Ventilatory support may affect the short- and long-term neurologic and respiratory morbidities of preterm infants. Ongoing monitoring of oxygenation and ventilation and control of adequate levels of oxygen, pressures, and volumes can decrease the incidence of such adverse outcomes. Use of pulse oximetry became a standard of care for titrating oxygen delivery, but continuous noninvasive monitoring of carbon dioxide (CO2) is not routinely used in NICUs. Continuous monitoring of CO2 level may be crucial because hypocarbia and hypercarbia in extremely preterm infants are associated with lung and brain morbidities, specifically bronchopulmonary dysplasia, intraventricular hemorrhage, and cystic periventricular leukomalacia. It is shown that continuous monitoring of CO2 levels helps in maintaining stable CO2 values within an accepted target range. Continuous monitoring of CO2 levels can be used in the delivery room, during transport, and in infants receiving invasive or noninvasive respiratory support in the NICU. It is logical to hypothesize that this will result in better outcome for extremely preterm infants. In this article, we review the different noninvasive CO2 monitoring alternatives and devices, their advantages and disadvantages, and the available clinical data supporting or negating their use as a standard of care in NICUs.

The goal of respiratory support among premature infants in the NICU is to maintain adequate oxygenation and ventilation while causing minimal harm. Although oxygenation is monitored continuously with pulse oximetry as a standard of care, in most units, ventilation is currently monitored intermittently by arterial, venous, or capillary blood gas but not routinely by continuous measurements.

Hypercarbia and hypocarbia are relatively common in the NICU. The incidence varies in different studies and according to the definitions at different ages. van Kaam et al1 reported an incidence of 31% for Pco2 >52 mm Hg and an incidence of 4% for Pco2 <30 mm Hg, and Kugelman et al2 reported an incidence of 17% for Pco2 >60 mm Hg and an incidence of 2.8% for Pco2 <30 mm Hg.

Hypercarbia and hypocarbia are associated with respiratory and neurologic complications.3,6 Therefore, gaps in carbon dioxide (CO2) monitoring might affect the short- and long-term outcome of premature infants receiving respiratory support.

Although invasive CO2 monitoring is more accurate, we do not have arterial lines for long periods. This is important because extremely preterm infants do get invasive or noninvasive respiratory support for prolonged periods. Furthermore, the blood gas does not allow continuous assessment, and arterial lines have complications. Thus, feasible and trustful noninvasive methods of continuous CO2 monitoring are warranted.

CO2 levels are of major clinical importance. Hypocarbia is associated with lung and brain morbidities.3,6 Alterations in Paco2 can significantly affect cerebral hemodynamics in preterm infants (ie, hypocarbia and hypercarbia decreases and increases cerebral blood flow, respectively).7,8 Both extremes and fluctuations of Paco2 are associated with severe intraventricular hemorrhage (IVH).3,4,6,9 Cumulative exposure to hypocarbia is independently related to risk of periventricular leukomalacia (PVL) in infants with low birth weight.10,12 A recent study in which end-tidal carbon dioxide (EtCO2) and near-infrared spectroscopy were used revealed that CO2 fluctuations are associated with changes in cerebral oxygenation and electrical activity in the first 72 hours of life in preterm infants.13 Thus, it may be prudent to avoid significant hypocarbia and hypercarbia and CO2 fluctuations especially during the first 3 days of life, when the risk for IVH is the highest.9,13 

In preterm infants who are ventilated, hypocarbia can be the result of administrating excessive tidal volumes, leading to volutrauma, and contributes to bronchopulmonary dysplasia (BPD) development. Volume-targeted ventilation that is aimed to keep a stable tidal volume decreases both events of hypocarbia and BPD.14 Retrospective studies revealed that persistent hypocarbia was associated with increased risk for BPD,15 whereas permissive hypercarbia (Paco2 levels of 55–60 mm Hg) was associated with lower incidence of BPD.16 In their randomized controlled trial, Mariani et al17 showed that targeting CO2 levels of 45 to 55 vs 35 to 45 mm Hg in preterm infants who receive assisted ventilation was feasible, seemed safe, and may reduce the duration of assisted ventilation. However, this study, which had a relatively small sample size and wide confidence intervals of the treatment effects, could not demonstrate a significant reduction in BPD, air leaks, IVH, PVL, mortality, or length of stay. Intriguing results were found by Thome et al.18 In their multicenter trial on permissive hypercarbia in infants with extremely low birth weight (PHELBI trial), they compared targeting higher versus lower CO2 values (55–65 vs 40–50 mm Hg on postnatal days 1–3, 60–70 vs 45–55 mm Hg on days 4–6, and 65–75 vs 50–60 mm Hg on days 7–14). They found that targeting higher CO2 values did not decrease the rate of BPD, air leaks, IVH, PVL, or death in preterm infants who were ventilated.18 The rate of necrotizing enterocolitis increased.18 When this cohort was assessed at ∼2 years’ corrected age, no influence on neurodevelopmental outcomes was found.19 Most of the infants did not reach the higher target CO2 range because they decreased their CO2 by spontaneous breathing. The policy of 2 target ranges was kept only when the infants were intubated; thus, the power of the study decreased daily when infants were extubated during the study period. In a post hoc analysis of the actual CO2 values obtained by blood gas analyzed during the first 14 days of life, rather than in the group to which infants were randomly assigned, the infants with the higher quartile of CO2 values (mean ± SD of 60 ± 4 mm Hg) had higher mortality and a higher likelihood of having BPD and worse neurodevelopmental outcomes.20 Birth weight and respiratory morbidity were the most predictive of death or BPD and necrotizing enterocolitis, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models were also used to identify Pco2. Thus, hypercapnia, in this analysis, seems to reflect greater disease severity associated with increased morbidity and not the intended ventilation strategy. To summarize, there is no conclusive proof that permissive hypercapnia is beneficial, despite the physiologic basis behind it.

