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(Chest. 2002;122:990-997.)
© 2002 American College of Chest Physicians

Lack of Agreement Between Thermodilution and Fick Cardiac Output in Critically Ill Patients*

Vinay K. Dhingra, MD; John C. Fenwick, MD; Keith R. Walley, MD; Dean R. Chittock, MD and Juan J. Ronco, MD, FCCP

* From the Division of Critical Care Medicine (Drs. Dhingra, Fenwick, Chittock, and Ronco), Vancouver Hospital and Health Sciences Center, and St. Paul’s Hospital (Dr. Walley), University of British Columbia, Vancouver, BC.

Correspondence to: Vinay K. Dhingra, MD, Critical Care Medicine, 360 Echelon Building, Vancouver Hospital and Health Sciences Center, 855 West 12th Ave, Vancouver, BC, Canada V5Z 1M9; e-mail: vdhingra{at}vanhosp.bc.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Individual comparison of cardiac output via intermittent thermodilution and Fick technique over a wide range of cardiac outputs.

Design: Prospective clinical investigation.

Setting: Multidisciplinary ICUs of two teaching hospitals in Vancouver, British Columbia.

Participants: Eighteen critically ill patients who had pulmonary and systemic arterial catheters and in whom active support was being withdrawn.

Interventions: Measurement of thermodilution cardiac output and calculation of Fick cardiac output while support was withdrawn. Active support was withdrawn in a three-step process: removal of vasopressors followed by decrease in fraction of inspired oxygen to 0.21, and finally removal of mechanical ventilation.

Measurements and results: Simultaneous Fick and thermodilution cardiac outputs were obtained over a wide range. Fick calculated cardiac outputs were obtained using the Fick equation with oxygen uptake (O2) being measured with indirect calorimetry. O2 determinations were made using five measurements over 5 min, with the mean being used for subsequent analysis. Thermodilution cardiac outputs were determined by the mean of five measurements, with the first being discarded. Coefficient of variation was calculated for the O2 and thermodilution cardiac outputs. One hundred thirty-six simultaneous cardiac outputs were obtained in 18 patients with a mean APACHE (acute physiology and chronic health evaluation) II score of 25.5. The range of cardiac outputs was 1.39 to 16.95 L/min. Linear regression analysis found a good correlation of the data sets, with an R of 0.85. Bias and precision calculations found a bias of - 0.17 L/min with the upper and lower limits of agreement being 2.96 L/min and - 3.30 L/min, respectively. In patients with high cardiac outputs (> 7 L/min), the bias was - 1.90 with the limits of agreement being 1.87 L/min and - 5.67 L/min. The coefficient of variation for O2 was 4.6% and for thermodilution cardiac output was 7.75%.

Conclusions: There was good consistency of each of the measurements with a low coefficient of variation. The bias for the whole group was small, but the limits of agreement extended into a clinically relevant area, resulting in a lack of agreement. In patients with high cardiac outputs, the Fick tended to consistently produce higher cardiac outputs compared to thermodilution, suggesting a systematic error.

Key Words: bias • cardiac output • critically ill • Fick • indirect calorimetry • precision • regression analysis • thermodilution


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Management of hemodynamic status is a crucial part of care in the critically ill. To assist the clinician, a variety of methods are available to assess cardiac function.1 2 3 4 Pulmonary artery catheters have helped us understand hemodynamic dysfunction in many clinical situations. Although many hemodynamic variables may be generated with a pulmonary artery catheter, assessment of the cardiac output is one of the most important.5 6 Intermittent thermodilution, being one of the most established methods of cardiac output determination, utilizes a computerized calculation of flow based on changes in temperature following an injection of a set amount of fluid via a pulmonary artery catheter.7 8

Recently, pulmonary artery catheter utilization has come under increasing scrutiny. Concerns regarding the risk/benefit ratio of this invasive monitoring technique have been raised by a number of authors,9 10 11 and scientific trials are being requested for its ongoing use. Hence, alternative techniques for the measurement of cardiac output over a wide range of cardiac outputs and clinical conditions may be of potential use in the critically ill.

