Pressure recording analytical method (PRAM) for measurement of cardiac output during various haemodynamic states

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1 British Journal of Anaesthesia 95 (): (5) doi:.93/bja/aei54 Advance Access publication May 3, 5 Pressure recording analytical method (PRAM) for measurement of cardiac output during various haemodynamic states S. Scolletta*, S. M. Romano, B. Biagioli, G. Capannini and P. Giomarelli Department of Surgery and Bioengineering, Thoracic and Cardiovascular Unit, University of Siena, Siena, Italy *Corresponding author: Department of Surgery and Bioengineering, Thoracic and Cardiovascular Unit, University of Siena, Viale Bracci 4, 53 Siena, Italy. scolletta@unisi.it Background. Cardiac output (CO) can be measured using the pressure recording analytical method (PRAM), which is a new, less invasive technique allowing beat-by-beat stroke volume monitoring from the pressure signals recorded in femoral or radial arteries. Methods. We investigated PRAM by comparing its cardiac output (PRAM-CO) with paired measurements obtained by electromagnetic flowmetry (EM-CO) and by standard thermodilution (ThD-CO) during various haemodynamic states in a swine model. Nine pigs were monitored with a pulmonary artery catheter and a femoral artery catheter at baseline, in a hyperdynamic state produced by administration of dobutamine and in a hypodynamic state induced by progressive exsanguination. Bland Altman analysis was used. Results. One hundred and eight paired cardiac output values over a range of EM-CO of.8.4 litre min resulted. We found close agreement between the techniques. Mean bias between EM-CO and PRAM-CO was.3 litre min (precision.58 litre min ). The 95% limits of agreement were.6 to +.55 litre min. Similar results between ThD-CO and PRAM-CO were found. Conclusions. In a porcine model we have demonstrated accuracy of PRAM during various haemodynamic states. PRAM is a reliable tool to detect changes in cardiac output in pigs and has ability as a basic research tool. Br J Anaesth 5; 95: Keywords: heart, cardiac output; measurement techniques, cardiac output; measurement techniques, pulse contour method; measurement techniques, thermodilution; model, pig Accepted for publication: April 4, 5 Thermodilution (ThD) is the most commonly used method of determining cardiac output (CO). It has been used for yr since its development with the catheter described by Ganz and Swan. However, the insertion of a pulmonary artery catheter (PAC) involves an invasive procedure associated with several risks and complications. Some authors are of the opinion that low-risk patients do not require perioperative assessment of CO by PAC. 3 Moreover, errors in measurements may be introduced by rewarming the injectate before injection and by heat loss during measurement. 4 7 Collectively, these factors have prompted efforts to develop alternatives to the ThD technique. Recently a new, less invasive system of pulse contour analysis has been developed: beat-to-beat values of CO can be obtained using the pressure recording analytical method (PRAM). 89 This new method is based on mathematical analysis of the arterial pressure profile changes. It allows continuous stroke volume (SV) assessment from the pressure signal recorded in radial and femoral arteries. In contrast with bolus ThD, PRAM is quick and simple to use, has minimal risks and provides continuous data. PRAM has been used in volunteers and during cardiac surgery, 89 but to date there have been no studies comparing PRAM with the ThD technique under hyperdynamic or hypodynamic laboratory conditions. Accordingly, we investigated the reliability of PRAM by comparing CO values obtained by this new method (PRAM-CO) with CO determined by electromagnetic flowmetry (EM-CO) and by conventional ThD (ThD-CO) during various haemodynamic states in pigs. This is the first study to investigate the accuracy of PRAM in a porcine model and to assess its value as a research tool. Materials and methods Experimental procedure After obtaining approval from the Institutional Ethics Committee, we studied nine pigs (body weight Downloaded from at Pennsylvania State University on February 7, 4 # The Board of Management and Trustees of the British Journal of Anaesthesia 5. All rights reserved. For Permissions, please journal.permissions@oupjournals.org