The use of EtCO2 for verifying endotracheal tube (ETT) position and monitoring CO2 levels is a common practice in the operating room and in PICUs.21 However, in the NICU, colorimetric CO2 detectors and EtCO2 are mostly used after intubation to confirm ETT position. Monitoring CO2 for longer periods is not commonly used because of technical problems found in neonates such as leakage around uncuffed ETTs that leads to mixing of the measured CO2 with inhaled air and due to small tidal volume, high respiratory rates with short exhalation time and relative inaccuracy in the presence of ventilation-perfusion mismatch.22,24 

EtCO2 monitoring is informative for technical and physiologic problems. CO2 is produced during cellular metabolism, transported to the lungs by the cardiovascular system, and exhaled after alveolar gas exchange (ie, EtCO2 reflects cell metabolism, blood perfusion, and alveolar ventilation).21,23,25 EtCO2 monitoring allows for the maintaining of stable CO2 values within an accepted target range while providing ventilatory support in the NICU as well as during delivery room resuscitation and transport.2,26,29 It also provides more rapid discrimination of tracheal versus esophageal intubation than standard clinical assessment30 and can be used for that purpose after intubation and during resuscitation and transport.30,31 However, it is important to note that during resuscitation, because of limited pulmonary blood flow, false-negative readings may occur (ie, no EtCO2 value will appear despite correct intratracheal placement).21 

Analyzing the changes in the EtCO2-to-Paco2 difference can theoretically give information about changes in ventilation-perfusion mismatch and the physiologic dead space.23,32 By using Bohr’s and Enghoff’s equations, it is possible to calculate the anatomic and physiologic dead space.24,33,34 

With capnography, the measured CO2 signal can be recorded and plotted as a function of time (time-based capnography, which is used in most of the available monitors; Fig 1A) or volume (volumetric capnography; Fig 1C), which further allows for calculations of alveolar ventilation and physiologic and apparatus dead spaces (Fig 1 B and C) to assess the accuracy of the EtCO2 measurement.24,35,36 Tolnai et al,35 using a model of lung injury in ventilated rabbits, showed that volumetric capnography, but not time-based capnography, is sensitive for detecting lung-volume loss and alveolar recruitment; hence, it can help to detect the development of lung injury and determine the best positive end-expiratory pressure.35 Volumetric capnography provides valuable information regarding functional lung alterations related to BPD in early infancy.37 Volumetric capnography may help in detecting the limitations of capnography in preterm infants with sick lungs. Preterm infants with sick lungs may have volumetric capnography with prolonged phase II and a reduced or absent phase III, which may represent ventilation-perfusion mismatch and can indicate that the measured EtCO2 does not reflect the alveolar CO2 pressure and Paco2.24,37 Furthermore, in that case, the alveolar dead space calculation might be misleading, too.23 

FIGURE 1

A, Time-based capnograph. Phase I represents the CO2 free interval due to anatomic and apparatus dead space (VD); phase II is characterized by a rapid increase in CO2 due to transition between airway gas and alveolar gas; phase III reflects alveolar gas (the alveolar plateau). The intersection of the slope line of phase II and the slope line of phase III is where phase III begins.24 B, VD compartments and the 3-alveoli ventilation-perfusion (V/Q) model (Riley’s model); 1 is the ideal condition (perfused and ventilated); 2 is for shunt (perfused but not ventilated [V/Q = 0]); and 3 is VD (ventilated but not perfused [V/Q = ∞]).38 C, Volumetric capnography allows for calculations of alveolar ventilation and VD by the Fletcher method by using Fowler’s equal areas (q = p). A perpendicular line divides p and q until they are equal. Area X (area under the capnograph curve) corresponds to the exhaled amount of CO2. The shaded area is the total VD for the breath. Area Z (dark-shaded area to the left of the solid line) is the airway + apparatus VD. Area Y (light-shaded area above the slope of phase III) is the alveolar VD.24,38 

