Effects of reduced rebreathing time, in spontaneously breathing patients, on respiratory effort and accuracy in cardiac output measurement when using a partial carbon dioxide rebreathing technique: a prospective observational study

Introduction New technology using partial carbon dioxide rebreathing has been developed to measure cardiac output. Because rebreathing increases respiratory effort, we investigated whether a newly developed system with 35 s rebreathing causes a lesser increase in respiratory effort under partial ventilatory support than does the conventional system with 50 s rebreathing. We also investigated whether the shorter rebreathing period affects the accuracy of cardiac output measurement. Method Once a total of 13 consecutive post-cardiac-surgery patients had recovered spontaneous breathing under pressure support ventilation, we applied a partial carbon dioxide rebreathing technique with rebreathing of 35 s and 50 s in a random order. We measured minute ventilation, and arterial and mixed venous carbon dioxide tension at the end of the normal breathing period and at the end of the rebreathing periods. We then measured cardiac output using the partial carbon dioxide rebreathing technique with the two rebreathing periods and using thermodilution. Results With both rebreathing systems, minute ventilation increased during rebreathing, as did arterial and mixed venous carbon dioxide tensions. The increases in minute ventilation and arterial carbon dioxide tension were less with 35 s rebreathing than with 50 s rebreathing. The cardiac output measures with both systems correlated acceptably with values obtained with thermodilution. Conclusion When patients breathe spontaneously the partial carbon dioxide rebreathing technique increases minute ventilation and arterial carbon dioxide tension, but the effect is less with a shorter rebreathing period. The 35 s rebreathing period yielded cardiac output measurements similar in accuracy to those with 50 s rebreathing.


Introduction
A partial carbon dioxide rebreathing technique has been developed to estimate cardiac output (CO) in mechanically ventilated patients undergoing surgery [1,2] or intensive care [3,4]. We previously reported that 50 s carbon dioxide rebreathing resulted in increased minute ventilation (V E ) and an irregular respiratory pattern [4]. Recently, an improved system with a shorter rebreathing time (35 s) was developed and is replacing the 50 s rebreathing system. We reasoned that shortening the carbon dioxide rebreathing period would lessen the CO = cardiac output; ICU = intensive care unit; NICO 2 = noninvasive partial CO 2 rebreathing technique; PaCO 2 = arterial carbon dioxide tension; PCO 2 = partial carbon dioxide tension; PETCO 2 = end-tidal carbon dioxide tension; PSV = pressure support ventilation; VCO 2 = carbon dioxide production; V E = minute ventilation; V T = tidal volume. increases in arterial carbon dioxide tension (PaCO 2 ) and respiratory effort during carbon dioxide rebreathing. We were concerned, however, that measurement of CO might be compromised by a shorter rebreathing period because there would be smaller changes in the measured variables, fewer sampled breaths and incomplete equilibrium [5]. We designed the present prospective study to investigate how, in spontaneously breathing patients, the shorter carbon dioxide rebreathing period affects respiratory effort during rebreathing and how it affects the accuracy of CO measurement.

Materials and methods
The study was approved by the ethics committee of the National Cardiovascular Center (Osaka, Japan), and written informed consent was obtained from each patient.

Patients
Thirteen consecutive patients (age 39-79 years) who had undergone elective cardiovascular surgery were enrolled in the study (Table 1). Enrolment criteria were similar to those of previous studies [3,4]: insertion of a pulmonary artery catheter, stable haemodynamics in the intensive care unit (ICU) and no leakage around the endotracheal tube. We excluded those patients who had central nervous system disorders, who might be adversely affected by induced hypercapnia, or who exhibited severe tricuspid regurgitation. After admission to the ICU each patient was ventilated with an 8400STi ventilator (Bird Corp., Palm Springs, CA, USA). Initial ventilatory settings were synchronized intermittent mandatory ventilation plus pressure support ventilation (PSV), volume controlled ventilation, tidal volume (V T ) 10 ml/kg, respiratory rate 10 breaths/min, inspiratory time 1.0 s, positive end-expiratory pressure 4 cmH 2 O, and PSV 10 cmH 2 O. The inspired fraction of oxygen was adjusted by attending physicians to maintain arterial oxygen tension greater than 100 mmHg. Using an inspiratory hold technique, we measured the effective static compliance and resistance of the respiratory system (Table 1) [6]. In all patients, arterial blood pressure, heart rate, pulmonary artery pressure, central venous pressure and pulse oximeter signal (PM-1000; Nellcor Inc., Hayward, CA, USA) were continuously monitored. Patients were sedated with propofol (2-3 mg/kg per hour). After waiting 1-2 hours for haemodynamics to stabilize, we decreased the dosage of propofol to 1-2 mg/kg per hour.

