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Heated and humidified inspired gas through heated humidifiers in comparison to non-heated and non-humidified gas in hospitalised neonates receiving respiratory support (Protocol) Doctor TN, Foster JP, Stewart A, Tan K, Todd DA, McGrory L

Doctor TN, Foster JP, Stewart A, Tan K, Todd DA, McGrory L. Heated and humidified inspired gas through heated humidifiers in comparison to non-heated and non-humidified gas in hospitalised neonates receiving respiratory support. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD012549. DOI: 10.1002/14651858.CD012549.

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Heated and humidified inspired gas through heated humidifiers in comparison to non-heated and non-humidified gas in hospitalised neonates receiving respiratory support (Protocol) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . .

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[Intervention Protocol]

Heated and humidified inspired gas through heated humidifiers in comparison to non-heated and non-humidified gas in hospitalised neonates receiving respiratory support Tejas N Doctor1 , Jann P Foster2 ,3,4 , Alice Stewart1 , Kenneth Tan5 , David A Todd6 , Lorraine McGrory7 1 Monash

Newborn, Monash Medical Centre, Clayton, Australia. 2 School of Nursing and Midwifery, Western Sydney University, Penrith DC, Australia. 3 Sydney Nursing School/Central Clinical School, Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Sydney, Australia. 4 Ingham Research Institute, Liverpool, Australia. 5 Department of Paediatrics, Monash University, Melbourne, Australia. 6 Neonatal Unit, The Canberra Hospital, Canberra, Australia. 7 Neonatal Services, The Royal Women’s Hospital, Parkville, Australia Contact address: Alice Stewart, Monash Newborn, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia. [email protected]. Editorial group: Cochrane Neonatal Group. Publication status and date: New, published in Issue 2, 2017. Citation: Doctor TN, Foster JP, Stewart A, Tan K, Todd DA, McGrory L. Heated and humidified inspired gas through heated humidifiers in comparison to non-heated and non-humidified gas in hospitalised neonates receiving respiratory support. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD012549. DOI: 10.1002/14651858.CD012549. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the effects of heated and humidified inspiratory gas through heated humidifiers (HHs) compared to non-heated and non-humidified inspiratory gas on mortality and morbidity in neonates receiving respiratory support during resuscitation immediately after birth and after the initial resuscitation. Comparison 1: Heated and humidified inspiratory gas through heated humidifiers (HHs) compared to non-heated and nonhumidified inspiratory gas on mortality and morbidity in neonates receiving respiratory support during resuscitation immediately after birth. Proposed subgroup analyses: • Gestational age: < 30 weeks, 30-36 weeks, 37 weeks and over; • Mode of respiratory support (e.g. mask continuous positive airway pressure, mask intermittent positive pressure ventilation, endotracheal intermittent positive pressure ventilation). Comparison 2: Heated and humidified inspiratory gas through heated humidifiers (HHs) compared to non-heated and nonhumidified inspiratory gas on mortality and morbidity in neonates receiving respiratory support after initial resuscitation. Proposed subgroup analyses: • Gestational age: < 30 weeks, 30-36 weeks, 37 weeks and over; • Mode of respiratory support (e.g. low flow oxygen, high flow nasal cannula, nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, conventional mechanical ventilation, high frequency ventilation). Heated and humidified inspired gas through heated humidifiers in comparison to non-heated and non-humidified gas in hospitalised neonates receiving respiratory support (Protocol) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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• Sites of intervention: Neonatal intensive care unit (NICU), operating theatre or neonatal transport. • Underlying respiratory conditions: respiratory distress syndrome, apnoea of prematurity, meconium aspiration syndrome, perinatal asphyxia, pneumonia.