FIGURE 1

A, Time-based capnograph. Phase I represents the CO2 free interval due to anatomic and apparatus dead space (VD); phase II is characterized by a rapid increase in CO2 due to transition between airway gas and alveolar gas; phase III reflects alveolar gas (the alveolar plateau). The intersection of the slope line of phase II and the slope line of phase III is where phase III begins.24 B, VD compartments and the 3-alveoli ventilation-perfusion (V/Q) model (Riley’s model); 1 is the ideal condition (perfused and ventilated); 2 is for shunt (perfused but not ventilated [V/Q = 0]); and 3 is VD (ventilated but not perfused [V/Q = ∞]).38 C, Volumetric capnography allows for calculations of alveolar ventilation and VD by the Fletcher method by using Fowler’s equal areas (q = p). A perpendicular line divides p and q until they are equal. Area X (area under the capnograph curve) corresponds to the exhaled amount of CO2. The shaded area is the total VD for the breath. Area Z (dark-shaded area to the left of the solid line) is the airway + apparatus VD. Area Y (light-shaded area above the slope of phase III) is the alveolar VD.24,38 

Close modal

Types of EtCO2 Detectors

Quantitative EtCO2 detectors measure the level of exhaled CO2. They can further be subdivided into capnography and capnometry. Capnometry provides a numeric display of the CO2 concentration, whereas capnography produces a graphic waveform. Their locations in the airway circuit are also used to further categorize them to mainstream or sidstream detectors (Fig 2).

FIGURE 2

A, The mainstream detector is positioned directly within the path of gas flow. It is connected between the proximal ETT and the ventilator circuit. A small chamber containing an infrared source and detector is located in an adaptor inserted into the breathing circuits. B, Sidestream detectors are located off the main path of flow in the airway circuit and often use small diameter tubing that removes gas continuously from the breathing circuit and measures the CO2 by a remote sensor.

FIGURE 2

A, The mainstream detector is positioned directly within the path of gas flow. It is connected between the proximal ETT and the ventilator circuit. A small chamber containing an infrared source and detector is located in an adaptor inserted into the breathing circuits. B, Sidestream detectors are located off the main path of flow in the airway circuit and often use small diameter tubing that removes gas continuously from the breathing circuit and measures the CO2 by a remote sensor.

Close modal

Mainstream Capnometry and Capnography

Figure 2A includes a detector with a fast response time and that is therefore capable of rapid CO2 analysis in rapid-breathing infants.39 However, its weight may kink or dislodge the ETT, and the circuit is even more cumbersome if a flow sensor is also connected inline. The detector itself adds dead space, which is not insignificant in infants who are ventilated with small tidal volumes.39 Mainstream capnometry and capnography can be used in patients who are intubated in conjunction with conventional ventilation but not with noninvasive ventilation or high-frequency ventilation (HFV).40 New devices are under development and are being tested for use with a facemask or mouthpiece in children and infants.41,43 

Sidestream Capnometry and Capnography

The advantage of sidestream capnometry and capnography (Fig 2B) is that they are less cumbersome and have lower dead space compared with the mainstream detectors. However, these instruments include extra sampling tubing with small a diameter that can be blocked with secretions.39,44 Conventional high-flow (150–200 mL/minutes) sidestream capnography can underestimate alveolar CO2 levels because of the relatively low tidal volumes and rapid respiratory rates in newborns.22,39,44 A low-flow (50 mL/minutes) microstream technique can improve the accuracy of sidestream EtCO2 in newborns.22,45 Sidestream EtCO2 may have an advantage of possible use in the distal part of the double-lumen ETT.33 Distal EtCO2 may be less susceptible to air leaks or mixing of the measured EtCO2 with inhaled air compared with a mainstream detector.25 However, the double-lumen ETTs are not routinely used in NICUs.

Unlike mainstream-positioned EtCO2, EtCO2 measurement by sidestream capnometry through nasal cannula can provide an accurate and noninvasive estimate of Paco2 levels in infants who are not intubated46,47 even if they get oxygen flow. Yet, there is currently no device for EtCO2 suitable for noninvasive ventilation.

Measuring EtCO2 is possible during conventional ventilation, but the physiologic concept is different during HFV. Although we use tidal breathing on conventional ventilation, the mechanism of gas exchange during HFV with smaller tidal volumes is more complicated, and several mechanisms of gas mixing may contribute to gas transport.48,49 Distal sidestream capnography with a designated algorithm enables one to measure an average carinal level of CO2 that represents and/or estimates alveolar CO2 levels.50 By using a double-lumen ETT, distal sidestream capnography during HFV may be helpful for trends and alarms for unsafe levels of Paco2, although agreement between its measurements and simultaneous Paco2 sampling is less than adequate.51 

Accuracy of ETCO2 Measurement

EtCO2 value measurement is usually lower compared with that of Paco2.40 This may be attributable to several factors, including dead space, leakage around an uncuffed ETT, ventilation-perfusion mismatch, and gas mixing proximal to the ETT.23 The latter can be decreased by using CO2 measurements from gas that was sampled in the distal end of the double-lumen ETT by using sidestream technology.25 

In infants, small tidal volume and higher respiratory rate result in shorter inspiratory and expiratory time. This is reflected in the capnography waveform as missing of an adequate plateau and could result in the lack of a true alveolar gas measurement and further explain wide variation in EtCO2 values compared with Paco2.39,52 Therefore, ideally, capnography should be integrated with EtCO2 measurements and should be considered useful only if the shape of the capnogram includes an adequate plateau.24 

The accuracy of EtCO2 and Paco2 measurements is judged by the agreement (the mean difference [bias] and the SDs of the differences [precision] assessed in Bland Altman plots53; Fig 3 is an example from Kugelman et al25) and the correlation coefficient of the 2 measurements. Good agreement between EtCO2 and Paco2 is considered to be a bias <5 mm Hg.22,40 The more severe the ventilation-perfusion mismatch, the higher the difference between EtCO2 and Paco2.22,40,54 Such conditions are common in NICUs.

