Thorax 1996;51:677-683

Breathing pattern and carbon dioxide retentionin severe chronic obstructive pulmonary disease

Massimo Gorini, Gianni Misuri, Antonio Corrado, Roberto Duranti, Iacopo Iandelli,Eduardo De Paola, Giorgio Scano

AbstractBackground - The factors leading tochronic hypercapnia and rapid shallowbreathing in patients with severe chronicobstructive pulmonary disease (COPD)are not completely understood. In thisstudy the interrelations between chroniccarbon dioxide retention, breathing pat-tern, dyspnoea, and the pressure requiredfor breathing relative to inspiratorymuscle strength in stable COPD patientswith severe airflow obstruction were stud-ied.Methods - Thirty patients with COPD ina clinically stable condition with forcedexpiratory volume in one second (FEV1)of <1 litre were studied. In each patientthe following parameters were assessed:(1) dyspnoea scale rating, (2) inspiratorymuscle strength by measuring minimalpleural pressure (PPLmin), and (3) tidalvolume (VT), flow, pleural pressure swing(PPLSW), total lung resistance (RiL),dynamic lung elastance (ELdyn), and pos-itive end expiratory alveolar pressure(PEEPi) during resting breathing.Results - Arterial carbon dioxide tension(Paco2) related directly to RLiPPLmin,and ELdynIPPLmin, and inversely to VTand PPLmin. There was no relationshipbetween Paco2 and functional residualcapacity (FRC), total lung capacity (TLC),or minute ventilation. PEEPi was similarin eucapnic and hypercapnic patients.Expressing Paco2 as a combined functionof VT and PPLmin (stepwise multiple re-gression analysis) explained 71% of thevariance in Paco2. Tidal volume wasdirectly related to inspiratory time (TI),and TI was inversely related to thepressure required for breathing relativeto inspiratory muscle strength (PPLSW,%PPLmin). There was an association be-tween the severity of dyspnoea and boththe increase in PPLSW (%PPLmin) and theshortening in TI.Conclusions - The results indicate that,in stable patients with COPD with severeairflow obstruction, hypercapnia is as-sociated with shallow breathing and in-spiratory muscle weakness, and rapid andshallow breathing appears to be linked toboth a marked increase in the pressurerequired for breathing relative to in-spiratory muscle strength and to the se-verity of the breathlessness.(Thorax 1996;51:677-683)

Keywords: chronic obstructive pulmonary disease, hyper-capnia, breathing pattern, respiratory muscle weakness,breathlessness.

The mechanisms which lead to chronic hyper-capnia in patients with chronic obstructivepulmonary disease (COPD) are not completelyunderstood. Although carbon dioxide retentionis dependent on the severity of airways ob-struction, there is considerable variability inthe relationship between arterial carbon dioxidetension (Paco2) and forced expiratory volumein one second (FEVI).' Other factors such asventilation-perfusion mismatch,2 abnormalitiesin ventilatory control,34 respiratory muscleweakness,56 the pattern of breathing,6-10 anddynamic pulmonary hyperinflation" have beenreported to contribute to chronic carbon di-oxide retention in patients with COPD. In thisconnection Begin and Grassino have recentlyshown that, in a large group of patients withCOPD with a variable degree of airflow ob-struction, the probability of developinghypercapnia increases with the severity of theobstruction, obesity, and inspiratory muscleweakness.'2 In that study, however, only halfof the variation in Paco2 could be explained,even when Paco2 was expressed as a functionof as many as five variables including total lungresistance, dead space, body weight, dynamiclung elastance, and maximal inspiratory mouthpressure. Thus, in the accompanying editorialRochester hypothesised that other factors mustbe involved in carbon dioxide retention inpatients with COPD and that rapid shallowbreathing is likely to be one of these.'3Although a more rapid and shallower pattern

of breathing has frequently been observed inhypercapnic than in eucapnic patients withCOPD,6`10 the mechanisms responsible for thisbreathing strategy have not been clearly de-fined. Increased activation of vagal afferentnerves consequent to chronic bronchitis7-9 andchronic hypoxaemia'4 may contribute to rapidshallow breathing. More recently it has beenhypothesised that rapid and shallow breathingin patients with COPD is the consequence ofan excessive load imposed on the inspiratorymuscles.'315 In these patients a reduction intidal volume could allow them to reduce thepressure required for breathing relative to in-spiratory muscle strength, thus minimising res-piratory effort and dyspnoea, and avoidingfatigue.'3 The shallow breathing reduces alve-olar ventilation and predisposes to hyper-capnia.713 To our knowledge, however, noprevious studies have specifically examinedthe interrelations between breathing pattern,breathlessness, and relative pressure required

Istituto di ClinicaMedica III,Universita di FirenzeR DurantiI IandelliG Scano

Unita di TerapiaIntensiva Pohmonare eFisiopatologiaToracica,Ospedale di CareggiM GoriniA CorradoE De Paola

