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Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 69-78

Best Compliance during a Decremental, But Not Incremental, Positive End-Expiratory Pressure Trial Is Related to Open-Lung Positive End-Expiratory Pressure
A Mathematical Model of Acute Respiratory Distress Syndrome Lungs

KEITH G. HICKLING

Department of Anaesthesia and Intensive Care, Healthcare Otago, University of Otago, Dunedin, New Zealand




    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

A mathematical model of the acute respiratory distress syndrome (ARDS) lung, incorporating simulated gravitational superimposed pressure and alveolar opening and closing pressures, was used to study the mean tidal pressure-volume (PV) slope ("effective compliance") during incremental and decremental positive end-expiratory pressure (PEEP) trials with constant tidal volume (VT) "ventilation." During incremental PEEP, the PEEP giving maximum mean tidal PV slope did not coincide with "open lung PEEP" (minimum PEEP preventing end expiratory collapse of 97.5% of alveoli inflated at end-inspiration), and it varied greatly with varying VT and "lung mechanics." Incremental PEEP with a low VT tests recruitment by the peak pressure, not prevention of collapse by PEEP. During decremental PEEP with a low VT, maximum mean tidal PV slope occurred with PEEP 2-3.5 cm H2O below open-lung PEEP, unless closing pressure was high. High VT, high "specific compliance," and high opening pressures caused slightly greater underestimation of open-lung PEEP. Maximum mean tidal PV slope was always higher (e.g., 93.7 versus 16.69 ml/cm H2O), and the variation in PV slope with PEEP was greater, during decremental PEEP. The maximum PV slope during a decremental PEEP trial with a low VT may be a useful method to determine open-lung PEEP in ARDS, and should be studied clinically.



    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Mechanical ventilation (MV) with injurious ventilatory strategies can cause acute parenchymal lung injury and a pulmonary and systemic inflammatory response (1), with increased concentrations of cytokines in lung lavage fluid (2), and in blood (3), recruitment of granulocytes into the lung (4), activation of recruited granulocytes (5) and circulating granulocytes (6), and increased pulmonary and systemic vascular permeability (4). A recent study showed that injurious ventilation can elevate plasma and lung lavage cytokine concentrations in patients with acute respiratory distress syndrome (ARDS), whereas they were reduced with "lung protective" ventilation (3).

In animal models, such ventilator-induced lung injury is greatly reduced by setting the positive end-expiratory pressure (PEEP) level slightly higher than the lower inflection point or zone (Pflex) of the thoracopulmonary pressure-volume (PV) curve, and using an appropriate tidal volume (VT) to avoid end-inspiratory overdistension (7). It is thought that PEEP protects against ventilator-induced lung injury by preventing high shear forces associated with repeated end-expiratory collapse and tidal reinflation (7). This strategy has also been suggested in patients with ARDS, and a recent randomized trial showed a reduced mortality rate and reduced barotrauma using this "open lung" approach (8). However, the best method of determining the amount of PEEP required to prevent end-expiratory collapse ("open-lung PEEP") is not clear. It is difficult to measure absolute lung volume at the bedside in ventilated patients, so the prevention of end-expiratory collapse with PEEP (resulting in a higher volume at equivalent pressure during inflation) cannot easily be determined. Therefore, in patients with ARDS, the PEEP level is often selected by evaluating the change in the mean tidal PV slope or "effective compliance" (VT/[plateau pressure - PEEP]), as PEEP is increased. Alternatively, PEEP is sometimes set at or above the pressure of the lower Pflex of the static respiratory PV curve. It has been suggested that the lower Pflex indicates the pressure and volume range over which reinflation (recruitment) of previously collapsed lung units occurs, and that no further recruitment could occur on the "linear" portion above the lower Pflex, because any further recruitment should result in a continued increase in slope (upward concavity). It has also been assumed that the upper Pflex indicates the beginning of lung overdistension. It has therefore been recommended that tidal ventilation should occur over a pressure range between the lower and upper Pflex (9). However, a simple mathematical model of the ARDS lung (10) suggested that the lower Pflex may not be closely related to open-lung PEEP, that recruitment of previously collapsed lung units could continue on the linear portion of the PV curve well above the lower Pflex, and that an upper inflection point at a relatively low pressure could occur as recruitment stopped or diminished, without alveolar overdistension. The slope of the inflation PV curve and the tidal PV plot were greatly affected by continuing recruitment and did not indicate well the amount of aerated lung. These findings have recently been supported by a clinical study (11), and suggest that neither the mean tidal PV slope during an incremental PEEP trial nor the lower Pflex of the PV curve is likely to indicate open-lung PEEP.

This study was undertaken using a modification of the previously described mathematical model (10) to address the following questions:

  1. 1. During an incremental PEEP trial (progressively increasing PEEP from zero with a constant VT), or a decremental PEEP trial (starting with a high PEEP level and progressively reducing it with constant VT), does the maximum mean tidal PV slope (VT/[plateau pressure - PEEP]) occur at open-lung PEEP?
  2. 2. What is the effect of varying VT on these relationships?
  3. 3. What is the effect of altering various parameters in the model on these relationships, that is, does the relationship between open-lung PEEP and the maximum mean tidal PV slope during incremental and decremental PEEP trials depend on the "lung mechanics" in the model?


