Reduction in minute alveolar ventilation causes hypercapnia in ventilated neonates with respiratory distress.

Hypercapnia occurs in ventilated infants even if tidal volume (VT) and minute ventilation (VE) are maintained. We hypothesised that increased physiological dead space (Vd,phys) caused decreased minute alveolar ventilation (VA; alveolar ventilation (VA) × respiratory rate) in well-ventilated infants with hypercapnia. We investigated the relationship between dead space and partial pressure of carbon dioxide (PaCO2) and assessed VA. Intubated infants (n = 33; mean birth weight, 2257 ± 641 g; mean gestational age, 35.0 ± 3.3 weeks) were enrolled. We performed volumetric capnography (Vcap), and calculated Vd,phys and VA when arterial blood sampling was necessary. PaCO2 was positively correlated with alveolar dead space (Vd,alv) (r = 0.54, p < 0.001) and Vd,phys (r = 0.48, p < 0.001), but not Fowler dead space (r = 0.14, p = 0.12). Normocapnia (82 measurements; 35 mmHg ≤ PaCO2 < 45 mmHg) and hypercapnia groups (57 measurements; 45 mmHg ≤ PaCO2) were classified. The hypercapnia group had higher Vd,phys (median 0.57 (IQR, 0.44-0.67)) than the normocapnia group (median Vd,phys/VT = 0.46 (IQR, 0.37-0.58)], with no difference in VT. The hypercapnia group had lower VA (123 (IQR, 87-166) ml/kg/min) than the normocapnia group (151 (IQR, 115-180) ml/kg/min), with no difference in VE.
Conclusion: Reduction of VA in well-ventilated neonates induces hypercapnia, caused by an increase in Vd,phys. What is Known: • Volumetric capnography based on ventilator graphics and capnograms is a useful tool in determining physiological dead space of ventilated infants and investigating the cause of hypercapnia. What is New: • This study adds evidence that reduction in minute alveolar ventilation causes hypercapnia in ventilated neonates.

Introduction

An optimal arterial carbon dioxide concentration, measured by the partial pressure of carbon dioxide (PaCO2), is critical during mechanical ventilation. Both hypercapnia and hypocapnia can contribute to brain damage in immature infants. Tighter control of PaCO2 may be achieved in mechanically ventilated infants by setting appropriate minute ventilation (VE), defined by tidal volume (VT) and the respiratory rate (RR) [1]. However, even when VT or VE are maintained, hypercapnia can occur. VT comprises Fowler dead space ((Vd,Fowler) volume of air in instruments and airways), alveolar dead space ((Vd,alv) volume of ventilated alveoli that do not receive blood flow and thus no gas exchange), and alveolar ventilation ((VA) volume of alveoli with gas exchange). Therefore, minute alveolar ventilation (VA), which is calculated as VA × RR, is the key contributor in maintaining appropriate PaCO2 [2, 3].

The physiological dead space (Vd,phys), which is the sum of Vd,Fowler and Vd,alv, is commonly calculated in ventilated patients using volumetric capnography (Vcap). This method employs a plot of expiratory CO2 (PECO2) versus expired tidal volume (VT,E), and specialised equipment with effective apparatus dead space for newborns with low VT [4]. We have previously reported the analysis of Vcap using ventilator graphics and capnograms with low dead-space cap-ONE (Nihon Kohden, Tokyo, Japan) mainstream capnometers [5].

We hypothesised decreased VA was caused by increased Vd,phys in well-ventilated infants with hypercapnia. The objective of this current study was to clarify the relationship between dead space and PaCO2, and to assess VA in intubated well-ventilated neonates with hypercapnia, using Vcap based on ventilator graphics and capnograms. We present evidence here that hypercapnia is attributed to decreased VA due to increased Vd,phys.

Materials and methods

Patient population

This was a single-centre, prospective, non-randomised study with consecutive patient enrolment, approved by the clinical ethics committee of the National Hospital Organization Maizuru Medical Center in Kyoto, Japan. Informed consent was obtained from all parents. Ventilated infants with arterial lines admitted to the NICU between December 2017 and December 2019 were enrolled. Infants with a greater than 10% air leak, or with extremely low birth weights, were excluded (Fig. 1). Infants received either volume-targeted or pressure-controlled time-cycled ventilation at the discretion of each neonatologist via a VN500 (Dräger Medical, Lübeck, Germany) in synchronous intermittent mandatory ventilation mode. Infants who weighed < 2500 g were intubated using either 2.5-mm or 3.0-mm endotracheal tubes without cuffs (Portex: Smiths Medical Japan, Tokyo, Japan). Infants weighing 2500 g or more were ventilated with 3.0-mm endotracheal tubes with cuffs (MicrocuffPET: Halyard, GA, USA) to reduce air leakage. We adjusted the positive end-expiratory pressure (PEEP) and fraction of inspired oxygen to maintain the saturation of percutaneous oxygen between 90 and 98%; we set the peak inspiratory pressure (PIP) to achieve a VT of approximately 5 mL/kg. We performed volumetric capnography when infants were well-ventilated (200 ml/kg/minute ≤ VE, and 3.5 ml/kg ≤ VT).