BACKGROUND

Description of the condition Some newborn infants require respiratory support for respiratory insufficiency or failure. The causes of respiratory insufficiency generally vary according to gestational age (Gnanaratnem 2000). Transient tachypnoea of the newborn, pneumonia, meconium aspiration syndrome, or congenital anomalies of the upper or lower airway are the predominant causes in term neonates (Gnanaratnem 2000; Parkar 2012); whereas, respiratory distress syndrome, apnoea of prematurity, sepsis, pneumonia, intracranial haemorrhage, and bronchopulmonary dysplasia are the main causes in preterm newborns (Gnanaratnem 2000; Qian 2008). See ’Glossary of terms’ in Appendix 1. Respiratory support can be broadly classified in two different groups invasive ventilation, which needs endotracheal intubation (Donn 2001; Duyndam 2011; Hummler 2009; Keszler 2009), and non-invasive ventilation which does not need intubation, consisting mainly of continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), or low flow and high flow nasal cannula (Bancalari 2012; Wiswell 2011). Numerous complications may arise from respiratory support. Complications associated with an endotracheal tube (ETT) are: subglottic stenosis (Walner 2001), palatal asymmetry (MaceyDare 1999), and palatal grooving (Fadavi 1992). Rarely serious complications such as tracheal perforation (Doherty 2005), tracheal ulceration and metaplasia (Todd 1991) may occur. Complications associated with nasal CPAP include local trauma to the nares ranging from skin breakdown to nasal septum necrosis (Korones 2011; Robertson 1996). Pulmonary complications of respiratory support include bronchopulmonary dysplasia, air-leak syndrome, pulmonary haemorrhage, atelectasis, and pneumonia (Korones 2011; Miller 2008). See ’Glossary of terms’ in Appendix 1.

Description of the intervention In newborn infants receiving respiratory support, preconditioning (heating and humidification) of inspired gas can be achieved by either active or passive humidification. Active humidification involves heated humidifiers (HH), where the gas is passed over the heated surface of a water reservoir, which is attached to the

ventilator by inspiratory circuits. There are several influencing factors affecting the performance of humidifiers. Todd and colleagues showed that temperature and humidity in the inspiratory circuit of the ventilator varies according to the type of humidifier chamber, the position of air temperature probe, the environmental temperature, and whether the circuit is insulated (see ’Glossary of terms’ in Appendix 1) (Todd 2001). Lellouche and coworkers noted significant variations in inspiratory humidity and temperature with changes in ambient temperature and ventilator output (Lellouche 2004). Variability in the performance of various models of HHs has also been noted (Lellouche 2004; Todd 2001). Attempts have been made to improve the consistency in performance of HHs with variable success (Schena 2011; Schena 2012). In contrast, heat and moisture exchangers (HMEs) are generally used to achieve passive humidification. These devices conserve moisture from expiration and moisten the inspiratory gas. Kelly and colleagues in their Cochrane Review comparing the use of HHs and HMEs in ventilated children and adults concluded that there was little evidence of difference between HHs and HMEs with regards to effect on body temperature, while costs were lower with the use of HMEs than HHs (Kelly 2010). The authors recognised the need for further research in the areas of neonatal ventilation and design of HMEs. Data about use of these devices in the neonatal population are limited. In a preliminary evaluation on ventilated neonates, Fasassi and coauthors found that it was possible to achieve absolute humidity of 28 mgH2 O/L or more and a temperature of 30 ºC or more with HMEs (Fassassi 2007). The American Association for Respiratory Care’s 1992 clinical guidelines listed several contraindications for the use of HMEs. Among the recommendations, HMEs were not to be used for people with an expired tidal volume less than 70% of delivered tidal volume (large broncho-pleurocutaneous fistulas or absent ETT cuffs) (AARC 1992). This precludes neonatal clinicians from using HMEs in neonates requiring respiratory support, and studies comparing HHs and HMEs are excluded from this review. The optimum humidity and temperature of the inspired gas from HHs for people receiving respiratory support is not well described in the literature. It is generally recommended that the inspired gas should be delivered at an absolute humidity of greater than 33 mgH2 O/L if bypassing the supraglottic area (i.e. in infants who are receiving respiratory support via ETT or tracheostomy) (see ’Glossary of terms’ in Appendix 1) (British Standard Institution 1970; ISO 1997). In the USA, the recommended absolute inspired humidity is greater than 30 mgH2 O/L (American National


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Standards Institute 1979). For inspired temperatures, a range of 32 ºC to 34 ºC has been suggested (Chatburn 1989). Davies and colleagues found that when using HHs, with a set inspiratory temperature of 37 ºC, proximal ETT temperatures were 34.9 ± 1.2 ºC for infants nursed in incubators and 33.1 ± 0.5 ºC for infants nursed under radiant warmers (Davies 2004). It has thus been suggested that inspired temperatures be set higher, at least 39 ºC, and many modern HHs are now set at 40 ºC (Preo 2013). In the clinical setting, staff caring for infants on respiratory support can readily measure the temperature of the inspired gas, while the level of humidification of inspired gas is less readily available. Level of humidification may be assessed directly using a hygrometer or by a surrogate marker such as the water consumption within the humidifier (Davies 2004; Schulze 2002; Schulze 2007).

