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Anesth Analg 2008; 106:775-785
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318162c20a
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PEDIATRIC ANESTHESIOLOGY

Section Editor:
Peter J. Davis

The Effect of Lung Expansion and Positive End-Expiratory Pressure on Respiratory Mechanics in Anesthetized Children

Athanasios G. Kaditis, MD*{dagger}, Etsuro K. Motoyama, MD*{ddagger}, Walter Zin, PhD§, Nobuhiro Maekawa, MD{ddagger}||, Isuta Nishio, MD{ddagger}, Taiyo Imai, MD*, and Joseph Milic-Emili, MD#

From the *Department of Pediatrics, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; {dagger}Department of Pediatrics, University of Thessaly School of Medicine, Larissa, Greece; {ddagger}Department of Anesthesiology University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; §Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; ||Department of Anesthesiology, Kobe University School of Medicine, Kobe, Japan; ¶Department of Anesthesiology, University of WA, Seattle, Washington; #Meakins-Christie Laboratories, Department of Physiology, McGill University Faculty of Medicine, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Etsuro K. Motoyama, MD, Children's Hospital of Pittsburgh, Department of Anesthesiology, 3705 Fifth Ave., Pittsburgh, PA 15213. Address e-mail to motoyamaek{at}anes.upmc.edu.

Abstract

BACKGROUND: Imaging studies have shown that general anesthesia in children results in atelectasis. Lung recruitment total lung capacity (TLC) maneuvers plus positive end-expiratory pressure (PEEP) are effective in preventing atelectasis. However, physiological changes in children during general anesthesia have not been elucidated.

METHODS: In eight anesthetized and mechanically ventilated children (median age: 3.5 years; range: 2.3–6.5), we measured static respiratory system elastance (Est), flow resistance (Rint), and elastance and resistance components resulting from tissue viscoelasticity ({Delta}E and {Delta}R, respectively) using the constant inflow, end-inspiratory occlusion method preceded by TLC maneuvers, both with zero PEEP (ZEEP) and PEEP (5 cm H2O) for comparison.

RESULTS: With constant inspiratory flow (VI) and ZEEP, increases in end-inspiratory lung volume above relaxation volume (tidal volume, VT) from 8 to 20 mL · kg–1 resulted in decreases in Est from 1.06 to 0.82 cm H2O · mL–1 · kg, {Delta}E from 0.16 to 0.09, and Rint from 0.13 to 0.11 cm H2O · mL–1 · s · kg, whereas {Delta}R increased from 0.08 to 0.12 (P < 0.05). Similar relationships were found with PEEP. Increases in VI (8 to 26 mL · s–1 · kg) with constant VT and ZEEP resulted in decreases in Est from 1.09 to 0.9 and {Delta}R from 0.17 to 0.06 (P < 0.01), whereas {Delta}E and Rint did not change. There was a similar flow and volume dependence of elastance and resistance with PEEP.

CONCLUSIONS: The observed steady decreases in Est with increasing VT (up to 16 mL/kg with PEEP) indicate marked reductions in end-expiratory relaxation volume (functional residual capacity) even with PEEP. Similarity in results with ZEEP and PEEP suggests that TLC-maneuvers and O2-N2 ventilation prevented airway closure throughout the study.

General anesthesia has been associated with the development of airway closure and pulmonary atelectasis in both adults and children.1–4 End-expiratory lung volume or functional residual capacity (FRC) decreases after induction of general anesthesia in adults from FRC in the awake state5,6 and this phenomenon is more pronounced in infants and young children7 because of the relaxation of thoracic inspiratory muscles whose static and cyclic contractions keep their compliant chest wall relatively rigid and maintain FRC. Reduction in FRC during general anesthesia is further exaggerated by breathing 100% oxygen, resulting in airway closure and resorption atelectasis in dependent lung regions.8–13

The reduction of FRC during general anesthesia can be minimized by a series of lung inflations to total lung capacity (TLC maneuvers) plus the positive end- expiratory pressure (PEEP) of at least 5 cm H2O with a mixture of oxygen and air (or nitrogen).14,15 The efficacy of TLC maneuvers and PEEP in anesthetized children has been confirmed by studies with computed tomography (CT) scanning and magnetic resonance imaging (MRI).1,2 However, physiological studies on the effect of TLC maneuvers and PEEP on respiratory mechanics in children have been limited.

The constant flow, end-inspiratory airway occlusion technique has been applied extensively in recent years to study respiratory mechanics in anesthetized and/or paralyzed adults and children in health and disease.16–20 Using this technique, total respiratory system resistance (Rrs) can be partitioned into two components, flow resistive or interrupter resistance (Rint) and the second component arising from viscoelastic properties of the lungs and chest wall ({Delta}R or Rvisc). Similarly, respiratory system elastance (Ers = 1/Crs) can be subdivided to static elastance (Est) and an additional component ({Delta}E or Evisc) that results from tissue viscoelasticity or stress adaptation21 (Fig. 1 and Discussion section for details).


