Although evaluation of cardiac output by the partial carbon dioxide rebreathing technique is as accurate as thermodilution techniques under controlled mechanical ventilation, it is less accurate at low tidal volume. It is not clear whether reduced accuracy is due to low tidal volume or low minute ventilation. The effect of spontaneous breathing on the accuracy of partial carbon dioxide rebreathing measurement has not been fully investigated. The objectives of the current study were to investigate whether tidal volume or minute ventilation is the dominant factor for the accuracy, and the accuracy of the technique when spontaneous breathing effort is present.
The authors enrolled 25 post-cardiac surgery patients in two serial protocols. First, the authors applied three settings of controlled mechanical ventilation in random order: large tidal volume (12 ml/kg), the same minute ventilation with a small tidal volume (6 ml/kg), and 50% decreased minute ventilation with a small tidal volume (6 ml/kg). Second, when the patient recovered spontaneous breathing, the authors applied three conditions of partial ventilatory support in random order: synchronized intermittent mandatory ventilation-pressure support ventilation, pressure support ventilation with an appropriately adjusted rebreathing loop, and pressure support ventilation with the shortest available loop. After establishing steady state conditions, the authors measured cardiac output using both partial carbon dioxide rebreathing and thermodilution methods. The correlation between the data yielded by the two methods was determined by Bland-Altman analysis and linear regression.
Cardiac output with the carbon dioxide rebreathing technique correlated moderately with that measured by thermodilution when minute ventilation was set to maintain normocapnia, regardless of tidal volumes. However, when minute ventilation was set low, the carbon dioxide rebreathing technique underreported cardiac output (y = 0.70x; correlation coefficient, 0.34; bias, -1.73 l/min; precision, 1.27 l/min; limits of agreement, -4.27 to +0.81 l/min). When there was spontaneous breathing, the correlation between the two cardiac output measurements became worse. Carbon dioxide rebreathing increased spontaneous tidal volume and respiratory rate (20% and 30%, respectively, during pressure support ventilation) when the rebreathing loop was adjusted for large tidal volume.
During controlled mechanical ventilation, minute ventilation rather than tidal volume affected the accuracy of cardiac output measurement using the partial carbon dioxide rebreathing technique. When spontaneous breathing is present, the carbon dioxide rebreathing technique is less accurate and increases spontaneous tidal volume and respiratory rate.
BECAUSE pulmonary artery catheterization is expensive and brings adverse effects such as venous thrombosis and catheter-related infection, 1a less expensive device has been developed to noninvasively measure cardiac output (CO) based on the partial carbon dioxide rebreathing technique. 2,3In comparison with CO data obtained by the thermodilution technique (COTD), CO readings obtained by the carbon dioxide rebreathing system (CONI) have proved reliable when tidal volume (VT) is constant and set to maintain normocapnia. This accuracy is maintained without regard to several key factors, such as whether ventilatory mode is pressure- or volume-controlled ventilation, inspired oxygen fraction (Fio2), or positive end-expiratory pressure (PEEP). 4However, when VTis reduced at a constant respiratory rate, CONIunderreports CO. The reason for this underreporting remains unknown.
Using a differential Fick equation, the partial carbon dioxide rebreathing technique calculates CO from the change in carbon dioxide production (V̇co2) and the change in end-tidal carbon dioxide pressure (Petco2) when periodic partial carbon dioxide rebreathing creates a carbon dioxide disturbance. 2Therefore, the accuracy of the technique depends on accurate measurement of both the change in V̇co2and the change in Petco2. Once a patient starts breathing spontaneously, V̇co2and Petco2vary from breath to breath. We speculate that irregular spontaneous breaths may affect the accuracy of the partial carbon dioxide rebreathing technique. Moreover, CONImeasurement may increase the work of breathing because, during the partial rebreathing phase, there is an increase in Petco2. Therefore, we designed this prospective study with three objectives: to investigate (1) whether small VTor small minute ventilation (V̇E) results in the underestimation of CONI; (2) the accuracy of the partial carbon dioxide rebreathing technique when spontaneous breaths are supported by partial ventilatory support, such as synchronized intermittent mandatory ventilation (SIMV) and pressure support ventilation (PSV); and (3) how respiratory efforts change during carbon dioxide rebreathing when spontaneous breathing is present. Our hypothesis is that the partial carbon dioxide rebreathing technique is less accurate when V̇Eis unstable or when patients are spontaneously breathing and that the carbon dioxide rebreathing increases respiratory efforts in spontaneous breathing patients.
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.
