**2.1.1 VO2 values during cardiac catheterization versus in the ICU after CPB**

In patients undergoing cardiac catheterization, there is a general *over-estimation* of VO2 introduced by the equations (Figure 1) (Li, Bush et al. 2003). The conditions of conscious sedation with spontaneous ventilation were used to generate the predictive equations decades ago. In contrast in current practice, general anesthesia and mechanical ventilation are used in most children undergoing cardiac catheterization. General anesthesia and muscle relaxants with mechanical ventilation may decrease the cardiopulmonary work and metabolic rate, resulting in a reduction in VO2 of up to 20 to 30%.(Nisbet, Dobbinson et al. 1973; Westenskow, Jordan et al. 1978)

In the ICU patients, a general *under-estimation* of VO2 is introduced by the equations, with very poor agreement to actual measurements, as the equations were generated in preoperative patients undergoing cardiac catheterization (Li, Bush et al. 2003). After CPB, VO2 is significantly increased and highly variable between patients and within each patient (Figure 2) (Li, Zhang et al. 2006; Li, Zhang et al. 2007; Li, Zhang et al. 2008). Thus, the direct measurement of VO2 is essential for these patients; continuous or repeated measurements are also essential to reflect the dynamic changes in these patients that occur over time.

Accurate Measurement of Systemic

3) (Rutledge, Bush et al. 2010)

(A) < 3 years old and (B) > 3 years old.

Oxygen Consumption in Ventilated Children with Congenital Heart Disease 297

Of the equations we tested initially, the LaFarge equation is the most commonly used and gives the closest estimation to measured results with the lowest bias and limits of agreement (Li, Bush et al. 2003). However, despite the fact that the LaFarge equation was generated and intended for use in patients between 3 and 40 years of age, it is applied in patients of all ages. With advances in surgical techniques and perioperative management, increasing numbers of younger patients with complex congenital heart defects, such as functionally single ventricular abnormalities, undergo cardiac surgery. This in turn increases the need for diagnostic cardiac catheterization in children younger than 3 years, often with the single

Our initial study, comparing measured and estimated VO2, excluded patients whose ages fell outside the range used in the derivation of LaFarge equation, that is, younger than 3 years. We revisited the data to compare estimates of VO2 in patients younger than 3 years to the earlier data from patients older than 3 years of age. Estimations were significantly poorer in the group younger than 3 years, with a bias of 55 mL/min/m2, compared to a bias of 11 mL/min/m2 in the older group. The limits of agreements were -42 to +153 mL/min/m2 for children < 3 years versus -39 to +61 mL/kg/m2 for those ≥ 3 years (Figure

Fig. 3. Agreement of measured and estimated VO2 during cardiac catheterization in patients

The LaFarge equation (LaFarge and Miettinen 1970) includes a logarithmic transformation

VO2 (mL/min/m2) = 138.1-(11.49 logeage) + (0.378 heart rate) (1)

 VO2 (mL/min/m2) = 138.1- (17.04 logeage)+(0.378 heart rate) (2) The logarithmic transformation of age intrinsically results in a faster increase in estimated VO2 as age decreases, particularly within the first 3 years of life (Figure 4A). Interestingly, the directly measured VO2 has almost exactly the opposite trend, being lowest in the youngest patients and quickly increasing in the first 3 to 4 years (Figure 4B). As a result, the errors of estimated VO2 are dramatically related to age (Figure 4C). The reasons for lower VO2 in younger children remain unclear, but body composition may be a factor. In

of age for male patients (equation 1) and for female patients (equation 2).

**2.1.2 VO2 values in patients > 3 years old versus ≤ 3 years old** 

goal of accurately evaluating pulmonary vascular resistance.

Fig. 1. Agreement of measured and estimated VO2. Measured VO2 minus estimated VO2 is plotted against average VO2; in patients undergoing cardiac catheterization, (A) using the LaFarge equation and (B) the Wessel equation; and after cardiac surgery in the ICU, (C) using the LaFarge equation and (D) the Wessel equation .

