Cuffed versus uncuffed endotracheal tubes for neonates

Abstract

Background

Endotracheal intubation is a commonly performed procedure in neonates, the risks of which are well‐described. Some endotracheal tubes (ETT) are equipped with a cuff that can be inflated after insertion of the ETT in the airway to limit leak or aspiration. Cuffed ETTs have been shown in larger children and adults to reduce gas leak around the ETT, ETT exchange, accidental extubation, and exposure of healthcare workers to anesthetic gas during surgery. With improved understanding of neonatal airway anatomy and the widespread use of cuffed ETTs by anesthesiologists, the use of cuffed tubes is increasing in neonates.

Objectives

To assess the benefits and harms of cuffed ETTs (inflated or non‐inflated) compared to uncuffed ETTs for respiratory support in neonates.

Search methods

We searched CENTRAL, PubMed, and CINAHL on 20 August 2021; we also searched trial registers and checked reference lists to identify additional studies.

Selection criteria

We included randomized controlled trials (RCTs), quasi‐RCTs, and cluster‐randomized trials comparing cuffed (inflated and non‐inflated) versus uncuffed ETTs in newborns. We sought to compare 1. inflated, cuffed versus uncuffed ETT; 2. non‐inflated, cuffed versus uncuffed ETT; and 3. inflated, cuffed versus non‐inflated, cuffed ETT.

Data collection and analysis

We used the standard methods of Cochrane Neonatal. Two review authors independently assessed studies identified by the search strategy for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence.

Main results

We identified one eligible RCT for inclusion that compared the use of cuffed (inflated if ETT leak greater than 20% with cuff pressure 20 cm H₂O or less) versus uncuffed ETT. The author provided a spreadsheet with individual data. Among 76 infants in the original manuscript, 69 met the inclusion and exclusion criteria for this Cochrane Review. We found possible bias due to lack of blinding and other bias.

We are very uncertain about frequency of postextubation stridor, because the confidence intervals (CI) of the risk ratio (RR) were very wide (RR 1.36, 95% CI 0.35 to 5.25; risk difference (RD) 0.03, −0.11 to 0.18; 1 study, 69 participants; very low‐certainty evidence).

No neonate was diagnosed with postextubation subglottic stenosis; however, endoscopy was not available to confirm the clinical diagnosis.

We are very uncertain about reintubation for stridor or subglottic stenosis because the CIs of the RR were very wide (RR 0.27, 95% CI 0.01 to 6.49; RD −0.03, 95% CI −0.11 to 0.05; 1 study, 69 participants; very low‐certainty evidence).

No neonate had surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis (1 study, 69 participants).

Neonates randomized to cuffed ETT may be less likely to have a reintubation for any reason (RR 0.06, 95% CI 0.01 to 0.45; RD −0.39, 95% CI −0.57 to −0.21; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 5; 1 study, 69 participants; very low‐certainty evidence).

We are very uncertain about accidental extubation because the CIs of the RR were wide (RR 0.82, 95% CI 0.12 to 5.46; RD −0.01, 95% CI −0.12 to 0.10; 1 study, 69 participants; very low‐certainty evidence).

We are very uncertain about all‐cause mortality during initial hospitalization because the CIs of the RR were extremely wide (RR 2.46, 95% CI 0.10 to 58.39; RD 0.03, 95% CI −0.05 to 0.10; 1 study, 69 participants; very low‐certainty evidence).

There is one ongoing trial. We classified two studies as awaiting classification because outcome data were not reported separately for newborns and older infants.

Authors' conclusions

Evidence for comparing cuffed versus uncuffed ETTs in neonates is limited by a small number of babies in a single RCT with possible bias. There is very low certainty evidence for all outcomes of this review. CIs of the estimate for postextubation stridor were wide. No neonate had clinical evidence for subglottic stenosis; however, endoscopy results were not available to assess the anatomy.

Additional RCTs are necessary to evaluate the benefits and harms of cuffed ETTs (inflated and non‐inflated) in the neonatal population. These studies must include neonates and be conducted both for short‐term use (in the setting of the operating room) and chronic use (in the setting of chronic lung disease) of cuffed ETTs.

Plain language summary

Cuffed versus uncuffed endotracheal tubes for neonates

Background: newborn babies rarely need a tube placed in the windpipe; however, this may occur before a procedure or to help with breathing. The tube may or may not have a cuff. The standard of care in newborn babies is a tube without a cuff. Cuffed tubes are used more frequently in older babies and children to reduce leaks of gas around the tube, the risk of aspiration (breathing food, saliva, or stomach contents into the airways or lungs), the need to change the tube, or the tube coming out.

Review question: in this review, we evaluated the evidence for or against using a cuffed tube in newborn babies.

Study characteristics: we collected and analyzed all relevant studies to answer the review question and found one study enrolling 76 babies, of whom 69 met eligibility for this review. This review is up‐to‐date as of 20 August 2021.

Key results: there is not enough evidence for or against tubes with a cuff to prevent airway problems. Newborn babies who have a tube with a cuff may require less frequent replacement of the tube for any reason and less frequent replacement of the tube to find the correct size than babies who had a tube without a cuff.

Reliability of the evidence: we judged the reliability of the evidence to be very low. This is because only a few babies were in a single trial and there was possible bias. There is one ongoing trial. We classified two studies as awaiting classification because outcome data were not reported separately for newborns and older infants.

Summary of findings

Summary of findings 1. Cuffed (inflated or not) compared to uncuffed endotracheal tubes for neonates.

Cuffed (inflated or not) compared to uncuffed ETTs for neonates
Patient or population: neonates Setting: neonatal and pediatric intensive care units in Western Australia Intervention: cuffed (inflated or not) ETT Comparison: uncuffed ETT
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)
				Risk with uncuffed ETT	Risk difference with cuffed (inflated or not) ETT
Postextubation stridor Time of measurement: during initial hospitalization	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,b	RR 1.36 (0.35 to 5.25)	Study population
				97 per 1000	35 more per 1000 (63 fewer to 412 more)
Postextubation subglottic stenosis Time of measurement: during initial hospitalization	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,c	Not estimabled	Study population
				0 per 1000	0 fewer per 1000 (60 fewer to 60 more)
Reintubation for stridor or subglottic stenosis Time of measurement: during initial hospitalization	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,b	RR 0.27 (0.01 to 6.49)	Study population
				32 per 1000	23 fewer per 1000 (32 fewer to 176 more)
Surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis Time of measurement: during initial hospitalization	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,c	Not estimabled	Study population
				0 per 1000	0 fewer per 1000 (60 fewer to 60 more)
Reintubation for any reason	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,b	RR 0.06 (0.01 to 0.45)	Study population
				419 per 1000	394 fewer per 1000 (230 fewer to 415 fewer)
Accidental extubation Time of measurement: during initial hospitalization	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,b	RR 0.82 (0.12 to 5.46)	Study population
				65 per 1000	12 fewer per 1000 (57 fewer to 290 more)
All‐cause mortality during initial hospitalization	69 (1 RCT)	⊕⊝⊝⊝ Very lowa,b	RR 2.46 (0.10 to 58.39)	Study population
				0 per 1000	30 more per 1000 (50 less to 100 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ETT: endotracheal tube; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded one level for serious study limitations (unclear or high risk of performance bias; detection bias; other bias).
^bDowngraded two levels for very serious imprecision (only one small study; very few events).
^cDowngraded two levels for very serious imprecision (only one small study; no events).
^dThe outcome was reported in the study, but there were no events in either study arm.

Background

Endotracheal intubation places neonates at risk for airway injury, including laryngeal edema (up to 17%), and subglottic stenosis (0.3% to 11%) (Greaney 2018; Koka 1977; Sathyamoorthy 2015; Schweiger 2013). While many studies have used stridor (abnormal, noisy breathing) as an outcome, the absence of stridor is not sufficient to rule out significant airway injury (Holzki 2009; Sherman 1986). Factors associated with a higher risk for airway injury include using an endotracheal tube (ETT) type or size that does not meet recommendations for age or weight, duration of intubation, and number of intubations (Contencin 1993; Laing 1986; Marston 2018; McMillan 1986; Sathyamoorthy 2015; Sherman 1986; Weiss 2017).

The anatomy of the pediatric airway is controversial (Holzki 2018; Park 2019; Tobias 2015). Autopsy data and direct laryngoscopy have described the airway of neonates and infants as funnel‐shaped, with the narrowest portion being the circular rigid cricoid cartilage (Bayeux 1897; Butz 1968; Eckenhoff 1951; Fayoux 2006; Fayoux 2008; Wailoo 1982). Another model was suggested by in vivo studies in asleep, sedated, or anesthetized (with or without paralysis) children and infants undergoing magnetic resonance imaging (MRI), video‐bronchoscopic imaging, or computed tomography (CT) scan, and 86 children and infants (60 intubated) undergoing CT scan for trauma. In this second model, the cricoid cartilage is circular or ellipsoid (narrower on the transverse than anteroposterior axis), and the narrowest portion of the airway is at the glottic opening and immediate subvocal cord level (Dalal 2009; Litman 2003; Mizuguchi 2019; Wani 2016a; Wani 2016b; Wani 2017a; Wani 2017b; Wani 2017c). These latter findings could be due to higher or oblique cross‐section; phase of respiration, status during the study (sleep, sedation, anesthesia, paralysis); or to comorbidities affecting softer laryngeal structures (Holzki 2018).

The first anatomic model led to the traditional use of uncuffed ETTs in neonates and children less than eight years of age, with a properly sized ETT allowing leak around the circular cricoid cartilage. The second model suggests that a properly sized uncuffed ETT with reasonable leak could exert undue pressure on the transverse tracheal wall at the cricoid level, whereas a smaller diameter micro‐cuffed ETT could provide an adequate seal without exerting excessive pressure on the transverse cricoid (James 2001; Park 2019).