FIGURE 3

A, Bland Altman plot of the difference between Paco2 and distal end-tidal carbon dioxide (dEtCO2). B, Bland Altman plot of the difference between Paco2 and proximal mainstream end-tidal carbon dioxide (petco2). (Reprinted with permission from Kugelman A, Zeiger-Aginsky D, Bader D, Shoris I, Riskin A. A novel method of distal end-tidal CO2 capnography in intubated infants: comparison with arterial CO2 and with proximal mainstream end-tidal CO2. Pediatrics. 2008;122(6). Available at: www.pediatrics.org/cgi/content/full/122/6/e1219.)

FIGURE 3

A, Bland Altman plot of the difference between Paco2 and distal end-tidal carbon dioxide (dEtCO2). B, Bland Altman plot of the difference between Paco2 and proximal mainstream end-tidal carbon dioxide (petco2). (Reprinted with permission from Kugelman A, Zeiger-Aginsky D, Bader D, Shoris I, Riskin A. A novel method of distal end-tidal CO2 capnography in intubated infants: comparison with arterial CO2 and with proximal mainstream end-tidal CO2. Pediatrics. 2008;122(6). Available at: www.pediatrics.org/cgi/content/full/122/6/e1219.)

Close modal

Mainstream capnometry was found in previous studies to be more accurate than sidestream capnometry,40,55 but using a distal microstream sidestream technique revealed comparable results.25,34 A recent study in which distal EtCO2 was measured with an epidural catheter inserted into the ETT revealed better accuracy compared with proximal measurements,56 but this method might be too cumbersome and might partially occlude the ETT.

Transcutaneous carbon dioxide (TcCO2) measurement makes use of the fact that CO2 gas diffuses through body tissue and skin and can be detected by a sensor at the skin surface. By warming the sensor, a local hyperemia is induced, which increases the supply of arterial blood to the dermal capillary bed below the sensor.57 The measurement usually requires several minutes of preheating.58 The thin skin layer of preterm infants may confer an advantage of highly reliable readings of TcCO2. The disadvantages include heat-induced skin damage and burns from the electrodes57,59 but have been rarely reported in the last decade since new devices with a safer lower local temperature are in use.60 Future devices and technology may abrogate the need for local elevated temperature and may expedite recording by measuring the transcutaneous diffusion rate, which is proportional to blood gas concentration.58,61 

Advantages of TcCO2 over EtCO2 are that it can be easily used for continuous CO2 monitoring in infants who are not ventilated28 and during noninvasive ventilation as well as during HFV.62,63 It has been shown to be superior to EtCO2 during neonatal transport because it has less under-recording bias.27 Unlike EtCO2 measurement, TcCO2 measurement is not influenced by ventilation-perfusion mismatch and was found to be as good as or more accurate than EtCO2 measurement in preterm infants.28,40,44,52 

The disadvantage of TcCO2 is that it cannot be used for confirming the ETT position in the trachea; another disadvantage is the time it takes for initial measurement because of the need for local preheating and calibration.58 Therefore, it cannot be used during neonatal resuscitation in the delivery room or the NICU.26 

The use of TcCO2 in the NICU might be complicated in some clinical situations. Skin edema, poor tissue perfusion, and acidosis may alter the TcCO2 correlation with Paco2. In addition, some technical limitations might affect TcCO2 reliability, such as sensor preparation; positioning; high humidity in incubators; and repeated changes of the sensor location, which are needed to avoid skin trauma.57,59 

Accuracy of TcCO2 Measurement

As opposed to EtCO2, the TcCO2 value is usually higher than the arterial value because of 2 main factors: first, the elevated skin temperature increases local blood and tissue CO2 levels by ∼4.5%/°C (termed “anaerobic factor”). In addition, some epidermal cells produce CO2, which contributes to the capillary CO2 level by ∼5 mm Hg (termed “metabolic constant”).57 Because of the aforementioned, a correction algorithm is applied to the transcutaneous value to provide a reading that corresponds as closely as possible to Paco2.57 

Discussion on the Available Noninvasive Technologies for CO2 Monitoring

A summary of the noninvasive techniques is presented in Table 1. In general, for infants treated with conventional ventilation EtCO2, both mainstream and sidestream EtCO2 and TcCO2 are optional when acknowledging the advantages and limitations of each method in different clinical and physiologic conditions.2,22,28,30,33 For noninvasive ventilation and HFV, TcCO2 is preferable. Mainstream and sidestream EtCO2 can be used for rapid discrimination of tracheal versus esophageal intubation, even during delivery room resuscitation.30 