Fondazione ProJuventute Don CGnocchiG Misuri

Firenze, Italy

Correspondence to:Dr M Gorini,Unita di Terapia IntensivaPolmonare,Villa D'Ognissanti,Ospedale di Careggi,Viale Pieraccini 24,50134 Firenze, Italy.Received 14 June 1995Retumed to authors23 October 1995Revised version received28 November 1995Accepted for publication9 January 1996

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A

Flow

B

I 1

I/s1 I/s

1 s

PPL

0cm H20 [0 cm H20

10 L10cm H20

Figure 1 Record of volume (V) (increased upward), flow, pleural pressure (PPL) andgastric pressure (PGA) during quiet breathing in two representative patients with severeCOPD with (A) hypercapnia (patient no. 22 in table 1) and (B) eucapnia (patient no.1 in table 1). Dynamic positive end expiratory alveolar pressure (1) and the rise in PGAduring expiration (2) are illustrated in (A).

for breathing in patients with COPD whenbreathing at rest.

In this study we have analysed the re-

lationship between chronic carbon dioxide re-

tention and the breathing pattern, respiratorymuscle load, and the pressure required forbreathing relative to inspiratory musclestrength, together with the factors associatedwith rapid and shallow breathing, in 30 stableCOPD patients with severe airflow obstruction.

MethodsSUBJECTSThe study was performed in 30 male out-patients with COPD.'6 Inclusion criteria were

severe airflow obstruction (FEV,< 1 litre) andage <80 years. Exclusion criteria were: (1)left ventricular dysfunction; (2) neuromusculardisorders; (3) neoplasia; (4) thoracic surgery;(5) moderate to severe obesity (body weight>130% ofideal weight'7); (6) clinical symptomssuggestive of sleep apnoea syndrome; and (7)functional evidence of restrictive lung disease(total lung capacity <80% of predicted value).All patients gave informed consent to the pro-tocol as approved by the institution's ethicscommittee. Each patient had been in a clinicallystable condition for at least four weeks beforethe study.

Respiratory symptoms were assessed in eachpatient by using the standardised questionnaireof the European Community for Coal andSteel.'8 In particular, dyspnoea was graded ac-

cording to a modified Medical Research Coun-cil (MRC) scale ranging from 1 (breathlessnessgoing up one flight of stairs at normal pace) to 4(breathlessness when dressing or undressing) .18

MEASUREMENTSAll measurements were made while the patientswere seated in a comfortable high-backed arm-chair. Spirometric values were measured bythe standard technique using a water-sealed

spirometer (Godart); functional residual capa-city (FRC) was measured by the helium di-lution technique. Predicted values for lungfunction variables are those proposed by theEuropean Community for Coal and Steel."9Arterial blood gas tensions were measured withan ABL-3 analyser (Radiometer, Copenhagen,Denmark).

Airflow was measured with a no. 3 Fleischpneumotachograph and a Validyne pressuretransducer (Validyne Corp, Northridge, Cali-fornia, USA) and the flow signal was integratedinto the volume. The dead space of the mouth-piece and flow meter was 70 ml and the equip-ment resistance was 0-92 cm H20/l/s. From thespirometric results we derived breath-by-breathtime and volume components ofthe respiratorycycle: inspiratory time (TI), expiratory time(TE), total time of the respiratory cycle (TTOT),and tidal volume (VT). The mean inspiratoryflow (VT/TI), duty cycle (TI/TToT), and res-piratory frequency (f) were also calculated.Mouth pressure (PM) was measured through

a side port at the mouthpiece using a differentialpressure transducer (Validyne, Northridge,California, USA). Oesophageal pressure (POES)was measured with a conventional balloon cath-eter system20 connected to a Validyne differ-ential pressure transducer as previouslydescribed.21 The balloon was positioned in themid oesophagus and contained 0-4 ml of air.Oesophageal pressure was used as an index ofpleural pressure (PPL). In 15 patients gastricpressure (PGA) was simultaneously measuredwith a similar balloon catheter system con-nected to a second differential pressure trans-ducer. This balloon was positioned in thestomach 65-70 cm from balloon tip to naresand contained 2 ml of air. Transpulmonarypressure (PL) was obtained as the differencebetween PM and PPL. All signals were recordedon a multichannel chart recorder.

