The Impact of Positive End-Expiratory Pressure on Functional Residual Capacity and Ventilation Homogeneity Impairment in Anesthetized Children Exposed to High Levels of Inspired Oxygen

Abstract

BACKGROUND: 

High fractions of inspired oxygen (Fio₂) result in resorption atelectasis shortly after their application. However, the impact of different levels of Fio₂ and their interaction with positive end-expiratory pressure (PEEP) on functional residual capacity (FRC) and ventilation distribution is unknown in anesthetized children. We hypothesized that the use of a Fio₂ of 1.0 results in a decrease of FRC and ventilation homogeneity compared with that of a Fio₂ of 0.3, and that this decrease is prevented by PEEP of 6-cm H₂O compared to a PEEP of 3-cm H₂O.

METHODS: 

Forty-six children (3–6 yr) without cardiopulmonary disease were randomly allocated to receive PEEP of 6-cm H₂O (PEEP 6 group) during the entire study period or PEEP of 3-cm H₂O (PEEP 3 group). The order of the Fio₂ (0.3 or 1.0) was also randomized. A defined recruitment maneuver was performed after tracheal intubation and 5 min later the first measurement. This procedure was then repeated with the second Fio₂ level. FRC and lung clearance index (LCI) were calculated by a blinded observer.

RESULTS: 

While FRC (mean ± sd) was similar at both levels of Fio₂ (0.3: 25.6 ± 2.9 mL/kg vs 1.0: 25.6 ± 2.8 mL/kg, P = 0.189) in the PEEP 6 group, FRC decreased in the PEEP 3 group (0.3: 24.9 ± 3.8 vs 1.0: 21.7 ± 4.1, P < 0.0001). Furthermore, with continuous PEEP of 6-cm H₂O a similar LCI was observed at both levels of Fio₂ (0.3: 6.45 ± 0.4 vs 6.43 ± 0.4, P = 0.668) while LCI increased at the higher Fio₂ in the PEEP 3 group (0.3: 6.5 ± 0.5 vs 1.0: 7.7 ± 1.2, P < 0.0001).

CONCLUSIONS: 

During the application of a very low PEEP of 3–cm H₂O, FRC and ventilation distribution decreased significantly at an Fio₂ of 1.0 compared with that at an Fio₂ of 0.3. This decrease could be counterbalanced by the administration of PEEP of 6-cm H₂O, indicating that a low level of PEEP is sufficient to maintain FRC and ventilation distribution regardless of the oxygen concentration.

In Brief

IMPLICATIONS: Functional residual capacity (FRC) and ventilation distribution decreased significantly at a fraction of inspired oxygen (Fio₂) of 1.0 compared with an Fio₂ of 0.3 when children were ventilated with a very low positive end-expiratory pressure (PEEP) of 3-cm H₂O. These changes in FRC and ventilation distribution were prevented by the continuous administration of PEEP of 6-cm H₂O.

High fractions of inspired oxygen (Fio₂) are commonly used, especially at induction and termination of anesthesia. However, the administration of high Fio₂ results in airway closure and, as a consequence, a decreased functional residual capacity (FRC) (¹). Airway closure appears within 5 min after the administration of 100% oxygen after a recruitment maneuver in adults (^2,3). In adults, the formation of atelectasis after induction of anesthesia with 100% oxygen is prevented by the application of positive end-expiratory pressure (PEEP) (²). In children undergoing anesthesia or sedation, optimizing FRC is of special importance because they have smaller elastic retraction forces and a lower relaxation volume, which makes them more prone to airway collapse (⁴). The present study compared the effects of high (100%) and low (30%) oxygen concentrations during the application of 3- and 6-cm H₂O PEEP on FRC and ventilation homogeneity in anesthetized, healthy children. We hypothesized that, in mechanically ventilated, paralyzed children, the use of a Fio₂ of 1.0 results in a decrease of FRC and an increase of ventilation inhomogeneity compared with that of a Fio₂ of 0.3. In addition, this decrease in FRC and ventilation inhomogeneity is prevented with the use of PEEP (6-cm H₂O).

METHODS

After approval by the local Ethics Committee, Basel, Switzerland, and obtaining parental written informed consent, 46 children (3–6 yr and >15 kg) undergoing elective surgery requiring general anesthesia were studied. Blocked randomization was obtained using a computer-generated random number, and randomization was concealed until clinical procedures were initiated. In this physiological cross-over study, patients were randomly allocated to receive PEEP of 6-cm H₂O (PEEP 6 group, n = 23) or PEEP of 3-cm H₂O (PEEP 3 group, n = 23) throughout the study period. The order of the two levels of Fio₂ (100% oxygen vs 30% oxygen [mixture of oxygen and air] was also randomized. Patients with known cardiopulmonary diseases (including respiratory tract infection during the 2 weeks before surgery) or thoracic deformities were excluded from participation.

