This single-center, prospective cohort study was conducted in the intensive care unit (ICU) of a tertiary hospital of Lisbon, between August 2014 and July 2015. Following approval of the ethic committee of Centro Hospitalar de Lisboa Central, informed consent was obtained from each patient's next of kin or a posteriori from the patient himself.

The study included all patients admitted to the ICU for therapeutic hypothermia following cardiac arrest, according to the unit protocol. The exclusion criteria were any condition that contraindicated the insertion of PiCCO® or impaired the transthoracic echocardiographic window, as neck and thoracic severe trauma, burning or skin infection. Additionally, patients were excluded if they had pathology that could diminish the accuracy of CO calculation using ECHO (chronic atrial fibrillation, cardiac valve disease, pulmonary thromboembolism or intracardiac shunts) or PiCCO (severe peripheral arterial disease or arterial bypass).

At ICU admission, patients received central venous catheter (Kimal®; 5-lumened, 8.5Fr×15cm) on the internal jugular or subclavian vein and a PiCCO® catheter (Pulsion Medical Systems, 5Fr×20cm) inserted in the femoral artery, connected to a Siemens MP 50 monitor with the appropriate software. Based on the modified Stewart-Hamilton equation, cardiac output is inversely related to the concentration and total passage time of an indicator solution measured after its transit through the heart.11

During the therapeutic hypothermia and rewarming period, CO was calculated through the PiCCO system followed by ECHO estimation (General Electric® VIVID S5, with 3.5MHz probe). The two measurements were performed by different, blinded investigators, as close as possible (maximum interval of time: 10minutes). At the same time, central temperature and hemodynamic data (heart rate, rhythm and mean arterial systemic pressure) were registered. It was assured the constancy of each interfering variable such as level of sedation, ventilation parameters, vasoactive drugs or any other IV infusion. Therefore, a pair of CO measurements (one by PiCCO and one by ECHO) for a determined temperature was obtained. Additionally, demographic data, severity scores at admission, cause and rhythm of arrest and final outcome were collected.

We considered 0.5L/min as the maximum clinically accepted difference between the values of COECHO and COPiCCO. In other words, the two methods were considered to agree when the difference fell in the interval (−0.5, 0.5).

For the CO calculation by thermodilution technique, 20ml of iced (<8°C) saline 0.9% was delivered in the proximal lumen of the central venous catheter and mixed with blood through the systemic and pulmonary circulation. The injection was performed as rapidly as possible, irrespective of the respiratory cycle. The thermistor-tipped arterial line, placed in the femoral artery, quantified the change in temperature over time. The thermodilution curve recorded by the arterial thermistor was automatically analyzed by the PiCCO® software, obtaining the value of CO. Triplicate injections were performed for each set of measurements and considered the mean value of the three.

The Doppler estimated CO was obtained multiplying the heart rate (HR) by the Doppler estimated stroke volume (SV). The last one uses the velocity-time integral of flow through the left ventricular outflow tract (VTILVOT) and the area of the left ventricular outflow tract (ALVOT) which, in turn, is calculated using the left ventricular outflow tract diameter (DLVOT) by the following formula:

The VTILVOT was recorded by pulsed-wave Doppler from an apical fiver chamber view, by placing the Doppler sample immediately below the aortic valve annulus, aligned with the center of the valve where the flow is maximum. The final value of VTILVOT was the mean of three consecutive determinations. DLVOT was measured in a parasternal long-axis view, just before the aortic annulus, from the inner edge to outer edge, parallel to the valve apparatus.

Five complete and consecutive measurements were performed, and considered the mean as the final value for COECHO.

In order to assure the reliability of the COECHO measurements, as the operator dependent errors are the major pitfall of this technique, a previous study was conducted to evaluate the echocardiographic skills of the five investigators involved in the major study. Repeating the procedure as described above (mean three determinations of VTILVOT and one of DLVOT), each investigator performed five COECHO measurements in a patient under therapeutic hypothermia and was followed by other blinded investigator who obtained another five measurements. This procedure was repeated in ten different patients so that every investigator was compared with each of the other four.

Continuous variables were described with mean and standard deviation (SD) or median and inter-quantile range (IQR: 25th percentile–75th percentile), as appropriate. Categorical data were presented as frequencies and percentages.

