The Deflation Limb of the Pressure–Volume Relationship in Infants during High-Frequency Ventilation
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《美国呼吸和危急护理医学》
Department of Neonatology, Royal Children's Hospital
Murdoch Children's Research Institute
Department of Pediatrics, University of Melbourne, Melbourne
Department of Pediatrics, Royal Hobart Hospital, Hobart, Australia
ABSTRACT
Rationale: The importance of applying high-frequency oscillatory ventilation with a high lung volume strategy in infants is well established. Currently, a lack of reliable methods for assessing lung volume limits clinicians' ability to achieve the optimum volume range.
Objectives: To map the pressure–volume relationship of the lung during high-frequency oscillatory ventilation in infants, to determine at what point ventilation is being applied clinically, and to describe the relationship between airway pressure, lung volume, and oxygenation.
Methods: In 12 infants, a partial inflation limb and the deflation limb of the pressure–volume relationship were mapped using a quasi-static lung volume optimization maneuver. This involved stepwise airway pressure increments to total lung capacity, followed by decrements until the closing pressure of the lung was identified.
Measurements and Main Results: Lung volume and oxygen saturation were recorded at each airway pressure. Lung volume was measured using respiratory inductive plethysmography. A distinct deflation limb could be mapped in each infant. Overall, oxygenation and lung volume were improved by applying ventilation on the deflation limb. Maximal lung volume and oxygenation occurred on the deflation limb at a mean airway pressure of 3 and 5 cm H2O below the airway pressure approximating total lung capacity, respectively.
Conclusions: Using current ventilation strategies, all infants were being ventilated near the inflation limb. It is possible to delineate the deflation limb in infants receiving high-frequency oscillatory ventilation; in doing so, greater lung volume and oxygenation can be achieved, often at lower airway pressures.
Key Words: high-frequency ventilation impedance infant, newborn plethysmography pressure–volume relationship
High-frequency oscillatory ventilation (HFOV) is a means of respiratory support that has been widely applied in newborn infants with respiratory failure. Meta-analysis of data from randomized controlled trials suggests that application of HFOV in preterm infants can reduce the risk of ventilator-induced lung injury (VILI), but only with the use of a high lung volume strategy (1, 2). The importance of lung volume is supported by evidence from studies in experimental animals indicating that VILI is minimized using an open lung approach to achieve a high lung volume (3–6). With this approach, lung units are recruited via inflation to total lung capacity (TLC), and ventilation is then applied on the deflation limb of the pressure–volume (PV) relationship of the lung (7). Once on the deflation limb, tidal ventilation (8) or HFOV (8, 9) can be achieved at lower pressures than elsewhere within the PV relationship, thereby minimizing the risk of overdistension or atelectasis, both of which have been implicated in the development of VILI (3, 8, 10–14).
In adult patients (both on conventional ventilation and HFOV), the PV relationship has been mapped in its entirety using a variety of methods (15, 16), allowing a portion of the deflation limb to be targeted as the optimal area in which to apply ventilation. This approach has not been used in neonates, in part due to the lack of a reliable and simple means to continually evaluate lung volume, especially during HFOV.
Respiratory inductive plethysmography (RIP) is a noninvasive method of measuring relative changes in lung volume (17–19), which has recently been shown in animal models to be reliable for measuring lung volume during HFOV and mapping the PV relationship of the lung to allow determination of the optimal pressure range during HFOV (20, 21). It has not been used in human infants for this purpose.
The aims of this study were as follows: (1) to map the PV relationship of the lung using RIP; (2) to determine at what point within the PV relationship ventilation was being applied clinically; and (3) to describe the relationships among airway pressure, lung volume, and oxygenation as the lung was inflated and deflated through its PV relationship in infants receiving HFOV. Some of the results of these studies have been previously reported in abstract form (22, 23).
METHODS
A detailed description can be found in the online supplement.
Study Population
The study was performed in the Neonatal Unit, Royal Children's Hospital, Melbourne. The Ethics in Human Research Committee approved the study, and informed parental consent was obtained for each infant. Muscle-relaxed infants receiving HFOV using the Sensormedics 3100A high-frequency oscillator (Sensormedics, Yorba Linda, CA) were eligible for enrollment. Infants were not studied if they had congenital heart disease, a known chromosomal anomaly, refractory hypotension, or an FIO2 of greater than 0.9.
Measurements
Preductal oxygen saturation (SpO2), heart rate, and arterial blood pressure were recorded every 60 s during the study. Proximal airway pressure (Paw) was measured from an endotracheal tube sideport (Florian respiratory monitor; Acutronic Medical Systems, Zug, Switzerland).