One hour before the induction of anesthesia, patches with an eutectic mixture of local anesthetics were applied to each child’s hands. Premedication consisted of 0.3 mg/kg midazolam administered orally or rectally 15 min before induction of general anesthesia. In uncooperative patients, nitrous oxide 70% in oxygen was administered for the insertion of an IV cannula. Nitrous oxide was immediately stopped when venous access was achieved.

General anesthesia was induced with a target-controlled infusion system (TCI, Asena PK, Alaris Medical systems, Baesweiler, Germany) using Kataria et al.’s pharmacokinetic model for children (⁵) in order to reach a calculated plasma concentration of 4 μg/mL propofol and a bolus of fentanyl 3 μg/kg. Neuromuscular blockade was achieved with rocuronium 0.6 mg/kg and was monitored with a nerve stimulator. Total neuromuscular blockade was defined as no tactile twitch on a train-of-four stimulation. The degree of muscle relaxation was tested throughout the study period by train-of-four stimulation every 12 s. If twitching reappeared, additional doses of rocuronium were given. The trachea was intubated with a cuffed endotracheal tube (Microcuff, Heidelberg, Germany) and all patients received 100% oxygen until correct placement of the endotracheal tube was confirmed. Anesthesia was maintained with a calculated propofol plasma concentration of 2.5 μg/mL. After setting the first Fio₂ (according to the randomization), a lung recruitment maneuver to achieve total lung capacity was performed by manually elevating the airway pressure up to 37–40 cm H₂O of peak inspiratory pressure for 10 consecutive breaths (⁶). The patients were then mechanically ventilated for 5 min before we performed the first set of measurements at the first Fio₂ level (^2,3). After a 5-min interval, we used the same sequence to measure the second level of Fio₂.

During anesthesia, a Centiva/5 critical care ventilator (Datex Ohmeda, Helsinki, Finland) was used with the tidal volume set at about 8 mL/kg body weight. Respiratory rate was adapted in order to achieve an end-tidal carbon dioxide of 4–5 kPa. The ventilator delivered a continuous bypass flow required to ensure an exact delivery of the tracer gas at all times. This bypass flow in the breathing system created a PEEP of 3-cm H₂O in the system. Therefore, the addition of PEEP (3-cm H₂O) in the PEEP 6 group created a total PEEP of 6-cm H₂O in our clinical setting, whereas the PEEP 3 group received a PEEP of 3-cm H₂O.

An ultrasonic transit-time airflow meter (Exhalyzer D with ICU insert, Eco Medics, Duernten, Switzerland) that simultaneously measures flow and molar mass of the breathing gas in the mainstream of the breathing gas was placed between the ventilator circuit and the endotracheal tube. This equipment has been described in detail previously (⁷). Briefly, this airflow meter combines accurate flow measurements with instantaneous mainstream gas analysis of molecular mass in a single sensor. This analysis is based on an ultrasonic transit time detection measured at a high sampling frequency (400 Hz) with piezoelectric sensors that demonstrate a high linearity over a wide amplitude range.

The introduction of sulfur hexafluoride (SF6, molecular mass 146 g · mol⁻¹) as a tracer gas into the inspiratory part of the breathing system increases the total molecular mass of the breathing gas until a steady-state is reached. After the discontinuation of sulfur hexafluoride, the molecular mass decreases breath by breath until a steady-state is reached when the sulfur hexafluride has been washed out of the lungs (multibreath washout technique). Analysis of the washout curve allows for calculation of the FRC, physiological dead-space volume, lung clearance index (LCI), and mean dilution number (MDN). LCI and MDN are commonly used to measure the degree of ventilation distribution, and are sensitive indicators of peripheral airway collapse (^8,9). The LCI is the cumulative expired volume required to decrease the end-tidal tracer gas (sulfur hexafluoride) concentration to 1/40 of the starting concentration divided by the FRC; i.e., the number of lung volume turnovers needed to clear the lungs of the marker gas (⁹). The MDN is the ratio between the first and the zeroth moments of the washout curve. The number of volume turnovers was calculated using the cumulative expired alveolar volume (^8,10). An increase in LCI or MDN reflects a decrease in ventilation homogeneity. A blinded reviewer performed FRC, dead-space volume, MDN, and LCI calculations using Spiroware software (Version 1.5.2, ndd Medizintechnik AG, Zürich, Switzerland). The physiological dead-space was calculated with the Fowler method using the molar mass signal.