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Definitions and Abbreviations Used for the Model

Airway pressure (Paw): simulated pressure in the airway and alveoli during static no-flow conditions. Superimposed pressure (SP): a simulation of the gravitationally determined superimposed pressure in each lung compartment; in the model this is subtracted from the airway pressure to obtain the transalveolar pressure. Transalveolar pressure (Pta): airway pressure minus superimposed pressure. Peak inspiratory pressure (PIP): the maximum static pressure reached during simulated tidal ventilation of the lung (equivalent to the end-inspiratory plateau pressure in patients). Maximum peak inspiratory pressure (PIPmax): the maximum PIP achieved at the highest PEEP level at the beginning of the decremental PEEP trial. This was 50 cm H2O in the simulations shown. PEEP: the minimum pressure reached during tidal ventilation of the lung. Threshold opening pressure (TOP): a transalveolar pressure that must be exceeded before a lung unit can increase its volume above zero, once it has collapsed. Threshold closing pressure (TCP): a transalveolar pressure at which an alveolus suddenly collapses during deflation and decreases its volume to zero. Open-lung PEEP: the minimum end-expiratory pressure required to prevent end-expiratory collapse of 97.5% of alveoli in the lowermost compartment that were aerated at end inspiration (i.e., alveoli in the lowermost compartment with a TCP =< mean + 2 SD). If the highest pressure in the range of TCP entered was less than 2 standard deviations above the mean TCP, then open lung PEEP was defined as the superimposed pressure plus the highest closing pressure. Mean tidal PV slope: VT/(PIP - PEEP). Recruitment: aeration of alveoli that were previously collapsed. End-expiratory recruitment: an increase in the number of aerated alveoli at end expiration following an increase in PEEP or PIP. End-inspiratory recruitment: an increase in the number of aerated alveoli at end inspiration following an increase in PIP. Tidal recruitment: repeated aeration of lung units during inflation, which collapse again during deflation. Total alveolar compliance: the volume increment produced by a 1 cm H2O pressure increment in alveoli that were aerated prior to the pressure increment. This definition excludes any volume increment contributed by alveoli that were collapsed initially but were recruited when their TOP was exceeded after the pressure increment. In the model, when such alveoli are recruited, their volume immediately increases from zero to the appropriate volume at the new transalveolar pressure, so that their volume increase is much greater than that of alveoli that were inflated before the pressure increment.

The Model

The lung was modeled as multiple lung units or "alveoli" each with a compliance that progressively decreased at increasing volume, simulating that in normal lungs. The model had 30 compartments representing horizontal "slices" of lung, with increasing gravitational superimposed pressure (SP) in each compartment from 0 in the uppermost (nondependent) to 14.5 cm H2O in the lowermost (dependent), according to the Gattinoni model (12). The SP was modeled as a constant pressure for each compartment, which was subtracted from the variable airway pressure (Paw) to derive the "transalveolar" pressure (Pta). TOPs could be entered to simulate alveolar or small airway opening after collapse. The TOP were modeled such that if an alveolus collapsed at end expiration, its volume remained zero during inspiration until the transalveolar pressure exceeded the TOP. The alveolar volume then immediately increased to the appropriate value for that transalveolar pressure, following which the volume continued to increase with increasing pressure according to the alveolar compliance, and was no longer affected by the TOP during the remainder of the inflation. Threshold closing pressures (TCP) could also be entered such that the alveolar volume during expiration suddenly fell to zero when the transalveolar pressure (Paw - SP) decreased to the level of the TCP but was not affected by the TCP at higher pressures. The TCP could not exceed the TOP for any alveolus. The TOP and TCP were normally distributed and were entered as a range of values and standard deviation (SD). The program used the mid-point of the range and the SD to calculate the normal distribution, and then deleted values that were outside the specified range. This eliminated any values < 0.

The model assumed that all alveoli were collapsed prior to the initiation of the assigned PEEP and PIP but that the lung had already been cycled between these pressures prior to the "breath" studied. Thus any alveoli that were aerated at end inspiration (PIP - SP > TOP) remained aerated at end expiration if PEEP - SP > TCP. When the TOP for any alveolus exceeded the maximum (end-inspiratory) transalveolar pressure achieved with the airway pressure range studied, the alveolus remained collapsed throughout the respiratory cycle. Therefore, during incremental PEEP, an alveolus was aerated during tidal inflation if (a) Paw - SP > TOP or (b) PIP - SP > TOP and PEEP - SP > TCP. In condition (a), the current transalveolar pressure (Pta) exceeds TOP, so the alveolus is inflated. In condition (b), the end-inspiratory Pta exceeded TOP, so the alveolus was inflated at end inspiration, and the end expiratory Pta > TCP, so it remained inflated at end expiration and therefore throughout the respiratory cycle. During tidal deflation, the alveolus was aerated if (a) Paw - SP > TOP or (b) PIP - SP > TOP and Paw - SP > TCP. Condition (a) is the same as for inflation, and in condition (b), the end-inspiratory Pta exceeded the TOP, so the alveolus was inflated at end inspiration, and the current Pta during deflation has not yet fallen to the TCP, so the alveolus remains inflated.

The use of decremental PEEP was simulated as follows. During tidal inflation, an alveolus was aerated if (a) Paw - SP > TOP or (b) PIP - SP > TOP and PEEP - SP > TCP or (c) PIPmax - SP > TOP and PEEP - SP > TCP, where PIPmax is the maximum end-inspiratory pressure reached at the beginning of the decremental PEEP trial; in these simulations this was 50 cm H2O. In fact, if condition (b) is satisfied, condition (c) will also always be satisfied.

During tidal deflation with decremental PEEP, an alveolus was aerated if (a) Paw - SP > TOP or (b) PIP - SP > TOP and Paw - SP > TCP or (c) PIPmax - SP > TOP and PEEP - SP > TCP. In each case, conditions (a) and (b) are the same as for incremental PEEP, but condition (c) allows the alveolus to remain inflated if it had been inflated at end inspiration at the beginning of the decremental PEEP trial (PIPmax - SP > TOP), and the end-expiratory Pta (PEEP - SP) has not yet fallen below the TCP during the decremental PEEP trial. These alveoli remain inflated throughout the respiratory cycle at the current PEEP level.