Description of the condition

The frequency of neonatal endotracheal intubation has progressively decreased with recognition of lack of evidence for routine endotracheal suctioning of neonates born to mothers with meconium‐stained fluid, and with increasing use of continuous positive airway pressure (CPAP), non‐invasive respiratory support and less invasive surfactant administration (LISA) (Foglia 2017; Kakkilaya 2019; Kattwinkel 2010; Trevisanuto 2020; Wyckoff 2015; Wyllie 2015).

Endotracheal intubation is either an emergency or an elective/semi‐elective procedure. When performed in the intensive care unit (ICU) environment, the most common diagnoses include acute and chronic respiratory failure, congenital anomaly requiring surgery, congenital heart disease, neurologic impairment, sepsis, and airway or facial anomalies. The indications are most commonly oxygenation failure, ventilation failure, or apnea and bradycardia events. The frequency of endotracheal intubation in the delivery room has decreased with changing international recommendations about routine endotracheal suctioning for meconium‐stained fluid and with evidence for decreased frequency of death or bronchopulmonary dysplasia with DR‐CPAP compared with intubation in very preterm infants (Foglia 2017; Kattwinkel 2010; Wyckoff 2015; Wyllie 2015).

The diagnosis of airway injury such as subglottic stenosis can only be ruled out by endoscopy (Holzki 2009). In the 1960s and 1970s, prolonged intubation was associated with 12% to 20% subglottic stenosis (Lesperance 2015). Optimization of ETT and ventilator management has decreased the rate of acquired subglottic stenosis in neonates with a history of prolonged intubation to as low as 1% (Choi 2000).

Description of the intervention

ETTs can either be cuffed or uncuffed. Cuffed ETTs are used to reduce gas leak around the ETT, ETT exchange, accidental extubation, and exposure of healthcare workers (HCW) to anesthetic gas during surgery.

For any ETT placement, the standard anesthetic practice is to demonstrate air leak around the ETT at peak inspiratory pressure of 20 cmH₂O to 25 cmH₂O to ensure that the ETT is not too tight (Thomas 2016).

Guidelines for uncuffed ETT: currently, the smallest available uncuffed ETT has an internal diameter of 2.0 mm. Current guidelines for ETT size (internal diameter) based on weight are those of the Neonatal Resuscitation Program (Niermeyer 2000).

Guidelines for cuffed ETT: currently, the smallest available micro‐cuffed ETT has an internal diameter of 3.0 mm and is recommended for neonates weighing 3 kg or less. Manufacturer guidelines and published guidelines for ETT size are available (Duracher 2008; Khine 1997; Salgo 2006), but the ideal formula to determine the appropriate sized cuffed ETT may yet require further study (Manimalethu 2020). The cuff is typically inflated to a maximum of 20 cmH₂O, which can be regulated by a pressure release valve (Weiss 2007). Pressure monitoring can be continuous or intermittent (Gopalakrishnan 2013; Krishna 2014; Kumar 2020; Thomas 2016; Tobias 2015).

The risks and benefits of cuffed versus uncuffed ETT in neonates are currently unknown. It is also important to determine risks and benefits of following versus not following the recommendations for ETT type and size and those of inflating versus not inflating the cuff.

Cuffed versus uncuffed endotracheal tube: history and center variation

1. History: the concern for damage to the narrow area of the circular cricoid cartilage led to the exclusive use of uncuffed ETT for all neonates and young children less than eight years of age for several years (James 2001). The use of cuffed ETT in small children and neonates started with the advent of polyvinyl chloride (PVC) high‐volume low‐pressure cuffed ETTs in the 1990s followed by in vivo assessment of laryngeal anatomy (Litman 2003), and the introduction of the ultra‐thin polyurethane micro‐cuffed pediatric ETT in 2004 (Thomas 2016). The use of cuffed ETTs by anesthesiologists in children has increased progressively since 2001 (Boerboom 2015; Flynn 2008; Orliaguet 2001). The percentage of anesthesiologists using cuffed ETTs for anesthesia in neonates in the UK was less than 10% in a 2008 survey (Flynn 2008), compared with greater than 60% in a 2016 survey predominantly involving the USA (Sathyamoorthy 2016).

2. Center variation: there is variation by type of ICU (neonatal [NICU] versus pediatric [PICU]) and by country. One 2016 survey in Australia and New Zealand showed that most NICUs used uncuffed ETT for neonates weighing more than 3 kg and infants less than three months of age, whereas most PICUs used cuffed ETT (Thomas 2016). When using a cuffed ETT, one‐third of the NICUs never inflated the cuff; in contrast, all PICUs inflated the cuff (Thomas 2016). The survey also found variable protocols for frequency of pressure checks and in maximum cuff pressure). The survey also reported that cuffed ETTs are sometimes used in neonates weighing less than 3 kg. Analysis of an international PICU database in 2018 showed that international PICUs (New Zealand, Japan, Singapore, Germany, India) used cuffed ETTs less often than North American PICUs (Lee 2019). Use of micro‐cuffed ETT is increasing in neonates including those weighing less than 3 kg (Williams 2021; Zander 2021). One randomized controlled trial (RCT) in children with cuffed ETT showed no difference in complications (postextubation stridor, reintubation rate, ventilator‐associated pneumonia rate, ventilator days, and length of PICU stay) in the group using protocolized monitoring of cuff pressures versus controls using no protocol (Shaikh 2021).

How the intervention might work

Compared to uncuffed ETT, cuffed ETT have the following potential benefits and harms.

Potential benefits of cuffed endotracheal tubes

1. Fewer tube changes.

   1. In the operating room: anesthesiologists typically change ETT size until meeting the criterion of air leak at peak inspiratory pressure of 20 cmH₂O to 25 cmH₂O. Because cuff inflation can be adjusted, cuffed ETT might reduce the frequency of ETT exchange in the OR compared with uncuffed ETTs (Weiss 2007).

   2. In the ICU: in one large observational study, the proportion of cuffed ETT use per PICU was inversely correlated with the rate of tube change (Lee 2019).

2. Fewer accidental extubations: one study in children showed an association of uncuffed ETT with higher frequency of accidental extubation during transportation to the PICU (Pearson 2018).

3. Less gas leak around the ETT: cuffed ETTs limit gas leak around the ETT compared with uncuffed ETTs (Mahmoud 2011). A large leak around the ETT could lead to unreliable end‐tidal carbon dioxide monitoring (Schmalisch 2012). A large leak could also limit the ability of the ventilator to compensate for the leak, to assure a given effective tidal volume and therefore to use tidal volume‐targeted ventilation or volume ventilation mode.

4. Less exposure of HCW to the following:

   1. inhaled anesthetics in the operative setting and less wastage of these agents (Chang 1997; Litman 2013; Taylor 2011);

   2. aerosolized particles. The 2019 severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2; known as COVID‐19) pandemic has raised concern about aerosolization that may lead to horizontal transmission of infection in HCW. Endotracheal intubation with an inflated cuffed ETT might minimize aerosolization. At least one neonate suspected of COVID‐19 with respiratory distress was intubated in the emergency room to avoid non‐invasive ventilation (Munoz 2020).

5. Less fluid leak around the ETT: studies of children ventilated with uncuffed but not those with inflated micro‐cuffed ETTs have shown evidence for fluid leakage or micro‐aspiration, which could be a factor of ventilator‐associated pneumonia (Dullenkopf 2003; Gopalareddy 2008).

6. Adjustable cuff inflation (Weiss 2007): if air leak around the ETT increases with a change in position of the ETT or the patient, patient's growth, level of sedation/relaxation, or change in lung compliance, increasing cuff inflation may compensate for that leak.

7. Decreased air leak via a tracheo‐esophageal fistula (TEF) during artificial ventilation: the cuff may help with effective ventilation of neonates with respiratory distress and distal TEF by limiting the air leak via the TEF, which may be localized very close to the carina (Gupta 2017).

8. Less oversized tube insertion as assessed by CT scan (Mizuguchi 2019).

Potential harms of cuffed endotracheal tubes

1. A standard cuff may be too large for the patient's anatomy and either compress the cricoid cartilage or go as far as the carina. The first available cuffed ETTs had a large cuff (with a Murphy eye that allowed exhalation in case the ETT tip was inadvertently placed against the tracheal wall) which could involve the cricoid cartilage. In contrast, micro‐cuffed ETTs, available since 2004, have a cuff‐free subglottic portion (Litman 2013; Taylor 2011).

2. Smaller internal diameter, because the recommended internal diameter of a cuffed ETT is smaller than that of an uncuffed ETT. This may lead to:

   1. increased airway resistance (especially in the smallest patients because resistance is inversely proportionate to the fourth exponential of the radius), work of breathing, and peak inspiratory pressure. In one in vitro lung model this was minimized by pressure support and automatic tube compensation (Thomas 2018);

   2. a smaller maximum allowable suction catheter.

3. Higher external diameter: different cuffed ETTs with the same internal diameter have different external diameters, yielding different guidelines for the same patient's weight (Imai 2017; Weiss 2017).

4. Airway damage when used in patients weighing less than 3 kg (Sathyamoorthy 2015). The smallest available micro‐cuffed ETT is recommended for neonates weighing 3 kg or greater. However, one recent retrospective cohort study reported use of micro‐cuffed ETT in 189 patients weighing less than 3 kg with less ETT exchange than with uncuffed ETT and no increase in postoperative airway effects including stridor (Williams 2021). Another retrospective study suggested that bodyweight was the strongest predictor of needing a cuffed ETT to seal the trachea, with a weight of 2.7 kg as threshold (Zander 2021).

