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Original Paper

Neonatology 2012;102:61–67 DOI: 10.1159/000337295

Non-Invasive Cardiac Output Monitoring in Neonates Using Bioreactance:A Comparison with Echocardiography

Dany E. Weisz a Amish Jain a–c Patrick J. McNamara b–e Afif EL-Khuffash a–c

a Department of Pediatrics, Mount Sinai Hospital, b Division of Neonatology, The Hospital for Sick Children, c Department of Pediatrics, University of Toronto, d Physiology and Experimental Medicine Program, The Hospital for Sick Children, and e Department of Physiology, University of Toronto, Toronto, Ont. , Canada

652], p ! 0.001). The NICOM LVO readings were lower than the echo readings by a mean of 153 8 56 ml/kg. NICOM con-sistently under-read LVO by 31 8 8%, and this systematic difference was constant across the range of LVOs obtained. There was a strong correlation between NICOM and echo measurements of LVO (r = 0.95, p ! 0.001). Conclusion: Non- invasive cardiac output monitoring is feasible in neonates. Further validation studies in neonatal animal experimental models and human neonates need to be conducted before routine clinical use. Copyright © 2012 S. Karger AG, Basel

Introduction

Continuous assessment of cardiac output would be a valuable tool in the management of a wide range of neo-natal illnesses. Until recently, continuous monitoring of cardiac output in pediatric and adult patients has been achieved by invasive methods such as continuous ther-modilution with a pulmonary artery catheter, an arterial catheter for pulse contour analysis, an intra-tracheal tube for partial CO 2 re-breathing, or an intra-esophageal probe for continuous Doppler velocity flow assessment. Although the thermodilution method is considered the

Key Words

Echocardiography � Non-invasive cardiac output monitoring � Neonate � Left ventricular output

Abstract

Objectives: Non-invasive cardiac output monitoring is a po-tentially useful clinical tool in the neonatal setting. Our aim was to evaluate a new method of non-invasive continuous cardiac output (CO) measurement (NICOM TM ) based on the principle of bioreactance in neonates. Methods: In this pro-spective observational study, 10 neonates underwent 97 paired NICOM and echocardiography (echo) assessments of left ventricular output (LVO). For each neonate, NICOM mea-surements of left ventricular stroke volume (SV) and LVO over a 2- to 4-hour period were correlated with blinded, si-multaneous, discrete echo measurements of SV and LVO. The precision and accuracy of the NICOM monitor relative to echo during periods of steady state were assessed. Results: The infants’ median birth weight was 2.72 kg (IQR 1.56–3.23 kg, range 1.44–4.00) and their median gestation was 37 weeks (IQR 31–40 weeks, range 31–41). Median NICOM SV and LVO readings were consistently lower than echo (2.6 ml [IQR 1.4–3.2, range 0.6–5.3] vs. 3.5 ml [IQR 2.1–4.4, range 1.1–6.8], and 400 ml/min [IQR 233–476] vs. 559 ml/min [IQR 386–

Received: November 3, 2011 Accepted after revision: February 15, 2012 Published online: April 11, 2012

Afif EL-Khuffash, MD, MRCPI Department of Pediatrics, Mount Sinai Hospital 600 University Ave., Room 794 Toronto, ON M5G1X5 (Canada) Tel. +1 416 586 4800, E-Mail afif_faisal   @   hotmail.com

© 2012 S. Karger AG, Basel1661–7800/12/1021–0061$38.00/0

Accessible online at:www.karger.com/neo

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clinical gold standard of central hemodynamic monitor-ing, it has been shown to have many risks and disadvan-tages [1] .

The ability to perform non-invasive monitoring of systemic hemodynamics is even more relevant in the neonatal intensive care unit (NICU) where small patient size prohibits invasive monitoring. Currently, measure-ment of cardiac output in neonates is performed periodi-cally and only in centers with access to neonatologists with the skill to perform targeted neonatal echocardiog-raphy (TnECHO). This modality is limited by the need for expensive equipment and extensive training to per-form cardiac output evaluations [1, 2] . In addition it only provides a single point estimate of cardiac output. Non-invasive monitoring has the advantages of being easy-to-use and provides continuous cardiac output data.