The volume in inflated alveoli was calculated using the exponential equation of Salazar and Knowles (13): V = Vo (1 - e P In 2/h) where V is the lung volume, Vo is the maximum volume at infinite pressure, P is the transalveolar pressure, and h is the half inflation pressure. This volume was divided by the number of alveoli to derive alveolar volume. This calculation was performed for each group of alveoli according to their transalveolar pressure (airway pressure - sp), and the total lung volume for the model determined at each airway pressure by adding the alveolar volumes. Collapsed alveoli had a volume of zero.

Input variables for the model were PIP, PEEP, TOP, and TCP (range [SD]), and PIPmax for decremental PEEP. The program generated a series of increasing values of pressure and calculated the volume for all aerated alveoli at each pressure level between the PEEP and PIP, for inflation and then deflation. To obtain a constant VT at different PEEP levels, it was necessary to perform multiple calculations at increasing PIP levels, and select the PIP giving the VT closest to that desired. The mean tidal PV slope was determined for the VT immediately above and that below the desired VT, and the mean tidal PV slope for the desired VT was then determined by assuming a linear relationship over this very small range of VT.

Simulations

All plots are equivalent to static PV plots obtained in patients (i.e., during no flow conditions), as the model did not incorporate airways resistance. For most simulations (except where stated otherwise), the half inflation pressure (h) was assigned a value of 4.9 cm H2O, but values of 3.5 and 8 cm H2O were also studied. Vo (the maximum lung volume at very high pressure) was assigned a value of 2.5 L, simulating a lung with some alveoli that could not be recruited even at high transalveolar pressures. The TOP used in most simulations had a range of 0-40 cm H2O [SD 4], but other ranges were also examined. The effect of varying TOP ranges on the PV curve was described with the original model (10). The TCP in most simulations had a range of 0-4 cm H2O [SD 1] but ranges of 0-10 [2], and 0-15 [2], and 5-9 [1] cm H2O were also evaluated. With the TCP range of 0-4 [1] cm H2O used for most of the simulations, the normal distribution assigned 97.5% of alveoli to a TCP =< 4 cm H2O (mean + 2 SD). Open-lung PEEP was therefore 18.5 cm H2O (maximum SP of 14.5 cm H2O + maximum TCP of 4 cm H2O), but because the program generated only integer values of pressure, a pressure of 19 cm H2O was required to prevent collapse of these alveoli. With TCP ranges of 0-10 and 0-15 cm H2O and SD 2, open-lung PEEP was 23.5 and 26 cm H2O, respectively (SP of 14.5 cm H2O + maximum TCP of 9 and 11.5 cm H2O, respectively). Tidal PV plots were derived using a VT from 140 to 750 ml, during inflation and deflation, at varying levels of incremental and decremental PEEP. The static PV curve over a pressure range of 0 to 50 cm H2O was obtained using the inflation and deflation PV plots generated by the model with PEEP of 0 and PIP of 50 cm H2O. PIPmax during the decremental PEEP trials was 50 cm H2O, the same as the highest pressure generated for the PV curve.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Figure 1a shows the PV curve for a single alveolus with TOP and TCP of zero. The half inflation pressure h is 2.5 (black circles), 4.9 (open circles), and 8 cm H2O (black triangles). The value of h is set at 4.9 for subsequent simulations, except where other values are specified. Figure 1b shows the PV curve for the whole lung. The plot with black circles is with no superimposed pressure (i.e., a single compartment model) with TOP and TCP of zero. Its shape is identical to that of the single alveolus with h = 4.9 (Figure 1a, open circles), but the volume is proportionally greater at each pressure. The other two graphs in Figure 1b show the effect of adding the SP of 0- 14.5 cm H2O (as used in all subsequent simulations) with TOP and TCP of zero (open circles), and SP and opening pressures (black triangles, TOP = 0-40 [6], TCP = 0). The curve with SP 0-14.5 and TOP 0 (open circles) is equivalent to the deflation PV curve with TCP of 0. The curve with SP 0-14.5 and TOP 0- 40 [SD 6] cm H2O (black triangles) is equivalent to the inflation PV curve in subsequent simulations. The difference between these curves (hysteresis) results from alveoli remaining collapsed during inflation until the transalveolar pressure exceeds their TOP, whereas during deflation they remain aerated until the transalveolar pressure falls below their TCP, which is lower (in this case zero).



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  		Figure 1.   (a) Plots of volume versus pressure for a single alveolus with threshold opening pressure (TOP) and threshold closing pressure (TCP) of zero. Values for h (half inflation pressure) are 2.5 (black circles), 4.9 (open circles), and 8.0 (black triangles). These graphs show the shape of the exponential function of Salazar without modification by superimposed pressure and opening or closing pressures, and illustrate the effect of the half-inflation pressure. (b) Plots of volume versus pressure for the whole lung with SP = 0 (i.e., a single compartment) and TOP = 0 (black circles); SP = 0-14.5 cm H2O, TOP = 0 (open circles); and SP = 0-14.5, TOP = 0-40 [SD 6] (black triangles). TCP = 0 and h = 4.9 for all plots. The graphs show the effect of adding superimposed pressure in the multicompartment model (black triangles, equivalent to the deflation PV curve in the model) and opening pressures (open circles, equivalent to inflation PV curve in the model).