TABLE 1

Noninvasive CO2 Monitoring Techniques

ModalityDescriptionAdvantagesDisadvantages
EtCO2 Measures the level of exhaled CO2 A fast response time enables CO2 analysis in rapid-breathing infants and for confirming ETT position Influenced by ventilation-perfusion mismatch 
Mainstream detector Adaptor inserted into the breathing circuits; attached to the proximal ETT EtCO2 reflects cell metabolism, blood perfusion, and alveolar ventilation Cumbersome; may kink or dislodge the ETT 
 Usually uses an infrared source and detector Changes in the EtCO2-to-Paco2 difference gives information about changes in ventilation-perfusion mismatch and in dead space Adds dead space 
 Measurement is usually lower compared with Paco2  Currently cannot be used during noninvasive ventilation or HFV 
EtCO2 Located off the main path; removes gas continuously from the breathing circuit Less cumbersome compared with mainstream detectors Extra tubing affected by secretions 
Sidestream detector Measures the CO2 in a remote infrared sensor Option for measurement in infants who are not ventilated but not in infants with noninvasive ventilation Need for a double-lumen ETT for distal capnography 
 Measurement is usually lower compared with Paco2 Can measure distal EtCO2 via a double-lumen ETT and allows limited use during HFV Not accurate in small tidal volume and higher respiratory rate (partially overcome with the use of the microstream technique) 
TcCO2 detector CO2 is measured by determining the pH of an electrolyte layer separated from the skin by a highly permeable membrane Used in infants who are not ventilated and those with noninvasive ventilation Heat-induced skin damage from the electrodes (overcome with new devices) 
 Warming the sensor induces local hyperemia for faster and more accurate reading Used in HFV Technical limitations affect reliability (skin edema, poor tissue perfusion, acidosis sensor preparation, positioning, repeated changes of location) 
 Measurement is usually higher compared with Paco2; a correction algorithm is applied to the transcutaneous value Not influenced by ventilation-perfusion mismatch Cannot be used for confirming the ETT position 
  Less cumbersome compared with EtCO2 It takes time for initial measurement and has slower response time compared with EtCO2 
ModalityDescriptionAdvantagesDisadvantages
EtCO2 Measures the level of exhaled CO2 A fast response time enables CO2 analysis in rapid-breathing infants and for confirming ETT position Influenced by ventilation-perfusion mismatch 
Mainstream detector Adaptor inserted into the breathing circuits; attached to the proximal ETT EtCO2 reflects cell metabolism, blood perfusion, and alveolar ventilation Cumbersome; may kink or dislodge the ETT 
 Usually uses an infrared source and detector Changes in the EtCO2-to-Paco2 difference gives information about changes in ventilation-perfusion mismatch and in dead space Adds dead space 
 Measurement is usually lower compared with Paco2  Currently cannot be used during noninvasive ventilation or HFV 
EtCO2 Located off the main path; removes gas continuously from the breathing circuit Less cumbersome compared with mainstream detectors Extra tubing affected by secretions 
Sidestream detector Measures the CO2 in a remote infrared sensor Option for measurement in infants who are not ventilated but not in infants with noninvasive ventilation Need for a double-lumen ETT for distal capnography 
 Measurement is usually lower compared with Paco2 Can measure distal EtCO2 via a double-lumen ETT and allows limited use during HFV Not accurate in small tidal volume and higher respiratory rate (partially overcome with the use of the microstream technique) 
TcCO2 detector CO2 is measured by determining the pH of an electrolyte layer separated from the skin by a highly permeable membrane Used in infants who are not ventilated and those with noninvasive ventilation Heat-induced skin damage from the electrodes (overcome with new devices) 
 Warming the sensor induces local hyperemia for faster and more accurate reading Used in HFV Technical limitations affect reliability (skin edema, poor tissue perfusion, acidosis sensor preparation, positioning, repeated changes of location) 
 Measurement is usually higher compared with Paco2; a correction algorithm is applied to the transcutaneous value Not influenced by ventilation-perfusion mismatch Cannot be used for confirming the ETT position 
  Less cumbersome compared with EtCO2 It takes time for initial measurement and has slower response time compared with EtCO2 

Numerous studies revealed conflicting results regarding the correlation between noninvasive CO2 measurements, EtCO2 and TcCO2 and Paco2 level. The literature on accuracy of the different methods of continuous CO2 measurements is summarized in Table 2.*