How the intervention might work Major functions of the upper respiratory tract are gas conditioning (heating and humidification) of the inspiratory gas, and mucous clearance (Williams 1996). Under normal conditions, the upper respiratory tract epithelium heats and humidifies inspiratory gas so that gas entering alveoli is warmed up to body temperature and fully saturated with water vapour (i.e. to 100% relative humidity; 44 mgH2 O/L absolute humidity). Most of the heat and moisture exchange occurs in the upper respiratory tract with minor contribution from the lower tract bronchioles (McFadden 1985; Schiffmann 2006; Schulze 2002; Schulze 2007; Williams 1996). The point where inspired gas reaches 37 ºC is called the isothermic saturation boundary. In adults, this is located in the main bronchi. In newborns, the condition of the inspired gas, pattern of ventilation and respiratory disease can influence this boundary. This physiological process of conditioning of inspired gas is bypassed in people receiving respiratory support through ETTs or tracheostomy tubes, requiring preconditioning (heating and humidification) of the inspired gas by artificial means. Suboptimal airway humidity results in decreased airway function due to increased mucous viscosity (Burton 1962; Williams 1996), and reduced cilia beat frequency (Burton 1962; Mercke 1976; Williams 1996). More serious complications, such as tracheal cell damage (Chalon 1972; Todd 1990), tracheal ulceration (Marfatia 1975), atelectasis (Keszler 1982), metaplasia of the trachea and main airway (Todd 1989), and necrotising tracheobronchitis (Circeo 1991), may occur. Heated and humidified inspired gas through HHs is a strategy that may reduce these complications. Tarnow-Mordi and colleagues analysed the inspired gas temperature in the first 96 hours of life for 149 infants at a single centre (Tarnow-Mordi 1989). They showed the risk of important respiratory morbidities, namely pneumothorax and chronic lung disease (defined as oxygen requirement at 28 days of life) was significantly reduced in infants weighing less than 1500 g at birth when the temperature of the inspired gas was greater than 36.5 ºC, but there was no difference in these morbidities for infants with birth

weight greater than 1500 g. However, this study was performed prior to the introduction of surfactant use for the treatment of hyaline membrane disease, and hence the result may not be totally transferable to current ventilated neonates (Tarnow-Mordi 1989). Conversely, supraoptimal humidity results in condensation and an overall reduction in mucociliary clearance and cellular damage via thermal or hypotonic mechanisms (Williams 1996), intra-alveolar oedema (John 1982; Williams 1996), and fibrosis (Todd 1989). One review by Jobe and colleagues concluded that the preterm lungs can be injured by mechanical ventilation at birth, which is further amplified by continued mechanical ventilation in the neonatal intensive care unit (NICU) (Jobe 2008). Animal studies conducted on near term lambs showed that humidity and oxygen content of inspired air influence markers of pulmonary inflammation (Pillow 2009). This is consistent with inflammatory changes to tracheal epithelium of newborn lambs with inadequate humidity (Todd 1990; Todd 1991). Currently, gas used during resuscitation at birth is not preconditioned, and this raises the question of whether the use of heated and humidified gas in newborn resuscitation might reduce the incidence of bronchopulmonary dysplasia. Optimum preconditioning of inspiratory gas also has a role in the maintenance of body temperature in neonates. Bissonnette and coworkers postulated that using humidified and heated gas during anaesthesia improves postoperative hypothermia in infants and children (Bissonnette 1989). Similarly, Fonkalsurd and colleagues found that there was a statistically significant drop in rectal temperature with the use of dry anaesthetic gas in comparison with heated and humidified gas at the end of one hour and at the end of anaesthesia (Fonkalsrud 1980). At the time of delivery, spontaneously breathing neonates tend to lose water constantly from the airway. Higher pulmonary water loss in neonates is related to a faster respiratory rate. Respiratory water loss, and hence the evaporative heat loss, is inversely proportional to the humidity of inspired gas (Sahni 2011). In intubated people receiving dry and non-humidified inspiratory gas, the body’s compensatory mechanisms to humidify and heat the gas results in additional loss of heat and water (Gross 2012), and this may account for hypothermia at admission to the NICU. It is common practice for a neonate requiring respiratory support at birth to receive unconditioned (non-heated and non-humidified) gas for a brief period of time until their arrival in the NICU. Despite this physiological rationale and research, currently heated or humidified gas is not routinely used in the delivery room. Current international neonatal resuscitation guidelines do not provide recommendations on conditioning inspired gas at delivery (Perlman 2010). The presence of hypothermia at nursery admission is an important risk factor for mortality, particularly in preterm newborns (Costeloe 2000; Laptook 2007). Various approaches such as polyethylene occlusive skin wrapping (Vohra 2004), vinyl bags (Mathew 2007), and polyethylene caps (Trevisanuto 2010) have been used to prevent hypothermia with variable success. However,