Fig. 2. Measured VO2 by respiratory mass spectrometry in 14 neonates in the first 72 hours after the Norwood procedure

Fig. 1. Agreement of measured and estimated VO2. Measured VO2 minus estimated VO2 is plotted against average VO2; in patients undergoing cardiac catheterization, (A) using the LaFarge equation and (B) the Wessel equation; and after cardiac surgery in the ICU, (C)

Fig. 2. Measured VO2 by respiratory mass spectrometry in 14 neonates in the first 72 hours

using the LaFarge equation and (D) the Wessel equation .

after the Norwood procedure

### **2.1.2 VO2 values in patients > 3 years old versus ≤ 3 years old**

Of the equations we tested initially, the LaFarge equation is the most commonly used and gives the closest estimation to measured results with the lowest bias and limits of agreement (Li, Bush et al. 2003). However, despite the fact that the LaFarge equation was generated and intended for use in patients between 3 and 40 years of age, it is applied in patients of all ages. With advances in surgical techniques and perioperative management, increasing numbers of younger patients with complex congenital heart defects, such as functionally single ventricular abnormalities, undergo cardiac surgery. This in turn increases the need for diagnostic cardiac catheterization in children younger than 3 years, often with the single goal of accurately evaluating pulmonary vascular resistance.

Our initial study, comparing measured and estimated VO2, excluded patients whose ages fell outside the range used in the derivation of LaFarge equation, that is, younger than 3 years. We revisited the data to compare estimates of VO2 in patients younger than 3 years to the earlier data from patients older than 3 years of age. Estimations were significantly poorer in the group younger than 3 years, with a bias of 55 mL/min/m2, compared to a bias of 11 mL/min/m2 in the older group. The limits of agreements were -42 to +153 mL/min/m2 for children < 3 years versus -39 to +61 mL/kg/m2 for those ≥ 3 years (Figure 3) (Rutledge, Bush et al. 2010)

Fig. 3. Agreement of measured and estimated VO2 during cardiac catheterization in patients (A) < 3 years old and (B) > 3 years old.

The LaFarge equation (LaFarge and Miettinen 1970) includes a logarithmic transformation of age for male patients (equation 1) and for female patients (equation 2).

$$\text{VO}\_2 \, (\text{mL/min/m2}) = 138.1 \text{-} (11.49 \times \text{logeage}) + (0.378 \times \text{heart rate}) \tag{1}$$

$$\text{VO}\_2 \text{(mL/min/m2)} = 138.1 \text{-} \,(17.04 \times \text{logeage}) \text{+} (0.378 \times \text{heart rate}) \tag{2}$$

The logarithmic transformation of age intrinsically results in a faster increase in estimated VO2 as age decreases, particularly within the first 3 years of life (Figure 4A). Interestingly, the directly measured VO2 has almost exactly the opposite trend, being lowest in the youngest patients and quickly increasing in the first 3 to 4 years (Figure 4B). As a result, the errors of estimated VO2 are dramatically related to age (Figure 4C). The reasons for lower VO2 in younger children remain unclear, but body composition may be a factor. In

Accurate Measurement of Systemic

Oxygen Consumption in Ventilated Children with Congenital Heart Disease 299

The concept of mass spectrometry (measuring fractional proportions of substances in a mixture, according to their molecular mass-charge ratios) was first introduced at the end of the 19th century. The recruitment of mass spectrometry into respiratory physiology in the 1940s, and its subsequent refinement over the decades, has established a 'state-of-the-art' method for measuring VO2 using highly accurate and rapid multiple gas analysis. The mixed expirate method (Davies and Denison 1979) enabled use of the mass spectrometer alone to measure metabolic gas exchange and ventilation volume. This technique has been used widely to measure VO2 in a broad spectrum of clinical and experimental conditions. We have adapted the method to continuously measure VO2 with a variety of pediatric ventilators and anesthesia ventilators before, during, and after CPB, using the AMIS 2000 Medical Respiratory Mass Spectrometer System (Innovision A/C Odense, Denmark). Our combination of techniques and equipment makes respiratory mass spectrometry a unique and powerful tool in multiple settings: in the cardiac catheterization laboratory (Schulze-Neick, Li et al. 2002 ; Shekerdemian, Bush et al. 1997; Shekerdemian, Bush et al. 1997), in the operating room (Li, Stokoe et al. 2004), and in the ICU (Li, Hoschtitzky et al. 2004; Li, Schulze-Neick et al. 2000; Li, Zhang et al. 2006; Li, Zhang et al. 2006; Li, Zhang et al. 2007; Li,