Study protocol
As each patient recovered spontaneous breathing, we gradually decreased synchronized intermittent mandatory ventilation rates, finally changing the ventilatory mode to continuous positive airway pressure with PSV at 10 cmH 2 O. The measurement protocol was started when the recruited patients satisfied the following conditions: recovery of cough reflex; V T ≥ 8 ml/kg and respiratory rate ≤ 20 breaths/min; arterial blood gas of pH 7.35-7.45; PaCO 2 35-45 mmHg; and arterial oxygen tension ≥ 100 mmHg at an inspired fraction of oxygen ≤ 0.5. We applied two systems of noninvasive partial carbon dioxide rebreathing technique in a random order. After waiting for at least 15 min, we recorded respiratory and haemodynamic data. Because the stimuli of partial carbon dioxide rebreathing increased spontaneous breathing, we recorded the data as displayed on the graphic monitors of the ventilators for respiratory rate and V E at the end of the normal breathing period and at the end of the rebreathing periods ( Fig. 1). At the same times arterial blood was drawn via radial artery cannulation and mixed venous blood via pulmonary artery catheter; samples were analyzed with a calibrated blood gas analyzer (ABL 505; Radiometer, Copenhagen, Denmark).

Cardiac output measurements
We randomly applied two systems of noninvasive partial carbon dioxide rebreathing technique to measure CO (CO NI ): 35 s rebreathing (version 4.5, fast mode; Novametrix Medical Systems Inc., Wallingford, CT, USA) and 50 s rebreathing (version 4.2, fast mode). Although the durations of carbon dioxide rebreathing were different, both the total cycle (3 min) and the calculation algorithm were the same. Sensors for noninvasive partial carbon dioxide rebreathing technique (NICO 2 ) were placed between the tracheal tube and Y-piece. The principle underlying this technique is described in detail elsewhere [3][4][5]. Briefly, carbon dioxide production (VCO 2 ) is calculated on a breath-by-breath basis and a differential Fick equation is Resistance of the respiratory system (cmH 2 O·s per l) 12.0 ± 2.9 Background disease Coronary artery disease 6 Acquired valve disease 6 Thoracic aortic aneurysm 1 Values are expressed as mean ± standard deviation. CO, cardiac output.
Available online http://ccforum.com/content/9/5/R569 R571 applied to establish the relationship between VCO 2 and CO as follows: Where CvCO 2 is the carbon dioxide content in mixed venous blood, and CaCO 2 is the carbon dioxide content in arterial blood. Assuming that both CO and CvCO 2 remains constant during carbon dioxide rebreathing and that the change in CaCO 2 between normal breathing and carbon dioxide rebreathing is proportional to the changes in PaCO 2 and endtidal carbon dioxide pressure (PETCO 2 ), the following equation is substituted for the previous one: Where ∆VCO 2 is the change in VCO 2 and ∆PETCO 2 is the change in PETCO 2 between normal breathing and carbon dioxide rebreathing, and S is the slope of the carbon dioxide dissociation curve from haemoglobin. After compensating, from the pulse oximeter signal, for the intrapulmonary shunt fraction, the partial carbon dioxide rebreathing technique obtains values for CO.
After we had acquired CO NI data, we measured thermodilution CO (CO TD ) via a 7.5-Fr pulmonary artery catheter (Abbott Laboratories, North Chicago, IL, USA; Fig. 1). During the latter half of the normal breathing period, injection of 10 ml cold saline (0°C) was done three times and the values obtained were averaged. We carefully standardized the timing of bolus injections to after the first half of the expiratory phase [7].

Statistical analysis
Data are presented as mean ± standard deviation, or as the median and interquartile range if the data were skewed. Comparison of respiratory rate, V E , PaCO 2 and mixed venous partial carbon dioxide tension (PCO 2 ) between different conditions (35 s versus 50 s rebreathing, and normal breathing versus rebreathing) were conducted using the Friedman test and the Wilcoxon signed rank test. We evaluated the agreement among CO NI with 35 s rebreathing, CO NI with 50 s rebreathing and CO TD using Bland-Altman analysis [8]. P < 0.05 was considered statistically significant.

Respiratory loads
Respiratory and blood gas results are summarized in Table 2.
There was no significant difference in respiratory rate, V E , PaCO 2 and mixed venous PCO 2 during normal breathing between 35 s rebreathing and 50 s rebreathing ( Table 2). With either duration of rebreathing, respiratory rate and V E increased during rebreathing. Similarly, the values for PaCO 2 and mixed venous PCO 2 were higher at the end of the rebreathing period. The changes in V E and PaCO 2 due to rebreathing were significantly less with 35 s rebreathing than with 50 s rebreathing (Fig. 2).

Cardiac output
The results of Bland-Altman analysis for 35 s and 50 s rebreathing systems are summarized in Fig. 3. The CO measured using both systems exhibited similar agreement (bias and precision, respectively: 0.02 l/min and 1.06 l/min with 35 s rebreathing, and -0.34 l/min and 1.08 l/min with 50 s rebreathing) with values measured by thermodilution. When comparing the CO between 35 s rebreathing and 50 s rebreathing, bias was 0.26 l/min and precision was 0.51 l/min (Fig. 3c).

