The Ventilatory Recruitment Threshold for Carbon Dioxide1- 3
GARY
c.
PRECHTER, STEVEN B. NELSON, and ROLF D. HUBMAYR
Introduction
Measurements of chemosensitivity and ventilatory drive in patients with respiratory disease are difficult to interpret (1-3). In patients with pulmonary emphysema, the ventilatory response to CO 2 is typically reduced, a finding consistent with a decrease in chemosensitivity and controller gain (4). However, because ventilation not only is a function of respiratory controller output but also depends critically on the mechanical efficiency of respiratory muscles, their contractile properties, and the mechanical impedance of the respiratory system, no simple conclusions about respiratory drive can be made from conventional ventilatory response measurements (1). In 1975,Whitelaw and coworkers (5) introduced the measurement of the airway occlusion pressure (P o• t ) in an attempt to define a variable that was more specific for respiratory controller output and independent of any mechanical impairments of the respiratory system. During the past decade, however, it has become apparent that the measurement of Pe.. does not fulfill these criteria and has its own set of limitations (6). Thus, important questions pertaining to the role of ventilatory control mechanisms in the pathophysiology of acute and chronic respiratory failure remain unanswered. In this report, we describe our initial experience with a method with which the chemosensitivity of the respiratory controller can be analyzed in terms of a ventilatory on-switch threshold to CO 2. This threshold measurement does not require spontaneous ventilation as output of respiratory controller activity and, thus, is independent of respiratory muscle function and the mechanics of the system. The technique has been adapted from experiments initially described by Altose and associates (7), who evaluated the effects of ventilator settings on respiratory activity in normal volunteers. Wemade measurements in normal subjects as well as in patients with respiratory failure who were mechanically hyperventilated to suppress phasic respiratory motor activity. The CO 2 recruitment threshold 758
SUMMARY Wereport our Initial experience with a technique with which the chemoresponslvenesa of the respiratory controller can be characterized In terms of an Inspiratory on-switch threshold to CO 2 • After suppression of phasic respiratory muscle activity by mechanical ventilation, a CO2 recruitment threshold (PC02 RT) was defined as the lowest alveolar CO2 tension at which CO 2 supplementation to Inspired gas caused a reappearance of Inspiratory efforts. Because PC02RT can be determined In the absence of a mechanical load on the ventilatory pump, respiratory system mechanics and Inspiratory muscle function should not Influence the measurement Itself. Thus, this technique may be helpful to study ventilatory requirements and load responses In critically III patients with respiratory failure. We haveshown that Inspiratory muscle recruitment can be equally well-Inferred from changes In the airway pressure and flow tracings during mechanical ventilation, from the pattern of chest wall displacement, and from the Integrated diaphragm electromyogram. Within a subject, PC02RT Is a reproducible measurement that Is not Influenced by ventilator settings and end-explratory lung volume; provided that phasic respiratory muscle has been suppl'8888dprior to CO2 supplementation. Details of the methodology, the lilely determinants of PC02RT', and the clinical utility of this technique are discussed. AM REV RESPIR DIS 1990; 141:758-7&4
(Peo2RT) was then defined as the lowest end-tidal Peo2 (PETeo2) at which the supplementation of CO 2 to inspired gas caused a reappearance of respiratory effort. The purpose of this report is to address the likely determinants of this test of chemosensitivity, to discuss its application as an investigative tool for the study of mechanisms in disease, to put the clinical usefulness of this information into perspective, and finally to discuss the limitations of the method. Methods Studies in Normal Volunteers Study population. Ten adult volunteers (nine men and one woman) 27 to 38 yr of age who werewithout acute or chronic illnessgavetheir informed consent to participate in this study. Most of them were familiar with physiologic measurement techniques and had some knowledge about the objectives of this study. However, they had no access to any information that was obtained during the experimental protocol. Measured Variables The subjects breathed through a mouthpiece with a noseclip in place while resting comfortably in the supine position. Inspired and expired CO 2 tensions were measured from a side port of the mouthpiece with a capnograph (Puritan-Bennett, Los Angeles, CAl with linear response characteristics for fractional CO2 concentrations up to 0.08. The capnograph was calibrated with 5070 CO 2 before
each study, and all reported values were converted to partial pressure by the measured barometric pressure. Subjects were mechanically ventilated with a Siemens 900B ventilator that delivered oxygen-enriched gas (Flo 2 > 0.9) through a standard ventilator tubing/mouthpiece assembly. During mechanical ventilation, airway pressure and expiratory flow signals were accessed directly from the analog output ofthe ventilator, which had been calibrated against known standards before this series of experiments. In three subjects, the presence of respiratory effort was also evaluated from the pattern of chest wall motion and the electromyographic activity of the diaphragm. Rib cage and abdominal dimensions were monitored with a calibrated inductive plethysmograph (Respigraph'", NIMS, Miami Beach, FL), and their relative change was displayed on an oscilloscope (8). The electromyographic activity of the diaphragm was recorded from esophageal leads using a modified Swan-Ganz catheter. The catheter was introduced through the nose into the stomach, a small distal bal-
(Received in original form February 13, 1989 and in revised form August 3, 1989) 1 From the Division of Thoracic Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. 2 Supported by Program Project Grants HL21584 and HL-38107 from the National Institutes of Health. 3 Correspondence and requests for reprints should beaddressed to Rolf D. Hubmayr, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
759
CO 2 RECRUITMENT THRESHOLD
loon was inflated, and the catheter was withdrawn such that the three ring leads came to rest at the gastroesophageal junction. Differential electrodes were chosen to maximize the output of the rectified, amplified, and filtered electrical signal. The amplitude of the moving time average electromyogram of the diaphragm (Edi) was taken as an index of diaphragm recruitment (9, 10). Carbon dioxide tensions measured at the airway opening, airway pressure, expiratory gas flow, and Edi were recorded on a four-channel stripchart recorder (HP-7414; Hewlett-Packard, Waltham, MA) and stored along with chest wall motion data on FM magnetic tape (Racal 7).
Experimental Protocol Experiment Series 1. In eight subjects PETc02 was measured during spontaneous breathing after 20 min of rest in the supine posture. By 5 min, all subjects had achieved a steady state after which PETc02 changed by lessthan 1 mm Hg, The mean PETC02 of 10 consecutive breaths was recorded and defined as the Pco2SB. Subsequently, mechanical ventilation was begun at a tidal volume of 10 to 12 ml/kg, an inspiratory time of 25070 of total breathing cycleduration (not), an end inflation hold time of 10070 not, and a frequency resulting in a minute ventilation slightly above that found during spontaneous breathing. The initial ventilator settings did not suppress phasic respiratory motor activity in any of the subjects. Therefore, the ventilator frequency was increased by 2 breaths/min every 3 to 5 min until objective evidence of spontaneous ventilatory efforts disappeared. The absence of phasic respiratory motor activity was based on specific criteria, all of which had to be met (figure lA). Because inspiratory flow was delivered in a square wave profile, the airway pressure time trace needed to show an initial step increase followed by a linear rise to some peak value. While the respiratory system was held at end inspiration for 10070 of not, the airway occlusion pressure was required to achieve a plateau value. Expiratory flow had to reach its peak value at the beginning of expiration and decline exponentially with time. The sensitivity and specificity of these criteria relative to Edi and chest wall motion were evaluated in three subjects in whom these additional measurements were made. Compared with spontaneous breathing, the minute ventilation required to suppress phasic respiratory muscle activity during mechanical ventilation was considerably greater. The PETC02 at which respiratory muscle recruitment disappeared defined an apnea threshold (Pco2AT) (figure lA). After 5 min at the "apnea level" of ventilation, CO 2 was added in a stepwise manner to the inspired gas without the subject's knowledge, increasing the PETC02 by approximately 3 mm Hg every 3 min. For this purpose, a pressurized circuit containing 100070 oxygen was connected in parallel with a CO 2tank from which the flow could be regulated between zero and 15
A. (~pnea threshold) 56
PETC02 mm Hg
B. (Recruitment threshold)
42 28
14
o
Edi
Pao em H20
Vex Lisee
20
10
o
0.8 0.4
o
5 sec Fig. 1. Representative tracings of CO 2 tension recorded at airway opening (PETC02 ) , moving time average of diaphragm electromyogram recorded from esophageal leads (Edi), airway pressure (Pao), and expiratory flow (Vex). Recordings were made during mechanical ventilation at settings that abolished phasic diaphragm activity (A) and after CO 2 supplementation led to respiratory muscle recruitment (B). Note the difference in Pao and Vex in the presence and in the absence of diaphragm activity.
L/min. The oxygenand CO 2sources wereconnected with a Y piece to the gas inlet port of the ventilator. The PETC02 at which phasic respiratory motor activity reappeared defmed a Pco2Rf, that is, the ventilatory threshold for CO 2 (figure IB). The presence of respiratory effort was defined by the absence of previously established relaxation criteria for 10 or more consecutive breaths. At this juncture, inspired CO 2 supplementation was discontinued for 5 min. This led to the disappearance of phasic respiratory motor activity within 1to 2 min in all subjects. Carbon dioxide was then added as before to determine the recruitment threshold for a second time (Pco2Rf 2). During this second run, the subject was asked to indicate any symptoms or perception of respiratory effort by raising his or her hand, at which time PETC02 was again noted (Pc 02SX). Experiment Series 2. On a different day we evaluated the dependence of Pc01Rf on ventilator settings, on time and CO 2 history preceding recruitment, and on the sequence in which individual experiments were performed. For this purpose we made a series of measurements in random order in six subjects. In one of the runs, the sequence of changes in ventilator rates and inspired CO 2 concentrations {FIcoJ was as described above. In another run, PETC02 was maintained between 34 and 38 mm Hg by CO 2 supplementation, whereas ventilator rate and minute ventilation were increased until respiratory effort became undetectable (test of CO 2 history). Then Pco2Rf was determined as before. In a third run, Pco2AT was approached more slowly, i.e., by increasing the machine rate ev-
ery 15 instead of every 3 min (test of time history).
