Exhaled CO2 to guide non-invasive ventilation at birth: NLS 5350; TFSR

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Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none

The following Task Force members and other authors declared an intellectual conflict of interest, and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees:
Tetsuya Isayama has been helping the company NIHON KODEN to develop a respiratory functioning monitoring (RFM) device for neonatal resuscitation. The RFM device does not have a CO2 detector, which the PICOST assessed.

Georg Schmölzer has written several papers on exhaled CO2 in the delivery room, including two studies analyzed in this review {Kang 2014 e102729; Ngan 2017 F525}, and he was excluded from decisions about these studies.

These authors acknowledged their potential intellectual conflicts of interest and participated in the Task Force discussion of the consensus on science and treatment recommendations.

CoSTR Citation

Solevåg AL, Monnelly VJ, Josephsen JB, Isayama T, de Almeida MF, Guinsburg R, Costa-Nobre DT, Davis PG, El-Naggar W, Fabres JG, Fawke J, Foglia EE, Kawakami MD, Lee HC, Madar RJ, McKinley CJD, Nakwa FL, Ruediger M, Schmölzer GM, Sugiura T, Trevisanuto D, Perlman JM, Wyllie JP, Rabi Y, Wyckoff MH, Weiner GM, Liley HG. Exhaled CO2 to Guide Ventilation at Birth Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2022 December 20. Available from:

Methodological Preamble and Link to Published Systematic Review

Exhaled CO2 application immediately after birth has been reviewed by ILCOR with the focus on the correct placement of an endotracheal tube {ILCOR 2006 e-978; Perlman 2010 S516; Perlman 2015 S204}. In 2010, ILCOR reviewed the use of colorimetric CO2 detection to assess ventilation in non-intubated, bradycardic neonates and made the following treatment recommendation: there is insufficient evidence to recommend routine use of colorimetric exhaled CO2 detectors during mask ventilation of newborns in the delivery room {Perlman 2010 S516}.

However, quantitative, and qualitative analysis of exhaled CO2 is being used in some centers to guide mask ventilation of preterm infants at birth {Blank 2014 1568; Blank 2018 1; Finer 2009 865; Hawkes 2017 74; Kakkilaya 2019 e20180201; Kong 2013 104;}. The rationale for this use is that exhaled CO2 may provide useful information related to potential airway obstruction {Finer 2009 865; Leone 2006 e202} or problems with lung aeration {Hooper 2013 e70895}, but there are concerns related to the dead space introduced into the ventilatory circuit {Brown 2016 1003} and the reliability of colorimetric devices {Blank 2014 1568}.

In this context, a search for evidence for utilizing exhaled CO2 to guide non-invasive positive pressure ventilation immediately after birth was performed. The continuous evidence evaluation process for the creation of Consensus of Science and Treatment Recommendations (CoSTR) started with a systematic review (PROSPERO 2022 CRD 42022344849) conducted by Anne Lee Solevåg, Vix Monnelly, Justin Josephsen, Tetsuya Isayama, Maria Fernanda de Almeida, and Ruth Guinsburg. Evidence from neonatal literature was sought and considered by the Neonatal Life Support Task Force and clinical content experts. These data were taken into account when formulating the Treatment Recommendations.

Systematic Review

Monnelly VJ, Josephsen JB, Solevåg AL, Isayama T, de Almeida MF, Guinsburg R, Schmölzer GM, Rabi Y, Wyckoff MH, Weiner GM, Liley HG; on behalf of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Exhaled CO2 monitoring to guide ventilation with non-invasive interfaces at birth: a systematic review. To be submitted


Population: Newborn infants receiving intermittent positive pressure ventilation (IPPV) by any non-invasive interface at birth

Intervention: Use of exhaled CO2 monitor in addition to clinical assessment, pulse oximetry and/or electrocardiogram (ECG)

Comparison: Clinical assessment, pulse oximetry and/or ECG only

Outcomes: The pre-specified primary outcome was endotracheal intubation in the delivery room. The secondary outcomes were divided as follows: 1) Resuscitation outcomes at birth: survival to neonatal intensive care unit (NICU) admission (critical); time to heart rate >100 bpm (important); duration of IPPV (important); use of IPPV corrective actions (important); and use of chest compressions (important); 2) Other major morbidities: survival to hospital discharge (critical); bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage (IVH) and periventricular leukomalacia (all three important) in infants born at <34 weeks’ gestation; and unexpected admission to special or intensive care unit (important) in infants born at ≥34 weeks’ gestation.

Outcomes ratings using the GRADE classifications of critical or important were decided according to a consensus for international neonatal resuscitation guidelines {Strand 2020 328}. Outcomes were converted into main outcomes and additional outcomes for submission to PROSPERO (CRD42022344849).