2 Scolletta et al. 7 6 kg). Premedication consisted of an i.m. injection of flunitrazepam. mg kg and ketamine hydrochloride 5 mg kg. A peripheral venous cannula ( gauge) was inserted in the dorsal vein and lactated Ringer s solution was infused at a rate of ml kg h. General anaesthesia was induced with pentobarbital sodium 5 mg kg and fentanyl 5 mgkg. After muscle relaxation with pancuronium bromide. mg kg, a tracheal tube was introduced. The lungs were mechanically ventilated (Servo Ventilator 9C; Siemens Elema, Solna, Sweden) at a tidal volume of 5 ml kg body weight. Minor adjustments of ventilator controls were used to maintain Pa CO at kpa. Anaesthesia was maintained with pentobarbital sodium 4 mg kg h and fentanyl.5 mg kg min. Temperature was monitored with a rectal probe and was maintained in the range C with a forced-air warming blanket. A pulmonary artery catheter (7 F; Baxter, Irvine, CA, USA) was advanced through the femoral vein to obtain a pulmonary artery tracing with the balloon deflated and a pulmonary capillary wedge pressure tracing with the balloon inflated with ml of air. Arterial blood pressure was monitored through one lumen of the femoral artery catheter (6 8 gauge). Lead II of the electrocardiogram (ECG) was monitored with subcutaneous electrodes introduced into the legs. At the conclusion of each experiment, the animal was killed by bleeding and an oral dose of pentobarbital sodium 9 mg kg. Measurement of cardiac output by electromagnetic flowmetry After median sternotomy, the probe of an electromagnetic flow meter (EFM) (model BL 63; Biotronex Laboratory, Chester, MD, USA) was placed around the ascending aorta for continuous measurement of CO (EM-CO). Calibration of the probe was checked in vitro at the end of each experiment. Values of EM-CO were recorded when the iced glucose solution was injected for ThD-CO measurement. Measurement of cardiac output by thermodilution Cardiac output was measured by ThD using the mean of triplicate injections of ml of iced 5% glucose injected into the right atrium as fast as possible by the same investigator during apnoea at end-expiration. Any ThD-CO measurement significantly different (more than %) from its pair was excluded, and a repeat measurement was obtained. Measurement of cardiac output by PRAM A standard arterial catheter was inserted into the femoral artery. A Baxter Truwave PX-6F transducer (Baxter- Edwards, Irvine, CA, USA) was connected to the monitoring system (Hewlett Packard, Andover, MA, USA) for continuous recording of the systemic arterial pressure waves and subsequent computation of CO. The pressure signals were acquired at Hz by means of an analogue digital multifunction card (DAQ Card-7; National Instruments Corporation, Austin, TX, USA) working on the tension signals with bits from.5 to.5 volts. All signals were recorded on a personal computer (TravelMate 57-DX; Acer, Taipei Hsien, Taiwan, ROC). The pressure signal was filtered at 5 Hz to avoid resonance effects caused by the catheter transducer system without degrading the pressure wave amplitude. PRAM-CO values were displayed on a dedicated personal computer at each time point and recorded. For each determination of ThD-CO, a corresponding value for PRAM was made by averaging the individual beats over the approximate time needed for ThD-CO measurements. PRAM provided arterial pressure and beat-by-beat CO values continuously throughout the study. Basic physical principles of PRAM Changes in volume which occur in all arterial vessels are mostly due to radial expansion of the wall in response to blood pressure changes. This depends on various physical factors, such as the force of cardiac contraction, arterial impedance and compliance, and resistance of peripheral vessels. These variables are closely interdependent and need to be evaluated simultaneously. To this end, a variable called Z, representing the relationship between changes in pressure and changes in volume with time, is taken into account for the evaluation of SV in the various approaches to determine CO by pulse contour methods (PCMs). Pulse pressure is converted to SV by calculating the area under the pulsatile portion of the pressure wave, and Z (mm Hg s cm 3 ) is calculated as a factor retrospectively approximated from the results of in vitro experiments or by calibration with an independent measure of SV (i.e. ThD bolus). At variance with other PCMs, PRAM is the practical application of a model developed completely a priori. The model did not require adjustments based on experimental data. 8 The concept behind PRAM is based on the physics theory of perturbations, by which each physical system under the effects of a perturbing term tends to react to reacquire its own condition of stability (i.e. the situation of minimal energy required). With PRAM, the whole instead of the pulsatile systolic area under the pressure curve is measured in each cardiac cycle. At the same time, Z is obtained directly from the morphological analysis of both the pulsatile and the continuous components of the pressure waveform. The derivation of Z requires no predicted data apart from the expected mean arterial pressure. Briefly, according to PRAM, 8 Z is equal to (P/t) K, and SV is calculated as follows (cm 3 ): SV¼A=ðP=t KÞ where A (mm Hg s) is the whole area under the systolic portion of the pressure curve, P/t (mm Hg s ) is a description of the pressure wave profile expressed as the variation in pressure (P) over time (t) during the entire cardiac cycle (systolic and diastolic portion) and K is a factor inversely Downloaded from at Pennsylvania State University on February 7, 4 6