Studies in Patients Population. Thirteen intubated ventilatordependent patients with respiratory failure were studied. Age, sex, duration of mechanical ventilation, length of stay in the intensive care unit, and principal cardiopulmonary diagnoses are listed in table 1. Informed consent was obtained from the patient or, when appropriate, from a responsible family member. Patients with hemodynamic instability, pulmonary edema, and metabolic acidosis were excluded. Sedatives and narcotics were withheld for 4 h before testing, and all other management decisions were made by the attending physician. Experimentalprotocol. Subjects were studied in a quiet room and mechanically ventilated with 100070 oxygen. Tidal volumes ranged between 10 and 15ml/kg, and the inspiratory time was between 15 and 33070 of the total breathing cycle duration. A pneumatic occlusion valve (No. 7200; Hans-Rudolph, Kansas City, MO) and a heated pneumotachograph (Fleisch no. 2) were placed between ventilator circuit and endotracheal tube. Flow at the airway opening was calculated from the pressure (Validyne 45 MP; Validyne Corp., Northridge, CAl drop across the pneumotachograph. Volume was derived by integration of the flow signal. Airway pressure was measured with a separate pressure transducer (Validyne DP9) at the oral end of the endotracheal tube. Capnograph and recording systems were otherwise identical to those described above. The ventilatory assist rate was increased by
760
PRECHTER, NELSON, AND HUBMAYR
TABLE 1
12
CLINICAL DATA ON 13 VENTILATOR-DEPENDENT PATIENTS WITH HYPERCARBIC RESPIRATORY FAILURE
10
(yr)
Sex
ICU Days/Days on Ventilator
Cardiopulmonary and Related Disease
1 2 3
82 54 69
M M
38/38
78n8
F
17/12
4 5* 6*
81
M
84
F F
13/8 50/44 68/43
Myxedema CAD CHF,ESRD Myasthenia gravis, CHF Pontine CVA COPD, CHF, MR, MI COPD, CHF, rib fractures from MVA COPD,CHF Asthma, COPD COPD COPO, obstructive sleep apnea COPD COPD, polymyositis, obesity COPD, upper abdominal surgery
Subject No.
Age
87
M
7 8 9 10
75 56 72 66
11 12
62 46
M F
59/59 78/48
13
66
F
24/12
F
M M
41/37 43/31 10/9
8n
Definitionof abbreviations: CAD = coronary artery disease; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; CVA = cerebral vascular accident; ESRD = end-stage renal
disease; ICU = intensive care unit; MI = myocardial infarction; MR = mitral regurgitation; MVA = motor vehicle accident. * Subject died during hospitalization.
two breaths every 5 min until phasic respiratory muscle activity disappeared. The mechanical characteristics of the relaxed respiratory system were then assessed with an interrupter technique (11). In brief, the static elastic recoil pressure of the respiratory system was determined at 5 to 10 lung volumes between end inspiration and static equilibrium volume and then related to expiratory flow. The expiratory flow at a recoil pressure of 6 em H 20 (VP6) was estimated from the pressure-flow curves and was taken as an index of the severity of the airway obstruction (12). We assumed that expiratory flow limitation was present when VP6 failed to decline with the addition of an expiratory resistive load. The resistance offered by the expiratory circuit of the ventilator was sufficient to make this determination. The Pc02AT and Pc02RTwere determined as described above. In seven patients, Pco2RT was measured in triplicate. The dependence of Pc02RT on ventilator settings and the lung volume at end expiration (VEE) was evaluated in five additional patients. All five patients had expiratory flow limitation during passive expiration, and the elastic recoil pressure of the respiratory system at end expiration (intrinsic positive end-expiratory pressure; PEEP) ranged between 5 and 15em H 20 (13). Thus, VEE during mechanical ventilation could be reduced by a proportionate increase in inspiratory flow and expiratory time before the measurement of Pco2RTwas repeated. In the same patients, VEE was increased with an extrinsic PEEP device, and Pc02RT was again determined.
Data Analysis To eliminate any bias as to the presence or
absence of phasic respiratory motor activity by the investigator who conducted the experiments, the records werescored by two observers who had no knowledge of the simultaneously recorded PETC02. The agreement with respect to phasic respiratory motor activity between blinded observerswas 100070 and consistently supported the assessment of the nonblinded investigator. Group mean data werecompared using Student's t tests for paired observations. Statistical significance was assumed when the p value was < 0.05. Correlations between variables were analyzed by least-squares linear regression. Differences between Pco2RT measurements obtained under varying experimental conditions (Experimental Series 2) were assessed using an analysis of variance for repeated measures.
Mechanical hyperventilation
o L-_...J.::!=~J==~=:::::I:=e~.1..-_.J 24
28
32
38
40
48
PETC02. mm Hg Fig. 2. Example of PETC02 and amplitude of the moving time average electromyogram of diaphragm (Edi). PETC02 and Ediduring spontaneous breathing(SB)are indicated by the solid triangle. Symbolsindicate mean values averagedover 30 s precedinga change in conditions. Sequence of these changes is representedby the arrows. Open circles indicate presence of spontaneous respiratory activity, and closed circles indicate its absence. Apnea threshold (AT) and recruitment threshold (AT) are shown as squares.
between relaxation criteria based on inspiratory pressure and expiratory flow profiles and the absence of electrical activity of the diaphragm (figures 1 and 2). During mechanical ventilation at apnea threshold, the cross-sectional area of the rib cage and abdomen changed along a similar path during inspiration and expiration (figure 4, left panel). As previously shown, this pattern of chest wall deformation is consistent with relaxation of respiratory muscles and differs from that observed during spontaneous breathing in the supine posture (14). Recruitment threshold Pcoi. The supplementation of CO2 to the inspired gas did not cause recruitment of respiratory muscles of the mechanically hyperventilated respiratory system until a threshold value in PETCOl was reached (figures 1 to 3). Phasic respiratory motor activityaltered the inspiratory pressure-time profile, reduced peak expiratory flow, changed
Results
Studies in Normal Volunteers Apnea threshold. Although subjects attempted to suppress spontaneous breathing efforts during positive-pressure ventilation, objective evidence of phasic respiratory motor activity persisted until the minute ventilation delivered by the ventilator reached 10to 19 L/min (figures 2 and 3). Pco,AT ranged between 22 and 29 mm Hg and was 12 to 18 mm Hg lower than Pco2SB. The assisted respiratory rate and mean inspiratory flow at which phasic respiratory muscle activity disappeared were 18.6 ± 2.8 breaths/min and 0.92 ± 0.18 L/s, respectively. In the three subjects in whom Edi was also determined, there was concordance
20
16
e
§ .~
AT
C02 supplementation
RT
"
12
8
O-----------.__ 24
28
32
36
~_..L--_
40
__I
48
PETC02. mm Hg Fig. 3. Exampleof PETC02 and minute ventilation(VE) during an experiment. Symbols indicate mean values averagedover 30 s preceding a change in conditions. Sequence of these changes is represented by the arrows.Open circles indicate the presenceof spontaneous respiratory activity, and closed circles indicate its absence.Apneathreshold(AT)and recruitmentthreshold (AT) are shown as squares.
761
CO 2 RECRUITMENT THRESHOLD
AT
Rib cage
TABLE 3
RT
mc~
mc/
VENTILATOR SETTINGS, RESPIRATORY SYSTEM MECHANICS, AND CO 2 THRESHOLDS IN 13 VENTILATOR-DEPENDENT PATIENTS WITH RESPIRATORY FAILURE Subject No.
VT (L)
f (breaths/min)
Ve (L)
VP6/EFL (L/s)
PEEPi (em H2O)
PC0 2AT (mmHg)
Pco2RT (mm Hg)
0.75 0.55 1.00 0.60 0.73 0.68 1.47 0.58 1.15 0.80 0.75 0.70 0.70 0.75
20 25 12 20 15 12 15 24 15 20 12 20 20 20
15.0 13.8 12.0 12.0 11.0 8.2 22.1 13.9 17.3 16.0 9.0 14.0 14.0 15.0
0.5000.8751.0500.3750.075+ 0.100+ 0.150+ 0.200+ 0.100+ 0.080+ 0.200+ 0.075+ 0.100+ 0.050+
1 0 2 0 6 5 12 8 10 5 5 10 6 15
26 34 30 29 26 28 19 21 55 29 41 34 37 20
33 40 48 35 43 44 30 41 > 64* > 62* 65 59 54 37
Abdomen 1 2 3 4 5 6 7 8 9 10 11t
Fig. 4. The relative displacements of rib cage and abdomen are contrasted during mechanical ventilation at apnea threshold (AT) and recruitment threshold (RT). Solid dot depicts FRC. Its location within plots was chosen arbitrarily. Note the hysteresis between inspiration and expiration (arrows) when respiratory muscles are recruited.
the pattern of chest wall deformation (figure 4, right panel), and led to an increase in Edi with each inspiration. Assisted breaths were frequently preceded by negative airway pressure swings, representing attempts to trigger a machine breath. Inspiratory efforts were not necessarily associated with an increase in respiratory rates. Abdominal excursions increased relative to the displacement of the rib cage, and the shape of the chest wall differed between inspiration and expiration (figure 4, right panel). The Pco2RT and Pco2SB were within 1.5 mm Hg in seven of the eight subjects (Experiment Series 1), and their mean values were not significantly different from each other (41.2 versus 40.5 mm Hg), The perception of respiratory effort coincided with objective evidence of phasic respiratory muscle activity in three subjects and followed Pco2RT by ~ 2 mm Hg in the five remaining subjects. By definition, no subject was able to suppress respiratory activity voluntarily at or beyond Pco2RT.
