Monitoring cardiac output (CO) allows early detection of haemodynamic instability and may be used to guide intensive care, aiming to reduce morbidity and mortality in high-risk patients 1. In the past decade, continuous cardiac output (CCO) was commonly obtained by pulmonary artery catheter (PAC) with integrated heating filaments. The risk–benefit ratio of right heart catheterisation simply for CO determination has been questioned due to associated complications and the availability of less invasive alternatives 2. Various monitor devices have been recently introduced into clinical practise that use the arterial pressure waveform to calculate CO on a beat-to-beat basis, such as the LiDCO™plus system using continuous cardiac output by pulse power analysis (PulseCO) and the PiCCO plus system using continuous cardiac output by pulse contour analysis (PCCO). Since arterial and central venous catheters are often already used to monitor critically ill patients, these techniques are not additionally invasive.

Several clinical studies have been performed on intensive care patients showing good agreement and correlation of the aforementioned methods of CCO determination with thermodilution or indicator-based techniques 345678910. Some authors, however, recently questioned the reliability of these methods when acute changes of CO occur 11121314. Therefore it is of high clinical interest to know whether the CCO method used is able to detect sudden CO changes, as frequently observed during haemorrhage, fluid loading or vasopressor administration 15. Moreover, critically ill patients often present with intra-abdominal hypertension (IAH) 16. Preliminary data by Malbrain and colleagues indicated unacceptable high limits of agreement of different invasive CCO measurements in 10 patients with IAH 17. Reliability of CCO measurement during IAH and volume loading has not yet been elucidated in a controlled experimental setup. Increased intra-abdominal pressure is likely to modify several factors known to impact arterial waveform, such as chest wall compliance and arterial elastance, thereby potentially deteriorating agreement between the CO derived from thermodilution and derived from the arterial waveform.

The aim of the present study was to investigate whether PulseCO and PCCO – methods derived from the arterial waveform – and continuous assessment of continuous cardiac output by pulmonary artery catheter thermodilution (CCO_PAC) are able to detect a volume-induced change of CO during IAH when compared with bolus transcardiopulmonary thermodilution cardiac output (CO_TCP). Further, the level of agreement between these CCO values and CO_TCP during IAH was determined. Finally, we analysed the impact of calibration on the accuracy of continuous beat-to-beat CO methods.

The present study was reviewed and approved by the local Animal Investigation Committee. The animals (10 healthy German domestic pigs, 58 ± 8 kg) were managed in accordance with our institutional guidelines, which are based on the Guide for the Care and Use of Laboratory Animals published by the National Institute of Health (NIH Publication No. 88.23, revised 1996).

The animals were fasted overnight, but had free access to water. The pigs were premedicated with the neuroleptic azaperone (4 to 8 mg/kg intramuscularly) and atropine (0.01 to 0.05 mg/kg intramuscularly) 1 hour before induction of anaesthesia with a bolus dose of ketamine (2 mg/kg intramuscularly), propofol (2 to 4 mg/kg intravenously) and sufentanil (0.3 μg/kg intravenously) given via an ear vein. After intubation with a cuffed endotracheal tube (internal diameter, 8.5 mm), the pigs were ventilated using a volume-controlled ventilator (Avea; Viasys Healthcare, Yorba Linda, CA, USA) with 10 ml/kg tidal volume, a positive end-expiratory pressure of 5 cmH₂O, an inspiration:expiration ratio of 1:1.5 and a fraction of inspired oxygenof 0.35. The respiratory rate (12 to 18 breaths/min) was adjusted to maintain normocapnea (pressure of end-tidal CO₂ = 35 to 45 mmHg). Oxygen saturation was monitored by a pulse oxymeter placed on the ear (M-CaiOV; Datex-Ohmeda, Helsinki, Finland).

Anaesthesia was maintained with a continuous infusion of propofol (6 to 8 mg/kg/hour) and sufentanil (0.3 μg/kg/hour), and muscle relaxation was provided by continuous infusion of pancuronium (0.2 mg/kg/hour) to ensure suppression of spontaneous gasping. In our experience, the animals do not respond to painful or auditory stimuli under this anaesthetic regimen when the paralysing agent is withheld, and the loading dose of ketamine and propofol subsides.