To assess the precision of the ECHO measurements, the intra-observer repeatability and inter-observer reproducibility were studied using intraclass correlation coefficients (ICCs), and corresponding 95% confidence intervals. These were estimated using a generalized linear mixed effects model with a random intercept and a random slope, taking into account the correlation structure between CO measures of the same patient. To evaluate the agreement between ECHO and PiCCO for measuring CO, Bland–Altman graphical method was used. Additionally, a stratified analysis by temperature (<36°C, ≥36°C) was performed using generalized linear mixed effects models with a random intercept, where the difference between the two methods was adjusted by temperature. Both generalized linear mixed effects models considered a variance–covariance matrix defined as a multiple of the identity matrix.

The best cut-off value that identifies patients who have a difference between COECHO and COPiCCO belonging to the interval (−0.5, 0.5), was calculated by maximizing specificity.12 After discretizing CO measures by the obtained cut-off value, diagnostic test performance measures (sensitivity, specificity, positive and negative predictive values as well as false positive and false negative rates) were calculated.

The level of significance α=0.05 was considered. Data analysis was performed using Stata (StataCorp. 2011; Stata Statistical Software: Release 12, College Station, TX: StataCorp LP.) and R software (R: A Language and Environment for Statistical Computing, R Core Team, R Foundation for Statistical Computing, Vienna, Austria, year=2014, http://www.R-project.org.).

Fifteen patients met the inclusion criteria of the study. The demographic characteristics, severity scores at admission as well as the arrest rhythm and cause are displayed in Table 1. Eleven patients (73%) initiated hypothermia protocol in the ICU, one started cooling in pre-hospital care and the remaining three began the protocol in the Emergency Department. In-hospital mortality was 47%.

Regarding the intra-observer repeatability and inter-observer reproducibility, the intraclass correlation coefficients were both equal to 0.998 (95% CI: 0.995–0.999) (Fig. 1).

Figure 1.

Echocardiography inter-observer and intra-observer variability analysis – Scatterplot of cardiac output versus patient.

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A total of 30 paired COECHO/COPiCCO measurements were analyzed. The mean time interval between the measurements was 7 (SD=2)minutes. Mean temperature during the measurements was 35°C, with 18 paired measurements performed under 36°C and 12 at a temperature equal or superior to 36°C.

In overall pairs of CO measurements, the mean difference between the two methods was −0.24L/min, with limits of agreement (−1.26, 0.77).

Considering the measurements at normothermia (≥36°C), the mean difference was 0.030L/min, with limits of agreement (−0.22, 0.28). All of the 12 pairs of CO measurements registered at this temperature, differed less than 0.5L/min, previously defined as an acceptable difference (Fig. 2a).

Figure 2.

Discrepancy between PiCCO and ECHO cardiac output measures with a temperature ≥36°C (a) and <36°C (b).

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In hypothermia (<36°C), the mean difference of CO measurements was −0.426L/min with limits of agreement (−1.60, 0.75) and only 44% (8/18) of the paired measurements fell in the interval (−0.5, 0.5). For the remaining 10 measurements that differed more than 0.5L/min, the difference COECHO−COPiCCO was negative in most cases (Fig. 2b).

Fig. 3 reinforces that the concordance between COPICCO and COECHO measurements was better when temperature was equal or above 36°C.

Figure 3.

Scatterplot of PiCCO versus ECHO cardiac output measures, considering the groups of temperature <36°C and ≥36°C. Dashed line represents the line where ECHO and PiCCO have equal values.

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The calculated temperature cut-off, in order to maximize specificity, was 35.95°C. Above this temperature, the specificity was 100% and the false positive rate was 0%, traducing a complete agreement between the methods.

Results of the linear mixed effects models (Table 2) are in accordance with those obtained previously. In fact, for temperatures <36°C the difference between the two methods, after adjusting for temperature, was statistically significant (p=0.001). However, for temperatures ≥36°C, no significant difference was found between the two methods (p=0.374). Additionally, the resulting ICC of the model for temperatures higher or equal 36°C was higher (0.998, 95% CI: 0.993–0.999) than that obtained for lower temperatures (0.843, 95% CI: 0.652–0.939).