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hypothermia remains a commonly observed outcome following neonatal resuscitation, particularly in preterm neonates (Laptook 2008). Research by Shearman and colleagues demonstrated that it is possible to heat and humidify inspiratory gas during resuscitation (Shearman 2012). In one prospective trial involving very preterm infants, te Pas and colleagues found a significant reduction of moderate hypothermia when heated and humidified gas was used during resuscitation at birth (te Pas 2010). There is an increasing number of neonates who receive respiratory support using non-invasive modalities such as CPAP or intermittent positive pressure ventilation (IPPV) through nasal prongs. In this form of ventilation, the normal conditioning mechanism of inspiratory gas is not bypassed. Despite this, inspired gas in these forms of ventilation is routinely preconditioned. Neonatal data about the routine conditioning of inspiratory gas in this form of ventilation is not available in current literature. In adults, one of the main reasons for conditioning (heated and humidified) inspired gas is to provide patient comfort. The use of heated and humidified gas during non-invasive ventilation in adults improves patient comfort, tolerance (Lellouche 2009; Nava 2009), nasal resistance, expired tidal volume (Tuggey 2007), airway function and secretion clearance (Branson 2010).

neonates receiving respiratory support during resuscitation immediately after birth and after the initial resuscitation. Comparison 1: Heated and humidified inspiratory gas through heated humidifiers (HHs) compared to non-heated and non-humidified inspiratory gas on mortality and morbidity in neonates receiving respiratory support during resuscitation immediately after birth. Proposed subgroup analyses: • Gestational age: < 30 weeks, 30-36 weeks, 37 weeks and over; • Mode of respiratory support (e.g. mask continuous positive airway pressure, mask intermittent positive pressure ventilation, endotracheal intermittent positive pressure ventilation). Comparison 2: Heated and humidified inspiratory gas through heated humidifiers (HHs) compared to non-heated and non-humidified inspiratory gas on mortality and morbidity in neonates receiving respiratory support after initial resuscitation. Proposed subgroup analyses:

Why it is important to do this review In the setting of neonatal resuscitation at birth or during delivery, temperature control is of paramount importance, particularly in preterm neonates. Hypothermia is associated with mortality and morbidity. To date, various measures to prevent hypothermia have been tried with variable success. Heating and humidifying inspired gas with HHs for use in neonatal resuscitation has shown promise in some studies. Hence the proposed review will determine the effect of heating and humidifying inspired gas with HHs during neonatal resuscitation. Outside the neonatal resuscitation setting, a neonate may require ongoing respiratory support in the NICU. Infants may also deteriorate and require escalation of respiratory support after NICU admission. Respiratory support may be required in the operating theatre or during neonatal transport. No systemic review has been conducted so far to compare heated and humidified gas with nonheated and non-humidified gas in these settings. Hence, it will be of benefit to conduct this review to determine the effect of heating and humidifying inspired gas with HHs during neonatal respiratory support.

• Gestational age: < 30 weeks, 30-36 weeks, 37 weeks and over; • Mode of respiratory support (e.g. low flow oxygen, high flow nasal cannula, nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, conventional mechanical ventilation, high frequency ventilation). • Sites of intervention: Neonatal intensive care unit (NICU), operating theatre or neonatal transport. • Underlying respiratory conditions: respiratory distress syndrome, apnoea of prematurity, meconium aspiration syndrome, perinatal asphyxia, pneumonia.

METHODS

Criteria for considering studies for this review

Types of studies

OBJECTIVES To determine the effects of heated and humidified inspiratory gas through heated humidifiers (HHs) compared to non-heated and non-humidified inspiratory gas on mortality and morbidity in

We will include randomised controlled trials and cluster randomised trials that compare preconditioned gas (heated and humidified) using HHs during neonatal resuscitation and outside the neonatal resuscitation setting with non-conditioned (non-heated and non-humidified) inspiratory gas. The review will not include studies that compare HHs versus HMEs.