Potential subgroups were defined a priori: methods of exhaled CO2 evaluation (capnography, capnometry, and colorimetric devices); non-invasive interfaces for IPPV (facemasks, supraglottic airways, and nasal cannulae); indication for IPPV (apnea/irregular respirations and/or bradycardia), and gestational age (<280/7; 280/7 -336/7; and 340/7 or more weeks).

Study Design: Randomized controlled trials (RCTs) and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, and cohort studies) were eligible for inclusion. Case series, case reports, animal studies and unpublished studies (conference abstracts, trial protocols) were excluded.

Timeframe: All years and all languages were included provided there was an English abstract. The literature was first searched on May 13, 2022 and updated on August 1, 2022.


  • Intermittent positive pressure ventilation (IPPV): Intermittent delivery of air or a mixture of oxygen and air by positive pressure into the lungs
  • Non-invasive interfaces: Interfaces used to deliver IPPV other than tracheal tube such as facemasks, supraglottic airways, and nasal cannulae
  • Exhaled CO2 monitor: Device that measures CO2 providing quantitative (waveform capnography or capnometry) or qualitative information (colorimetric devices)

PROSPERO registration: 2022 CRD 42022344849

Risk of Bias:

It was planned to use the GRADE approach {Guyatt 2008 924} to determine the certainty in evidence for each outcome deemed critical or important with the relevant risk of bias instrument: Cochrane risk of bias tool 2 for RCTs or Robbins I for observational studies {Sterne 2016 i4919}.

Consensus on Science

A search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials identified 2386 references. After de-duplication, 2370 titles and abstracts were reviewed. Full text review was conducted for 23 papers. No studies were identified which addressed the PICOST question.

Although no eligible studies were identified, those ineligible studies that may provide useful data relevant to non-invasive IPPV and CO2 monitoring immediately after birth were summarized. Twenty-three studies discussed data on exhaled CO2 in infants receiving IPPV at birth by facemask, but none of them had a comparator group of infants receiving IPPV without exhaled CO2 monitoring {Blank 2014 1568; Blank 2018 1; Ersdal 2020 71; Finer 2009 865; Hawkes 2016 F62; Hawkes 2017 74; Holte 2019 e000544; Holte 2020 e20200494; Holte 2021 121; Hooper 2013 e70895; Hunt 2019 17; Hunt 2019 665; Kang 2014 e102729; Kong 2013 104; Linde 2018 1; Mizumoto 2015 186; Murthy 2012 783; Murthy 2015 235; Ngan 2017 F525; Pahuja 2018 1617; Palme-Kilander 1993 11; Thallinger 2017 66; van Vonderen 2015 F514}. In eight of these studies, CO2 presence or values were available to providers {Blank 2014 1568; Blank 2018 1; Finer 2009 865; Hawkes 2017 74; Kang 2014 e102729; Kong 2013 104; Mizumoto 2015 186; Ngan 2017 F525}. The main topics covered by these eight studies were: 1) Exhaled CO2 and airway obstruction; 2) Exhaled CO2 to assess lung aeration; 3) Exhaled CO2 as a predictor of increase in heart rate (HR); and 4) Exhaled CO2 and pCO2 at NICU admission.