Change in lung volume was measured with a low-pass-filtered, DC-coupled, Respitrace 200 monitor (Non-invasive Monitoring Systems, Inc., North Bay Village, FL), sampling at 200 Hz. After thermal stabilization (24), the outputs were zeroed. An uncalibrated volume signal (VRIP) in volts was derived from the sum of chest and abdominal RIP voltages (range ± 2 V) (18).
FIO2 was adjusted to maintain SpO2 between 90 and 94% for 30 min before each study, and then not changed. The ventilator amplitude and frequency had been set by the treating clinicians before the study and were not altered. An inspiratory-to-expiratory ratio of 1:2 was used in all infants.
Mapping the PV Relationship
The experimental protocol consisted of a lung volume optimization maneuver based on the open lung concept described by Lachmann (7). Starting at the Paw set by the clinical team (Pinitial), the Paw was increased by 2 cm H2O every 10 min (inflation series) until no further increase in SpO2 was achieved, or the SpO2 decreased over more than two Paw settings (Pmax). Lachmann has shown that at this Paw, the lung should be recruited and near TLC (7). Paw was then decreased every 10 min (deflation series), by 2 cm H2O until Pinitial + 2 cm H2O and then by 1 cm H2O, until SpO2 fell below 85% for more than 5 min or Paw reached 5 cm H2O (Pfinal). Lung volume was then reestablished by increasing Paw to Pmax for 10 min, and then returned to Pinitial. The study was stopped if the heart rate or blood pressure was unstable for more than 2 min (25).
Data Collection and Analysis
Paw, VRIP, and SpO2 data were digitized and recorded using LabView (National Instruments, Austin, TX). Paw and VRIP were recorded for the last 5 min of each 10-min period at each new Paw setting to allow time for volume equilibration. The final lung volume at each Paw setting was defined as the mean end-expiratory voltage for the final 5-s epoch, with the corresponding Paw value derived from the same epoch. At each Paw setting, the average SpO2 value for the final minute was calculated. To allow for intersubject variability, Paw and VRIP values were normalized by referencing to the corresponding values at Pmax (100%) and Pfinal (0%), these being the upper and lower limits of the deflation series. From these, a PV curve was drawn, using the model described by Venegas and colleagues (26). Data at different Paw levels were compared using mean differences and 95% confidence intervals (CIs). Combined SpO2 data during the deflation series were plotted against Paw and VRIP, and optimum SpO2 ranges determined. Statistical analysis was performed with SPSS 12.0 (SPSS, Inc., Chicago, IL).
RESULTS
Twelve infants were studied and completed the protocol without complications, in particular hypotension or bradycardia. Their demographic characteristics and clinical details are shown in Table 1.
Relationship between Pressure and Volume
It was possible to map a PV relationship in each infant (Figure 1). VRIP, and thus lung volume, increased during the inflation series in all infants, with a significant difference in the group overall between the VRIP at Pmax and VRIP at Pinitial (mean difference, 0.54 V; 95% CI, 0.32, 0.76 V). It was possible to identify a deflation limb in each infant. Apart from subject 1, all PV relationships showed hysteresis, with a mean difference in VRIP between Pinitial and the same Paw during the deflation series of 0.43 V (CI 0.26, 0.6 V). The degree of hysteresis exhibited was variable. Of note, the greatest lung volume occurred at Pmax in only three infants (subjects 4, 5, and 6). In eight of the other nine infants, a VRIP greater than the VRIP at Pmax could be achieved early in the deflation series. The greatest mean lung volume (109% [SD, 13%] of that at Pmax) occurred at a Paw of approximately 79% [SD, 18%] of Pmax (3.1 [SD, 2.8] cm H2O below Pmax; Figure 2).
Relationship between Airway Pressure and SpO2
Individual Paw versus SpO2 plots are shown in Figure 3. The SpO2 data were variable; generally the highest SpO2 occurred during the deflation series but not at Pmax. In most infants, a bell-shaped relationship between SpO2 and Paw could be demonstrated during the deflation series, and a wide optimal SpO2 range identified. SpO2 was maximized during the deflation series in all but two subjects (4 and 7), and improved from the initial SpO2 in all but one (subject 7). The mean difference between the highest SpO2 and initial SpO2 was 3.6% (CI 1.8, 5.4%), although SpO2 values near that resulting in the highest SpO2 occurred through a wide range of Paw during the deflation series. Recruitment through TLC from Pinitial to the same Paw during the deflation series improved SpO2 by a mean of 2.2% (CI 0.5, 3.9%). In three infants (subjects 2, 3, and 12), SpO2 remained above 85% during the deflation series, despite Paw being decreased to 5 cm H2O or less. This was despite an ongoing loss of lung volume and a distinct change in the slope of the PV deflation series (Figure 1). Combined data from all subjects show that the highest SpO2 occurred during the deflation series at a Paw of 63% (SD, 21%) of Pmax or 5.2 (SD, 3.1) cm H2O below Pmax and a mean volume of 84% (SD, 34%) of the volume at Pmax (Figure 2).
