Cardiac output (CO) measurement is still regarded as one of the key haemodynamic variables in the assessment of cardiac function and as an essential parameter for the therapy of critically ill patients . Currently, the most common method for measurement of CO is based on the thermodilution technique requiring the insertion of a pulmonary artery catheter (PAC), although the accuracy of these derived CO values in septic patients has been questioned .
Arterial trans-cardiopulmonary thermodilution (ATD) represents an alternative, less invasive technique for CO measurement, which is based on the same principles as pulmonary arterial thermodilution (PATD) . It is generally accepted by intensive care physicians, that CO monitoring is necessary in patients with septic shock who depend on vasopressor support . The vast majority of studies about the concordance of ATD and PATD derived CO has been carried out in the perioperative period by direct comparison between the two thermodilution methods [5,6]. While under stable clinical conditions a satisfactory agreement between PATD and Fick calculated CO measurements could be demonstrated , other studies revealed discrepancies between the two methods in critical illness [8,9]. In contrast, a comparison between ATD and Fick calculated CO in critically ill children revealed a good correlation . Surprisingly, there is a lack of data comparing the concordance of both PATD and ATD thermodilution CO, to the Fick calculation in septic shock, which is regarded as the ‘physiological’ gold standard . In view of the controversy about the risk-benefit balance of right heart catheterization [12,13], it is important to gain more knowledge about alternative methods in situations where CO measurements are necessary.
The aim of our investigation was to compare ATD and PATD derived CO measurements in experimental septic shock to CO values calculated by the Fick method in an experimental setting, which mirrors the clinical situation of human intensive care patients as closely as possible.
Experiments were performed in 20 German landrace pigs at the animal laboratory of Hannover Medical School (Germany). Animals had an average weight of 20.9 ± 1.9 kg. The study protocol was approved by the University Animal Care Committee as well as the federal authorities for animal research of the Bezirksregierung Hannover, Niedersachsen, Germany and the principles of laboratory animal care were followed. Animals were fasted for 24 h with water ad libidum.
After premedication with 5 mg kg−1 of Azaperon (Stressnyl®; Jansen, Neuss, Germany) intramuscularly a peripheral venous catheter was placed in an ear vein. Anaesthesia was induced by intravenous (i.v.) injection of propofol (Disoprivan®; Zeneca, Plankstadt, Germany) until intubating conditions were achieved. Pigs were orally intubated and placed in the supine position. Anaesthesia was maintained with an infusion of 5 mg kg−1 h−1 thiopentone (Trapanal®; Byk Gulden, Konstanz, Germany), and 0.01 mg kg−1 h−1 fentanyl (Fentanyl Curamed®; Curamed, Karlsruhe, Germany). Controlled mode ventilation was chosen to ventilate the animals (Servo 900; Siemens-Elema, Solna, Sweden) with an inspiratory oxygen fraction of 0.4, an inspiratory/expiratory ratio of 1: 2, and a respiratory rate of 16 breaths min−1. The tidal volume was adjusted to maintain a PaCO2 of 4.6-5.9 kPa. The body core temperature was kept at 37-39°C by using an infrared lamp, a circulating water-mattress and warmed solutions.
A standard cutdown technique to the right neck vessels was performed. After exposure of right jugular vein and right carotid artery, five French (FG) (arterial) and eight FG (venous) introducer catheters shortened to 4 cm (Arrow, Reading, PA, USA) were placed, a balloon-tipped thermodilution pulmonary artery catheter was inserted via the right jugular vein (131F7; Baxter-Healthcare, Irvine, CA, USA) and connected to a bedside CO monitor (Vigilance®; Baxter-Healthcare, Irvine, CA, USA). Correct position was assumed by advancing the catheter until a pulmonary occlusion pressure tracing was obtained from the distal infusion port. The correct position of the right atrial lumen was assured as the catheter was advanced until a right ventricular pressure tracing was obtained. Afterwards the catheter was pulled back until a right atrium pressure tracing curve was obtained and therefore it was assured that the thermodilution injections took place in the right atrium. The pulmonary and central venous pressures (CVP) were measured and the pressure traces monitored continuously.