Figure 114
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  		Figure 1. A schematic drawing of the end-inspiratory airway occlusion technique (see text for details). Ers = total respiratory system elastance or an inverse of compliance (Ers = 1/Crs = P/V); Est= static respiratory system elastance; {Delta}E= Evisc or viscolelastic elastance; P = pressure; Pao = airway opening pressure; Rrs = total respiratory system resistance; Rint = interrupter resistance or frictional resistance; {Delta}R = Rvisc or viscoelastic resistance; V = volume; Vt = inspiratory tidal volume or end-inspiratory volume above FRC (relaxation volume, Vr); V = flow; VI = inspiratory flow.

 

In the past, the viscoelastic or tissue component of resistance had been thought to be a small component of total Rrs. However, studies using the end-inspiratory airway occlusion technique over the last 20 years have demonstrated that {Delta}R is a much larger component of Rrs and varies with changes in flow rate and/or with end-inspiratory lung volume. These relationships have been described as "flow (or volume) dependence of Rrs (or Ers)" in the literature (Discussion section).18,21

In a study in adults, Rint increased with increasing inspiratory flow (i.e., positive flow dependence) as expected from increasing turbulence, whereas Est did not change.18 In contrast, in a similar study from our laboratory in anesthetized children,20 we found that both Rint and Est decreased, rather than increased with increasing inspiratory flow (negative or inverse flow dependence). As was the case in the previous study in adults,18 this first study in children20 had been performed without prior TLC maneuvers and PEEP to maintain the same experimental conditions for the purpose of comparison. We therefore postulated that these unexpected changes in Rint and Est found in children20 could have been related to the presence of airway closure and/or atelectasis; hence the stepwise increase in inspiratory flow (and concomitant driving pressure) could have resulted in a stepwise recruitment of previously closed airways and lung units. In young children during general anesthesia, the reduction of FRC would be expected to be more profound in view of higher chest wall compliance than in adults.20

Thus, the specific aims of the present investigation were (i), to study flow and volume dependence of Ers and Rrs (and their components, Est, {Delta}E, Rint, and {Delta}R), and especially possible changes in flow dependence of Rint and Est after eliminating atelectasis with TLC maneuvers; (ii) to compare the difference in Rrs and Est between zero end-expiratory pressure (ZEEP) and PEEP and see if recruited air spaces would be sustained with ZEEP immediately after TLC maneuvers, using a gas mixture of 30% oxygen and 70% nitrogen; and (iii), to evaluate if the TLC maneuvers and PEEP of 5 cm H2O would be sufficient to restore and maintain relaxation volume (Vr) or FRC close to physiological FRC in the awake state in preschool children during general anesthesia.

METHODS

Study Subjects
We studied eight otherwise healthy children (six girls, two boys) undergoing general anesthesia for complete oral rehabilitation. The median age was 3.5 years (range, 2.3–6.5 yr). Patients' characteristics are summarized in Table 1. Children with a history of cardiopulmonary disorders or upper respiratory tract infection within the last 3 mo were excluded from this study. Preanesthetic oxygen saturation of hemoglobin by pulse oximetry (Spo2) was within normal limits (>97%) in all subjects. The study was approved by the IRB for human experimentation at Children's Hospital of Pittsburgh. Informed consent was obtained from parents of all subjects.


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  		Table 1. Patients' Characteristics

 

Children were premedicated with transmucosal midazolam via the nose, 0.3 mg · kg–1, approximately 30 min before the induction of anesthesia. Anesthesia was induced with the inhalation of sevoflurane in nitrous oxide and oxygen (2:1). A venous access was then established and the patients were tracheally intubated after IV cisatracurium, 0.2 mg · kg–1 for muscle relaxation. The size of the cuffed endotracheal tube (ETT) varied between 5.0 and 6.0 mm (ID) and was selected by the anesthesiologist in charge of anesthesia so that air-leak around the ETT without inflating the cuff occurred around 20 cm H2O of positive airway pressure.20

After induction and intubation, inhaled anesthetics were discontinued and anesthesia was maintained thereafter with IV propofol (a bolus dose of 2 mg · kg–1, followed by 150 to 200 mg · kg–1 · min continuous infusion), fentanyl (1–2 µg · kg–1 · h), and cisatracurium as needed while the patients were mechanically ventilated with a mixture of 30% oxygen and 70% nitrogen. Standard monitoring included a pulse oximeter (Nellcor, Palo Alto, CA) and a capnograph (Datex Capnomac Ultima, Helsinki, Finland), a noninvasive automated arterial blood pressure (BP) device, and an axillary temperature probe throughout the period of experiments during general anesthesia. Spo2 remained above 98% and hemodynamic indices stayed within normal limits during the study period.