Relationship among Airway Pressure, Volume, and SpO2
The PV relationship using normalized data from all infants is shown in Figure 4A. The deflation series was similar to the upper regions of a PV curve and could be fitted with the model proposed by Venegas and colleagues (R2 = 0.78) (26). During the deflation series, there was little change in SpO2 until Paw fell below 20% of Pmax (Figure 4B), indicating that optimal SpO2 was achieved over a large range of Paw settings, and well below Pmax once ventilation was applied on the deflation limb. During the deflation series, SpO2 generally improved with increasing VRIP (Figure 4C), and this relationship was similar to the PV relationship described in Figure 4A. Similarly, during the deflation series, SpO2 changed little until lung volume fell below 50% of that at TLC (Figure 4C). These findings highlight the imprecision of SpO2 as a proxy indicator of optimal lung volume.
DISCUSSION
These data show that, using an open lung approach and DC-coupled RIP, the deflation limb of the PV relationship can be mapped at the bedside during HFOV in human infants, after recruitment to TLC. In addition, applying ventilation on the deflation limb resulted in better lung volume and improved oxygenation, often at a lower Paw.
There is compelling experimental evidence that ventilation, by whatever mode, should be applied on or near the deflation limb of the PV relationship. This requires brief recruitment of the lung to near TLC (3). Such an approach results in greater alveolar stability without overdistension (11, 12), better lung compliance (4, 5, 27–29), and significantly better oxygenation than ventilation applied elsewhere within the PV relationship (3–5, 8, 30). Furthermore, both with conventional ventilation (4, 5, 8, 30, 31) and HFOV (3, 8, 9, 32), ventilation on the deflation limb is associated with less lung injury, emphasizing the potential importance of optimizing lung volume in protecting the neonatal lung from VILI (2, 6).
In animal models of lung injury (3, 4, 15, 20, 21) and in adult humans (33–36), the deflation limb has been mapped using an open lung approach, after first recruiting the lung to TLC (7, 10). To our knowledge, this study is the first to do so in human infants. We found that there was a distinct deflation limb in each infant studied, and that oxygenation was better in 10 of 12 infants when placed on the deflation limb, not at TLC but at a volume 84% of TLC, and a Paw 5.2 cm H2O below that at TLC. This relationship among Paw, VRIP, and SpO2 (Figures 2 and 4) during HFOV is similar to the relationship described in animal studies, in which oxygenation was optimal at a Paw correlating to the point of maximum curvature on the deflation limb of the PV relationship (32), although, as would be expected in a heterogeneous human population, greater variability existed. Our data clearly show that there is no oxygenation benefit in sustaining high airway pressures once ventilation is being applied on the deflation limb. The uniformity of SpO2 readings over a range of airway pressures and lung volumes on the deflation limb highlights the limitation of SpO2 in targeting the optimal point of ventilation.
Although a point of optimal oxygenation could often be identified on the deflation limb, the difference in SpO2 values was usually minimal through much of the deflation limb. Further research is required to determine whether other indicators of lung mechanics have greater precision in identifying the point of optimum ventilation. It remains to be completely elucidated whether, within the region of the deflation limb, there also exists a point of best carbon dioxide clearance, most stable alveoli and the least lung injury.
Our data also show that none of the infants were being ventilated on the deflation limb before commencing PV mapping, although clinicians were attempting to apply HFOV using the principles of a high lung volume strategy (1). Despite this, our study suggested that, in infants receiving HFOV, it was clinically practical to apply ventilation on the deflation limb, as has been observed in adults (34, 36). There were no deleterious effects associated with this maneuver, although a larger series will be required to assess its safety with more confidence. Rimensberger and colleagues found that a stepwise recruitment strategy of up to 25 cm H2O in 32 preterm infants receiving first-intention HFOV was well tolerated (37). Similarly, the stability of lung volume on the deflation limb needs further exploration. It may be that repeated recruitment through TLC may be periodically required to maintain lung volume at the desired point.