Trans-thoracic bioreactance is a new technique of non-invasive continuous cardiac output (NICOM) mon-itoring. It is based on an analysis of relative phase shifts of oscillating currents that occur when an injected cur-rent traverses the thoracic cavity. In the adult population, NICOM has acceptable accuracy and precision for car-diac output monitoring in patients with hemodynamic instability when compared to thermodilution, aortic ar-tery catheterisation, and cardiopulmonary bypass pumps [3–5] . There are no published studies using NICOM in neonates. Validation studies in small animal experimen-tal models, with stroke volumes comparable to those of preterm infants (1–3 ml/s/kg/min) showed a close corre-lation with invasive measurement of aortic blood flow [5] .

The objectives of this study were to assess the feasibil-ity of using NICOM in neonates and compare the results of NICOM-derived estimates of left ventricular output (LVO) with those obtained using TnECHO. Although the latter is not the recognised gold standard method, it is cur-rently the only method used in routine clinical practice.

Methods

This was a prospective observational study carried out at Mount Sinai Hospital, Toronto, Ont., Canada. Institutional Re-search Ethics Board approval was obtained. Informed consent was obtained from the parents of all participants. Infants admit-ted to the NICU with weights greater than 1,500 g and/or a gesta-tional age greater than 30 completed weeks were eligible for inclu-sion. All infants were clinically stable. Infants with congenital heart disease, other than a patent foramen ovale (PFO), were not considered for inclusion. Each infant underwent 5–10 paired LVO measurements using echo and NICOM simultaneously, over a 2- to 4-hour period. The infants’ weight, gestation, ventilator re-quirement and primary diagnosis were noted.

Echocardiography Measurement Echocardiography evaluations of LVO were performed with

the Sonosite MicroMaxx portable ultrasound system (www.sonosite.com) using a 10-MHz probe. All the infants underwent a full structural examination by a pediatric cardiologist to rule out major shunts prior to enrolment. Infants with a small PFO were included in this study, as this will not have a hemodynamic impact. Infants with a patent ductus arteriosus (PDA) were ex-cluded. All LVO measurements were performed by a single echo-cardiographer (A.K.), who was blinded to the NICOM measure-ments (see below). LVO was calculated as follows: the aortic root diameter was measured at the hinges of the aortic valve leaflets using the long axis parasternal view. To minimize intra-observer variability, this measurement was taken once at the start of the examination. The velocity time index (VTI) of the ascending aor-ta was obtained from measuring the pulsed wave Doppler from the apical 5-chamber view. The cursor was aligned to become par-allel to the direction of flow. No angle correction was used and an average of three consecutive Doppler wave forms was used to es-timate VTI. LV stroke volume was then calculated as the product of VTI and aortic cross-sectional area (AoCSA) using the follow-ing formula: AoCSA = � (aortic radius) 2 . LVO was determined as the product of LV stroke volume and heart rate [5, 6] . The LVO measurements were not indexed to weight for the purposes of cor-relation and assessing agreement.

NICOM Measurements LVO measurement using bioreactance was facilitated by the

NICOM system. Bioreactance is the analysis of the variation in the frequency spectra of a delivered oscillating current when it traverses the thoracic cavity. This was obtained by placing four emitting and receiving electrodes in a manner that ‘boxes’ the heart. Each electrode sensor strip consisted of two contact points. Upper thoracic electrode strips were placed over the mid-clavicles and upper back bilaterally. The lower electrode sensors were placed between the 6th and 7th intercostal spaces at the mid-ax-illary line ( fig. 1 ). The system’s signal processing unit determines the relative phase shift ( � ) between the input and output signals. Stroke volume (SV) can be estimated by: SV = C ! VET ! d � /dt max , where C is a constant of proportionality, VET is ventricular ejection time (determined from the NICOM and ECG signals) and d � /dt max is the peak rate of change of � [2, 3] . The value of C has been optimized in prior studies and accounts for patient age, gender and body size [7] . SV and LVO measurements were pro-vided in 60-second intervals [4] . NICOM measurements of SV and LVO were blinded to the echocardiographer by covering the screen displaying the values. The echocardiographic measure-ment of SV and LVO were paired with the corresponding NICOM readings following study completion. The NICOM system stores each reading of SV and LVO. The time of aortic VTI acquisition was identified and related to the corresponding time of SV read-ing on the NICOM machine. Both internal clocks were synchro-nised prior to starting the study.