5. Risk of cuff overinflation or high pressure limiting perfusion of mucosal capillaries. Overinflation may occur with nitrous oxide anesthesia or manual inflation (Bernet 2005; Weiss 2007). New ultrathin (10 μm) polyurethane, high‐volume low‐pressure cuffed ETTs have allowed good tracheal seal with a cuff pressure less than 15 cmH₂O (mean 9.7 cmH₂O) (Dullenkopf 2004), that is, lower than estimated perfusion pressure of mucosal capillaries (20 mmHg to 25 mmHg) (Litman 2003; Thomas 2016).

6. Presence of folds and channels when using a cuff that is too large (Weiss 2007). This is not observed with micro‐cuffed ETT (Imai 2017; Thomas 2016).

7. Risk of inadequate depth of intubation due to lack of intubation depth mark in some cuffed ETTs.

Why it is important to do this review

The available reviews addressed the benefits and risks of cuffed ETT for anesthesia in children less than eight years of age but not specifically in neonates or for prolonged intubation in the ICU. The current Cochrane Review will address neonates only.

At this time, there exists great variability and much ambiguity in many aspects of care surrounding the use of cuffed ETTs within the neonatal population. Even though the manufacturers do not recommend the use of cuffed ETT in babies weighing less than 3 kg and those that are preterm, an increasing amount of observational cohort studies are reporting the use of cuffed ETT in such infants. There are several different manufacturers of cuffed ETT, each with a unique design and equipment specifications.

The SARS outbreaks, including the COVID‐19 pandemic, have raised significant concerns about the risk of aerosolization that may lead to horizontal transmission of infection to HCW. Aerosol‐generating procedures include the process of endotracheal intubation, non‐invasive ventilation, tracheotomy, and manual ventilation before intubation but not after intubation (Ng 2020; Raboud 2010; Tran 2012). This warrants an evidence‐based evaluation of all available measures that would limit HCW exposure to aerosolized particles.

Comparison of cuffed versus uncuffed endotracheal tubes in children

Cuffed and uncuffed ETT use in PICUs and operating suites were compared in a systematic review including RCTs and observational studies in children including neonates (Shi 2016). The meta‐analysis showed no difference between cuffed and uncuffed ETT in postextubation stridor, reintubation rate, or duration of mechanical ventilation; however, cuffed ETT use was associated with lower risk for need for ETT change. Cochrane Anaesthesia summarized data from three RCTs comparing cuffed and uncuffed ETTs for anesthesia in children aged eight years or under including neonates (De Orange 2017). They found no difference in postextubation stridor, need for tracheal reintubation, need for epinephrine, need for corticosteroids, or admission to the ICU for stridor, but a lower rate of ETT exchange in the cuffed ETT group. However, the authors were unable to draw definitive conclusions about the comparative effects of cuffed or non‐cuffed ETTs in children undergoing general anesthesia because their confidence was limited by risks of bias, imprecision, and indirectness.

Objectives

To assess the benefits and harms of cuffed ETTs (inflated or non‐inflated) compared to uncuffed ETTs for respiratory support in neonates.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs, quasi‐RCTs, and cluster‐randomized trials.

Types of participants

We included full‐term neonates 28 days of age or greater, and preterm infants less than 45 weeks' postmenstrual age (PMA) requiring endotracheal intubation for any indication.

Types of interventions

We included studies that considered the following comparisons.

1. Cuffed ETT (inflated or not) versus uncuffed ETT:

   1. cuffed not inflated versus uncuffed;

   2. cuffed inflated versus uncuffed.

2. Cuffed inflated versus cuffed not inflated.

Types of outcome measures

Outcome measures of interest did not form part of the eligibility criteria for RCTs, quasi‐RCTs, and cluster‐randomized trials.

Outcome measures were counted once for each patient except for number of reintubations.

Primary outcomes

Postextubation airway complication:

1. stridor;

2. subglottic stenosis.

Secondary outcomes

1. Racemic epinephrine for stridor.

2. Systemic steroid for stridor.

3. Reintubation for stridor or subglottic stenosis.

4. Endoscopy for stridor or subglottic stenosis.

5. Surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis.

6. Reintubation for inadequate ETT size (number of reintubations).

7. Reintubation for any reason.

8. Accidental extubation.

9. Ventilator‐associated pneumonia.

10. Ventilator‐associated tracheobronchitis (culture of pathogen in tracheal culture with abundant white cells).

11. Air leak around the ETT (percentage of inspired tidal volume; greater than accepted by the author).

12. Pneumothorax.

13. Bronchopulmonary dysplasia/chronic lung disease:

    1. 28 days (NIH 1979);

    2. 36 weeks' PMA (Jobe 2001);

    3. physiologic definition (Walsh 2004).

14. Length of hospital stay (days).

15. All‐cause neonatal mortality (during the first 28 days postnatal).

16. All‐cause mortality during initial hospitalization.

17. Horizontal transmission of aerosolized infections such as COVID‐19 to HCW.

Search methods for identification of studies

Electronic searches

We ran a literature search in September 2020 and updated it in August to September 2021. In September 2020, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9) in the Cochrane Library; PubMed (1946 to 28 September 2020); and CINAHL Complete (via EBSCOhost, 1981 to 28 September 2020).

For the updated search in 2021, we searched CENTRAL (2021, Issue 8) in the Cochrane Library; PubMed (1946 to 20 August 2021); and CINAHL Complete (via EBSCOhost, 1981 to 20 August 2021). In addition, we also searched ISRCTN registry (www.isrctn.com; searched 22 September 2021); US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 22 September 2021); and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) portal (apps.who.int/trialsearch; searched 22 September 2021).

We applied no language restrictions. Our search strategies are illustrated in Appendix 1.

Searching other resources

We reviewed the reference lists of all identified articles for relevant articles not located in the primary search. We also searched PubMed for errata or retractions for included studies.

Data collection and analysis

We collected information regarding the method of randomization, blinding, intervention, stratification, and whether the trial was single or multicenter for each included study. We noted information regarding trial participants including those mentioned in Data extraction and management. We analyzed the clinical outcomes noted above in the Types of outcome measures.

Selection of studies

We used Cochrane's Screen4Me workflow to assess the search results. Screen4Me comprises three components: known assessments – a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labeled as an RCT or as Not an RCT; the RCT classifier – a machine learning model that distinguishes RCTs from non‐RCTs, and if appropriate, Cochrane Crowd – Cochrane's citizen science platform where the Crowd help to identify and describe health evidence. For more information about Screen4Me, see community.cochrane.org/organizational-info/resources/resources-groups/information-specialists-portal/crs-videos-and-quick-reference-guides#Screen4Me. Detailed information regarding evaluations of the Screen4Me components can be found in the following publications: Marshall 2018; Noel‐Storr 2020; Noel‐Storr 2021; Thomas 2020.

We included all RCTs, quasi‐RCTs, and cluster‐RCTs fulfilling our inclusion criteria. Two review authors (VD, LM) reviewed the results of the search and independently selected studies for inclusion. We resolved any disagreements by discussion or, when necessary, by a third review author.

We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and Characteristics of excluded studies table (Moher 2009).

Data extraction and management

Two review authors (VD, LM) independently extracted data using a data extraction form integrated with a modified version of the Cochrane Effective Practice and Organisation of Care Group data collection checklist (Cochrane EPOC Group 2017). We piloted the form within the review team using a sample of included studies.

We extracted the following characteristics from each included study:

1. administrative details: study author(s); published or unpublished; year of publication; year in which study was conducted; presence of vested interest (conflict of interest); details of other relevant papers cited;

2. study: study design; type, duration, and completeness of follow‐up (e.g. greater than 80%); country and location of study; informed consent; ethics approval;

3. participants: sex, birth weight, gestational age, number of participants, current weight;

4. interventions: size, model, and manufacturer of the ETT;

5. outcomes as mentioned above under Types of outcome measures.

We resolved any disagreements by discussion. We described ongoing studies identified by our search, when available, detailing the primary author, research question(s), methods, and outcome measures, together with an estimate of the reporting date and reported them in the Characteristics of ongoing studies table. We detailed studies requiring further information in the Characteristics of studies awaiting classification table.

We contacted authors of studies that recruited children including neonates and asked them for neonatal data that could be extracted for this review. When queries arose, or in cases for which additional data were required, we contacted study investigators/authors for clarification. Two review authors (VD, LM) used Cochrane's tool Review Manager Web for data entry (Review Manager Web 2019). We planned to replace any standard error of the mean (SEM) by the corresponding standard deviation (SD).

Assessment of risk of bias in included studies

Two review authors (VD, LM) independently assessed the risk of bias (low, high, or unclear) of included trials using the Cochrane risk of bias tool for the following domains (Higgins 2011).

1. Sequence generation (selection bias).

2. Allocation concealment (selection bias).

3. Blinding of participants and personnel (performance bias).

4. Blinding of outcome assessment (detection bias).

5. Incomplete outcome data (attrition bias).

6. Selective reporting (reporting bias).

7. Any other bias.

We resolved any disagreements by discussion or by consulting a third review author. See Appendix 2 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

We performed the statistical analyses using Review Manager Web (Review Manager Web 2019). We analyzed categorical data using risk ratio (RR) and risk difference (RD). For statistically significant outcomes, we calculated the number needed to treat for an additional beneficial outcome (NNTB), or number needed to treat for an additional harmful outcome (NNTH). We analyzed continuous data using mean difference (MD) when studies used the same scales. We reported 95% confidence intervals (CIs) for all outcomes.

Dichotomous data

For dichotomous data, we presented results using RRs and RDs with 95% CIs. We calculated the NNTB, or NNTH with 95% CIs if there was a statistically significant reduction (or increase) in RD.

Continuous data

We used MD for the analysis of length of hospital stay. For future updates where we may include more studies, we will use the MD when continuous outcomes are measured in the same way between studies. We will use the standardized mean difference (SMD) to combine studies that measured the same outcome using different methods. Where trials reported continuous data as median and interquartile range (IQR) and data passed the test of skewness, we converted median to mean and estimated the SD as IQR/1.35.