12 13
Definition of abbreviations: EFL = expiratoryflow limitation;f = respiratoryrate; PC02AT = apnea threshold; PCo 2RT = CO2 recruitmentthreshold; PEEPj = intrinsic positiveend-expiratory pressure; VE = minute ventilation; VP6, expiratoryflow at a system recoil pressureof 6 cm H2O. • Recruitment could not be demonstrated. t Two studieswere obtained 14 days apart.
Individual and group mean data of CO2 threshold measurements and minute volumes in six normal volunteers obtained under different experimental conditions (Experimental Series 2) are listed in table 2. Despite significant differences in minute ventilation, inspiratory flow, assist rate, and Pco~T, the Pco2RT values were similar at all experimental settings. Differences in minute ventilation and flow between the runs reflect differences in the assist rate necessary to suppress phasic motor activity. These differences are entirely explained by the run sequence, that is, the assist rate necessary to suppress inspiratory recruitment
TABLE 2 DEPENDENCE OF RECRUITMENT THRESHOLD ON EXPERIMENTAL SETTING IN NORMAL SUBJECTS* Run At Subject No. 1 2 3 4 5 6 Mean SO
Pco2RT 1
46.2 39.6 1 39.9 3 46.43 41.91 41.33 42.6 3.0
Run C§
Run Bt Ve
Pco2RT
18.4 22.1 10.6 9.6 13.2 9.0 13.8 5.3
46.0 2 41.0 2 43.3 1 45.8 1 41.2 3 42.02 43.2 2.2
Ve 16.2 18.9 18.5 14.4 11.0 9.0 14.7 4.0
Pco2RT 3
45.5 39.6 3 43.3 2 44.4 2 40.5 2 42.0 1 42.6 2.3
Ve 13.9 15.6 13.2 9.6 9.6 11.2 12.2 2.4
Definition of abbreviations: Pco 2RT = CO2 recruitmentthreshold; VE = minute ventilation.
• During all runs the tidal volumewas 12 mllkg and the inspiratorytime was 25% of the total cycle duration. The inspired CO2 tension was always raised between 2 to 4 mm Hg every 3 to 5 min once the initialconditionswere met.A, B, andC identifythe differentexperimental runs.The numbersabove and to the right of the Pco2 RT values indicate the order in which individualruns were performed. t Increasein ventilatorassistrateby two breathsevery 3 min until apnea(absence of phasicrespiratory motor activity)was observed. Same as run A except that PETC02 was kept> 34 mm Hg throughoutby CO2 supplementation. § Increasein ventilator assist rate by 2 breaths every 15 minutes unit apneawas observed.
*
was always greater during the initial experimental run (p ~ 0.05).
Studies in Patients The ages of the 13 patients (seven male and six female) ranged from 46 to 87 yr (table 1). Various cardiopulmonary disorders were present. The most common cause of respiratory failure in this group of patients was COPD complicated by some other illness, All nine patients with a clinical diagnosis of COPD (Subjects 5 through 13) were flow-limited during passive expiration near static equilibrium volume and were hyperinflated at ventilator settings necessary to abolish phasic respiratory muscle activity (table 3). Accordingly, intrinsic PEEP ranged between 5 and 15 em H 20 , and VP6 was 0.2 Lis or less. There was no overlap in either intrinsic PEEP or VP6 between patients with and without COPD. In patients without a clinical diagnosis of COPD (Subjects 1 through 4), intrinsic PEEP was less than 5 em H 20 , and VP6 ranged between 0.4 and 1.1 Lis. On average, as shown in tables 1 and 3, Pco2RT was lower in patients without airflow obstruction unless COPD was associated with left heart failure (Subjects 1 through 7; median = 40 mm Hg), The Pco2RT was highest in those with COPD without heart disease (Subjects 8 through 13; median = 57 mm Hg). In figure 5, Pco~T and Pco2RT from all patients are plotted against each other. One patient (Subject 11) had two
762
PRECHTER, NELSON, AND HUBIIAYR
88 58 CJ)
%:
E
E
~N
0
~
Fig. 5. Relationship between CO 2 tensions at apnea threshold (Pco 2AT) and recruitment threshold (Pco 2RT)in 13 patients. One patient had two studies 2 wk apart (open circles). In two patients, recruitment was not achieved, and highest PETC02 values are plotted (triangles). The solid line is the line of identity.
50
42
0
•
34
•
28
• 28
42
34
0
• ••
PC02RT,
• 68
58
50
mm Hg
Repeated recruitment threshold measurements (measured in triplicate) were within 2 mm Hg in six of seven patients and within 3 mm Hg in the remaining patient. In everypatient in whom Pco 21IT was reexamined after VEE had been altered by 0.3 to 1.2 L, Pco2RT remained within 10070 of baseline.
studies 14 days apart. In the seven patients in whom more than one estimate of Pco2Rf was obtained on the same day, mean values are shown. In two instances (Subjects 9 and 10), Pco2RT could not be determined safely because further CO 2 supplementation might have caused acidemia. In these two patients, the highest observed PETC02 values are shown. In general, Pco"AT and Pco2RT were correlated with each other, but more remarkable was the large difference between apnea and recruitment thresholds within subjects and the large range in either value across patients. The group mean ± SD of Pco"AT was 30.6 ± 9.5 mm Hg. This value was significantly lower than the Pco2RT value of 44.1 ± 10.7mm Hg, The difference between apnea and recruitment thresholds ranged from 6 mm Hg (Subject 3) to more than 33 mm Hg in a patient who had COPD and obstructive sleep apnea (Subject 10). The relationship between Pco2 RT and arterial bicarbonate concentration is shown in figure 6. The mean arterial bicarbonate was 27 mEq/L, and it was ~ 30 mEq/L in 12 of 13 patients. In Subject 11, who had two studies 2 wk apart, there was a decrease in PC021IT from 65 to 59 mm Hg, which corresponded with a decrease in bicarbonate from 38 to 32 mEq/L.
Discussion
The Technique The accuracy of this technique rests with the timely detection of phasic respiratory motor activity. During controlled mechanical ventilation (the term is used to indicate the absence of respiratory muscle recruitment), airway pressure and flow tracings show a characteristic pattern (figure IA). This occurs because the respiratory system behaves like a onecompartment model consisting of a resistive and elastic element in series (11, 15). When it is inflated with a constant flow, there is an initial step increase in pressure corresponding to the pressure drop across the resistive element, which is followed by a linear rise as the elastic element expands. When deflation is driven only by the recoil pressure of the respiratory system, expiratory flow reaches a sharp initial peak and declines with time. If inspiratory muscles act in concert
40 0
38
Fig. 6. Relationship between arterial plasma bicarbonate concentration (HCO~ and recruitment threshold (Pco 2 RT) in 13 patients. One patient had two studies 2 wk apart (open circles). In two patients, recruitment was not achieved, and highest PETC02 values are plotted
-I
~
32
i. 0
28
0
E
•
0 J:
•
•
24
..
••
•
• • • •
•
(triangles).
20
30
~ --..
34
38
42
48
50
54
PC02 RT, mm Hg
58
82
86
with the ventilator, inspiratory airway pressure and/or expiratory flow patterns deviate from model predictions. This is because respiratory muscles and ventilator are mechanically arranged in parallel. Therefore, the work performed by the respiratory muscles during mechanical ventilation can be estimated from pressure and flow tracings (16). The example in figure IB illustrates that once inspiratory muscles were recruited, their activity persisted beyond the inspiratory machine cycle, causing a decrease in end inflation pressure and peak expiratory flow. Assessing onset of muscle recruitment from pressure and flow has certain advantages over electromyographic techniques. Pressure and flow can be easily recorded in a clinicalsetting from the output of most ventilators, avoiding the placement of esophageal leads. In three volunteers in whom simultaneous measurements of pressure, flow, Edi, and chest wall motion were made, there was excellent concordance between invasive EMG monitoring and mechanical recruitment criteria (figure 1). In our hands, any of these measurements were superior to surface EMG recordings from the lower rib cage (preliminary studies preceding these experiments).
The Determinants of Pco2AT and PC02KT In humans, the ventilatory CO 2response curve has two distinct regions with different slopes (17). In the hypocapnic range, breathing is irregular and ventilation is essentially independent of CO 2 tensions. Most investigators have studied this region while stimulating ventilation either voluntarily, by inducing hypoxia, or by raising body temperature (18). The causes of respiratory muscle recruitment in the hypocapnic range are unclear. Respiratory memory (19), state of arousal (20), and local after-discharge within respiratory centers have all been implicated (21). Whatever the cause, the hysteresis in the PETco2-ventilatory output relationships (figures 2 and 3) indicates that feedback inhibition related to mechanical ventilation can abolish inspiratory muscle recruitment in awake subjects and that in the hypocapnic range the ventilator settings necessary to achieve inspiratory suppression are independent of the arterial CO 2 tension (7). The state of arousal plays an important role in the regulation of breathing in the hypocapnic range. During sleep, relatively small reductions in CO 2cause a prolongation of expiratorytime, ultimately resulting in apnea (22). In other words,
763
CO 2 RECRUITMENT THRESHOLD
the large difference between Peo~T and Peo2RT in awake subjects may be arousal-state-specific. At least during anesthesia there remains a 5 to 9 mm Hg difference between these CO 2 on- and off-' switch thresholds (23). Whether the state of arousal influences apnea threshold and the control of breathing through changes in chemoreceptor activity per se, or mediates changes in their central integration with inhibitory vagal afferents, is not known. One may view Peo2RT as the breakpoint between the hypocapnic and hypercapnic region of the ventilatory CO 2 response curve. This raises the question whether the degree of mechanical-ventilation-induced feedback inhibition alters the breakpoint and thereby affects the relationship between Peo2RT and Peo2SB. Although the difference between Peo2RT and Peo2SB was small and statistically insignificant, Pe02RT was greater in five of eight normal subjects. Mechanical breaths were delivered through a mouthpiece requiring active support by jaw and cheek muscles, which may have offset some of the effects of negative feedback inhibition on inspiratory muscle recruitment (Simon and Skatrud, personal communication). In a study on intubated patients with respiratory failure, we found Peo2RT to exceed Peo2SB by 2 mm Hg, consistent with this hypothesis (24). However, these data also suggest that once the CO2 tension approaches the hypercapnic range, the increase in controller gain to the CO 2 stimulus largely supersedes the effects of feedback inhibition on inspiratory recruitment. Differences in CO2 gain between the hypocapnic and hypercapnic regions may also explain why Altose and associates (7) found ventilator setting and, thus, feedback inhibition-dependent differences in recruitment thresholds. They observed recruitment of inspiratory muscles after reductions in ventilator assist rates and/or tidal volumes at CO 2 tensions in the hypocapnic range. In contrast, if measurements are made in response to CO 2 supplementation at settings that abolish phasic respiratory muscle activity, recruitment does not occur until CO 2tensions approach the normocapnic range. Under those conditions, end-expiratory lung volume, inspiratory flow, and assist rate have comparatively little influence on inspiratory on-switch thresholds.