Sample size calculation was performed using the nQuery Advisor 4.0 software program (Statistical Solutions Ltd., Boston, MA), and was based on pilot data and data from previous studies (unpublished observations). A sample size of 23 patients per group had an 80% power to detect a difference of at least 8% between the FRC at the two levels of Fio₂, assuming a standard deviation of differences of 8.4%, using an ANOVA for repeated measures with a 0.025 two-sided significance level to adjust for multiple comparisons.

Demographic and procedural data were analyzed for normal distribution by the Shapiro-Wilk test, and data are reported as mean (sd) or median (interquartile range). Repeated measures were analyzed with regression techniques using PROC MIXED procedures in SAS software version 9.1 (SAS Institute, Cary, NC). The regression model used the patient’s group assignment (G), the repeated measures factor (I, indicates the measurements at the different Fio₂ levels), and the interaction between the two (GI) as independent variables [Y = b₀ + b₁ (G) + b₂ (I) + b₃ (GI)]. Here, the interaction parameter b₃ is of interest because a statistically significant nonzero value for b₃ indicates that the two patient groups reacted differently to the intervention. When there was a statistically significant interaction, pairwise t-tests were used within groups to determine the extent of changes within groups. Since two tests were performed for each variable, a P < 0.025 was considered statistically significant to control for Type I error.

RESULTS

All 46 children were successfully studied. Intubation was preformed at the first attempt in all patients and clinical evidence of episodes of laryngospasm or bronchospasm was not observed. Patient characteristics are shown in Table 1. Additional doses of rocuronium were needed in 18 children. FRC was similar at both levels of Fio₂ in the PEEP 6 group, whereas FRC significantly decreased in the PEEP 3 group (Table 2, Fig. 1). Furthermore, in the PEEP 6 group similar LCIs and MDN were observed at both levels of Fio₂ while LCI and MDN increased with a higher Fio₂ in the PEEP 3 group (Table 2, Fig. 2). Dead-space volume was larger in the PEEP 6 group but did not change throughout the study period in both groups (Table 2).

Table 1: Characteristics of Patients (n = 46)

Table 2: Measured Variables

Figure 1.: Functional residual capacity (FRC [mL/kg]) at 2 oxygen concentrations in children receiving positive end-expiratory pressure (PEEP) of 6-cm H₂O and in children receiving PEEP of 3-cm H₂O.

Figure 2.: Lung clearance index (LCI) at 2 oxygen concentrations in children receiving positive end-expiratory pressure (PEEP) of 6-cm H₂O and in children receiving PEEP of 3-cm H₂O.

DISCUSSION

This study examined the effects Fio₂ 0.3 [in air] versus Fio₂ 1.0 and its reversibility by the application of continuous PEEP of 6-cm H₂O compared with PEEP of 3-cm H₂O on FRC and ventilation distribution in children undergoing elective surgery under general anesthesia. An increase of Fio₂ from 0.3 to 1.0 with a PEEP of 3-cm H₂O decreased the measured FRC, whereas FRC remained unchanged when 6-cm H₂O PEEP was applied. Similarly, ventilation distribution remained unchanged when Fio₂ was increased from 0.3 to 1.0 during 6-cm H₂O of PEEP whereas during PEEP of 3-cm H₂O an increase of Fio₂ from 0.3 to 1.0 caused significant ventilation maldistribution.

In contrast to numerous studies in adult patients (^{1–3,11–16}), the impact of different levels of Fio₂ on FRC and ventilation homogeneity has not been studied in the pediatric population. In adult patients undergoing anesthesia, impaired oxygenation and intermittent hypoxemia is often encountered (¹¹). In children, changes in perioperative respiratory function can be more pronounced because their chest walls are more compliant compared with adults (¹⁷). Because the balance between chest and lung recoil pressure determines the static resting volume of the lung, a child reaches equilibrium at a relatively lower lung volume compared with adults, which makes them particularly prone to collapse of the small peripheral airways (^4,17–21).