Statistical Analysis LVO measurements using the two methods were non paramet-

ric, continuous variables. The absolute and percentage differenc-es between the two methods were normally distributed. Skewed data were presented as medians, interquartile ranges (IQR), and ranges and the Wilcoxon rank sum test was used for intergroup

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NICOM in Neonates Using Bioreactance Neonatology 2012;102:61–67 63

comparisons. Normally distributed data were presented as means and standard deviations (SD). Spearman’s correlation coefficient was used to determine the correlation between NICOM and echo SV and LVO measurements. The differences in measurement be-tween the two values are expressed as absolute (LVO – NICOM), and a percentage ([LVO – NICOM]/LVO). We assessed agreement between the two methods using Bland-Altman methods. Both the absolute and percentage differences between the LVO and NICOM measurements were calculated. A modification of the Bland and Altman methods, which takes into account repeated measure-ments on the same subjects, was used to calculate the 95% limits of agreement [6] . We assessed the precision of NICOM in all 10 infants by measuring stroke volume and calculating the mean (SD) and coefficient of variation of 20 consecutive readings over 20 min. We considered a p value of ! 0.05 as significant.

Results

Ten neonates underwent a total of 97 paired NICOM and echo assessments of LV stroke volume and LVO. Their median birth weight was 2.72 kg (IQR 1.56–3.23 kg, range 1.44–4.00) and median gestational age was 37

weeks (IQR 31–40 weeks, range 31–41). Three neonates were male (30%). Respiratory support at the time of the study included high frequency oscillation (1 infant), nasal continuous positive airway pressure (2 infants), low flow oxygen (4 infants), and room air (3 infants). The underly-ing diagnosis and reason for admission included prema-turity (n = 7), pulmonary hypertension (n = 2) and me-conium aspiration syndrome (n = 1). NICOM monitoring was tolerated well in all infants with no evidence of skin irritation.

The results of the two methods are presented in ta-ble  1 . Median NICOM-derived SV and LVO readings were lower than echocardiography (2.6 vs. 3.5 ml and 400 vs. 559 ml/min, p ! 0.001). NICOM-derived LVO read-ings were lower than echo readings by 153 8 56 ml/kg (95% limits of agreement: 43–267 ml/kg). NICOM con-sistently under-read LVO by 31 8 8% (95% limits of agreement: 15%, 46%); this systematic difference was constant across the range of LVOs obtained ( fig. 2 ). There was a strong correlation between NICOM- and echocar-diography-derived estimates of LVO (r = 0.95, p ! 0.001;

Fig. 1. Schematic diagram of electrode positioning during the study. The upper pair of electrodes (white arrows) is placed over the mid-clavicle. The lower pair of electrodes (black arrows) is placed over the anterior axillary line. The same lead placement is also performed on the left side of the infant. The aim is to ‘box’ the heart by the 4 pairs of electrodes. NICOM LVO readings were on average 31 8 8% lower than LVO.

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Table 1. NICOM and echo readings of SV and LVO

NICOM SVml

ECHO SVml

NICOM LVO ml/min

ECHO LVO ml/min

Absolutedifference

Percentagedifference

Median 2.6 3.8 400 559 163 31IQR 1.4–3.2 2.1–4.3 233–476 386–652 115–190 26–36Range 0.6–5.3 1.1–6.8 84–700 152–896 33–302 9–50

M edian absolute difference and percentage difference between NICOM and LVO are also displayed.

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fig. 3 ). Four infants had a patent foramen ovale (PFO). The systematic difference between NICOM and echo similar in infants with and without a PFO (34 vs. 29%,p = 0.45). The mean bias in the infant on HFO was 28%. The precision of NICOM was high with a median CV of 7% (range 5–16) ( table 2 ).

Discussion

This study evaluated a new bioreactance method of non-invasive cardiac output measurement in a cohort of hemodynamically stable preterm and term neonates. We compared NICOM to echocardiography because it is the only method available in neonates for LVO measurement [2] . In a cohort of 10 infants, we demonstrated that NICOM is feasible in neonates. Although there was a strong correlation between NICOM and echocardiogra-phy, a systematic bias of 31% was detected. The magni-tude of the bias was consistent across the range of LVO values. Although NICOM is not an accurate measure of

Table 2. Mean 8 standard deviation (SD) of the stroke volume of 20 consecutive readings over 20 min of the ten infants and the coefficient of variation of the readings

Patient No. Mean 8 SD Coefficient of variation, %

1 3.0980.32 102 2.5980.41 163 2.3180.15 64 1.3580.12 95 3.1180.22 76 1.2780.09 77 1.0280.10 108 1.1180.06 59 4.2080.30 7

10 3.2580.16 5

200 400 600 800 1,0000

R2 linear = 0.938

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Fig. 3. Correlation between echo and NICOM LVO readings in the cohort.

