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Continuous cardiac output measured with a Swan‐Ganz catheter reacts too slowly in animal experiments with sudden circulatory failure

Abstract Background In many animal experiments, it is vital to detect sudden changes in cardiac output (CO). This porcine study compared CO that was measured with a Swan‐Ganz pulmonary catheter with the gold standard (which was a transit‐time flow probe around the pulmonary artery) during interventions that caused hemodynamic instability. Methods In one series, 7 pigs were exposed to sudden changes in CO. In another series, 9 pigs experienced more prolonged changes in CO. All the pigs had a Swan‐Ganz catheter placed into the pulmonary artery and a flow probe around the pulmonary artery. Adrenaline infusion and controlled hemorrhage were used to increase and decrease CO, respectively. The measurements of CO before and after each intervention were compared for correlation, agreement, and the time delay that it took each method to detect at least a 30% change in CO. A Bland–Altman test was used to identify correlations and agreements between the methods. Results In the first series, there was a delay of 5–7 min for the Swan Ganz catheter to register a 30% change in cardiac output, compared with the flow probe. However, during prolonged changes in CO in the second series, there was a good correlation between the 2 methods. Mixed venous oxygen saturation reacted faster to changes than did CO; both were measured via the Swan‐Ganz catheter. Conclusions In many animal studies, the use of Swan‐Ganz catheters is suitable; however, in experiments with sudden hemodynamic instability, the flow probe is the most advantageous method for measuring CO.


| INTRODUC TI ON
Cardiac output (CO) is an important hemodynamic variable and is the major determinant of oxygen delivery and blood pressure. In many animal experiments, it is vital to detect sudden changes in CO.
There are many methods to monitor CO, which vary in their invasiveness and continuousness, and some of them can also monitor other parameters. Moreover, all these methods may have advantages that are dependent on the experiment that must be performed.
From the time that Swan and Ganz described the use of right heart catheterization with a balloon-tipped catheter in 1970, the use of a Swan-Ganz (SG) catheter has become widespread. 1,2 The principle is based on Fick's technique that was described 100 years earlier. 3 This pulmonary artery catheter uses thermodilution and a computer-calculated estimate for CO. The system that we used performed a measurement every 54 s; on the basis of this method, average CO was calculated. This is a commonly used system in human intensive care units; in contrast to the first system, it is semicontinuous and allows for the monitoring of CO over time, measurement of mixed venous oxygenation, measurement of blood pressure on the right side of the heart, and an estimate of the pressure in the left atrium. However, the system is invasive, with catheters inserted via the veins to the right side of the heart and further inserted to the pulmonary artery. There is some delay in the reactions to sudden changes in the parameters, and the monitoring of left atrial pressure is an indirect evaluation based on an intermittent pulmonary capillary wedge pressure test. In 25-year-old experiments in sheep, there was a clinically important time delay in the detection of CO changes in response to sudden interventions that affect the circulation. 4 As a reference, the researchers used a transit-time ultrasound blood flow probe (FP) around the pulmonary artery. The transit-time ultrasound method has been described as being very accurate. 5 This specific procedure may be the most accurate method, but it is also the most invasive, and it is often referred to as being the gold standard. 6,7 In other experiments, a flow probe around the ascending aorta was used, but this method cannot measure the circulation in the coronary arteries, which, in many experiments with toxic agents or hypoxia, can vary by up to 300%. [8][9][10][11] We are aware that there are other methods for continuous CO monitoring, such as pulse wave analysis and the PICCO monitor. [12][13][14] The intermittent monitoring of CO via transthoracic echocardiography by trained personnel is also possible in humans. 15 The concentration of carbon dioxide (CO 2 ) in end-tidal expired air is often used as a substitute for cardiac output changes; in a new and more sophisticated method, it seems possible to measure CO via the capnodynamic determination of CO 2 before and after the blood passes the lungs by constantly changing the relationship between inspiration and expiration. This procedure has been tested in both animals and small children undergoing cardiac surgery. [16][17][18] Furthermore, it is possible to measure CO by using a method involving a small arteriovenous shunt with stable blood flow and with intermittent saline dilution into the venous side. Ultrasound detectors that measure blood from the artery and the blood returning to the venous side after a saline bolus make it possible to calculate CO. This method appears to be promising, especially in small children and in small animals, wherein a SG catheter cannot be used because of the size. 7,19,20 Moreover, there is a well-established standard for accuracy in CO monitoring, with a percentage error of no more than 30% 21 ; however, we are not aware of any standard for acceptable delays in the measurements. [22][23][24] In the present study, errors greater than 30% were considered unacceptable.
In a recent porcine experiment with carbon dioxide poisoning, we used a highly invasive method of measuring CO and pulmonary vascular resistance (PVR), with a transit-time flow probe being used around the pulmonary artery and direct pressure monitoring being used in the left atrium and in the central aorta after sternotomy. 25 In this type of study using life-threatening intoxication, it was important to immediately detect a serious decrease in CO, and we were not convinced of the simultaneous use of SG catheters in that experiment. For this reason, we decided to compare the use of SG catheters with the gold standard with a transit-time FP around the pulmonary artery in both situations; additionally, we aimed to consider sudden changes in CO and the use of more prolonged measurements. For this study, we used pigs because their size allows the use of much of the equipment used in human clinics and because we have experience with pigs from other experiments.
The null hypothesis of the study was that the use of a SG catheter and the use of a transit-time flow probe around the pulmonary catheter are comparable in precision, especially in the first minutes after serious events affecting CO; additionally, we hypothesized that would be no large bias.