Figure 2a shows the inflation (black symbols) and deflation (open symbols) tidal PV plots with VT of 400 ml, with incremental PEEP levels from 0 to 20 cm H2O. As expected, the volumes at equivalent pressure progressively increase with increasing PEEP levels, as a result of greater end-inspiratory recruitment by the higher PIP, and end-expiratory recruitment by PEEP. Figure 2b shows these tidal PV plots superimposed on the PV curve. The end-inspiratory points of the tidal PV plots are aligned with the inflation PV curve; this is expected, because with incremental PEEP, the number of inflated alveoli at end inspiration is the same as at the same pressure on the inflation PV curve. However, during tidal deflation, more alveoli are inflated than at the equivalent pressure during inflation, because their closing pressures are lower than their opening pressures. Thus, the end-expiratory volume during tidal ventilation is higher than the volume at the same pressure on the inflation PV curve, and the mean tidal PV slope is lower than the slope of the inflation PV curve over the same pressure range.



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  		Figure 2.   (a) Inspiratory (black symbols) and expiratory (open symbols) tidal PV plots with incremental PEEP and VT of 400 ml. TOP = 0-40 [6], TCP = 0-4 [1] cm H2O, h = 4.9. (b) Tidal PV plots with incremental PEEP as in (a) superimposed on inflation and deflation PV curves. VT = 400 ml. TOP = 0-40 [6], TCP = 0-4 [1] cm H2O, h = 4.9.

Figure 3a shows the inflation tidal PV plots with incremental (black symbols) and decremental (open symbols) PEEP, with VT of 140 ml. With decremental PEEP, the end-expiratory points are aligned with the deflation PV curve. This is also expected, because in these simulations, the highest PIP reached at the beginning of the decremental PEEP trial (PIPmax) was the same as the maximum pressure at the beginning of the deflation PV curve (50 cm H2O), so that the maximum number of aerated alveoli was the same in each instance. During the decremental PEEP trial, the number of aerated alveoli at end expiration at each PEEP level was therefore equal to the number of aerated alveoli at the same pressure on the deflation PV curve. All possible variations of lung volume history during a PEEP trial would result in a tidal PV plot somewhere within the envelope of the inflation and deflation PV curve, providing that the PV curve measurement had reached a maximum pressure at least as high as PIPmax. At each PEEP level, the volumes and mean tidal PV slope were substantially higher with decremental PEEP, because more alveoli had been recruited by PIPmax at the beginning of the decremental PEEP trial than during incremental PEEP. Figure 3b shows the mean tidal PV slope (the mean slope of the tidal PV plots in Figure 3a) plotted against incremental and decremental PEEP, also with VT of 140 ml. With incremental PEEP, there was little change in mean tidal PV slope as PEEP increased, the maximum occurring at a PEEP of 20 cm H2O. In contrast, with decremental PEEP, there was a much greater change in mean tidal PV slope, and the maximum slope occurred at a PEEP of 16 cm H2O, a little below open-lung PEEP (18.5 cm H2O). Below a PEEP of 16 cm H2O, the mean tidal PV slope fell again as alveolar collapse occurred and the number of aerated alveoli decreased.



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  		Figure 3.   (a) Inspiratory tidal PV plots with VT 140 ml with incremental (black symbols) and decremental (open symbols) PEEP levels from 0 to 25 cm H2O. TOP = 0-40 [4], TCP = 0-4 [1], h = 4.9. At each PEEP level the volume at equivalent pressures and the mean tidal PV slope are greater during decremental PEEP. With zero PEEP, the plots for incremental and decremental PEEP are superimposed. (b) The mean tidal PV slope (slope of the tidal PV plots in a) plotted against PEEP for incremental (black symbols) and decremental (open symbols) PEEP. VT = 140 ml, TOP = 0-40 [4], TCP = 0-4 [1], h = 4.9. Maximum PV slope with incremental PEEP is at 20 cm H2O PEEP, and with decremental PEEP 16 cm H2O. Open-lung PEEP is 18.5 cm H2O.

Effect of Tidal Volume

Figure 4 shows mean tidal PV slope plotted against incremental and decremental PEEP, with a VT of 500 ml. During incremental PEEP, maximum mean tidal PV slope occurred at a PEEP of 11 cm H2O (compared with 20 cm H2O with VT 140 ml), whereas during decremental PEEP it occurred at the same PEEP level (16 cm H2O, a little below open-lung PEEP) as with VT of 140 ml. The maximum mean tidal PV slope was again higher during decremental PEEP. Simulations using other values of VT confirmed that with decremental PEEP, there was a consistent relationship between open-lung PEEP and the PEEP level giving maximum mean tidal PV slope. In contrast, with incremental PEEP, the PEEP level resulting in maximum mean tidal PV slope varied greatly with VT, from 11 to 20 cm H2O. An increase in VT at the same PEEP level results in upward displacement of the tidal PV plot on the volume axis (data not shown). The higher PIP causes more end-inspiratory recruitment, and some of these newly recruited alveoli (all of them if PEEP > open-lung PEEP) remain inflated at end expiration, so end-expiratory recruitment also occurs. This is similar to the effect of a recruitment maneuver.



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  		Figure 4.   The mean tidal pressure-volume (PV) slope plotted against incremental (black symbols) and decremental (open symbols) positive end-expiratory pressure (PEEP) with VT = 500 ml. Maximum PV slope with incremental PEEP is at 11 cm H2O PEEP, and with decremental PEEP 16 cm H2O. Open-lung PEEP is 18.5 cm H2O.