The mathematical equation for modeling the PV curve described by Venegas and colleagues assumes that the greatest lung volume will occur at TLC (26). The finding that, in nine infants, the maximum VRIP was not achieved at Pmax is curious. Brazelton and colleagues reported a similar finding in pigs during HFOV; the maximum uncalibrated RIP volume occurred on the deflation limb at a Paw approximately 10 cm H2O below the maximum Paw (40 cm H2O) (21). We suggest two possible explanations for this. First, alveolar recruitment is not uniform, even at high airway pressures; alveolar opening pressures vary and overdistension of some alveoli may compress adjacent, atelectatic alveoli at Pmax (11, 12, 38). Only at Paw below Pmax may these compressed alveoli be able to open after alveoli recruitment. Second, changes in intrathoracic blood volume and impaired cardiac output may have occurred at Pmax (39). RIP is unable to discriminate between gas and liquid.
RIP
Currently, no reliable bedside tool exists to indicate lung volume during HFOV. Chest radiograph is not a reliable indicator of lung volume during HFOV (40) and does not indicate where within the PV relationship ventilation is being applied. Direct measures of lung volume, such as inert gas sulfur hexafluoride washout (41, 42), whole body plethysmography (43), and computed tomography (44), are useful research tools, but in each case are impractical for repeated measurement of lung volume at the bedside during HFOV.
This study shows that RIP is a practical technique for determining relative change in lung volume during HFOV. RIP has the advantage of being noninvasive, unaffected by endotracheal tube leak, and simple to use, without the need to interrupt mechanical ventilation. Uncalibrated DC-coupled RIP has been validated in animal studies as a measure of change in thoracic gas volume, allowing the complete PV relationship of the lung to be described and optimum lung volume and pressure determined during HFOV (20, 21, 45).
Limitations of the Study
This study has some limitations. First, unlike adult patients (34), constructing a complete PV relationship is not possible in human infants. For reasons of safety, we did not allow the lung to passively deflate before commencing PV mapping, nor was the lung allowed to fully deflate beyond closing pressure. Thus, the inspiratory limb of the PV relationship is incompletely mapped, with the final section of the deflation limb beyond closing pressure absent. Even so, the data we have obtained closely resemble the PV relationships described by Brazelton and colleagues using RIP in pigs during HFOV (21). We contend that even incomplete mapping of the PV relationship in human infants is of practical value, as it allows the deflation limb to be accurately defined within the confines of clinically acceptable SpO2 ranges.
All infants enrolled in this study were given muscle relaxants. The lung mechanics of this population may be different from those of self-ventilating infants receiving HFOV. The focus on this population was intentional to minimize the effect of artifact and to reproduce the optimal ventilation strategy identified in animal studies (3–5, 7, 8, 28).
Although SpO2 monitoring is the most commonly used bedside indicator of oxygenation, it has limitations as a surrogate of arterial partial pressure of oxygen. Pulse oximetry is known to have an error of ± 4 to 6% of the arterial oxygen saturation (46); SpO2 values are influenced by tissue perfusion and are unable to identify any further improvement in oxygenation once an SpO2 of 100% is obtained. This limitation is noticeable in the Paw versus SpO2 curves of subjects 3 and 12 and the greater variability in the Paw versus SpO2 relationships compared with the PV relationships.
A final limitation of this study refers to the limitations of RIP technology. Although not essential, calibration of the raw RIP voltage signal to a known volume change would be advantageous. This is difficult during HFOV, and currently, no practical method is validated. RIP bands are sensitive to temperature change and movement (20), both of which may lead to baseline drift during the recording. Drift is greatest if a 30-min thermal stabilization is not allowed (17, 21). After allowing for thermal stabilization, in bench testing, we found a positive drift of less than 0.07 V/h in our RIP device (data not shown), consistent with a previous report (47). The software used for RIP has been developed largely for application in sleep medicine. There is no integrated RIP software currently available to track neonatal lung volume, hampering the progression of RIP from a research to a clinical tool. Electrical impedance tomography, which allows measurement of regional volume differences and global volume changes, offers potential as a future alternative to RIP (48).
Conclusions
This study has shown that it is possible to delineate the deflation limb of the PV relationship in ventilated infants requiring HFOV. By doing so, better lung volume and oxygenation may be achievable, implying the deflation limb should be the target region after any recruitment maneuver. RIP offers promise as a bedside method of allowing clinicians to quantify the response to a recruitment maneuver. Further investigation of the relationships among airway pressure, lung volume, and gas exchange is warranted to refine the optimal point of ventilation on the deflation limb during HFOV.
Acknowledgments
The authors thank Peter McDougall for his suggestions about the manuscript.
FOOTNOTES
Supported by a National Health and Medical Research Council Medical Postgraduate Research Scholarship (D.G.T.) and a Murdoch Children's Research Institute Trainee Research Scholarship (A.P.).