Ringer solution (5 ml/kg/hour) was administered during instrumentation. For induction of IAH, a Verres needle was inserted via a small infra-umbilical incision into the intra-abdominal cavity. The Verres needle was then connected to an electronic variable-flow insufflator (Wolf 2154701; Wolf GmbH, Knittlingen, Germany) for direct intra-abdominal pressure measurement and induction of IAH due to carbon dioxide pneumoperitoneum. The intra-abdominal pressure was measured in a supine position at end expiration.

Nine animals were included in the final analysis. One pig was excluded from further analysis due to injury of the splenic vein by the Verres needle and a fatal outcome. All haemodynamic devices were installed and calibrated properly and no complications were associated with any of the devices. All animals were haemodynamically stable throughout the study period, no arrhythmias occurred, and no inotropic or antihypertensive drugs were administered. Pneumoperitoneum increased the intra-abdominal pressure by 17.7 ± 3.5 mmHg, and reduced chest wall compliance significantly by 64 ± 8%.

The haemodynamic variables are displayed in Table 1. The mean arterial pressure, GEDV, PulseCO, PCCO_pre, PCCO_recal, CO_TCP and CCO_PAC significantly increased after fluid loading at baseline, whereas the heart rate, CVP and PAOP remained unchanged. IAH significantly increased CVP and PAOP, but did not change the mean arterial pressure, heart rate, GEDV or CO values. Fluid loading during IAH did not significantly change the mean arterial pressure, heart rate, CVP, PAOP or GEDV, while CO_TCP, CCO_PAC and PCCO_recal indicated a significant increase in CO. PulseCO and PCCO_pre, however, were unable to reflect an increase of CO following fluid loading during IAH. Changes of CO determined by different methods throughout the experimental period are presented in Figure 2a. Individual time responses of each CO parameter are presented in detail (see Additional file 1, Figure S2).

Results of ΔCO comparison by Bland–Altman analysis and linear regression analysis are presented in Table 2 (for further details, see Additional file 1, Figure S1). ΔCCO_PAC and ΔPCCO_recal showed better agreement with ΔCO_TCP than uncalibrated ΔPulseCO or ΔPCCO_pre.

Bland–Altman analysis revealed an overall (pooled data) bias ± SD (PE) between CO_TCP and PulseCO of 1.0 ± 1.5 l/min (41.7%), between CO_TCP and PCCO_pre of 1.0 ± 1.1 l/min (27.5%), and between CO_TCP and CCO_PAC of 0.0 ± 0.9 l/min (23.3%). Figure 3a to 3f present Bland–Altman plots and correlation of pooled data comparing PulseCO, PCCO_pre and CCO_PAC with CO_TCP.

The bias and precision (SD) between the examined CO methods and CO_TCP at individual experimental steps are displayed in Figure 2b. The bias between CO_TCP and the different CO methods was low at baseline, as criteria of interchangeability (PE <30%) were observed for all CO methods 21. Fluid loading did not change the bias between methods significantly. After application of IAH, the bias between CO_TCP and PulseCO and between CO_TCP and PCCO_pre increased, but this was only significant for PCCO_pre (P < 0.05). Whereas fluid loading at baseline did not affect the bias between methods, the bias between CO_TCP and PulseCO and between CO_TCP and PCCO_pre was significantly increased after fluid loading at IAH (P < 0.05). Calibration of PCCO_pre reduced the bias significantly, as the bias between PCCO_recal and CO_TCP was low. Detailed results of Bland–Altman analysis and Pearson correlation comparisons between the different CCO methods and CO_TCP at individual steps are available (see Additional file 1, Table S1).

The main findings of our experimental animal study are as follows. Firstly, at baseline without IAH, all CO methods showed acceptable agreement and reflected volume loading with an increase in CO. In contrast, IAH affects CO methods based on arterial waveform analysis in their ability to accurately indicate an increase in CO following fluid loading. Finally, recalibration of PCCO restored the system's accuracy.

The present study is the first on the agreement between three CCO methods and one intermittent bolus-thermodilution CO method during IAH and subsequent fluid loading. Research in the field of CCO monitoring has increased in recent years, as better evaluation of changes in a patient's haemodynamic status can facilitate therapy. Therefore it is of great interest whether these methods are able to reflect acute changes in CO induced by fluid loading under clinically relevant settings such as IAH.