Pco2RT as Investigative Tool The CO 2 recruitment threshold is an exacting measure that may be of use in the
clinical assessment of respiratory system control in patients with respiratory failure. To our knowledge, CO2 threshold measurements have not been previously reported in patients with respiratory failure. By shifting the work of breathing from the respiratory muscles to a machine, we eliminated the acute effects of the mechanical load and respiratory muscle performance on controller function. Many of our patients would have been unable to reach a new steady state in ventilation after withdrawal of mechanical support. Similarly, it would be hazardous to interpret the CO 2 tension during assisted ventilation as measure of the ventilatory requirement of patients, given its dependence on ventilator settings. The interpretation of Peo2RT as measure of the breakpoint (hockey stick) of the ventilatory response curve provides interesting insights into controller function of patients with respiratory failure. Although PETeo2 is not an adequate measure of arterial Pe02 in patients with lung disease (24), the large range of Peo2RT values between 30 and> 65 mm Hg in our patients is still remarkable. The intersubject variation in Pe02RT is much larger than could be accounted for by serum bicarbonate (figure 6). The point we wish to make is not to dispute the influence of pH and buffer reserve on ventilation, but to illustrate the multifactorial nature of the determinants of the recruitment threshold (25, 26). A deviation in CO 2 breakpoint from normal values is either the result of a primary abnormality in respiratory controller function or, more likely, the consequence of a secondary adjustment to disease state and ventilatory loads. Although our small sample size precludes firm statistical conclusions, it is of note that patients with heart failure had significantly lower Pe02RT values than did patients with COPD alone. Patients with acute lung injury could not be studied at all because we found it difficult to suppress respiratory muscle activity solely with mechanical hyperventilation. These preliminary observations suggest the following hypothesis. In patients with pulmonary edema, signals arising from mechanoreceptors within the lungs, and possibly within the heart, cause respiratory motor output and ventilatory requirement to increase. The increase in ventilation, which is now driven by nonchemical factors, acutely shifts Pe02away from its set point to the left onto the hockey stick region of the ventilatory response curve. This is a nonsteady state with respect to the chemical control of
breathing. If it is allowed to persist, chronic hyperventilation may result in a secondary adjustment in CO 2 responsiveness to lower threshold levels. Similarly, patients with a sustained imbalance between load and performance capacity of respiratory muscles (e.g., patients with COPD) could shift their CO 2 threshold upward in an attempt to reduce their ventilatory requirement. The recent success in reducing Pco, in hypercarbic patients with COPD with intermittent mechanical ventilation may be explained by this mechanism (27, 28). The neurophysiologic basis for the adjustment in CO 2 set point is unlikely to be resolved by clinical studies alone. However, the recruitment threshold technique provides an excellent tool to evaluate the changes in "chemostat" in response to disease state and in response to the host of medical interventions to which patients with respiratory failure are subjected. Furthermore, this technique offers an opportunity to study the time course over which the control system adapts to a change in input. The critical care practitioner is encouraged to consider the need for this information since Pe02RT is the best measure of the ventilatory requirement that patients must sustain during weaning from mechanical ventilation (29). Acknowledgment The writers thank Patricia A. Muldrow and Lori L. Oeltjenbruns for their secretarial assistance. References 1. Dempsey JA. CO 2 response: stimulus definition and limitations. Chest 1976; 70:114-8. 2. Fencl V. Ventilatory response to carbon dioxide in humans. Chest 1976; 70(Suppl):113-4. 3. Lourenco RV, Miranda JM. Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Eng}J Moo 1968; 279:53-9. 4. Tenney SM. Ventilatory response to carbon dioxide in pulmonary emphysema. J Appl Physiol 1954; 6:477-84. 5. Whitelaw WA, Derenne J-P, Milic-Emili J. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 1975; 23:181-99. 6. Marazzini L, Cavestri R, Gori D, Gatti L, Longhini E. Difference between mouth and esophageal occlusion pressure during CO2 rebreathing in chronic obstructive pulmonary disease. Am Rev Respir Dis 1978; 118:1027-33. 7. AltoseMD, CasteleRJ, ConnorsAF Jr, Dimarco AF. Effects of volume and frequency of mechanical ventilation on respiratory activity in humans. Respir Physiol 1986; 66:171-80. 8. Konno K, Mead J. Measurement of the separate volume changes of rib cage and abdomen during breathing. J Appl Physiol 1967; 22:407-22. 9. Lopata M, Evanich MJ, Lourenco RV. Quantification of diaphragmatic EMG response to CO 2 rebreathing in humans. J Appl Physiol 1977; 43:262-70.
764 10. Evanich MJ, Lopata M, Lourenco RV. Analytical methods for the study of electrical activity in respiratory nerves and muscles. Chest 1976; 70:158-62. 11. Hubmayr RD, Gay PC, Thyyab M. Respiratory system mechanics in ventilated patients: techniques and indications. Mayo Clin Proc 1987; 62:358-68. 12. Gay PC, Rodarte JR, Thyyab M, Hubmayr RD. Evaluation of bronchodilator responsiveness in mechanically ventilated patients. Am Rev Respir Dis 1987; 136:880-5. 13. Pepe PE, Marini JJ. Occult positive endexpiratory pressure in mechanically ventilated patients with airflow obstruction: The auto-PEEP effect. Am Rev Respir Dis 1982; 126:166-70. 14. Sharp JT, Goldberg NB, Druz WS, Danon J. Relative contributions of rib cage and abdomen to breathing in normal subjects. J Appl Physiol 1975; 39:608-18. 15. Lavietes MH, Rochester DF. Assessment of airway function during assisted ventilation. Lung 1981; 159:219-29. 16. Marini JJ, Capps JS, Culver BH. The inspiratory work of breathing during assisted mechanical ventilation. Chest 1985; 87:612-8. 17. Cunningham DJC, Robbins PA, Wolff CB.
PRECHTER, NELSON, AND HUBMAYR
Integration of respiratory responses to changes in alveolar partial pressures of COl and 0 1 and in arterial pH. In: Geiger SR, ed. Handbook of physiology, Section 3: The respiratory system. VoL 2. Bethesda: American Physiological Society, 1986; 475-528. 18. Cunningham DJC, O'Riordan JLH. The effect of a rise in the temperature of the body on the respiratory response to carbon dioxide at rest. Q J Exp Physiol 1957; 42:329-45. 19. Smith AC, Spalding JMK, Watson WE. Ventilation volume as a stimulus to spontaneous ventilation after prolonged artificial ventilation. J Physiol (Lond) 1962; 160:22-31. 20. Fink BR, Hanks EC, Ngai SH, Papper EM. Central regulation of respiration during anesthesia and wakefulness. Ann NY Acad Sci 1963; 109:892-9. 21. Eldridge FL. Central neural respiratory stimulatory effect of activerespiration. J Appl Physiol 1974; 37:723-35. 22. Henke KG, Arias A, Skatrud JB, Dempsey JA. Inhibition of inspiratory muscle activity during sleep: chemical and nonchemical influences. Am Rev Respir Dis 1988; 138:8-15. 23. Fink BR, Ngai SH, Hanks EC. The central regulation of respiration during halothane anesthe-
sia. Anesthesiology 1962; 23:200-6. 24. Yamanaka MK, Sue DY. Comparison of arterial end-tidal PC01 difference and dead space/tidal volume ratio in respiratory failure. Chest 1987; 92:832-5. 25. Goldring RM, Thrino GM, Heinemann HO. Respiratory-renal adjustments in chronic hypercapnia in man: extracellular bicarbonate concentration and the regulation of ventilation. Am J Med 1971; 51:772-84. 26. Goldring RM, Heinemann HO, Thrino GM. Regulation of alveolar ventilation in respiratory failure. Am J Med Sci 1975; 269:160-70. 27. Braun NMT, Marino WD. Effect of daily intermittent rest of respiratory muscles in patients with severe chronic airflow limitation (CAL). Chest 1984; 85(Suppl:59-6O). 28. Cropp A, Dimarco AF. Effects of intermittent negative pressure ventilation on respiratory muscle function in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135:1056-61. 29. Dunn WF, Nelson SB, Hubmayr RD. The CO 2 recruitment threshold predicts the ventilatory requirement during weaning (abstract). Am Rev Respir Dis 1989; 139:A99.