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Fig. 2. Bland-Altman analysis of the absolute difference ( a ) and the percentage difference ( b ) between the two methods. Mean absolute and percentage differences are indicated by the dotted line, and the 95% limits of agreement are indicated by the solid lines.

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LVO, the uniformity of the bias suggests consistency of NICOM in this population. The narrow coefficient of variation further supports this observation and confirms that NICOM is precise. It is important to recognize that these data are representative of healthy newborns only.

There are several possible explanations for the system-atic bias. First, there may be systematic inaccuracy with the intrinsic NICOM calculation in the neonatal setting, leading to underestimation of LVO. NICOM determines LV stroke volume as: SV = C ! VET ! d � /dt max , where C is a constant of proportionality, VET is ventricular ejec-tion time and d � /dt max is the peak rate of change of the phase shift of the injected electrical current. The value of C was extrapolated from adult studies to account for pa-tient age, gender and body size, but this constant may not be applicable for neonates. An inappropriately low C val-ue for neonates would result in systematic underestima-tion of LVO, but maintaining a strong correlation, as was demonstrated in this study. In addition the algorithm does not use true aortic diameter [3, 4] . Anatomical and developmental aortic differences in neonates may result in a relationship between SV, VET and d � /dt max which is underestimated by C. Left ventricular ejection time (LVET) is also used by the NICOM system to calculate stroke volume. Error in estimation of LVET in neonates, particularly at faster heart rates, may account for some bias. Unfortunately, we did not track LVET in this study to investigate this factor. Fluid shifts in the thoracic cav-ity may also affect the signal and LVO estimation. The d � /dt max is mainly impacted by blood ejected from the left ventricle, therefore readings obtained from the ma-chine reflect LVO. In adults, blood flow form the pulmo-nary artery is known to have a negligible effect on the phase shift. It is possible that the impact of pulmonary artery flow on the phase shift may be greater in neonates leading to bias. The presence of small PFO or PDA shunts may also affect the readings.

Second, echocardiography may overestimate LVO. Es-timation of LVO relies on accurate measurement of the aortic root diameter (AoD). LVO is subsequently calcu-lated as VTI ! aortic cross-sectional-area (AoCSA), where AoCSA = � (aortic radius) 2 . The calculation is based on the assumption that aortic diameter is estimat-ed at a point where VTI is also measured. Discordance in the location of these measurements and overestimation of the aortic diameter would result in a squaring of this error. This may also account for the consistent discrep-ancy between NICOM and echocardiography.

The ability to perform continuous non-invasive car-diac output measurement would be clinically advanta-

geous in the neonatal intensive care unit (NICU). The use of bioreactance as a noninvasive measure of LVO has ac-ceptable accuracy, precision and responsiveness in adults with both stable and changing cardiac output states. In adult patients following cardiac surgery, Squara et al. found a strong correlation between NICOM and thermo-dilution (r = 0.82; bias of +0.16 8 0.52 l/min) with a rela-tive error of 9.1 8 7.8% [4] . Similarly, Marque et al. [7] found a strong correlation between estimates of cardiac output using the NICOM and themodilution methods(r = 0.77 and a bias of –0.01 8 0.84 l/min). Heerdt et al. [5] obtained data from 5 anesthetised, open-chest beagles weighing 2–3 kg. LVO was measured with a probe on the aortic root and averaged over 30-second intervals (AoQ). NICOM-derived LVO measurements were simultane-ously obtained every 30 s. They found an AoQ-NICOM difference of 63 8 38 ml/min and NICOM precision of 6.1%. They concluded that continuous, non-invasive measurement of LVO by bioreactance provides data that satisfactorily approximates invasive measurement of aor-tic blood flow in beagles, and suggested NICOM to be an alternative to open chest instrumentation for LVO mea-surement. The results of Ballestero et al. [8] are contradic-tory. They compared the NICOM method to femoral ar-tery (FATD) and pulmonary artery thermodilution (PATD) in 9 immature pigs weighing 9–12 kg. They found little correlation between FATD/PATD and NICOM. In a subsequent study, Ballestero et al. [9] measured cardiac index (CI) in a group of 10 children, without evidence of hemodynamic compromise, ranging in weight from 3.6 to 30 kg. Significant differences in CI estimation (p = 0.001) were detected between children weighing ! 10 kg (1.9 8 0.73 l/min/1.73 m 2 ; range 1–3.2), 10–20 kg (2.07 8 0.7 l/min/1.73 m 2 ; range 1–3.6), and 1 20 kg (3.7 8 0.8 l/min/1.73 m 2 ; range 2.4–4.9). When compared to normal reference ranges for CI obtained by invasive methods, only children with a weight 1 20 kg had CI values within the normal range. NICOM derived estimates were con-sistently lower in children ! 20 kg, further supporting the theory of a calibration issue in smaller infants.