Total lung resistance (RL) and dynamic lungelastance (ELdyn) were measured during rest-ing breathing. Total lung resistance was ob-tained using the isovolume method.22 Dynamiclung elastance was determined by dividing thedifference in PL between points of zero flowby VT. To evaluate end expiratory alveolarpressure we used the indirect method recentlydescribed by Haluszka and coworkers" andDal Vecchio and colleagues23 rather than thedirect method of airways occlusion. In fact,awake subjects react to airways occlusion inan unpredictable fashion so that no reliablemeasurement of alveolar pressure can be ob-tained. We thus looked for the presence of atime lag between the fall in PPL at the onset ofthe inspiratory effort and the onset of in-spiratory airflow and measured the negativedeflection in PPL that preceded the start ofinspiratory flow (fig 1). This negative deflectionin PPL will be referred to here as PEEPi forconsistency with previous investigations."12324We also assessed the change in PGA resultingfrom the contraction of the abdominal musclesduring expiration in 15 patients. In agreementwith Ninane and colleagues24 the increase inPGA which occurred during the expiratoryphase ofthe breathing cycle (PGAexp) was taken

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Table 1 Anthropometric characteristics, clinical symptoms, pulmonary function data, and inspiratory muscle strength in30 patients with COPD and severe airflow obstruction

Patient Age Weight Dyspnoea FEV1 VC FRC PPLmin Pao2 Paco2no. (years) (00WI9) (grade) (olopred) (01opred) (cmH20) (kPa) (kPa)

(7) (0%pred)1 69 111-5 3 0-53 20-4 72-0 141-2 77 11-1 5-72 69 125-0 3 0-83 29-9 87-0 150-6 58 10-0 5-83 58 121-0 2 0-80 29-5 81-0 141-2 78 10-0 5-04 61 110-7 4 0 73 23-6 90-0 179-4 83 9-2 5-95 80 100-8 2 0-70 27-1 98-0 156-5 56 11-3 5-66 71 117-3 3 0-80 33 0 124-0 160-0 56 10-1 5-87 70 94-4 2 0 73 26-2 68-0 145-8 43 9-6 6-08 67 84-1 2 0 70 25-1 94-1 155-3 80 10-6 6-09 56 66-8 4 0 53 16-0 43-0 161-0 53 7-5 5-910 53 115-0 3 0-80 23-8 62-0 140-9 84 11-4 5-711 63 101-4 3 0-85 28-3 53.0 175-0 50 8-7 5-512 63 85-0 3 0-98 37 0 110-0 206-6 74 11-0 5 013 64 125-0 2 0 90 31-3 56-0 157-4 68 12-4 6-014 63 101-0 3 0-52 17-3 53-0 150-0 75 9-6 5-615 74 78-0 3 0-48 19-0 44 0 163-0 20 7-7 7.716 68 100-0 3 0-84 30 0 80-2 183-0 69 6-8 6-517 75 99.0 4 0-67 26-0 58-0 187-0 50 7-7 6-518 65 79-0 3 0-82 37 0 58-1 140-0 38 8-0 7-719 70 80-0 3 0-60 24-0 54-2 161-0 49 8-8 7-220 71 80-8 2 0-51 17-0 27-0 159-0 42 6-9 7-521 72 90-2 4 0-76 24-0 59-1 152-0 40 5-7 8-022 63 114-0 4 0-64 19-4 50-0 168-3 51 8-2 7-723 53 80-0 4 0-59 19-0 68-0 196-0 50 6-5 6-924 80 101-0 3 0-60 26-8 99-1 178-0 50 8-0 7-125 63 81-7 4 0-43 16-0 63-0 148-0 42 8-2 7-126 58 93-8 4 0-32 11-5 66-0 207-5 40 9-6 6-727 60 85-0 3 0 50 19-0 57-0 194-4 44 7-2 8-028 62 102-0 2 0 75 24-0 63-0 150-0 61 10-7 6-129 73 90.0 3 0-95 39-6 83-0 144-0 62 10.5 6-730 64 88-0 4 0-71 24-7 73.9 205-3 37 8-0 7.7

%IW % of ideal weight; PpLmin =minimal pleural pressure.

as a reflection of the mechanical effect of ab-dominal muscle contraction (fig 1).

Inspiratory muscle strength was assessed bymeasuring minimal (that is, greatest negative)inspiratory pleural pressure (PPLmin) at FRCduring both maximal inspiratory efforts againstan obstructed mouthpiece25 and during sniffmanoeuvres.2 The patients were repeatedlyencouraged to try as hard as possible and theyhad a visual feedback of generated pressure.27Both PPLmin manoeuvres were repeated untilthree measurements with less than 5% vari-ability were recorded. The highest PPLminvalue obtained was used for analysis.

PROTOCOLTreatment was withheld for 12 hours beforethe study and all subjects were tested in theafternoon. Before the experiments each subjectwas well acquainted with the laboratory andequipment. Lung function tests were per-formed first and then, after a 40 minute restperiod, an arterial blood sample was obtainedand changes in volume, flow, PM, PPL, andPGA were recorded during three periods of quietbreathing over 30 minutes. Finally, tests ofrespiratory muscle strength were performed ineach patient. It is important to emphasise thatpatients had not previously been involved inrespiratory experiments; furthermore, duringthe periods of resting breathing each subjectwas distracted with non-rhythmic music toavoid any acoustic feedback.