Mechanical ventilation was maintained in all patients in the supine position using a Servo 900C ventilator (Siemens, Elema, Sweden). The mode of ventilation was volume control with constant inspiratory flow (VI). Each patient received a minute volume of approximately 300 mL · kg–1 · min with a mechanical respiratory rate of 25 breaths per min and inspiratory time 33% of the total respiratory cycle duration (duty cycle, TI/TTOT = 0.33). With these settings each subject received a tidal volume (VT) of approximately 12 mL · kg–1 (to compensate for an added dead-space by instrumentation) and VI of 15 mL · s–1 · kg (baseline settings). With these settings, end-tidal carbon dioxide tension (Petco2) remained within acceptable clinical limits (30–45 mm Hg).

Equipment
Airway opening pressure (Pao) was measured through a side port connected proximally to the ETT, using a differential pressure transducer (Hewlett-Packard 267BC, Palo Alto, CA). There was no frequency dependence in amplitude of the Pao signals up to 20 Hz. VI was measured with a Hewlett-Packard 47304A assembly using a heated pneumotachograph (Fleisch no.1, Lausanne, Switzerland), inserted between the ventilator circuit and the ETT. The response of the pneumotachograph was linear over the experimental range of flow. Equipment dead-space without the ETT was 32 mL.

Before each experiment, the pressure transducer was calibrated by means of a water manometer and the flow transducer by a standard flow meter. Electrical signals from pressure and flow transducers were amplified and passed through a 12-bit analog-to-digital converter (DT2801A; Data Translation, Marlboro, MA). Digital data were sampled at a frequency of 200 Hz and stored on a personal computer. The software used was ANADAT-LABDAT (RHT InfoDat, Montreal, Canada). Measurement of VT was obtained by integration of the flow signal.

Procedures
For the duration of each experiment (approximately 40–45 min), the standard ventilator circuit was replaced with a short (60 cm) rigid ventilator tubing (Tygon; Norton Performance Plastic, Akron, OH) connecting the patient directly to the Servo 900C ventilator. This setup minimized the effects of the ventilator circuit compliance on mechanics measurements.22 Before any measurements were done, the ETT cuff was inflated and the ventilator-ETT circuit was examined for possible presence of air leaks at an increased Pao. An air leak would invalidate measurements and thus subjects or experiments demonstrating air leaks were excluded from the study.

At the end of preset tidal lung inflation, inspiratory flow was rapidly interrupted (<20 ms) by the closure of inspiratory and expiratory valves located within the Servo 900C ventilator. Pao reached Pmax at end-inspiratory occlusion and decreased precipitously to P1 as airway occlusion was maintained for at least 5 s (Fig. 1). The initial rapid decrease in Pao is followed by a slower decay to an apparent plateau or trough pressure (P2), usually within 3 s. The initial rapid drop in Pao (Pmax – P1) reflects pressure dissipation due to the intrinsic flow resistance of the total respiratory system (upper airway excluded) and across the equipment (connector of the pneumotachograph to the distal end of the ETT), whereas P2 is the static recoil pressure of the respiratory system at end-expiration.18,21 The (Pmax – P1) value divided by the preceding constant inflow (VI) provides the Rint of the total respiratory system (the lungs and thorax tissues), again upper airway excluded, and the equipment (Fig. 1). The equipment resistance is then subtracted to obtain the true Rint:



Formula 1

The slower decay in pressure (P1 – P2) is divided by the preceding constant VI to obtain the additional or viscoelastic resistance ({Delta}R):18



Formula 2

This additional resistance results from thoracic tissue viscoelasticity and possibly from regional time constant inequality in diseased lungs.18 The sum of Rint and {Delta}R (Rrs = Rint + {Delta}R) reflects the total pressure dissipation across the respiratory system (upper airways excluded) during constant flow inflation (Fig. 1).

Ers, an inverse of respiratory system compliance (Ers = 1/Crs), can be estimated according to the equation:



Formula 3

where VT is inspiratory tidal volume, whereas the total Ers in the absence of PEEP or intrinsic PEEP is provided by:18,21



Formula 4

The difference between Ers and Est (Ers – Est = {Delta}E) is the additional or viscoelastic elastance of the respiratory system of the pulmonary and thoracic structure.18

In each patient the experiment was conducted in two conditions, without PEEP added (ZEEP) or with PEEP (5 cm H2O), and the order of the study was randomized. With each setting (ZEEP or PEEP), two types of measurements were made: (i) constant V (isoflow) with variable VT; and (ii), constant VT (isovolume) with variable VI. With a constant VI of 15 mL · kg–1 · s (baseline settings), measurements were made at VT of 8, 12, 16, and 20 mL · kg–1. The procedure was repeated with a fixed VT of 12 mL · kg–1 (baseline settings) at VI of 7.5, 10, 15, and 25 mL · kg–1 · s. The order of combinations of ventilator settings was randomly chosen. For each combination of ventilator settings, measurements were repeated six times. Each patient had seven sets of measurements that were collected at various combinations of VT and VI. Between occlusions, patients received at least five regular mechanical breaths. Before each set of measurements, the lungs were slowly inflated three times to Pao of 40 cm H2O for at least 5 s (TLC maneuver) to set a constant volume history. In all subjects static intrinsic PEEP (PEEPi), as measured by the end-expiratory airway occlusion method,23 was absent.