Effect of Varying Half Inflation Pressure

Figures 5a and 5b show plots of mean tidal PV slope against incremental and decremental PEEP with VT of 140 ml, with values of h of 2.5 (Figure 5a) and 8 cm H2O (Figure 5b) (h was 4.9 cm H2O in the previous simulations). The PEEP level giving maximum mean tidal PV slope during incremental PEEP increased from 14 cm H2O with h = 2.5 to 25 cm H2O with h = 8. With decremental PEEP it increased from 15 cm H2O with h = 2.5 to 17 cm H2O with h = 8. Increasing values of h in this model represent a reduction in specific compliance of aerated lung units at low volume, with the result that the PV curve for each alveolus is shifted downward and to the right. The volume in inflated alveoli therefore increases more rapidly as pressure increases from 15 to 30 cm H2O, as shown in Figure 1a. During incremental PEEP with a low VT, end-inspiratory recruitment can continue up to high levels of PEEP (well above open-lung PEEP) because the PIP is only slightly higher than the PEEP level. The increasing total alveolar compliance resulting from a greater number of inflated alveoli as the PIP increases is opposed by the reducing compliance of each alveolus at higher pressures; the latter effect becomes less as h is increased, so that maximum mean tidal PV slope occurs at a higher PEEP level. Figure 6 shows the relationship between VT (Figure 6a) and h (Figure 6b) and the PEEP level resulting in maximum mean tidal PV slope. Open-lung PEEP (18.5 cm H2O) is indicated as black triangles.



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  		Figure 5.   (a) Plot of mean tidal PV slope against incremental (black symbols) and decremental (open symbols) PEEP with h = 2.5. TOP = 0- 40 [4], TCP = 0-4 [1], VT = 140 ml. Open-lung PEEP is 18.5 cm H2O. (b) Plot of mean tidal PV slope against incremental (black symbols) and decremental (open symbols) PEEP with h = 8. TOP = 0-40 [4], TCP = 0-4 [1], VT = 140 ml. Open-lung PEEP is 18.5 cm H2O. The higher value of h has a large effect on the PEEP level giving maximum mean tidal PV slope during incremental PEEP, but much less during decremental PEEP.



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  		Figure 6.   (a) Plot of VT against the incremental (black circles) and decremental (open circles) PEEP level resulting in maximum mean tidal PV slope. Open-lung PEEP (18.5 cm H2O) is indicated as black triangles. (b) Plot of h against the incremental (black circles) and decremental (open circles) PEEP level resulting in maximum mean tidal PV slope. Open-lung PEEP (18.5 cm H2O) is indicated as black triangles.

Effect of TOP and TCP Ranges

Figure 7a shows the effect of different TOP ranges on the PEEP level giving maximum mean tidal PV slope. With very high TOP ranges, many alveoli remain collapsed throughout the respiratory cycle even at high PEEP levels. The amount of aerated lung is therefore less relative to the VT, and inflated alveoli are more overdistended at end inspiration, and on a less compliant part of their alveolar PV curve than with a lower TOP range. This causes the maximum mean tidal PV slope to occur at a lower PEEP level than with a lower TOP range. However, the PEEP level giving maximum mean tidal PV slope is affected by TOP range much more during incremental than decremental PEEP. Figure 7b shows the effect of different TCP ranges on the PEEP level giving maximum mean tidal PV slope. As the mean TCP increases, alveolar collapse occurs at higher pressures during deflation, and so open-lung PEEP increases. A higher PEEP level is therefore required to maintain aeration of most alveoli, and this places the inflated alveoli at a less compliant position on their PV curve. Maximum mean tidal PV slope therefore occurs at a pressure further below open-lung PEEP than with a lower mean TCP. Again, the effect is greater during incremental PEEP.



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  		Figure 7.   (a) Plot of TOP range [SD] against the incremental (black circles) and decremental (open circles) PEEP level resulting in maximum mean tidal PV slope. Open-lung PEEP (18.5 cm H2O) is indicated as black triangles. (b) Plot of TCP range [SD] against the incremental (black circles) and decremental (open circles) PEEP level resulting in maximum mean tidal PV slope. Open-lung PEEP is indicated as black triangles, and increases from 18.5 cm H2O with TOP range of 0-4 [1] to 26 cm H2O (maximum SP of 14.5 cm H2O + mean TCP + 2 SD) with TOP range of 0-15 [2].


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The main finding from this study was that during an incremental PEEP trial, there was no consistent relationship between the PEEP level giving maximum mean tidal PV slope and open-lung PEEP; the mean tidal PV slope could therefore not be used to predict open-lung PEEP. The PEEP level giving maximum PV slope varied from 11 to 20 cm H2O as VT was changed, and from 14 to 25 cm H2O as h was changed. It was also greatly affected by the TOP and TCP range. In contrast, during a decremental PEEP trial, the relationship between PEEP and mean tidal PV slope was consistent. The PEEP level giving maximum mean tidal PV slope was always lower than open-lung PEEP in the model, and the magnitude of the difference was increased by a high VT, a high range of TOP, a low half-inflation pressure, and a high mean TCP. However, these factors had much less effect than with incremental PEEP. With a low VT and the TCP range (0-4 cm H2O SD 1) and h (4.9 cm H2O) used for most simulations, maximum mean tidal PV slope was only slightly below open-lung PEEP.

Factors Affecting the Mean Tidal PV Slope

On the inflation PV curve, when inflation commences from a Paw of zero, all alveoli are collapsed. However, as soon as the transalveolar pressure in the uppermost compartment exceeds the lowest TOP, the alveoli with that TOP "snap" open, and immediately increase their volume to the value appropriate for that transalveolar pressure. As Paw increases further, these aerated alveoli increase their volume according to their compliance, and additional alveoli are also recruited. Between the lower and upper Pflex on the inflation PV curve (Figure 3a), most of the volume increase with each pressure increment results from the incremental volume increase as newly recruited alveoli "snap open," that is, to recruitment (10). As the rate of recruitment diminishes at higher pressures, the PV slope decreases, and this can produce an upper inflection point (10). This can be seen at pressures above 35 cm H2O on the inflation PV curve in Figure 3a. The total compliance of all alveoli that were aerated at a pressure of 50 cm H2O (total alveolar compliance) is indicated by the slope of the deflation PV curve above a pressure of 18.5 cm H2O in Figure 3a; below this pressure the PV slope increases again due to incremental volume decreases as each group of alveoli collapses. Thus the slope of most of the inflation PV curve, and of the deflation PV curve below open-lung PEEP, is greater than the total alveolar compliance at each pressure, because of recruitment or derecruitment.