| Animals
All experiments were performed at the Biomedical Research Laboratory at Aalborg University Hospital, Aalborg, Denmark. Seven landrace female pigs weighing 32.8 kg (standard deviation [SD] 2.87 kg) were used for the first series in this experiment, and 9 landrace female pigs weighing 46.47 kg (SD 8.83 kg) were used for the second series. The differences in size among the groups of pigs were not planned, but logistical conditions made us accept this situation.
The reason for using only female pigs was that it is difficult to place a urinary catheter into male pigs. The animals were allowed 2 weeks of acclimation after arrival at the research facility. They were housed in groups with free access to water and feed (Altromin Spezialfutter GmbH & Co., 32 791 Lage, Germany and Special Diet Services, Essex, England).  GmbH, Germany). The monitor was operated in the "stat" mode, in which the measurements were updated every 54 s. After insertion and calibration of the SG catheter, continuous measurements of CO were initiated. After each intervention during the experiments, the SG catheter was recalibrated by using mixed-venous blood gases.

| Anesthesia and surgery
After sternotomy, a 16 mm transit-time vascular probe (Medi-Stim, Vedbaek, Denmark) was placed around the pulmonary artery.
The probe was connected to a flow monitor (Medi-Stim, Copenhagen, Denmark), thus allowing for measurements of cardiac output.
After 30 min of steady state, baseline measurements for cardiac output were conducted with both the FP and SG catheters. A total of 2500 IE heparin was administered to prevent the coagulation of blood in the catheters. The animal characteristics before experimental changes in cardiac output are presented in Table 1.

| Study design
The experiments consisted of the following 2 parts:

| First series
The aim of this part of the experiment was to elicit a sudden doubling or halving of CO, after which the time it took to detect at least a 30% change in CO using FP and SG would be compared. First, a doubling of CO, as measured by the flow probe, was obtained via the infusion of an adrenaline solution (adrenalin, 1 mg/ml, Amgros I/S, Copenhagen, Denmark), which included 2.7 mg of adrenaline in 97.3 ml of NaCl. After 10 min or less, if both the FP and SG catheters obtained the planned level of CO, the infusion was stopped.
Thereafter, baseline CO was re-established before the next intervention. Second, a quick, controlled hemorrhage was used to decrease CO. Blood was collected in blood bags (Macopharma, Mouvaux, France) that were prefilled with citrate (CPD-50, 250 ml, HAEMONETICS, Massachusetts, USA) to prevent coagulation.
When the CO was halved, as measured by FP, the drainage was stopped. Measurements were continued every 54 s for 10 min or less if both the FP and SG catheters obtained the same change in the level of CO. After the first drainage, the blood was reinfused, and the pig baseline CO was re-established before both interventions (doubling and halving of CO) were repeated. In this manner, more measurements could be made per animal, thus reducing the total number of animals that were used. Changes in SvO2 were registered at each measurement. After the interventions, the animals were euthanized