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200502-299OC on December 1, 2005
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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Murdoch Children's Research Institute
Department of Pediatrics, University of Melbourne, Melbourne
Department of Pediatrics, Royal Hobart Hospital, Hobart, Australia
ABSTRACT
Rationale: The importance of applying high-frequency oscillatory ventilation with a high lung volume strategy in infants is well established. Currently, a lack of reliable methods for assessing lung volume limits clinicians' ability to achieve the optimum volume range.
Objectives: To map the pressure–volume relationship of the lung during high-frequency oscillatory ventilation in infants, to determine at what point ventilation is being applied clinically, and to describe the relationship between airway pressure, lung volume, and oxygenation.
Methods: In 12 infants, a partial inflation limb and the deflation limb of the pressure–volume relationship were mapped using a quasi-static lung volume optimization maneuver. This involved stepwise airway pressure increments to total lung capacity, followed by decrements until the closing pressure of the lung was identified.
Measurements and Main Results: Lung volume and oxygen saturation were recorded at each airway pressure. Lung volume was measured using respiratory inductive plethysmography. A distinct deflation limb could be mapped in each infant. Overall, oxygenation and lung volume were improved by applying ventilation on the deflation limb. Maximal lung volume and oxygenation occurred on the deflation limb at a mean airway pressure of 3 and 5 cm H2O below the airway pressure approximating total lung capacity, respectively.
Conclusions: Using current ventilation strategies, all infants were being ventilated near the inflation limb. It is possible to delineate the deflation limb in infants receiving high-frequency oscillatory ventilation; in doing so, greater lung volume and oxygenation can be achieved, often at lower airway pressures.
Key Words: high-frequency ventilation impedance infant, newborn plethysmography pressure–volume relationship
High-frequency oscillatory ventilation (HFOV) is a means of respiratory support that has been widely applied in newborn infants with respiratory failure. Meta-analysis of data from randomized controlled trials suggests that application of HFOV in preterm infants can reduce the risk of ventilator-induced lung injury (VILI), but only with the use of a high lung volume strategy (1, 2). The importance of lung volume is supported by evidence from studies in experimental animals indicating that VILI is minimized using an open lung approach to achieve a high lung volume (3–6). With this approach, lung units are recruited via inflation to total lung capacity (TLC), and ventilation is then applied on the deflation limb of the pressure–volume (PV) relationship of the lung (7). Once on the deflation limb, tidal ventilation (8) or HFOV (8, 9) can be achieved at lower pressures than elsewhere within the PV relationship, thereby minimizing the risk of overdistension or atelectasis, both of which have been implicated in the development of VILI (3, 8, 10–14).
In adult patients (both on conventional ventilation and HFOV), the PV relationship has been mapped in its entirety using a variety of methods (15, 16), allowing a portion of the deflation limb to be targeted as the optimal area in which to apply ventilation. This approach has not been used in neonates, in part due to the lack of a reliable and simple means to continually evaluate lung volume, especially during HFOV.
Respiratory inductive plethysmography (RIP) is a noninvasive method of measuring relative changes in lung volume (17–19), which has recently been shown in animal models to be reliable for measuring lung volume during HFOV and mapping the PV relationship of the lung to allow determination of the optimal pressure range during HFOV (20, 21). It has not been used in human infants for this purpose.
The aims of this study were as follows: (1) to map the PV relationship of the lung using RIP; (2) to determine at what point within the PV relationship ventilation was being applied clinically; and (3) to describe the relationships among airway pressure, lung volume, and oxygenation as the lung was inflated and deflated through its PV relationship in infants receiving HFOV. Some of the results of these studies have been previously reported in abstract form (22, 23).
METHODS
A detailed description can be found in the online supplement.
Study Population
The study was performed in the Neonatal Unit, Royal Children's Hospital, Melbourne. The Ethics in Human Research Committee approved the study, and informed parental consent was obtained for each infant. Muscle-relaxed infants receiving HFOV using the Sensormedics 3100A high-frequency oscillator (Sensormedics, Yorba Linda, CA) were eligible for enrollment. Infants were not studied if they had congenital heart disease, a known chromosomal anomaly, refractory hypotension, or an FIO2 of greater than 0.9.
Measurements
Preductal oxygen saturation (SpO2), heart rate, and arterial blood pressure were recorded every 60 s during the study. Proximal airway pressure (Paw) was measured from an endotracheal tube sideport (Florian respiratory monitor; Acutronic Medical Systems, Zug, Switzerland).