  • Exhaled CO2 and airway obstruction:
  • Finer et al {Finer 2009 865} reviewed data from 18 infants with GA <32 weeks’ gestation that received IPPV by facemask from a trial that randomly assigned patients to resuscitation with room air or 100% oxygen. Colorimetric CO2 detectors were used to assist with IPPV in all patients. These 18 infants received a median of 14 (range: 4-37) consecutive obstructed breaths delivered over a median duration of 45 seconds (range 10-220) diagnosed by no color change in the CO2 detector. The interventions to correct the obstruction included repositioning of the head (n=10), checking the mask seal (n=5), a new operator (n=2), and increasing the pressure (n=1). The authors concluded that the use of a colorimetric detector provides the resuscitation team with a visible signal that can indicate airway patency.
  • Blank et al {Blank 2014 1568} reviewed the data of 41 preterm infants with bradycardia receiving PPV with T-piece and facemask at birth. All infants were monitored with colorimetric CO2 detectors. Although assessing airway obstruction and ventilation corrective actions was not the aim of the study, ventilation corrective actions were reported. The interventions performed preceding the change of color of the CO2 detector were increasing the inspiratory pressure (37%) and readjusting the position of the infant’s airway or the position of the mask (24%).
  • Exhaled CO2 to assess lung aeration:
  • Kang et al {Kang 2014 e102729} performed a pilot study in 51 infants <37 weeks’ gestation and found that those on CPAP (n=31) had higher exhaled CO2 values with lower tidal volumes compared to infants who received IPPV by T-piece and facemask (n=20). The authors concluded that exhaled CO2 monitoring confirms that infants maintained on CPAP achieve better gas exchange (resulting from sufficient lung aeration) than infants requiring IPPV.
  • Ngan et al {Ngan 2017 F525} randomized infants <33 weeks’ gestation to IPPV (n=86) or a 20-second sustained inflation (n=76) with facemask at birth. Exhaled CO2 increased more rapidly after the sustained inflation. The authors concluded that sustained inflation resulted in better lung aeration compared with IPPV.
  • Blank {Blank 2018 1} used exhaled CO2 to determine lung aeration prior to umbilical cord clamping in 44 infants >32 weeks’ gestation. A T-piece with facemask was used in infants needing respiratory support, and gold/yellow color change (colorimetric devices) or an exhaled CO2-value >15 mmHg (quantitative) was used as a measure of established gas exchange. The authors concluded that it is feasible to provide resuscitation and monitor infants during delayed cord clamping using physiologic targets to indicate when the infant is ready for umbilical cord clamping.
  • Exhaled CO2 as a predictor of increase in HR in initially bradycardic infants:
  • Blank et al {Blank 2014 1568} reviewed the data of 41 preterm infants with bradycardia receiving IPPV with T-piece and facemask at birth. All infants were monitored by colorimetric CO2 detection. The median heart rate 10 seconds prior to CO2 detector color change was 75 bpm (IQR 62-85) and increased to 136 bpm (IQR 113-158) 30 seconds after color change. The authors concluded that colorimetric CO2 detection during mask IPPV at birth precedes a significant increase in HR.
  • Mizumoto et al {Mizumoto 2015 186} evaluated seven infants ventilated with flow-inflating bag and facemask. They found that an exhaled CO2 >15mmHg preceded a HR increase to >100 bpm by 8-73 seconds.
  • Exhaled CO2 and pCO2 at NICU admission:
  • Kong et al {Kong 2013 104} randomized infants <34 weeks’ gestation to receive respiratory support with continuous exhaled CO2 values being visible (n=18) or not visible (n=19) to the resuscitation team at birth. All infants had a colorimetric CO2 detector during ventilation with T-piece and facemask. Guiding delivery room ventilation with continuous exhaled CO2 measurement did not result in more infants having the admission pCO2 within the recommended range of 40-60 mmHg.
  • Hawkes et al {Hawkes 2017 74} randomized 59 infants <32 weeks’ gestation receiving IPPV by T-piece and facemask to be monitored with quantitative (n=33) or qualitative (n=26) exhaled CO2. Health care providers were instructed to make ventilation corrective actions to prevent airway obstruction whenever exhaled CO2 could not be detected. There was no difference in the rate of the admission pCO2 within the target range between the two groups. Due to the lack of differences between study groups in primary or secondary outcomes, the authors concluded that the use of either form of exhaled CO2 monitoring should be considered during newborn stabilization.

No data were found on pre-specified subgroups: methods of exhaled CO2 evaluation, types of non-invasive interface used in IPPV, indications of IPPV, and gestational age.

Treatment Recommendations

There is insufficient evidence to suggest for or against the use of exhaled CO2 to guide IPPV with non-invasive interfaces, such as facemasks, supraglottic airways, and nasal cannulae in newborns immediately after birth.

Justification and Evidence to Decision Framework Highlights

In making this recommendation for newborns receiving non-invasive IPPV in the delivery room, the Task Force considered that there were no studies reporting outcomes comparing active CO2 monitoring to guide IPPV with non-invasive interfaces to a group not using CO2 monitoring. Therefore efficacy, effectiveness, and safety of exhaled CO2 monitoring when being used via non-invasive devices could not be assessed.

The eight studies that reported data on infants receiving IPPV by facemask with exhaled CO2 information available to the resuscitation team suggest that exhaled CO2 monitoring may help recognize airway obstruction and inadequate tidal volume delivery/lung aeration during IPPV. The detection of exhaled CO2 may precede an increase in HR in bradycardic neonates during IPPV with facemask {Blank 2014 1568; Blank 2018 1; Finer 2009 865; Hawkes 2017 74; Kang 2014 e102729; Kong 2013 104; Mizumoto 2015 186; Ngan 2017 F525}. Despite these findings, monitoring of exhaled CO2 immediately after birth did not result in more infants having admission pCO2 within the recommended range {Hawkes 2017 74; Kong 2013 104}. Survival was not assessed in any of these eight studies. In a study by Linde et al {Linde 2018 1}, measured exhaled CO2 data by a sidestream quantitative sensor were retrospectively assessed. Higher expired CO2 (as % of expired air) was noted in infants receiving IPPV by facemask with self-inflating bag who survived vs. those who died (2.8 vs. 1.7%, respectively, p=0.001), possibly reflecting better CO2 exchange in surviving newborns. Tidal volumes in both groups were within the recommended range. Because CO2 data were retrospectively obtained after the resuscitation, the impact of real time CO2 monitoring to the providers to guide ventilatory actions could not be assessed.