During tidal inflation, recruitment can also occur (tidal recruitment), but as PEEP is increased during an incremental PEEP trial, more alveoli remain inflated at end expiration (end-expiratory recruitment). However, with a constant VT, end-inspiratory pressure also increases as PEEP is increased, resulting in inflation of more alveoli at end inspiration (end-inspiratory recruitment). End-expiratory recruitment increases the end expiratory volume (tending to decrease mean tidal PV slope) and end-inspiratory recruitment increases the end-inspiratory volume (tending to increase mean tidal PV slope). The difference between the amount of end-inspiratory and end- expiratory recruitment is tidal recruitment; tidal recruitment increases the mean tidal PV slope.

The following three variables in the model affect the mean tidal PV slope with alterations of PEEP (either incremental or decremental):

  1. 1. An increase in the number of alveoli that are inflated throughout the respiratory cycle increases the total compliance of all aerated alveoli (total alveolar compliance). This tends to increase mean tidal PV slope with increasing PEEP.
  2. 2. The decreasing compliance of each alveolus at high transalveolar pressures tends to decrease mean tidal PV slope with increasing PEEP.
  3. 3. Increasing tidal recruitment increases mean tidal PV slope; a reduction in tidal recruitment tends to decrease mean tidal PV slope as PEEP approaches open-lung PEEP during an incremental PEEP trial. This is partly why the mean tidal PV slope may increase only slightly (Figure 3b) or even decrease (Figure 4) as incremental PEEP is increased from around 10 cm H2O up to open-lung PEEP. The final effect on mean tidal PV slope is a result of the interaction of these three factors.

PV Slope during Incremental PEEP

During ventilation with zero PEEP, all inflated alveoli at end inspiration collapse again at end expiration, so the mean tidal PV slope is increased by extensive tidal recruitment. A high VT increases the slope, because the end-inspiratory point moves higher up the inflation PV curve, while the end-expiratory point is unchanged. As PEEP is increased the mean tidal PV slope initially increases as the end-inspiratory point moves further up the inflation PV curve; the end-expiratory volume does not increase greatly, because there is still substantial end-expiratory collapse. The number of alveoli that are inflated throughout the respiratory cycle also increases, increasing mean tidal PV slope. As PEEP is increased further, however, end-expiratory collapse (and therefore tidal recruitment) is progressively reduced, and finally eliminated at open-lung PEEP. This reduction of tidal recruitment tends to reduce mean tidal PV slope, but this is opposed by increased end-inspiratory recruitment and total alveolar compliance as PIP increases. As PEEP is increased above open-lung PEEP, there is no further reduction in tidal recruitment to decrease mean tidal PV slope, but more end-inspiratory recruitment occurs as the PIP increases, resulting in greater total alveolar compliance and tending to increase mean tidal PV slope. As PEEP and PIP increase, the compliance of each alveolus decreases, and eventually this effect predominates, causing mean tidal PV slope to decrease again. The PEEP level at which the decreasing compliance of each alveolus has a greater effect on mean tidal PV slope than increasing end-inspiratory recruitment depends on VT, h, and TOP range. Thus, the interactions affecting mean tidal PV slope during incremental PEEP are complex, and the PEEP level giving maximum slope is greatly affected by VT and by the lung mechanics of the model. Especially with a low VT, the response of the mean tidal PV slope to an incremental PEEP trial indicates the recruiting ability of the PIP rather than the ability of PEEP to prevent end-expiratory collapse.

At any PEEP level, the mean tidal PV slope is much higher with decremental rather than incremental PEEP (see Figure 3a and 3b); the PIP is therefore much lower, resulting in less tidal recruitment. To illustrate the effect of tidal recruitment, Figure 8 shows a plot of mean tidal PV slope against incremental (black circles) and decremental (open circles) PEEP with a VT of 500 ml, as in Figure 4. Also shown is the component of the mean tidal PV slope contributed by alveoli that collapse at end expiration (i.e., tidal recruitment), during incremental (black triangles) and decremental (open triangles) PEEP. With incremental PEEP, tidal recruitment contributes nearly half of the maximum mean tidal PV slope at 11 cm H2O PEEP. In contrast, with decremental PEEP there is much less tidal recruitment at all PEEP levels, and virtually none at PEEP of 16 cm H2O, which produced the maximum mean tidal PV slope. A low VT also greatly reduces the amount of tidal recruitment.



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  		Figure 8.   Plots of mean tidal PV slope against incremental (black circles) and decremental (open circles) PEEP with VT = 500 ml as in Figure 4. Also shown is the component of the mean tidal PV slope contributed by alveoli that collapse at end expiration and are inflated at end inspiration, that is, tidal recruitment. This is shown as black triangles for incremental PEEP and open triangles for decremental PEEP.