Change in lung volume was measured with a low-pass-filtered, DC-coupled, Respitrace 200 monitor (Non-invasive Monitoring Systems, Inc., North Bay Village, FL), sampling at 200 Hz. After thermal stabilization (24), the outputs were zeroed. An uncalibrated volume signal (VRIP) in volts was derived from the sum of chest and abdominal RIP voltages (range ± 2 V) (18).
FIO2 was adjusted to maintain SpO2 between 90 and 94% for 30 min before each study, and then not changed. The ventilator amplitude and frequency had been set by the treating clinicians before the study and were not altered. An inspiratory-to-expiratory ratio of 1:2 was used in all infants.
Mapping the PV Relationship
The experimental protocol consisted of a lung volume optimization maneuver based on the open lung concept described by Lachmann (7). Starting at the Paw set by the clinical team (Pinitial), the Paw was increased by 2 cm H2O every 10 min (inflation series) until no further increase in SpO2 was achieved, or the SpO2 decreased over more than two Paw settings (Pmax). Lachmann has shown that at this Paw, the lung should be recruited and near TLC (7). Paw was then decreased every 10 min (deflation series), by 2 cm H2O until Pinitial + 2 cm H2O and then by 1 cm H2O, until SpO2 fell below 85% for more than 5 min or Paw reached 5 cm H2O (Pfinal). Lung volume was then reestablished by increasing Paw to Pmax for 10 min, and then returned to Pinitial. The study was stopped if the heart rate or blood pressure was unstable for more than 2 min (25).
Data Collection and Analysis
Paw, VRIP, and SpO2 data were digitized and recorded using LabView (National Instruments, Austin, TX). Paw and VRIP were recorded for the last 5 min of each 10-min period at each new Paw setting to allow time for volume equilibration. The final lung volume at each Paw setting was defined as the mean end-expiratory voltage for the final 5-s epoch, with the corresponding Paw value derived from the same epoch. At each Paw setting, the average SpO2 value for the final minute was calculated. To allow for intersubject variability, Paw and VRIP values were normalized by referencing to the corresponding values at Pmax (100%) and Pfinal (0%), these being the upper and lower limits of the deflation series. From these, a PV curve was drawn, using the model described by Venegas and colleagues (26). Data at different Paw levels were compared using mean differences and 95% confidence intervals (CIs). Combined SpO2 data during the deflation series were plotted against Paw and VRIP, and optimum SpO2 ranges determined. Statistical analysis was performed with SPSS 12.0 (SPSS, Inc., Chicago, IL).
RESULTS
Twelve infants were studied and completed the protocol without complications, in particular hypotension or bradycardia. Their demographic characteristics and clinical details are shown in Table 1.
Relationship between Pressure and Volume
It was possible to map a PV relationship in each infant (Figure 1). VRIP, and thus lung volume, increased during the inflation series in all infants, with a significant difference in the group overall between the VRIP at Pmax and VRIP at Pinitial (mean difference, 0.54 V; 95% CI, 0.32, 0.76 V). It was possible to identify a deflation limb in each infant. Apart from subject 1, all PV relationships showed hysteresis, with a mean difference in VRIP between Pinitial and the same Paw during the deflation series of 0.43 V (CI 0.26, 0.6 V). The degree of hysteresis exhibited was variable. Of note, the greatest lung volume occurred at Pmax in only three infants (subjects 4, 5, and 6). In eight of the other nine infants, a VRIP greater than the VRIP at Pmax could be achieved early in the deflation series. The greatest mean lung volume (109% [SD, 13%] of that at Pmax) occurred at a Paw of approximately 79% [SD, 18%] of Pmax (3.1 [SD, 2.8] cm H2O below Pmax; Figure 2).
Relationship between Airway Pressure and SpO2
Individual Paw versus SpO2 plots are shown in Figure 3. The SpO2 data were variable; generally the highest SpO2 occurred during the deflation series but not at Pmax. In most infants, a bell-shaped relationship between SpO2 and Paw could be demonstrated during the deflation series, and a wide optimal SpO2 range identified. SpO2 was maximized during the deflation series in all but two subjects (4 and 7), and improved from the initial SpO2 in all but one (subject 7). The mean difference between the highest SpO2 and initial SpO2 was 3.6% (CI 1.8, 5.4%), although SpO2 values near that resulting in the highest SpO2 occurred through a wide range of Paw during the deflation series. Recruitment through TLC from Pinitial to the same Paw during the deflation series improved SpO2 by a mean of 2.2% (CI 0.5, 3.9%). In three infants (subjects 2, 3, and 12), SpO2 remained above 85% during the deflation series, despite Paw being decreased to 5 cm H2O or less. This was despite an ongoing loss of lung volume and a distinct change in the slope of the PV deflation series (Figure 1). Combined data from all subjects show that the highest SpO2 occurred during the deflation series at a Paw of 63% (SD, 21%) of Pmax or 5.2 (SD, 3.1) cm H2O below Pmax and a mean volume of 84% (SD, 34%) of the volume at Pmax (Figure 2).