Unit of analysis issues

The unit of analysis was the participating infant in individually randomized trials, and an infant was considered only once in the analysis. The participating neonatal unit or section of a neonatal unit or hospital would be the unit of analysis in cluster‐randomized trials. We would analyze them using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), or from a similar trial or from a study with a similar population as described in Section 16.3.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). If we used ICCs from a similar trial or from a study with a similar population, we reported this and conducted a sensitivity analysis to investigate the effect of variation in the ICC.

If we identified both cluster‐randomized trials and individually randomized trials, we would only combine the results from both if there was little heterogeneity between the study designs, and the interaction between the effect of the intervention and the choice of randomization unit was considered to be unlikely. We acknowledged any possible heterogeneity in the randomization unit and perform a sensitivity analysis to investigate possible effects of the randomization unit.

We excluded crossover studies as they are not feasible for this intervention.

Dealing with missing data

Where feasible, we intended to carry out analysis on an intention‐to‐treat basis for all outcomes. Whenever possible, we would analyze all participants in the treatment group to which they were randomized, regardless of the actual treatment received. When we identified important missing data (in the outcomes) or unclear data, we requested the missing data by contacting the original investigators. We made explicit assumptions of any methods used to deal with missing data. We planned to perform sensitivity analysis to assess how robust results were while performing reasonable changes in the undertaken assumptions. We addressed the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine heterogeneity among trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic (Higgins 2020). We planned to grade the degree of heterogeneity as:

1. less than 25%: no heterogeneity;

2. 25% to 49%: low heterogeneity;

3. 50% to 75%: moderate heterogeneity;

4. more than 75%: substantial heterogeneity.

If we noted statistical heterogeneity (I² > 50%), we planned to explore the possible causes (e.g. differences in study quality, participants, intervention regimens, or outcome assessments).

Assessment of reporting biases

We assessed reporting bias by comparing the stated primary outcome and secondary outcomes and reported outcomes. Where study protocols were available, we compared these to the full publications to determine the likelihood of reporting bias. We planned to document studies using the interventions in a potentially eligible infant population, but not reporting on any of the primary and secondary outcome, in the Characteristics of included studies table. We planned to use the funnel plots to screen for publication bias where there were a sufficient number of studies (more than 10) reporting the same outcome. If publication bias was suggested by a significant asymmetry of the funnel plot on visual assessment, we would have incorporated that in our assessment of certainty of evidence.

Data synthesis

If we identified multiple studies that we considered to be sufficiently similar, we planned to perform meta‐analysis using Review Manager Web (Review Manager Web 2019). For categorical outcomes, we would have calculated the typical estimates of RR and RD, each with its 95% CI; for continuous outcomes, we would have calculated the MD or SMD, each with its 95% CI. We planned to use a fixed‐effect model to combine data where it was reasonable to assume that studies were estimating the same underlying treatment effect. If we judged meta‐analysis to be inappropriate (because of differences in patient population or intervention), we planned to analyze and interpret individual trials separately. If there was evidence of clinical heterogeneity, we would have tried to explain this based on the different study characteristics and subgroup analyses.

Subgroup analysis and investigation of heterogeneity

We planned to explore high statistical heterogeneity in the outcomes by visually inspecting the forest plots and by removing the outlying studies in the sensitivity analysis (Higgins 2020). Where statistical heterogeneity was significant, we would have interpreted the results of the meta‐analyses accordingly; and would have downgraded the certainty of evidence in the summary of findings table, according to the GRADE recommendations.

We considered the following groups for subgroup analysis where data were available.

1. Gestational age:

   1. preterm (less than 37 weeks' gestation);

   2. term (37 weeks' gestation or greater).

2. Study design:

   1. all studies;

   2. RCTs only.

3. Size of cuff:

   1. all studies;

   2. micro‐cuffed ETT only.

4. Cuff pressure:

   1. monitored;

   2. not monitored.

5. Indication:

   1. for procedure (e.g. surgery; MRI);

   2. for (short‐ or long‐term) respiratory support.

6. ETT size and type:

   1. as recommended for patient's size and age;

   2. different type from or larger than recommended for patient's size and age.

7. Weight at enrollment:

   1. less than 3 kg;

   2. 3 kg or greater.

We would have restricted these analyses to the primary outcome.

Sensitivity analysis

We planned to present results of the sensitivity analyses only if these were significantly different from the primary results. We planned sensitivity analyses in the following situations.

1. An unexplained moderate to high heterogeneity, we would have explored this by removing the outlying study/studies causing heterogeneity (if feasible).

2. Study with high risk of bias was included in the meta‐analysis of an outcome where the other studies had low risk of bias, we would have removed the study with high risk of bias.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook to assess the certainty of evidence for the following (clinically relevant) outcomes (Schünemann 2013):

1. postextubation stridor;

2. postextubation subglottic stenosis;

3. reintubation for stridor or subglottic stenosis;

4. surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis;

5. reintubation for any reason;

6. accidental extubation;

7. all‐cause mortality during initial hospitalization.

Two review authors (VD, LM) independently assessed the certainty of the evidence for each of the outcomes above. We considered evidence from RCTs as high certainty, downgrading 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 used GRADEpro GDT to create Table 1 to report the certainty of the evidence.

The GRADE approach results in an assessment of the certainty of a body of evidence as one of four grades.

1. High certainty: further research is very unlikely to change our confidence in the estimate of effect.

2. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

3. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

4. Very low certainty: we are very uncertain about the estimate.

Results

Description of studies

The search ran on 28 September 2020 and updated on 20 August 2021 identified 4060 search results. In assessing the studies we used Cochrane's Screen4Me workflow to help identify potential reports of randomized trials. The results of the Screen4Me assessment process can be seen in Figure 1. One additional study was identified through other sources: the Pediatric Academic Societies (PAS) abstracts (www.pas-meeting.org/scientific-abstracts/). We initially assessed the 456 records in Screen4Me and the additional 169 references following the search update run in August 2021.

1.

Screen4Me summary diagram.

Results of the search

The literature search ran in September 2020 and updated in August 2021 identified 625 references (Figure 2). After reading the titles and abstract we excluded 615 irrelevant articles. We assessed the full text of 10 studies.

2.

Study flow diagram.

We included one study (Thomas 2021). We identified one study which was considered potentially eligible and classified as ongoing (UMIN000017213). The authors of this study compared cuffed versus uncuffed ETTs in children from birth to six years old undergoing elective surgery or exam requiring endotracheal intubation for general anesthesia. The results are not available. We wrote to the first author of this study, and the UMIN‐Clinical Trials Registry, without response so far. We classified two studies as awaiting classification since neonate‐specific data for these pediatric trials were unavailable (Arana 2007; Fernandes 2014). We were unable to contact the authors of these studies. We excluded six studies since they included no neonates (Chambers 2018; Chand 2018; Eschertzhuber 2010; Khine 1997; Ozden 2016; Weiss 2009). We contacted the authors of these studies who confirmed the lack of/unavailability of 'neonate‐specific' data.

See Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; and Characteristics of ongoing studies tables.

Included studies

We identified one eligible, completed RCT for inclusion that compared the use of cuffed (inflated if ETT leak was greater than 20% with cuff pressure less than 20 cmH₂O) versus uncuffed ETT in neonates at 35 weeks' gestation or greater and infants up to three months of age who weighed 3 kg or greater requiring mechanical ventilation (Thomas 2021). This single‐center RCT was conducted in the NICU and PICU of the Princess Margaret Hospital for Children, Perth (now Perth Children's Hospital), the sole tertiary children's hospital in Western Australia. The study recruited 76 infants between February 2015 and August 2016, of which 40 were randomized to cuffed and 36 to uncuffed ETTs. The author provided a spreadsheet with individual data. Among 76 infants in the original manuscript, seven were term infants older than 28 days postnatal and thus were excluded from our review as per the predefined eligible criteria. Of note, these seven infants (five randomized to uncuffed ETT and two randomized to cuffed ETT) were enrolled with a weight less than 3 kg. Among the 69 eligible infants who met the predefined age criterion for this Cochrane Review, the mean gestational age was 38.3 (SD 2.0) weeks (range 31 weeks 3 days to 41 weeks 3 days), birth weight was 3340 (SD 508) g (range 1440 g to 4459 g), PMA at enrollment 39.2 (SD 2.0) weeks, weight at enrollment 3446 (SD 407) g (range 2800 g to 4459 g), and median postnatal age at enrollment 1 day (IQR 1 to 7 days, range 0 to 68 days). Reason for study intubation was surgery (33 neonates), respiratory (32 neonates), neurologic (three neonates) and anesthesia (one neonate). Total ventilation time was similar in both groups (median: 63 hours, IQR 37 to 100 for cuffed ETT versus 72 hours, IQR 37 to 91 for uncuffed ETT; P = 0.90). Follow‐up was done by medical record review at a mean of 34.6 (SD 5.3) months (cuffed ETT, 36 neonates) and 33.8 (SD 7.7) months (uncuffed ETT, 29 neonates).

Outcomes assessed in Thomas 2021 included the following.

1. Primary outcome:

   1. achievement of optimal ETT leak in target range (10% to 20%).

2. Secondary outcomes:

   1. reintubations, accidental extubations, ETT size, reason for reintubation, ETT blockage.

   2. ventilatory parameters: leakage, duration of leakage, duration of leakage <10% or 20%, percentage time leakage <10% or 20%.

   3. ventilatory complications: pneumothorax, atelectasis, pneumonia, total ventilation time.

   4. postextubation complications: stridor, subglottic stenosis (planned endoscopy), steroids, epinephrine/adrenaline, noninvasive positive pressure ventilation, reintubation for airway, need for airway procedure, death during hospital stay, date of death, cause of death.