GARY
c.
PRECHTER, STEVEN B. NELSON, and ROLF D. HUBMAYR
Introduction
Measurements of chemosensitivity and ventilatory drive in patients with respiratory disease are difficult to interpret (1-3). In patients with pulmonary emphysema, the ventilatory response to CO 2 is typically reduced, a finding consistent with a decrease in chemosensitivity and controller gain (4). However, because ventilation not only is a function of respiratory controller output but also depends critically on the mechanical efficiency of respiratory muscles, their contractile properties, and the mechanical impedance of the respiratory system, no simple conclusions about respiratory drive can be made from conventional ventilatory response measurements (1). In 1975,Whitelaw and coworkers (5) introduced the measurement of the airway occlusion pressure (P o• t ) in an attempt to define a variable that was more specific for respiratory controller output and independent of any mechanical impairments of the respiratory system. During the past decade, however, it has become apparent that the measurement of Pe.. does not fulfill these criteria and has its own set of limitations (6). Thus, important questions pertaining to the role of ventilatory control mechanisms in the pathophysiology of acute and chronic respiratory failure remain unanswered. In this report, we describe our initial experience with a method with which the chemosensitivity of the respiratory controller can be analyzed in terms of a ventilatory on-switch threshold to CO 2. This threshold measurement does not require spontaneous ventilation as output of respiratory controller activity and, thus, is independent of respiratory muscle function and the mechanics of the system. The technique has been adapted from experiments initially described by Altose and associates (7), who evaluated the effects of ventilator settings on respiratory activity in normal volunteers. Wemade measurements in normal subjects as well as in patients with respiratory failure who were mechanically hyperventilated to suppress phasic respiratory motor activity. The CO 2 recruitment threshold 758
SUMMARY Wereport our Initial experience with a technique with which the chemoresponslvenesa of the respiratory controller can be characterized In terms of an Inspiratory on-switch threshold to CO 2 • After suppression of phasic respiratory muscle activity by mechanical ventilation, a CO2 recruitment threshold (PC02 RT) was defined as the lowest alveolar CO2 tension at which CO 2 supplementation to Inspired gas caused a reappearance of Inspiratory efforts. Because PC02RT can be determined In the absence of a mechanical load on the ventilatory pump, respiratory system mechanics and Inspiratory muscle function should not Influence the measurement Itself. Thus, this technique may be helpful to study ventilatory requirements and load responses In critically III patients with respiratory failure. We haveshown that Inspiratory muscle recruitment can be equally well-Inferred from changes In the airway pressure and flow tracings during mechanical ventilation, from the pattern of chest wall displacement, and from the Integrated diaphragm electromyogram. Within a subject, PC02RT Is a reproducible measurement that Is not Influenced by ventilator settings and end-explratory lung volume; provided that phasic respiratory muscle has been suppl'8888dprior to CO2 supplementation. Details of the methodology, the lilely determinants of PC02RT', and the clinical utility of this technique are discussed. AM REV RESPIR DIS 1990; 141:758-7&4
(Peo2RT) was then defined as the lowest end-tidal Peo2 (PETeo2) at which the supplementation of CO 2 to inspired gas caused a reappearance of respiratory effort. The purpose of this report is to address the likely determinants of this test of chemosensitivity, to discuss its application as an investigative tool for the study of mechanisms in disease, to put the clinical usefulness of this information into perspective, and finally to discuss the limitations of the method. Methods Studies in Normal Volunteers Study population. Ten adult volunteers (nine men and one woman) 27 to 38 yr of age who werewithout acute or chronic illnessgavetheir informed consent to participate in this study. Most of them were familiar with physiologic measurement techniques and had some knowledge about the objectives of this study. However, they had no access to any information that was obtained during the experimental protocol. Measured Variables The subjects breathed through a mouthpiece with a noseclip in place while resting comfortably in the supine position. Inspired and expired CO 2 tensions were measured from a side port of the mouthpiece with a capnograph (Puritan-Bennett, Los Angeles, CAl with linear response characteristics for fractional CO2 concentrations up to 0.08. The capnograph was calibrated with 5070 CO 2 before
each study, and all reported values were converted to partial pressure by the measured barometric pressure. Subjects were mechanically ventilated with a Siemens 900B ventilator that delivered oxygen-enriched gas (Flo 2 > 0.9) through a standard ventilator tubing/mouthpiece assembly. During mechanical ventilation, airway pressure and expiratory flow signals were accessed directly from the analog output ofthe ventilator, which had been calibrated against known standards before this series of experiments. In three subjects, the presence of respiratory effort was also evaluated from the pattern of chest wall motion and the electromyographic activity of the diaphragm. Rib cage and abdominal dimensions were monitored with a calibrated inductive plethysmograph (Respigraph'", NIMS, Miami Beach, FL), and their relative change was displayed on an oscilloscope (8). The electromyographic activity of the diaphragm was recorded from esophageal leads using a modified Swan-Ganz catheter. The catheter was introduced through the nose into the stomach, a small distal bal-
(Received in original form February 13, 1989 and in revised form August 3, 1989) 1 From the Division of Thoracic Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. 2 Supported by Program Project Grants HL21584 and HL-38107 from the National Institutes of Health. 3 Correspondence and requests for reprints should beaddressed to Rolf D. Hubmayr, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
759
CO 2 RECRUITMENT THRESHOLD
loon was inflated, and the catheter was withdrawn such that the three ring leads came to rest at the gastroesophageal junction. Differential electrodes were chosen to maximize the output of the rectified, amplified, and filtered electrical signal. The amplitude of the moving time average electromyogram of the diaphragm (Edi) was taken as an index of diaphragm recruitment (9, 10). Carbon dioxide tensions measured at the airway opening, airway pressure, expiratory gas flow, and Edi were recorded on a four-channel stripchart recorder (HP-7414; Hewlett-Packard, Waltham, MA) and stored along with chest wall motion data on FM magnetic tape (Racal 7).
Experimental Protocol Experiment Series 1. In eight subjects PETc02 was measured during spontaneous breathing after 20 min of rest in the supine posture. By 5 min, all subjects had achieved a steady state after which PETc02 changed by lessthan 1 mm Hg, The mean PETC02 of 10 consecutive breaths was recorded and defined as the Pco2SB. Subsequently, mechanical ventilation was begun at a tidal volume of 10 to 12 ml/kg, an inspiratory time of 25070 of total breathing cycleduration (not), an end inflation hold time of 10070 not, and a frequency resulting in a minute ventilation slightly above that found during spontaneous breathing. The initial ventilator settings did not suppress phasic respiratory motor activity in any of the subjects. Therefore, the ventilator frequency was increased by 2 breaths/min every 3 to 5 min until objective evidence of spontaneous ventilatory efforts disappeared. The absence of phasic respiratory motor activity was based on specific criteria, all of which had to be met (figure lA). Because inspiratory flow was delivered in a square wave profile, the airway pressure time trace needed to show an initial step increase followed by a linear rise to some peak value. While the respiratory system was held at end inspiration for 10070 of not, the airway occlusion pressure was required to achieve a plateau value. Expiratory flow had to reach its peak value at the beginning of expiration and decline exponentially with time. The sensitivity and specificity of these criteria relative to Edi and chest wall motion were evaluated in three subjects in whom these additional measurements were made. Compared with spontaneous breathing, the minute ventilation required to suppress phasic respiratory muscle activity during mechanical ventilation was considerably greater. The PETC02 at which respiratory muscle recruitment disappeared defined an apnea threshold (Pco2AT) (figure lA). After 5 min at the "apnea level" of ventilation, CO 2 was added in a stepwise manner to the inspired gas without the subject's knowledge, increasing the PETC02 by approximately 3 mm Hg every 3 min. For this purpose, a pressurized circuit containing 100070 oxygen was connected in parallel with a CO 2tank from which the flow could be regulated between zero and 15
A. (~pnea threshold) 56
PETC02 mm Hg
B. (Recruitment threshold)
42 28
14
o
Edi
Pao em H20
Vex Lisee
20
10
o
0.8 0.4
o
5 sec Fig. 1. Representative tracings of CO 2 tension recorded at airway opening (PETC02 ) , moving time average of diaphragm electromyogram recorded from esophageal leads (Edi), airway pressure (Pao), and expiratory flow (Vex). Recordings were made during mechanical ventilation at settings that abolished phasic diaphragm activity (A) and after CO 2 supplementation led to respiratory muscle recruitment (B). Note the difference in Pao and Vex in the presence and in the absence of diaphragm activity.
L/min. The oxygenand CO 2sources wereconnected with a Y piece to the gas inlet port of the ventilator. The PETC02 at which phasic respiratory motor activity reappeared defmed a Pco2Rf, that is, the ventilatory threshold for CO 2 (figure IB). The presence of respiratory effort was defined by the absence of previously established relaxation criteria for 10 or more consecutive breaths. At this juncture, inspired CO 2 supplementation was discontinued for 5 min. This led to the disappearance of phasic respiratory motor activity within 1to 2 min in all subjects. Carbon dioxide was then added as before to determine the recruitment threshold for a second time (Pco2Rf 2). During this second run, the subject was asked to indicate any symptoms or perception of respiratory effort by raising his or her hand, at which time PETC02 was again noted (Pc 02SX). Experiment Series 2. On a different day we evaluated the dependence of Pc01Rf on ventilator settings, on time and CO 2 history preceding recruitment, and on the sequence in which individual experiments were performed. For this purpose we made a series of measurements in random order in six subjects. In one of the runs, the sequence of changes in ventilator rates and inspired CO 2 concentrations {FIcoJ was as described above. In another run, PETC02 was maintained between 34 and 38 mm Hg by CO 2 supplementation, whereas ventilator rate and minute ventilation were increased until respiratory effort became undetectable (test of CO 2 history). Then Pco2Rf was determined as before. In a third run, Pco2AT was approached more slowly, i.e., by increasing the machine rate ev-
ery 15 instead of every 3 min (test of time history).
