RELATIONSHIP BETWEEN TIDAL VOLUME AND DEADSPACE DURING HIGH FREQUENCY VENTILATION

Transcription

1 Br.J. Anesth. (1986), 58, RELATIONSHIP BETWEEN TIDAL VOLUME AND DEADSPACE DURING HIGH FREQUENCY VENTILATION M. K. CHAKRABARTI, G. GORDON AND J. G. WHITWAM In recent yers interest hs developed in the use of low tidl volumes (FT) to prevent the brotrum nd dverse circultory effects of mechnicl ventiltion. In order to mintin blood-gs homeostsis with these smll tidl volumes, techniques of high frequency ventiltion (HFV) (up to 600 b.p.m.) or high frequency oscilltion (HFO) (up to 3000 b.p.m.) hve been used. It hs been postulted by some workers (Klin nd Smith, 1977; Butler et l., 1980; Rossing et l., 1981) tht during HFV nd HFO it is possible to mintin lveolr ventiltion (FA) with FT which is substntilly less thn the ntomicl dedspce (FD 1 " 1111 ) s result of the enhnced diffusion nd ugumented dispersion which occur during HFV nd HFO. However, in ll the previous studies in which cceptble mesurements hve been mde, the ntomicl (FD*"*') nd physiologicl (FD phys ) dedspces were mesured t norml FT nd norml ventiltion frequency, nd no further mesurements were obtined during HFV nd HFO when the FT ws decresed substntilly. The reltiohip between FD nd FT is well estblished (Willims nd Ryford, 1956; Severinghus nd Stupfel, 1957; Nunn nd Hill, 1960) but, except in the study by Chkrbrti nd Sykes (1980) hs not been coidered in previous ppers on HFV, nd hs not yet been fully investigted in mn during HFV. In the present study FD nd FT were mesured in ptients ventilted t frequencies up to 120 b.p.m. using progressively smller tidl volumes whilst mintining physiologicl bloodgs teio within nrrow limits. M. K. CHAKRABART:, BJC., M.PHIL.; G. GORDON, M.B., CH.B., F.F.A.R.C.S.; J. G. WHITWAM, M.B., CH.B., PH.D., F.R.C.P., F.F.A.R.C.S.; Deprtment of Anesthetics, Royl Postgrdute Medicl School, DuCne Rod, London W12 0HS. SUMMARY Physiologicl (V/y' 1 *") nd ntomicl (Wo*"") dedspces were mesured in seven nesthetized, prlysed nd intubted dult ptients ventilted t norml nd high frequencies. To mintin cotnt P COt while incresing the ventiltion frequency from 15 to 120 b.p.m., the men Vr ws decresed from 454±62ml (men±sd) to 117±9 ml. The men Vo"*' nd \JoPhys decresed from 130 ±11 ml to 74 ± 12 ml nd 165±24ml to 92±3ml, respectively, by 80 b.p.m., bove which frequency there ws no further significnt reduction in either. The men Vo/Vr rtio incresed from 0.36±0.04 to 0.76±0.05. This study showed tht the dedspce volume mesured conventionlly ws not cotnt fctor, ws minly function of Vr nd ws determinnt of tidl nd minute volume requirement even during high frequency ventiltion. The vrible WD phys showed wide vrition between subjects, nd ppered to hve men miniml vlue of pproximtely 1.1 ml kg' 1 t 80 b.p.m. in dult humn subjects with trche/ tube in situ vlue bout hlf the \jd" hy ' mesured t conventionl norml tidl volumes nd ventiltion frequencies. PATIENTS AND METHODS Selection of ptients All the ptients were bout to undergo myocrdil revsculriztion nd hd no history or rdiologicl evidence of pulmonry disese. All hd good left ventriculr function, s judged by exercise tolernce, ejection frction nd intrventriculr pressures. None hd occlusion of either of the two min coronry rteries nd there ws no evidence of recent cute myocrdil infrction s judged by clinicl history, ECG nd