Fig. 1

Flow diagram showing the number of included neonates with diagnosis. RDS, respiratory distress syndrome; PPHN, persistent pulmonary hypertension of the newborns; MAS, meconium aspiration syndrome

Medical records were reviewed for information regarding the patients’ characteristics, and clinical, prenatal, and perinatal data. The diagnosis of respiratory distress syndrome (RDS) was defined as infants who had clinical manifestations (tachypnoea, nasal flaring, and or grunting), and radiologic signs such as air bronchogram or widespread granular opacities. We administered surfactant to infants diagnosed with RDS who had severe clinical symptoms. The diagnosis of persistent pulmonary hypertension of the newborns (PPHN) was confirmed by echocardiography with evidence of increased pulmonary pressure with demonstrable right-to-left shunts across the ductus arteriosus or foramen ovale. Pneumothorax and meconium aspiration syndrome (MAS) were diagnosed according to medical history, clinical manifestations, and chest X-ray.

Waveform sampling and Vcap based on waveforms

PECO2 was continuously monitored using cap-ONE (sampling frequency, 40 Hz; dead space, 0.5 mL) placed between the endotracheal tube and flow sensor of the ventilator circuit. While ventilated neonates received arterial blood sampling necessary for treatment, we simultaneously obtained the capnogram waveforms of cap-ONE and volume waveforms of the ventilator in the supine position, using a screen capture programme, with ventilator parameters. Our method of analysis has previously been described [5]. Briefly, we manually superimposed the capnogram waveforms and volume waveforms at the beginning of inspiration, and measured the PECO2 and VT,E values at the same time at 30–50 points from the start to the end of expiration using ImageJ software (http://rsb.info.nih.gov/ij/). Subsequently, PECO2 was plotted against VT,E for a single breath. Vd,Fowler, Vd,alv, and VA were calculated from the resulting curve, as described by Fletcher [6] (Fig. 2). The mean of at least three consecutive breaths was normalised to body weight at measurement. Vd,phys was calculated as Vd,Fowler + Vd,alv. VE and VA were calculated as follows: VE = VT × RR, and VA = VA × RR, respectively.

Fig. 2

Volumetric capnography and calculation of the dead space. The resulting curve comprises three phases: phase 1 represents carbon dioxide–free gas from the airways and apparatus dead space, phase 2 represents the volume of transition between the airway and alveolar gas, and phase 3 reflects the pure alveolar gas compartment and volume exhaled from the rest of the alveoli. A tangential line was constructed at the alveolar plateau between 90 and 98% of VT, and a vertical line was inserted in the middle of phase 2, such that two equal triangles were created. The area below the arterial carbon dioxide line can be divided into three parts: X, which represents VA; Y, which represents Vd,alv; and Z, which represents Vd,Fowler. Vd,Fowler, Vd,alv, and VA were calculated from respective area ratios to VT.

We performed regression analysis to evaluate the correlation between PaCO2 and VT/kg or dead space from the obtained samples. Next, hypocapnia measurements (PaCO2 < 35 mmHg) were excluded due to the small sample number and the remaining data points were classified as either normocapnia (35 mmHg ≤ PaCO2 < 45 mmHg), or hypercapnia (45 mmHg ≤ PaCO2) to clarify the normative reference data.

Statistical analyses

The data were tested for normality with the Kolmogorov–Smirnov test; data were non-normally distributed. We analysed the correlation between PaCO2 and each dead space using Spearman’s correlation coefficients, and compared normocapnia and hypercapnia using the Mann–Whitney U test with Excel Tokei 2019 (Social Survey Research Information, Tokyo, Japan). Statistical significance was set at p < 0.05.

Results

The study population consisted of 33 ventilated infants with a mean gestational age of 35.0 ± 3.3 weeks and a mean birth weight of 2257 ± 641 g (Table 1). The predominant reasons for mechanical ventilation were as follows: RDS (66%), PPHN (12%), asphyxia (12%), pneumothorax (6%), and MAS (3%).

