Accuracy of Transcutaneous Carbon Dioxide Measurement in Premature Infants

Background. In premature infants, maintaining blood partial pressure of carbon dioxide (pCO2) value within a narrow range is important to avoid cerebral lesions. The aim of this study was to assess the accuracy of a noninvasive transcutaneous method (TcpCO2), compared to blood partial pressure of carbon dioxide (pCO2). Methods. Retrospective observational study in a tertiary neonatal intensive care unit. We analyzed the correlation between blood pCO2 and transcutaneous values and the accuracy between the trends of blood pCO2 and TcpCO2 in all consecutive premature infants born at <33 weeks' gestational age. Results. 248 infants were included (median gestational age: 29 + 5 weeks and median birth weight: 1250 g), providing 1365 pairs of TcpCO2 and blood pCO2 values. Pearson's R correlation between these values was 0.58. The mean bias was −0.93 kPa with a 95% confidence limit of agreement of −4.05 to +2.16 kPa. Correlation between the trends of TcpCO2 and blood pCO2 values was good in only 39.6%. Conclusions. In premature infants, TcpCO2 was poorly correlated to blood pCO2, with a wide limit of agreement. Furthermore, concordance between trends was equally low. We warn about clinical decision-making on TcpCO2 alone when used as continuous monitoring.


Background
The partial pressure of carbon dioxide (pCO 2 ) strongly influences cerebral perfusion in premature infants that have reduced autoregulation capacity. Thus, monitoring pCO 2 to avoid hyper-or hypocapnia and associated brain injury has become standard of care [1,2]. Although some studies advocate "permissive hypercapnia" to limit lung injury due to mechanic ventilation, this attitude remains controversial [3]. In any case, most neonatologists consider it best practice to closely monitor pCO 2 in premature infants, especially when they are ventilated.
Currently, the gold standard to measure tissue pCO 2 is the blood gas analysis. However, this method has disadvantages, as it might contribute to spoliative anemia and is painful if done by capillary sampling. Therefore, other pCO 2 monitoring methods have been developed during the last three decades [4].
End-tidal CO 2 measurement provides a noninvasive estimate of the blood pCO 2 in ventilated patients. However, its use in premature infants is limited by the small tidal volumes and increased dead space caused by the measurement device inserted into the ventilation circuit. Furthermore, it is impossible or unreliable to use during alternate ventilation methods such as high frequency oscillation ventilation [5] or spontaneous breathing with or without continuous positive airway pressure.
Transcutaneous pCO 2 (TcpCO 2 ) was developed in the 1960s. A calibrated skin sensor, heated to 40-45 ∘ C (100-110 ∘ F) in order to arterialize the capillary bed and facilitate CO 2 diffusion, can then measure the pCO 2 in a thin liquid film between skin and sensor. Such devices are widely used in neonatal intensive care settings [6]. Several small studies in neonatal populations (the largest including 60 patients) have analyzed the correlation and concordance between the TcpCO 2 and blood pCO 2 [7][8][9][10][11]. The quality of the concordance between the two methods remains debated. One study in healthy adults has shown that very short-term trends appear accurate, with a mean TcpCO 2 lag of about one minute after acute changes in arterial pCO 2 [12]. However, no published study investigated the accuracy of TcpCO 2 trends over longer periods.  The objective of our study was to assess, in a large neonatal population, the accuracy point values as well trends of TcpCO 2 compared to blood pCO 2 .

Methods
This retrospective observational study included all consecutive premature infants born <33 weeks of postmenstrual age, admitted to our tertiary Neonatal Intensive Care Unit (NICU) at Geneva University Hospital over a period of four years starting from 1/1/2009. All data during the first 28 days of life of these neonates were prospectively recorded in our electronic clinical data system (CliniSoft5, General Electric Healthcare, Milwaukee, WI, USA). 2 Determinations. The blood pCO 2 was immediately analyzed after sampling on a Radiometer ABL800 analyzer (Radiometer, Brønshøj, Denmark). All results were automatically retrieved into our clinical data system including the time of determination. As several studies suggest that arterial, venous, and capillary blood pCO 2 levels can be considered identical [13,14], we did not differentiate the type of blood sample.

2.2.
Transcutaneous pCO 2 (TcpCO 2 ) Determinations. All TcpCO 2 sensors (TCM45, Radiometer, Copenhagen, Denmark) were applied according to the manufacturer's recommendations and to our unit protocol: the sensor was calibrated every two to four hours, the skin cleaned with sterile water, two to three drops of specific contact gel were applied, and sensor was placed on the inside of the infant's thigh (on alternate sides, after each recalibration). The sensor temperature was set according to the manufacturer's guidelines (41 ∘ C for infants 500 g to 750 g and 42 ∘ C for infants 751 g to 2000 g). The membrane was changed every 14 days.
At least once an hour, the nurse in charge of the patient manually entered the TcpCO 2 value into the electronic clinical data system.