PV Slope during Decremental PEEP

In contrast, during a decremental PEEP trial, the lung has already been fully recruited (or nearly so) at the commencement of the trial. As PEEP is reduced from its highest level, the mean tidal PV slope initially increases because the alveolar compliance increases at lower alveolar volumes; the tidal PV plot remains superimposed on the deflation PV curve as shown in Figure 3a. Only when the PEEP level falls below open-lung PEEP does end-expiratory collapse occur, thus reducing the number of aerated alveoli and therefore total alveolar compliance, and tending to decrease mean tidal PV slope. However, this effect is opposed by the increasing alveolar compliance at lower alveolar volume, and also by the development of some tidal recruitment (much less than with incremental PEEP), both tending to increase mean tidal PV slope. Both of the latter two effects are less pronounced with a low VT. Because of these effects, the maximum mean tidal PV slope occurs at a PEEP level a little below open-lung PEEP; the lower the VT used, the less difference there is between open-lung PEEP and that giving maximum mean tidal PV slope. As PEEP is further reduced below open-lung PEEP, the mean tidal PV slope decreases as further collapse occurs. A very high TOP range reduces the number of aerated alveoli, and has a similar effect to a large VT. A low value of h reduces the pressure at which alveolar compliance reaches a plateau. A high mean TCP increases open-lung PEEP, so that the alveolar compliance is lower at this pressure. All of these effects reduce the PEEP level resulting in maximum mean tidal PV slope, but the effects are less, and more consistent, than with incremental PEEP. Thus, with decremental PEEP, the relationship between PEEP and mean tidal PV slope is less complex, because there is no increasing end-inspiratory recruitment up to high PEEP levels, and there is less tidal recruitment at moderate PEEP levels. The relationship is affected much less by changes in VT or by the construction of the model.

Relationship to Existing Literature

It has been suggested previously (14) that in patients with ARDS the mean tidal PV slope should increase when PEEP is increased to a level above the lower Pflex of the PV curve, so that ventilation occurs on the steep portion of the PV curve above the lower Pflex. Ranieri and coworkers showed that this is true in patients with ARDS who show no recruitment (i.e., upward displacement on the volume axis) as PEEP is increased (15). In these patients, PEEP simply moved the end-expiratory point further up on the same PV curve. These patients showed little improvement in oxygenation with increasing PEEP. Thus, in patients who do not show recruitment with PEEP, the mean tidal PV slope may increase progressively during an incremental PEEP trial, yet these patients may gain little benefit from PEEP. In contrast, other patients in Ranieri's study did show recruitment as PEEP was increased, associated with a greater improvement in oxygenation (15); in the example shown, there was little change in mean tidal PV slope with increasing PEEP, but if anything it decreased. In another study, the same authors (16) illustrated examples of nine patients showing recruitment with PEEP during ventilation with a low VT. In most of these patients, the mean tidal PV slope decreased slightly as PEEP was increased from 0 to 10 cm H2O, and the tidal PV plot was displaced upward, suggesting recruitment. We have also found that the PV slope in ARDS may show little change during incremental PEEP (10). These findings are consistent with the present study, and suggest that in patients who show recruitment as PEEP is increased (in whom PEEP may improve oxygenation and reduce ventilator-induced lung injury), the maximum PV slope during an incremental PEEP trial may be very misleading in trying to determine open-lung PEEP. The best method to select open-lung PEEP may be to measure absolute lung volume during tidal ventilation, and to select the lowest PEEP level giving the maximum upward displacement on the volume axis as PEEP is decreased after a recruitment maneuver. However, this is difficult to achieve at the bedside. According to the present study, the maximum PV slope during a decremental PEEP trial could be a useful approach that would be easier to apply at the bedside if this method is validated in clinical studies.

Other Methods of Determining Open-lung PEEP

In the previous study describing this model (10), the lower Pflex of the PV curve was poorly related to open-lung PEEP. This is predictable from the construction of the model, because the main determinant of the lower Pflex is the lowest TOP, whereas the determinants of open-lung PEEP are the superimposed pressure and the TCP, which were low. Amato's group has also shown in a clinical study that the lower Pflex may substantially underestimate open-lung PEEP (17). During a decremental PEEP trial, they showed that in some patients PaO2 consistently fell, suggesting derecruitment, at PEEP levels substantially higher than the lower Pflex (17). During an incremental PEEP trial, even the maximum PaO2 may not indicate open-lung PEEP, as the lung may not be fully recruited at open-lung PEEP, and complex hemodynamic alterations may occur. In the model, hysteresis is absent at PEEP levels above or equal to open-lung PEEP (i.e., the inspiratory and expiratory plots are superimposed; see Figure 2), because recruitment is the only cause of hysteresis in the model. However, in patients this may not be the case. Some hysteresis may result from stress relaxation or from the visco elastic properties of the lung even if no tidal recruitment occurs, although hysteresis should be minimized when tidal recruitment is prevented. In any case, to determine minimum hysteresis clinically is difficult; it requires the measurement of multiple points on the static tidal PV plot at each PEEP level, during inflation and deflation. Points on the inspiratory plot could be identified using the multiple occlusion technique (although during ventilation with a low VT, there could be difficulties in obtaining 4 or 5 points accurately), or the constant slow inflation method could be used. However, there is no simple, readily available method to identify these points on the expiratory plot. In contrast, the mean static tidal PV slope can easily be obtained at the bedside using a single end-inspiratory occlusion (i.e., the plateau pressure) and the PEEP level.

Limitations of the Model

The model is very simplistic, and makes a number of assumptions based on limited evidence, so the findings must be interpreted with caution, and the use of a decremental PEEP trial cannot be recommended for clinical use at present. In reality, hysteresis of the PV curve results from variation of surface tension from inspiration to expiration and from low to high lung volume, and from other factors, in addition to inspiratory recruitment. Both collapse and recruitment show some time dependence, and this was not incorporated into this simple model. Time dependence of recruitment and collapse could limit the amount of tidal recruitment occurring in ARDS. However, a recent study of oleic acid-induced pulmonary edema in pigs, using computed tomography (CT) scans, showed that most of the recruitment during inspiration and collapse during expiration occurred within 1.4 s (18). This would allow considerable tidal recruitment to occur during conventional ventilatory patterns, although it could limit tidal recruitment at higher frequencies with shorter inspiratory and expiratory times. Gattinoni and coworkers also showed using CT scans that substantial tidal recruitment could occur during conventional ventilation in ARDS (19). The exponential function for alveolar compliance used in the model was validated in normal lungs. However, Gattinoni and coworkers estimated that the specific compliance of the aerated lung in ARDS may be relatively normal (20) and it may be reasonable to use this function for the aerated alveoli in the model. However, recruitment during measurement of the PV curve in Gattinoni's study could have caused slight overestimation of specific compliance (10). The use of a half-inflation pressure (h) in most simulations a little higher that the values found by Salazar and Knowles (13) for the deflation curve in normal humans (4.9 versus 2.2-4.3 cm H2O) allows for a slightly lower than normal specific compliance associated with surfactant depletion. In spite of these limitations, the model does allow an examination of the effect of different values of opening pressures, closing pressures, half-inflation pressure, superimposed pressures, and tidal volume on the slope and shape of the tidal PV plots. The conclusions seem likely to have some validity, and can be used to generate hypotheses that could be tested clinically.