ATD was measured with an arterial thermistor-tipped catheter inserted into the right carotid artery (4F-PV-2024; Pulsion-Medical-Systems, Munich, Germany) connected to a bedside computer (COLD-Z021; Pulsion-Medical-Systems, Munich, Germany) with an inline injectate sensor connected to the central venous line. This catheter was advanced 10 cm through the right carotid artery into the aortic arch.
As the FiO2 was kept constant at 0.4, systemic oxygen uptake (VO2) and systemic CO2 production (VCO2) were continuously measured directly from the respiratory gases and recorded minute by minute using a Deltatrac® Metabolic Monitor (Datex, Helsinki, Finland). This device is an open-system indirect calorimeter and its accuracy has been assessed in lung models . VCO2 is first measured by drawing all expired gas into a fixed-flow generator that entrains air to a total flow rate which is usually set at 45L min−1. An infrared analyser measures the CO2 fraction in the resulting mixture and VCO2 is calculated by multiplying the fractional concentration by the total flow rate. The respiratory quotient (RQ) is calculated from the equation:
where FiO2: inspired fraction of oxygen; FeO2: expired fraction of oxygen; FeCO2: expired fraction of CO2.
This equation is derived by substitution into the Haldane transformation, which states the relationship between inspiratory and expiratory volume and enables the calculation of RQ from gas fractions alone, assuming all other inert gases are in equilibrium. Inspired and expired oxygen and CO2 fractions are measured by paramagnetic and infrared analysers at appropriate points in the system. VO2 is then derived as VCO2/RQ on the assumption that a steady state is present. Before each use, the machine was allowed to warm up for 30 min and was then calibrated for atmospheric pressure using an aneroid barometer. A gas calibration was carried out before each measurement against a standard mixture (95% oxygen and 5% CO2).
Mesurements were performed over a 5 min period at the end of which arterial and mixed venous blood gases were taken simultaneously and measured by co-oximetry (System-860 including co-oximetry system-835; Chiron Diagnostics GmbH, Germany). CO was calculated from the Fick equation:
where CaO2 = (1.36 × Hb × SaO2) + (PaO2 × 0.003) and CvO2 = (1.36 × Hb × SvO2) + (PvO2 × 0.003). Hb: haemoglobin concentration (g L−1); CaO2, CvO2: arterial and mixed venous oxygen content (mL L−1); SaO2, SvO2: arterial and mixed venous oxygen saturation (%); PaO2, PvO2: partial pressure of dissolved arterial and mixed venous oxygen (torr).
During haemodynamic stability (mean arterial pressure (MAP) and heart rate (HR) were constant over 5 min) simultaneous CO-measurements were performed over a period of 8 h. Data reported are the mean of four injections of 5 mL ice-cold 5% dextrose randomly spread over the respiratory cycle. CO was calculated by the Stewart-Hamilton method and compared to the CO calculated from the Fick equation.
All intravascular pressure measurements were referenced to midchest level. MAP, CVP and pulmonary arterial occlusion pressure (PAOP) were recorded from calibrated pressure transducers (Peter von Berg, Medizintechnik GmbH, Engelharting, Germany), and values obtained at end expiration. The haemodynamic treatment scheme was aimed at maintenance of CVP of 12 mmHg using fluids. No vasoactive drugs were used during the course of the study.
Septic shock model
In all animals a midline laparotomy and cystotomy were performed using standardized sterile surgical techniques. A urinary catheter was placed to drain and determine urine output. An opening of 2 cm was made in the caecum and 1g kg−1 body weight of its contents was aspirated. Then the caecotomy was closed and a sterile catheter was positioned intra-abdominally before the abdomen was closed with a suture. The catheter was tunnelled out through the subcutaneous tissue of the lateral flank. After the surgical preparation animals were allowed to recover for 120 min. Continuous i.v. infusion of Ringer's solution (10 mL kg−1 h−1) was given during surgery and in the post-surgical period. To induce sepsis, autologous faeces (1g kg−1) suspended in 150 mL of warm isotonic NaCl (37°C) was injected through the abdominal catheter.