After the experiment with ZEEP (or PEEP), ventilator settings were changed back to baseline and the second part of the study was conducted with PEEP of 5 cm H2O (or with ZEEP), preceded by 3 TLC maneuvers. End-inspiratory occlusion measurements were repeated under both isovolume and isoflow conditions and with the same settings used with ZEEP (or PEEP). After completion of the entire experiment, resistive pressure due to equipment (including ETT) was measured at the bedside, using the same Servo 900C ventilator setup and with the same air-oxygen mixture and an ETT of the same size used for the experiment. Such measurements were made in triplicate at the four different VI settings used in the study. Pressure and flow signals were stored in the computer for later corrections of Rint and Rrs values.

Data Analysis
Using the ANADAT-LABDAT software, a second order polynomial function was fitted to the pressure-flow data pertaining to the equipment resistance.24 K1 and K2 values from Rohrer's equation, {Delta}P=K1·VI+K2·VI2, were obtained. The estimated mean K1 and K2 values were used to compute the pressure decrease due to equipment resistance ({Delta}P) for any given experimental VI.

Interpretation of Pao changes after end-inspiratory airway occlusion is shown schematically in Figure 1 and has been presented in detail in a review article elsewhere.21 Vr (or FRC) is defined as the lung volume at end-expiration in patients during general anesthesia and muscle relaxation when Pao = 0 (ZEEP). End-inspiratory volume is defined as inspiratory VT + (PEEP/Est) above Vr. When changes in elastance are presented graphically in relation to end-inspiratory volume above Vr, it is possible to compare elastance components with different conditions of end-expiratory pressure (ZEEP vs. PEEP) (Fig. 3). To compare patients of different sizes, all elastance and resistance values were expressed per unit of body weight.


Figure 314
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  		Figure 3. Mean (±sem) pressure–volume (P-V) relationships between end-inspiratory volume above the relaxation volume, Vr (mL · kg–1) and static recoil pressure of the respiratory system (Pst,rs) with zero end-expiratory pressure (ZEEP) (closed circles) and with PEEP (5 cm H2O). The first point of the PEEP plot represents the lung volume (VT) above Vr with Pst,rs (PEEP) of 5 cm H2O. Pst,rs at 0 cm H2O corresponds to Vr (or FRC). Values are means of eight subjects.

 

Statistical Analyses
The sample size calculation was based on our previously published data that used essentially the same methodology on a similar group of anesthetized children.20 To investigate flow dependence of resistance (Rrs, Rint) the sample size of 8 would more than suffice to give the power of >0.99 in determining the slope, different from 0, with the {alpha} error of <0.05. Elastance and resistance values with ZEEP and with PEEP with different VT or VI settings were compared with two-way repeated measures analysis of variance (ANOVA). After ANOVA, the Student–Newman–Keuls method was selected for pairwise multiple comparisons. In all cases, P < 0.05 was considered as statistically significant. To compare pressure–volume (P-V) curves of the respiratory system, we compared the estimates of the slopes of two regression lines obtained from four data points (each representing six measurements) on each P-V curve and the pooled standard errors of those estimates.

RESULTS

In all subjects, data collection was completed in about 40 to 45 min. During and after completion of the procedure, none of the participants had clinically significant changes in Spo2, Petco2, or arterial blood pressure.

Elastance (Est and {Delta}E)
When Est was expressed per unit of body weight, there was no statistically significant relationship of Est with patients' ages or height.

Figure 2 shows changes of the components of Ers (Est and {Delta}E) on y axis in relation to end-inspiratory volume above Vr on x axis which is adjusted for an additional volume increase with PEEP. With isoflow conditions, mean Est, adjusted for PEEP, was similar between ZEEP and PEEP. {Delta}E was much smaller than Est and the values with ZEEP and with PEEP were similar (Fig. 2, Table 2). With increasing VT, Est and {Delta}E decreased both with ZEEP and with PEEP (P < 0.01), indicating end-inspiratory volume dependence of Est and {Delta}E (Table 2 and Fig. 2). Est with ZEEP continued to decrease (Cst to increase) without a plateau to the highest VT above Vr of 20 mL · kg–1 (Fig. 2). In contrast, with PEEP, Est reaches its lowest level with VT at 16 mL · kg–1 or end-inspiratory volume above Vr of 24 mL–1 · kg with corresponding static airway pressure, P2 of 17 cm H2O including PEEP (Fig. 2). There was no further decrease in Est (or increase in Cst) with a further increase of inspiratory VT to 20 mL · kg–1 (P2 ~ 15.2 cm H2O).