2 12 BRITISH JOURNAL OF ANAESTHESIA FIG. 1. Digrm of ventilting circuit. Dimeters of the ipirtory nd expirtory tubes were 3 mm nd 12 mm, respectively. F = rotmeter; RV = reducing vlve; A = ccumultor; VC = occlusion device determining V with 5 % ipirtory-expirtory overlp; E = smpling line for end-tidl crbon dioxide nd irwy pressure; P = connection to endotrchel tube; B = sfety vlve; W = Wright respiromcter; G = gs meter; T = thermometer; M = mixed expired gs smpling port. enzyme studies. There ws no mesurble renl or heptic decompetion; the ptients were not dibetic nor hd they symptoms or sig referble to peripherl or cerebrovsculr disese. Hemoglobin concentrtio were norml nd the ptients were not obese. Thus, they could be clssified ASA II. Their ges nd weights were in the rnges yr nd kg, respectively. All were receiving tenolol, nd their hert rtes nd rteril pressures were well controlled in the period before opertion. Approvl from the surgeo concerned, the ptients nd the locl ethics committee ws sought for n extended period of nesthesi of pproximtely 90 min (i.e. before surgery) to llow this study to be performed. Anesthesi After overnight sedtion (lorzepm 3-5 mg) ptients received ppveretum mg, hyoscine mg nd droperidol 5 mg i.m. 1 h before the induction of nesthesi. On rrivl in the nesthetic room they were well-sedted nd normoteive with hert rtes slower thn 70 bet min"1. A routine 4-led ECG ws recorded nd cnnultion of peripherl vein nd rdil rtery performed under locl nesthesi. Anesthesi ws induced with midzolm 0.1 mg kg"1, thiopentone 4.5 mg kg"1 nd ppveretum 0.2 mg kg"1. Neuromusculr blockde ws induced with pncuronium 0.1 mg kg"1 nd the trche ws intubted, fter which two cnnule were introduced to the right internl jugulr vein. Subsequently, while the study ws being performed, further doses of midzolm nd ppveretum were dministered every 20 min to totl dose for midzolm of 0.2 mg kg"1 nd ppveretum 0.5 mg kg"1. The ptients remined sleep nd both hert rte nd rteril pressure remined close to control vlues for the durtion of the study. Recovery t the end of the surgery followed norml pttern. Ventiltion Artificil ventiltion ws produced using purpose-built mchine with frequency rnge of b.p.m. nd n ipirtory: expirtory rtio (i: E) of 1:2 with n occlusion overlp (5 % of one ventilting cycle) during both ipirtory to expirtory nd expirtory to ipirtory chnges, euring lek-free system (fig. 1). The ipirtory nd expirtory tubes hd internl dimeters of 3 mm nd 12 mm respectively nd the totl volume of the ptient circuit ws only 80 ml. This system eured negligible dilution of the expired gs mixture with fresh gs, nd llowed the ccurte mesurement of expired volume with gs meter (Thoms Glover & Co. Ltd) which ws clibrted git dry spirometer (P. K. Morgn). The ventilting fresh gs ws 100% oxygen, supplied either from Boyle nesthetic mchine or piped through rotmeter, nd the lungs were ventilted t incresing frequencies from 15 to 120 b.p.m. After ech chnge in the frequency of ventiltion there ws only smll chnge in PCOt nd the fresh gs minute volume could be djusted redily to mintin the blood-gs teio within very nrrow limits close to their control vlues. Thus not more thn pproximtely 10 min ws

3 DEADSPACE AND HIGH FREQUENCY VENTILATION 13 TABLE I. Crdiorespirtorydl(men±SD)t differentfrequencies ofventiltion (b. p.m.)from sevenplients.v D" k " = physiologicl dedspce; WD""* 1 = ntomicl dedspce; EEP = end-expirtory pressure; MAP = men rteril pressure; HR = hert rte. P vlues in the finl column refer to sttisticl significnce for two-v>y nlysis of vrince. The letters indicte sttisticlly significnt differences from the vlue in the first column (t test; P < 0.05). The chnges in VDP*"' nd VD " were not significnt (pired t tests) between 80, 100 nd 120 b.p.m. 15 b.p.m. b 30 b.p.m. c 45 b.p.m. d 60 b.p.m. e 80 b.p.m. f 