| Second series
The aim of this part of the experiment involved more prolonged changes in CO over a period of time, in which the values of CO and SvO 2 measured by SG and FP were compared every 15 min to determine if long-term measurements were more consistent for the 2 methods than for those with rapid changes.
The first intervention included the infusion of the same adrenaline solution that was used in the first series (adrenalin, 1 mg/ml, Amgros I/S, Copenhagen, Denmark) until the pig had doubled its CO, as measured by the FP. Measurements were made for 30 min, after which the adrenaline infusion was stopped; thereafter, a baseline CO was re-established.
After obtaining a steady state, CO was reduced by 50% via controlled hemorrhage. Blood was collected as in the first series. When the CO was halved, measurements were made for 30 min. After 30 min, the blood was infused again. In this manner, the pigs could be used for more than 2 interventions.
At the end of the study, the animal was euthanized with an intravenous injection of pentobarbiturate (Euthasol, 400 mg/ml, Virbac Denmark A/S, Kolding, Denmark).

| Statistics
For the sample size calculation, the KISS approach was used, 26 wherein the power analysis showed that a sample size of 7-9 animals would have 80% power to detect an effect size of 2-3 min,

| RE SULTS
After sternotomy, all the animals were hemodynamically stable (

| Series 1
One animal had ventricular fibrillation during placement of the SG catheter and was excluded from the study.
In another animal, the SG catheter could not be correctly placed with a closed thorax. After a sternotomy, the SG catheter could be guided through the heart and into the pulmonary artery. versus the FP at 0.9 min (0.9-3.6 min) (P < .05). The median time for a 10% increase in SvO 2 was 4.5 min (0.9-9.0 min). Figure 1A demonstrates the changes in CO and SvO 2 (in percentages) over a time period of 8 min. Measurements were conducted every 54 s.   Figure 2B demonstrates the changes in a 4-quadrant plot, wherein the concordance rate was only 50%.

| Series 2
CO varied across a 5-fold range (1.7 L per minute to 10.2 L per minute). During these lengthier experiments with changes in CO, the SG catheter better reflected the changes in CO, as the FP demonstrated. Linear regression and a Bland-Altman test showed a relatively good correlation between measurements that were made with FP compared with measurements that were made with SG. The agreement between the 2 measures showed that a bias of 0.75 L per minute was always higher for the SG than for FP, and the difference was statistically significant (P < .001). The 4-quadrant plot showed a concordance rate of only 68% (Figure 3).    In many experiments, the use of FP may be too invasive, and the  There were several limitations to the study. For example, this was a small-scale animal study. In addition, the fast reduction in CO was artificial with massive bleeding, which may interfere with the SG measurements, although no simultaneous infusion of cold fluid was performed. Finally, there were different body weights in the 2 groups.

| CON CLUS ION
In these animal experiments with sudden changes in CO that were measured with the SG catheter, the reactions were delayed by 5-8 min. FP reacted immediately, but its use requires invasive surgery.
For more prolonged experiments, the relationship between the 2 methods was better.

ACK N OWLED G M ENTS
Not applicable.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Pros Cons
Swan-Ganz catheter Many clinicians are accustomed to using it.
Measures pulmonary blood pressure.
Can indirectly indicate left atrial pressure. Measures mixed venous oxygenation. Little risk of bleeding.
Reacts slowly and not with exact values. Risk of arrhythmias.

Flow probe
Measures cardiac output beat-to-beat. Reacts almost immediately.
Highly invasive, requires surgical skill. Risk of bleeding.