   5. long‐term follow‐up: chart review, airway symptoms, laryngoscopy, subglottic stenosis, vocal cord palsy (VCP).

SeeCharacteristics of included studies table for further details.

Excluded studies

We excluded six studies from this Cochrane Review either because they did not include any neonates or because no neonates could be analyzed (Chambers 2018; Chand 2018; Eschertzhuber 2010; Khine 1997; Ozden 2016; Weiss 2009).

See Characteristics of excluded studies table for further details.

Studies awaiting classification

We identified two studies awaiting classification since neonate‐specific data for these pediatric trials were unavailable (Arana 2007; Fernandes 2014).

1. Arana 2007 designed a study to compare postextubation airway morbidity as measured as postextubation stridor after using cuffed ETTs with cuff pressure release valve versus using uncuffed ETTs in children from birth up to five years of age.

2. Fernandes 2014 (abstract only) randomized 285 children under eight years of age admitted to the PICU that required an expected endotracheal intubation for more than eight hours to receive cuffed or uncuffed ETTs.

See Characteristics of studies awaiting classification table for further details.

Ongoing studies

We identified one ongoing study comparing cuffed ETT with uncuffed ETT in children aged from birth to six years (UMIN000017213). See Characteristics of ongoing studies table for further details.

Risk of bias in included studies

The risk of bias for the included study is summarized in Figure 3 and Figure 4.

3.

Risk of bias graph: review authors' judgments about each risk of bias item for the included study.

4.

Risk of bias summary: review authors' judgments about each risk of bias item for the included study.

Allocation

Low risk of selection bias: study used computer‐generated randomization sequences. Participants were stratified as (NICU or PICU) and (medical or surgical). Infants were randomized immediately prior to intubation using sealed, opaque, sequentially numbered envelopes.

Blinding

Unclear bias: no blinding: this may affect subjective outcomes more than objective outcomes (physiologic parameters or mortality).

Incomplete outcome data

Low risk of bias: the study reported stridor in 66/69 infants and subglottic stenosis in 48/69 infants. Reported secondary outcomes were available in all randomized neonates during their stay in the NICU. Airway symptoms at follow‐up were reported in 26 infants randomized to cuffed ETT and 21 randomized to uncuffed ETT.

Selective reporting

Low risk of bias: outcome measures were reported as specified in the registered protocol.

Other potential sources of bias

High risk of bias: a flexible videolaryngoscopy was planned for the time of extubation. Eleven participants had a recorded videolaryngoscopy at extubation. Unfortunately, due to the technical difficulties in obtaining pictures, on expert review, the videos were not of sufficient quality to make firm conclusions. Therefore, the assessment of subglottic stenosis was clinical only.

Three babies randomized to uncuffed ETTs were switched to cuffed ETT: two at the time of intubation and one during ventilation.

Effects of interventions

See: Table 1

We identified one trial the included 69 neonates fitting the criteria for this review (see Table 1; Thomas 2021).

Data were extracted from a spreadsheet with individual data provided by the study author. Tests of heterogeneity were not applicable for any analysis since there was only one study. Due to lack of data, we were unable to carry any of the following comparison groups:

1. cuffed not inflated versus uncuffed;

2. cuffed inflated versus uncuffed; and

3. cuffed inflated versus cuffed not inflated.

Primary outcome

Postextubation airway complication

Stridor

Thomas 2021 reported stridor in 66/69 randomized neonates. We are very uncertain about frequency of postextubation stridor in cuffed ETT versus uncuffed ETT because the CIs of the RR were wide (RR 1.36, 95% CI 0.35 to 5.25; RD 0.03, 95% CI −0.11 to 0.18; 1 study, 69 participants; very low‐certainty evidence; Analysis 1.1; Analysis 1.2). We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. We downgraded one level for serious study limitations and two levels for serious imprecision.

1.1. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 1: Stridor

1.2. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 2: Stridor

Subglottic stenosis

Thomas 2021 reported subglottis stenosis in 48/69 randomized neonates. Since no neonate had clinical evidence of subglottic stenosis, the RR could not be estimated. However, there was no valid information from endoscopy procedures performed after extubation (Analysis 1.3; Analysis 1.4). The certainty of the evidence was very low; we downgraded one level for serious study limitations and two levels for serious imprecision. At medical record review at follow‐up, no participant had developed clinical evidence of subglottic stenosis in either group.

1.3. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 3: Subglottic stenosis

1.4. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 4: Subglottic stenosis

Secondary outcomes

Racemic epinephrine for stridor

We are very uncertain about using racemic epinephrine for stridor because the CIs of the RR were wide (RR 0.27, 95% CI 0.01 to 6.49; RD −0.03, 95% CI −0.11 to 0.05; 1 study, 69 participants; Analysis 1.5; Analysis 1.6).

1.5. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 5: Racemic epinephrine for stridor

1.6. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 6: Racemic epinephrine for stridor

Systemic steroid for stridor

We are very uncertain about using systemic steroid for stridor because the CIs of the RR were wide (RR 3.26, 95% CI 0.38 to 27.72; RD 0.07, 95% CI −0.04 to 0.19; 1 study, 69 participants; Analysis 1.7; Analysis 1.8).

1.7. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 7: Systemic steroid for stridor

1.8. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 8: Systemic steroid for stridor

Reintubation for stridor or subglottic stenosis

We are very uncertain about the risk of reintubation for stridor or subglottic stenosis because the CIs of the RR were wide (RR 0.27, 95% CI 0.01 to 6.49; RD −0.03, 95% CI −0.11 to 0.05; 1 study, 69 participants; Analysis 1.9; Analysis 1.10). We have very little confidence in the effect estimate and the true effect is likely to be substantially different from the estimate of effect; we downgraded one level for serious study limitations and two levels for serious imprecision.

1.9. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 9: Reintubation for stridor or subglottic stenosis

1.10. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 10: Reintubation for stridor or subglottic stenosis

Endoscopy for stridor or subglottic stenosis

Thomas 2021 reported that none of the study participants underwent an airway procedure for stridor. Some underwent endoscopy as part of the protocol and not because of stridor or subglottic stenosis.

Surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis

None of the neonates underwent surgical procedures for stridor or subglottic stenosis (Analysis 1.13; Analysis 1.14). The certainty of the evidence was very low, downgraded one level for serious study limitations and two levels for serious imprecision.

1.13. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 13: Surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis

1.14. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 14: Surgical intervention (e.g. endoscopic balloon dilatation, cricoid split, tracheostomy) for stridor or subglottic stenosis

Reintubation for inadequate endotracheal tube size

Neonates randomized to cuffed ETT group were less likely to have a reintubation to find correct‐sized ETT (RR 0.04, 95% CI 0.00 to 0.64; RD −0.32, 95% CI −0.49 to −0.16; NNTB 3, 95% CI 2 to 6; 1 study, 69 participants; Analysis 1.15; Analysis 1.16).

1.15. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 15: Reintubation for inadequate ETT size

1.16. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 16: Reintubation for inadequate ETT size

Reintubation for any reason

Neonates randomized to cuffed ETT group may be less likely to have re‐intubation for any reason at any time during the ventilation period (RR 0.06, 95% CI 0.01 to 0.45; RD −0.39, 95% CI −0.57 to −0.21; NNTB 3, 95% CI 2 to 5; one study, 69 participants; very low certainty evidence; Analysis 1.17 and Analysis 1.18). We downgraded one level for serious study limitations and two levels for serious imprecision.

1.17. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 17: Reintubation for any reason

1.18. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 18: Reintubation for any reason

Accidental extubation

We are very uncertain about accidental extubation because the CIs of the RR were wide (RR 0.82, 95% CI 0.12 to 5.46; RD −0.01, 95% CI −0.12 to 0.10; 1 study, 69 participants; Analysis 1.19; Analysis 1.20). We downgraded one level for serious study limitations and two levels for serious imprecision.

1.19. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 19: Accidental extubation

1.20. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 20: Accidental extubation

Ventilator‐associated pneumonia

We are very uncertain about ventilator‐associated pneumonia because the CIs of the RR were wide (RR 0.27, 95% CI 0.01 to 6.49; RD −0.03, 95% CI −0.11 to 0.05; 1 study, 69 participants; Analysis 1.21; Analysis 1.22).

1.21. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 21: Ventilator‐associated pneumonia

1.22. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 22: Ventilator‐associated pneumonia

Ventilator‐associated tracheobronchitis (culture of pathogen in tracheal culture with abundant white cells)

Thomas 2021 did not report ventilator‐associated tracheobronchitis.

Air leak around the endotracheal tube (percentage of inspired tidal volume; greater than accepted by the author)

We are very uncertain about air leak around the ETT greater than 20% during the study because the CIs of the RR were wide (RR 1.41, 95% CI 0.93 to 2.16; RD 0.20, RD −0.03 to 0.43; 1 study, 69 participants; Analysis 1.23; Analysis 1.24).

1.23. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 23: Air leak around the ETT (greater than accepted by the author)

1.24. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 24: Air leak around the ETT (greater than accepted by the author)

Pneumothorax

We are very uncertain about pneumothorax because the CIs of the RR were wide (RR 0.27, 95% CI 0.01 to 6.49; RD −0.03, 95% CI −0.11 to 0.05; 1 study, 69 participants; Analysis 1.25; Analysis 1.26).

1.25. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 25: Pneumothorax

1.26. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 26: Pneumothorax

Bronchopulmonary dysplasia/chronic lung disease

Thomas 2021 did not report bronchopulmonary dysplasia/chronic lung disease.

Length of hospital stay (days)

There was no evidence of a difference in length of hospital stay between groups (MD 0.40, 95% CI −7.42 to 8.22; 1 study, 69 participants; Analysis 1.27).

1.27. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 27: Length of stay

All‐cause neonatal mortality

We are very uncertain about all‐cause mortality because the CIs of the RR were wide (RR 2.46, 95% CI 0.10 to 58.39; RD 0.03, 95% CI −0.05 to 0.10; 1 study, 69 participants; Analysis 1.28; Analysis 1.29).