100 b.p.m. g 120 b.p.m. P l^ (litre min" 1 ) KT (ml kg" 1 ) I'D"* 1 " (ml kg" 1 ) r/d""' (ml kg" 1 ) Airwy pressure (kp) Pek Men EEP HR (bet mur 1 ) MAP(mmHg) Po^kP) Pco (kp) PH." 6.6 ± ± ± ± ± ± ± ± ± ± ± ±0.95 defg 3.3±0.5 cdefg 1.6±0.3 cdefg 1.2 ±0.2 efg 0.82 ± ±0.06 defg 0.08 ±0.002 defg 68±8.9 80± ± ± ± defg 2.4 ±0.4 befg 1.3±0.3 befg befg 0.76 ± ±0.08 defg 0.08 ±0.04 defg 69± ± ± ± ± ±0.94 befg bfg beg 1.0±0.2 befg 0.80± ±0.06 befg 0.18 ±0.05 befg 66 ±8.8 8O± ± ± ± ± 1.12 befg bc 1.1 ± ± ± ±0.09 beg 0.26 ±0.04 beg 64± ± ± ± ± ± 1.68 e ± ± ± ±0.04 bc 66±9.1 80± ± ± ± ± 1.03 e ± ± ± bc 65± ± ± ± ±0.05 <o.io- 4 <0.10' 4 < 0.10-" <o.io- 4 <0.05 <0.05 < 0.05 required fter ech chnge in ventiltion to chieve new equilibrium so tht the next group of mesurements could be mde. The expired minute volume (KE) ws mesured nd mesurements were mde of the CO 2 concentrtion in the mixed expired gs (FE COt ) s rteril blood smples were obtined nerobiclly in heprinized syringes. The FEco, nd end-tidl crbon dioxide concentrtion (FE' CO,) were mesured with n infr-red crbon dioxide nlyser (Gould Medicl Cpnogrph Mrk III), which hd mesured respoe time of 0.2 s, nd the clibrtion of which ws verified repetedly with pre-nlysed gs mixtures. Thorough mixing of expired gs ws determined by recording the crbon dioxide concentrtion nd observing no "ripple" in the trce. The ptient's temperture nd the expired gs temperture ner the gs meter were lso mesured. The FE' COt bove 40 b.p.m. cnnot be mesured becuse of the long respoe time of the nlyser. However, it would be expected in norml lungs tht the men lveolr crbon dioxide concentrtion would remin pproximtely the sme when the P COt is mintined cotnt, whtever the frequency of ventiltion. Therefore, the FE' COI will be similr, but the slope of the plteu will be different to tht t norml ventiltion frequencies with lrger tidl volumes. Thus the simple mnoeouvre of decresing the frequency of ventiltion to 30 b.p.m. (tht is, to within the respoe time of the crbon dioxide nlyser) llowed the mesurement of the FE' COf provided this ws recorded within two to three breths before new equilibrium strted to become estblished. The technique hs been described previously using different ventiltor (Whitwm et l., 1983). Thus FE' CO, ws determined by decresing the ventiltion frequency to 30 b.p.m., the FE' COI reched its pek within 2-3 breths (in less thn 6 s) nd this vlue ws ccepted s the crbon dioxide concentrtion present in the lveoli t the higher frequency. The Gould system used llowed hold of the disply of this pek vlue. The irwy pressure ws mesured by clibrted strin guges nd displyed on heted stylus recorder (Devices MX2). Arteril blood smples were nlysed in duplicte, immeditely fter withdrwl (Rdiometer ABL 1 system). The VD*"* 1 nd KD phys were clculted using

4 14 BRITISH JOURNAL OF ANAESTHESIA "% Frequency (b.pr) FIG. 2. Chnges in dedspce nd tidl volume (O) t different frequencies of ventiltion while mintining cotnt P^O( within the norml rnge. A = Physiologicl dedspce; D = ntomicl dedspce ;# = mesured physiologicl dedspce to tidl volume rtio. the Bohr eqution nd EnghofF s modifiction of this eqution, respectively, fter the gs volumes were corrected to the ptient's temperture (Sykes, McNicol nd Cmpbell, 1976) FDnt = ((FE' COJ - FE COI )/FE' C O 5 ) * ^ nd FDp hy8 = ((P COl - PE co J/P c. Ol ) x FT where FE'CQ. is the end-tidl crbon dioxide concentrtion. Becuse there were no further mesurble chnges in the dedspces bove 80 b.p.m., observtio were discontinued bove 120 b.p.m. to prevent n unnecessrily prolonged period of observtion. Sttisticl nlysis