Twenty-five adult patients aged 19–75 yr (median age, 63 yr) who had undergone cardiac surgery were enrolled in this study (table 1). They were consecutively admitted patients whose cases matched the following criteria: insertion of a pulmonary artery catheter, stable hemodynamics in the intensive care unit, and no leakage around the endotracheal tube. We excluded candidates who had central nervous system disorders, might be adversely affected by induced hypercapnia, or demonstrated severe tricuspid regurgitation. 4Arterial blood pressure, heart rate, pulmonary artery pressure, central venous pressure, and pulse oximeter signal (PM-1000; Nellcor Inc., Hayward, CA) were continuously monitored in all patients. After waiting 1–2 h for hemodynamics to stabilize after surgery, we started the measurements. First, using an inspiratory-hold technique, 5we measured the effective static compliance and resistance of the respiratory system.
We measured CO using two methods: thermodilution (COTD) and noninvasive partial carbon dioxide rebreathing technique (CONI). COTDwas obtained using a 7.5-French pulmonary artery catheter (Abbott Laboratories, North Chicago, IL). Injection of 10 ml cold saline (0°C) was performed in triplicate, and the values were averaged. We standardized the timing of bolus injection after the first half of the expiratory phase. 6CONImeasurement was performed with the partial carbon dioxide rebreathing technique (NICO2software version 3.1, fast mode; Novametrix Medical Systems Inc., Wallingford, CT). This procedure has been described in detail elsewhere. 1,2Briefly, V̇co2is calculated on a breath-by-breath basis, and the differential Fick equation is applied to establish the relation between V̇co2and CO as follows:
where Cv̄co2represents the carbon dioxide content in mixed venous blood, and Caco2represents the carbon dioxide content in arterial blood. In the NICO2system of the current version, carbon dioxide rebreathing is performed for 50 s every 3 min. Assuming that CO remains constant during the carbon dioxide rebreathing procedure, the following equation is substituted for the previous one:
where ΔV̇co2is the change in V̇co2between normal breathing and carbon dioxide rebreathing, ΔCv̄co2is the change in mixed venous carbon dioxide content, and ΔCaco2is the change in arterial carbon dioxide content. Then, assuming that Cv̄co2also remains constant during the carbon dioxide rebreathing procedure, the following equation is introduced:
When end-capillary content (Ccco2) is used in place of Caco2, pulmonary capillary blood flow (PCBF), the blood flow that participates in alveolar gas exchange, is measured rather than CO, and the following equation is plotted:
Assuming here that ΔCcco2is proportional to changes in Petco2, the following equation can be plotted:
where ΔPetco2is the change in Petco2between normal breathing and carbon dioxide rebreathing, and S is the slope of the carbon dioxide dissociation curve from hemoglobin. CO is the sum of PCBF and intrapulmonary shunt flow (Q̇S); then, CO is expressed in the following equation:
where Q̇S/Q̇Tis the intrapulmonary shunt fraction. The noninvasive method for estimating shunt fraction in the NICO2system is adapted from Nunn's iso-shunt plots, which are a series of continuous curves indicating the relation between arterial oxygen pressure (Pao2) and Fio2for different levels of shunt. 3Pao2is a function of arterial blood oxygen saturation (Sao2), which is noninvasively determined using the pulse oximeter signal. Before the start of the study protocol, the NICO2system was calibrated for zero CO2. We entered the results of Pao2, arterial carbon dioxide pressure (Paco2), Fio2, and hemoglobin concentration into the machine when each patient was undergoing the baseline ventilation.
After admission to the intensive care unit, each patient was ventilated with an 8400 STi ventilator (Bird Corp., Palm Springs, CA). Initial ventilatory settings were as follows: SIMV, volume-controlled ventilation, inspired VTof 10 ml/kg, respiratory rate of 10 breaths/min, inspiratory time of 1.0 s, PEEP of 4 cm H2O, and pressure support of 10 cm H2O. The Fio2settings were adjusted by attending physicians to maintain Pao2greater than 100 mmHg. With the patients maintained in the supine position, sedated with continuous intravenous injection of propofol (2 to 3 mg · kg−1· h−1), we started the measurements.