3 PRAM for measurement of cardiac output related to the instantaneous acceleration of the vessel s cross-sectional area (c cm ) ( cm ). The variables A, P/t and K are closely interdependent in each cardiac cycle. 8 The value of K is obtained from the ratio between expected and measured mean blood pressures. The numerator of the relationship is constant (theoretical mean arterial pressure), and the denominator is measured. As a consequence, K may change from cardiac cycle to cardiac cycle, and the constant value at the numerator is taken as a reference to gauge the deviation from normality of mean arterial pressure. Because mean arterial pressure is lower peripherally with respect to central arteries, PRAM applies two different values of expected mean pressure for the computation of K at central (aorta) and peripheral levels (e.g. radial or femoral), namely the values originally indicated by Burton and Guyton (i.e. mm Hg centrally and 9 mm Hg peripherally). Since PRAM allows the use of two proper algorithms for central or peripheral arteries to obtain SV for each cardiac cycle, we were able to monitor CO by applying the correct formula (i.e. expected mean arterial pressure = 9 mm Hg) for femoral artery. 8 The value of K will differ from unity in the presence of physical phenomena that may affect pressure wave transmission (e.g. low stroke output from the left ventricle or backward wave reflections from the peripheral vasculature). Because perturbations of the pressure wave are reflected in the instantaneous acceleration of the arterial vessel cross-sectional area, the correction of P/t by a value of K above or below unity yields a corrected value of Z that takes into account the effect of the wave reflection. 8 Study intervals After baseline measurements had been obtained (T, baseline ), haemodynamic status was changed from baseline to a hyperdynamic state ( 4% increase in CO monitored with EM-CO) by continuous infusion of dobutamine at the rate of 5 mg kg min (T, hyperdynamic), and then returned to baseline (T3, baseline ). Next, the status was changed from baseline to a hypodynamic state by removal of 5 5 ml kg of blood (T4, haemorrhage). After obtaining haemodynamic stability for at least min, CO was measured. Three paired measurements of CO were made in each animal under each haemodynamic condition. Statistical analysis Paired values obtained by ThD and PRAM were divided into four groups, namely the periods T, T, T3 and T4. Data from all pigs were used to compute the mean and standard deviation (SD). Bland Altman analysis was used. 3 Bias (mean difference between measurements) and the 95% limits of agreement (within which 95% of the difference will lie) of PRAM-CO compared with EM-CO and ThD-CO were computed. Bias and 95% limits of agreement as a percentage of the mean value of EM-CO and ThD-CO measurements were also calculated (i.e. bias %= bias/em- CO; 95% limits of agreement %= lower limit/em-co upper limit/em-co). Finally, comparison of CO values among phases was performed using repeated-measures analysis of variance. Results A total of 8 paired data points (7 for each interval) were collected over a range of EM-CO values from.8 to.4 litre min. The CO range was.9.5 litre min for PRAM and.9.7 litre min for ThD. All data are presented in Table. EM-CO values were obtained at each time in all pigs, and no data were rejected. Eleven aberrant ThD-CO readings (different from their pair by more than %) were observed. These measurements were rejected and repeated. The biases of PRAM-CO and ThD-CO compared with EM-CO were negative in all conditions except haemorrhage. The 95% limits of agreement for each moment are reported in Table and Figs and. By taking the means of the values obtained in each of the four phases of the study, mean bias between EM-CO and PRAM-CO was.3 litre min (precision.58 litre min ). The 95% limits of agreement were.6 to Mean bias between ThD-CO and PRAM-CO was.5 litre min (precision.6 litre min ). The 95% limits of agreement were.67 to Analysis Downloaded from at Pennsylvania State University on February 7, 4 Table CO values, bias and 95% limits of agreement (LoA) in each haemodynamic state. Cardiac output values are expressed as mean (SD). PRAM-CO, pressure recording analytical method of cardiac output measurement; EM-CO, cardiac output measured by electromagnetic flowmetry; ThD-CO, thermodilution cardiac output measurement. *Significant changes (P<.) within the study period (analysis of variance) T Baseline T Hyperdynamic T3 Baseline T4 Haemorrhage PRAM-CO (litre min )* 5.3 (.4) 7.8 (.63) 5.7 (.3) 3.3 (.5) EM-CO (litre min )* 5.9 (.36) 7. (.55) 5. (.38) 3.34 (.44) Bias (litre min ) % LoA (litre min ).5 to to to to +.73 Bias (%) % LoA (%). to to to to +.85 ThD-CO (litre min )* 5.4 (.47) 7. (.65) 5. (.5) 3.6 (.69) Bias (litre min ) % LoA (litre min )*.59 to to to to +.88 Bias (%) % LoA (%).47 to to to to