1.28. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 28: All‐cause neonatal mortality

1.29. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 29: All‐cause neonatal mortality

All‐cause mortality during initial hospitalization

We are very uncertain about all‐cause mortality during initial hospitalization because the CIs of the RR were wide (RR 2.46, 95% CI 0.10 to 58.39; RD 0.03, 95% CI −0.05 to 0.10; 1 study, 69 participants; Analysis 1.30; Analysis 1.31). We downgraded one level for serious study limitations and two levels for serious imprecision.

1.30. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 30: All‐cause mortality during initial hospitalization

1.31. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 31: All‐cause mortality during initial hospitalization

Horizontal transmission of aerosolized infections such as COVID‐19 to healthcare workers

Thomas 2021 did not report horizontal transmission of aerosolized infections such as COVID‐19 to HCW. The study assessed airway symptoms at follow‐up in 36 neonates at 35 (SD 5) months of age (cuffed ETT) and 29 neonates at 34 (SD 8) months of age (uncuffed ETT). Airway obstructive symptoms (mild tracheomalacia on endoscopy) were present in 1/26 neonates randomized to cuffed ETT and 0/21 neonates randomized to uncuffed ETT.

Five participants (two from the cuffed ETT group and three from the uncuffed group) later presented with VCP, and each of them had cardiac surgery. All were diagnosed on laryngoscopy, but the exact time point and the symptoms prompting the diagnosis in each case were not identified. Some infants had cardiac surgery at other institutions, some at the institution of the study; of which, some were within days of extubation and some later. At long‐term follow‐up, six neonates had a diagnosis of VCP and all but one had recovered.

Discussion

Summary of main results

We identified one eligible, completed RCT for inclusion that compared the use of cuffed (inflated if ETT leak greater than 20% with cuff pressure of 20 cmH₂O or less) versus uncuffed ETT (Thomas 2021). We are very uncertain if there is any difference in the frequency of postextubation stridor because the CIs of the RR were wide. No neonate was diagnosed with subglottic stenosis; however, endoscopy was not available to confirm the clinical diagnosis.

Neonates randomized to the cuffed ETT group may be less likely to have a reintubation to find a correct sized ETT or reintubation at any time during the ventilation period. We are very uncertain if there is any difference in the frequency of postextubation dexamethasone, postextubation nebulized racemic epinephrine, or reintubation for airway obstruction between the cuffed and uncuffed ETT groups.

For subglottic stenosis and surgical intervention for stridor or subglottic stenosis, the study reported the outcome, but there were no events in either study arm.

Overall completeness and applicability of evidence

We identified one eligible RCT with data for 69 neonates for inclusion in this review, of whom three neonates had a weight less than 3 kg (Thomas 2021). This single‐center RCT was conducted in the NICU and PICU of the Princess Margaret Hospital for Children, Perth (now Perth Children's Hospital), the sole tertiary children's hospital in Western Australia. Mean gestational age was 38.3 (SD 2.0) weeks, birthweight 3340 (SD 508) g, PMA at enrollment 39.2 (SD 2.0) weeks, weight at enrollment 3446 (SD 407) g, and median postnatal age at enrollment one (range 0 to 68, IQR 1 to 7) day. Reason for study intubation was surgery (33 neonates), respiratory (32 neonates), neurological (three neonates), and anesthesia (one neonate). Follow‐up was done by medical record review at a mean of 34.6 (SD 5.3) months (cuffed ETT, 36 neonates) and 33.8 (SD 7.7) months (uncuffed ETT, 29 neonates).

We are very uncertain if there is any difference in the frequency of postextubation stridor. No neonate had clinical evidence of subglottic stenosis. However, endoscopy results were not available to assess the anatomy, therefore, we are uncertain whether any neonates developed asymptomatic subglottic stenosis. Nevertheless, endoscopy is not performed routinely after extubation in current clinical practice. Furthermore, no participant had developed clinical evidence of subglottic stenosis at follow‐up.

Neonates randomized to cuffed ETTs may have fewer reintubations for size and fewer reintubations for any reason.

The ongoing trial will evaluate postextubation inspiratory stridor as a primary outcome in the cuffed and uncuffed ETT groups (UMIN000017213). Secondary outcomes in this trial include:

1. tube exchange;

2. therapy for inspiratory stridor postextubation (nebulized epinephrine or CPAP, or both);

3. time from extubation to leaving recovery room;

4. "impaired airway track" due to intubation (laryngospasm or tracheal hemorrhage);

5. reintubation;

6. unexpected ICU admissions due to airway issues;

7. need for oxygen at the time of leaving the recovery room;

8. residual inspiratory stridor at the time of leaving the recovery room.

Quality of the evidence

There is very low certainty evidence for all the outcomes of this review. This is because of possible bias due to lack of blinding and other bias and because of wide CIs due to the small sample size for all outcomes (Table 1).

Potential biases in the review process

We did not search Embase separately, therefore, the retrieval of available studies on ETT may have been reduced. While trial records from Embase are included in CENTRAL, we acknowledge a publishing delay from when study records are first available in their original sources and when they are available in CENTRAL. This publishing delay may have prevented recent trial records and reports from being identified. Further, searching only CENTRAL for records from this source may have lessened the likelihood of retrieving eligible studies due to the limited number of fields that are published to CENTRAL compared to the original source database. For future updates of this review, we will search Embase separately to ensure maximum retrieval of eligible study records.

We minimized any potential biases through the strict criteria for considering studies for inclusion in this review. We excluded studies based on the lack of availability of neonate‐specific data, or if neonates were excluded from the study population.

Agreements and disagreements with other studies or reviews

Results in this review are similar to those in children. Two systematic reviews in children found no difference in stridor between cuffed and uncuffed ETTs (De Orange 2017; Shi 2016). De Orange 2017 found statistically significantly lower rate of ETT exchange in the cuffed ETT group.

We excluded three studies on infants from this Cochrane Review because they did not include neonates.

1. Chand 2018 showed that micro‐cuff pediatric ETTs are associated with significantly lower incidence of stridor, tube changes, and anesthetic gas requirement. This led to significant cost reduction that offset the higher costs associated with use of cuffed ETTs.

2. Khine 1997 demonstrated that the use of cuffed ETTs avoided repeated laryngoscopy, used less fresh gas flow, and reduced the concentration of anesthetics detectable in the operating room. They concluded that cuffed ETTs may be used routinely during controlled ventilation in full‐term newborns and children during anesthesia. However, no neonates were included in this study (confirmed by email with the author).

3. Ozden 2016 found no significant differences in number of intubation attempts, gastric insufflation, airway pressures, hemodynamic parameters, laryngospasm, coughing, bleeding, treatment of stridor, or desaturations in uncuffed versus cuffed ETTs. They did demonstrate significant differences in leak volume and leak fractions between uncuffed and cuffed ETTs.

Two related systematic reviews in children have been published.

Shi 2016 is a systematic review comparing cuffed ETT with uncuffed ETT in children. The analysis included two RCTs and two prospective cohort studies including 3782 participants (1979 participants received cuffed tubes and 1803 participants received for uncuffed tubes). The authors found that the use of cuffed ETTs had no effect on the incidence of postextubation stridor (RR 0.88, 95% CI 0.67 to 1.16; P = 0.36), and the ETT exchange rate was lower in participants receiving cuffed tubes intubation (RR 0.07, 95% CI 0.05 to 0.10; P < 0.00001). The need for reintubation following planned extubations and duration of tracheal intubation did not differ between the cuffed tube group and the uncuffed ETT group.

De Orange 2017 is a Cochrane Review comparing cuffed ETT with uncuffed ETT for general anesthesia in children. Two trials comparing cuffed versus uncuffed ETTs found no difference between the groups for postextubation stridor (RR 0.93, 95% CI 0.65 to 1.33; 2734 children; very low‐certainty evidence). However, those two trials demonstrated a lower rate of ETT exchange in the cuffed ETT group (RR 0.07, 95% CI 0.05 to 0.10; 2734 children; very low‐certainty evidence). There was no clear evidence to suggest a difference between cuffed and uncuffed tubes for outcomes such as the need to treat postextubation stridor with tracheal reintubation (RR 1.85, 95% CI 0.17 to 19.76; 2 RCTs, 115 children; very low‐certainty evidence), need for epinephrine (RR 0.70, 95% CI 0.38 to 1.28; 2 RCTs, 115 children; very low‐certainty evidence), need for corticosteroid (RR 0.87, 95% CI 0.51 to 1.49; 1 RCT, 102 children; very low‐certainty evidence), or need for ICU admission to treat postextubation stridor (RR 2.77, 95% CI 0.30 to 25.78; 1 trial, 102 children; very low‐certainty evidence).

Authors' conclusions

Implications for practice.

Evidence for comparing cuffed versus uncuffed endotracheal tubes (ETTs) in neonates is limited by a small number of babies in one RCT with possible bias. There is very low‐certainty evidence for all outcomes of this review. The confidence intervals of the estimate for postextubation stridor were wide. No neonate had clinical evidence for subglottic stenosis; however, endoscopy results were not available to assess the anatomy.

Implications for research.

Neonatal data from a single study included in this review are encouraging for neonates and support the performance of further trials in neonates. The additional RCTs are necessary to fully evaluate the benefits and harms of cuffed ETTs (inflated and non‐inflated) in the neonatal population. These studies must include neonates eligible for cuffed ETTs (currently weighing 3 kg or greater) and be conducted both for short‐term use (in the setting of the operating room) and chronic use (for chronic lung disease) of cuffed ETTs. Observational studies are needed to assess the range of leaks that is associated with the best outcomes in neonates on artificial ventilation.