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Types of participants

Types of interventions

⋄ mild hypothermia: core body temperature 36 ºC to 36.4 ºC or skin temperature of 35.5 ºC to 35.9 ºC; ⋄ moderate hypothermia: core body temperature 32 ºC to 35.9 ºC or skin temperature of 31.5 ºC to 35.4 ºC; ⋄ severe hypothermia: core body temperature of less than 32 ºC or skin temperature less than 31.5 ºC. 2. Respiratory support outside of the newborn resuscitation setting: ◦ mortality (neonatal mortality, i.e. less than 28 days, or mortality prior to discharge from NICU); ◦ hypothermia as described above.

Preconditioned (heated and humidified by HH only) inspiratory gas versus non-heated, non-humidified inspiratory gas.

Secondary outcomes

We will include two different groups of participants: • newborn infants requiring respiratory support during resuscitation in the delivery room or operation theatre at birth, and • neonates requiring respiratory support after the newborn resuscitation period in the NICU, operating theatre or during transport.

Types of outcome measures It is likely that there will be studies with participants who were not randomised to heated and humidified gases during newborn resuscitation but they received preconditioned gases during respiratory support following resuscitation at birth. This situation appears to confound some of the outcomes. However, routine conditioning of inspired gases for neonates receiving respiratory support is an accepted standard of practice worldwide, hence, participants assigned to the non-heated and non-humidified group will have the same follow-on care as the participants assigned to humidified and heated gases. In this situation, primary outcomes such as admission temperature, blood sugar level and mortality will not be affected. Based on animal experiments (Pillow 2009; Todd 1990), we believe it is worth exploring whether or not non-heated and non-humidified gases used during initial newborn resuscitation is responsible for more long-term outcomes such as chronic lung disease. For the same reason, we also believe this measure may affect duration of ventilation and hospital stay.

Primary outcomes

1. Respiratory support during newborn resuscitation at birth or at the time of delivery: ◦ mortality (neonatal mortality, i.e. less than 28 days, or mortality prior to discharge from NICU); ◦ hypothermia (defined according to the World Health Organization (WHO) as core body temperature less than 36.5 ºC or skin temperature less than 36 ºC). We will use the temperature of the infant taken on admission to the NICU or up to two hours after birth to ascertain the presence of hypothermia. We will accept rectal, axillary, oral or tympanic temperature measurements as equivalent to core body temperature, and abdominal skin temperature for skin temperature. Where both core temperature and skin temperature are recorded, core temperature will take priority. We will use following to define subcategories of hypothermia (WHO 1997):

1. Respiratory support during newborn resuscitation: ◦ morbidity: ⋄ hypoglycaemia defined as proposed by American Academy of Pediatrics (Adamkin 2011) or as defined by Cornblath 2000, or any other definition accepted by study authors; ⋄ duration of respiratory support (minutes, hours or days); ⋄ duration of oxygen therapy (minutes, hours or days); ⋄ duration of hospital stay (days); ⋄ chronic lung disease (defined as either oxygen requirement at corrected 36 weeks’ postmenstrual age for an infant who was born at 32 weeks’ gestation or less OR oxygen at 28 days for an infant born at greater than 32 weeks’ gestation) (Lee 2000; Shennan 1988). 2. Respiratory support outside of the newborn resuscitation setting: ◦ pulmonary air leak (see ’Glossary of terms’ in Appendix 1); ◦ ventilator-associated pneumonia or tracheobronchitis (see ’Glossary of terms’ in Appendix 1 or as defined by study authors); ◦ duration of ventilation (minutes, hours or days); ◦ duration of hospital stay (days); ◦ duration of oxygen therapy (minutes, hours or days); ◦ duration of oxygen therapy (minutes, hours or days). Adverse outcomes due to the intervention: • hyperthermia (defined by an admission temperature to NICU or within two hours of birth of 38 ºC or greater).

Search methods for identification of studies

Electronic searches We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (to current), MEDLINE (1948 to current), Embase


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(1980 to current) and CINAHL (1982 to current) using the following strategy: • MeSH term for newborn “Infant” OR “Newborns” other text words are “Neonat*”, OR “baby*” AND • MeSH term for humidity “Humidity” OR other text word “Humid*”OR Mesh term for Heat- “Hot temperature” OR other Text words “Heat*”, OR “Warm*”, OR “Condition*ADJ” AND • MeSH term for gas/es “Gas, natural” OR other text words “Inspir* gas/es” OR “Respiratory gas/es” OR “Gas/es” AND • MeSH term for randomised controlled trial “Randomized Controlled trial as topic” OR other text words “Randomized controlled Trial” OR “Controlled Clinical Trial” OR “Randomized” OR “Placebo” OR “Clinical trials as topic” OR “Randomly” OR “Trial”

Searching other resources The search strategy will also include communication with expert informants; handsearching bibliographies of reviews and trials for references to other trials; and cross-references, abstracts and conferences and symposia proceedings of the Perinatal Society of Australia and New Zealand and Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Paediatric Research) from 1990 to current. If we identify any unpublished trial, we will contact the corresponding investigator for information. We will consider unpublished studies or studies only reported as abstracts as eligible for review if methods and data can be confirmed by the author. We will also contact the corresponding authors of identified randomised controlled trials for additional information about their studies when further data are required. We will search clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; www.who.int/ictrp).