We performed the two protocols serially. In the first protocol, to prevent spontaneous breathing, if needed, we administered bolus vecuronium bromide (4–8 mg). We applied three settings of volume-controlled ventilation in random order as follows: (1) inspired VTof 12 ml/kg and respiratory rate of 10 breaths/min; (2) VTof 6 ml/kg and respiratory rate of 20 breaths/min; and (3) VTof 6 ml/kg and respiratory rate of 10 breaths/min. The first and second settings should result in identical V̇E, and the last setting should result in half the V̇Evalue. At each setting, the rebreathing loop was size adjusted according to the manufacturer's instructions recommended for a VTsetting of 12 ml/kg. PEEP and Fio2identical to baseline were used throughout the measurement period. After establishing steady state conditions (approximately 15 min) and confirming stable values of CONI(< 5% change in the successive readings), we measured both COTDand CONI. The values of expired VTand V̇Ewere recorded from the digital display of the ventilator. Arterial blood samples were analyzed with a calibrated blood gas analyzer (ABL 505; Radiometer, Copenhagen, Denmark). Hemodynamic data were also recorded. Dead space fraction (VD/VT) and venous admixture fraction (Q̇S/Q̇T) were calculated as described elsewhere. 4
In the second protocol, we examined the measurement of CO when there was spontaneous breathing effort. We stopped the infusion of vecuronium and decreased the propofol infusion rate to 0.5 mg · kg−1· h−1. When the patient recovered spontaneous breathing and satisfied our extubation criteria (recovery of cough reflex; VT≥ 8 ml/kg and respiratory rate ≤ 20 breaths/min under pressure support of 10 cm H2O; arterial blood gas of pH, 7.35–7.45; Paco2, 35–45 mmHg; and Pao2≥ 100 mmHg at Fio2≤ 0.5), we started the measurements. In random order, we applied three settings of partial ventilatory support: (1) SIMV plus PSV, mandatory breath rate of 5 breaths/min, mandatory VTof 12 ml/kg, and 6 cm H2O of pressure support; (2) continuous positive airway pressure plus PSV, 10 cm H2O of pressure support; and (3) the same setting of PSV with the shortest length of rebreathing loop. In the first and second settings, the rebreathing loop was sized according to the manufacturer's instructions recommended for a VTsetting of 12 ml/kg; at the other setting, the loop was fully retracted (150 ml). After establishing steady state, we measured both COTDand CONI. Because VT, respiratory rate, and V̇Eincreased according to the stimulus of carbon dioxide rebreathing, we recorded VT, respiratory rate, and V̇Eat the end of the normal breathing period and at the end of the carbon dioxide rebreathing period. We limited ourselves to performing a single measurement for each ventilatory setting per patient.
Data are presented as mean ± SD. Using analysis of variance with repeated measures, mean values were compared across different settings. When significance was observed, the mean values were tested by multiple comparison with the Bonferroni correction. We evaluated the correlation between CONIand COTDwith linear regression and Bland-Altman analysis. 7Statistical significance was set at P < 0.05.
Patients had respiratory system compliance of 48.4 ± 8.7 ml/cm H2O and resistance of 9.6 ± 2.8 cm H2O · s · l−1. All patients safely underwent all the measurements and were extubated within 1 h after the measurement protocol.
Controlled Mechanical Ventilation
Table 2shows respiratory and hemodynamic results during controlled mechanical ventilation. Although V̇Ewas identical, there was higher Paco2and VD/VTat the ventilatory setting of VTof 6 ml/kg and respiratory rate of 20 breaths/min than at VTof 12 ml/kg and respiratory rate of 10 breaths/min. When V̇Ewas set to a smaller value (VTof 6 ml/kg and respiratory rate of 10 breaths/min), Paco2and Petco2were significantly higher, and CONIand V̇co2were significantly lower, compared with the other two settings that provided twice as much V̇E. The values of COTD, a ratio of Pao2to Fio2, and Q̇S/Q̇Tdid not differ significantly at any of ventilatory settings.
The results of Bland-Altman analysis and regression analysis are summarized in table 3and figures 1 and 2. CONIcorrelated moderately with COTDwhen V̇Ewas high, regardless of the VT(figs. 1 and 2). However, when V̇Ewas set at half, CONIunderestimated CO (y = 0.70x; bias, −1.73 l/min) and the correlation coefficient (R) was small (0.34;table 3). Analysis of the results obtained at the setting of 6 ml/kg VTand 20 breaths/min respiratory rate showed bias values and slope of linear regression between those of the other two ventilatory settings.