All data are presented as mean ± standard deviation (SD). Data were statistically analysed using SPSS for Windows (release 10.07) (SPSS Inc., Chicago, IL, USA). CO obtained from ATD and PATD were compared to the Fick calculation with the mean bias (with 95% confidence interval (CI)) and limits of agreement in the manner outlined by Bland and Altman . Regression analyses and the influence of the mean value on the bias were also performed. Differences were considered significant at P < 0.05.
A total of 80 measurements were performed in 20 animals. Changes of systemic haemodynamics during sepsis are given in Table 1.
Fick derived CO estimation and PATD CO were correlated (r = 0.94, r2 = 0.87, P < 0.001; Fig. 1a). Mean CO measured by PATD was 94.3 ± 40.1 mL min−1 kg−1 (range: 25.2-218.7 mL min−1 kg−1). Bias between Fick derived CO and PATD was 10.1 mL min−1 kg−1 (95% CI: 6.0- 14.2 mL min−1 kg−1) with limits of agreement of −26.8 to 47.0 mL min−1 kg−1 and a precision of 14.5 mL min−1 kg−1 (Fig. 1b). The analysis of the influence of the mean value on the bias was: CO Fick − PATD CO (mL min−1) = 0.2(CO Fick + PATD CO)/2 (mL min−1 kg−1) − 9.8; r = 0.48, r2 = 0.23, P < 0.05.
Correlation between Fick derived CO estimation and ATD CO was similar (r = 0.91, r2 = 0.83, P < 0.001; Fig. 2a). Mean CO measured by ATD was 104.3 ± 43.2 mL min−1 kg−1 (range: 27.0- 235.0 mL min−1 kg−1). Bias between Fick derived CO and ATD was 0.75 mL min−1 kg−1 (95% CI: −3.8 to 5.3 mL min−1 kg−1) with limits of agreement of −39.7 to 41.2 mL min−1 kg−1 and a precision of 17.8 mL min−1 kg−1 (Fig. 2b). The analysis of the influence of the mean value on the bias revealed: CO Fick − ATD CO (mL min−1 kg−1) = 0.1(CO Fick + ATD CO)/2 (mL min−1 kg−1) − 12.9; r = 0.29, r2 = 0.08, P < 0.05.
In this study we compared ATD derived CO measurements and PATD derived CO measurements with the ‘physiological’ gold standard using the Fick method. Our results demonstrate that the concordance of ATD and PATD derived CO measurements compared to the Fick calculation is good even in septic shock with severe haemodynamic disturbances.
In non-septic conditions several validation studies have compared ATD and PATD. Similar to our results Tibby and Collegues reported a good correlation and agreement comparing ATD with Fick derived CO in critically ill children . In patients undergoing coronary artery bypass grafting a significant correlation between ATD and PATD was found . The use of the carotid artery for placement of the arterial thermistor-tipped catheter might be considered as a limitation for the extrapolation of the clinical scenario. On the other hand, Segal and colleagues could demonstrate that measurement of arterial thermodilution CO using the axillary artery yielded accurate and reproducible results in comparison to the femoral arterial access . Thus, in clinical practice the axillary artery is routinely used for insertion of arterial thermodilution cathethers to measure CO in critically ill patients. Therefore, our results are meaningful in the clinical scenario. In previous studies, the limits of agreement have been reported as: ±52 mL min−1 m−2 in mixed general intensive care patients  and +3 to −33 mL min−1 m−2 in post-coronary artery bypass surgery patients . Similar to our results Sakka and colleagues reported a good agreement between ATD and PATD with Fick derived CO measurements in haemodynamically stable septic patients . In their study the bias between Fick derived CO and ATD was ±0.02 L min−1 with limits of agreement of 2.38 L min−1 and the bias between Fick derived CO and PATD was 0.75L min−1 with limits of agreement of ±2.26 L min−1. In contrast, Dhingra and colleagues reported recently a lack of agreement between PATD and Fick derived CO in critically ill patients . Especially in patients with high CO, the Fick tended to consistently produce higher CO compared to PATD, suggesting a systematic error, whereas the two methods were probably interchangeable up to 6 L min−1. Of note, the results should be considered carefully before applying to critically ill patients as they have been extrapolated from terminally ill patients just before death . Yet, in another recent clinical