Assessment of cardiac output in neonates: Techniques using the fick principle, indicator dilution technology, doppler ultrasound, electrical biosensing technology, and arterial pulse contour analysis

Key points

Cardiac output monitoring in preterm and term neonates is feasible but remains challenging despite the availability of different technologies.
The best systems to monitor cardiac output in the clinical setting in neonatal intensive care at present are transthoracic echocardiography, transpulmonary indicator dilution, electrical biosensing technology, and arterial pulse contour analysis.
Noninvasive cardiac output monitoring is inversely related to accuracy; hence there will always be a compromise between these two characteristics.
A normal cardiac output does not imply adequate perfusion of all tissues; cardiac output assessment will only provide information about global blood flow.
Advanced hemodynamic monitoring in itself will not improve outcome; it is the correct interpretation of the acquired variables and the resultant, appropriately tested hemodynamic management approaches that may result in better outcomes.

Introduction

Appropriate monitoring of the cardiovascular system and thus treatment of critically ill neonates with cardiovascular compromise hinge on the ability to monitor at least two of the three interdependent cardiovascular parameters (blood pressure, cardiac output, and systemic vascular resistance), determining systemic blood flow and thus systemic oxygen delivery. In the following equation the Hagen-Poiseuille law is applied to systemic blood flow (similar to Ohm law in electrical circuits):

SVR = \frac{SABP − RAP}{CO}

$SVR = \frac{SABP − RAP}{CO}$

where CO is the cardiac output (i.e., systemic blood flow); (SABP − RAP) is the pressure difference between systolic arterial blood pressure (SABP) and right atrial pressure (RAP); and SVR is systemic vascular resistance.

Oxygen delivery can be calculated when cardiac output and arterial oxygen content are known:

{DO}_{2} = CO × {CaO}_{2}

${DO}_{2} = CO × {CaO}_{2}$

where DO ₂ denotes oxygen delivery to the tissues, CO is the cardiac output, and CaO ₂ is the arterial oxygen content.

At present, only blood pressure can be monitored continuously in absolute numbers in real time, albeit only invasively (see Chapter 3 ). Since reliable monitoring of SVR is not possible at present, continuous, noninvasive real-time assessment of beat-to-beat cardiac output has become the “holy grail” of modern-day neonatal intensive care. This is even more relevant considering the limited ability to clinically assess cardiac output using indirect parameters of systemic blood flow irrespective of the experience level of the clinician. With the ability to continuously monitor both blood pressure and cardiac output in real time, the neonatologist is able to more accurately diagnose and perhaps treat neonatal shock (see Chapters 1 , Chapter 21, Chapter 22, Chapter 23, Chapter 24 ).

Several methods of cardiac output measurement are available. However, not all technologies are feasible in neonates due to size restraints, potential indicator toxicity, risk of fluid overload, difficulties in vascular access, and the presence of shunts during the transitional phase and in patients with congenital heart defects. A classification of the different methods used for cardiac output measurement is depicted in Box 12.1 .

BOX 12.1

CLASSIFICATION OF METHODS FOR CARDIAC OUTPUT ASSESSMENT

Fick principle–based methods

Oxygen Fick (O ₂ -Fick)
Carbon dioxide Fick (CO ₂ -Fick)
- Modified carbon dioxide Fick method (mCO ₂ F)
- Carbon dioxide rebreathing technology (CO ₂ -R)

Indicator dilution techniques

Pulmonary artery thermodilution (PATD)
Transpulmonary thermodilution (TPTD)
Transpulmonary lithium dilution (TPLiD)
Transpulmonary ultrasound dilution (TPUD)
Pulse dye densitometry (PDD)

Doppler ultrasound

Transesophageal echocardiography/Doppler (TEE/TED)
Transcutaneous Doppler (TCD)
Transthoracic echocardiography (TTE)

Electrical biosensing techniques (EBTS)

Thoracic bioimpedance (TBI)
Thoracic bioreactance (TBR)
Whole-body bioimpedance (WBBI)

Arterial pulse contour analysis (APCA)

As an adjunct to and calibrated by indicator dilution methods
Modelflow method
Pressure recording analytical method (PRAM)

Cardiac magnetic resonance imaging (MRI)

In this box different methods used for cardiac output measurement are summarized, divided into six categories.