Table 4shows respiratory and hemodynamic results when patients had spontaneous breaths. At the phase of normal breathing, all of the three ventilatory settings showed similar V̇E(mean value of 0.11 l · min−1· kg−1) and respiratory rate (12.3–12.4 breaths/min). When the ventilatory mode was PSV, VTat the phase of normal breathing was similar for different sizes of rebreathing loop. When PSV was applied with the rebreathing loop adjusted for 12 ml/kg VT, at the phase of carbon dioxide rebreathing, V̇Eincreased by 46%, VTincreased by 20%, and respiratory rate increased by 30%. Similarly, when SIMV–PSV was applied with the same size of rebreathing loop, at the phase of carbon dioxide rebreathing, V̇Eincreased by 28%, VTof spontaneous breaths increased by 23%, and total respiratory rate increased by 28%. By contrast, when the shortest rebreathing loop was used with PSV, carbon dioxide rebreathing caused smaller increases in V̇E(+17%), VT(+10%), and respiratory rate (+10%). There were no significant differences at the three ventilatory settings in blood gas analysis data, V̇co2, Petco2, VD/VT, and Q̇S/Q̇T.
The results of Bland-Altman analysis and regression analysis when spontaneous breaths were present are summarized in table 5and figures 3 and 4. During SIMV–PSV mode, the correlation between the CONIand COTDwas poor (precision, 1.41 l/min and R = 0.23). When PSV was applied with the rebreathing loop adjusted for 12 ml/kg VT, the correlation was moderate (precision, 1.26 l/min and R = 0.75). When the shortest rebreathing loop was used during PSV, CONIoverestimated COTD(bias, 1.2 l/min and slope = 1.19) with large precision (1.80 l/min).
The main findings of this study are as follows. (1) Rather than small VT, low V̇Eled to less accuracy of CONI. (2) When spontaneous breathing effort was present, CONIwas less accurate than during controlled mechanical ventilation. (3) During carbon dioxide rebreathing, spontaneous breathing VTand respiratory rate increased. (4) Shortening the rebreathing loop reduced the accuracy of CONI, although causing less increase in VTand respiratory rate during carbon dioxide rebreathing.
Controlled Mechanical Ventilation
We had previously shown that, when VTis constant during controlled mechanical ventilation, CONIcorrelates well with COTD, regardless of inspired oxygen fraction, PEEP, or whether ventilation was pressure or volume controlled. 4At constant respiratory rate, however, reduced VTresults in an underestimation of CONI, and the reason for this discrepancy remained to be clarified. We designed the first part of this study to investigate whether VTor V̇Eis the dominant factor for the accuracy of CONI. For VT, when V̇Eof volume-controlled ventilation was set to maintain normocapnia, a correlation between CONIand COTDwas clinically acceptable (bias < 1 l/min, precision ≤ 1 l/min), whether VTwas large or small (table 3). The percentage error, which was calculated from the precision divided by the mean CO value, was also acceptable (18% for large VTsetting, 13% for small VTsetting) because acceptable range is reported to be less than 20%. 8By contrast, when V̇Ewas reduced to half, CONIunderestimated COTDwith worse precision (1.27 l/min) and percentage error (29%). These findings clearly indicate that V̇Eis more important than VTfor CONIaccuracy. The NICO2system, by using the following equation, assumes that Cv̄co2is constant during the measurement period:
Cv̄co2may increase during carbon dioxide rebreathing, however, when VD/VTis large and alveolar ventilation is low. When using the above equation, the neglecting of ΔCv̄co2could lead to an underestimation of CO. At the end of the 50-s rebreathing period in the NICO2system, mixed venous Pco2was reported to increase by 0.53 mmHg (median) or by 2.5% (average) from the initial value. 9,10Even at identical V̇E, we observed that CONIunderestimated CO at a high respiratory rate (20 breaths/min) and small VT, compared to ventilation at a low respiratory rate (10 breaths/min) and large VT(table 3). We speculate that increased VD/VTand decreased alveolar V̇Eat high respiratory rate leads to this inaccuracy and that a change in VTcan also affect CONIaccuracy by this mechanism. It is clear that controlled mechanical ventilation with constant V̇Eand constant VTprovides more reliable CONImeasurement.
Spontaneous Breathing Efforts
There have been few clinical reports on the accuracy of the NICO2system when spontaneous breathing is allowed. It is now common for patients receiving intensive care to be ventilated with modes that allow some spontaneous breathing. Consequently, we need to confirm whether the NICO2technique provides effective monitoring when spontaneous breathing is present, such as during mixed ventilation consisting of spontaneous breaths and mandatory ventilation. Although several reports have compared CONIwith continuous COTDmeasurement under mixed ventilation, actual ventilatory settings were not specified, 11–13and modified algorithms were used. 11,12Meanwhile, using a system different from the NICO2, Gama de Abreu et al. 14have reported that the intraindividual variability of CO measured by partial carbon dioxide rebreathing technique was significantly larger during irregular spontaneous breathing than when respiratory rate and VTwere fixed. In this study, when spontaneous breathing effort was present, precision (1.26–1.80 l/min) and percentage error (20–30%) were large, indicating less accuracy of the NICO2system. 8The exact reason for this inaccuracy remains unknown, but there are several plausible reasons.