The refinement of systems of indirect calorimetry, through the analysis of respiratory gases, has allowed the measurement of oxygen uptake (O2) at the bedside in the critically ill. By applying the Fick principle, cardiac output can be obtained as O2 divided by the arteriovenous oxygen content difference.12 13

These two methods of obtaining cardiac output have been validated independently.14 15 16 Published comparisons of Fick and thermodilution have been done in subjects not critically ill,17 18 19 20 21 22 23 have only correlation and not agreement,17 20 21 used improper agreement analysis,24 25 26 or limited patient groups with a small range of cardiac outputs.22 27 The studies are also limited by having a small range of cardiac outputs on any given patient even though the entire set may be broad. The objective in this study was to assess the agreement, precision, and bias of these two different methods of cardiac output determination in a critically ill population over a wide range of cardiac outputs on individual patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Simultaneous determinations of cardiac output were obtained in 18 critically ill patients admitted to the ICUs of Vancouver General Hospital and St. Paul’s Hospital, Vancouver, British Columbia. A part of this data set has been previously reported.28 Patients were prospectively studied if they met the following inclusion criteria: mechanical ventilation support, systemic and pulmonary artery catheters in place, and agreement of the attending physician and families to discontinue life support. Patients were classified into septic and nonseptic groups. Sepsis was defined by presence of positive culture findings and the presence of tachypnea (minute ventilation > 10 L/min), tachycardia (pulse > 90 beats/min), and hyperthermia or hypothermia (core temperature > 38.3°C or < 35.6°C) along with a manifestation of altered organ perfusion. Altered organ perfusion was defined as a PaO2/fraction of inspired oxygen < 280, urine output < 0.5 mL/kg for at least 1 h, or an increased serum lactate level. Sepsis was supported in all patients by autopsy evidence of a source of infection.

Ethics
This study was approved by the University of British Columbia clinical screening committee for research involving human subjects and by the ethics committee of St. Paul’s Hospital and the research coordinating committee of Vancouver General Hospital. Consent for the study was obtained from the patient’s next of kin. Withdrawal of life support was in the usual manner in our ICUs, with all patients receiving therapy to maintain comfort.

Protocol
Age, sex, height, associated illness, APACHE (acute physiology and chronic health evaluation) II score, and presence of multisystem organ failure (MSOF) were recorded for the 24 h preceding the study. The cardiac outputs were determined simultaneously by both thermodilution and Fick methods as withdrawal of support was taking place. Withdrawal of support was in a three-step process: first, removal of vasopressors, followed by a decrease in the fraction of inspired oxygen 0.21, and, lastly, removal of mechanical ventilatory support.

Thermodilution cardiac outputs were obtained by the injection of 10 mL of iced 5% dextrose in water in < 8 s by a single operator at end-expiration. Five measurements were obtained, with the first being discarded. The mean and the coefficient of variation were calculated from the other four measurements. The mean value was used in the subsequent analysis. The coefficient of variation was 7.75% for thermodilution cardiac output. The time response of our cardiac computers was too slow at cardiac outputs < 1.4 L/min to allow repeated measurements of thermodilution cardiac outputs. Fick cardiac outputs were obtained by dividing the O2 by the arteriovenous oxygen content difference. O2 was continuously measured by means of a portable system of indirect calorimetry (Deltatrac Metabolic Monitor; Datatex Instrumentarium; Helsinki, Finland). This system measures carbon dioxide and oxygen concentrations in the inspired and expired gases each minute and then calculates and records the carbon dioxide production and O2. This system has been previously validated for accuracy, sensitivity, and reproducibility of O2 determinations.11 O2 determinations were made using five measurements over a 5-min period immediately before each change in vasopressor or ventilatory support. The mean and coefficient of variation were calculated with the mean O2 being used for the subsequent analysis. The coefficient of variation for O2 via indirect calorimetry was 4.6%.

Hemoglobin concentration (Coulter STKS; Coulter Electronics; Hialeah, FL), arterial and mixed venous oxygen tensions (model ABL3; Radiometer; Copenhagen, Denmark), and arterial and mixed venous oxygen saturation co-oximetry (Radiometer models OSM3 and IL480; Instrumentation Laboratories; Lexington, MA) were all measured. Oxygen content was then calculated using standard formulae. Coefficient of variation for the hemoglobin, oxygen tension, and oxygen saturation were calculated by partitioning one blood sample five times from 10 different patients. The coefficient of variation was 1% for hemoglobin, 4.8% for arterial oxygen tension, 4.1% for mixed venous oxygen tension, and 0.3% and 1.1% for arterial and mixed venous oxygen saturations, respectively.