Figure 214
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  		Figure 2. Mean (±sem) static respiratory system elastance (Est) and elastance due to viscoelasticity ({Delta}E) on y axis in relation to end-inspiratory volume above the relaxation volume (Vr), which is adjusted for an additional volume increase with PEEP, with fixed inspiratory flow (VI = 15 mL · s–1 · kg) in eight anesthetized children with zero end-expiratory pressure (ZEEP) (filled circles) and with PEEP of 5 cm H2O (open circles). Est and {Delta}E decreased significantly with increasing Vt (*P < 0.01). There was no difference in elastance values between ZEEP and PEEP (P > 0.05).

 

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  		Table 2. Static Respiratory System Elastance (Est) and Viscoelastic Elastance ({Delta}E) of eight Anesthetized Children During Isoflow Conditions (VI = 15 mL · s–1 · kg) and Variable End-Inspiratory or Tidal Volume (VT)

 

Figure 3 compares the P-V relations of the respiratory system constructed from the four mean end-inspiratory volume points without PEEP (ZEEP) versus with PEEP. There was no statistical difference between the slopes of the two P-V curves.

With inspiratory VT kept constant (isovolume conditions), there was a significant inverse correlation between Est and VI (P < 0.01) both with ZEEP and with PEEP. The mean Est was higher with ZEEP than with PEEP but the difference was not significant. {Delta}E did not change significantly with increasing inspiratory flow (Table 3 and Fig. 4).


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  		Table 3. Static Respiratory System Elastance (Est) and Viscoelastic Elastance ({Delta}E) of Eight Anesthetized Children During Isovolume Conditions (VT = 12 mL · kg–1) and Variable Inspiratory Flow (VI)

 

Figure 414
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  		Figure 4. Mean (±sem) static respiratory system elastance (Est) and elastance due to viscoelasticity ({Delta}E) versus inspiratory flow (VI), with fixed tidal volume (VT = 12 mL · kg–1) above Vr in eight anesthetized children with zero end-expiratory pressure (ZEEP) (filled circles) and with PEEP of 5 cm H2O (open circles). Est, but not {Delta}E, decreased significantly with increasing VI (*P < 0.01), but there was no difference in elastance values between ZEEP and PEEP (P > 0.05).

 

Resistance (Rrs, Rint, and {Delta}R)
While inspiratory flow was kept constant (isoflow conditions), Rint decreased (P < 0.05) and {Delta}R increased (P < 0.01) with increasing end-inspiratory volume with both ZEEP and PEEP settings (i.e., volume dependence of Rint and {Delta}R) (Table 4, Fig. 5). As a result, Rrs did not change with increasing volume within the volume range studies. Rint and {Delta}R were not significantly different between ZEEP and PEEP at the different VT (Table 4).


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  		Table 4. Flow Resistance (Rint) and Viscoelastic Resistance ({Delta}R) of Eight Anesthetized Children During Isoflow Conditions (VI = 15 mL · s–1 · kg) and Variable End-Inspiratory (Tidal) Volume (VT)

 

Figure 514
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  		Figure 5. Mean (±sem) total respiratory system resistance (Rrs), interrupter (flow) resistance (Rint) and resistance due to viscoelasticity ({Delta}R) versus end-inspiratory volume above the relaxation volume (Vr) with a fixed inspiratory flow (VI = 15 mL · s–1 · kg) in eight anesthetized children with PEEP (5 cm H2O). Rint significantly decreased ({dagger}P < 0.05) and {Delta}R significantly increased (*P < 0.01) with increasing VT. Rrs did not change significantly with VT (P > 0.05). Similar changes in Rrs and its components with changes in VT were also observed with ZEEP but were not plotted (see Table 4).

 

With isovolume conditions, there was a significant inverse correlation between {Delta}R and VI whereas Rint did not increase significantly with increasing flow, although with PEEP the mean Rint increased with flow (Table 5, Fig. 6). Consequently, Rrs decreased with increasing flow. Rint and {Delta}R were not different between ZEEP and PEEP.


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  		Table 5. Flow Resistance (Rint) and Viscoelastic Resistance ({Delta}R) of Eight Anesthetized Children During Isovolume Conditions (VT = 12 mL · kg–1) and Variable Inspiratory Flow (VI)

 

Figure 614
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  		Figure 6. Mean (±sem) total respiratory system resistance (Rrs), flow resistance (Rint), and resistance due to viscoelasticity ({Delta}R) with a fixed end-inspiratory (tidal) volume (VT = 12 mL · kg–1) in eight anesthetized children with PEEP (5 cm H2O). {Delta}R and Rrs decreased significantly with increasing VI (*P < 0.01). Rint did not change significantly with VI (P > 0.05). Similar relationships between Rrs and its components with increasing VI were also observed with ZEEP but were not plotted (see Table 5).