Table 1

Descriptive characteristics of the enrolled patients

Parameter	Clinical data of the study population (n = 33)
Gestational age,weeks	35.0 ± 3.3
32–36 weeks, n (%)	14 (42)
< 32 weeks, n (%)	7 (21)
Birth weight, g	2257 ± 641
1500–2500 g, n (%)	13 (39)
1000–1500 g, n (%)	5 (15)
Male/female, n	20/13
Cesarean section, n (%)	22 (66)
Twin birth, n (%)	7 (21)
Apgar score at 1 min	5.8 ± 3.0
Apgar score at 5 min	7.1 ± 2.6
Surfactant treatment n (%)	15 (45)
Antenatal corticosteroids n (%)	12 (33)
Endotracheal tubes
3.0 mm with cuff n (%)	13 (39)
3.0 mm without cuff n (%)	15 (45)
2.5 mm without cuff n (%)	5 (15)

Values are represented as means (± standard deviations) or medians (interquartile ranges), unless specified otherwise

One hundred fifty-four measurements obtained from 33 ventilated infants were used for the regression analysis of the relationship between PaCO2 and VT/kg or each dead space. Figure 3 shows that PaCO2 values were positively correlated with Vd,alv/VT (r = 0.54, p < 0.001) and Vd,phys/VT (r = 0.48, p < 0.001), but not with VT/kg (r = 0.09, p = 0.35) and Vd,Fowler/VT (r = 0.14, p = 0.12).

Fig. 3

Correlation analysis between PaCO2 and dead space. PaCO2 values were positively correlated with Vd,alv (r = 0.54, p < 0.001) and Vd,phys (r = 0.48, p < 0.001), but not VT/kg (r = 0.09, p = 0.35) and Vd,Fowler (r = 0.14, p = 0.12). PaCO2, pressure of carbon oxide; Vd,Fowler, Fowler dead space; Vd,alv, alveolar dead space; VT, tidal volume; Vd,phys, physiological dead space

There were 82 normocapnia and 57 hypercapnia measurements. Table 2 presents the ventilator parameters and measurement values for each group. Higher respiratory settings such as PIP and MAP, but not PEEP, were needed in the hypercapnia group than in the normocapnia group. The difference in Vd,alv, Vd,phys, and VA was statistically significant between the normocapnia and hypercapnia groups, while VT and Vd,Fowler showed no difference. Vd,alv and Vd,phys were higher in the hypercapnia group (median Vd,alv/VT = 0.17 (IQR, 0.11–0.24); median Vd,phys/VT = 0.57 (IQR, 0.44–0.67)), compared with the normocapnia group (median Vd,alv/VT = 0.12 (IQR, 0.07–0.16); median Vd,phys/VT = 0.46 (IQR, 0.37–0.58)]. VA was lower in the hypercapnia group (median VA/VT = 0.43 (IQR, 0.33 to 0.54)) compared with the normocapnia group (median VA/VT = 0.54 (IQR, 0.42–0.62)).

Table 2

Ventilator parameters and measurements by volumetric capnography

Parameter	Normocapnia (82 samples)	Hypercapnia (57 samples)	p
Days of measurement	2 (1–5)	2 (1–4)	p = 0.30
PaCO2	41.0 (38.9–42.7)	52.3 (48.2–56.8)	p < 0.001
FiO2	0.30 (0.25–0.4)	0.35 (0.28–0.55)	p = 0.06
PIP, cmH2O	14.1 (12.1–16.1)	17.0 (14.1–18.1)	p = 0.004
PEEP, cmH2O	6.1 (5.1–6.4)	6.1 (5.4–6.6)	p = 0.30
RR	59 (46–64)	60 (50–72)	p = 0.14
MAP, cmH2O	8.2 (7.4–9.4)	9.1 (7.8–10.1)	p = 0.007
VT/kg, mL/kg	5.2 (4.7–5.9)	5.1 (4.5–5.5)	p = 0.13
Vd,Fowler/kg, mL/kg	1.8 (1.4–2.4)	1.8 (1.4–2.4)	p = 0.40
Vd,Fowler/VT	0.35 (0.26–0.44)	0.37 (0.27–0.48)	p = 0.18
Vd,alv/kg, mL/kg	0.6 (0.4–0.8)	0.9 (0.5–1.3)	p = 0.001
Vd,alv/VT	0.12 (0.07–0.16)	0.17 (0.11–0.24)	p < 0.001
Vd,phys/kg, mL/kg	2.4 (1.9–3.1)	2.8 (2.3–3.3)	p = 0.01
Vd,phys/VT	0.46 (0.37–0.58)	0.57 (0.44–0.67)	p < 0.001
VA/kg, mL/kg	2.7 (2.2–3.3)	2.1 (1.6–2.8)	p < 0.001
VA/VT	0.54 (0.42–0.62)	0.43 (0.33–0.54)	p < 0.001
VE/kg, mL/kg/min	295 (235–362)	304 (241–372)	p = 0.55
VA/kg, mL/kg/min	151 (115–180)	123 (87–166)	p = 0.006