• correspond with investigators, when appropriate, to clarify study eligibility; • at all stages, note reasons for inclusion and exclusion of articles; • make final decisions on study inclusion and proceed to data collection.

Data extraction and management Two review authors will independently extract data from the fulltext articles using a specifically designed spreadsheet to manage the information. We will resolve discrepancies through discussion or, if required, we will consult a third review author. We will enter data into Review Manager 5 software (RevMan 2012) and check them for accuracy. When information regarding any of the above is missing or unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies Two review authors will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane ’Risk of bias’ tool for the following domains (Higgins 2011): • sequence generation (selection bias); • allocation concealment (selection bias); • blinding of participants and personnel (performance bias); • blinding of outcome assessment (detection bias); • incomplete outcome data (attrition bias); • selective reporting (reporting bias); • any other bias. We will resolve any disagreements by discussion. See Appendix 2 for a more detailed description of risk of bias for each domain.

Data collection and analysis Measures of treatment effect Selection of studies Two review authors will independently assess for inclusion all the potential studies identified as a result of the search strategy. We will resolve any disagreements through discussion or, if required, we will consult a third author. Specifically, we will: • merge search results using reference management software and remove duplicate records of the same report; • examine titles and abstracts to remove irrelevant reports; • retrieve full text of the potentially relevant reports; • link multiple reports of the same study; • examine full-text reports for compliance of studies with eligibility criteria;

We will use Review Manager 5 to analyse the results of the studies (RevMan 2012). We will summarise data in a meta-analysis if they are sufficiently homogeneous, both clinically and statistically. For dichotomous data, we will present results as risk ratios (RR) with 95% confidence intervals (CI). We will report risk differences (RD) and if there is a statistically significant difference we will calculate the number needed to treat for additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH), and associated 95% CIs for all estimates. We will analyse continuous data using mean difference (MD), if outcomes are measured in the same way between trials. We will use the standardised mean difference (SMD) to combine trials that measure the same outcome, but use different methods.


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Unit of analysis issues The unit on analysis will be the participating infant in individually randomised trials.

Cluster randomised trials

We will include cluster-randomised trials in the analyses along with individually randomised trials. We will analyse them using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), or from another source (Higgins 2011). If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually randomised trials, we will synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta-analysis.

Dealing with missing data We will contact the authors of all published studies if clarifications are required, or to request additional information. In the case of missing data, we will describe the number of participants with missing data will be described in the ’Results’ section and the ’Characteristics of included studies’ table. The results will be only presented for the available participants. We will discuss the implications of the missing data in the ’Discussion’ of the review.

Where there is evidence of apparent or statistical heterogeneity, we will assess the source of the heterogeneity using sensitivity and subgroup analysis looking for evidence of bias or methodological differences between trials. Assessment of reporting biases We will try to obtain the study protocols of all included studies and we will compare outcomes reported in the protocol to those reported in the findings for each of the included studies. We will investigate reporting and publication bias by examining the degree of asymmetry of a funnel plot. Where we suspect reporting bias (see selective reporting bias above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including/ excluding such studies in the overall assessment of results using a sensitivity analysis. Also, for included trials that were recently performed (and therefore prospectively registered), we will explore possible selective reporting of study outcomes by comparing the primary and secondary outcomes in the reports with the primary and secondary outcomes proposed at trial registration, using the WHO International Clinical Trials Registry Platform website ( www.who.int/ictrp). If we find such discrepancies, we will contact the primary investigators to obtain missing data on outcomes prespecified at trial registration. Data synthesis We will use the fixed-effect model in Review Manager 5 for metaanalysis (RevMan 2012). Quality of evidence