Echocardiography evaluations of SV have been com-pared to invasive methods in the adult population. Bouchard et al. [10] showed a strong correlation and agree-ment between echo measurements of LV stroke volume and thermodilution in 41 patients (r = 0.91). The mean stroke volume obtained by echo was 59.1 ml (range 24–137) compared to a mean of 58.8 ml (range 27–148) using thermodilution. Spahn et al. [12] compared thermodilu-tion measurement of LVO to Doppler assessment in pa-tients following coronary bypass surgery. Interestingly,

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they found that when the aortic diameter was measured by echocardiography, echo overestimated LVO. The de-gree of overestimation was reduced when the aortic diam-eter was directly measured during surgery. The correla-tion between the two methods was also improved when the surgical aortic diameter was used (r = 0.89 vs.r = 0.84). To our knowledge, there is no direct comparison between echocardiography and invasive methods of LVO in neonates. Alverson et al report that echo-derived esti-mates of LVO values obtained in a group of 22 neonates are similar to values obtained in healthy newborns using catheterisation methods [11] . No previous studies have evaluated the accuracy and precision of bioreactance non-invasive LVO measurements in preterm and term neo-nates. This may be due, in part, to the lack of an agreed gold standard method. Nevertheless, although NICOM has a bias of 30%, it is consistent; this suggests that NICOM may be useful in trending LVO after initial echocardiog-raphy. One concern, however, is that the use of 4 paired electrodes in a premature infant may limit the ability to apply further monitoring electrodes on the infant’s chest.

Study Limitations

The study has many limitations. NICOM-derived LVO measurements are averaged over 1-min intervals, while the corresponding LVO measurement is an average of 3 cardiac cycles (i.e. 2–3 s). Therefore, it is possible that some of the differences in LVO between the two methods stem from measurement in different cardiac cycles. In ad-dition, the use of 4 paired electrodes in a premature infant may limit the ability to apply further monitoring elec-trodes on the infant’s chest. The small sample size and heterogeneity of the study population may further mag-nify ascertainment bias, particularly as the gestational age range span was over 10 weeks. Some of the differ-ences in the measurements could be accounted by poten-

tial error in measuring the aortic root diameter, for ex-ample. Another limitation is that our echocardiographic measurements were obtained by a single operator (A.K.). Although this minimizes inter-observer variability, it may lead to consistent operator dependent bias.

Conclusion

This study demonstrated that bioreactance can detect LVO in neonates, but this does not obviate the need for comprehensive echocardiography evaluation to determine the physiologic or anatomic nature of changes in LVO. It is important to recognize that routine clinical application of this device in the neonatal population should be prohib-ited until further validation studies are performed. There remains a need for animal experimental models, mimick-ing the neonatal circulation, to compare NICOM with in-vasive cardiac output monitoring techniques. This experi-mental paradigm could be used to examine the impact of common neonatal disease states, such as respiratory dis-tress syndrome, PDA and pulmonary hypertension, on NICOM accuracy and precision. Clinical validation of this tool in premature infants is challenging due to the lack of a non-invasive method of cardiac output evaluation. Its use is likely to be restricted to monitoring trends in cardiac output, after initial TnECHO evaluation. Our group is currently investigating the utility of NICOM in monitor-ing LVO in neonates undergoing PDA ligation due to the significant changes in cardiac output after surgery [12–14] . Until more evidence is available, we recommend that the use of NICOM in the neonatal population should be re-stricted to the research setting.

Disclosure Statement

None.

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