An ideal method for the assessment of cardiac output is expected to include appropriate validation for accuracy and precision in real-time and absolute numbers, as well as trending ability. In addition, the ideal method should be continuous, reliable, practical, affordable, and easy to use and document. Finally, its ability to assess systemic blood flow in neonates with extra- and intracardiac shunting is an important requirement. Currently, none of the available methods are even close to fulfilling all these requirements.

The importance of validation

It is of the utmost importance to pay attention to the validation of cardiac output monitoring systems prior to their introduction into clinical practice. Validation studies, especially in preterm neonates, are scarce and generally include only small numbers of patients. A new technology for cardiac output measurement must be validated against a gold standard reference method that is known to be accurate and precise and does not affect the technology being tested. Ideally, this means validation against transit time flow probes, since this is considered the optimal in vivo reference method with a variability of less than 10%. The flow probe should be positioned around the pulmonary artery, since this will represent true systemic blood flow in the absence of shunts. Placing the flow probe around the ascending aorta will underestimate systemic blood flow, because coronary blood flow is not taken into account. Given the invasiveness of this reference method, its use is generally limited to animal studies. The Fick technology and the transpulmonary thermodilution (TPTD) cardiac output measurement are considered the clinical gold-standard methods in pediatric critical care. However, these technologies are not feasible in newborn infants.

Bland-Altman analysis is the most appropriate statistical method for comparing cardiac output measurements using two different technologies. Correlation and regression analysis are not sufficient for this purpose. With Bland-Altman analysis, the difference between the two methods (bias) is plotted against their mean. The accuracy is expressed as the mean bias, while precision is defined as the limits of agreement (LOA). The LOA can be calculated from the standard deviation (SD) of the mean bias (LOA = ±1.96 × SD). The LOA provides us with a range of the difference in cardiac output between two methods for 95% of the study population. It is recommended to express both accuracy and precision as a percentage of mean cardiac output instead of an absolute value. Bias percentage (bias%) is defined as the mean bias divided by mean cardiac output multiplied by 100 (%), while the error percentage (error%) is calculated as 100% × LOA/mean cardiac output. The difference between accuracy and precision is further explained in Figure 12.1 .

Fig. 12.1, Validation of the new method of cardiac output measurement expressed as accuracy and precision.

For acceptance of a new technology, the accuracy (bias%) and precision (error%) should at least be comparable with the reference method. This stresses the importance of the use of a valid, and preferably gold-standard, technique for reference. A new technology is generally accepted when the error% is ±30% or less. However, this cutoff value is based on the assumption that the precision of the reference method is ±10% to 20% with the acceptance of a new technology when the error% is no more than ±20%. When using a reference method with an error% of more than 20%, the cutoff value for acceptance of the tested technique should be adjusted. ^, The combined error% can be calculated using the following formula:

{error}_{COMP + REF} = \sqrt{{({error}_{COMP})}^{2} + {({error}_{REF})}^{2}}

${error}_{COMP + REF} = \sqrt{{({error}_{COMP})}^{2} + {({error}_{REF})}^{2}}$

where error% _COMP+REF is the combined error%, error% _COMP is the error% of the comparator (new method), and error% _REF is the error% of the reference method.

The resultant error percentage as a function of the error percentage of the tested method (comparator) and the reference method, respectively, is displayed as an error-gram, as shown in Figure 12.2 .

Fig. 12.2, Resultant error% as a function of the error percentages of the used reference method and tested comparator (error-gram).