Analysis
Correlation was determined via linear regression analysis of the mean cardiac outputs. Agreement was determined via the Bland and Altman29 technique. Bias (mean difference between the means) and precision (2 SDs around the mean) along with their 95% confidence intervals were calculated.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 18 patients were studied, with an average age of 56.1 year and a mean APACHE II score of 25.5. There were 9 septic patients and 10 patients with MSOF (Table 1 ). A total of 136 measurements of cardiac output were obtained simultaneously by thermodilution and Fick, with a range of 1 to 16 measurements per patient.


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  		Table 1.. Patient Characteristics*

 
The mean Fick determined cardiac outputs were higher than thermodilution (5.03 ± 2.82 L/min and 4.85 ± 1.96 L/min, respectively). The correlation coefficient of the two data sets was 0.85 (Fig 1 ).



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  		Figure 1.. Scatterplot of paired cardiac outputs using Fick and intermittent thermodilution with the solid line representing linear regression and the dotted line representing the line of equality.

 
The cardiac output ranges were 1.39 to 16.95 L/min for Fick and 1.43 to 10.10 L/min for thermodilution. The bias of all measurements was - 0.17 ± 1.56 L/min; the 95% confidence limits (mean difference ± 2 SD) were - 0.43 to 0.09 L/min. The upper and lower limits of precision were 2.96 L/min and - 3.30 L/min, with their 95% confidence intervals being 2.50 to 3.42 L/min and - 3.77 to - 2.83 L/min, respectively (Fig 2 ).



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  		Figure 2.. Representation of agreement between the two techniques. The solid line represents the mean difference between Fick (FK) and thermodilution (TH), and the dotted line defines the limits of agreement.

 
The wide ranges of each patient’s simultaneous thermodilution and Fick cardiac outputs are represented in Figure 3 . Analyses of the bias, limits of agreement, and correlation on an individual basis (Table 2 ) show that the lack of agreement extends over the majority of patients negating individual effects as a cause of the lack of agreement.



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  		Figure 3.. Individual simultaneous determinations of thermodilution and Fick cardiac outputs over a wide range.

 

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  		Table 2.. Bias, Limits of Agreement, and Correlation for Each Patient*

 
There were 34 simultaneous measurements of cardiac outputs > 7 L/min. In this group, there seemed to be a systematic difference with a bias and SD of - 1.90 ± 1.88 L/min between the two methods with Fick producing a higher value. The upper and lower limits of agreement were 1.87 L/min and - 5.67 L/min, respectively (Fig 4 ). The correlation coefficient was 0.51 (Fig 5 ).



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  		Figure 4.. Representation of agreement between the two techniques in cardiac outputs > 7 L/min. The solid line represents the mean difference between Fick and thermodilution, and the dotted line defines the limits of agreement. See Figure 2 for expansion of abbreviations.

 


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  		Figure 5.. Scatterplot of paired cardiac outputs > 7 L/min using Fick and intermittent thermodilution, with the solid line representing linear regression and the dotted line representing the line of equality.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The comparison of two methods of clinical measurement may have many approaches. When comparing agreement between two different monitoring methods the factors of importance include the bias and precision. Precision assesses the reproducibility of the same results within an individual. The bias quantifies the absence of a systematic error, and ideally the mean of which should be zero with the majority of measurements within the 95% confidence intervals. The SD of the bias is an estimate of error, whereas the mean difference ± 2 SD represents the limit of agreement. Agreement or equality between different methods is determined if the limits of agreement are less than clinically relevant values. In this study of critically ill patients, the bias was relatively small (- 0.17 L/min), with the 95% confidence intervals encompassing the zero point. The precision or the upper and lower limits of agreement however are relatively large at 2.96 L/min and - 3.30 L/min, respectively. The value for the precision of the sets is within a clinically relevant range, and therefore the two methods for cardiac output determination do not agree. Therefore, in a critically ill population, these two independent means of cardiac output determination are not interchangeable.

Correlation coefficients have a role to play in validity testing but cannot answer the question as to whether two methods of measurement can be used interchangeably. In our study, the two methods trended well for the entire population with an acceptable correlation coefficient of 0.85. It is more important however to know whether this trend would be accurate on individual patients over changing cardiac outputs. Figure 3 illustrates individual simultaneous determinations of cardiac output by both techniques over a broad range. The many different slopes demonstrated in Figure 3 would indicate difficulty in knowing, which slope any individual patient, may fall on. This is further illustrated in Table 2 showing the broad range of correlation coefficients on any given patient (0.13 to 0.99). Therefore, even though the two methods trended well for the entire population, they are unsuccessful at the individual level over changing cardiac outputs.