DATA ANALYSISVolume and time components ofthe respiratorycycle, inspiratory PPL swings (PPLSW), RL, EL-dyn, PEEPi and PGAexp were averaged in eachpatient over 30 consecutive breaths from each

run. Unless otherwise specified, data are pre-sented as means (SE). Single and stepwisemultiple regression analyses were performedto assess relationships between variables. Theproportion of total variance in the dependentvariable accounted for by the predictor vari-able(s) is reported as the square of correlationcoefficient (r2), expressed as a percentage. Datacomparisons were performed using the Stu-dent's unpaired t test and one-way analysis ofvariance (ANOVA) when appropriate. A pvalue of <0-05 was considered statistically sig-nificant.

ResultsAnthropometric, clinical, pulmonary functiondata, and PPLmin of patients are shown in table1. Fourteen patients (nos 1-14) were eucapnic(Paco2 .6 kPa) and 16 (nos 15-30) were hyper-capnic (Paco2 >6kPa). The highest PPLminwas obtained by the sniff manoeuvre in 18patients (nos 2-4, 6-8, 10-14, 16, 18-22, and28) and by inspiratory effort against an ob-structed mouthpiece in 12. Body weight wassignificantly lower in hypercapnic than in eu-capnic patients (90-1 (2-7) and 104-2 (4 6)%of ideal weight, respectively, p =00 1), and sixhypercapnic patients and one eucapnic patienthad a body weight below 85% of ideal weight.The tracings of volume, flow, PPL, and PGAobtained during quiet, resting breathing in tworepresentative subjects with hypercapnia andeucapnia are shown in fig 1. The breathingwas more rapid and shallower, and PPLSW wasgreater in the hypercapnic patient than in theeucapnic patient. In both patients PEEPi wasassociated with an increase in gastric pressureduring expiration indicating abdominal musclecontraction.

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Table 2 Correlation coefficients of Paco, to respiratoryfunction parameters in 30 patients with severe COPD

Parameter r p

FEV, (% pred) -0-27 NSVC (% pred) -0 45 0 01FRC (% pred) 0 35 NSTLC (% pred) 0-29 NSPpLmin (cm H2O) -0-74 <0-001RL (cm H20/l/s) 0-38 <0 05ELdyn (cm H2O/1) 0 58 <0-001PPLsw (cm H2O) 0-28 NSRiJPPLmin (s/i) 0-70 <0-001ELdyn/PPLmin (/1) 0-71 <0-001PPLSW (% pPLmin) 0-65 <0-001VT (1' -0-79 <0-001f (cycles/min) 0-66 <0-001VE (1/min) -0 05 NS

FEV, =forced expiratory volume in one second; VC =vital cap-acity; FRC = functional residual capacity; TLC = total lung cap-acity; PPLmin = minimal pleural pressure; RL = total lungresistance; ELdyn = dynamic lung elastance; PPLSW = pleuralpressure swing; VT = tidal volume; f=respiratory frequency;VE = minute ventilation.

8

2

0IEC.,

LUw0-

6

4

0

0

.

* 7 e

0

.

_

t0 2 4

PGAeXp (cm H20)6 8

FACTORS INFLUENCING CARBON DIOXIDERETENTIONThe correlation coefficients of Paco2 withdifferent mechanical, inspiratory muscle, andventilatory parameters are shown in table 2.Paco2 did not relate to FEVI, TLC, or FRC,whereas a weak but significant inverse re-lationship was found between Paco2 and VC.As shown in fig 2, there was a significant inverserelationship between Paco2 and PPLmin. In-spiratory PPLSW was greater in hypercapnicthan in eucapnic patients (14 8 (1O0) and 11 3(1 2) cm H20, respectively, p<005). Paco2 re-lated well to RL/PPLmin and ELdyn/PPLmin,the higher the Paco2 the greater both the res-istive and elastic loads relative to inspiratorymuscle strength. Positive end expiratory alveolarpressure was present in all patients but one andwas similar in eucapnic and hypercapnic patients(2-8 (06) and 3-4 (0-4) cm H20, respectively).In the 15 patients in whom PGA was measuredthere was a significant relationship betweenPEEPi and expiratory rise in gastric pressure(r2=66 7%, p<0001, fig 3).There was a significant inverse relationship

between PacO2 and VT such that Paco2 washighest in patients with the smallest VT (fig 4).

Figure 3 Relationship between dynamic positive endexpiratory alveolar pressure (PEEPi) and expiratory risein gastric pressure (PGAexp) in 15 patients with severeCOPD. The solid line is the regression line and the closedcircles are individual data points.

8

7

(-

0Cu0m

00

S 0 S

.0

.

00

S0 0

6 -

5

0 . 00

00

103 04 0.5

VT (I)0.6 0.7 0.8

Figure 4 Relationship between Paco2 and tidal volume(VT) in 30 patients with severe COPD. The solid line isthe regression line and the closed circles are individual datapoints.

* .