In addition, the agreement in monitoring temporal changes in cardiac output (trending ability) should be studied by analysis of four-quadrant plots and polar plot methodology. In a concordance plot the changes in cardiac output, assessed with the comparator (ΔCO _COMP ), are plotted against the changes in cardiac output, assessed with the reference method (ΔCO _REF ). When the changes in cardiac output are in the same direction within the two methods, these changes are concordant. Discordant measurements occur when the changes in one method are in the opposite direction of the other technology. The concordance rate is calculated as the number of concordant measurements divided by the total number of measurements (concordant plus discordant). A concordance rate of >95% is considered good, 90–95% marginal, and <90% poor trending ability. Polar plot analysis considers not only the direction but also the magnitude of temporal changes in cardiac output. In a polar plot each data point (ΔCO _REF vs ΔCO _COMP ) is determined by an angle (the direction of change) and a radius (the magnitude of change). This enables the calculation of:

the angular bias , that is, the average angle between all polar plot data and the polar axis (0°). An angular bias ≤±5° is considered a good trending ability.
the radial limits of agreement (LOA), the radial sector that encompasses 95% of all data points, defined as mean angular bias ± 1.96 SD. Radial LOA ±27 to 37° is classified as good, ±37 to 45° as moderate, and ≥±45° as poor trending. In general, radial LOA of <±30° is acceptable.
the angular concordance rate , that is, the percentage of data points within the ±30° radial zone. An angular concordance rate of >92% represents a good trending ability.

This chapter will provide an overview of all available technologies for the assessment of cardiac output, with emphasis on their applicability in (preterm) newborn infants. A summary of the characteristics, advantages, and limitations of each method is presented in Table 12.1 . When available, the results of neonatal validation studies are shown in tables within the appropriate paragraphs.