Studies in Patients Population. Thirteen intubated ventilatordependent patients with respiratory failure were studied. Age, sex, duration of mechanical ventilation, length of stay in the intensive care unit, and principal cardiopulmonary diagnoses are listed in table 1. Informed consent was obtained from the patient or, when appropriate, from a responsible family member. Patients with hemodynamic instability, pulmonary edema, and metabolic acidosis were excluded. Sedatives and narcotics were withheld for 4 h before testing, and all other management decisions were made by the attending physician. Experimentalprotocol. Subjects were studied in a quiet room and mechanically ventilated with 100070 oxygen. Tidal volumes ranged between 10 and 15ml/kg, and the inspiratory time was between 15 and 33070 of the total breathing cycle duration. A pneumatic occlusion valve (No. 7200; Hans-Rudolph, Kansas City, MO) and a heated pneumotachograph (Fleisch no. 2) were placed between ventilator circuit and endotracheal tube. Flow at the airway opening was calculated from the pressure (Validyne 45 MP; Validyne Corp., Northridge, CAl drop across the pneumotachograph. Volume was derived by integration of the flow signal. Airway pressure was measured with a separate pressure transducer (Validyne DP9) at the oral end of the endotracheal tube. Capnograph and recording systems were otherwise identical to those described above. The ventilatory assist rate was increased by
760
PRECHTER, NELSON, AND HUBMAYR
TABLE 1
12
CLINICAL DATA ON 13 VENTILATOR-DEPENDENT PATIENTS WITH HYPERCARBIC RESPIRATORY FAILURE
10
(yr)
Sex
ICU Days/Days on Ventilator
Cardiopulmonary and Related Disease
1 2 3
82 54 69
M M
38/38
78n8
F
17/12
4 5* 6*
81
M
84
F F
13/8 50/44 68/43
Myxedema CAD CHF,ESRD Myasthenia gravis, CHF Pontine CVA COPD, CHF, MR, MI COPD, CHF, rib fractures from MVA COPD,CHF Asthma, COPD COPD COPO, obstructive sleep apnea COPD COPD, polymyositis, obesity COPD, upper abdominal surgery
Subject No.
Age
87
M
7 8 9 10
75 56 72 66
11 12
62 46
M F
59/59 78/48
13
66
F
24/12
F
M M
41/37 43/31 10/9
8n
Definitionof abbreviations: CAD = coronary artery disease; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; CVA = cerebral vascular accident; ESRD = end-stage renal
disease; ICU = intensive care unit; MI = myocardial infarction; MR = mitral regurgitation; MVA = motor vehicle accident. * Subject died during hospitalization.
two breaths every 5 min until phasic respiratory muscle activity disappeared. The mechanical characteristics of the relaxed respiratory system were then assessed with an interrupter technique (11). In brief, the static elastic recoil pressure of the respiratory system was determined at 5 to 10 lung volumes between end inspiration and static equilibrium volume and then related to expiratory flow. The expiratory flow at a recoil pressure of 6 em H 20 (VP6) was estimated from the pressure-flow curves and was taken as an index of the severity of the airway obstruction (12). We assumed that expiratory flow limitation was present when VP6 failed to decline with the addition of an expiratory resistive load. The resistance offered by the expiratory circuit of the ventilator was sufficient to make this determination. The Pc02AT and Pc02RTwere determined as described above. In seven patients, Pco2RT was measured in triplicate. The dependence of Pc02RT on ventilator settings and the lung volume at end expiration (VEE) was evaluated in five additional patients. All five patients had expiratory flow limitation during passive expiration, and the elastic recoil pressure of the respiratory system at end expiration (intrinsic positive end-expiratory pressure; PEEP) ranged between 5 and 15em H 20 (13). Thus, VEE during mechanical ventilation could be reduced by a proportionate increase in inspiratory flow and expiratory time before the measurement of Pco2RTwas repeated. In the same patients, VEE was increased with an extrinsic PEEP device, and Pc02RT was again determined.
Data Analysis To eliminate any bias as to the presence or
absence of phasic respiratory motor activity by the investigator who conducted the experiments, the records werescored by two observers who had no knowledge of the simultaneously recorded PETC02. The agreement with respect to phasic respiratory motor activity between blinded observerswas 100070 and consistently supported the assessment of the nonblinded investigator. Group mean data werecompared using Student's t tests for paired observations. Statistical significance was assumed when the p value was < 0.05. Correlations between variables were analyzed by least-squares linear regression. Differences between Pco2RT measurements obtained under varying experimental conditions (Experimental Series 2) were assessed using an analysis of variance for repeated measures.
Mechanical hyperventilation
o L-_...J.::!=~J==~=:::::I:=e~.1..-_.J 24
28
32
38
40
48
PETC02. mm Hg Fig. 2. Example of PETC02 and amplitude of the moving time average electromyogram of diaphragm (Edi). PETC02 and Ediduring spontaneous breathing(SB)are indicated by the solid triangle. Symbolsindicate mean values averagedover 30 s precedinga change in conditions. Sequence of these changes is representedby the arrows. Open circles indicate presence of spontaneous respiratory activity, and closed circles indicate its absence. Apnea threshold (AT) and recruitment threshold (AT) are shown as squares.
between relaxation criteria based on inspiratory pressure and expiratory flow profiles and the absence of electrical activity of the diaphragm (figures 1 and 2). During mechanical ventilation at apnea threshold, the cross-sectional area of the rib cage and abdomen changed along a similar path during inspiration and expiration (figure 4, left panel). As previously shown, this pattern of chest wall deformation is consistent with relaxation of respiratory muscles and differs from that observed during spontaneous breathing in the supine posture (14). Recruitment threshold Pcoi. The supplementation of CO2 to the inspired gas did not cause recruitment of respiratory muscles of the mechanically hyperventilated respiratory system until a threshold value in PETCOl was reached (figures 1 to 3). Phasic respiratory motor activityaltered the inspiratory pressure-time profile, reduced peak expiratory flow, changed
Results
Studies in Normal Volunteers Apnea threshold. Although subjects attempted to suppress spontaneous breathing efforts during positive-pressure ventilation, objective evidence of phasic respiratory motor activity persisted until the minute ventilation delivered by the ventilator reached 10to 19 L/min (figures 2 and 3). Pco,AT ranged between 22 and 29 mm Hg and was 12 to 18 mm Hg lower than Pco2SB. The assisted respiratory rate and mean inspiratory flow at which phasic respiratory muscle activity disappeared were 18.6 ± 2.8 breaths/min and 0.92 ± 0.18 L/s, respectively. In the three subjects in whom Edi was also determined, there was concordance
20
16
e
§ .~
AT
C02 supplementation
RT
"
12
8
O-----------.__ 24
28
32
36
~_..L--_
40
__I
48
PETC02. mm Hg Fig. 3. Exampleof PETC02 and minute ventilation(VE) during an experiment. Symbols indicate mean values averagedover 30 s preceding a change in conditions. Sequence of these changes is represented by the arrows.Open circles indicate the presenceof spontaneous respiratory activity, and closed circles indicate its absence.Apneathreshold(AT)and recruitmentthreshold (AT) are shown as squares.
761
CO 2 RECRUITMENT THRESHOLD
AT
Rib cage
TABLE 3
RT
mc~
mc/
VENTILATOR SETTINGS, RESPIRATORY SYSTEM MECHANICS, AND CO 2 THRESHOLDS IN 13 VENTILATOR-DEPENDENT PATIENTS WITH RESPIRATORY FAILURE Subject No.
VT (L)
f (breaths/min)
Ve (L)
VP6/EFL (L/s)
PEEPi (em H2O)
PC0 2AT (mmHg)
Pco2RT (mm Hg)
0.75 0.55 1.00 0.60 0.73 0.68 1.47 0.58 1.15 0.80 0.75 0.70 0.70 0.75
20 25 12 20 15 12 15 24 15 20 12 20 20 20
15.0 13.8 12.0 12.0 11.0 8.2 22.1 13.9 17.3 16.0 9.0 14.0 14.0 15.0
0.5000.8751.0500.3750.075+ 0.100+ 0.150+ 0.200+ 0.100+ 0.080+ 0.200+ 0.075+ 0.100+ 0.050+
1 0 2 0 6 5 12 8 10 5 5 10 6 15
26 34 30 29 26 28 19 21 55 29 41 34 37 20
33 40 48 35 43 44 30 41 > 64* > 62* 65 59 54 37
Abdomen 1 2 3 4 5 6 7 8 9 10 11t
Fig. 4. The relative displacements of rib cage and abdomen are contrasted during mechanical ventilation at apnea threshold (AT) and recruitment threshold (RT). Solid dot depicts FRC. Its location within plots was chosen arbitrarily. Note the hysteresis between inspiration and expiration (arrows) when respiratory muscles are recruited.
the pattern of chest wall deformation (figure 4, right panel), and led to an increase in Edi with each inspiration. Assisted breaths were frequently preceded by negative airway pressure swings, representing attempts to trigger a machine breath. Inspiratory efforts were not necessarily associated with an increase in respiratory rates. Abdominal excursions increased relative to the displacement of the rib cage, and the shape of the chest wall differed between inspiration and expiration (figure 4, right panel). The Pco2RT and Pco2SB were within 1.5 mm Hg in seven of the eight subjects (Experiment Series 1), and their mean values were not significantly different from each other (41.2 versus 40.5 mm Hg), The perception of respiratory effort coincided with objective evidence of phasic respiratory muscle activity in three subjects and followed Pco2RT by ~ 2 mm Hg in the five remaining subjects. By definition, no subject was able to suppress respiratory activity voluntarily at or beyond Pco2RT.