These results were obtained using quite high values for opening pressures and would be somewhat different if lower values of TOP had been used. However, unless unrealistically low values of TOP were used, the maximum PV slope during an incremental PEEP trial was still not consistently related to open-lung PEEP, whereas during a decremental PEEP trial, it was. There are some data to suggest that opening pressures at least as high as the values used in this study occur in patients with early ARDS. A sustained inflation with an airway pressure of 30-40 cm H2O was needed to reinflate postoperative atelectasis even in patients with normal lungs (21). It has also been observed that sustained inflations with relatively high pressures are sometimes effective in improving oxygenation in ARDS (22), suggesting recruitment of lung regions with high TOP. A CT scan study of patients with ARDS showed that end-inspiratory aeration of the lowermost lung regions increased as plateau pressure was increased up to a mean of 46 cm H2O (19). Higher levels of plateau pressure were not reported, so it is possible that greater aeration may have occurred at even higher pressures. A study of saline-lavaged pigs showed that 10 min of ventilation with a plateau pressure of 55 cm H2O was required to achieve full aeration of the lungs on CT scan after previous collapse, whereas aeration could be maintained after this with lower levels of peak and mean airway pressure (23). A recent study of patients with ARDS showed that after expiration to ambient pressure, recruitment during a slow inflation continued up to a pressure of at least 30 cm H2O (11). These findings are not at all surprising; it is well known that alveoli or small airways have higher critical opening than critical closing pressures, as previously discussed, and as represented in the model. Thus, it is likely that such high TOP do occur in ARDS. However, the distribution of TOP throughout the lung in ARDS is unknown.

The values of TCP used were substantially lower than the those of TOP (0-4 versus 0-40 cm H2O). This is in keeping with the "Gattinoni model" of the ARDS lung (12), in which PEEP is only required to reach the level of the maximum superimposed pressure to prevent end-expiratory collapse. However, it seems unlikely that surface tension forces, tending to cause alveolar collapse, can have no effect in ARDS, and some patients with severe ARDS do appear to require higher PEEP levels to maintain oxygenation than the reported values for superimposed pressure of 15-20 cm H2O in dependent lung regions (12). Therefore, moderate values were chosen for the TCP rather than zero as required for the Gattinoni model. The use of higher values of TCP (Figure 7b) did not change the overall conclusions, although open-lung PEEP was underestimated to a greater extent by the maximum mean tidal PV slope even during decremental PEEP.

The compliance of the chest wall in ARDS may sometimes vary at different volumes, and in some patients, a lower Pflex on the PV curve may result from an increase in chest wall rather than lung compliance as volume increases (24). Variation of chest wall compliance with lung volume could modify the mean tidal PV slope with changes in PEEP in some patients. This model did not attempt to simulate variable chest wall compliance.

The model did not incorporate any simulation of small airway closure, which may act to prevent true alveolar collapse at end expiration. The use of a range of TOP allows for differences in opening pressure that could occur with small airway closure in some lung regions and true alveolar collapse in others. Small airway closure during deflation also results in "gas trapping," and therefore a higher end-expiratory volume. This would slightly decrease the slope of both the deflation PV curve below the onset of collapse, and of much of the inflation PV curve. It would also decrease the mean tidal PV slope when tidal recruitment occurs, because the end-expiratory volume would be higher, but it should not affect the main conclusions from the model.

In the model, the lung was completely collapsed at end expiration with PEEP of zero. This is unrealistic, because patients with ARDS have some aerated lung even with no PEEP. This situation can easily be simulated with the model either by adding a negative chest wall recoil pressure, or by not reducing the PEEP level to zero. The effect is to reduce the magnitude of the changes in PV slope with PEEP, so that they are less obvious visually, but it does not affect the direction of the changes. Increasing the amount of aerated lung at end expiration with zero PEEP simply "dilutes" the effect of changes in PEEP on PV slope. This should therefore have no effect on the conclusions of the study. The model assumes a "cubic" shape for the lung; that is, there are the same number of units in each compartment. It might be more realistic to have fewer units in the anterior, nondependent regions. This would result in lower lung volumes at low pressures as the non dependent regions are recruited, and a more rapid loss of volume during deflation as the dependent regions start to collapse, but it should not alter the main conclusions of the study. The cubic shape was used for simplicity. The compression of underlying lung by the heart, and of lung in the posterior diaphragmatic recess by the abdominal contents, was also ignored.


    Footnotes

Correspondence and requests for reprints should be addressed to Keith G. Hickling, Department of Anaesthesia and Intensive Care, Healthcare Otago, Private Bag 1921, Dunedin, New Zealand. E-mail: keith.hickling{at}healthotago.co.nz

(Received in original form May 24, 1999 and in revised form August 4, 2000).

Acknowledgments: Supported by Tyco, Mallinckrodt Healthcare Asia Pacific, who have agreed to provide a small educational grant to cover the publication charges for this study.
    References
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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