TABLE 12.1

Overview of Different Methods of Cardiac Output Monitoring

Method	Invasive?	Continuous (C) or Intermittent (I)	Equipment	Feasible in Neonates?	Validation Studies in Neonates?	Advantages	Limitations
Fick Principle
O ₂ -Fick	+	I	AC, CVC	+	−	Accurate, especially in low flow state	Need for multiple, multisite blood sampling; accuracy limited in the presence of cardiopulmonary disease, air leakage, and enhanced pulmonary oxygen consumption (as in preterms with bronchopulmonary dysplasia); affected by shunts; less reliable in high flow state
mCO ₂ F	+	I	AC, CVC	+	−	No specific additional equipment required; reliable in the presence of significant left-to-right shunt; use of regular arterial and central venous catheters	Need for multiple, multisite blood sampling; inaccuracy related to calculation error of carbon dioxide concentration in blood
CO ₂ -R	−	I	ET	−	−	Easy to use; noninvasive	Not feasible/accurate in children with BSA <0.6 m ² and tidal volume <300 mL; only applicable in intubated patients; contraindicated in patients susceptible to fluctuating arterial carbon dioxide levels
Indicator Dilution
PATD	+++	I (& C)	PAC	−	−	Clinical gold standard of cardiac output monitoring in adults; ancillary hemodynamic variables provided	Very invasive; not feasible in small children; relatively high complication rate; transient bradycardia in response to fast injection of cold saline; results affected by shunt
TPTD	++	I (& C)	Dedicated AC, CVC	−	−	Clinical gold standard in pediatric patients; continuous monitoring when used to calibrate APCA; ancillary hemodynamic variables provided; reliable in presence of significant LtR-shunt	Dedicated thermistor-tipped arterial catheter required; catheterization of femoral, brachial, or axillary artery needed; repetitive measurements affect fluid balance
TPLiD	++	I (& C)	AC, CVC	−	−	Regular catheters used; continuous monitoring when used to calibrate APCA; ancillary hemodynamic variables provided	Lithium toxicity; need to withdraw blood; limited repeated measurements possible; not compatible with non-depolarizing muscle relaxants; influenced by hyponatremia; results affected by shunts
TPUD	++	I (& C)	AC, CVC	+	−	Nontoxic indicator; small indicator volume; ancillary hemodynamic variables provided; safe with regard to cerebral and systemic oxygenation and circulation; reliable in presence of significant LtR-shunt or heterogeneous lung injury	Repetitive measurements affect fluid balance; necessity to use extracorporeal loop
PDD	+	I	CVC	+	−	Noninvasive detection of indocyanine green; intravascular volume measurement possible	Limited repeated measurements possible; inaccuracy due to poor peripheral perfusion, motion artifact, or excess light; rarely side effects; difficulty in the acquisition of reliable pulse waveforms in small children and newborns
Doppler Ultrasound
TEE	+	I	Esophageal probe	±	−	Less invasive; evaluation of cardiac function and structure	Significant training required; highly operator dependent; inaccuracy due to errors in the calculation of velocity time integral, cross-sectional area and angle of insonation; not feasible in infants <3 kg; small risk of complications; not tolerated by conscious patients
TED	+	I	Esophageal probe	±	−	Less invasive; continuous monitoring	Inaccuracy due to errors in the calculation of velocity time integral, cross-sectional area, and angle of insonation; not feasible in infants <3 kg; small risk of complications; not tolerated by conscious patients
TCD	−	I	External probe	+	+	Noninvasive; easy to use	Blind aiming of transducer for signal acquisition; error due to insonation angle deviation; no real measurement of cross-sectional area of outflow tract; large interobserver variability; questionable accuracy and precision
TTE	−	I	Echocardiograph	+	+	Noninvasive; evaluation in detail of cardiac function and structure; additional information about potential intra- and extracardiac shunting; most used method of cardiac output monitoring in neonatal clinical care	Significant training required; highly operator dependent; not an easy, bedside method; high intra- and interobserver variability; inaccuracy due to errors in the calculation of velocity time integral, cross-sectional area, and angle of insonation
Electrical Biosensing Technology
EC	−	C	Surface electrodes on thorax	+	+	Only real noninvasive technology; continuous monitoring; user-independent; ancillary hemodynamic variables provided; easy to apply	Sensitive to motion artifact; inaccuracy due to alteration in position or contact of the electrodes, irregular heart rates, and acute changes in tissue water content; compromised reliability on high-frequency ventilation; questionable accuracy and precision
BR	−	C	Surface electrodes on thorax	+	+
WBEBT	−	C	Surface electrodes on wrist and contralateral ankle	+	−		Sensitive to motion artifact; inaccuracy due to alteration in position or contact of the electrodes, irregular heart rates, and acute changes in tissue water content
Arterial Pulse Contour Analysis
PulseCO	++	C	AC, CVC	−	−	Less invasive; continuous monitoring	Repeated calibration required; use of small arterial catheters can cause distortion of the shape of the pressure wave and overdamped curves; accuracy influenced by changes in arterial compliance, changes in vasomotor tone, and irregular heart rate
PICCO	++	C	Dedicated AC, CVC	−	−	Less invasive; continuous monitoring	Repeated calibration required; accuracy influenced by changes in arterial compliance, changes in vasomotor tone, and irregular heart rate
PRAM	+	C	AC	+	+	Less invasive; continuous monitoring; no calibration required	Use of small arterial catheters can cause distortion of the shape of the pressure wave and overdamped curves; accuracy influenced by changes in arterial compliance, changes in vasomotor tone, and irregular heart rate; questionable accuracy and precision

AC , Arterial catheter; APCA , arterial pulse contour analysis; BR , bioreactance; BSA , body surface area; CO ₂ -R , CO ₂ rebreathing; CVC , central venous catheter; EC , electrical cardiometry; ET , endotracheal tube; LtR , left-to-right; mCO ₂ F , modified CO ₂ -Fick method; O ₂ -Fick , oxygen Fick; PAC , pulmonary artery catheter; PATD , pulmonary artery thermodilution; PDD , pulse dye densitometry; PICCO , APCA calibrated by TPTD; PRAM , pressure recording analytical method; PulseCO , APCA calibrated by TPLID; TCD , transcutaneous Doppler; TED , transesophageal Doppler; TEE , transesophageal echocardiography; TPLiD , transpulmonary lithium dilution; TPTD , transpulmonary thermodilution; TPUD , transpulmonary ultrasound dilution; TTE , transthoracic echocardiography; WBEBT , whole-body electrical biosensing technology.