ws performed using two-wy nlysis of vrince followed by pired t tests where pproprite. Vlues refer to men ± SD throughout VT (mo FIG 3. Chnges in dedspce volumes (KD) t different tidl volumes (KT) while mintining cotnt P C0( within the norml rnge t ventiltion frequencies between 15 nd 120 b.p.m. O = Physiologicl dedspce; #= ntomicl dedspce. RESULTS In ech ptient, blood-gs teio were mintined within nrrow limits throughout the study nd these re presented in tble I. The chnges in i/ D nnt ^j T/ D piiys (expressed s ml kg" 1 ) s the frequency of ventiltion ws incresed nd the tidl volume decresed re shown lso. It ws observed tht, s the frequency of ventiltion ws incresed in steps from 15 to 120 b.p.m., the FT required to mintin blood-gs homeostsis decresed progressively from 454 ± 62 ml to 117 ±9 ml. However, the reduction in FT ws much less bove 60 b.p.m. (fig. 2). The Fry-"" 11 decresed from 130±llml to 74 ± 13 ml (P < 10~ 4 ) s the FT ws reduced nd the rnge of minimum FD ili1! " ws ml. The T/rji.iiy* i so decresed, from 165 ±24 ml to 88±2 ml (P < 10" 11 ), nd the rnge of minimum V D \*>» ws ml. The chnges in FD : " 1: " nd j/rji' 1 'v :< were virtully complete by 80 b.p.m. nd, therefter, there were no further sttisticlly

5 DEADSPACE AND HIGH FREQUENCY VENTILATION 15 significnt chnges in either between 80 nd 120 b.p.m. (tble I, figs 2 nd 3). DISCUSSION In this study both the physiologicl (VB phys ) nd ntomicl (Fry 01 ") dedspces decresed with decrese in FT findings which re similr to those in other studies in dogs (Willims nd Ryford, 1956; Severinghus nd Stupfel, 1957; Chkrbrti nd Sykes, 1980). The FD/FT rtio incresed progressively nd, therefore, the minute volume (F) of the fresh gs supply hd to be more thn doubled to mintin cotnt P COl s the frequency of ventiltion ws incresed from 15 to 120 b.p.m. It is well known tht, during high frequency ventiltion, the minimum pek irwy pressure occurs in the frequency rnge b.p.m. nd tht it increses therefter. In ddition, when the frequency of ventiltion increses bove the respoe time of the lungs, incomplete emptying of the lungs occurs nd stnding pressure develops in the irwys (i.e. PEEP) which is ssocited with n increse in functionl residul cpcity (Sri et l., 1984). This increse in irwy pressure prevents ny further decrese in FDP hys nd FD*"* 1 even though the FT is smller. Evidence from studies in dogs suggests tht t ventiltory frequencies bove b.p.m., the volumes of both dedspces strt to increse gin (Chkrbrti nd Sykes, 1980). As mentioned bove, vrious uthors hve shown tht the dedspce volume is directly relted to FT; it decreses with decrese in FT whether this is spontneous or rtificil. The internl volume of the irwys depends on the trmurl pressure nd, for exmple, it hs been shown tht the volume of the isolted trche cn increse by more thn 27% s the internl pressure increses bove 10 cm H S O (Mckenzie et l., 1982). Compred with conventionl ventiltion, the end-ipirtory pressure is lower during HFV, until n pprecible PEEP develops nd, hence, decrese in Fry" 1 * 1 t lest up to ventiltion frequencies of b.p.m. would be nticipted. Alveolr dedspce lso depends on FT s shown by Severinghus nd Stupfel (1957) in dogs nd they postulted tht lveolr dedspce is reltively cotnt frction of lveolr tidl volume (pproximtely 20%). Hence, it seems tht the distribution of the tidl volume remi proportiontely the sme over physiologicl rnge of vlues. Therefore, with smller tidl volumes the lveolr dedspce will lso decrese. During HFV, s result of the reltively high velocity of the fresh gs flow, gs molecules with high kinetic energy