 

DISCUSSION

Overview
General anesthesia in adults as well as in children is often associated with atelectasis secondary to a reduction in the end-expiratory lung volume (FRC or Vr) and the resultant airway closure, as demonstrated by the presence of densities in dependent lung regions on CT scans and MRIs.1–4 FRC decreases during general anesthesia as a consequence of thoracic inspiratory muscle relaxation5 and has been reported to be 9% to 25% below that of FRC in the awake state in adults.6,25

In children younger than 12-yr-of-age, FRC was reported to decrease more than 46% from their awake FRC levels.7 It is highly likely that the extent of airway closure and atelectasis may be far greater in infants and young children, with their extremely compliant chest wall.26–28 The TLC maneuver describes the use of static peak airway pressures above the opening pressure of collapsed lung units (>35 cm H2O) in patients on mechanical ventilation followed by added PEEP (>5 cm H2O) to stabilize the newly recruited small airways and alveoli.14 These maneuvers decrease or eliminate atelectasis in the dependent lung regions, increase Crs (decrease Ers) and improve oxygenation in anesthetized adults.14 More recently, beneficial effects of the TLC strategy in anesthetized young children with normal lungs have been demonstrated by means of CT scans1,2 but its effect on respiratory mechanics in children has been scarce.

Flow and Volume Dependence of Ers and Rrs and Their Subdivisions
The constant flow, end-inspiratory airway occlusion method has been applied to study respiratory mechanics in adults18,21 and in children16,20 (Fig. 1 and Procedures in the Methods section). With this technique, dynamic Ers can be partitioned into Est and an additional component ({Delta}E or Evisc), reflecting viscoelasticity of the respiratory system.



Formula 5

Total Rrs can also be partitioned into Rint (interrupter resistance reflecting flow resistance) and a second component ({Delta}R or Rvisc), resulting from viscoelastic pressure dissipation within the tissues of the lungs and chest wall as well as time constant inequality among lung subunits21 (Fig. 1).



Formula 6

Both Ers and Rrs and their subdivisions can be altered with increases or decreases in inspiratory flow or volume (termed as "flow or volume dependence").18,21 Such flow and volume dependence of Ers and Rrs can be assessed by means of the constant flow, end-inspiratory occlusion technique using variable inspiratory VT (with constant inspiratory flow rate, VI) and variable VI (while end-inspiratory volume is kept constant).18,21

Studies have shown that {Delta}R is a major component of Rrs especially at VI <1 L · s–1 in adults, where {Delta}R is larger than Rint.18 Consequently, the direction of flow and volume dependence of Rrs follows changes of {Delta}R, rather than those of Rint, as has been assumed until recently.18,21 On the other hand, the viscoelastic component ({Delta}E) of Ers was found to be relatively small in relation to Est, both in adults and in children.18,20

Previously, we reported the effects of general anesthesia on respiratory mechanics, especially focusing on the effects on Rrs and its components in healthy children using the constant inflow, end-inspiratory occlusion technique.20 The first study, however, had been planned to use the same technique previously used in the studies in adults for comparison and did not use TLC maneuvers or the addition of PEEP. Thus, the current investigation was performed in a similar age group of otherwise healthy children undergoing general anesthesia but after TLC maneuvers to minimize atelectasis, considering the recent radiographic evidence of atelectasis in dependent lung regions in children.1,2,20 The study was focused on the effects of general anesthesia on Ers as well as Rrs and their components with ZEEP versus PEEP using 30% oxygen in nitrogen.

Elastance
In the present study, we demonstrated that, with increasing end-inspiratory volume with larger VT (with constant VI), both Est and {Delta}E decreased (or compliance increased), despite TLC maneuvers before each measurement to eliminate or minimize airway closure and atelectasis (Fig. 2). This decrease in Est with increasing end-inspiratory volume (volume dependence) persisted even after the addition of PEEP (5 cm H2O), which is recommended during mechanical ventilation of anesthetized children to counter reductions in Vr well below physiological FRC in awake children and prevent airway closure. Est finally reached a plateau at added VT of 16 mL · kg–1 (corresponding static airway pressure of about 17 cm H2O, including PEEP). Although FRC was not directly measured, these findings provide indirect evidence that FRC (or, more accurately, Vr) during general anesthesia was still at decreased levels compared with physiological FRC in awake children while breathing spontaneously even with an addition of PEEP (5 cm H2O) and was well below the mid-portion of the P-V curve of the respiratory system, where {Delta}V/{Delta}P (compliance) is the steepest and fairly constant.