History

Protocol first published: Issue 9, 2020

Appendices

Appendix 1. Search strategies

August/September 2021 search strategies

PubMed, 20 August 2021

#1 ("intubation, intratracheal"[MeSH Terms] OR endotracheal* OR tracheal* OR intratracheal*) 107,477

#2 ("infant, Newborn"[Mesh] OR newborn* OR "new born" OR "new borns" OR "newly born" OR baby*[TIAB] OR babies[TIAB] OR premature OR prematures OR prematurity OR preterm OR preterms OR "pre term" OR “low birth weight” OR “low birthweight” OR vlbw[TIAB] OR lbw[TIAB] OR neonat*[TIAB] OR infan*[TIAB]) 1,299,555

#3 (tube OR tubes OR cuffed OR uncuffed)) 214,763

#4 #1 AND #2 AND #3 2,492

#5 #4 NOT ((animals [mh] NOT humans [mh])) 2,364

#6 #5 AND (("2020/09/28"[Date ‐ Entry]: "3000"[Date ‐ Entry])) 94

CINAHL Complete via EBSCOhost, 20 August 2021

S1	infant or infants or infant's or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW	535,003
S2	(MH "Intubation, Intratracheal+") OR endotracheal* OR tracheal* OR intratracheal*	26,185
S3	tube OR tubes OR cuffed OR uncuffed	34,612
S4	(S1 AND S2 AND S3)	1,115
S5	Limit: Published Date: 20200601‐20211231	67

CENTRAL via Cochrane Library, 2021, Issue 8

#1 MeSH descriptor: [Infant, Newborn] explode all trees 16,573

#2 (infant or infants or infant's or “infant s” or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW or NICU) :ti,ab,kw 93,094

#3 #1 OR #2 93,094

#4 MeSH descriptor: [Intubation, Intratracheal] explode all trees 4,518

#5 (endotracheal* OR tracheal* OR intratracheal*):ti,ab,kw 14,399

#6 #4 OR #5 14,936

#7 (tube OR tubes OR cuffed OR uncuffed) :ti,ab,kw 20,014

#8 #3 AND #6 AND #7 610

#9 Limit to last year 44

Number of hits from all databases: 205

Number after deduplication 176

ClinicalTrials.gov, 22 September 2021

Advanced search – Other terms: cuffed OR uncuffed OR "tracheal tubes" OR "tracheal tube" OR "endotracheal tube" OR "endotracheal tubes"

Trial status: Recruiting, Not yet recruiting, Active, not recruiting, Enrolling by invitation Studies

Age filter: children

Number of hits: 69

WHO ICTRP portal, 22 September 2021

Advances search – Title: cuffed OR uncuffed OR "tracheal tube" OR "tracheal tubes" OR "endotracheal tube" OR "endotracheal tubes"

Filter: trials in children

Recruitment status: All

Number of hits: 157

ISRCTN, 22 September 2021

Simple search: cuffed OR uncuffed OR "tracheal tube" OR "tracheal tubes" OR "endotracheal tube" OR "endotracheal tubes"

Filters: age range Neonate

Number of hits: 68

September 2020 search strategies

PubMed, 28 September 2020

#1 ("intubation, intratracheal"[MeSH Terms] OR endotracheal* OR tracheal* OR intratracheal*) 103,567

#2 ("infant, Newborn"[Mesh] OR newborn* OR "new born" OR "new borns" OR "newly born" OR baby*[TIAB] OR babies[TIAB] OR premature OR prematures OR prematurity OR preterm OR preterms OR "pre term" OR “low birth weight” OR “low birthweight” OR vlbw[TIAB] OR lbw[TIAB] OR neonat*[TIAB] OR infan*[TIAB]) 1,250,158

#3 (tube OR tubes OR cuffed OR uncuffed)) 205,764

#4 #1 AND #2 AND #3 2,380

#5 #4 NOT ((animals [mh] NOT humans [mh])) 2,256

CINAHL via EBSCO, 28 September 2020

S1	infant or infants or infant's or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW	507,552
S2	(MH "Intubation, Intratracheal+") OR endotracheal* OR tracheal* OR intratracheal*	24,909
S3	tube OR tubes OR cuffed OR uncuffed	32,757
S4	(S1 AND S2 AND S3)	1,059

CENTRAL via Cochrane Library, 2020, Issue 9

#1 MeSH descriptor: [Infant, Newborn] explode all trees 15,787

#2 (infant or infants or infant's or “infant s” or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW or NICU) :ti,ab,kw 86,933

#3 #1 OR #2 86,933

#4 MeSH descriptor: [Intubation, Intratracheal] explode all trees 4,358

#5 (endotracheal* OR tracheal* OR intratracheal*):ti,ab,kw 13,271

#6 #4 OR #5 13,791

#7 (tube OR tubes OR cuffed OR uncuffed) :ti,ab,kw 18,251

#8 #3 AND #6 AND #7 569

Number of hits from all databases: 3,884

*Searches performed by Matthias Bank, Lund University, Faculty of Medicine, Library & ICT

Appendix 2. Risk of bias tool

Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorized the method used to generate the allocation sequence as:

1. low risk (any truly random process, e.g. random number table; computer random number generator);

2. high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

3. unclear risk.

Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorized the method used to conceal the allocation sequence as:

1. low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

2. high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

3. 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 categorized the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorized the methods as:

1. low risk, high risk, or unclear risk for participants; and

2. 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 categorized the methods used to blind outcome assessment. Blinding was assessed separately for different outcomes or class of outcomes. We categorized the methods as:

1. low risk for outcome assessors;

2. high risk for outcome assessors; or

3. unclear risk for outcome assessors.

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 described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we reincluded missing data in the analyses. We categorized the methods as:

1. low risk (< 20% missing data);

2. high risk (≥ 20% missing data); or

3. unclear risk.

Selective reporting bias. Were reports of the study free of suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we compared prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we contacted study authors to gain access to the study protocol. We assessed the methods as:

1. low risk (where it was clear that all the study's prespecified outcomes and all expected outcomes of interest to the review were reported);

2. 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); or

3. 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 described 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 assessed whether each study was free of other problems that could have put it at risk of bias as:

1. low risk;

2. high risk; or

3. unclear risk.

If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.

Data and analyses

Comparison 1. Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Stridor	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.2 Stridor	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.11, 0.18]
1.3 Subglottic stenosis	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4 Subglottic stenosis	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.06, 0.06]
1.5 Racemic epinephrine for stridor	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.01, 6.49]
1.6 Racemic epinephrine for stridor	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.03 [‐0.11, 0.05]
1.7 Systemic steroid for stridor	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	3.26 [0.38, 27.72]
1.8 Systemic steroid for stridor	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.07 [‐0.04, 0.19]
1.9 Reintubation for stridor or subglottic stenosis	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.01, 6.49]
1.10 Reintubation for stridor or subglottic stenosis	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.03 [‐0.11, 0.05]
1.11 Endoscopy for stridor or subglottic stenosis	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.12 Endoscopy for stridor or subglottic stenosis	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.06, 0.06]
1.13 Surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.14 Surgical intervention (e.g. endoscopic balloon dilatation, cricoid split, tracheostomy) for stridor or subglottic stenosis	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.06, 0.06]
1.15 Reintubation for inadequate ETT size	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.00, 0.64]
1.16 Reintubation for inadequate ETT size	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.32 [‐0.49, ‐0.16]
1.17 Reintubation for any reason	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.01, 0.45]
1.18 Reintubation for any reason	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.39 [‐0.57, ‐0.21]
1.19 Accidental extubation	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.12, 5.46]
1.20 Accidental extubation	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.12, 0.10]
1.21 Ventilator‐associated pneumonia	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.01, 6.49]
1.22 Ventilator‐associated pneumonia	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.03 [‐0.11, 0.05]
1.23 Air leak around the ETT (greater than accepted by the author)	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.93, 2.16]
1.24 Air leak around the ETT (greater than accepted by the author)	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.20 [‐0.03, 0.43]
1.25 Pneumothorax	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.01, 6.49]
1.26 Pneumothorax	1	69	Risk Difference (M‐H, Fixed, 95% CI)	‐0.03 [‐0.11, 0.05]
1.27 Length of stay	1	69	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐7.42, 8.22]
1.28 All‐cause neonatal mortality	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	2.46 [0.10, 58.39]
1.29 All‐cause neonatal mortality	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.05, 0.10]
1.30 All‐cause mortality during initial hospitalization	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	2.46 [0.10, 58.39]
1.31 All‐cause mortality during initial hospitalization	1	69	Risk Difference (M‐H, Fixed, 95% CI)	0.03 [‐0.05, 0.10]

1.11. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 11: Endoscopy for stridor or subglottic stenosis

1.12. Analysis.

Comparison 1: Cuffed (inflated or not) versus uncuffed endotracheal tube (ETT), Outcome 12: Endoscopy for stridor or subglottic stenosis

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Thomas 2021.