The following is the list of abbreviations used in the above table along with their full terms: PaCO, pressure of carbon oxide; FiO, fraction of inspired oxygen; PIP, positive inspiratory pressure; PEEP, positive end-expiratory pressure; RR, respiratory rates; MAP, mean airway pressure; V, tidal volume; V, Fowler dead space; V, alveolar dead space; V, physiological dead space; V, alveolar ventilation volume; V minute tidal volume; V, minute alveolar ventilation volume. Values are represented as medians (interquartile ranges)

Moreover, the hypercapnia group had a lower median VA (123 (IQR, 87–166) ml/kg/min) relative to the normocapnia group (151 (IQR, 115–180) ml/kg/min), even though there was no difference in VE.

Discussion

The present study demonstrated that PaCO2 values and dead-space ratios were correlated, and that ventilated infants with hypercapnia had a higher Vd,phys, which resulted in a decrease of VA in the absence of a difference in either VT or VE.

A previous study of low-birth-weight infants ventilated for RDS showed that PaCO2 correlates reasonably well with VE, and that setting appropriate VE may allow closer targeting of PaCO2 [1]. However, it is known that the dead-space ratio depends on birth weight or gestational weeks, the volume of devices such as endotracheal tubes, and various respiratory conditions [2, 3, 7–9]. In our study, the regression analysis revealed that PaCO2 values were positively correlated with Vd,phys and Vd,alv, but not Vd,Fowler. Generally, Vd,alv increases with high PEEP and lung hypoperfusion [2]. Although PEEP remained unchanged between the two groups in our study, low pulmonary circulation in the hypercapnia group could be responsible for the observed increase in Vd,alv. The pulmonary transition at birth relies on an immediate drop in pulmonary vascular resistance with a concomitant increase in pulmonary blood flow. The main reasons for ventilator management in the NICU (RDS, MAS, infection, and asphyxia) may increase pulmonary vascular resistance [10]. Even in well-ventilated infants, a reduction in effective ventilation volumes can lead to hypercapnia, due to higher Vd,phys because of decreased pulmonary blood flow.

Few studies have reported neonate Vd,alv values [7, 11]. Dassios et al. reported a median Vd,alv of 0.3 ml/kg in prematurely born infants with a median weight of 1.18 kg, and 0.1 ml/kg for infants with a median weight of 3.3 kg; we report a higher mean Vd,alv 0.6–1.0 ml/kg [7]. This discrepancy might be explained by the fact that the previous study investigated infants during a clinically stable state when they were ready for extubation, while the present study examined infants during respiratory failure.

Several clinical implications can be derived from our study. Cases with a higher dead space could be detected at bedside to determine suitable ventilator settings, including a moderate level of PEEP and higher respiratory rates to maintain appropriate VA. In addition, measurements of Vd,alv are useful for the diagnosis of PPHN with lung hypoperfusion, as these techniques could estimate the effectiveness of inhaled nitric oxide, which induces pulmonary vasodilation.

The limitations of our study included the absence of an evaluation of pulmonary blood flow and calculations of the physiological dead space using the Enghoff approach, which estimates not only the true dead space but also intrapulmonary right to left shunting and low ventilation–perfusion regions of the lung [12-14]. Enghoff’s Vd,alv may be overestimated in infants with collapsed alveoli caused by surfactant deficiency. Furthermore, the term and preterm neonates included in this study were intubated for various reasons. In future studies, it will be important to study more homogenised samples to clarify the pathophysiology of the infants’ respiratory diseases.

Conclusion

We discovered that volumetric capnography in ventilated neonates with hypercapnia presents with a reduction of minute alveolar ventilation volume, in the absence of a decrease in minute ventilation volume. We believe that hypercapnia in newborns with otherwise good ventilation is attributable to an increase in physiological dead space.

What is Known: • Volumetric capnography based on ventilator graphics and capnograms is a useful tool in determining physiological dead space of ventilated infants and investigating the cause of hypercapnia.

What is New: • This study adds evidence that reduction in minute alveolar ventilation causes hypercapnia in ventilated neonates.