It is interesting to note that Thorsteinsson et al.29 reported that a PEEP of 12.2 ± 1.4 cm H2O yielded the maximum value of respiratory system compliance (Crsmax) at about 60% of TLC in their study in healthy anesthetized children. They estimated Crsmax from the expiratory P-V curve obtained with stepwise reductions from TLC preceded by lung recruitment (TLC) maneuvers, which would have produced much lower pressures than those obtained with inspiratory P-V curves as in the current study.

The P-V curves in Figure 3 were constructed from four sets of mean values with different added VT (and thus different end-inspiratory lung volumes) with ZEEP versus with PEEP, each preceded by TLC maneuvers. These P-V curves are, therefore, different from the inspiratory or expiratory P-V curves normally seen in the literature.30 There is no apparent lower inflection point (PFLEX) or a "knee" in the P-V curve with ZEEP in the present study.30,31 It is therefore unlikely that significant airway closure was present in our subjects, even without PEEP; repeated TLC maneuvers within minutes before the experimental maneuvers with an oxygen–nitrogen mixture most likely kept the airways open, at least temporarily, although airway closure during general anesthesia has been reported within 5 min after the induction of anesthesia when 100% oxygen was used32,33 or when oxygen–nitrous oxide mixture was used.1 This assumption was further supported by the fact that there was no significant difference between two P-V curves with ZEEP versus with PEEP. It is not known how long do airways and air spaces remain open after TLC maneuvers in anesthetized and paralyzed children without PEEP in clinical conditions even with an oxygen–air mixture.

Resistance
In a study using the constant flow, end-inspiratory occlusion technique in anesthetized adult patients, Rint increased with increasing inspiratory flow (while VT was kept constant or at isovolume conditions), as expected from increasing turbulence,34 whereas Est did not change.18 In contrast, in our previous study in children using essentially the same end-inspiratory occlusion technique as in the present study but without prior TLC maneuvers or PEEP, Rint decreased, rather than increased and Est decreased with increasing VI (isovolume conditions).20 This finding was unexpected and puzzling and it was speculated that, in these studies without prior TLC maneuvers, significant airway closure and atelectasis had occurred and progressive increases in VI had generated sufficient pressure to reopen previously closed airways and, consequently, Rint decreased with increasing flow, since the critical opening pressure for reopening the airways are relatively lower than that for reopening the atelectatic air spaces.30

FRC (or Vr) decreases during general anesthesia in recumbent adults from the FRC in awake subjects before anesthetic induction but the decrease is relatively mild (9%–25%).6,25 In contrast, a reduction in FRC in infants and young children under similar circumstances is much greater than in adults, because their compliant chest wall would readily collapse with the loss of inspiratory muscle tone during general anesthesia or with muscle relaxants.7,27,28,35

The results from the current study are consistent with the above findings. In contrast to our previous study, the current investigation in children using a nearly identical experimental set up, but after repeated TLC maneuvers, the mean Rint during constant VT tended to increase with flow, as was seen in adults, rather than significantly decreasing with flow, as was demonstrated in our previous study. The historical comparison of flow dependence of Rint between the previous and current studies demonstrates a significant difference (P < 0.02) between the two slopes of Rint with increasing flow. These contradictory results of the previous and the current study probably indicate that TLC maneuvers prevented airway closure induced by general anesthesia. In contrast, {Delta}R decreased significantly with increasing flow (Table 5, Fig. 6). The total Rrs also decreased significantly in the same direction as with changes in {Delta}R.

With increasing end-tidal lung volume during isoflow settings, the flow resistive component (Rint) of Rrs decreased as an increase in lung volume increases airway caliber due to interdependence between the airways and lung tissues,36 whereas the viscoelastic component ({Delta}R) increased. Consequently, Rrs was essentially unchanged in both with ZEEP and PEEP conditions within the range of inspiratory VT studied (Table 4, Fig. 5). In adults, Rint decreased but {Delta}R increased both significantly with increasing end-inspiratory lung volumes and, in contrast, Rrs also increased under these conditions.18 In a similar study in adults, in whom the effects of ZEEP and PEEP were compared, there was a significant decrease in Rint and K1 values (intercept) with PEEP as compared with those with ZEEP while K2 values (slope) were not significantly different.37 In this study, the lungs were ventilated with 50% nitrous oxide in oxygen and there was no mention of TLC maneuvers before PEEP. In contrast, in the present study in children with ZEEP and PEEP, both preceded by TLC maneuvers, we did not find a significant difference in Rrs and its components, Rint and {Delta}R, between ZEEP and PEEP. These differences between adults and children may provide additional evidence to support the speculation that, in the present study in children, airway closure did not yet take place when the measurements were performed with ZEEP immediately preceded by TLC maneuvers.