12 13
Definition of abbreviations: EFL = expiratoryflow limitation;f = respiratoryrate; PC02AT = apnea threshold; PCo 2RT = CO2 recruitmentthreshold; PEEPj = intrinsic positiveend-expiratory pressure; VE = minute ventilation; VP6, expiratoryflow at a system recoil pressureof 6 cm H2O. • Recruitment could not be demonstrated. t Two studieswere obtained 14 days apart.
Individual and group mean data of CO2 threshold measurements and minute volumes in six normal volunteers obtained under different experimental conditions (Experimental Series 2) are listed in table 2. Despite significant differences in minute ventilation, inspiratory flow, assist rate, and Pco~T, the Pco2RT values were similar at all experimental settings. Differences in minute ventilation and flow between the runs reflect differences in the assist rate necessary to suppress phasic motor activity. These differences are entirely explained by the run sequence, that is, the assist rate necessary to suppress inspiratory recruitment
TABLE 2 DEPENDENCE OF RECRUITMENT THRESHOLD ON EXPERIMENTAL SETTING IN NORMAL SUBJECTS* Run At Subject No. 1 2 3 4 5 6 Mean SO
Pco2RT 1
46.2 39.6 1 39.9 3 46.43 41.91 41.33 42.6 3.0
Run C§
Run Bt Ve
Pco2RT
18.4 22.1 10.6 9.6 13.2 9.0 13.8 5.3
46.0 2 41.0 2 43.3 1 45.8 1 41.2 3 42.02 43.2 2.2
Ve 16.2 18.9 18.5 14.4 11.0 9.0 14.7 4.0
Pco2RT 3
45.5 39.6 3 43.3 2 44.4 2 40.5 2 42.0 1 42.6 2.3
Ve 13.9 15.6 13.2 9.6 9.6 11.2 12.2 2.4
Definition of abbreviations: Pco 2RT = CO2 recruitmentthreshold; VE = minute ventilation.
• During all runs the tidal volumewas 12 mllkg and the inspiratorytime was 25% of the total cycle duration. The inspired CO2 tension was always raised between 2 to 4 mm Hg every 3 to 5 min once the initialconditionswere met.A, B, andC identifythe differentexperimental runs.The numbersabove and to the right of the Pco2 RT values indicate the order in which individualruns were performed. t Increasein ventilatorassistrateby two breathsevery 3 min until apnea(absence of phasicrespiratory motor activity)was observed. Same as run A except that PETC02 was kept> 34 mm Hg throughoutby CO2 supplementation. § Increasein ventilator assist rate by 2 breaths every 15 minutes unit apneawas observed.
*
was always greater during the initial experimental run (p ~ 0.05).
Studies in Patients The ages of the 13 patients (seven male and six female) ranged from 46 to 87 yr (table 1). Various cardiopulmonary disorders were present. The most common cause of respiratory failure in this group of patients was COPD complicated by some other illness, All nine patients with a clinical diagnosis of COPD (Subjects 5 through 13) were flow-limited during passive expiration near static equilibrium volume and were hyperinflated at ventilator settings necessary to abolish phasic respiratory muscle activity (table 3). Accordingly, intrinsic PEEP ranged between 5 and 15 em H 20 , and VP6 was 0.2 Lis or less. There was no overlap in either intrinsic PEEP or VP6 between patients with and without COPD. In patients without a clinical diagnosis of COPD (Subjects 1 through 4), intrinsic PEEP was less than 5 em H 20 , and VP6 ranged between 0.4 and 1.1 Lis. On average, as shown in tables 1 and 3, Pco2RT was lower in patients without airflow obstruction unless COPD was associated with left heart failure (Subjects 1 through 7; median = 40 mm Hg), The Pco2RT was highest in those with COPD without heart disease (Subjects 8 through 13; median = 57 mm Hg). In figure 5, Pco~T and Pco2RT from all patients are plotted against each other. One patient (Subject 11) had two
762
PRECHTER, NELSON, AND HUBIIAYR
88 58 CJ)
%:
E
E
~N
0
~
Fig. 5. Relationship between CO 2 tensions at apnea threshold (Pco 2AT) and recruitment threshold (Pco 2RT)in 13 patients. One patient had two studies 2 wk apart (open circles). In two patients, recruitment was not achieved, and highest PETC02 values are plotted (triangles). The solid line is the line of identity.
50
42
0
•
34
•
28
• 28
42
34
0
• ••
PC02RT,
• 68
58
50
mm Hg
Repeated recruitment threshold measurements (measured in triplicate) were within 2 mm Hg in six of seven patients and within 3 mm Hg in the remaining patient. In everypatient in whom Pco 21IT was reexamined after VEE had been altered by 0.3 to 1.2 L, Pco2RT remained within 10070 of baseline.
studies 14 days apart. In the seven patients in whom more than one estimate of Pco2Rf was obtained on the same day, mean values are shown. In two instances (Subjects 9 and 10), Pco2RT could not be determined safely because further CO 2 supplementation might have caused acidemia. In these two patients, the highest observed PETC02 values are shown. In general, Pco"AT and Pco2RT were correlated with each other, but more remarkable was the large difference between apnea and recruitment thresholds within subjects and the large range in either value across patients. The group mean ± SD of Pco"AT was 30.6 ± 9.5 mm Hg. This value was significantly lower than the Pco2RT value of 44.1 ± 10.7mm Hg, The difference between apnea and recruitment thresholds ranged from 6 mm Hg (Subject 3) to more than 33 mm Hg in a patient who had COPD and obstructive sleep apnea (Subject 10). The relationship between Pco2 RT and arterial bicarbonate concentration is shown in figure 6. The mean arterial bicarbonate was 27 mEq/L, and it was ~ 30 mEq/L in 12 of 13 patients. In Subject 11, who had two studies 2 wk apart, there was a decrease in PC021IT from 65 to 59 mm Hg, which corresponded with a decrease in bicarbonate from 38 to 32 mEq/L.
Discussion
The Technique The accuracy of this technique rests with the timely detection of phasic respiratory motor activity. During controlled mechanical ventilation (the term is used to indicate the absence of respiratory muscle recruitment), airway pressure and flow tracings show a characteristic pattern (figure IA). This occurs because the respiratory system behaves like a onecompartment model consisting of a resistive and elastic element in series (11, 15). When it is inflated with a constant flow, there is an initial step increase in pressure corresponding to the pressure drop across the resistive element, which is followed by a linear rise as the elastic element expands. When deflation is driven only by the recoil pressure of the respiratory system, expiratory flow reaches a sharp initial peak and declines with time. If inspiratory muscles act in concert
40 0
38
Fig. 6. Relationship between arterial plasma bicarbonate concentration (HCO~ and recruitment threshold (Pco 2 RT) in 13 patients. One patient had two studies 2 wk apart (open circles). In two patients, recruitment was not achieved, and highest PETC02 values are plotted
-I
~
32
i. 0
28
0
E
•
0 J:
•
•
24
..
••
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• • • •
•
(triangles).
20
30
~ --..
34
38
42
48
50
54
PC02 RT, mm Hg
58
82
86
with the ventilator, inspiratory airway pressure and/or expiratory flow patterns deviate from model predictions. This is because respiratory muscles and ventilator are mechanically arranged in parallel. Therefore, the work performed by the respiratory muscles during mechanical ventilation can be estimated from pressure and flow tracings (16). The example in figure IB illustrates that once inspiratory muscles were recruited, their activity persisted beyond the inspiratory machine cycle, causing a decrease in end inflation pressure and peak expiratory flow. Assessing onset of muscle recruitment from pressure and flow has certain advantages over electromyographic techniques. Pressure and flow can be easily recorded in a clinicalsetting from the output of most ventilators, avoiding the placement of esophageal leads. In three volunteers in whom simultaneous measurements of pressure, flow, Edi, and chest wall motion were made, there was excellent concordance between invasive EMG monitoring and mechanical recruitment criteria (figure 1). In our hands, any of these measurements were superior to surface EMG recordings from the lower rib cage (preliminary studies preceding these experiments).
The Determinants of Pco2AT and PC02KT In humans, the ventilatory CO 2response curve has two distinct regions with different slopes (17). In the hypocapnic range, breathing is irregular and ventilation is essentially independent of CO 2 tensions. Most investigators have studied this region while stimulating ventilation either voluntarily, by inducing hypoxia, or by raising body temperature (18). The causes of respiratory muscle recruitment in the hypocapnic range are unclear. Respiratory memory (19), state of arousal (20), and local after-discharge within respiratory centers have all been implicated (21). Whatever the cause, the hysteresis in the PETco2-ventilatory output relationships (figures 2 and 3) indicates that feedback inhibition related to mechanical ventilation can abolish inspiratory muscle recruitment in awake subjects and that in the hypocapnic range the ventilator settings necessary to achieve inspiratory suppression are independent of the arterial CO 2 tension (7). The state of arousal plays an important role in the regulation of breathing in the hypocapnic range. During sleep, relatively small reductions in CO 2cause a prolongation of expiratorytime, ultimately resulting in apnea (22). In other words,
763
CO 2 RECRUITMENT THRESHOLD
the large difference between Peo~T and Peo2RT in awake subjects may be arousal-state-specific. At least during anesthesia there remains a 5 to 9 mm Hg difference between these CO 2 on- and off-' switch thresholds (23). Whether the state of arousal influences apnea threshold and the control of breathing through changes in chemoreceptor activity per se, or mediates changes in their central integration with inhibitory vagal afferents, is not known. One may view Peo2RT as the breakpoint between the hypocapnic and hypercapnic region of the ventilatory CO 2 response curve. This raises the question whether the degree of mechanical-ventilation-induced feedback inhibition alters the breakpoint and thereby affects the relationship between Peo2RT and Peo2SB. Although the difference between Peo2RT and Peo2SB was small and statistically insignificant, Pe02RT was greater in five of eight normal subjects. Mechanical breaths were delivered through a mouthpiece requiring active support by jaw and cheek muscles, which may have offset some of the effects of negative feedback inhibition on inspiratory muscle recruitment (Simon and Skatrud, personal communication). In a study on intubated patients with respiratory failure, we found Peo2RT to exceed Peo2SB by 2 mm Hg, consistent with this hypothesis (24). However, these data also suggest that once the CO2 tension approaches the hypercapnic range, the increase in controller gain to the CO 2 stimulus largely supersedes the effects of feedback inhibition on inspiratory recruitment. Differences in CO2 gain between the hypocapnic and hypercapnic regions may also explain why Altose and associates (7) found ventilator setting and, thus, feedback inhibition-dependent differences in recruitment thresholds. They observed recruitment of inspiratory muscles after reductions in ventilator assist rates and/or tidal volumes at CO 2 tensions in the hypocapnic range. In contrast, if measurements are made in response to CO 2 supplementation at settings that abolish phasic respiratory muscle activity, recruitment does not occur until CO 2tensions approach the normocapnic range. Under those conditions, end-expiratory lung volume, inspiratory flow, and assist rate have comparatively little influence on inspiratory on-switch thresholds.