On the contrary, no significant relationship wasfound between PacO2 and minute ventilation.The variables that related significantly to

* PacO, were entered into a multiple regression\ analysis. The regression equation generated by

* \ stepwise multiple regression analysis for Paco2* \ * included VT and PPLmin. These variables ac-

counted for 709% ofthe total variance in PaCO2.*0 The coefficient and F value of both variables in

0 S* the final equation, and the model r2 as eachi variable is added, are shown in table 3.

.

70 80 90 Table 3 Stepwise multiple regression analysis for Paco,Variable Coefficient Model r'(0o) F p value

VT -3-45 60 5 61-6 <0-001PpLmin -0-02 709 11 1 <0005Constant 9-93

VT = tidal volume; PpLmin = minimal pleural pressure.

10 20 30 40 50 60PPLmin (cm H20)

8

0

'a0-C4

7

6

5 -I -

Figure 2 Relationship between Paco2 and minimalpleural pressure (PPLmin) in 30 patients with severeCOPD. The solid line is the regression line and the closedcircles are individual data points.

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2-2

2.0 K0

.

1.8 K

1.6+

cn

0S

1.44

1.2 K

1.0 e-

0.8 ;

0.6

. .* S S

*\ S*55 0

* in0

I0

0 10 20 30 40 50 60PPLSW (%PPLmin)

Figure 5 Relationship between inspiratory time (TI) andinspiratory pleural pressure swing expressed as a percentageof minimal pleural pressure (PPLsw (%PIPLmin)) in 30patients with severe COPD. The solid line is the regressionline and the closed circles are individual data points.

FACTORS INFLUENCING BREATHING PATTERNCompared with eucapnic patients, hypercapnicpatients exhibited a significantly smaller VT(074 (002) and 0-52 (0 03) 1, respectively,p<0001), a significantly greater f(15-1 (0 7)and 22-7 (0 9) cycles/min, respectively,p<0001), and a similar minute ventilation.Both resistive (RL) and dynamic elastic (EL-

dyn) loads for the respiratory muscles weresignificantly greater in hypercapnic than in eu-capnic patients (11 9 (0 7) versus 9 1 (0 8) cmH20/l/min, p = 0 01; and 11 7 (1I0) versus 6 7(0 5) cm H20/1, p<0001), VT/TI being similarin the two groups (0 57 (0 03) and 0 53 (0.02)l/s, respectively).

Tidal volume was directly related to Ti(r2 = 55.3%, p<0OO0 1), indicating that shallowbreathing in severe COPD patients was mainlyaccounted for by changes in respiratory timing.As shown in fig 5, there was a significant curvi-linear (multiplicative) relationship betweenTi and PPLSW (%PPLmin) (r2 = 49-6%,p<0J001), such that the shortening in Ti was

associated with the increase in the pressurerequired for breathing relative to inspiratorymuscle strength. A weak, direct relationship(r2 = 25-3%, p = 0 005) was observed be-tween Ti and Pao2. However, stepwise multipleregression analysis showed that expressing Tias a combined function of PPLSW (%PPLmin)and Pao2 did not significantly increase the ex-plained variance in Ti beyond the contributionof PPLSW (%PPLmin).

Inspiratory time and PPLSW (%PPLmin) inpatients grouped according to dyspnoea scalerating are shown in fig 6. There was a significantassociation between dyspnoea rating and bothPPLSW (%PPLmin) (p<0 001, ANOVA) and Ti(p<0 005, ANOVA), the patients withsevere dyspnoea exhibiting the greatestPPLSW (%PPLmin) and the shortest Ti.

DiscussionThe main findings of this study can be sum-marised as follows: (1) in patients with stableCOPD with severe airflow obstruction there isa significant association between hypercapniaand both shallow breathing and inspiratorymuscle weakness, and these variables explainmore than 70% ofthe variance in Paco2; (2) VTrelates well to Ti, and the latter is significantlyrelated to PPLSW (%PPLmin), the shorter the Tithe greater the pressure required for breathingrelative to inspiratory muscle strength; (3) thereis a significant association between the severityof dyspnoea and both the increase in PPLSW(%PPLmin) and the shortening in Ti.

CRITIQUE OF METHODSBefore discussing these results it is pertinentto consider the limitations of the procedureused in this study. Inspiratory muscle strengthwas evaluated by measuring PPLmin duringvoluntary manoeuvres. In this condition thedevelopment of PPLmin depends not only onthe strength and coordination of inspiratorymuscles, but also on the motivation and co-operation of subjects. To minimise this prob-

i~

1.6 B

1.2 K

-C 0.8 F-

0.4 K

0.0

2 3 4

qK

L

2 3 4

Dyspnoea scale rating

Figure 6 (A) Mean (SE) inspiratory pleural pressure swing expressed as a percentage of minimal pleural pressure

(PPLsw (%oPPLmin)) and (B) inspiratory time (TI) in 30 patients with severe COPD grouped by dyspnoea scale rating.