Our results showed acceptable agreement of pooled CO data between CO_TCP, PCCO_pre + PCCO_recal and CCO_PAC, whereas continuous beat-to-beat analysis by PulseCO calibrated only once underestimated the CO and failed interchangeability as defined by Critchley and Critchley 21.

With respect to CCO_PAC versus CO_TCP and CCO_PAC versus PCCO, comparable agreement and correlation have been reported in several previous studies 2223. Compared with CO_TCP, PCCO_recal showed lower bias and lower PE than PCCO_pre, a result expected intuitively. Volume loading in addition to IAH resulted in a significant increase of the CO measured by thermodilution techniques (CCO_PAC and CO_TCP). In contrast, beat-to-beat CO methods such as PulseCO and PCCO_pre did not reflect the increase in CO accurately in the presence of IAH. The bias between PulseCO and PCCO_pre versus CO_TCP was significant after the second fluid load. Since the variability of bolus thermodilution is about 15%, we suggest that a mean bias within 15% of average CO can be clinically accepted. Recalibration of PCCO, as indicated by PCCO_recal, results in a significant reduction of bias.

Taken together these findings emphasise that monitors tracking beat-to-beat CO benefit from frequent calibrations during changing loading conditions or changes of variables potentially influencing the underlying calculation algorithm, such as IAH.

All of the CO monitors showed clinically acceptable 21 agreement at baseline. The increase of CO due to fluid loading without IAH was also comparably reflected by all CO methods. The bias between methods remained unchanged. PulseCO failed interchangeability with CO_TCP, however, as the PE increased clearly above 30% after fluid loading. Our data therefore suggest that PulseCO does not reliably indicate rapid haemodynamic changes following fluid loading. Similarly, Cooper and Muir recently reported PE >90% between PulseCO and lithium dilution CO after fluid resuscitation in haemorrhagic dogs 12.

While IAH reduced chest wall compliance and increased the CVP and PAOP, it did not significantly influence the CO. It is well known that cardiac filling pressures such as the CVP or PAOP in patients with IAH may be misleading, by falsely indicating increased preload 24. Contrarily, preload during IAH may even be decreased due to substantial reductions in venous return, which is more pronounced in hypovolaemic patients. In the present study, however, the GEDV indicated normovolaemic conditions at baseline and no changes of preload due to IAH occurred. Consequently, it is not surprising that CO was not affected by IAH, which has been described previously 25.

There is still an ongoing debate about CO measurement derived from arterial waveform analysis and its ability to track changes of CO. In the present study, uncalibrated CCO methods were not able to reflect changes in CO appropriately. Several studies have shown good agreement of PulseCO with thermodilution or indicator-based CO methods in postsurgical intensive care patients 789. On the other hand, Yamashita and colleagues reported that CO measured by PulseCO was not interchangeable with thermodilution during cardiac surgery 14. Cooper and Muir 12 have shown only a moderate decline of PulseCO after induced haemorrhage in healthy dogs, with significant bias between PulseCO and lithium indicator dilution CO. The CO changes due to changes of intravascular volume might therefore not be adequately tracked by PulseCO. The authors concluded that false transformation of arterial pressure difference by PulseCO and changes of arterial compliance are possible explanations for the lack of accuracy to depict changes in CO. In the present study, PulseCO was only calibrated by the lithium dilution technique at baseline. Because of continuous application of neuromuscular blocking agents, a repeated calibration with lithium may be hampered due to interactions at the lithium electrode 9. A calibration with another thermodilution technique is possible but this does not represent clinical practise and loses the advantage of being less invasive.