cused by the high pek ipirtoryflowrte my penetrte further into the distl irwys nd, in ddition, "streming" my occur becuse of jet or otherflow ptter, thereby reducing the functionl FD nt. It cn be rgued tht the mesured VD nl bove 40 b.p.m. my not ws be ccurte, s the ^E'cot mesured by momentrily decresing the frequency to 30 b.p.m. However, within such short time (within two to three breths) nd t reltively smll tidl volumes, it would be expected tht the FE' COt will not chnge significntly. In ddition, it hs been shown tht good correltion cn be obtined between P COt nd FE' COJ using this technique (Whitwm et l., 1983). Some workers hve suggested tht during HFO ( b.p.m.) conventionl bulkflow into the distl irwys is replced by some form of enhnced diffusion or ugmented dispersion (Butler et l., 1980; Rossing et l., 1981). They imply tht, with the increse in frequency, the required tidl volume will be less thn the ntomicl dedspce s result of such mechnisms. However, it is interesting to observe tht, to mintin crbon dioxide homeostsis, Butler nd collegues (1980) required FT in the rnge of ml, even t frequency of oscilltion of 15 Hz (900 b.p.m.), in intubted dult ptients vlue slightly higher thn the FT required in the present study using ventilting frequency of only 120 b.p.m. In mn, reduction of ml of FT will be expected fter trcheotomy nd, in such ptients, Rossing nd collegues (1981) required FT in the rnge ml to mintin blood-gs homeostsis t ventiltion frequencies up to 900 b.p.m. Using cotnt FT of 50 ml, they observed no further effect on crbon dioxide elimintion s the frequency ws incresed bove b.p.m. nd they could not mintin eucpni in two of six ptients with this tidl volume t ny frequency of ventiltion. Therefore, it cn be postulted tht incresing the frequency of ventiltion beyond certin limit, tht is, fter the development of pprecible PEEP, my not decrese FT further nd enhnced diffusion my not be mjor fctor in the decreses in Kn*" 111 nd FD phys. The subject hs recently been reviewed by Chng (1984). It is known tht FD l, s mesured by the Bohr

6 16 BRITISH JOURNAL OF ANAESTHESIA eqution t norml ventiltion frequencies, is subject to over-estimtion nd errors resulting from the slope of the crbon dioxide plteu (Fletcher, 1984) nd is, theoreticlly, pplicble only in the unlikely event tht the gs from ll the lveolr units hs the sme crbon dioxide concentrtion. The mesured ntomicl dedspce is, therefore, sometimes clled the Bohr dedspce to differentite it from the true ntomicl dedspce. The single breth technique of mesuring ntomicl dedspce is lso not free from ssumptio, specificlly in reltion to phses II nd III of the expired crbon dioxide curve nd the unknown error cused by the ipirtory puse. Hitherto, neither technique (Bohr or single breth) hs been pplied for the mesurement of during high frequency ventiltion. The simple technique used here to mesure FD nt ws incorported in the report of the study becuse it ws found tht it my provide resonble estimte of VuP nt. If FE^"" ws under-estimted with this technique, then the totl minute lveolr ventiltion (f x (FT {/ D nt)) should hve shown n increse with the increse in ventiltion frequency bove 30 b.p.m. However, in fct, the estimted lveolr ventiltion showed very little chnge s the frequency of ventiltion incresed, which is in keeping with the nlysis of Chkrbrti, Loh nd Gilchrist (1984). Therefore, becuse the clculted vlues for lveolr ventiltion in the present study follow the trend predicted from work on lung models, it seems likely tht the Bohr eqution provides better estimte of FD*" 1 ' t lower tidl volumes during