The data set in this study is unique because each patient had their cardiac output determined over a variety of hemodynamic conditions. This has resulted in the broadest range of simultaneous cardiac output determinations on a per patient basis as opposed to simply a broad range of cardiac outputs in a set. There is also a wide range of cardiac outputs for the entire group (1.39 to 16.5 L/min). Previous analytical errors such as comparison analysis using only regression analysis17 20 or using only 1 SD to define the limits of agreement24 25 have led to the false conclusion that these two methods agree. Regression analysis is essentially a calibration of one technique in terms of another, rather than a direct answer to the question of agreement.30

The data were unaffected by the presence of sepsis or multiple organ failure. However, in patients who have high cardiac outputs (> 7 L/min), the Fick almost universally produced higher cardiac outputs. The bias for this group was - 1.90 L/min, suggesting a systematic error. There was also poor correlation, with an R of only 0.51 in this group. The study of patients with extremely low cardiac outputs < 1.4 L/min could not be performed due to technical difficulties.

A more clinically relevant analysis may be in patients with low cardiac outputs (< 4 L/min). Cardiac output manipulation in this group may potentially have the greatest impact on outcome, hence the need for reliable measurements within this subset. There were 58 simultaneous measurements of cardiac output < 4 L/min. The bias and SD was 0.32 ± 0.89 with thermodilution producing slightly higher values, the upper and lower limits of precision being 2.10 and - 1.45 L/min, respectively. The correlation coefficient was, however, 0.64. The precision of this subset was better than that of the entire cohort, suggesting better agreement despite a worsening correlation. This improved agreement would imply better interchangeability between the two methods at lower cardiac outputs.

Although many different methods for obtaining cardiac output exist, there must be some assessment as to the comparability of different methods. Thermodilution is considered the most established method for determining cardiac output although there are many limitations.31 32 Accuracy of intermittent thermodilution ranges from ± 3% to ± 30%.33 The accuracy of thermodilution cardiac output is dependent on the timing within the respiratory cycle, homogeneity of injection, temperature of injectate, and other factors.34 35 36 37 In our study, all injections were performed by a single operator and at end-expiration to minimize the noise within the data. This resulted in good consistency, with a coefficient of variation of 7.75% for thermodilution.

In contrast to intermittent thermodilution, a different set of factors may modify the accuracy of Fick calculated cardiac outputs. Individual patient characteristics and errors in the measurement of O2 by indirect calorimetry may affect the exactness and consistency of Fick cardiac outputs. Errors in the measurement of hemoglobin and arterial or mixed venous oxygen content may also adversely alter the accuracy. There may also be amplification of these errors when the oxygen content difference is low, such as in high cardiac output states. Pulmonary O2 may increase in the presence of lung inflammation, leading to a false underestimation of whole body O2 by the Fick method, resulting in a false increase in cardiac output.38 The effect of errors in the measurements altering the accuracy of the cardiac output determinations should be minimal in this study. The measurement of the O2 by indirect calorimetry has been previously validated in the critically ill population.14 The coefficient of variation for the determinants of the Fick cardiac output were low, and the mixed venous blood sample was drawn in a manner to minimize its arterialization, again minimizing error. Lung injury and pulmonary inflammation may be a prominent feature of sepsis. This theoretical effect of increased pulmonary O2 altering Fick accuracy may be most prominent in patients with sepsis or MSOF. There was, however, no difference observed in either the septic or MSOF groups compared to those without these complications.

Whether any degree of cardiac monitoring will affect outcome is currently a source of much controversy. Many authors have suggested that perhaps the use of invasive monitoring with a pulmonary artery catheter may actually increase mortality.9 If we are to abandon the use of pulmonary artery catheters, other tools to measure cardiac output and function will be required and an appropriate evaluation of any of these must be undertaken.

Interchangeability between methods still requires validation in the critically ill. In this study, the Fick and intermittent thermodilutional methods for determining cardiac output were not precise enough to agree over the wide ranges observed in critically ill patients. This may be especially true in patients with high cardiac outputs.


   Footnotes
 
Abbreviations: APACHE = acute physiology and chronic health evaluation; MSOF = multisystem organ failure; O2 = oxygen consumption

Received for publication March 3, 2000. Accepted for publication March 5, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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