In contrast to PulseCO, PCCO was calibrated at each experimental step. A direct comparison of PCCO and PulseCO in the present study is therefore difficult. By calibrating PCCO repeatedly, it was already adjusted to the latest changes of vascular impedance. Interestingly, both PCCO_pre and PulseCO underestimated CO after fluid loading in the presence of IAH with high bias compared with CO_TCP. Our group recently reported high bias between uncalibrated PCCO and bolus pulmonary artery thermodilution CO in pigs during haemorrhage and norepinephrine administration 11. In this study, uncalibrated PCCO did not reflect decreased CO as indicated by the PAC during a phlebotomy of almost 2 l – most probably due to failure to identify the dicrotic notch during a substantially increased heart rate. These findings were confirmed by Piehl and colleagues 26. Additionally, Rodig and colleagues 2 reported a significant increase in bias between PCCO and CO_TCP after cardiopulmonary bypass and vasopressor administration, most probably due to an increase in systemic vascular resistance. Sander and colleagues recommended frequent recalibration of PCCO after cardiopulmonary bypass due to changes in systemic vascular resistance 27. In our study, however, systemic vascular resistance had no influence on the bias between methods.

The PCCO algorithm is based on the windkessel model by Otto Frank 28, including three major individual properties: aortic/arterial compliance, characteristic impedance, and peripheral vascular resistance. Calibration of PCCO by CO_TCP enables the PCCO algorithm to correct for these three elements by calculating individual aortal compliance and systemic vascular resistance, and furthermore adjusting to aortic impedance. The ability of PCCO_pre to accurately detect changes in CO due to fluid loading was hampered in the presence of IAH, however, whereas it was preserved at baseline. With respect to the effects of IAH, our results suggest that, due to reduced chest wall compliance, increased pleural and airway pressures are increasingly transmitted to the cardiac chambers, thereby reducing effective transmural pressure. Methods based on arterial waveform analysis are consequently prone to error in reflecting abrupt changes in CO, without an implemented algorithm to detect and correct for changes in vascular impedance as induced by IAH. The clinician therefore needs to consequently recalibrate the CCO based on arterial waveform analysis before any major change in therapy is initiated.

Our study has some limitations. The present study is an animal study and extrapolation to humans should be done with caution, and the reader should have this in mind. CCO_PAC was obtained 2 minutes after bolus thermodilution, and hence a minor influence by recirculation of cold fluid is possible.

All of the examined CO methods showed good agreement at baseline. There are limitations, however, in the ability of uncalibrated continuous CO methods based on arterial waveform analysis to accurately track changes in CO after fluid loading during IAH. The trend for underestimation of CO by PulseCO and PCCO_pre documented in the present study could have clinical consequences. PCCO and PulseCO should be used with caution when assessing changes in CO after fluid loading, and should be recalibrated before any major change in therapy is initiated.

• CO measured by PulseCO, PCCO and CCO_PAC showed good agreement with CO_TCP without IAH, and reflected an increase in CO following fluid loading.

• Induction of IAH due to pneumoperitoneum did not significantly influence CO measured by PulseCO, PCCO, CCO_PAC and CO_TCP.

• At IAH, an increase in CO following fluid loading was indicated by calibrated PCCO, CCO_PAC and CO_TCP but not by uncalibrated CCO methods using arterial waveform analysis, such as PulseCO and PCCO.

• Recalibration of CCO parameters based on arterial waveform analysis should be done before any major change in therapy is initiated.

CCO: continuous cardiac output; CCO_PAC: continuous cardiac output by pulmonary artery catheter thermodilution; CO: cardiac output; CO_TCP: bolus transcardiopulmonary thermodilution cardiac output; CVP: central venous pressure; GEDV: global end-diastolic volume; IAH: intra-abdominal hypertension; PAC: pulmonary artery catheter; PAOP: pulmonary artery occlusion pressure; PCCO: continuous cardiac output by pulse contour analysis; PCCO_pre: continuous cardiac output by pulse contour analysis before calibration; PCCO_recal: continuous cardiac output by pulse contour analysis after recalibration; PE: percentage error; PulseCO: continuous cardiac output by pulse power analysis; SD: standard deviation.

MG and JH declare that they have no competing interests. JR, PM, JS and BB have served as honorary lecturers for Pulsion Medical Systems, Inc.

MG conceived of the study design, performed experiments, carried out statistical analysis and drafted the manuscript. JR conceived of the study design, carried out experiments and helped to draft the manuscript. PM and JH carried out data analysis and helped to draft the manuscript. JS coordinated the study. BB conceived of the study design, coordinated the study and helped with statistical analysis and drafting the manuscript. All authors read and approved the final manuscript.