Mass spectrometers analyze substances in the gas phase by performing a sequence of five operations: *1)* accept and vaporize a minute controlled quantity of sample; *2)* reduce the sample vapor to a very low pressure; *3)* ionize a representative part of the vapor; *4)* separate the ionized particles produced, according to their mass-to-charge ratio; and *5)* read the

A Teflon capillary tubing (A) with an internal diameter 0.3 mm and a length of 3 to 6 m provides the gas transport from the sampling site (B) to the vacuum system. There are three sample inlets, one for the on-line continuous monitoring of O2 and CO2 fractional concentrations, the other two for the inspiratory and expiratory gas sampling. The gas sample at atmospheric pressure is drawn at a sampling rate of 10 to 20 mL/min down the tubing (A), passing through the three static electro-magnetic valves (C), which are selected in turn as appropriate to the sequence of gas analysis needed for the metabolic calculations. The sample is drawn by the inlet rotary vacuum pump (D) into the sample chamber (E), and all but a small fraction of it is pumped away continuously at the low-pressure end of the inlet tubing. The turbo molecular pump (F), supported by a second backing rotary pump (G), provides a very high vacuum environment of around 5 10-7 mBar in the dispersion chamber (H), housing ionization chamber (I), mass filter (J), and ion detector (K). Thus, the high vacuum provided by the turbo molecular pump draws the remaining gas sample through the molecular leak (L) into the ionization chamber, where the gas molecules are ionized. The ions are focused into a tight beam, enter the aperture of the quadrupole mass filter, and are separated by the quadrupole mass filter (J). The use of appropriate voltages in this field allows only ions of a definite mass interval to pass and reach the ion detector (K),

**3. Direct measurement of VO2 using respiratory mass spectrometry** 

Zhang et al. 2007; Li, Zhang et al. 2008; Schulze-Neick, Li et al. 2001).

abundance of particles at specific values of the mass-to-charge ratio.

Features of a mass spectrometer are outlined in Figure 5.

**3.1 Principles of mass spectrometry** 

**3.2 Hardware design** 

particular, 'fat mass' is relatively higher in younger children (Fomon, Haschke et al. 1982; Moukarzel, Salas et al. 2003) and VO2 in fat mass is about 20 times lower than in muscular mass (Moukarzel, Salas et al. 2003).

Fig. 4. The trends in relation to age of (A) estimated VO2, (B) measured VO2, and (C) their difference, in 75 patients undergoing cardiac catheterization.

We conclude that estimation of VO2 is unacceptably inaccurate for clinical decision-making and research. Direct measurement of VO2 is appropriate for young children with congenital heart defects undergoing cardiac catheterization and in the ICU after CPB. Direct and continuous measurement of VO2 is essential, particularly in those younger than 3 years and in the early postoperative period after CPB.

#### **2.2 Inadequacy of the reverse Fick method**

VO2 can also be calculated by the reverse Fick method from the cardiac output, directly measured by the thermodilution technique, for example. This method has obvious limitations for clinical application in patients with congenital heart defects. First, the calculation is clearly intermittent. Second, the presence of intracardiac shunting and tricuspid regurgitation can significantly affect the accuracy of the calculation. Most important, certain complex circulations preclude the use of the thermodilution technique (e.g., after the Norwood procedure, bidrectional caval pulmonary shunt, or the Fontan operation), because of anatomical (e.g., parallel systemic and pulmonary circulations) and methodological (e.g., inadequate mixing) limitations.