First, under the influence of spontaneous breathing, V̇Emay both drift by time and increase in response to carbon dioxide rebreathing. These changes in V̇Emay foul the assumption of constant Cv̄co2and affect accuracy of the NICO2system. 9,10Second, it may be possible that the stimulus of carbon dioxide rebreathing increases CO in spontaneously breathing patients. Because only minimal dosage of propofol (0.5 mg · kg−1· h−1) was used in our experiment, it is likely that the sympathetic nerve of the patient, as well as the respiratory center, is stimulated during carbon dioxide rebreathing. Third, when there is spontaneous breathing effort, VTchanges breath by breath, which may affect accurate measurement of V̇co2or Petco2.
Figure 5shows representative V̇co2and Petco2traces from a patient during controlled mechanical ventilation, SIMV–PSV, and PSV. During controlled mechanical ventilation, both V̇co2per breath and Petco2produced a stable plateau during normal breathing and carbon dioxide rebreathing. On the other hand, during SIMV–PSV, the V̇co2per breath changed drastically on a breath-by-breath basis because of the variation in VTbetween mandatory breaths (830 ml) and spontaneous breaths (540–620 ml). In the NICO2system, values for V̇co2and Petco2during 60-s baseline normal ventilation were calculated as the average of samples of 33–60 s, and those during the 50-s rebreathing period were calculated for intervals of 25–50 s. 3Because CONIis derived from changes in V̇co2and Petco2, during SIMV–PSV, the presence of marked breath-by-breath changes in V̇co2and Petco2may affect CONIaccuracy. During PSV, breath-by-breath changes in V̇co2or Petco2are smaller than during SIMV–PSV. Even so, neither V̇co2nor Petco2produced a steady plateau during normal breathing or rebreathing periods, probably because V̇Echanged under the influence of carbon dioxide rebreathing. Worse precision during SIMV–PSV and PSV supports the speculation that irregular spontaneous breathing affects the accuracy of the current version of the NICO2system. In fact, a correlation between CONIand COTDwas better even during PSV in the previous study 4than in the current one, probably because the patients had been sedated more deeply with 2 to 3 mg · kg−1· h−1propofol, resulting in more regular spontaneous breathing. 4
Rebreathing Loop Length and Respiratory Efforts
Once the rebreathing loop is adjusted for a given VT, it is possible that an awake patient may increase VT, making the rebreathing loop relatively too short. In light of this, it may be rational to adjust the rebreathing loop for the largest anticipated VT. In this case, however, when the rebreathing loop is adjusted for large VT, carbon dioxide rebreathing stimulates the respiratory center of the patient, resulting in increased VT, respiratory rate, and V̇E. The increase in V̇Ewas 28% during SIMV–PSV and 46% during PSV (table 4), suggesting that respiratory efforts increase during carbon dioxide rebreathing. Although fully retracting the rebreathing loop minimized respiratory efforts due to carbon dioxide rebreathing, minimal loops resulted in overestimation and poor correlation (table 5).
The current study has several limitations. First, we waited for approximately 15 min to establish steady state after each change of ventilatory condition. However, when spontaneous breathing effort is present and V̇Eis changed, more time may be required to attain stable conditions and more accurate CONI, which impairs clinical usefulness of NICO2monitoring. Second, all patients in this study were sedated, but awake patients may respond differently to carbon dioxide rebreathing. Third, effects of gas compression on the V̇Eor VTmeasurement should be considered in patients with low compliance or high resistance, although the patients enrolled in this study showed normal lung mechanics. Finally, the range of CO measured in this study was relatively small (3.26–9.6 l/min) and only one steady state CO was studied in each patient. Further study is needed to evaluate the accuracy and reproducibility of the NICO2system under various hemodynamic conditions.
In conclusion, the change in V̇Eor alveolar ventilation rather than VTaffects the accuracy of CO measurement using noninvasive partial carbon dioxide rebreathing. When spontaneous breathing efforts are present, the CO measurement using the partial carbon dioxide rebreathing method becomes less accurate. Moreover, during the carbon dioxide rebreathing phase, the respiratory efforts during SIMV–PSV or PSV mode increase.