Pco2RT as Investigative Tool The CO 2 recruitment threshold is an exacting measure that may be of use in the
clinical assessment of respiratory system control in patients with respiratory failure. To our knowledge, CO2 threshold measurements have not been previously reported in patients with respiratory failure. By shifting the work of breathing from the respiratory muscles to a machine, we eliminated the acute effects of the mechanical load and respiratory muscle performance on controller function. Many of our patients would have been unable to reach a new steady state in ventilation after withdrawal of mechanical support. Similarly, it would be hazardous to interpret the CO 2 tension during assisted ventilation as measure of the ventilatory requirement of patients, given its dependence on ventilator settings. The interpretation of Peo2RT as measure of the breakpoint (hockey stick) of the ventilatory response curve provides interesting insights into controller function of patients with respiratory failure. Although PETeo2 is not an adequate measure of arterial Pe02 in patients with lung disease (24), the large range of Peo2RT values between 30 and> 65 mm Hg in our patients is still remarkable. The intersubject variation in Pe02RT is much larger than could be accounted for by serum bicarbonate (figure 6). The point we wish to make is not to dispute the influence of pH and buffer reserve on ventilation, but to illustrate the multifactorial nature of the determinants of the recruitment threshold (25, 26). A deviation in CO 2 breakpoint from normal values is either the result of a primary abnormality in respiratory controller function or, more likely, the consequence of a secondary adjustment to disease state and ventilatory loads. Although our small sample size precludes firm statistical conclusions, it is of note that patients with heart failure had significantly lower Pe02RT values than did patients with COPD alone. Patients with acute lung injury could not be studied at all because we found it difficult to suppress respiratory muscle activity solely with mechanical hyperventilation. These preliminary observations suggest the following hypothesis. In patients with pulmonary edema, signals arising from mechanoreceptors within the lungs, and possibly within the heart, cause respiratory motor output and ventilatory requirement to increase. The increase in ventilation, which is now driven by nonchemical factors, acutely shifts Pe02away from its set point to the left onto the hockey stick region of the ventilatory response curve. This is a nonsteady state with respect to the chemical control of
breathing. If it is allowed to persist, chronic hyperventilation may result in a secondary adjustment in CO 2 responsiveness to lower threshold levels. Similarly, patients with a sustained imbalance between load and performance capacity of respiratory muscles (e.g., patients with COPD) could shift their CO 2 threshold upward in an attempt to reduce their ventilatory requirement. The recent success in reducing Pco, in hypercarbic patients with COPD with intermittent mechanical ventilation may be explained by this mechanism (27, 28). The neurophysiologic basis for the adjustment in CO 2 set point is unlikely to be resolved by clinical studies alone. However, the recruitment threshold technique provides an excellent tool to evaluate the changes in "chemostat" in response to disease state and in response to the host of medical interventions to which patients with respiratory failure are subjected. Furthermore, this technique offers an opportunity to study the time course over which the control system adapts to a change in input. The critical care practitioner is encouraged to consider the need for this information since Pe02RT is the best measure of the ventilatory requirement that patients must sustain during weaning from mechanical ventilation (29). Acknowledgment The writers thank Patricia A. Muldrow and Lori L. Oeltjenbruns for their secretarial assistance. References 1. Dempsey JA. CO 2 response: stimulus definition and limitations. Chest 1976; 70:114-8. 2. Fencl V. Ventilatory response to carbon dioxide in humans. Chest 1976; 70(Suppl):113-4. 3. Lourenco RV, Miranda JM. Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Eng}J Moo 1968; 279:53-9. 4. Tenney SM. Ventilatory response to carbon dioxide in pulmonary emphysema. J Appl Physiol 1954; 6:477-84. 5. Whitelaw WA, Derenne J-P, Milic-Emili J. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 1975; 23:181-99. 6. Marazzini L, Cavestri R, Gori D, Gatti L, Longhini E. Difference between mouth and esophageal occlusion pressure during CO2 rebreathing in chronic obstructive pulmonary disease. Am Rev Respir Dis 1978; 118:1027-33. 7. AltoseMD, CasteleRJ, ConnorsAF Jr, Dimarco AF. Effects of volume and frequency of mechanical ventilation on respiratory activity in humans. Respir Physiol 1986; 66:171-80. 8. Konno K, Mead J. Measurement of the separate volume changes of rib cage and abdomen during breathing. J Appl Physiol 1967; 22:407-22. 9. Lopata M, Evanich MJ, Lourenco RV. Quantification of diaphragmatic EMG response to CO 2 rebreathing in humans. J Appl Physiol 1977; 43:262-70.
764 10. Evanich MJ, Lopata M, Lourenco RV. Analytical methods for the study of electrical activity in respiratory nerves and muscles. Chest 1976; 70:158-62. 11. Hubmayr RD, Gay PC, Thyyab M. Respiratory system mechanics in ventilated patients: techniques and indications. Mayo Clin Proc 1987; 62:358-68. 12. Gay PC, Rodarte JR, Thyyab M, Hubmayr RD. Evaluation of bronchodilator responsiveness in mechanically ventilated patients. Am Rev Respir Dis 1987; 136:880-5. 13. Pepe PE, Marini JJ. Occult positive endexpiratory pressure in mechanically ventilated patients with airflow obstruction: The auto-PEEP effect. Am Rev Respir Dis 1982; 126:166-70. 14. Sharp JT, Goldberg NB, Druz WS, Danon J. Relative contributions of rib cage and abdomen to breathing in normal subjects. J Appl Physiol 1975; 39:608-18. 15. Lavietes MH, Rochester DF. Assessment of airway function during assisted ventilation. Lung 1981; 159:219-29. 16. Marini JJ, Capps JS, Culver BH. The inspiratory work of breathing during assisted mechanical ventilation. Chest 1985; 87:612-8. 17. Cunningham DJC, Robbins PA, Wolff CB.
PRECHTER, NELSON, AND HUBMAYR
Integration of respiratory responses to changes in alveolar partial pressures of COl and 0 1 and in arterial pH. In: Geiger SR, ed. Handbook of physiology, Section 3: The respiratory system. VoL 2. Bethesda: American Physiological Society, 1986; 475-528. 18. Cunningham DJC, O'Riordan JLH. The effect of a rise in the temperature of the body on the respiratory response to carbon dioxide at rest. Q J Exp Physiol 1957; 42:329-45. 19. Smith AC, Spalding JMK, Watson WE. Ventilation volume as a stimulus to spontaneous ventilation after prolonged artificial ventilation. J Physiol (Lond) 1962; 160:22-31. 20. Fink BR, Hanks EC, Ngai SH, Papper EM. Central regulation of respiration during anesthesia and wakefulness. Ann NY Acad Sci 1963; 109:892-9. 21. Eldridge FL. Central neural respiratory stimulatory effect of activerespiration. J Appl Physiol 1974; 37:723-35. 22. Henke KG, Arias A, Skatrud JB, Dempsey JA. Inhibition of inspiratory muscle activity during sleep: chemical and nonchemical influences. Am Rev Respir Dis 1988; 138:8-15. 23. Fink BR, Ngai SH, Hanks EC. The central regulation of respiration during halothane anesthe-
sia. Anesthesiology 1962; 23:200-6. 24. Yamanaka MK, Sue DY. Comparison of arterial end-tidal PC01 difference and dead space/tidal volume ratio in respiratory failure. Chest 1987; 92:832-5. 25. Goldring RM, Thrino GM, Heinemann HO. Respiratory-renal adjustments in chronic hypercapnia in man: extracellular bicarbonate concentration and the regulation of ventilation. Am J Med 1971; 51:772-84. 26. Goldring RM, Heinemann HO, Thrino GM. Regulation of alveolar ventilation in respiratory failure. Am J Med Sci 1975; 269:160-70. 27. Braun NMT, Marino WD. Effect of daily intermittent rest of respiratory muscles in patients with severe chronic airflow limitation (CAL). Chest 1984; 85(Suppl:59-6O). 28. Cropp A, Dimarco AF. Effects of intermittent negative pressure ventilation on respiratory muscle function in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135:1056-61. 29. Dunn WF, Nelson SB, Hubmayr RD. The CO 2 recruitment threshold predicts the ventilatory requirement during weaning (abstract). Am Rev Respir Dis 1989; 139:A99.
