Appropriate monitoring of the cardiovascular system and thus the treatment of critically ill neonates with cardiovascular compromise hinges on the ability to monitor at least two of the three interdependent cardiovascular parameters (blood pressure, cardiac output, and systemic vascular resistance), determining systemic and organ blood flow and thus oxygen delivery to the tissues. Despite the availability of many technologies, cardiac output monitoring remains very challenging in newborn infants. Not all available technologies are feasible in neonates, due to size restraints, potential indicator toxicity, risk of fluid overload, difficulties in vascular access, and the presence of shunt flow during the transitional phase and in patients with congenital heart defects. An overview is given of all available technologies for the assessment of cardiac output with emphasis on the applicability in (preterm) newborn infants.
Keywordsarterial pulse contour analysis, cardiac output, Doppler ultrasound, echocardiography, Fick principle, hemodynamics, indicator dilution, thoracic electrical impedance
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, thoracic electrical bioimpedance, and arterial pulse contour analysis.
Non-invasiveness of 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.
As discussed in Chapter 1 , Chapter 10 , Chapter 21 , appropriate monitoring of the cardiovascular system and thus the treatment of critically ill neonates with cardiovascular compromise hinges 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’s law in electrical circuits):
S V R = S A B P − R A P C O
where CO = cardiac output (i.e., systemic blood flow), (SABP − RAP) = pressure difference between systolic arterial blood pressure (SABP) and right atrial pressure (RAP), and SVR = systemic vascular resistance.
Oxygen delivery can be calculated when cardiac output and arterial oxygen content are known:
D O 2 = C O × C a O 2
where DO 2 = oxygen delivery to the tissues, CO = cardiac output, and CaO 2 = 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 monitoring 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 Chapter 1 , Chapter 21 , Chapter 22 , Chapter 27 ).
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 14.1 .
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 re-breathing 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)
Transesophageal echocardiography/Doppler (TEE/TED)
Transcutaneous Doppler (TCD)
Transthoracic echocardiography (TTE)
Thoracic electrical impedance
Electrical velocimetry (EV)
Arterial pulse contour analysis (APCA)
As an adjunct to and calibrated by indicator dilution methods
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 that the method is continuous, reliable, practical, affordable, and easy to use and document. In addition, its ability to assess systemic blood flow in neonates with extra- and intracardiac shunting is an important requirement. Currently none of the available and routinely used methods come even close to fulfilling these requirements.
The Importance of Validation
It is of the upmost importance to pay attention to the validation of cardiac output monitoring systems prior to the 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 and 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 and Altman analysis the difference between the two methods (bias) is plotted against their mean. The accuracy is expressed as the mean bias, while the 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 Fig. 14.1 .
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, 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% 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:
e r r o r % C O M P + R E F = ( e r r o r % C O M P ) 2 + ( e r r o r % R E F ) 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 errorgram as shown in Fig. 14.2 .
In addition, the agreement in monitoring temporal changes in cardiac output should be analyzed, for example by polar plot methodology.
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, the advantages, and limitations for each method is presented in Table 14.1 . When available, the results of neonatal validation studies are shown in tables within the appropriate paragraphs.
|Method||Invasive?||Continuous (C) or Intermittent (I)||Equipment||Feasible in Neonates?||Validated in Neonates?||Advantages||Limitations|
|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|
|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 nondepolarizing 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|
|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|
|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|
|Thoracic Electrical Impedance|
|EC/BR||C||Surface electrodes||+||+||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|
|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|
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 the 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.
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, and cardiac output measurement by MRI is now considered by many as the gold standard for the measurement of cardiac output. However, MRI-based cardiac output measurement is only feasible in stable patients fit enough to undergo MRI scanning (see Chapter 15 ). 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 nonintubated 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, the oxygen taken up in the pulmonary system (pulmonary oxygen uptake) equals the oxygen consumption in the tissues ( Fig. 14.3 ). 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,
C O = V O 2 C a O 2 − C m v O 2
where CO = cardiac output in L/min, VO 2 = pulmonary oxygen uptake in mL O 2 /min, CaO 2 = oxygen concentration of arterial blood in mL O 2 /L, and CmvO 2 = oxygen concentration of mixed venous blood (preferably determined in the pulmonary artery) in mL O 2 /L.
Pediatric and adult patients differ significantly in oxygen consumption. Cardiac index is higher in neonates and infants by 30% to 60% to help meet their increased oxygen consumption. Fetal hemoglobin, present in fetal life and, in decreasing concentration, up to 3 to 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% to 100% after birth. In neonates, the combination of a higher hemoglobin concentration (16 to 19 g/dL compared with 13.5 to 17.5 g/dL in men and 12 to 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.