Clinical Significance
The concept of flow and volume dependence of elastance and resistance (i.e., changes in elastance and resistance with increasing flow and VT) is important not only for a better understanding of respiratory mechanics in health and disease but, more importantly, for determining clinical strategies, particularly in deciding the optimal ventilator settings in patients with pulmonary insufficiency of varying etiologies.16,17,19,38 Patients with primary airway obstruction, such as those in respiratory failure with status asthmaticus, demonstrate predominant increases in Rint over {Delta}R.16 Under these circumstances, a relatively slow flow rate and a large VT appear beneficial in reducing the flow resistance as well as total resistance (Rint and Rrs) and the work of breathing. On the other hand, in patients with interstitial lung disease or pulmonary edema, the primary problem would be an increase in viscoelastic or tissue component ({Delta}R) of Rrs, as we have demonstrated previously in pediatric patients in the intensive care unit.16 In the latter case, a high flow rate with a small VT (such as high-frequency oscillatory ventilation) would decrease {Delta}R and consequently, decreasing Rrs and work of breathing.16,38 In addition, an appropriate increase in the level of PEEP would be necessary to increase FRC (or Vr) toward physiological levels and thus minimize Ers (increase compliance).

It is of interest to attempt to interpret our results in relation to findings from previous reports that used imaging methods. In the current study, a gas mixture with 30% oxygen in nitrogen was administered during the maintenance of anesthesia. This gas composition was chosen because studies in children and adults show the development of pulmonary atelectasis after ventilation with 100% oxygen before tracheal extubation at the conclusion of inhaled anesthesia. In one study, atelectasis remained high even after TLC maneuvers when 100% oxygen was used.8,39,40

In another study involving 24 otherwise healthy preschool children during general anesthesia (age range, 6 months to 6 years) undergoing MRI, ventilation was maintained with 100% oxygen during the entire study period.2 The investigators were able to prevent atelectasis by applying TLC maneuvers but high PEEP levels were required (up to 15 cm H2O in eight subjects). They did notice atelectasis in children breathing spontaneously with ZEEP (10 children) and with continuous positive airway pressure of 5 cm H2O (8 children).

Serafini et al.1 studied CT imaging in 10 preschool children (age range, 1–5 yr) tracheally intubated and anesthetized with halothane and 40% oxygen in nitrous oxide. After TLC maneuvers, these children were ventilated without PEEP. Within 5 min of induction, they developed densities in dependent lung regions. Interestingly, the density on CT disappeared within 5 min of adding PEEP (5 cm H2O) while being ventilated with end-inspiratory pressures <25 cm H2O and without the second TLC maneuvers (G. Serafini, personal communication). Since recruitment of closed airways requires far lower opening pressures than does atelectasis,30 the density observed on CT scan with ZEEP was probably due to airway closure, rather than fully developed atelectasis. It also appears that the oxygen–nitrous oxide mixture might have some protective effect against atelectasis as compared with 100% oxygen breathing (but it is not likely to be as effective as breathing an oxygen–air mixture). In the present study, children who were pretreated with TLC maneuvers but without PEEP showed decreasing Est (increasing compliance), as the end-inspiratory lung volume increased. Therefore, results of both studies are consistent with the concept that general anesthesia in children is associated with a decrease in FRC (or Vr) and airway closure or atelectasis eventually develops even when a gas mixture of 30% to 40% oxygen in nitrogen is administered in an attempt to avoid or minimize resorption atelectasis.39 In the present study, the mean Est after the addition of PEEP (5 cm H2O) was essentially unchanged from Est with ZEEP. Probably the airways, filled with 30% oxygen in nitrogen, stayed open at least for a relatively short period of time (<5 min) after TLC maneuvers.

In summary, in eight otherwise healthy children during general endotracheal anesthesia and muscle paralysis, Ers, Rrs and their components (Est and {Delta}E, and Rint and {Delta}R, respectively) were studied by means of a constant inflow, end-inspiratory occlusion technique. We demonstrated that Ers and Rrs (and their components) change with increasing VI or VT (known as flow and volume dependence) and that tissue viscoelastic component ({Delta}R) is a major fraction of total Rrs and appears to be clinically important. Although FRC was not directly measured, these findings provide indirect evidence that FRC during general anesthesia (or, more accurately, Vr) was still at decreased levels compared to physiological FRC in awake children while breathing spontaneously even with an addition of PEEP (5 cm H2O) and was well below the mid-portion of the P-V curve of the respiratory system, where {Delta}V/{Delta}P (compliance) is the steepest and fairly constant. Further studies are needed to explore the volume and flow dependence of resistance and elastance, especially of those arising from tissue viscoelastic properties, in infants and children with respiratory insufficiency of various etiologies. These studies would be helpful in the development of a more physiology-based strategy for ventilatory management of these patients.

ACKNOWLEDGMENTS

The authors thank Michael Young, MS, the North American Malignant Hyperthermia Registry, located at Children's Hospital of Pittsburgh, for consultations in statistics, and David Chasey for editorial assistance.

Footnotes

Accepted for publication November 8, 2007.

Supported, in part, by intramural funds of the Department of Anesthesiology, Children's Hospital of Pittsburgh.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2008 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press