TABLE 2

Accuracy of Different Methods of Continuous CO2 Measurements

ReferencePopulationMean Bias ± SDCorrelation Coefficient
EtCO2     
 Conventional ventilation     
  Mainstream Rozycki et al40 (prospective) 411 pairs, 45 infants 28.4 ± 5 GA 6.9 ± 11.5 0.83 
 Aliwalas et al52 (prospective) 27 pairs, 27 infants <28 wk GA at 24 h of age 1.9 ± 1.8 0.57 
 Bhat and Abhishek64 (prospective) 133 pairs, 32 newborns 34.6 ± 3.6 wk GA 6.7 ± 7.5 0.73 
 Kugelman et al25 (prospective) 220 pairs, 27 infants 24–40 wk GA 10.2 ± 13.7 0.21 
  Sidestream (microstream) Hagerty et al22 (prospective) 20 pairs, 13 preterm and term infants with respiratory disease 7.4 ± 3.3 NS 
 — 7 matched infants without pulmonary disease 3.4 ± 2.4 NS 
 Singh et al34 (prospective) 286 pairs, 48 infants 23–41 wk GA who were ventilated 7.8 ± 9.9 0.76 
 Lopez et al65 (prospective) 99 pairs, 37 infants 27.7 ± 1.9 GA who were ventilated 11.2 ± 8 0.28 
 Kugelman et al25 (prospective) 212 pairs, 27 infants 24–40 wk GA (distal sidestream) 1.5 ± 8.7 0.77 
 Kugelman et al2 (prospective) 761 pairs, 55 infants with a median GA of 28.6 wk (range 23–39 wk) (distal sidestream) 3.0 ± 8.5 0.73 
 HFV     
  Distal sidestream Kugelman et al51 (prospective) 332 pairs, 24 infants 23.6–38.6 wk GA 11.7 ± 10.3 0.7 
TcCO2     
 Conventional ventilation Aliwalas et al52 (prospective) 27 pairs, 27 infants <28 wk GA who were ventilated at 24 h of age 2.6 ± 1.8 0.53 
 Lopez et al65 (prospective) 99 pairs, 37 infants 27.7 ± 1.9 GA who were ventilated 0 ± 7.8 0.78 
 Palmisano and Severinghaus66 (prospective) 336 pairs, 116 neonates under CV 1.8 ± 4.2 0.92 
 HFV Berkenbosch and Tobias63 (prospective) 100 pairs, 14 patients age 1 d–16 y 2.1 ± 2.7 0.96 
 Mixed ventilation modes (no separated data) Mukhopadhyay et al67 (retrospective) 1338 pairs, 52 neonates 27.7 ± 3.9 GA on CV or HFV 5.2 ± 17.3 NS 
 Aly et al60 (prospective) 124 pairs, 50 neonates 28.1 ± 2.4 GA on CV, HFV, or noninvasive ventilation NS (Bland Altman performed) 0.6 
 Janaillac et al68 (retrospective) 1365 pairs, 248 neonates with a median GA of 29.5 wk on invasive or noninvasive ventilation 7 ± 23 0.58 
ReferencePopulationMean Bias ± SDCorrelation Coefficient
EtCO2     
 Conventional ventilation     
  Mainstream Rozycki et al40 (prospective) 411 pairs, 45 infants 28.4 ± 5 GA 6.9 ± 11.5 0.83 
 Aliwalas et al52 (prospective) 27 pairs, 27 infants <28 wk GA at 24 h of age 1.9 ± 1.8 0.57 
 Bhat and Abhishek64 (prospective) 133 pairs, 32 newborns 34.6 ± 3.6 wk GA 6.7 ± 7.5 0.73 
 Kugelman et al25 (prospective) 220 pairs, 27 infants 24–40 wk GA 10.2 ± 13.7 0.21 
  Sidestream (microstream) Hagerty et al22 (prospective) 20 pairs, 13 preterm and term infants with respiratory disease 7.4 ± 3.3 NS 
 — 7 matched infants without pulmonary disease 3.4 ± 2.4 NS 
 Singh et al34 (prospective) 286 pairs, 48 infants 23–41 wk GA who were ventilated 7.8 ± 9.9 0.76 
 Lopez et al65 (prospective) 99 pairs, 37 infants 27.7 ± 1.9 GA who were ventilated 11.2 ± 8 0.28 
 Kugelman et al25 (prospective) 212 pairs, 27 infants 24–40 wk GA (distal sidestream) 1.5 ± 8.7 0.77 
 Kugelman et al2 (prospective) 761 pairs, 55 infants with a median GA of 28.6 wk (range 23–39 wk) (distal sidestream) 3.0 ± 8.5 0.73 
 HFV     
  Distal sidestream Kugelman et al51 (prospective) 332 pairs, 24 infants 23.6–38.6 wk GA 11.7 ± 10.3 0.7 
TcCO2     
 Conventional ventilation Aliwalas et al52 (prospective) 27 pairs, 27 infants <28 wk GA who were ventilated at 24 h of age 2.6 ± 1.8 0.53 
 Lopez et al65 (prospective) 99 pairs, 37 infants 27.7 ± 1.9 GA who were ventilated 0 ± 7.8 0.78 
 Palmisano and Severinghaus66 (prospective) 336 pairs, 116 neonates under CV 1.8 ± 4.2 0.92 
 HFV Berkenbosch and Tobias63 (prospective) 100 pairs, 14 patients age 1 d–16 y 2.1 ± 2.7 0.96 
 Mixed ventilation modes (no separated data) Mukhopadhyay et al67 (retrospective) 1338 pairs, 52 neonates 27.7 ± 3.9 GA on CV or HFV 5.2 ± 17.3 NS 
 Aly et al60 (prospective) 124 pairs, 50 neonates 28.1 ± 2.4 GA on CV, HFV, or noninvasive ventilation NS (Bland Altman performed) 0.6 
 Janaillac et al68 (retrospective) 1365 pairs, 248 neonates with a median GA of 29.5 wk on invasive or noninvasive ventilation 7 ± 23 0.58 

CV, conventional ventilation; HFV, high frequency ventilation; GA, gestational age; NS, not specified; —, not applicable.