Data Analysis.
We considered pairs of TcpCO 2 and blood pCO 2 when both values were measured within an interval of 10 minutes.
The accuracy of point values was then assessed by three methods: (1) The proportion of values where the difference between TcpCO 2 and blood pCO 2 was less than 10% and its 95% confidence interval of agreement. (2) The correlation between TcpCO 2 and blood pCO 2 values; we considered, a priori, a good correlation defined by a Pearson > 0.8. (3) A Bland-Altman plot, to report the mean bias and 95% confidence limits of agreement between the two methods [15]; TcpCO 2 and blood pCO 2 values were averaged across the range and the mean bias was calculated as the mean difference between TcpCO 2 and blood pCO 2 , and the 95% confidence limits of agreement between the two methods were defined as 1.96 times the standard deviation of the mean difference between TcpCO 2 and blood pCO 2 .
The accuracy of trends was assessed for all consecutive pairs of TcpCO 2 and blood pCO 2 , when pairs were measured within a six-hour interval. The trends of both values were expressed in percentage of change. Concordance between TcpCO 2 and blood pCO 2 trends was defined, a priori, as good if the difference between the values was ≤10%, moderate if the difference was 11 to 20%, and poor if the difference was >20% (see examples in Table 1). All statistical analyses were performed with SPSS version 20 for Mac (SPSS, Chicago, IL, USA).

Sample Size.
We anticipated 75% of good concordance between trends of TcpCO 2 and blood pCO 2 . To obtain a 95% confidence interval smaller than ±5% around the proportion of good concordance, we calculated that at least 288 trends for each method would be required. We planned to include as many patients as possible, over a four-year period (to avoid historical biases), as long as the required number of inclusions would be matched.
The ethics committee of Geneva University Hospital approved the study. 1365 pairs of TcpCO 2 and blood pCO 2 point values were analyzed. The median interval between TcpCO 2 and blood pCO 2 measures was 4 minutes (IQR 2; 7). The median number of tests per patient was 4 (IQR 2; 9).

Discussion
Our results suggest that transcutaneous pCO 2 with the TCM45 is not accurate in a general neonatal intensive care setting. The correlation between TcpCO 2 and blood pCO 2 was poor (Pearson's = 0.58) and the 95% confidence limits of agreement wide (−4.05 kPa to 2.16 kPa) in the Bland-Altman analysis. The concordance between the six-hour trends of blood pCO 2 and TcpCO 2 was also poor, with only 39.6% of good concordance. Several studies have analyzed the accuracy and the reliability of TcpCO 2 monitoring, with conflicting results. Whereas some have described poor correlation between TcpCO 2 and blood pCO 2 [10,16], others have shown better results [11,[17][18][19]. Kesten et al. have suggested very shortterm trends, of a few minutes, to be accurate in healthy adults [12]. Two studies have described poor correlation blood pCO 2 values for high values [7,10].

Critical Care Research and Practice
Our study reports 1365 pairs of TcpCO 2 and blood pCO 2 in 248 different neonatal subjects, to assess the reliability of the noninvasive technique. Our Bland-Altman analysis is in line with a worsening correlation for high values (>10 kPa), but the rather low number of data points does not allow concluding in this matter ( Figure 2). However, our study, with the largest number of matching samples published so far, strongly supports the studies with poor agreement between TcpCO 2 and blood pCO 2 .
Our study is the first to report concordance between trends of TcpCO 2 and blood pCO 2 in premature infants. Indeed, although the point value correlation might be poor, most clinicians would rely on the trend of the TcpCO 2 as a surrogate of the blood pCO 2 's changes over time. Only onethird of the samples showed a good concordance of trends over a six-hour period.
It is legitimate to wonder if such monitoring may not lead to wrong clinical decisions or increased blood sampling to confirm values. Furthermore, as the sensor heats the skin to 41-42 ∘ C, it might cause discomfort and even injure the youngest infants' very fragile skin. Finally, the use of TcpCO 2 is expensive. According to the manufacturer, the sensor needs recalibration every three to four hours using a specific gas cylinder. The skin fixation rings have to be relocated every 12 to 24 hours, and the sensor's membrane changed every one to two weeks. In our unit, the average yearly cost for one device used 24/7 is 10500$.
Some limitations to our study must be recognized. First, it is a retrospective study, and although the TcpCO 2 values were recorded prospectively into the electronic clinical data system, it is impossible to retrospectively assess the skin's perfusion at the precise time. Second, our data system does not report the heating power or the sensor temperature or the precise site of use of the sensor. Therefore, we cannot ascertain the quality of each measured value. However, our nurses are instructed to use the probe according to the manufacturer's guidelines and to record the TcpCO 2 value only when it has stabilized, and the large number of data points analyzed increases the credibility of our findings. Finally, the Bland-Altman analysis was not modified to adjust for multiple measures in the same patient [20]. However, the median of median number of repeated measures was low (4) compared to the number of patients (248). Furthermore, adjusting for multiple measures would only have increased the agreement limit. Despite the limitations, we would argue that our results represent very closely real life use of TcpCO 2 and certainly those used in our own clinical practice to take decisions.

Conclusion
Our data show that TcpCO 2 with the TCM45 poorly correlate to blood pCO 2 , with a wide confidence limit of agreement. A low concordance was also noted between trends of TcpCO 2 and blood pCO 2 . We therefore warn about the sole use of TcpCO 2 for clinical decision-making. Prospective, shortterm correlations for value points and trends need to be assessed in further research as well as in nonneonatal populations.

Abbreviations
VLBW: Very low birth weight pCO 2 : Partial pressure of carbon dioxide (pCO 2 ) TcpCO 2 : Transcutaneous partial pressure of carbon dioxide NICU: neonatal intensive care unit.

Disclosure
In particular, Radiometer did not provide funding, equipment, or consumables.