high frequency ventiltion. However, further work is required to estblish this point. The importnt spect of this study is tht, s the ventiltion rte ws incresed nd the tidl volume decresed, the wsted prt of the tidl volume, which is mesured s physiologicl dedspce, lso decresed, but reched minimum vlue t frequency of between 80 nd 120 b.p.m. Vn nt From the present study, the FD phys would pper to rech n pproximte verge miniml vlue of 1.1 ml kg" 1 in intubted dult ptients nd determine the miniml FT required to eure crbon dioxide elimintion. This my hve profound implictio. Even in norml lungs, s the frequency of ventiltion is incresed, since the FT cnnot be decresed below miniml FD phys, nd becuse of the shorter ipirtory times during HFV nd HFO, very high ipirtory gs flows will be required, generting incresingly higher pek irwy pressures. This problem will be mde much worse in the presence of high irwys resistnce. Moreover, if, s result of ventiltion/perfusion mismtch, the VDP*** were to increse, this would require n increse in tidl volume which would further increse pek ipirtoryflowsnd pressures t higher ventiltion frequencies (for exmple, bove b.p.m.). This will defet the min im of HFV which is to reduce irwy pressures nd, hence, prevent brotrum. Perhps new term, "functionl dedspce" to describe this FD phys volume my be helpful to differentite it from the conventionl physiologicl dedspce volumes mesured t norml frequencies of ventiltion nd t physiologicl tidl volumes. By the term functionl dedspce (FDO is ment the wsted prt of FT which hs to be dded to the idel lveolr ventiltion to mintin crbon dioxide homeostsis during high frequency ventiltion. It my vry widely in different subjects nd is function of the tidl volume, ventilting frequency, irwy pressures, the ventilting system used nd possibly other fctors prt from the respirtory dedspce s defined by the structure nd function of the pulmonry system. We conclude tht the reltiohip between tidl volume nd the mesured physiologicl dedspce volume is such tht, during high frequency ventiltion, decrese in tidl volume is ssocited widi decrese in this volume, until n pprecible PEEP develops s result of non-emptying of the lung. This miniml dedspce will determine the tidl volume required to mintin blood-gs homeostsis during high frequency ventiltion. A men miniml vlue of 1.1 ml kg" 1 ws mesured in seven intubted dult humn subjects during high frequency ventiltion with smll tidl volumes, nd in whom norml P COl ws mintined. This is bout hlf the vlue mesured t conventionl norml tidl volumes nd frequencies of ventiltion. ACKNOWLEDGEMENTS We wish to thnk Mr R. N. Spsford nd Mr R. Stnbridge for permission to study these ptients, the stff of the workshop t the Royl Postgrdute Medicl School who developed the ventiltor, nd Shirley Riche for typing the mnuscript. REFERENCES Butler, W. J., Bohn, D. J., Bryn, A. C, nd Froese, A. B. (1980). Ventiltion by high frequency oscilltion in humn*. Anth. Anlg., 59, 577.

7 DEADSPACE AND HIGH FREQUENCY VENTILATION 17 Chkrbrti, M. K., Loh, L., nd GUchrist, I. (1984). High frequency ventiltion nd gs diffusion. Act Anesthesiol. Scnd., 28, 544. Sykes, M. K. (1980). Crdiorespirtory effects of high frequency intermittent positive pressure ventiltion in the dog. Br. J. Anesth., 52, 475. Chng, H. K. (1984). Mechnism of gs trport during ventiltion by high frequency oscilltion. J. Appl. Physiol., S, 553. Fletcher R. (1984). Airwy ded spce, end tidl CO, nd Christin Bohr. Act Anesthesiol. Scnd., 28, 408. Klin, M., nd Smith, R. B. (1977). High frequency percutneous trtrchel jet ventiltion. Crit. