the treatment of neonatal bacterial pneumonia. The postulated mechanisms of action are the reversal of surfactant inactivation (that is a feature of bacterial pneumonia) and local immunomodulating effects . A report of two ex-preterm infants with acute respiratory distress syndrome (ARDS) secondary to Chlamydia pneumoniae (C. pneumoniae) provides the first human evidence on possible benefits of surfactant during bacterial pneumonia. The diagnoses were made from the clinical presentation, chest x-ray appearances, chlamydia specific antigen from tracheal aspirates and isolation of the microorganism (in one infant). Both infants responded to surfactant administration and survived without chronic lung disease (Harms 1994). Other types of respiratory distress, for example, secondary to respiratory syncytial virus (RSV) infections, have also been shown to respond to surfactant therapy (Ventre 2006).

However, there is concern that certain types of surfactant appear to promote the growth of specific bacterial species (Rauprich 2000). Furthermore, there is a suggestion that surfactant administration may be associated with pulmonary haemorrhage (Raju 1993; Soll 2004). In addition, there are the risks associated with initial surfactant instillation including a brief period of hypoxia and hypotension as well as altered cerebral haemodynamics (Cowan 1991; Kaiser 2004).

Fetter 1995 reported that neonates with respiratory distress associated with sepsis, but without a specific diagnosis of bacterial pneumonia, may demonstrate improvement in their respiratory status after surfactant treatment. Given the difficulty of accurately differentiating between pneumonia and ARDS with (non-pulmonary) sepsis in this group of infants, there is a possibility of inadvertent surfactant treatment (or assignment) if the diagnosis at study entry was incorrect. Any study of interventions for treating respiratory distress in these groups of infants should also analyse outcomes in the subgroups separately, to ascertain that the overall treatment effect size is not under- or overestimated.

Why it is important to do this review

There is a strong rationale to consider surfactant treatment for neonates with bacterial pneumonia. In this review, we aim to assess the clinical benefits and safety of exogenous surfactant for term or late preterm newborns diagnosed with bacterial pneumonia.

Cochrane reviews that address trials of pulmonary surfactant in neonates

Sinclair J, Bracken M. Effective Care of the Newborn. Oxford University Press

Original controlled trials

Soll R, Ozek E. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001079. Review.

Soll R, Özek E. Protein free synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews. 1998, Issue 3. Art. No.: CD001149. DOI: 10.1002/14651858.CD001149. Updated 2011.

Soll R, Özek E. Prophylactic animal derived surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 4. Art. No.: CD000511. DOI: 10.1002/14651858.CD000511. Updated 2010.

Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007836. Review.

Comparisons of surfactant preparations

Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2001;(2):CD000144. Review.

Pfister RH, Soll R, Wiswell TE. Protein-containing synthetic surfactant versus protein-free synthetic surfactant for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006180. Review.

Pfister RH, Soll RF, Wiswell T. Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD006069. Review.

Singh N, Hawley KL, Viswanathan K. Efficacy of porcine versus bovine surfactants for preterm newborns with respiratory distress syndrome: systematic review and meta-analysis. Pediatrics. 2011 Dec;128(6):e1588-95. Epub 2011 Nov 28. Review. (NON COCHRANE REVIEW)

Comparison of treatment strategies

Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD000510. DOI: 10.1002/14651858.CD000510.pub2 .

Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2000;(2):CD001456. Review.

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 Jan 21;(1):CD000141. Review.

Stevens TP, Harrington EW, Blennow M, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003063. Review. PMID: 17943779 [PubMed - indexed for MEDLINE]

Methods of instillation

Abdel-Latif ME, Osborn DA. Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD008309. Review.

Abdel-Latif ME, Osborn DA. Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD008311. Review.

Abdel-Latif ME, Osborn DA. Nebulised surfactant for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD008310. DOI: 10.1002/14651858.CD008310

Surfactant for conditions other than RDS

El Shahed AI, Dargaville P, Ohlsson A, Soll RF. Surfactant for meconium aspiration syndrome in full term/near term infants. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD002054. Review.

Aziz A, Ohlsson A. Surfactant for pulmonary hemorrhage in neonates. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005254. Review.

Tan K, Lai NM, Sharma A. Surfactant for bacterial pneumonia in late preterm and term infants. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008155.

Hahn S, Choi HJin, Soll R, Dargaville PA. Therapeutic lung lavage for meconium aspiration syndrome in newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD003486. DOI: 10.1002/14651858.CD003486 .

Objectives

To evaluate the effect of exogenous surfactant administration on death and respiratory morbidity and the safety of this therapy in term and near-term infants with bacterial pneumonia.

Bacterial pneumonia was defined as either proven bacterial pneumonia or clinical pneumonia.

  1. Proven pneumonia is defined as meeting clinical and radiological criteria for pneumonia and identification of the bacteria through isolation or antibody identification.
  2. Clinical pneumonia involves assessment by the treating clinician that the infant has a pulmonary infection that has been treated with a complete course of antibiotics (the type and length of antibiotic course, as specified by the study), but where the cultures have not isolated any microorganisms.

We had planned to perform the following subgroup analyses, if possible:

  1. Diagnosis of pneumonia: proven versus clinical.
  2. Period of infection: primary intrauterine infection; early (less than/or equal to 48 hours) and late onset (> 48 hours) infection.
  3. Type of infection: nosocomial and community-acquired infections; VAP and non-VAP; Group B streptococcal gram negative pneumonia and C. pneumoniae.
  4. Type of surfactant given: animal derived; synthetic and protein containing synthetic surfactant.
  5. Dosing of surfactant: single and multiple doses.
  6. Administration of surfactant: bolus administration; lavage or nebulised.
  7. Concurrent administration of immunoglobulin.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised control studies.

Types of participants

Late preterm (35 to 36 weeks completed gestation) or term infants (37 to 41 weeks completed gestation) up to 28 days of life with a diagnosis of pneumonia (proven or clinical) as defined by the original study authors (by clinical, radiological, blood or tracheal cultures). We defined bacterial pneumonia as either proven bacterial pneumonia or clinical bacterial pneumonia.

  1. Proven pneumonia is defined as meeting clinical, radiological and identification of the bacteria through isolation or antibody identification.
  2. Clinical pneumonia involves assessment by the treating clinician that the infant has a pulmonary infection that has been treated with a complete course of antibiotics (the type and length of antibiotic course, as specified by the study), but where the cultures have not isolated any microorganisms.

Tracheal aspirates results alone will not be used as a criterion for diagnosis of pneumonia, as often they will culture organisms that have colonised the respiratory tract. We will not include studies dealing with the outpatient treatment of neonatal pneumonia. This will be infants who are treated in Level II or III NICUs.

We excluded infants with meconium aspiration syndrome (MAS), aspiration pneumonia, primary persistent pulmonary hypertension of the newborn (PPHN) and those diagnosed with surfactant deficiency due to other causes.

Types of interventions

Supportive care:

exogenous surfactant therapy with standard care versus standard care alone. In this case standard care included the full spectrum of neonatal intensive care therapy, including inhaled nitric oxide.

Surfactant regimens:

exogenous surfactant included both animal derived and synthetic surfactant. Surfactant may be given via a bolus (via routes as specified by the respective authors) or lavage. We planned to include studies describing nebulised surfactant therapy provided by any therapeutic regimen (combination of specific product, dosage, dosing frequency and total number of doses).

Ancillary care for pneumonia:

we planned to standardise concurrent interventions for bacterial pneumonia, such as antibiotic regime, supporting treatment and the administration of other adjuncts (for example immunoglobulin), between the treatment and thecontrol group (unless they are part of the study investigating combination therapy).

We had planned to include trials studying combination therapy involving surfactant and other treatment modalities otherwise standard for neonatal intensive care.

Types of outcome measures

Primary outcomes
  1. Neonatal death (all cause mortality) < 28 days.
  2. Time to resolution of bacterial pneumonia (as variously defined by the authors, but must include the following parameters: resolution of clinical signs like fever and/or improvement in respiratory distress, or haematological, microbiological or radiological evidence of resolution of pneumonia).
  3. Incidence of chronic lung disease/bronchopulmonary dysplasia (defined as oxygen or ventilation requirement at 28 days of life).
  4. Incidence of pneumothorax.
  5. Incidence of pulmonary haemorrhage (to be based on the reporting by original study authors).
  6. Ventilation (yes or no).
Secondary outcomes
  1. Secondary episodes of sepsis (defined as positive cultures from blood, cerebrospinal fluid (CSF) or urine after five days from the initial diagnosis of pneumonia).
  2. Number of days on mechanical ventilation.
  3. Number of days on supplemental oxygen.
  4. Proportion of infants treated with extracorporeal membrane oxygenation (ECMO).
  5. Proportion of infants treated with inhaled nitric oxide (for PPHN), as evidenced by oxygenation failure, oxygenation index (OI) > 20 or echographic evidence of PPHN i.e. elevated right ventricular pressure (tricuspid regurgitant jet) or right to left shunting across the patent ductus arteriosus.
  6. Length of stay: in ICU and overall hospital stay (days).
  7. Long-term pulmonary outcomes (at discharge from hospital or at two years of age); incidence of wheeze or diagnosed asthma and respiratory function measurements by spirometry.
  8. Abnormalities detected by neuroimaging, for example cranial ultrasound (periventricular leukomalacia, intraventricular haemorrhage or parenchymal haemorrhage), CT scan (ischaemic or haemorraghic lesions) or MRI examination of the brain (ischaemic or haemorraghic lesions).
  9. Long-term neurological outcomes (cerebral palsy, development measured by the Bayley or Griffith scales, intellectual function measured by IQ score and presence of visual or hearing impairments) at 18 months of age or greater.
  10. Adverse events: i.e. pulmonary haemorrhage, hypotension, hypoxic episodes and others as reported in the individual separate studies.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group.

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2011, Issue 6); MEDLINE (accessed via Ovid SP to June 2011); EMBASE (via Ovid SP 1980 to June 2011); and CINAHL Plus (accessed via EBSCOHost in June 2011).

We used a search strategy utilising the Medical Subject Heading (MESH) terms: "Pulmonary Surfactants", "Pneumonia" and "Respiratory Tract Infections" and keywords: “pneumonia”, “pneumonitis”, “chest infection(s)”, “lung infection(s)”, “pulmonary infection”. The search strategy is set out below:

  1. explode PNEUMONIA/
  2. pneumonia
  3. pneumonitis
  4. explode Respiratory Tract Infections/
  5. "chest infection$"
  6. "lung infection$"
  7. "pulmonary infection"
  8. explode Pulmonary Surfactants/
  9. surfactant$
  10. Combine 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7
  11. Combine 8 OR 9
  12. Combine 10 AND 11
  13. limit 12 to ("all infant (birth to 23 months)" and clinical trial, all)

We used a search filter for "clinical trials" and "human" studies. We used an age restriction filter "infants (0 - 23 months)". We imposed no language restrictions.

We searched the trial registry ClinicalTrials.gov External Web Site Policy in June 2011. We also searched the ISI Web of Science database in June 2011.

Searching other resources

We handsearched the journals as listed by the Cochrane Neonatal Review Group. We searched the proceedings of relevant paediatric and perinatal conferences, including the American Academy of Pediatrics (1990 to 2011), the European Academy of Paediatrics (1990 to 2011), the United Kingdom Perinatal Society (1990 to 2011) and the Perinatal Society of Australia and New Zealand (1990 to 2011) to identify published abstracts.

We contacted the authors of all selected studies (if appropriate) about ongoing trials they are conducting and whether they had any relevant unpublished data from their own studies. We searched the references cited in previous Cochrane reviews, in other studies investigating the use of surfactant in near-term or term infants with bacterial pneumonia, in review articles on this subject and textbooks or manuals of neonatal medicine.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

We reviewed the title and abstract of the studies to select studies based on the criteria above. Each of the three authors independently reviewed the full text of any study to be considered for inclusion. We resolved any disagreement through discussion.

Data extraction and management

We intended to extract data according to standard forms (if appropriate) and enter into RevMan 5 (RevMan 2011). We planned to have another investigator independently check the accuracy of data extraction and data entry if studies were identified.

Assessment of risk of bias in included studies

We intended to assess the trials on the following criteria: a) allocation concealment; b) blinding of intervention; c) completeness of follow-up;
d) intention to treat (ITT) analysis; and e) blinding of outcome assessment.
The outcomes of the assessment were 'low', 'high' and 'unclear' risk of bias.

This information was to be included in the table "Characteristics of Included Studies".

In addition, we intended to independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

We planned to assess the methodological quality of the studies using the following criteria.

  • Sequence generation (evaluating possible selection bias).

For each included study, we intended to describe the method used to generate the allocation sequence as: low risk of bias (any truly random process e.g. random number table, computer random number generator); high risk of bias (any non-random process e.g. odd or even date of birth, hospital or clinic record number); or unclear risk of bias.

  • Allocation concealment (evaluating possible selection bias).

For each included study, we intended to describe the method used to conceal the allocation sequence as: low risk of bias (e.g. telephone or central randomisation, consecutively numbered sealed opaque envelopes); high risk of bias (open random allocation, unsealed or non-opaque envelopes, alternation, date of birth); or unclear risk of bias.

  • Blinding (evaluating possible performance bias).

For each included study, we intended to describe the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was to be assessed separately for different outcomes or classes of outcomes. We intended to assess the methods as: low risk, high risk or unclear risk of bias for participants; low risk, high risk or unclear risk of bias for study personnel; and low risk, high risk or unclear risk of bias for outcome assessors and specific outcomes.

  • Incomplete outcome data (evaluating possible attrition bias through withdrawals, dropouts and protocol deviations).

For each included study and for each outcome, we intended to describe the completeness of data including attrition and exclusions from the analysis. We were to have stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We were to have assessed methods as: low risk (< 20% missing data); high risk (> 20% missing data) or unclear risk of bias.

  • Selective reporting bias.

For each included study, we intended to describe how we investigated the possibility of selective outcome reporting bias and what we found. We intended to consult ClinicalTrials.gov External Web Site Policy and attempt to obtain a trial protocol in order to assess for reporting bias. In particular, we intended to assess the methods as: low risk of bias (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported); high risk of bias (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or unclear risk.

  • Other sources of bias.

For each included study, we intended to describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We would have assessed whether each study was free of other problems that could put it at low, high or unclear risk of bias.

Measures of treatment effect

We had intended to perform statistical analysis following the procedures of the Cochrane Neonatal Review Group. For categorical data, we would have used relative risk (RR), risk difference (RD) and the number needed to treat for an additional beneficial outcome (NNTB) with their respective 95% confidence intervals (CIs). For continuous data, we would have used a weighted mean difference (WMD) with 95% CI.

Dealing with missing data

We intended to contact the authors of studies included in the review for any missing data; however, we did not do this as we did not find any eligible studies.

Assessment of heterogeneity

We would have assessed the treatment effects of individual trials and the heterogeneity between trial results by inspecting the forest plots. We would have used the I2 statistic to measure inconsistency in the studies' results; with an I2 statistic of less than 0.25 representing low heterogeneity, 0.25 to 0.5 moderate heterogeneity and more than 0.5 high levels of heterogeneity (Guyatt 2008). If we had detected high levels of heterogeneity (> 50%) we would have explored the causes (for example, difference in study quality, participants, intervention or outcome assessment) via post hoc subgroup analyses.

Assessment of reporting biases

We had intended to perform a funnel plot to assess for publication bias.

Data synthesis

We had intended to perform meta-analysis of the included trials in RevMan 5 with a fixed-effect model.

Subgroup analysis and investigation of heterogeneity

We would have performed subgroup analyses if possible, based on the following.

  1. Diagnosis of pneumonia: proven versus clinical.
  2. Period of infection: primary intrauterine infection; early (less than/or equal to 48 hours) and late onset (> 48 hours) infection.
  3. Type of infection: nosocomial and community-acquired infections; VAP and non-VAP; Group B streptococcal gram negative pneumonia and C. pneumoniae.
  4. Type of surfactant given: animal derived; synthetic and protein containing synthetic surfactant.
  5. Dosing of surfactant: single and multiple doses.
  6. Administration of surfactant: bolus administration; lavage or nebulised.
  7. Concurrent administration of immunoglobulin.

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Results

Description of studies

We identified 28 studies in our initial search. Closer study of the titles and abstracts showed that only two of these studies (Brehmer 1993; Herting 2000) dealt with our research question. We had to exclude these two studies however, as they did not meet the criteria for inclusion in the review (see Characteristics of excluded studies).

Included studies

  • None noted.

Excluded studies

We excluded three studies on the basis of limitations in study design and the choice of study population (Brehmer 1993; Herting 2000; Herting 2002).

In both Brehmer 1993 and Herting 2000, the authors compared the clinical course of infants diagnosed with bacterial pneumonia with infants diagnosed with predominantly surfactant-deficiency respiratory distress syndrome (RDS). Both studies were non-randomised and in both studies, all infants received surfactant. Brehmer 1993 limited the participants to preterm, very low birthweight (VLBW) infants, while Herting 2000 included preterm and term infants, but restricted their participants to only those with proven Group B Streptococcal (GBS) infection with respiratory failure (see Characteristics of excluded studies).

Herting 2002 was a case series spanning 10 years looking at the experience of a single centre in treating eight children and infants with ARDS due to pneumonia or sepsis from a variety of viral and bacterial pathogens, who were treated with porcine surfactant (poractant). We excluded this study as it did not fit our population criterion and was primarily an observational study.

Risk of bias in included studies

Not applicable, as we did not include any studies.

Effects of interventions

Not applicable, as we did not include any studies.

Discussion

In this review, we did not find any eligible studies that addressed our research question. We identified two relevant studies (Brehmer 1993; Herting 2000), but we excluded both due to limitations in their designs and the choice of study populations. Both studies compared infants with bacterial pneumonia against infants with surfactant-deficiency respiratory distress syndrome (RDS). As all infants in the studies received surfactant, they did not address the question of whether surfactant was effective in neonatal bacterial pneumonia. To date, there is a lack of high quality evidence on the effectiveness of surfactant for bacterial pneumonia in newborn infants.

To assess the effects of surfactant therapy for bacterial pneumonia, a randomised controlled trial (RCT) would be required to minimise biases and confounding factors. However, RCTs on the use of surfactant in newborn infants have been conducted predominantly on preterm infants with RDS. Although it was possible that some of these infants had concurrent bacterial pneumonia, this was usually not listed as the major inclusion criterion, and some studies even excluded infants with bacterial infections like pneumonia. Nonetheless, through an assessment of these studies, any possible effect of surfactant on bacterial pneumonia could be postulated by evaluating the overall effects of surfactant in these studies and the differences in the effect sizes between studies that excluded infants with bacterial pneumonia and studies that did not exclude these infants. These assessments are possible in two Cochrane reviews that examine the use of surfactant in preterm infants (Seger 2009; Soll 2009a), as they included studies that excluded infants with bacterial pneumonia.

Seger and colleagues included RCTs that assessed the use of animal derived surfactant against no surfactant in preterm infants. Seven out of 13 included studies had explicitly excluded infants with bacterial pneumonia or sepsis. The review shows significant overall benefits of surfactants in reducing neonatal mortality, pulmonary interstitial emphysema (PIE), air leak and pneumothorax, while no differences were observed on bronchopulmonary dysplasia, sepsis and intraventricular haemorrhage or periventricular leukomalacia (Seger 2009).

There appears to be no major difference in the effects of surfactant in all the aforementioned outcomes between the studies that excluded infants with bacterial pneumonia and the studies that did not exclude these infants. In another Cochrane review comparing prophylactic against rescue surfactant in preterm infants (Soll 2009a), only one out of eight included studies excluded infants with congenital sepsis. This review also shows overall benefits of surfactant in reducing neonatal mortality, PIE and pneumothorax. Again, there was no major difference between the results of the study in which infants with sepsis were excluded versus those with no such exclusion criterion. The findings of these two Cochrane reviews provide indirect evidence that surfactant might not have conferred additional important benefits to preterm infants with bacterial pneumonia on top of their benefits for RDS, although stronger evidence provided by individual patient meta-analysis of these studies is necessary to support or refute this hypothesis.

Both Cochrane reviews (Seger 2009; Soll 2009a) included studies in which the upper limits of infant gestation was 32 weeks. Their findings do not apply to the population assessed in our review. However, along with two excluded studies in our review, they provide insights on the planning of future studies. In any research that aims to directly examine the effects of surfactant on bacterial pneumonia in newborn infants, the presence of bacterial pneumonia will need to be the major inclusion criterion. Currently, such studies appear more likely to be conducted on term or near-term infants, in whom primary surfactant deficiency does not usually occur. This is due to the difficulty in selecting a group of preterm infants who have bacterial pneumonia without concurrent surfactant deficient RDS, hence justifiably withholding surfactant in the infants who are assigned to the control group.

Apart from the choice of study population, consideration needs to be given to the design of the intervention in future studies. Given the presence of well established treatment regimes for bacterial pneumonia, mainly involving the use of antibiotics, it is only ethically possible to conduct RCTs that compare surfactant as an adjunct to the standard treatment for bacterial pneumonia versus standard treatment alone. The questions that will need to be addressed include the dose of surfactant (specifically, whether the dose used per body weight should be higher than that required for replacement therapy in preterm infants with surfactant deficient RDS) and the need for repeat doses. Important outcomes to be considered include mortality, time to resolution of bacterial pneumonia, incidence of pneumothoraces, pulmonary haemorrhage, secondary episodes of sepsis, days on mechanical ventilation, supplemental oxygen, infants needing extracorporeal membrane oxygenation (ECMO), nitric oxide, incidence of chronic lung disease/bronchopulmonary dysplasia and length of stay in intensive care. Long-term neurological outcomes and long-term respiratory morbidities (including the incidence of asthma) also need to be considered. Adverse effects from surfactant administration, such as instability in oxygenation and haemodynamic status, should also be evaluated. Given the cost of surfactant in relation to other treatment for bacterial pneumonia, cost-effectiveness should also be included as a secondary outcome.

Another major consideration in such studies is the issue of case ascertainment, and the feasibility and reliability of a diagnosis of bacterial pneumonia, especially in the early stages. Newer diagnostic modalities (such as bacterial DNA isolation through polymerase chain reaction (PCR) or DNA micro-array analysis) that do not require isolation of the organism (Chan 2007), if well validated, may be utilised to ascertain cases of bacterial pneumonia and form the inclusion criterion.

Authors' conclusions

Implications for practice

At present, there is no evidence from RCTs to support or refute the efficacy of surfactant in term and near-term infants with proven bacterial pneumonia. The lack of high-level evidence precludes any recommendation on the use of surfactant for bacterial pneumonia in term and near-term infants.

Implications for research

High quality evidence in the form of carefully designed RCTs is necessary to answer this question. We suggest that future studies should focus on term or near-term infants with proven bacterial pneumonia without primary surfactant deficient RDS, and use surfactant as an adjunctive treatment compared with standard treatment alone, including for example, antibiotics and other supportive measures. The presence of bacterial pneumonia should be determined using well validated modes of diagnosis. Clinically relevant short- and long-term outcomes, including cost-effectiveness, should be evaluated.

Acknowledgements

We thank Drs Roger Soll, John Sinclair, Jeffrey Horbar, G Suresh and A Ohlsson for their comments on the draft review. We thank Ms Diane Haugthon, Managing Editor, and Ms Yolanda Montage, Trials Search Co-ordinator of the Neonatal Review Group for her assistance leading to the publication of the protocol.

Contributions of authors

K Tan and NM Lai prepared the protocol for the review.
K Tan, NM Lai and A Sharma undertook the review (searching for studies, assessing eligibility of studies and writing the review).

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

  • None noted.

Characteristics of excluded studies

Brehmer 1993

Reason for exclusion

This was not a randomised or quasi-randomised trial comparing surfactant against non-surfactant-treated controls. The study assessed the effects of surfactant on infants with pneumonia versus infants with surfactant-deficiency respiratory distress syndrome. The population in this study were very low birth weight infants (24 to 33 gestational weeks, 640 to 1560g) which did not fit the inclusion criteria as set out in the review. The study showed that there were no differences between the pneumonia group and the RDS group in all the acute and long-term outcomes