40F A

30 -

20 [-

0-

0~101

0

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lem, PPLmin was obtained from differentmanoeuvres (see Methods) and all patientshad a visual feedback of generated pressure assuggested by Laporta and Grassino.27The breathing pattern was assessed with a

noseclip and mouthpiece that may increase VTand decrease respiratory frequency comparedwith natural breathing.28 In particular, whenthe breathing pattern in patients with COPDwas evaluated from body surface movementsusing the technique of inductive plethys-mography,'029 VT was found to be somewhatlower than that observed in studies in whichonly a mouthpiece was used."9 In our study thesimultaneous measurement ofvolume, flow andPPL was necessary to assess the relationshipsbetween Paco2, breathing pattern, and mech-anical factors such as RL, ELdyn, and PEEPiduring quiet breathing. To minimise the effectsof the mouthpiece, however, we used a mouth-piece and flowmeter system with a small deadspace; in addition, subjects were well acquaintedwith the laboratory and equipment before theexperiments and each patient was distractedwith non-rhythmic music to avoid any acousticfeedback during periods of quiet breathing. Fur-thermore, our data showing a significant inverserelationship between Paco2 and VT in patientswith severe COPD are in agreement with thoseobtained by Loveridge and coworkers using in-ductive plethysmography.'0

CARBON DIOXIDE RETENTION IN SEVERE COPDThe present data showing that Paco2 did notrelate significantly to FEV, and related onlyweakly to VC are in line with previous studies' 12indicating that many patients with COPD withsevere airflow obstruction do not developchronic hypercapnia.Our results showed that, in stable patients

with severe COPD, Paco2 related directly toboth RL/PPLmin and ELdyn/PPLmin, and in-versely to both VT and PPLmin. Furthermore,multiple regression analysis showed that ex-pressing Paco2 as a combined function of VTand PPLmin explained more than 70% of thetotal variance in Paco2. These results confirmand extend previous reports5 11in that chroniccarbon dioxide retention is primarily associatedwith shallow breathing and inspiratory muscleweakness in patients with stable COPD withsevere airflow obstruction. It is important tostress however that, although correlation is anessential prerequisite to establish a cause andeffect relationship, correlation alone does notimply causation. In particular, whether chronichypercapnia itselfmay affect inspiratory musclecontractility in patients with severe COPD, asshown for acute respiratory acidosis in normalsubjects,30 remains to be established.

Begin and Grassino12 have recently reportedthat obesity enhanced the probability of hyper-capnia at any level of airflow obstruction andinspiratory muscle weakness in more than 300patients with COPD with a variable degree ofairflow obstruction. In the present study, how-ever, hypercapnic patients had a signific-antly lower body weight than eucapnic patients;furthermore, in agreement with a previous re-port,5 we found that body weight had a direct

relationship with PPLmin (r2=28 8%, p<0005)such that underweight was associated with in-spiratory muscle weakness. Differences in theselection of patients may partly explain thesediscrepancies. In fact, in the present study onlypatients with severe airflow obstruction wereincluded, and obesity - that may be associatedwith carbon dioxide retention even in the absenceof lung disease" - was an exclusion criterion.

It has recently been shown"2' that, in mostpatients with stable COPD breathing at rest,alveolar pressure at end expiration is positive.Assuming that expiration is a passive processand, as a consequence, that alveolar pressureat end expiration is the elastic recoil pressure ofthe respiratory system, these studies concludedthat dynamic pulmonary hyperinflation is fre-quent in patients with stable COPD."12' Fur-thermore, Haluszka and colleagues have shownthat, in patients with stable COPD, Paco2 wassignificantly related to PEEPi which suggeststhat dynamic pulmonary hyperinflation couldplay a part in chronic carbon dioxide re-tention. " In the present study a positive alveolarpressure at end expiration was present in allbut one patient and was similar in eucapnicand hypercapnic patients. In agreement withNinane and coworkers24 we observed that ex-piration was an active process in many patients,and there was a close relationship between theexpiratory rise in gastric pressure and PEEPi,such that alveolar pressure at end expirationwas greater as the expiratory rise in gastricpressure was larger. These data indicate that,in patients with severe COPD, positive alveolarpressure at end expiration is, to a large extent,the consequence of the transmission throughthe relaxed diaphragm of the rise in abdominalpressure due to abdominal muscle contraction.The present findings therefore confirm thatdynamic PEEPi cannot be used to quantify thedegree of dynamic pulmonary hyperinflation inmany patients with severe COPD.24

BREATHING PATTERN IN SEVERE COPDCompared with eucapnic COPD patients,those with hypercapnia exhibited more rapidand shallower breathing. Inspiratory PPLSW wasgreater in hypercapnic than eucapnic patientsand, although the elastic and resistive loadswere higher in the former than in the latter,VT/TI was similar in the two groups. Thesedata are in agreement with previousreports6 81229 and clearly suggest that shallowbreathing in patients with severe COPD is notassociated with a reduction in inspiratory neuraldrive. Furthermore, in our patients VT wasrelated directly to TI, indicating that a smalltidal volume was primarily the consequence ofalteration in respiratory timing.The mechanisms leading to alteration in res-

piratory timing in patients with COPD havenot yet been clearly defined. It has been shownthat chronic hypoxaemia may contribute torapid shallow breathing in these patients.14 Theweak but significant relationship between TIand Pao2 observed in our patients is in linewith these observations. However, expressingTI as a combined function ofPPLSW (%PPLmin)and Pao2 did not significantly increase the ex-