Relationship among Airway Pressure, Volume, and SpO2
The PV relationship using normalized data from all infants is shown in Figure 4A. The deflation series was similar to the upper regions of a PV curve and could be fitted with the model proposed by Venegas and colleagues (R2 = 0.78) (26). During the deflation series, there was little change in SpO2 until Paw fell below 20% of Pmax (Figure 4B), indicating that optimal SpO2 was achieved over a large range of Paw settings, and well below Pmax once ventilation was applied on the deflation limb. During the deflation series, SpO2 generally improved with increasing VRIP (Figure 4C), and this relationship was similar to the PV relationship described in Figure 4A. Similarly, during the deflation series, SpO2 changed little until lung volume fell below 50% of that at TLC (Figure 4C). These findings highlight the imprecision of SpO2 as a proxy indicator of optimal lung volume.
DISCUSSION
These data show that, using an open lung approach and DC-coupled RIP, the deflation limb of the PV relationship can be mapped at the bedside during HFOV in human infants, after recruitment to TLC. In addition, applying ventilation on the deflation limb resulted in better lung volume and improved oxygenation, often at a lower Paw.
There is compelling experimental evidence that ventilation, by whatever mode, should be applied on or near the deflation limb of the PV relationship. This requires brief recruitment of the lung to near TLC (3). Such an approach results in greater alveolar stability without overdistension (11, 12), better lung compliance (4, 5, 27–29), and significantly better oxygenation than ventilation applied elsewhere within the PV relationship (3–5, 8, 30). Furthermore, both with conventional ventilation (4, 5, 8, 30, 31) and HFOV (3, 8, 9, 32), ventilation on the deflation limb is associated with less lung injury, emphasizing the potential importance of optimizing lung volume in protecting the neonatal lung from VILI (2, 6).
In animal models of lung injury (3, 4, 15, 20, 21) and in adult humans (33–36), the deflation limb has been mapped using an open lung approach, after first recruiting the lung to TLC (7, 10). To our knowledge, this study is the first to do so in human infants. We found that there was a distinct deflation limb in each infant studied, and that oxygenation was better in 10 of 12 infants when placed on the deflation limb, not at TLC but at a volume 84% of TLC, and a Paw 5.2 cm H2O below that at TLC. This relationship among Paw, VRIP, and SpO2 (Figures 2 and 4) during HFOV is similar to the relationship described in animal studies, in which oxygenation was optimal at a Paw correlating to the point of maximum curvature on the deflation limb of the PV relationship (32), although, as would be expected in a heterogeneous human population, greater variability existed. Our data clearly show that there is no oxygenation benefit in sustaining high airway pressures once ventilation is being applied on the deflation limb. The uniformity of SpO2 readings over a range of airway pressures and lung volumes on the deflation limb highlights the limitation of SpO2 in targeting the optimal point of ventilation.
Although a point of optimal oxygenation could often be identified on the deflation limb, the difference in SpO2 values was usually minimal through much of the deflation limb. Further research is required to determine whether other indicators of lung mechanics have greater precision in identifying the point of optimum ventilation. It remains to be completely elucidated whether, within the region of the deflation limb, there also exists a point of best carbon dioxide clearance, most stable alveoli and the least lung injury.
Our data also show that none of the infants were being ventilated on the deflation limb before commencing PV mapping, although clinicians were attempting to apply HFOV using the principles of a high lung volume strategy (1). Despite this, our study suggested that, in infants receiving HFOV, it was clinically practical to apply ventilation on the deflation limb, as has been observed in adults (34, 36). There were no deleterious effects associated with this maneuver, although a larger series will be required to assess its safety with more confidence. Rimensberger and colleagues found that a stepwise recruitment strategy of up to 25 cm H2O in 32 preterm infants receiving first-intention HFOV was well tolerated (37). Similarly, the stability of lung volume on the deflation limb needs further exploration. It may be that repeated recruitment through TLC may be periodically required to maintain lung volume at the desired point.