Herting 2000

Reason for exclusion

This was not a randomised or quasi-randomised trial comparing surfactant against non-surfactant-treated controls. This study assessed the prognosis of two groups of infants after receiving surfactant: infants with proven GBS infections and those without GBS infections. All infants were less than 33 weeks of gestation at study entry. Specifically the median gestation (25th to 75th centiles range) was 30 weeks (27 to 33) in the group with GBS while in the group without GBS infection the median gestation was 29 weeks (28 to 31). The data of 42% of participants were obtained retrospectively. In addition, only 19% of the GBS population in this study was greater than 35 weeks gestation, and there was no separate analysis for this group of infants. The study showed that the respiratory status of the GBS group improved slower than the RDS group, although there were excessive complications in the GBS group, including higher rates of death, pneumothoraces and intraventricular haemorrhage

Herting 2002

Reason for exclusion

This was a case-series of 8 patients ranging from a one month-old infant (actually this was an ex-preterm corrected to 44 weeks postmenstrual age) to a 13 year old child who all had pneumonia and ARDS. The causative organisms included RSV, Staphylococcus aureas (S. aureus) (sepsis), influenza A and Pneumocystis carinii. They were treated with poractant (Curosurf, Nycomed, Ismaning, Germany) at total treatment doses ranging from 170 to 1050 mg/kg. The outcome measures were paO2/FiO2 ratio, duration of ventilation, pneumothoraces and survival

Footnotes

ARDS: acute respiratory distress syndrome.
GBS: Group B streptococcus.
RDS: respiratory distress syndrome.
RSV: respiratory distress syndrome.

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

Additional tables

  • None noted.

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References to studies

Included studies

  • None noted.

Excluded studies

Brehmer 1993

Brehmer U, Jorch G. Surfactant therapy in severe neonatal respiratory failure-multicenter study-III. Surfactant therapy in 41 premature infants < 34 weeks with suspected congenital infection (case-control analysis). Klinische Padiatrie 1993;205:78-82.

Herting 2000

Herting E, Gefeller O, Land M, Van Sonderen L, Harms K, Robertson B. Surfactant treatment of neonates with respiratory failure and group B streptococcal infection; the Collaborative European Multicenter Study Group. Pediatrics 2000;106:957-64.

Herting 2002

Herting E, Möller O, Schiffmann JH, Robertson B. Surfactant improves oxygenation in infants and children with pneumonia and acute respiratory distress syndrome. Acta Paediatrica 2002;91:1174-8.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

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Abdel-Latif 2011

Abdel-Latif ME, Osborn DA. Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD008309. DOI: 10.1002/14651858.CD008309.pub2.

Abdel-Latif 2011a

Abdel-Latif ME, Osborn DA. Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD008311. DOI: 10.1002/14651858.CD008311.pub2.

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Herting 1999

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Horan 2008

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Jobe 2006

Jobe AH. Mechanisms to explain surfactant responses. Biology of the Neonate 2006;89:298-302.

Jobe 2008

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Kaiser 2004

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Lejeune 2005

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LeVine 1996

LeVine AM, Lotze A, Stanley S, Stroud C, O'Donnell R, Whitsett J et al. Surfactant content in children with inflammatory lung disease. Critical Care Medicine 1996;24:1062-7.

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McCormack 2002

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Raju 1993

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Rauprich 2000

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Other published versions of this review

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Classification pending references

Brehmer 1993

Brehmer U, Jorch G. Surfactant therapy in severe neonatal respiratory failure - multicenter study - III. Surfactant therapy in 41 premature infants < 34 weeks with suspected congenital infection (case-control analysis). [Surfactanttherapie bei schwerer neonataler Ateminsuffizienz - Multizentrische Studie - III. Surfactanttherapie bei 41 Frühgeborenen < 34 SSW mit Verdacht auf konnatale Infektion (Fallkontrollanalyse)]. 1993;205:78-82.

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Data and analyses

  • None noted.

Figures

  • None noted.

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Sources of support

Internal sources

  • Kenneth Tan, Australia
  • K Tan is employed by Southern Health (Monash Medical Centre) and Monash University
  • Nai Ming Lai, Malaysia
  • NM Lai is employed by Monash University, Malaysia.
  • Ajay Sharma, Australia
  • A Sharma was a neonatal fellow with Southern Health (Monash Medical Centre)

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human
  • Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

Feedback

  • None noted.

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.