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Breathing pattern and hypercapnia in COPD

plained variance in Ti beyond the contributionof PPLSW (%PPLmin). Moreover, it has beenreported that respiratory muscle fatigue in-duced by breathing against an inspiratory res-istive load may result in a rapid and shallowbreathing."2 However, muscle fatigue is an un-

likely explanation for the short Ti and the smallVT we observed in hypercapnic patients duringresting breathing. In line with previous studieswhich show that respiratory muscle fatigue can

be demonstrated in less than 10% of patientswith severe COPD during exacerbations of thedisease,33 and in agreement with the study ofBegin and Grassino,'2 the present results showthat, in patients with severe COPD, PPLSW(%PPLmin) was below 60% (fig 6) - that is,the threshold value associated with inspiratorymuscle fatigue in normal subjects.'4

Finally, it has recently been hypothesisedthat, in patients with chronic hypercapnicCOPD, a rapid and shallow pattern of breath-ing is the result of an excessive load on theinspiratory muscles in relation to their maximalstrength."'5 In this condition, shortening Tiand reducing VT could be a strategy for re-

ducing inspiratory muscle effort and distressand avoiding fatigue." In line with the conceptthat the perception of inspiratory effort anddyspnoea is closely linked to the pressure re-

quired for breathing relative to inspiratorymuscle strength,'5 it has also been suggested"that a reduction in Ti involves an integratedresponse of the respiratory system to the per-

ception of breathlessness. Our data, whichshow an inverse relationship between Ti andPPLSW (%PPLmin) and a significant associationbetween the severity of dyspnoea and both theincrease in PPLSW (%PPLmin) and the short-ening in Ti, strongly support the above hypo-theses. These findings are also consistentwith previous studies which have shown thatbreathlessness during exercise is significantlyrelated to the PPLSW/MIP and Ti/TToT ratiosboth in normal subjects and in patients withcardiorespiratory disorders.36 3' Furthermore,our data are in line with the observation thatVT and respiratory timing responses to resistiveloading are impaired in patients with COPDwith severe inspiratory muscle weakness.'8

In conclusion, we have shown that, inpatients with stable COPD and severe airflowobstruction, chronic carbon dioxide retentionis primarily associated with shallow breathingand inspiratory muscle weakness. It also ap-

pears that rapid, shallow breathing is mainlylinked to both an excessive increase in thepressure required for breathing relative to in-spiratory muscle strength, and to the severityof breathlessness.

This study was supported by grants from the Ministerodell'Universiti e della Ricerca Scientifica e Tecnologica of Italy.

1 Lane DJ, Howell JBL, Giblin B. Relation between airwaysobstruction and CO2 tension in chronic obstructive airwaysdisease. BMJ 1968;3:707-9.

2 West JB. Causes of carbon dioxide retention in lung disease.N Englj Med 197 1;284:1232-6.

3 Lourenco RV, Miranda JM. Drive and performance of theventilatory apparatus in chronic obstructive lung disease.N Engl_J Med 1968;279:53-9.

4 Mountain R, Zwillich C, Weil J. Hypoventilation in ob-structive lung disease: the role of familial factors. N EnglJtMed 1978;298:521-5.

5 Rochester DF, Braun NMT. Determinants of maximal in-spiratory pressure in chronic obstructive pulmonary dis-ease. Am Rev Respir Dis 1985;132:42-7.

6 Gorini M, Spinelli A, Ginanni R, Duranti R, Gigliotti F,Scano G. Neural respiratory drive and neuromuscularcoupling in patients with chronic obstructive pulmonarydisease (COPD). Chest 1990;98:1179-86.

7 Sorli J, Grassino A, Lorange G, Milic-Emili J. Control ofbreathing in patients with chronic obstructive lung disease.Clin Sci Mol Med 1978;54:295-305.

8 Parot S, Saunier C, Gautier H, Milic-Emili J, Sadoul P.Breathing pattern in patients with chronic obstructive lungdisease. Am Rev Respir Dis 1980;121:985-91.

9 Javaheri S, Blum J, Kazemi H. Pattern of breathing andcarbon dioxide retention in chronic obstructive lung dis-ease. Am Jf Med 1981;71:228-34.

10 Loveridge B, West P, Kriger MH, Anthonisen NR. Alterationin breathing pattern with progression of chronic obstructivepulmonary disease. Am Rev Respir Dis 1986;134:930-4.