Study characteristics
Methods	Single center RCT Setting: NICU and PICU of Princess Margaret Hospital for Children, Perth (now Perth Children’s Hospital), the sole tertiary children's hospital in Western Australia Recruitment: 76 infants recruited between February 2015 and August 2016. 69 infants were included in our analysis (7 infants (5 randomized to uncuffed ETT and 2 to cuffed ETT) were excluded as enrolled with a weight < 3 kg) Randomization was consistent whether intubation was done prior to parental consent or emergently (parental consent done after) (personal communication with the author).
Participants	Inclusion criteria: neonates ≥ 35 weeks' gestation and infants up to 3 months who weighed ≥ 3 kg and required mechanical ventilation and intubation for mechanical ventilation expected to be for ≥ 12 hours. Exclusion criteria: infants who were ex‐preterm infants < 32 weeks' gestation at birth and previously intubated, had a suspected airway abnormality, or infants being intubated prior to air retrieval. Among the 69 eligible infants who met the predefined age criterion for this Cochrane Review: mean gestational age 38.3 (SD 2.0) weeks (range 31 weeks 3 days to 41 weeks 3 days) birthweight 3340 (SD 508) g (range 1440–4459 g) postmenstrual age at enrollment 39.2 (SD 2.0) weeks weight at enrollment 3446 (SD 407) g (range 2800–4459 g) median postnatal age at enrollment 1 day (IQR 1–7 days, range 0–68 days) reason for study intubation was surgery (33 neonates), respiratory (32 neonates), neurologic (3 neonates) and anesthesia (1 neonate) total ventilation time similar in both groups (median: 63 hours, IQR 37–100 for cuffed ETT vs 72 hours, IQR 37–91 for uncuffed ETT; P = 0.90) Follow‐up: by medical record review at a mean of 34.6 (SD 5.3) months (cuffed ETT, 36 neonates) and 33.8 (SD 7.7) months (uncuffed ETT, 29 neonates).
Interventions	Group 1: 38 infants intubated with cuffed ETT (Avanos Microcuff) Group 2: 31 infants intubated with uncuffed ETT (Smiths Medical Portex) Infants were randomized to ETT for the duration of mechanical ventilation.
Outcomes	Primary outcome Achievement of optimal ETT leak in target range (10–20%). Secondary outcomes Reintubations, accidental extubations, ETT size, reason for reintubation, ETT blockage Ventilatory parameters: leakage, duration of leakage, duration of leakage < 10% or < 20%, percentage time leakage < 10% or < 20% Ventilatory complications: pneumothorax, atelectasis, pneumonia, total ventilation time Postextubation complications: stridor, subglottic stenosis (planned endoscopy), steroids, epinephrine, non‐invasive positive pressure ventilation, reintubation for airway, need for airway procedure, death during hospital stay, date of death, cause of death Long‐term follow‐up; chart review, airway symptoms, laryngoscopy, subglottic stenosis, vocal cord palsy
Notes	Funding: Rebecca Thomas (first author) received a fully funded Telethon Fellowship to carry out this project.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Low risk: computer‐generated randomization sequences were used. Participants were stratified as (NICU or PICU) and (medical or surgical).
Allocation concealment (selection bias)	Low risk	Infants were randomized immediately prior to intubation via sealed, opaque, sequentially numbered envelopes.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No blinding; this may affect subjective outcomes more than objective outcomes (physiologic parameters or mortality).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No blinding; this may affect subjective outcomes more than objective outcomes (physiologic parameters or mortality).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Stridor was reported in 66/69 infants and subglottic stenosis in 48/69 infants. Reported secondary outcomes were available in all randomized neonates during their stay in the NICU. Airway symptoms at follow‐up were reported in 26 infants randomized to cuffed ETT and 21 randomized to uncuffed ETT.
Selective reporting (reporting bias)	Low risk	Outcome measures were reported as specified in the registered protocol.
Other bias	High risk	A flexible videolaryngoscopy was planned for the time of extubation. 11 participants had a recorded videolaryngoscopy at extubation. Due to technical difficulties in obtaining pictures, on expert review, no video was of sufficient quality from which to make firm conclusions. Therefore, the assessment of subglottic stenosis was clinical only. 3 infants randomized to uncuffed ETTs were switched to cuffed ETT: 2 immediately after intubation and 1 during ventilation.

ETT: endotracheal tube; NICU: neonatal intensive care unit; PICU: pediatric intensive care unit; RCT: randomized controlled trial.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Chambers 2018	Neonate‐specific data unavailable for review and analysis (confirmed via email communication with study authors in March 2021).
Chand 2018	The youngest participant was 4 months old and there were no preterm babies (confirmed via email communication with Dr Narayan in January 2021).
Eschertzhuber 2010	Neonate‐specific data unavailable for review and analysis (confirmed via email communication with study authors in March 2021).
Khine 1997	Newborns were excluded from the study (confirmed via email communication with study author in March 2021).
Ozden 2016	No neonates included in the study.
Weiss 2009	Neonate‐specific data unavailable for review and analysis (confirmed via email communication with study authors in March 2021).

Characteristics of studies awaiting classification [ordered by study ID]

Arana 2007.

Methods	Primary aim was to compare postextubation airway morbidity as measured as postextubation stridor after using cuffed tracheal tubes with cuff pressure release valve vs using uncuffed tubes in children aged 0–5 years.
Participants	Inclusion criteria: aged from birth (weighing ≥ 3 kg) to < 5 years of age; requiring oro‐tracheal or naso‐tracheal intubation as a part of their anesthetic care and planned ventilatory support during the surgical, interventional, or diagnostic procedure; tracheal intubation performed using direct laryngoscopy; extubation after the procedure in the operating theater; procedure performed in the supine position; patients for elective and emergency surgery or interventions if there was no risk of regurgitation or pulmonary aspiration ASA 1 and 2 patients (i.e. normal or mild systemic disease); written parental consent.
Interventions	Group 1: intubated with cuffed ETT Group 2: intubated with uncuffed ETT
Outcomes	Not available
Notes	Outcome data unavailable for review and analysis (unable to contact primary contact for the study)

Fernandes 2014.

Methods	Between March 2010 to April 2013 all children under 8 years of age admitted to the PICU that required an expected endotracheal intubation for > 8 hours were randomized to receive cuffed or uncuffed ETTs. Exclusion criteria were applied. Postintubation laryngitis was defined as a Downes and Raphaelly score ≥ 4. Extubation failure was defined as a score > 7 or need for reintubation
Participants	Children under 8 years of age admitted to the PICU that required an expected endotracheal intubation for more than 8 hours
Interventions	Group 1: intubated with cuffed ETT Group 2: intubated with uncuffed ETT
Outcomes	Postextubation complications and need for reintubation based on objective clinical score were addressed. There were 136 participants for the cuffed group and 118 for the uncuffed group included in the study. Incidence of postintubation laryngitis of 58.8% in the cuffed tube group and 62.7% in the uncuffed tube group (P = 0.52). Extubation failure (defined as a score > 7 or need for reintubation) occurred in 8.8% of children in the cuffed group and 9.3% in the uncuffed group (P = 0.89). Multivariate analysis found that the tube type was not associated with postintubation laryngitis (P = 0.83) or extubation failure (P = 0.88).
Notes	Neonate‐specific data unavailable for review and analysis. Unable to contact any of the study authors.

ASA: American Society of Anesthesiologists; ETT: endotracheal tube; PEEP: positive end‐expiratory pressure; PICU: pediatric intensive care unit.

Characteristics of ongoing studies [ordered by study ID]

UMIN000017213.

Study name	Cuffed vs uncuffed endotracheal tube – randomized controlled trial in pediatric patients younger than 6‐year‐old including neonates at single institute
Methods	RCT
Participants	Aged 0–6 years old undergoing elective surgery or examination requiring endotracheal intubation for general anesthesia
Interventions	Group 1: intubated with cuffed tracheal tube (microcuffed tube/Halyard Healthcare, Inc.) Group 2: intubated with uncuffed tracheal tube (PORTEX tube/Smiths Medical)
Outcomes	Primary outcomes Presence of inspiratory stridor after extubation in operation room or recovery room (or both) Key secondary outcomes Tube exchange Therapy for inspiratory stridor after extubation (nebulized epinephrine or CPAP, or both) Time from extubation to leaving recovery room "Impaired airway track" due to intubation itself (laryngospasm or tracheal hemorrhage, or both) Reintubation Unexpected ICU admission due to airway problems Need for oxygen at the time of leaving recovery room Residual inspiratory stridor at the time of leaving recovery room Experimental endpoints Accidental 1 lung ventilation Adjustment of tube position after intubation Reliability of end‐tidal carbon dioxidewave Need for fresh gas flow > 4 L/minute Adjustment of cuff pressure due to accidental change in cuff pressure (Group 1) Change in length of tube position ≥ 1 cm Need for pharyngeal gauze packing Inappropriate location of tube tip detected with chest X‐ray
Starting date	23 April 2015
Contact information	Yasuhiro Kogure Organization: National Center for Child Health and Development Division: Department of intensive care and anesthesia Address: 2‐10‐1 Okura, Setagaya Tokyo 157‐8535, Japan TEL: +81‐3‐3416‐0181 Email: kogure‐y@ncchd.go.jp
Notes	Unable to contact study authors. No response from UMIN Clinical Trials Registry by 21 April 2021.

ICU: intensive care unit; RCT: randomized controlled trial.

Differences between protocol and review

We made the following changes to the published protocol (Dariya 2020).

1. We added the description of the Cochrane's Screen4Me workflow.

2. We replaced 'need for ETT exchange to yield a good fit' with 'reintubation for stridor/subglottic stenosis' and 'reintubation for any reason' for GRADE assessment and inclusion in the summary of findings table.

3. We decided to remove 'weighing less than 3 kg at enrollment' as an exclusion criterion because of increasing use of cuffed ETT in neonates within that range.

Contributions of authors

VD and LPB reviewed the background literature and wrote the review.

LM and MB commented on and reviewed the review.

All authors read and approved the final version.

Sources of support

Internal sources

• Institute for Clinical Sciences, Lund University, Lund, Sweden

  MB is employed by this organization

External sources

• Vermont Oxford Network, USA

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

• Region Skåne, Skåne University Hospital, Lund University and Region Västra Götaland, Sweden, Sweden

  Cochrane Sweden is supported from Region Skåne, Skåne University Hospital Lund University and Region Västra Götaland

Declarations of interest

VD: none.

LM: none.

MB received public funding (not related to Cochrane work) from Skåne University Hospital, Lund, Sweden.

LPB has received funding from the National Institutes of Health, from the Gerber Foundation, and from the Children's Medical Center Foundation in Dallas TX for unrelated research and is employed by the University of Texas Southwestern at Dallas, Texas, USA.

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