Discussion
The main findings of the present study, conducted in spontaneously breathing patients, are that respiratory rate, V E , PaCO 2 and mixed venous PCO 2 increased during the rebreathing period; that increases in V E and PaCO 2 during carbon dioxide rebreathing were less with the shorter rebreathing period; and that the two systems, with different rebreathing periods, provided similarly accurate CO measurements. The NICO 2 system is appealing as a noninvasive method for measuring CO in patients in whom pulmonary artery catheterization is not possible or desirable. Because it is now common for ICU patients to receive partial ventilatory support that allows spontaneous breathing [9], we must determine how the reduction in carbon dioxide rebreathing time affects respiratory effort and how accurate the NICO 2 system is in such patients.

Figure 1
Schedule of measurements Schedule of measurements. Respiratory rate (RR), minute ventilation (V E ), arterial carbon dioxide tension (PaCO 2 ) and mixed venous carbon dioxide tension (PvCO 2 ) were recorded both at the end of the normal breathing period (NB) and at the end of the partial rebreathing period (RB). At the middle of normal breathing period cardiac output using partial carbon dioxide rebreathing technique (CO NI ) was measured; then, cardiac output using thermodilution technique (CO TD ) was measured in triplicate and the values were averaged.

Respiratory effort
One disadvantage of the partial carbon dioxide rebreathing technique is that rebreathing increases the respiratory effort of spontaneously breathing patients [4]. Consequently, the effect on respiratory effort of different durations of carbon dioxide rebreathing requires clarification. To our knowledge, no other investigations into this issue have been published. First, we found that the increase in PaCO 2 during 50 s rebreathing was 5.9 mmHg (median; Fig. 2). These increases were greater than values (2-5 mmHg) previously reported in applications of controlled mechanical ventilation [10,11]. We assume that the greater metabolic rate in awake and spontaneously breathing patients accounted for the higher increase in PaCO 2 during carbon dioxide rebreathing. Next, as we had conjectured, the shorter period of carbon dioxide rebreathing resulted in lesser increases in PaCO 2 and, as a result, reduced the increases in V E during carbon dioxide rebreathing (Fig. 2). Although NICO 2 monitoring is relatively noninvasive under controlled mechanical ventilation, it increases PaCO 2 and respiratory effort under partial ventilatory support, even during 35 s rebreathing.

Accuracy of cardiac output measurement
Although we previously found this technique to be less accurate when there were spontaneous breathing efforts [4], in the present study CO NI correlated moderately well with CO TD . We reason that we were able to obtain more stable V T and V E findings during CO measurement in the present study by using a larger dosage of propofol (1-2 mg/kg per hour) than in the previous study (0.5 mg/kg per hour). It is likely that stable V T and V E resulted in more accurate CO measurement. Gama de Abreu and coworkers [12], using a system different from ours, also reported that results were less precise when there was irregular spontaneous breathing than when respiratory rate and V T were fixed.
Because of smaller changes in the measured variables, fewer sampled breaths and incomplete equilibrium, we expected that the shorter duration of rebreathing would lead to less accurate CO measurement [5]. However, CO measurement with 35 s rebreathing was as accurate as with 50 s rebreathing (Fig. 3). Although the exact reason is unknown, we speculate as follows; Because the CO NI value is calculated from the ratio of change in VCO 2 and PETCO 2 during carbon dioxide rebreathing, the measurement is corrupted by noise and by variations in V T and respiratory rate [5]. Smaller carbon dioxide stimuli during 35 s rebreathing probably result in a more stable ventilatory pattern, whereas the smaller changes in VCO 2 and PETCO 2 during 35 s rebreathing lead to a poorer signal-to- Values are expressed as median (interquartile range). *P < 0.05 versus normal breathing.

Figure 2
Changes in respiratory values in each patient due to carbon dioxide rebreathing Changes in respiratory values in each patient due to carbon dioxide rebreathing. (a) Increases in minute ventilation (V E ) due to carbon dioxide rebreathing. (b) Increases in arterial carbon dioxide tension (PaCO 2 ) due to carbon dioxide rebreathing. Medians (triangles) and interquartile ranges are also shown. *P < 0.05 versus 35 s rebreathing.

Figure 3
Bias analysis between cardiac output measurements Bias analysis between cardiac output measurements. (a) Cardiac output obtained by partial carbon dioxide rebreathing of duration 35 s (CO NI,35s ) and thermodilution technique (CO TD ). (b) Cardiac output obtained by partial carbon dioxide rebreathing of duration 50 s (CO NI,50s ) and CO TD . (c) CO NI,35s and CO NI,50s . Dotted lines show bias and limits of agreement between the two methods.

Key messages
• The NICO 2 monitor is claimed to measure CO noninvasively using the partial carbon dioxide rebreathing technique.
• When there are spontaneous breaths, partial carbon dioxide rebreathing increases V E and PaCO 2 .
• Use of a shorter duration of rebreathing (35 s versus 50 s) has smaller effects on respiratory effort in spontaneously breathing patients.
• The shorter duration of carbon dioxide rebreathing system yields a CO measurement that is similar in accuracy to that obtained with the previously used, longer duration of rebreathing.