11 Haluszka J, Chartrand DA, Grassino AE, Milic-Emili J.Intrinsic PEEP and arterial PCO2 in stable patients withchronic obstructive pulmonary disease. Am Rev Respir Dis1990;141:1194-7.

12 Begin P, Grassino A. Inspiratory muscle dysfunction andchronic hypercapnia in chronic obstructive pulmonarydisease. Am Rev Respir Dis 1991;143:905-12.

13 Rochester D. Respiratory muscle weakness, pattern ofbreathing, and CO2 retention in chronic obstructive pul-monary disease. Am Rev Respir Dis 199 1;143:901-3.

14 Bradley CA, Fleetham JA, Anthonisen NR. Ventilatory con-trol in patients with hypoxemia due to obstructive lungdisease. Am Rev Respir Dis 1979;120:21-30.

15 Roussos C, Moxham J. Respiratory muscle fatigue. In:Roussos C, Macklem PT, eds. The thorax (part B). NewYork: Marcel Dekker, 1985: 829-70.

16 American Thoracic Society. Standards for the diagnosis andcare ofpatients with chronic obstructive pulmonary disease(COPD) and asthma. Am Rev RespirDis 1987;136:225-44.

17 Metropolitan Life Insurance Company. New weight standardsfor men and women. New York: Metropolitan Life, 1983.

18 Minette A. Questionnaire of the European Community forCoal and Steel (ECSC) on respiratory symptoms. EurRespir J 1989;2:165-77.

19 European Community for Coal and Steel. Standardizationof lung function test. Bull Eur Physiopathol Respir 1983;19:1-95.

20 Agostoni E, Rahn H. Abdominal and thoracic pressures atdifferent lung volumes. JAppl Physiol 1960;15:1087-92.

21 Estenne M, Gorini M. Action of the diaphragm during coughin tetraplegic subjects. J Appl Physiol 1992;72:1074-80.

22 Frank NR, Mead J, Ferris BG Jr. The mechanical behaviourof the lungs in healthy elderly persons. J Clin Invest 1957;36:1680-7.

23 Dal Vecchio L, Polese G, Poggi R, Rossi A. "Intrinsic"positive end-expiratory pressure in stable patients withchronic obstructive pulmonary disease. Eur RespirJt 1990;3:74-80.

24 Ninane V, Yernault JC, De Troyer A. Intrinsic PEEP inpatients with chronic obstructive pulmonary disease: role ofexpiratory muscles. Am Rev Respir Dis 1993;148:1037-42.

25 De Troyer A, Yernault JC. Inspiratory muscle force innornal subjects and patients with chronic interstitial lungdisease. Thorax 1980;35:92-100.

26 Laroche CM, Mier AK, Moxham J, Green M. The valueof sniff esophageal pressures in the assessment of globalinspiratory muscle strength. Am Rev Respir Dis 1988;138:598-603.

27 Laporta D, Grassino A. Assessment of transdiaphragmaticpressure in humans. J Appl Physiol 1985;58:1469-76.

28 Gilbert R, Auchincloss JH, Brodsky J, Boden W. Changesin tidal volume, frequency, and ventilation induced bytheir measurements. J Appl Physiol 1972;33:252-4.

29 Tobin MJ, Chadha TS, Jenouri G, Birch SJ, Gazeroglu HB,Sackner RA. Breathing patterns. 2. Diseased subjects.Chest 1983;84:286-94.

30 Juan G, Calverley P, Talamo C, Schnader J, Roussos C.Effect of carbon dioxide on diaphragmatic function inhuman beings. N Engl 3 Med 1984;310:874-9.

31 Weinberger SE, Schwartzstein RM, Weiss JW. Hypercapnia.N Engl 3 Med 1989;321:1223-31.

32 Gallagher CG, Im Hof V, Younes M. Effect of inspiratorymuscle fatigue on breathing pattern. J Appl Physiol 1985;59:1152-8.

33 Efthimiou J, Fleming J, Spiro SG. Sternomastoid musclefunction and fatigue in breathless patients with severe res-piratory disease. Am Rev Respir Dis 1987;136:1099-105.

34 Roussos C, Fixley M, Gross D, Macklem PT. Fatigue ofthe inspiratory muscles and their synergistic behaviour. JAppl Physiol 1977;46:897-904.

35 Killian KJ, Jones NL. Respiratory muscles and dyspnoea.Clin Chest Med 1988;9:237-48.

36 El-Manshawi A, Killian KJ, Summers E, Jones NL. Breath-lessness during exercise with and without resistive loading.J ApplPhysiol1986;61:896-905.

37 Leblanc P, Bowie DM, Summers E, Jones NL, Killian KJ.Breathlessness and exercise in patients with cardio-respiratory disease. Am Rev Respir Dis 1986;133:21-5.

38 Oliven A, Kelsen SG, Chandler Deal E, Cherniack NS.Mechanism underlying CO2 retention during flow-resistiveloading in patients with chronic obstructive pulmonarydisease.J Clin Invest 1983;71:1442-9.

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