In a prospective study of preterm infants in the first 24 hours of age, only a moderate correlation with a wide variation in individual values was observed between noninvasive methods, both EtCO2 and TcCO2, and Paco2.52 The EtCO2 findings could be explained by active respiratory distress syndrome, with significant ventilation-perfusion mismatch. Only 27 pairs of measurements were performed in this study, and 1 value from each patient was used to avoid a bias of many pairs related to 1 infant. However, the low sample size could explain the relative low correlation.

In a large study, Janaillac et al68 retrospectively analyzed 1365 pairs of TcCO2 and blood CO2 values from 248 preterm infants treated with invasive or noninvasive ventilation. They found that TcCO2 was poorly correlated to blood CO2, with a wide limit of agreement. This study was limited by the fact that pairs of blood gas and TcCO2 measures were matched retrospectively according to the nursing charts if they were within 10 minutes apart. A relatively long gap of time that could affect the outcome.68 

Authors of other studies reported more accurate results.63,65 A recent study60 with the new technology (by using 41°C) revealed that TcCO2 is feasible and reliable in infants with very low birth weight using different modes of ventilation. Studies on sidestream EtCO2 in which the authors used a distal microstream technique during conventional ventilation25,50,56 revealed adequate agreement and correlations better than or equal to proximal measurements. A subanalysis that included 13 infants with very low birth weight (84 pairs of measurement) revealed a good linear correlation for distal EtCO2 and Paco2 (r = 0.72; P < .001) and a bias of −0.3 ± 11.1 mm Hg, as opposed to poor correlation of the mainstream EtCO2 (r = 0.11; P = .32) with a bias of −14.8 ± 18.7 mm Hg.25 

To summarize, despite an adequate bias and correlation in some studies, a relatively high SD was noticed in the available devices by some researchers. According to these data, noninvasive CO2 monitoring should not replace Paco2 measurements but rather serve as a complementary tool for trending and for real-time continuous assessment of CO2 levels. It can also serve as an alarm for abnormal Paco2 values.25,40,64,65 

Continuous noninvasive monitoring of CO2 to assess adequacy of ventilation may allow for decreased use of blood gases69 and thus may potentially decreasing blood sampling, pain and discomfort, risk of infection, and the need for blood transfusions.70 There is no randomized control trial in which these outcomes are assessed. Mukhopadhyay et al67 analyzed clinical outcomes for 123 neonates intubated for >48 hours before and after the introduction of TcCO2-monitoring devices in a single tertiary care unit. In this study, they demonstrated statistically decreased blood gas frequency among neonates who were ventilated without affecting the duration of mechanical ventilation or other clinical outcomes at discharge. However, there was no standard for clinical management of using the CO2 results in this retrospective study, so it would not have been possible to discern any effect on practice.

In their Cochrane review from 2016, Bruschettini et al71 aimed to assess whether the use of continuous TcCO2 monitoring in newborn infants reduced mortality and improved short- and long-term respiratory and neurodevelopmental outcomes. Searching for randomized controlled trials or quasi–randomized controlled trials, they did not find any completed studies for inclusion nor ongoing trials and concluded that there was no evidence to recommend or refute the use of TcCO2 monitoring in neonates.71 

In the same year, Kugelman et al2 published a randomized control trial in which they compared the time spent within a predefined safe range of CO2 (30 mm Hg < Pco2 <60 mm Hg) during conventional ventilation between 25 infants who were continuously monitored with distal microstream sidestream EtCO2 measurement and 30 infants with masked EtCO2 monitoring. In this multicenter study, the monitored group spent significantly less time within an unsafe EtCO2 level. IVH or PVL rate was significantly and independently lower in infants who were continuously monitored by EtCO2.2 However, this study was limited by a small number of extremely preterm infants; thus, we should be cautious in concluding that monitoring of CO2 reduced the neurologic complications.

EtCO2 monitoring allows for more rapid discrimination of tracheal versus esophageal intubation than standard clinical assessment. Repetto et al30 found that the median time for confirming tracheal or unintended esophageal intubation at the delivery room in preterm infants was 9 seconds using capnography and was >30 seconds using clinical assessment only. Using CO2 detectors, including EtCO2 and colorimetric CO2, for confirming tracheal intubation became the current practice during delivery room resuscitation of preterm infants and is part of the Neonatal Resuscitation Program guidelines.72 