Pulmonary Oxygen Uptake
Pulmonary oxygen uptake (VO 2 ), or oxygen consumption, can be measured via a Douglas bag, by mass spectrometry, spirometry, or metabolic monitors (indirect calorimetry). Table 14.2 depicts VO 2 measurements obtained in different patient populations and under different clinical conditions.
|Group||VO 2 (Mean ± SD)||Notes|
|Adults||125 mL O 2 /min/m 2||Indexed for body surface area|
|Healthy newborns (Bauer, 2002)||6.7 ± 0.6 to 7.1 ± 0.4 mL O 2 /min/kg||Indexed for body weight ( n = 7)|
|Neonates with sepsis (Bauer, 2002)||7.0 ± 0.3 to 8.2 ± 0.4 mL O 2 /min/kg||n = 10|
|Mechanically ventilated preterm infants (Shiao, 2006)||8.0 ± 3.73 mL O 2 /min/kg||<8 h after blood drawn( n = 202)|
|11.3 ± 5.65 mL O 2 /min/kg||≥8 h after blood drawn( n = 65)|
|Preterm and term infants before and 1 hour after feeding (Stothers and Warner, 1979)||4.8 mL O 2 /min/kg (estimated from Fig. 6.1 )||n = 9 preterm infants |
n = 9 term infants
|Term infants during sleep||5.97 mL O 2 /min/kg during REM sleep||n = 30|
|5.72 mL O 2 /min/kg during non-REM sleep|
Instead of actually measuring pulmonary oxygen uptake, this can also be estimated with the use of different regression equations. However, the estimation of VO 2 , which is also referred to as the indirect Fick method, is subject to errors for the determination of cardiac output potentially exceeding 50%. Because of the potential errors and its questionable adaptability to neonates, the cardiac output obtained by the indirect Fick method may be used in neonates for orientation purposes only.
Oxygen Concentration Gradient
Oxygen concentration ( c O 2 ) is calculated by determining hemoglobin concentration (Hb) and oxygen saturation ( s O 2 ), which traditionally is obtained by blood gas analysis:
c O 2 = ( H b × s O 2 × 1.36 ) + ( p O 2 × 0.0032 )
where Hb = hemoglobin in g/dL, s O 2 = oxygen saturation as gradient, 1.36 = oxygen binding capacity of hemoglobin in mL O 2 /g, 0.0032 = solubility coefficient of oxygen in mL O 2 /mm Hg, and p O 2 = partial pressure of oxygen in mm Hg.
Note that the aforementioned equation obtains oxygen content ( c O 2 ) in mL O 2 /dL. To obtain oxygen concentration ( c O 2 ) in mL O 2 /L, one needs to multiply the result by 10 (1 L = 10 dL).
Because in the normal range of p O 2 , dissolved oxygen contributes very little to the total oxygen-carrying capacity, oxygen content can be approximated by
c O 2 = H b × s O 2 × 1.36
and the gradient by
c O 2 = H b × 1.36 × ( S a O 2 − S m v O 2 )
where Hb = hemoglobin in g/dL, SaO 2 = arterial (pulmonary vein) oxygen saturation as gradient, and SmvO 2 = mixed venous (pulmonary artery) oxygen saturation as gradient.
Alternative to blood gas analysis, SaO 2 and SvO 2 may be obtained via catheters (e.g., Opticath catheter in combination with Oximetric-3 monitors, Abbott Critical Care Systems, Abbott Laboratories, Abbott Park, Illinois). The limitation is, however, that not mixed venous but central venous blood is sampled, and these are not interchangeable regarding oxygen saturation or oxygen content. Arterial oxygen saturation (SaO 2 ) may be approximated noninvasively by SpO 2 obtained via pulse oximetry.
Cardiac Output (Calculation Examples)
Assuming a neonate with VO 2 of 7 mL O 2 /min/kg, Hb of 17 g/dL, SaO 2 of 99%, and SmvO 2 of 75%,
c O 2 = H b × 1.36 × ( S a O 2 − S m v O 2 ) = 17 ( g d L ) × 1.36 ( m L O 2 g ) × ( 99 − 75 ) % = 5.55 m L O 2 d L
With VO 2 normalized for weight, the cardiac output is
C I = V O 2 C a O 2 − C m v O 2 = 7.0 ( m L O 2 min . k g ) 5.55 ( m L O 2 d L ) = 1.26 ( d L min . k g ) = 0.126 L min . k g