The mathematical equation for modeling the PV curve described by Venegas and colleagues assumes that the greatest lung volume will occur at TLC (26). The finding that, in nine infants, the maximum VRIP was not achieved at Pmax is curious. Brazelton and colleagues reported a similar finding in pigs during HFOV; the maximum uncalibrated RIP volume occurred on the deflation limb at a Paw approximately 10 cm H2O below the maximum Paw (40 cm H2O) (21). We suggest two possible explanations for this. First, alveolar recruitment is not uniform, even at high airway pressures; alveolar opening pressures vary and overdistension of some alveoli may compress adjacent, atelectatic alveoli at Pmax (11, 12, 38). Only at Paw below Pmax may these compressed alveoli be able to open after alveoli recruitment. Second, changes in intrathoracic blood volume and impaired cardiac output may have occurred at Pmax (39). RIP is unable to discriminate between gas and liquid.
RIP
Currently, no reliable bedside tool exists to indicate lung volume during HFOV. Chest radiograph is not a reliable indicator of lung volume during HFOV (40) and does not indicate where within the PV relationship ventilation is being applied. Direct measures of lung volume, such as inert gas sulfur hexafluoride washout (41, 42), whole body plethysmography (43), and computed tomography (44), are useful research tools, but in each case are impractical for repeated measurement of lung volume at the bedside during HFOV.
This study shows that RIP is a practical technique for determining relative change in lung volume during HFOV. RIP has the advantage of being noninvasive, unaffected by endotracheal tube leak, and simple to use, without the need to interrupt mechanical ventilation. Uncalibrated DC-coupled RIP has been validated in animal studies as a measure of change in thoracic gas volume, allowing the complete PV relationship of the lung to be described and optimum lung volume and pressure determined during HFOV (20, 21, 45).
Limitations of the Study
This study has some limitations. First, unlike adult patients (34), constructing a complete PV relationship is not possible in human infants. For reasons of safety, we did not allow the lung to passively deflate before commencing PV mapping, nor was the lung allowed to fully deflate beyond closing pressure. Thus, the inspiratory limb of the PV relationship is incompletely mapped, with the final section of the deflation limb beyond closing pressure absent. Even so, the data we have obtained closely resemble the PV relationships described by Brazelton and colleagues using RIP in pigs during HFOV (21). We contend that even incomplete mapping of the PV relationship in human infants is of practical value, as it allows the deflation limb to be accurately defined within the confines of clinically acceptable SpO2 ranges.
All infants enrolled in this study were given muscle relaxants. The lung mechanics of this population may be different from those of self-ventilating infants receiving HFOV. The focus on this population was intentional to minimize the effect of artifact and to reproduce the optimal ventilation strategy identified in animal studies (3–5, 7, 8, 28).
Although SpO2 monitoring is the most commonly used bedside indicator of oxygenation, it has limitations as a surrogate of arterial partial pressure of oxygen. Pulse oximetry is known to have an error of ± 4 to 6% of the arterial oxygen saturation (46); SpO2 values are influenced by tissue perfusion and are unable to identify any further improvement in oxygenation once an SpO2 of 100% is obtained. This limitation is noticeable in the Paw versus SpO2 curves of subjects 3 and 12 and the greater variability in the Paw versus SpO2 relationships compared with the PV relationships.
A final limitation of this study refers to the limitations of RIP technology. Although not essential, calibration of the raw RIP voltage signal to a known volume change would be advantageous. This is difficult during HFOV, and currently, no practical method is validated. RIP bands are sensitive to temperature change and movement (20), both of which may lead to baseline drift during the recording. Drift is greatest if a 30-min thermal stabilization is not allowed (17, 21). After allowing for thermal stabilization, in bench testing, we found a positive drift of less than 0.07 V/h in our RIP device (data not shown), consistent with a previous report (47). The software used for RIP has been developed largely for application in sleep medicine. There is no integrated RIP software currently available to track neonatal lung volume, hampering the progression of RIP from a research to a clinical tool. Electrical impedance tomography, which allows measurement of regional volume differences and global volume changes, offers potential as a future alternative to RIP (48).
Conclusions
This study has shown that it is possible to delineate the deflation limb of the PV relationship in ventilated infants requiring HFOV. By doing so, better lung volume and oxygenation may be achievable, implying the deflation limb should be the target region after any recruitment maneuver. RIP offers promise as a bedside method of allowing clinicians to quantify the response to a recruitment maneuver. Further investigation of the relationships among airway pressure, lung volume, and gas exchange is warranted to refine the optimal point of ventilation on the deflation limb during HFOV.
Acknowledgments
The authors thank Peter McDougall for his suggestions about the manuscript.
FOOTNOTES
Supported by a National Health and Medical Research Council Medical Postgraduate Research Scholarship (D.G.T.) and a Murdoch Children's Research Institute Trainee Research Scholarship (A.P.).
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200502-299OC on December 1, 2005
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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