Fick principle

Methods using the Fick principle might utilize the direct Fick method or one of its modifications to render the technique more clinically applicable. However, the modifications often come at the expense of accuracy. In 1870 German physiologist Adolf Eugen Fick stated that the volume of blood flow in a given period (cardiac output) equals the amount of a substance entering the bloodstream in the same period divided by the difference in concentrations of the substance upstream and downstream, respectively.

Oxygen fick

Determination of cardiac output according to the original or direct Fick method requires the application of a face mask (or some means of assessing oxygen consumption) and consideration of arterial and venous oxygen concentration, which is usually obtained by taking blood samples for laboratory analysis. The direct Fick method employing a measurement of pulmonary oxygen uptake (discussed later) is considered the gold standard for assessing cardiac output, despite several disadvantages. It is of note though that recent advances in magnetic resonance imaging (MRI) technology have initiated a shift in our thinking; specifically, MRI-derived estimates of cardiac output measurement are now considered by many experts as the gold standard for the measurement of cardiac output. However, MRI-based cardiac output measurement is only feasible in stable patients who are fit enough to undergo MRI scanning (see Chapter 13 ). According to the direct Fick principle, cardiac output is calculated by dividing oxygen consumption (VO ₂ ) by the difference in the oxygen content of the aortic blood (CaO ₂ ) and the mixed venous blood (CmvO ₂ ).

The applicability in its original form, measuring VO ₂ instead of assuming it, is limited by the fact that in non-intubated patients a face mask must be used. With respect to the application in neonates, a further limitation is that multiple and multisite blood sampling is required. With oxygen being the substance for this method, the Fick principle states that during steady state, oxygen uptake in the pulmonary system equals the oxygen consumption in the tissues ( Figure 12.3 ). Cardiac output (pulmonary blood flow) can be calculated by dividing the pulmonary oxygen uptake by the oxygen concentration gradient (difference) between arterial blood (CaO ₂ ) and CmvO ₂ . Under steady-state condition, tissue oxygen consumption is equal to pulmonary oxygen uptake (VO ₂ ). Hence

CO = \frac{{VO}_{2}}{{CaO}_{2} − {CmvO}_{2}}

$CO = \frac{{VO}_{2}}{{CaO}_{2} − {CmvO}_{2}}$

where CO is the cardiac output in L/min, VO ₂ is pulmonary oxygen uptake in mL O ₂ /min, CaO ₂ is oxygen concentration of arterial blood in mL O ₂ /L, and CmvO ₂ is oxygen concentration of mixed venous blood (preferably determined in the pulmonary artery) in mL O ₂ /L.

Pediatric and adult patients differ in oxygen consumption. Cardiac index is 30–60% higher in neonates and infants to help meet their increased oxygen consumption. Fetal hemoglobin is present in decreasing concentration up to 3–6 months following birth, has higher oxygen affinity, and thus does not deliver oxygen to the tissues as effectively as does adult hemoglobin, when arterial oxygen saturation increases from the fetal levels of 75% in the ascending aorta to 98–100% after birth. In neonates the combination of a higher hemoglobin concentration (16–19 g/dL compared with 13.5–17.5 g/dL in men and 12–16 g/dL in women), higher blood volume per kilogram of body weight, and increased cardiac output compensate for the decreased release of oxygen from hemoglobin to the tissues.

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