Ventilatory assistance and respiratory muscle activity. 1: Interaction in healthy volunteers

Transcription

1 British Journal of Anaesthesia 1998; 80: CLINICAL INVESTIGATIONS Ventilatory assistance and respiratory muscle activity. 1: Interaction in healthy volunteers J. S. MECKLENBURGH AND W. W. MAPLESON Summary We have investigated the response of 12 normal, healthy subjects to resistance loading and ventilator assistance of spontaneous breathing. Three ventilators, the Hamilton Veolar, Engström Erica and Puritan Bennett 7200, were used to provide synchronized intermittent mandatory ventilation and two levels of pressure assistance. Total respiratory elastance and resistance were measured. The equivalent (negative) pressure of respiratory muscle activity (p mus ) was then calculated from measurement of flow and pressure at the mouth. With ventilatory assistance, subjects maintained frequency, decreased inspiratory time and the magnitude of p mus, but increased tidal volume, thus not taking full advantage of ventilatory assistance. The waveform of p mus varied in detail within and between subjects and conditions, but the all-subject mean waveforms showed for all conditions a consistency of trajectory. Increasing the level of assistance decreased the duration and hence the (negative) peak value of p mus. The results suggest that some waveforms of flow or pressure from the ventilators may be more acceptable to patients than others, and that different patients may prefer different waveforms. (Br. J. Anaesth. 1998; 80: ) Keywords: ventilation, spontaneous; ventilation, artificial; muscle respiratory; equipment, ventilators; measurement techniques, respiratory muscle activity The respiratory muscles apply a waveform of force to the impedance of the respiratory system (total respiratory compliance (C) and total respiratory resistance (R)) in series with the impedance of any breathing system to which the subject is connected. If the breathing system is part of a ventilator, the ventilator applies a waveform of flow or pressure to the opposite end of the two impedances. The action of the respiratory muscles is equivalent to a waveform of (negative) generated pressure, p mus, applied to the outside of the subject s thorax 1 (fig. 1). It has been shown 1 that if the subject s compliance and resistance are first measured, then the waveform of p mus can be calculated from continuous measurements of flow (v) and pressure at the subject s mouth (p mo ). Thus the combination of compliance, resistance and an appropriately applied waveform of p mus constitutes a model of the respiratory system of a spontaneously breathing patient. Previous work in this department 1 has validated a mechanical form of the model and this form is included in the models specified in BS 5724:3:12 2 for the comparative testing of ventilators in respect of their use in spontaneously breathing patients. The p mus waveform specified in BS 5724:3:12 for use with the model is based on measurements made in the course of our previous work, but in only three volunteers under a limited range of conditions. Therefore, we perceived a need to determine p mus waveforms in a wider range of subjects under a wider range of conditions to assess what range of waveforms occurred and whether the waveforms could be related to characteristics of the different conditions. For practical reasons, the present study was restricted to healthy volunteers but included a range of conditions in three different ventilators. Subjects and methods EXPERIMENTAL DESIGN We investigated healthy subjects while breathing air under five different conditions: (i) spontaneous breathing from atmosphere the unloaded reference condition; (ii) simple resistance load, 0.5 kpa s litre 1 (at 1 litre s 1 ), simulating a solely resistive breathing system; (iii) pressure assistance of 0.5 kpa, considered to be the lowest level of assistance likely to be used clinically; (iv) pressure assistance of 1.0 kpa, thought to be sufficient to completely unload the respiratory muscles; and (v) synchronized intermittent mandatory ventilation (SIMV) at a frequency of 6 bpm. The ventilators used were the Hamilton Veolar, Engström Elvira and Puritan Bennett The conditions involving ventilator assistance were always applied in the same sequence: pressure assistance at 0.5 kpa, pressure assistance at 1.0 kpa and SIMV (i.e. progressively more abnormal). These three conditions were applied by each of the three ventilators to each subject a total of nine ventilatorassisted conditions. The nine ventilator-assisted conditions were bracketed by both unloaded and resistance-loaded conditions. There were six different orders in which the three ventilators could be used and these were randomized (using computergenerated random number sequences) between J. S. MECKLENBURGH, PHD, W. W. MAPLESON, DSC, FINSTP, FRCA (HON), Department of Anaesthetics and Intensive Care Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN. Accepted for publication: November 25, Correspondence to J. S. M.

2 Ventilatory assistance and respiratory muscle activity: Figure 1 Left: simplified mechanical conceptual model, equivalent to the physiological reality except as follows. There is no inertance. The alveolar compartment is separated from the mouth by R (resistance of entire respiratory system) not just airways resistance (therefore p is the pressure in the alveoli of the model, not true alveolar pressure). Respiratory muscles (both inspiratory and expiratory) are combined in a single muscle component (M). E is the elastance (reciprocal of compliance) of the respiratory system. Centre: alternative model, directly equivalent to the first: a waveform of negative pressure (p mus ) applies the same waveform of force to the base plate of the bellows as do the respiratory muscles, M. p mo is the pressure at the mouth or airway opening. Right: equivalent electrical analogue of both models with p mus represented by an ac voltage generator. successive subjects. This pattern was applied three times, using a total of 18 subjects. Respiratory resistance and elastance (the reciprocal of compliance) were estimated from periods of continuous mandatory ventilation (CMV) at the beginning and end of the experimental sequence. The ventilator used for CMV runs in any one subject was the one in the middle of the random order of the ventilators for that subject. EXPERIMENTAL PROCEDURE After obtaining approval from the relevant Research Ethics Committee and written informed consent, we studied subjects, aged yr, not suffering from any disease. It was essential that subjects could relax their respiratory muscles completely during a period of CMV for determination of elastance and resistance. During trial CMV runs, acceptable subjects showed a mouth pressure pattern with no negative phases, a steady increase in pressure during the inspiratory phase and a similar pattern in every breath. The experimental sequence consisted of 15 runs, with the subject seated: CMV, unloaded, loaded, the nine ventilator-assisted conditions, loaded, unloaded and CMV. For each run, the subject breathed under the specified conditions via a sensing manifold, for a total of 4 min (2 min for acclimatization and 2 min for recording). This was followed by 2 min of recovery, breathing room air directly. All symptoms of inadequate technique (e.g. leaks from the mouth piece, swallowing, breath-holding and airway restriction during inflation) were noticeable on a rolling display during the acclimatization and recording periods, and instructions were given to try to correct such inadequacies. End-tidal carbon dioxide partial pressure ( P E CO ) 2 was monitored. The run was terminated if hyperventilation caused P E CO to decrease to 3 kpa. 2 SETTING OF THE VENTILATORS For the CMV runs, frequency was initially set to 15 bpm with an inspiratory to expiratory (I:E) ratio of 1:2, and a tidal volume of approximately 1.5 times the spontaneous tidal volume recorded during the trial runs. The inspiratory flow pattern of the ventilators was set to sine-wave (or the nearest approximation to it in the Engström Elvira increasing flow ). The initial frequency, I:E ratio and tidal volume were adjusted until subjects were comfortable and best able to suppress normal respiratory activity. A degree of hyperventilation and hence hypocapnia was aimed for to reduce respiratory drive and make relaxation easier for the subject. The different ventilators were connected initially to a bellows lung model (Medishield) with a compliance of 0.5 litre kpa 1 and resistance of 0.5 kpa s litre 1, and the controls adjusted to give, as closely as possible, the same levels of pressure assistance. These settings of the controls were noted and used in all subjects. In the SIMV runs, frequency was set to 6 bpm and the other inflation characteristics were initially set as in the initial CMV runs for each subject. However, tidal volume and duration of the inspiratory phase or amplitude of the inspiratory flow waveform were sometimes adjusted at the request of the subject. A standard Intersurgical breathing system was used throughout. It consisted of a Y-piece and two 1.8-m lengths of corrugated polyethylene tubing. In all ventilators the display and control of airway pressure was based on sensing the breathing system pressure within the ventilator. INSTRUMENTATION The sensing manifold consisted of a mouth piece, followed by a heat and moisture exchanger and filter (HMEF) (Portex Humid Vent), a T-piece for mouth pressure measurement, a screen pneumotachograph for flow measurement and a T-piece for extracting a

3 424 British Journal of Anaesthesia 200-ml min 1 sampling flow of gas for end-tidal carbon dioxide measurement. Pressure was measured by a strain-gauge differential pressure transducer (Pioden type UP) driven by a conditioning amplifier (Analog Devices Strain-gauge Amplifier 1B31). Flow was measured by a screen pneumotachograph (Mercury Electronics C100) and differential pressure transducer (Valodyne MP45) driven by a conditioning amplifier (P. K. Morgan pressure transducer monitor). End-tidal carbon dioxide partial pressure was monitored using a Datex Capnomac Ultima multi-gas analyser which was calibrated with a certified gas mixture (5 % carbon dioxide in air; BOC Ltd) before and after measurements in each subject. Pressure and flow calibration was by reference to a Timeter RT200 calibration analyser verified to National Accreditation of Measurement and Sampling (NAMAS) standards by Universal Calibration Ltd. The pneumotachograph was calibrated with dry air; therefore inspiratory flows in the ventilatorassisted runs would be correct. In the unassisted runs, when room air was inspired, the effect of ambient humidity reduced the viscosity of air so producing an error of approximately 0.3 % in inspired flow, which was ignored. The sensitivity of the pneumotachograph in the expired direction was not measured directly. As the conditions during expiration were different and unknown, an empirical calibration factor was calculated so that the drift in end-expired volume was eliminated from the recording as a whole, but breath-to-breath variations were preserved. Thus all flows and volumes are expressed at ambient conditions, ATPD. The resistances of the sensing manifold and the resistance load (a 7-mm diameter orifice) conformed to the equations p v and p v 2, respectively, where p pressure across the manifold or load in kpa and v flow in litre s 1. The internal volume of the sensing manifold was 144 ml, 45 ml being within the HMEF. In the unassisted runs a short tube of 15 ml internal volume was added to the open end of the manifold to match approximately the dead space of the Y-piece of the ventilator breathing system. In the resistance-loaded, unassisted runs, the tube incorporated the 7-mm diameter orifice. Thus there was comparable rebreathing in all runs. Pressure and flow data were captured using an interface board (MIO-16 25, National Instruments), microcomputer (Apple Macintosh IIcx running system 7.1) and data acquisition software (Lab- View ver. 2, National Instruments), and stored on magnetic disk. 3 ESTIMATION OF ELASTANCE AND RESISTANCE FROM CMV RUNS Elastance (E) and resistance (R) were estimated using a multiple regression method. 1 Initially, separate estimates were made for the inspiratory and expiratory phases of each breath. The breaths were then ranked on the basis of each of three variables: inspiratory expiratory s in elastance (1) and in resistance (2), and residual SD of the regression fit (3). Good relaxation was indicated by small s and small SD values. The chosen cut-off point (a rank of 500 for all three ranked variables) yielded 310 acceptable breaths of the original 836 (37%). To maintain the balance of the experimental design, even with two examples of each of the six sequences of the three ventilators, would have involved including one subject with no acceptable breaths. The best compromise that could be obtained was a set of 12 subjects which included only one example of one sequence and three examples of another. Therefore, the balance of the experimental design was upset, but all subjects had at least 10 breaths with satisfactory relaxation. In each of the 12 selected subjects, those breaths from the CMV run at the end of the experimental sequence which had shown good relaxation were re-submitted to regression analysis, but single estimates of resistance and elastance were obtained for each whole breath (rather than separate estimates for each phase). In this way, breath-by-breath estimates of resistance, elastance and residual variance of the regression were obtained for each of the 12 selected subjects. The reciprocal of the residual variance for each breath was used to calculate weighted means 4 of resistance and elastance for each subject. CALCULATION OF PMUS WAVEFORM IN THE MAIN EXPERIMENTAL RUNS The waveforms of mouth pressure, flow and volume from the main experimental runs were processed continuously for each 2-min recording to give waveforms of p mus. This was done by using the equation in appendix 1. pmus = pmo ( PmoE' Rv! E' ) Rv! Ev+ PmusE' where p mo mouth pressure, v flow (positive for inspiration), v volume of gas in the lungs relative to a reference level, and P moe, P muse and v E the end-expiration values of p mo, p mus and v, respectively (see below). The unknown P muse in the equation was assumed to be zero, so that the shape of the p mus waveform could be obtained, but there is uncertainty over the true zero. EXTRACTION OF NUMERICAL RESPIRATORY VARIABLES FROM THE WAVEFORMS OF FLOW, VOLUME, MOUTH PRESSURE AND PMUS From each breath in each experimental run (other than the CMV runs), 14 variables were obtained (volume in litre and ventilation in litre min 1 (both ATPD), pressure in kpa, time in s, frequency in bpm): VT inspired tidal volume. T respiratory period (from the start of inspiratory flow in one breath to the start of inspiratory flow in the next). f 60/T. TI inspiratory time (from the start of inspiratory flow to the start of expiratory flow). TE expiratory time (T TI). T c contraction phase time of the p mus waveform (time from the start of the inspiratory effort to the peak).

4 Ventilatory assistance and respiratory muscle activity: V total ventilation (VT f). (This is calculated for each individual breath so that the mean is not equal to mean VTεmean f.) v instantaneous flow (inspiratory direction positive). P mo pk peak magnitude of a smoothed (rolling average of three points) waveform of mouth pressure (negative in unassisted conditions) during the inspiratory flow phase. P mo mn mean value of mouth pressure over the inspiratory flow phase. P mus pk peak negative value of a smoothed (as for P mo pk ) waveform of p mus. P trig most negative mouth pressure occurring in the 0.3 s before the start of inspiratory flow. P moe (PEEP) end-expired mouth pressure derived from the mean pressure over the 0.2 s period ending 0.15 s before mouth pressure becomes negative before the next breath. P muse value of p mus at end-expiration, derived using the same time window as used for P moe (PEEP). v E value of flow at end-expiration, derived using the same time window as used for P moe (PEEP). The time windows used to determine P trig, P muse, v E and PEEP were based on inspection of many overlay recordings. For each variable, except P E CO 2, mean values for all breaths in each run were calculated before statistical analysis. Mandatory and spontaneous breaths in the SIMV condition were averaged separately. The mean P E CO2 for each run was taken as the average of the pair of values at the beginning and end of each 2-min run. Therefore, this mean P E CO applied to both 2 mandatory and spontaneous breaths in the SIMV condition. Four factors pertained to each run: for the unassisted runs (1) subject (1 12), (2) condition (unloaded and resistance-loaded), (3) occasion (before and after the ventilator-assisted runs) and (4) last (the last ventilator in the sequence of ventilatorassisted runs (relevant only to the after runs); and for the ventilator-assisted runs (1) subject (1 12), (2) condition (pressure assistance at 0.5 kpa and 1.0 kpa and mandatory and spontaneous breaths in SIMV), (3) ventilator (Hamilton Veolar, Engström Elvira and Puritan Bennett 7200) and (4) serial position (the position of the ventilator in the sequence of ventilator-assisted runs, 1 3). In the case of the unassisted runs, the factor last was included because it was anticipated that the characteristics of the ventilator used last might have an effect on the after runs of unassisted breathing. Two-way and three-way mixed-effect analyses of variance (ANOVA) and t tests were performed on the numerical data using the Minitab statistical package (version 8.1 running on various models of Apple Macintosh using system 7.1 or 7.5). As this study was exploratory in nature and not a definitive clinical trial, a fixed P 0.01 was used as the threshold for significance, partly as a token recognition of the large number of comparisons performed, but primarily to provide an internally consistent threshold for selecting s in the variables for comment. AVERAGING OF PMUS WAVEFORMS A complex averaging process which preserved the shapes of the waveform (appendix 2) yielded a mean contraction phase waveform (from the start to the peak of p mus ) and a mean relaxation phase waveform (from the peak onwards) for each subject in each condition. In the SIMV condition, the waveforms of p mus for the mandatory and spontaneous breaths were very different and were therefore averaged separately. Thus the original three ventilator-assisted conditions became four, for each of the three ventilators. Together with the four, bracketing, unassisted conditions, this gave a total of 16 average waveforms for the contraction and relaxation phases, for each of the 12 subjects. The 12 subject waveforms were similarly averaged for each condition to produce overall mean waveforms, for each phase for each condition. Results We recruited 21 subjects; two were unable to relax during the trial period of CMV and one subject fell asleep, producing an erratic breathing pattern during one of the runs. The remaining 18 subjects satisfactorily completed the experimental procedure, each producing 2-min recordings from each of 15 runs. Of these 18 subjects, 12 provided good estimates of elastance and resistance. ESTIMATES OF ELASTANCE AND RESISTANCE In the 12 selected subjects (10 males, two females), mean age was 26.7 (range 20 44) yr, mean height 1.81 (SD 0.11) m, mean weight 74.4 (10.1) kg, with total respiratory elastance of 1.13 (0.21) kpa litre 1 and resistance of 0.56 (0.12) kpa s litre 1. The 95 % confidence limits for elastance and resistance in individual subjects were all within 12 %, mostly within 5 %. 3 As the remainder of the results depend on the validity of these estimates, it is worth noting that mean elastance (1.13 kpa litre 1 ) was close to the values of Altman and Dittmer 5 and Diem and Lentner 6 (both 1 kpa litre 1 ) and to the geometric midpoint (1.04 kpa litre 1 ) of the range ( kpa litre 1 ) given by Cotes 7 for the sum of lung and chest wall elastance. resistance (0.56 kpa s litre 1 ) included resistance of the HMEF and mouth piece (0.16 kpa s litre 1 ). Therefore, mean total respiratory resistance for comparative purposes was 0.40 kpa s litre 1. This is approximately 50 % greater than the total respiratory resistance given by Cotes (0.26 kpa s litre 1 ) but is in agreement with that of Diem and Lentner (0.396 kpa s litre 1 ). MEAN RESPONSE TO THE DIFFERENT VENTILATORY CONDITIONS Numerical variables Table 1 compares the mean values for the different conditions for each numerical variable. PEEP and triggering pressure (P trig ) are omitted because, in the unassisted runs, the former is zero and the latter is irrelevant.

5 426 British Journal of Anaesthesia Table 1 Comparison of all conditions for numerical variables (volumes expressed at ATPD). of all subjects for each condition for nine variables, where the values for each subject was the mean for the two occasions (before and after) or the three ventilators. Also, P values from the two-way ANOVA (subject by condition 55 df) and from paired t tests of the s from the unloaded condition (11 df). PA Pressure assistance, SIMVm mandatory breaths in SIMV, SIMVs spontaneous breaths in SIMV Tidal volume (litre) Frequency (bpm) Ventilation (litre min 1 ) Condition (%) P by t test (%) P by t test (%) P by t test Unloaded Res. loaded PA 0.5 kpa PA 1.0 kpa SIMVm SIMVs P by ANOVA Inspiratory time (s) Contraction phase time (s) End-tidal PCO 2 (kpa) Condition (%) P by t test (%) P by t test (%) P by t test Unloaded Res. loaded PA 0.5 kpa PA 1.0 kpa SIMVm SIMVs P by ANOVA P mus pk (kpa) P mo mn (kpa) P mo pk (kpa) Condition (%) P by t test actual P by t test actual P by t test Unloaded Res. loaded PA 0.5 kpa PA 1.0 kpa SIMVm SIMVs P by ANOVA The first column for each variable gives the mean value for each of the six conditions. Two-way ANOVA (condition by subject, with subject as a random variable) of the mean values for each subject showed significant s between conditions for all variables (P always in the first column of table 1). As the interest is in the comparison with normal, unloaded, unassisted breathing, the remaining columns for each variable show percentage s for the other conditions, and P values by t test for each. Resistance loading led to an increase in contraction phase time, and in inspiratory time, with a decrease in frequency, and slightly more negative mouth pressures. Other changes were not significant but formed a pattern consistent with the above changes: an increase in the (negative) magnitude of P mus pk and an increase in tidal volume which, with the matching decrease in frequency, led to little change in ventilation or P E CO. 2 In the ventilator-assisted conditions, there were large increases in P mo pk with lesser decreases in the magnitude of P mus pk. Consequently, tidal volume increased markedly, especially with pressure assistance (PA): 37 % and 52 % for 0.5 and 1.0 kpa PA, respectively. In the SIMV runs, mandatory tidal volume was deliberately set to the high value found most appropriate for determination of elastance and resistance of subjects (in the CMV runs). Yet subjects did not take advantage of this to reduce tidal volume of spontaneous breaths in SIMV (SIMVs) compared with unloaded, unassisted breathing. The reduction in inspiratory time in the ventilatorassisted conditions was marked (12 % to 33 %) and similar to the reduction in duration of the contraction phase of the p mus waveform (14% to 39%). The reduction was significant in all conditions except for spontaneous breaths in SIMV. The increases in ventilation (35 59 %) and the corresponding decreases in E CO 2 P (16 27%) reflected the increases in tidal volume with only small changes in frequency. The increases also illustrated that despite considerable reductions in P mus pk, subjects did not take full advantage of the assistance provided by the ventilators. Waveform of p mus Contraction phase. For the contraction phase, figure 2 shows for each subject, the mean of the unassisted, unloaded condition before (solid line) and after (dotted line) the sequence of ventilator-assisted runs and the overall mean (and confidence limits) of the 24 waveforms for those two occasions the reference mean waveform. Figure 3 shows, for each of the 14 combinations of condition and ventilator, the allsubject mean waveforms (solid lines), with confidence limits, overlaid with the mean reference waveform.

6 Ventilatory assistance and respiratory muscle activity: For conditions where the relaxation phase is short, the waveform coincides with the later part of the mean reference waveform. RESPONSE TO INDIVIDUAL VENTILATORS AND OCCASIONS Figure 2 contraction phase waveform of p mus for each subject for the unassisted, unloaded condition before (solid line) and after (dotted line) the sequence of ventilator-assisted runs and the overall mean and 95 % confidence limits (CL) (broken line) of the 24 waveforms for these two occasions the reference mean waveform. The waveforms are synchronized to the start of inspiratory flow. The waveforms of the subjects (A L) are offset from one another, the zero for each waveform being indicated by a faint line at the level of each identification label. The trajectories of the waveforms are essentially the same in all conditions: the reference waveform is almost always entirely within the confidence limits. However, the durations, and hence amplitudes, differ between conditions. Relaxation phase. For the relaxation phase, a similar procedure was followed, but with the 24 mean before and after waveforms (fig. 4) individually time-shifted to a midway synchronization point (appendix 2) so that there is no common time reference (hence the 1-s time bar, instead of a time scale). The overall mean, the relaxation phase reference mean waveform is also shown. Figure 5 shows, for each of the 14 combinations of condition and ventilator, the all-subject mean waveforms (with confidence limits (CL)) overlaid with the relaxation phase reference mean waveform. As in the contraction phase, the trajectory is essentially the same for all conditions (the reference mean waveform lies almost entirely within the confidence limits for each condition) but the durations differ. The duration of the phase up to the most positive value (as plotted in fig. 5) is lengthened by resistance loading and shortened by SIMV and, in the PB 7200, by pressure assistance. Numerical variables Three-way ANOVA was used to assess the effect of the series of ventilator runs on the unassisted conditions. The three factors were occasion (before vs after), condition (unloaded vs loaded) and subject (the last as a random variable). The only significant change from before to after the ventilatorassisted runs was an 8 % reduction in P E CO 2 (P 0.008) (table 2) and there were no significant interactions between occasion and condition, that is the effects of adding a resistance load were similar before and after the ventilator-assisted runs. Another three-way ANOVA (condition, ventilator, subject) revealed significant s between ventilators for some variables and significant ventilator condition interactions (P for s between runs ) for a different set of variables (table 3). For each variable, the least significant (lsd) 8 for P 0.01 between ventilators allows identification of which systematic s between ventilators led to overall significance, and the between-run lsd allows identification of s between ventilators which are significant only in particular conditions. This leads to the following qualitative summary of table 3. Two variables are determined almost entirely by ventilator design: PEEP, which was consistently low in the PB7200, and P trig, which was consistently high in the Veolar and low in the Elvira, especially in SIMVs. Other variables depended partly on how the operator set the ventilators: nominally the same for all three for P mo pk in pressure assistance, but in accord with what suited the subject in terms of tidal volume and inspiratory time in SIMV. Contraction phase time and P mus pk depended on how the subjects reacted to each ventilator condition combination. Finally, tidal volume, frequency and total ventilation were consequences of the values of all of the other variables. Differences between ventilators in particular conditions we re as follows. In SIMV (both the mandatory and spontaneous breaths), the Elvira produced (compared with the Veolar and PB 7200) large values of P mo pk (and P mo mn ), small values of inspiratory time and P mus pk, and large values of frequency and total ventilation, with no significant s in tidal volume. In pressure assistance, the PB7200 produced small values of inspiratory time and P mus pk, large values of frequency and, compared with the Veolar, small values of tidal volume, with generally no significant for total ventilation. A final three-way ANOVA used the position of the ventilator in the sequence of three, rather than the type. This revealed some acclimatization to the ventilator-assisted runs: from the mean for the first exposure to the four conditions to the mean of the means for the second and third exposures, tidal volume decreased by 10%, ventilation by 5% and P mus pk by 20%.

7 428 British Journal of Anaesthesia in load or assistance. Simple graphs for each variable, with a line for each subject, 3 showed that the subjects responded consistently to the resistance load, but showed variable after-effects of the sequence of ventilator-assisted runs. Also, in the ventilatorassisted runs there were significant subject ventilator inte ractions for all variable s e xce pt the large ly ventilator-controlled P mo. The spread of responses between subjects was generally similar for all three ventilators and for all variables, except P trig. This was much more consistent between subjects, but less so in the Veolar or Elvira than in the PB7200, despite the sensitivity within each ventilator being set the same for all subjects. p mus waveform For each ventilator condition combination, there was variation between subjects in the shape of the p mus waveform in both the contraction and relaxation phases. In some combinations the variation was slight; in others very marked. 3 Despite these wide variations, the mean waveforms for all subjects were, for all conditions, similar in trajectory to the reference waveforms (figs 3, 5). Discussion Figure 3 All-subject mean contraction phase waveform of p mus (solid line) for the resistance-loaded and ventilator-assisted conditions with 95 % confidence limits (CL) (broken line), overlaid with the overall mean waveform for the unloaded, unassisted condition (the reference mean waveform of figure 2 dotted line). For the ventilator-assisted conditions, the reference waveform has been time-shifted to match the waveforms for each ventilator. The same shift has been used for all four conditions in each ventilator. The time shifts are reflected in the different times at which the dotted waveforms end. The zero for each waveform is indicated by a faint line. p mus waveform There were no striking systematic s in mean waveform (figs 3, 5) between the sets for different ventilators, or between occasions (before or after the ventilator runs) for a resistive load. RESPONSE OF INDIVIDUAL SUBJECTS Numerical variables In all three types of ANOVA, the s between subjects were significant (compared with the residual, ventilator condition subject interaction mean square) for all variables except P mo. This was broadly to be expected: subjects differ from one another, and P mo was zero, or near zero, in the unassisted runs and set to the same nominal 0.5 or 1.0 kpa in pressure assistance. Only in the mandatory breaths of SIMV did P mo depend on the response of the patient to a preset tidal volume. Although subjects differ from one another, they might be expected to respond consistently to changes AVERAGE RESPONSE OF PMUS TO DIFFERENT CONDITIONS One striking feature of the results is that our subjects, on average, preserved the trajectory of the waveform of p mus but changed the duration of the contraction phase, and hence the amplitude of p mus, in response to the different conditions (fig. 3). The other method by which p mus amplitude could be changed would be to maintain the duration of the contraction phase but change the slope of the trajectory of p mus. This occurred occasionally in four subjects: in some ventilator-assisted conditions the trajectory became much less steep soon after the start of inspiratory flow. On the other hand, in three subjects, the slope actually increased in similar conditions, leading to the essentially constant average trajectory for all conditions. Resistance loading increased the contraction phase time (table 1), matching the increased inspiratory time reported by Milic-Emili and Zin 9 ; on the other hand, pressure assistance and SIMV decreased contraction phase time. In SIMV this applied to both spontaneous and mandatory breaths. Corresponding changes occurred in relaxation phase time: resistance loading extended the early part of the relaxation phase leading to a decrease in frequency with load; pressure assistance and SIMV truncated the early part of the relaxation phase (fig. 5) but increased the pause part of the phase (after p mus had reached its most positive value) leading to small, non-significant changes in frequency. Thus the changes were in the expected direction and, with the resistance load, of a magnitude sufficient to maintain alveolar ventilation (negligible change in P E CO 2 ) (table 2). This is in accordance with the classical response to resistance loading. 9 However, the second striking feature of the results is that in pressure assistance and SIMV, the changes were generally inadequate to compensate for the assist-

8 Ventilatory assistance and respiratory muscle activity: for subjects to become accustomed to assisted ventilation, if they ever do. The fact that ventilation decreased only 10% between measurements with the first ventilator in the sequence and those with the second and third, supports this possibility. Another factor is that it may have been an instinctive response to minimize the unusual feeling of positive pressure in the lungs and this may be the reason for the increased slope of the p mus trajectory in three subjects. All subjects had experienced this positive pressure during the period of CMV for estimation of elastance and resistance, but only three were well accustomed to the experience from preliminary studies and only two of these greatly reduced their contraction phase time and hence p mus amplitude. A third factor is that the request to each subject to breathe normally may have been interpreted as an instruction to maintain the normal p mus waveform rather than the expectation, which was to maintain normal ventilation. Finally, it may be that, even if subjects wanted to maintain the same ventilation, they did not know how to do so, except with the resistance load. They would all be familiar with resistance to breathing, from upper respiratory tract infections, whereas most of them had no experience of ventilator assistance. Figure 4 relaxation phase waveform of p mus for each subject for the unassisted, unloaded condition before (solid line) and after (dotted line) the sequence of ventilator-assisted runs and overall mean waveform and 95 % confidence limits (CL) for these two occasions the relaxation phase reference mean waveform. Time shifts have been applied to each before and after waveform so that the synchronization points (the times when a polynomial fitted to each waveform reached 0.75 of the amplitude of the smallest of the 24 waveforms) are all vertically aligned. The zero for each waveform is indicated by a faint line. ance; consequently, ventilation increased substantially. There were exceptions: in some subjects, with pressure assistance at 1.0 kpa, the contraction phase ended almost immediately inspiratory flow began, and there were several instances of the phase ending within 0.5 s. Thus some subjects took advantage of the assistance to reduce the work done by the inspiratory muscles; on the other hand, the three subjects who increased the slope of their p mus trajectory in the contraction phase actually increased the work done during ventilatory assistance. It remains that, on average, the reduction in p mus was much less than that needed to maintain normal ventilation. POSSIBLE REASONS FOR LIMITED REDUCTION IN P MUS WITH ASSISTANCE The limited reduction in p mus with ventilatory assistance is difficult to explain: the resulting increase in ventilation reduced P E CO (to 4 kpa with 1.0 kpa 2 of pressure assistance) which would be expected to reduce respiratory drive. Being connected to a ventilator is not a natural state and it may be that considerable time is required EVIDENCE OF CHANGES IN PMUS IN OTHER STUDIES The only study to measure p mus in the manner described here 10 gave no information on the change in p mus with ventilatory assistance. However, several surrogate measures have been used: motor nerve input to respiratory muscles, 11 integrated EMG and oesophageal pressure It is interesting to see how the responses vary between different circumstances. Response to assistance In this study, subjects were breathing at only a small fraction of their maximum breathing capacity so that ventilatory assistance was superfluous. However, when the maximum breathing capacity is reduced to near the current level of ventilation, or when the ventilatory demand is increased (e.g. by exercise) towards the maximum breathing capacity, assistance might be more welcome. One study 16 measured oesophageal pressure in five patients with chronic obstructive airways disease; applying triggered nasal pressure assistance decreased the peak p oes by 80%. Unfortunately, it is not possible to tell if the reduction was caused by a change in duration or a change in slope of p oes. The complementary circumstance was investigated 15 by measuring oesophageal pressure in four volunteers who were exercising to 80 % of their maximum breathing capacity. Providing assistance to these subjects roughly halved the pressure time integral of p oes. In two subjects, this was achieved by a reduction in the duration of the contraction phase with no change in trajectory; in the other two, the trajectory started in the same manner in each breath, but subsequently flattened, with no change in the duration of the contraction phase.

9 430 British Journal of Anaesthesia Table 2 Effect of hangover of the ventilator-assisted runs on the after unassisted runs: means values for all subjects for each condition on each occasion of the unassisted runs for end-tidal PCO2 (kpa). Marginal means together with P values and standard errors of the s (SED) between occasions, between conditions and between runs from mixed-effect ANOVA Occasion Condition Before After s Differences between conditions (df 11) P (SED) Unloaded Resistance loaded (0.052) s Diffs between: Occasions (df 11) Runs (df 11) P SED Figure 5 All-subject mean relaxation phase waveforms of p mus (solid line) for the resistance-loaded and ventilator-assisted conditions with 95 % confidence limits (broken line). Each waveform is terminated at its most positive value (that the waveform subsequently returned to zero can be seen in fig. 3) and is overlaid with the relaxation phase reference mean waveform of figure 4 (dotted line). In each case the reference waveform has been pressure-shifted to match the pressure at the end of each of the 14 mean waveforms. The mean waveforms have then been time-shifted, relative to the (time-fixed) reference waveform, so that each is coincident with the reference waveform at its synchronization point (see caption to fig. 4). Response to load In this study, the resistive load (0.5 kpa s litre 1 ) was approximately equal to the total respiratory resistance (0.4 kpa s litre 1 ) and subjects responded by a small increase in contraction phase duration with no change in slope. However, as might be expected, when the load is much greater, the slope increases: when a resistive load was imposed on ponies 14 (approximately 40 times the normal total respiratory resistance of a pony 17 ) a very large increase in slope resulted. The ultimate load is total occlusion and when, in anaesthetized animals 11 and humans, the airway was suddenly occluded at the end of one expiration, the integrated EMG at the next breath followed the previous trajectory for a greater duration. POSSIBLE CONTROL MECHANISMS Two possible control mechanisms are clearly not supported by the present data. First, response of the respiratory centre to metabolic input is contradicted by the marked decrease in end-tidal, and hence arterial, P CO2 during (table 1) and after (table 2) ventilator-assisted runs. Second, if the -motor drive of the spindle reflex (the primary load-compensation mechanism of skeletal muscle) operated in the respiratory muscles in the circumstances of the present study, it would lead to changes in the slope of the p mus waveform, not in its duration. Other possible control mechanisms include the response of the respiratory centre to proprioceptive inputs from muscles, tendons, joints and lung tissue. Such proprioceptive information could modify the output of the respiratory centre over several breaths or it could lead to immediate, and even within-breath, modification. To determine the relative importance of longer-term compared with immediate control requires studies where the load or assistance is varied within a single breath or between adjacent breaths, and where monitoring is continuous, whereas our study did not record the immediate effects of the various imposed conditions, only the relatively steadystate responses after 2 min of acclimatization. The classical Hering Breuer inspiratory-off reflex can be stated as: inspiratory effort is terminated at a time that is dependent on the volume inhaled and on the rate of increase of volume. 10 Our results are consistent with this to the extent that the contraction phase was shortened during assistance, even though not enough to compensate. However, it is not possible to determine if the response is the result of lung stretch receptors (the classical Hering Breuer inputs) or a slow integrative adaptation of the respiratory centre output in response to a variety of neural and metabolic inputs. Although this study does little to discriminate between different possible control mechanisms, the results include novel features which need to be explicable by any universal theory of respiratory control. INDIVIDUAL FEATURES OF THE VENTILATORS Some features of the p mus waveform can be attributed to characteristics of a particular ventilator. The oscillation in the PB7200 waveform during pressure assistance (fig. 3) occurred with all subjects. It can be explained in terms of the rapid pressure oscillations generated by the PB7200 at the start of a pressure-assisted breath corrupting the calculated p mus waveform. 3

10 Ventilatory assistance and respiratory muscle activity: The Elvira in SIMV and the PB7200 in pressure assistance demonstrated a pattern of anomalous behaviour. These ventilator condition combinations were associated (table 3) with smaller values of p mus, shorter contraction phase times and higher frequencies than with the other ventilators for each of those conditions. In pressure assistance, it is mouth pressure that is controlled by the ventilator. How- Table 3 Comparison of ventilators with classification by type: mean values for all subjects for each condition with each ventilator for nine variables. Marginal means together with P values and the least significant (lsd) 8 for P HV Hamilton Veolar, EE Engström Erica, PB Puritan Bennett 7200, PA pressure assistance, SIMVm mandatory breaths in SIMV, SIMVs spontaneous breaths in SIMV Ventilator Condition HV EE PB s Differences between conditions (df 33) Tidal volume (litre) PA 0.5 kpa PA 1.0 kpa SIMVm (0.151) SIMVs s (0.096) (0.114) Frequency (bpm) PA 0.5 kpa PA 1.0 kpa SIMVm (1.16) SIMVs s (1.78) (1.26) Inspiratory time (s) PA 0.5 kpa PA 1.0 kpa SIMVm (0.15) SIMVs s (0.24) (0.25) Contraction phase time (s) PA 0.5 kpa PA 1.0 kpa SIMVm (0.15) SIMVs s (0.14) (0.25) Ventilation (litre min -1 ) PA 0.5 kpa PA 1.0 kpa SIMVm (1.43) SIMVs s (1.22) (1.16) P mus peak (kpa) PA 0.5 kpa PA 1.0 kpa SIMVm (0.156) SIMVs s (0.136) (0.161) P mo peak (kpa) PA 0.5 kpa PA 1.0 kpa SIMVm (0.076) SIMVs s (0.126) (0.123) PEEP (kpa) PA 0.5 kpa PA 1.0 kpa SIMVm (0.011) SIMVs s (0.019) 0.11 (0.015) P trig (kpa) PA 0.5 kpa PA 1.0 kpa SIMVm (0.011) SIMVs s (0.024) (0.02)

11 432 British Journal of Anaesthesia ever, P mo pk was not significantly greater in the PB7200 than in the Veolar or (except at 1.0 kpa PA) in the Elvira. Therefore, it may be that the more rapid initial increase in pressure or the initial oscillation in the PB7200 was in some way responsible. In SIMV it is flow and tidal volume which are controlled by the ventilator. In the Elvira, the short inspiratory time, combined with a tidal volume similar to that of the other ventilators, led to a much larger P mo mn and P mo pk, but the flow waveform was notably different in the Elvira (more of a ramp than a sine wave). There is also the question of why subjects preferred a shorter inspiratory time on the Elvira for CMV (and hence had it imposed on them in SIMV). Again it seems that waveform, this time of flow, may be responsible. Thus there may still be opportunities to improve the acceptability of ventilator assistance by experimenting with the shape of the pressure or flow waveforms. The low trigger pressures found with the Elvira are probably because it is flow-triggered whereas the versions of the Veolar and PB7200 used were pressuretriggered. (The PB7200 can be flow-triggered in the flow-by mode and a new version of the Veolar has flow-triggering as an option.) When discussing trigger sensitivity it is also important to consider the response time of the trigger a sensitive trigger with a slow response can appear the same to a patient as an insensitive trigger with a rapid response. This is because, in both cases, the inspiratory assistance could occur at approximately the same time after the start of a given p mus waveform, and therefore at the same magnitude of p mus. In pressure triggering, the ventilator controls the triggering pressure; in flow triggering it does not. This can explain why P trig was more consistent between subjects with the pressure-triggered PB7200 than with the flow-triggered Elvira. However, it does not explain why P trig was more variable with the pressure-triggered Veolar than with the PB7200. However, in pressure assistance, once triggered, the pressure generated by the ventilator increases more rapidly in the PB7200 than in the Veolar. Therefore, the decrease in p mo which occurs at the start of the contraction phase might be reversed immediately the triggering pressure was reached in the PB7200, so that the minimum mouth pressure (which was recorded as P trig ) was indeed very close to the triggering pressure of the ventilator. In the Veolar, however, varying rates of increase in p mus (in different subjects) might lead to a variable further decrease in p mo, below the true triggering pressure of the ventilator, before the more gradually increasing generated pressure reversed the effect of the increasing p mus. The s in the responses of subjects to different ventilators suggest that, apart from consistent s between ventilators, different subjects might prefer different ventilators. Indeed, although nine subjects voiced a preference for the Veolar at the end of the experimental run, one preferred the Elvira, one the PB7200 and one abstained. A companion article 18 investigated the factors influencing the reduction in contraction phase time and provides a standard p mus waveform in addition to a method of adapting such a waveform to simulate the response of a normal healthy subject to the conditions investigated here. The next stage is to obtain similar information from patients when they are receiving ventilatory assistance. Appendix 1 CALCULATION OF PMUS The equation of motion of Mead and Agostoni 19 is: pm pmus = Rv! + Ev where p mo and p mus mouth pressure and respiratory muscle equivalent pressure, R and E total respiratory resistance and total respiratory elastance, respectively, v instantaneous flow, and v instantaneous volume in the lungs, expressed as a from the equilibrium volume. In the experimental work, v is still instantaneous flow, so that the pressure across the resistance, R, is: pmo pα = Rv! (A1) where p pressure in the alveoli (fig. 1), not true alveolar pressure because R, resistance which separates the alveoli from the mouth, is total respiratory resistance. However, after various corrections, 3 the experimentally measured volume is expressed as the from the mean end-expired volume instead of the from the equilibrium volume. The discrepancy can be resolved as follows. The definition of elastance, E (total elastance between the alveoli and the ambient atmosphere) is the change in pressure across the elastance unit, per unit change in volume within the unit: ( pα pmus ) E = (A2) v The pressure across E is therefore given by: ( pα pmus ) = E v (A3) At the mean end-expired volume let p P E and p mus =P muse Then equation (A3) becomes: (p P E ) (p mus P muse ) Ev (A4) where v is now experimentally measured volume. Eliminating p from equations (A4) and (A1) gives: P mus p mo Rv Ev (P muse P ae ) (A5) If the subjects completely relax their respiratory muscles during CMV for determination of elastance and resistance, then p mus and P muse are both ze ro. Also, at e nd-e xpiration, p mo =P moe =P E +Rv E (from equation (A1)). Therefore, rearranging equation (A5), p mo P moe R(v v E ) Ev (A6) P moe can be obtained from the pressure recording. Therefore, with measurement of p mo, v and v, elastance and resistance can be estimated by a multiple regression technique. For the main, spontaneous breathing runs, equation (A5) can be rearranged to: p mus p mo (P moe Rv E ) Rv Ev P muse (A7) Thus with elastance and resistance known, and p mo, v and v measured continuously, p mus can be calculated, apart from the unknown constant P muse. Therefore, the shape of the p mus waveform can be determined but there is uncertainty about its zero position. Appendix 2 AVERAGING OF PMUS WAVEFORMS Simply averaging all p mus waveforms in an overlay graph could distort the waveform. For instance, if the duration of the contraction phase varies from breath to breath in a run, this would result in an average waveform with a blunt peak that is not typical of any of the breaths in the run. Examination of the overlay plots from all the runs in the study showed that the waveforms in the contraction phases of successive breaths generally set off on the same trajectory, but dropped off at different times. It was the duration to, and magnitude of, the peak, rather than the shape of the contraction phase which varied from breath to breath during a run. Therefore each p mus waveform was divided, at its (negative) peak, into the contraction and relaxation phases which were averaged separately. This preserved the trajectories of the two phases. 3 To obtain the mean waveform of the contraction phase for a run, a segment of the waveform, from 1 s before the start of inspiratory flow to the time of P mus pk, was extracted for each breath and stored in successive rows of a two-dimensional matrix. For