4 Scolletta et al. (EM.CO PRAM.CO) (litre min ) A (EM.CO PRAM.CO) (litre min ) B (EM.CO+PRAM.CO)/ (litre min ) (EM.CO+PRAM.CO)/ (litre min ) (EM.CO PRAM.CO) (litre min ) C (EM.CO+PRAM.CO)/ (litre min ) of variance showed significant changes in CO values within the study period (P<.). No adverse effects related to the use of the pulmonary artery catheter were observed. PAC was correctly positioned in each pig at necropsy. Discussion Several researchers have investigated the reliability and accuracy of CO measurement techniques during various haemodynamic states in animals. 4 8 Two established invasive methods (EFM and ThD) were used simultaneously in this study. The accuracy of PRAM compared with EFM and ThD was assessed under general anaesthesia at baseline and during hyperdynamic and hypodynamic states. The biases of PRAM-CO and ThD-CO compared with EM-CO were negative in all conditions except haemorrhage. In a similar study, Kurita and colleagues 9 compared a continuous lithium dilution technique (LiDCO) with ThD and EFM in pigs during various haemodynamic states. They found that the precision values of the new technique calculated for all haemodynamic states were less than those measured using the ThD method. Moreover, ThD and LiDCO CO values were higher than those obtained by EFM. Since EFM (EM.CO PRAM.CO) (litre min ) D (EM.CO+PRAM.CO)/ (litre min ) Fig Bland and Altman plots for comparison between EM-CO and PRAM-CO in each haemodynamic state: (A) baseline ; (B) hyperdynamic; (C) baseline ; (D) haemorrhage. The unbroken lines show the mean difference (bias) and the dotted lines show the 95% limits of agreement. cannot measure CO including the coronary blood flow, which constitutes about 5% of the left ventricular output in the resting condition and increases to about 5% under hypoxia, they concluded that ThD-CO and LiDCO exceeded the values of EM-CO. 9 Our findings are in line with those of Kurita and colleagues 9 and with the results later observed by the same study group again comparing the lithium dilution technique with ThD and EFM. In the present study, bias values in the PRAM CO/EM CO comparison, calculated for all haemodynamic states, were less than those in the ThD CO/EM CO comparison, suggesting that the variation in prediction of CO by PRAM was lower than that by ThD, and that PRAM provided better repeatability than ThD. PRAM is based on the principle that, in any given vessel, volume changes occur mainly because of radial expansion in response to variations in pressure. 8 Similar approaches have been studied by several authors in the course of the last three decades, and have led to the development of important clinical applications (e.g. the PiCCO and LiDCO systems and the Modelflow method). 3 6 However, the PiCCO system does not start without a ThD-CO; moreover, even though both the LiDCO system and the Modelflow method starts pulse contour CO computations directly after Downloaded from at Pennsylvania State University on February 7, 4 6

5 PRAM for measurement of cardiac output (ThD.CO PRAM.CO) (litre min ) A (ThD.CO PRAM.CO) (litre min ) B (ThD.CO+PRAM.CO)/ (litre min ) (ThD.CO+PRAM.CO)/ (litre min ) (ThD.CO PRAM.CO) (litre min ) C (ThD.CO+PRAM.CO)/ (litre min ) connection to a radial artery pressure signal with a trending of CO, these two methods have a higher accuracy only after considering age, sex and external calibration data. 3 6 In contrast, PRAM can measure absolute values of SV, independently from calibration, by determining parameters able to characterize the elastic properties of the arteries from the objective analysis of the pressure wave profile. 89 Generally, PCMs and PRAM may have advantages over PAC-derived ThD measurements. 9 6 PRAM seems to be easy to use. It provides a fast response time (beat-to-beat readout), and abrupt changes in CO resulting from blood loss, tamponade, off-pump cardiac surgery and changes in arterial resistance may be detected more quickly than with ThD. More importantly, PRAM does not require external calibration by ThD, and requires no other additional invasive procedure. Since it does not require injection of thermal solution a central line is not required, avoiding both timeconsuming and potential complications due to the insertion of a central catheter. 89 Moreover, the positioning of a pulmonary artery catheter for ThD measurements may be contraindicated in minor surgical procedures and in low-risk patients. 3 Therefore, PRAM might be considered a practical alternative to the traditional ThD method when siting (ThD.CO PRAM.CO) (litre min ) D (ThD.CO+PRAM.CO)/ (litre min ) Fig Bland and Altman plots for comparison between ThD-CO and PRAM-CO in each haemodynamic state: (A) baseline ; (B) hyperdynamic; (C) baseline ; (D) haemorrhage. The unbroken lines show the mean difference (bias) and the dotted lines show the 95% limits of agreement. a PAC is deemed harmful or not essential for clinical management. Despite some disadvantages of bolus ThD, this is the most commonly used clinical method of CO determination and continues to be considered as the standard for comparison with other methods. Nevertheless, the bolus ThD technique only measures CO over a variable time period of 5 45 s, and it may not be so appropriate as a gold standard technique for evaluation of a new, continuous method of measuring systemic blood flow. Therefore, the thermal filamentwrapped PAC employing the ThD principle to measure CO continuously might be more appropriate for comparison of beat-by-beat techniques. 