In a quality improvement effort, Kakkilaya et al {Kakkilaya 2019 e20180201} implemented a resuscitation bundle, including an exhaled CO2 detector to optimize facemask IPPV in infants ≤29 weeks’ gestation at birth. Comparing pre- vs. post- (n=180 vs. n=134) quality improvement intervention cohorts, the latter had lower intubation rate in the delivery room (58 vs. 37%), lower administration of mechanical ventilation (85 vs 70%), lower rates of BPD (26 vs 13%), and severe retinopathy of prematurity (14 vs 5%). Despite these results, it is not possible to know the effectiveness of the isolated components of the bundle.

There are some potential concerns with the use of exhaled CO2 to guide IPPV by facemask at birth. It is possible that dead-space ventilation of the mask, oropharynx, and trachea causes insufficient renewal of the expired volume, causing an overestimation of exhaled CO2 levels {van Vonderen 2015 F514}. The exhaled CO2 monitors may also be inadequate to detect periods of adequate ventilation during low pulmonary blood flow and/or low cardiac output {Blank 2014 1568}. Even in the absence of airway obstruction, exhaled CO2 may be low in infants born at <29 weeks’ gestation maybe due to insufficient inflation pressures to overcome the resistance of fluid filled small airways and the absence of fully vasodilated pulmonary circulation {Hunt 2019 665}.

The reliability of colorimetric devices may be affected by contamination with gastric contents and medications {Blank 2014 1568; Muir 1990 41}. The potential harms of exhaled CO2 monitoring could include distraction from other important aspects of observing the infant and other monitoring devices, or anchoring bias (over-dependence on one observed value rather than consideration of all clinically important information). Furthermore, the implications for training and implementation of introducing CO2 monitoring devices into routine practice have not been sufficiently explored.

In making the treatment recommendation, the Task Force noted the lack of studies to support the decision to use or not use exhaled CO2 monitors to guide IPPV with non-invasive interfaces, such as facemasks, supraglottic airways and, nasal cannulae, immediately after birth.

Knowledge Gaps

  • Efficacy and effectiveness of CO2 monitoring to guide IPPV with non-invasive interfaces in newborns immediately after birth, considering different methods of measurement and different non-invasive interfaces.
  • Efficacy and effectiveness of CO2 monitoring to guide IPPV with non-invasive interfaces in newborns immediately after birth with different indications of IPPV, such as apnea/irregular respirations or bradycardia/asystole, and different gestational ages, such as <280/7; 280/7 -336/7; and 340/7 or more weeks.
  • Potential risk due to undetected exhaled CO2 in newborns with absent or insufficient circulation during effective IPPV.
  • Impact of cord management strategies on exhaled CO2 detection.
  • Impact of the presence of gastric reflux, other secretions, blood, meconium, or medications on the reliability of colorimetric CO2 detection.
  • Potential harm due to the distraction of attention of resuscitation providers by exhaled CO2 monitors.
  • Cost-effectiveness of the use of exhaled CO2 monitors.

Attachment: NLS 5350 Exhaled CO2 Et D


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Racire Silva
In our service we never had access.
Norma Suely Oliveira
We don’t have ETCO2
Colin Morley
The review mentions potential concerns with the use of exhaled CO2 to guide IPPV by facemask at birth. It is possible that dead-space ventilation of the mask, oropharynx, and trachea causes insufficient renewal of the expired volume. Although dead space ventilation might be a problem it is unlikely because there is commonly a leak around the face mask or ETT and so there is a continuous flushing of gas in the mask.
Jamie Tegart
We currently use a colorometric for intubation. There has been discussion, at our site, about the use of CO2 detectors during IPPV, however it has not been a common practice. I do see the potential benefit from it as another indicator that PPV is successful, and would be interested in seeing if more sites adopt this into practice
Elene Vanderpas
If available, CO2 detector can be another method to assist in determining if you have a face-mask seal. But since a rising HR is the most important indicator of successful PPV, you will still need to do corrective steps as needed, aside from CO2 detector results.

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