Assessment of heterogeneity We will use Review Manager 5 to assess the heterogeneity of treatment effects between trials (RevMan 2012). We will use the two formal statistics described below. • The Chi2 test for homogeneity. We will calculate whether statistical heterogeneity is present using the Chi2 test for homogeneity (P < 0.1). Since this test has low power when the number of studies included in the meta-analysis is small, we will set the probability at the 10% level of significance (Higgins 2011). • The I2 statistic, to ensure that pooling of data is valid. The impact of statistical heterogeneity will be quantified using the I2 statistic, which describes the percentage of total variation across studies due to heterogeneity rather than sampling error. We will grade the degree of heterogeneity as: ◦ less than 25% = no heterogeneity; ◦ 25% to 49% = mild heterogeneity; ◦ 50% to 74% = moderate heterogeneity; ◦ 75% or greater = high heterogeneity.

We will use the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes. 1. For infants given heated and humidified inspiratory gas for respiratory support during newborn resuscitation at birth or at the time of delivery: mortality (neonatal mortality, i.e. less than 28 days, or mortality prior to discharge from NICU); hypothermia (defined according to WHO as core body temperature less than 36.5 ºC or skin temperature less than 36 ºC); duration of respiratory support (minutes, hours or days); duration of oxygen therapy (minutes, hours or days); duration of hospital stay (days); chronic lung disease (defined as either oxygen requirement at corrected 36 weeks’ postmenstrual age for an infant who was born at 32 weeks’ gestation or less OR oxygen at 28 days for an infant born at greater than 32 weeks’ gestation) (Lee 2000; Shennan 1988). 2. For infants given heated and humidified inspiratory gas for respiratory support outside of the newborn resuscitation setting: mortality (neonatal mortality i.e. less than 28 days, mortality


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prior to discharge); hypothermia (defined according to WHO as core body temperature less than 36.5 ºC or skin temperature less than 36 ºC); ventilator associated pneumonia; duration of respiratory support (minutes, hours or days); duration of oxygen therapy (minutes, hours or days); duration of hospital stay (days); chronic lung disease (defined as either oxygen requirement at corrected 36 weeks’ postmenstrual age for an infant who was born at 32 weeks’ gestation or less OR oxygen at 28 days for an infant born at greater than 32 weeks’ gestation)(Lee 2000; Shennan 1988). Two review authors will independently assess the quality of the evidence for each of the outcomes above. We will consider evidence from randomised controlled trials as high quality but downgrade the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We will use the GRADEpro 2014 Guideline Development Tool to create ’Summary of findings’ tables to report the quality of the evidence. The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades. • High: we are very confident that the true effect lies close to that of the estimate of the effect. • Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. • Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

• For Comparison 1: Respiratory support during newborn resuscitation at birth or at the time of delivery: ◦ gestational age (less than 30 weeks, less than 37 weeks; 37 weeks or greater); ◦ mode of respiratory support (e.g. mask CPAP, mask IPPV, endotracheal IPPV). • For Comparison 2: Respiratory support outside of the newborn resuscitation setting: ◦ gestational age: less than 30 weeks, less than 37 weeks; 37 weeks or greater); ◦ mode of respiratory support (e.g. low flow oxygen, high flow nasal cannulae, nasal CPAP, NIPPV, conventional mechanical ventilation, high-frequency oscillatory ventilation); ◦ respiratory conditions: respiratory distress syndrome, apnoea of prematurity, meconium aspiration syndrome, perinatal asphyxia, pneumonia.

Strategies for exploring heterogeneity

• Identification of the methodological differences between studies. • Subgroup analysis.

Sensitivity analysis If sufficient data are available, we plan to explore methodological heterogeneity using sensitivity analyses. We plan to perform these through including trials of higher quality, based on the presence of any of the following: adequate sequence generation, allocation concealment and less than 10% loss to follow-up.

Subgroup analysis and investigation of heterogeneity

ACKNOWLEDGEMENTS

We plan to carry out the following subgroup analyses:

None.