study, Gonzalez and colleagues could confirm a good agreement between PATD and Fick derived measurements for CO values of less than 5L min−1, but the agreement was lost in the higher range of CO values . In our study, the analysis of the influence of the mean on the bias revealed that both PATD and ATD tended to overestimate lower CO values and underestimate higher CO values. However, this tendency was more pronounced between PATD and Fick derived measurements for CO values compared to ATD. As a potential explanation for this phenomenon the loss of the injected cold thermal indicator using ATD was considered as it traverses the lung tissue and great vessels before reaching the arterial detector . Böck and colleagues demonstrated that early recirculation of the cold indicator using ATD is responsible for the broadened thermodilution curve resulting in about 3-4% higher CO values . Another explanation could be due to the fact that CO measured by PATD is affected to a greater extent by the transient decrease of the HR at the time of cold injection .
It appears, that in our study the severity of the induced septic shock with substantial haemodynamic disturbances explains the large proportion of low CO values (Fig. 2). Therefore, based on our results we cannot comment on the accuracy at high CO values, but due to the concordance between both PATD and ATD with Fick derived CO measurements for low CO values our data suggest that such a value can be relied on to build a clinical decision regardless of the method used to determine it.
In this respect, Dhingra emphasized a clinically relevant thought : ‘CO manipulation is likely to have the greatest impact on outcome when CO is low’.
As all CO measurement methods have methodological limitations it is worth mentioning some specific sources for inaccuracy of the methods used in our study. The Deltatrac metabolic monitor has been widely used in studies of VO2 in the critically ill and has an accuracy of about ±4% when used appropriately . The machine calculates VO2 from the RQ and VCO2. The accuracy of the VO2 determination is dependent on the accuracy of RQ and VCO2 measurements and on the assumption of a steady state. Using an experimental setting we avoided potential pitfalls of the metabolic method. We could exclude the potential effects of lung metabolism on the measurements because there was no significant lung injury or pneumonia present in the animals. All animals were sedated and minute ventilation was held constant to provide steady-state conditions. RQ was determined from inspired and expired oxygen and CO2 fractions, which were measured by paramagnetic and infrared analysers. The delivered FiO2 of 0.4 was within the acceptable range of accuracy of the metabolic computer, which was recalibrated after each experiment. The mean VO2 decreased from 5.0 ± 0.7 mL min−1 kg−1 to 4.0 ± 1.1 mL min−1 kg−1 8 h after the induction of sepsis. Thus VO2 was stable enough in our septic model to permit reliable application of the Direct Fick method.
As with any CO measurement technique, in the case of ATD and PATD, the presence of severe dysrhythmias, valvular regurgitation or the presence of intra- or extracardiac shunts will lead to inaccurate results. A specific disadvantage of ATD is the higher sensitivity to baseline alteration, which can be reduced by increasing the amount of the indicator injected .
In view of the possible complications of the pulmonary artery catheter like the recently reported increase in the incidence of pulmonary embolism , a clinically important advantage of ATD is its reduced invasiveness.
In conclusion, even during haemodynamic instability in septic shock the correlation of ATD and PATD derived CO with direct Fick was good. As thermodilution CO by ATD is less invasive than by PATD, it may offer practical advantages.
This study has been presented in part at the European Society of Anaesthesiologist's meeting in Gothenburg, 7-10 April 2001 and published as an abstract in Eur J Anaesthesiol 2001; 18 (Suppl 21): 32. The authors thank Prof. H. Hecker, Department of Biometry Hannover Medical School, for reviewing the statistical analyses.
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