In a study performed by Tracy et al,73 in which chest rise was used to determine ventilating pressures in the delivery room, 26% of infants had admission Paco2 levels <30 mm Hg. In theory, continuous capnography starting in the delivery room can reduce hypocarbia or hypercarbia on admission to the NICU. However, although Hawkes et al74 determined that EtCO2 monitoring of preterm infants in the delivery room was feasible, they failed to show a difference on arrival to the NICU between the proportions of Paco2 values within the range of normocapnia (40–55 mm Hg) among infants who received EtCO2 monitoring and those of infants who did not (56.8% vs 47.9%; P = .39). In a more recent study, Hawkes et al43 demonstrated that quantitative or qualitative EtCO2 detection methods are both feasible for face mask ventilation via a NeoPuff T-piece resuscitator (Fisher and Paykel, Auckland, New Zealand) in the delivery room. Although there was no difference in the incidence of normocarbia, the intubation rate, the days of ventilation, or the incidence of BPD, the authors suggested that the use of either form of EtCO2 should be considered during newborn stabilization, especially in infants <28 weeks’ gestation. To note, in both studies,43,74 Paco2 on admission was defined within 1 hour of arrival; thus, it was not a strict criterion for the levels of CO2 during the delivery room care or on admission. Kong et al75 also found that EtCO2 monitoring in the delivery room did not reduce the proportion of admission Pco2 levels outside of the prespecified range (40–55 mm Hg) in preterm infants (33.3% vs 37.5%; P = .76). There is a need for further research into capnography as a means of confirming effective and safe ventilatory support during neonatal resuscitation.26 

During long-distance transport, maintenance of the ETT position is of the utmost importance. However, EtCO2 detectors can have technical problems in measuring during transport.76 EtCO2 was found by Tingay et al28 to have unacceptable under-recording bias. In their study, they found that TcCO2, although not indicating tracheal intubation, had good correlation with Paco2 and thus could decrease episodes of hypocarbia and hypercarbia and should be considered the preferred method of noninvasive CO2 monitoring for neonatal transport.28 O’Connor and Grueber27 also demonstrated the benefit of TcCO2 during transport and found that TcCO2 monitoring decreased ventilator peak pressures and increase the chance of arriving after transport with a pH and Paco2 within an acceptable range. Probably, the combination of both methods could lead to a safer transport.

A potential limitation of a narrative review (such as this review), as opposed to a systematic review, is a subjective selection of information from primary articles that could lead to a biased review. However, we could not find randomized controlled trials that could be integrated into a systematic review71 nor publications with consistent methods using same technologies to allow for a meta-analysis. To minimize a potential bias, Ovid Medline, Embase, and PubMed were searched for relevant literature in English up to December 2018. We included articles in which predetermined sections of this review were addressed, including relevant physiology, technological details, clinical implications, use and outcome, and correlation of noninvasive CO2 measurement to Paco2. Two authors chose separately the key articles with added value to these topics. Furthermore, the limitations of the quoted literature are detailed in our review.

EtCO2 and TcCO2 monitoring should be viewed as complementary technologies of assessing Paco2 in various clinical scenarios in the NICU. To potentially minimize the harmful effect of ventilatory support and to promote gentle treatment in the NICU, continuous noninvasive monitoring of ventilation (CO2) is recommended, similar to pulse oximetry used for continuous noninvasive control of oxygenation. However, because both methods are currently limited in their agreement and correlation with Paco2, they should be used concomitantly with Paco2 analysis. We suggest correlating EtCO2 and TcCO2 with Paco2 for monitoring in the individual patient. The frequency of this assessment depends on specific considerations, including the actual agreement and trending and knowing the limitations and advantages of each method in the actual clinical condition. In the acute phase of respiratory distress syndrome, when arterial lines are in place and the bias of EtCO2 is larger, blood gases should be used more frequently and TcCO2 might be more accurate for Paco2 assessment. When a relation is established between the noninvasive and Paco2 readings, a trend and a real-time assessment of Paco2 can be monitored continuously and noninvasively. It can also alarm for out-of-range Paco2 values. This might improve ventilatory treatment by optimizing tidal volumes, thus reducing the amount of volutrauma, reducing the exposure time to hypocarbia and hypercarbia, and reducing the number and total volume of blood samples. Well-designed and adequately powered randomized controlled studies are necessary to address the beneficial effect of continuous noninvasive CO2 monitoring in neonates on short- and long-term outcomes, specifically in the vulnerable population of extremely preterm infants.

All authors drafted the initial manuscript, reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

*

Refs 2,22,34,40,51,52,60,63,68.

FUNDING: Medtronic (Covidien Ltd, Jerusalem, Israel) supported our studies on end-tidal carbon dioxide, and SenTec AG (Therwil, Switzerland) supplied part of the equipment for our study on transcutaneous carbon dioxide.

BPD

bronchopulmonary dysplasia

CO2

carbon dioxide

EtCO2

end-tidal carbon dioxide

ETT

endotracheal tube

HFV

high-frequency ventilation

IVH

intraventricular hemorrhage

PVL

periventricular leukomalacia

TcCO2

transcutaneous carbon dioxide

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Kugelman’s studies on end-tidal carbon dioxide were supported by Medtronic (Covidien Ltd, Jerusalem, Israel), and SenTec AG (Therwil, Switzerland) supplied part of the equipment for his study on transcutaneous carbon dioxide; both companies supported 2 of his lectures on noninvasive carbon dioxide monitoring in neonatal meetings by honorarium 3 years ago; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.