REFERENCES

Additional references

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APPENDICES

Appendix 1. Glossary of terms • Humidity is the amount of water vapour in a gaseous environment. It is usually described in terms of absolute or relative humidity. ◦ Absolute humidity (AH) is the mass of water in a given volume of gas and is generally expressed as milligrams of water per litre (mg H2 O/L). ◦ Relative humidity (RH) is the amount of water vapour present in a volume of gas, expressed as a percentage of the amount of water vapour that is required to fully saturate the same volume of gas at the same temperature and pressure (Gross 2012;Schulze 2002;Schulze 2007). • Indoor atmospheric air has a temperature of 20 ºC to 25 ºC with AH of 10 mg H2 O/L and RH of 55% to 60%. In the alveoli, the air temperature is 37 ºC and AH of 44 mg H2 O/L (100% relative humidity). • Respiratory support or assisted ventilation is defined as the movement of gas into and out of the lungs by an external source connected directly to the patient (Goldsmith 2011a). • Respiratory failure usually includes two or more criteria from the following clinical and laboratory categories (Spitzer 2011). ◦ Clinical criteria: ⋄ retractions (intercostal, supraclavicular, suprasternal); ⋄ grunting; ⋄ respiratory rate more than 60 breaths per minute; ⋄ central cyanosis; ⋄ intractable apnoea; ⋄ decreased activity and movements. ◦ Laboratory criteria: ⋄ partial pressure of carbon dioxide in arterial blood (PaCO2 ) greater than 60 mmHg; ⋄ partial pressure of oxygen in arterial blood (PaO2 ) less than 50 mmHg or oxygen saturation less than 80% when fraction of inspired oxygen (FiO2 ) is 1.0; ⋄ pH greater than 7.20. • Ventilator-associated pneumonia (VAP) is: ◦ pneumonia occurring more than 48 hours after intubation and ventilation. Diagnosis of VAP requires a high degree of suspicion combined with bedside examination, radiological examination and microbiological analysis of respiratory secretion. (Koenig 2006), OR •


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◦ defined by the Centers for Disease Control and Prevention (CDC) as pneumonia in people who had a device to assist or control respiration continuously through a tracheostomy or by endotracheal tube within the 48-hour period before the onset of infection (Goldsmith 2011b). • Early-onset neonatal sepsis (EOS) is recovery of one or more pathogens from blood/cerebrospinal fluid samples taken within 72 hours of life and treatment with antibiotic for five or more days (Stoll 2011). • Late-onset neonatal sepsis is one or more positive blood culture obtained after 72 hours (Stoll 2002). • Pulmonary air leak is a collection of air in the space around the lungs which can cause difficulty in breathing (Chow 2013).

Appendix 2. ’Risk of bias’ tool We will use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality (to meet the validity criteria) of the trials. For each trial, we will seek information regarding the method of randomisation, and the blinding and reporting of all outcomes of all the infants enrolled in the trial. We will assess each criterion as low, high, or unclear risk. Two review authors will separately assess each study. We will resolve any disagreement by discussion. We will add this information to the ’Characteristics of included studies’ table. We will evaluate the following issues and enter the findings into the risk of bias table.

Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated? For each included study, we will categorise the method used to generate the allocation sequence as: • low risk (any truly random process e.g. random number table; computer random number generator); • high risk (any non-random process e.g. odd or even date of birth; hospital or clinic record number); • unclear risk.

Allocation concealment (checking for possible selection bias). Was allocation adequately concealed? For each included study, we will categorise the method used to conceal the allocation sequence as: • low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); • high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); • unclear risk.

Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? For each included study, we will categorise the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding will be assessed separately for different outcomes or class of outcomes. We will categorise the methods as: • low risk, high risk or unclear risk for participants; • low risk, high risk or unclear risk for personnel.

Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment? For each included study, we will categorise the methods used to blind outcome assessment. Blinding will be assessed separately for different outcomes or class of outcomes. We will categorise the methods as: • low risk for outcome assessors; • high risk for outcome assessors; • unclear risk for outcome assessors.


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Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed? For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note 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. Where sufficient information is reported or supplied by the trial authors, we will re-include missing data in the analyses. We will categorise the methods as: • low risk (less than 20% missing data); • high risk (20% or greater missing data); • unclear risk. Selective reporting bias. Were reports of the study free of suggestion of selective outcome reporting? For each included study, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. We will assess the methods as: • low risk (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review were reported); • high risk (where not all the study’s prespecified outcomes were reported; one or more reported primary outcomes were not prespecified outcomes of interest and were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported); • unclear risk. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias? For each included study, we will describe any important concerns we had about other possible sources of bias (e.g. 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 will assess whether each study was free of other problems that could put it at risk of bias as: • low risk; • high risk; • unclear risk. If needed, we plan to explore the impact of the level of bias through undertaking sensitivity analyses.

CONTRIBUTIONS OF AUTHORS TND led the development of the protocol. JPF, AS, KT, DAT and LM contributed to the writing of this protocol.

DECLARATIONS OF INTEREST None.


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SOURCES OF SUPPORT

Internal sources • No sources of support supplied

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. HHSN275201600005C


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