Impact of Fio₂

Atelectases appear within 5 min of induction of anesthesia, even in healthy, normal-weight patients, resulting in an increased intrapulmonary shunt (^3,15,22–25). This increases the risk of desaturation, especially in children because of their high oxygen demand. After induction of anesthesia in adults, a Fio₂ of 0.3 results in only minor atelectasis that minimally increases after 40 min if the Fio₂ is kept at 0.3; however there is significant atelectasis if the Fio₂ is changed to 1.0 after induction (¹³). Consistent with this, a reduction of Fio₂ to 0.8, or even 0.6, at induction in adults reduces the formation of atelectasis compared with that of a Fio₂ of 1.0 (¹).

In the present study, after the application of randomized Fio₂, a recruitment maneuver was performed at each level to minimize the effect of the previous level as well as the effect of 100% oxygen during induction of anesthesia. In line with the present results in the PEEP 3 group, in a computed tomographic analysis in adults, a recruitment maneuver has a sustained effect when the lungs are ventilated with a Fio₂ of 0.4, whereas a Fio₂ of 1.0 is associated with atelectasis formation within a few minutes after recruitment. This suggests that gas resorption plays an important role in the recurrence of alveolar collapse after a previous recruitment (³).

The LCI and MDN are sensitive parameters for detecting peripheral airway collapse (^26,27). Alveolar collapse after a high level of oxygen leads to decreased ventilation homogeneity that is reflected by an increased LCI. However, we cannot exclude the possibility that the changes in LCI after a Fio₂ of 1.0 in the PEEP 3 group were under-estimated because the SF6 multibreath washout technique detects only the volume and ventilation distribution of the gas in the pulmonary units that communicate with the airway during the period of measurement.

Impact of PEEP

Under general anesthesia, PEEP prevents end-expiratory airway closure due to decreased FRC below the closing capacity in the dependent lung segments and therefore helps airways to remain open (also reflected by the higher dead-space in the PEEP 6 group compared to the PEEP 3 group), which is crucial to maintain adequate gas exchange (²⁸). While very low PEEP levels might not be sufficient to prevent alveolar collapse, high levels of PEEP result in over-distension of already expanded alveoli, reduced perfusion, and an increase in alveolar dead-space.

In healthy adults, atelectasis formation during induction of anesthesia using a Fio₂ of 1.0 can be prevented by administering PEEP 6–10 cm H₂O, which results in a 2-min prolongation of the nonhypoxic apnea time and an indirect measure of FRC (^2,12,29). In adults, however, a PEEP of 3-cm H₂O at induction of anesthesia does not prevent atelectasis formation after a Fio₂ of 1.0 compared with a Fio₂ of 0.6 or 0.8 (¹).

In the present study in children, in contrast to a PEEP of 3-cm H₂O, PEEP of 6-cm H₂O, prevented an adverse effect of a high Fio₂. A very low level PEEP (3-cm H₂O) was not sufficient to prevent an impairment of FRC. Nevertheless, our results indicated that low levels of PEEP are needed to prevent the decrease of FRC and ventilation homogeneity caused by 100% oxygen. This is consistent with the computed tomographic finding that a PEEP of 5-cm H₂O is sufficient to recruit all available alveolar units at a Fio₂ of 0.4 in anesthetized children (³⁰).

All children in the present study were paralyzed during the entire study. Because it is difficult to predict the clinical depth of anesthesia elicited by propofol, as reflected by the wide interindividual range of responses despite the use of a target-controlled infusion regimen, the use of neuromuscular blockade improved conditions during FRC measurements and allowed for a better comparison among all children. However, with the use of a cross-over study design, each patient served as his/her own control for the two measurements in each group.

The long-term effects of high levels of inspired oxygen have not been assessed and are a limitation of our study. However, airway closure occurs within 5 min after administration of 100% oxygen after a recruitment maneuver in adults, whereas FRC at low oxygen concentrations decreases directly after induction of anesthesia and then remains constant for at least 30 min in children (⁷).

In conclusion, a very low PEEP of 3-cm H₂O is insufficient to prevent a decrease in FRC in anesthetized, paralyzed, healthy children when a Fio₂ of 1.0 is applied. In contrast, a low level of PEEP (6-cm H₂O) effectively counterbalances the negative effects on FRC and ventilation distribution even at high levels of oxygen.

ACKNOWLEDGMENTS

The authors thank all the children and their families who participated in this study, Damian M. Craig, M.H.S. (Department of Cardiovascular Surgery, Duke University, Durham, NC 27710) for his advice with statistical analyses, and Joan Etlinger, B.A. (Department of Anesthesia, University of Basel, CH-4031 Basel, Switzerland) for her help with manuscript preparation.