7 9 However, the CO displayed is updated every 3 s and reflects the average flow from the previous 3 4 min. Since this could generate errors in collecting CO data due to the lack of an exact event marker to synchronize continuous ThD-CO with PRAM-CO measurements, we rejected the idea of using the continuous ThD method and compared PRAM with the bolus ThD technique. With regard to ThD, the results of the present study agree with those of Romano and Pistolesi, who demonstrated an excellent correlation with ThD and PRAM in haemodynamically stable patients undergoing cardiac catheterization. 8 Downloaded from at Pennsylvania State University on February 7, 4 63

6 Scolletta et al. In a recent study, our research group investigated PRAM in low-risk and haemodynamically stable patients undergoing coronary artery bypass surgery, and concluded that PRAM was accurate for real-time monitoring of CO during cardiac surgery and in the postoperative period. 9 However, in that previous study we did not obtain good agreement between PRAM-CO and ThD-CO measurements after the end of extracorporeal circulation, and considered the hypothesis that our results may be accounted for by the loss of reliability of ThD after the end of ECC. 459 Notoriously, variability in ThD method occurs because of differences in injection technique, fluctuations in blood temperature, electrical interference, and cyclical variations in CO with ventilation. 673 Moreover, variations in pulmonary artery blood temperature transiently increase after extracorporeal circulation, and the increased thermal noise may cause significant errors in the results of ThD techniques. 45 To date, only two studies provide an indication of the intrinsic accuracy of PRAM. 89 However, they do not give a direct answer to the questions arising from the accuracy of the methods in measuring CO in various haemodynamic states. We performed this study on PRAM under various haemodynamic conditions in animals since it enabled us to evaluate the performance of the system over a wide range of COs that could not be tested ethically in humans. Some interesting findings emerged from the present study. CO estimates obtained by PRAM at baseline state showed good agreement with those simultaneously obtained by EFM and conventional bolus ThD. Over the intervals studied and a wide range of blood flow values, no significant difference between PRAM and the established techniques emerged. This agreement persisted despite changes in the use of vasoactive drugs and blood volume losses (hyperdynamic and hypodynamic states, respectively). These findings confirm the reliability and accuracy of this new method in CO monitoring during various haemodynamic states. However, we selected specific clinical patterns to gain familiarity with this new method, avoiding any random factor that could have influenced animal management. Further studies will be required to assess PRAM in the setting of extreme haemodynamic conditions and of severe haemorrhage. Some disadvantages of PRAM remain to be addressed. (i) Several factors could affect the accuracy of CO measurements based on the analysis of arterial waveforms, 3 such as stenosis of the arterial tree, arterial pathology in the proximal segments, etc., which need to be further investigated. Moreover, damped waveforms and inadequate pulse detection (e.g. severe arrhythmias, catheter dislodgement) may influence the precision of the pressure wave analysis. 3 (ii) The additional data regarding the loading conditions of the heart (e.g. wedge pressure) represent important information that allows accurate interpretation (and therapy) of low CO states. 9 The absence of preload measures may be a disadvantage of many pulse contour methods. In our opinion, this is the penalty we have to accept for being less invasive. In summary, under the conditions studied, we have demonstrated that PRAM gives results comparable to CO determined by electromagnetic flowmetry, and by conventional ThD during various haemodynamic states in a swine model. Moreover, this is the first study to investigate the accuracy of PRAM in a porcine model and to assess its value as a research tool. References Ganz W, Swan HJC. Measurement of blood flow by thermodilution. Am J Cardiol 97; 9: 4 6 Patel C, Laboy V, Venus B, Mathru M, Wier D. Acute complications of pulmonary artery catheter insertion in critically ill patients. Crit Care Med 986; 4: Connors AF Jr, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterisation in the initial care of critically ill patients. SUPPORT investigators. JAMA 996; 76: Bazaral MG, Petre J, Novoa R. Errors in thermodilution cardiac output measurements caused by rapid pulmonary artery temperature decreases after cardiopulmonary by-pass. 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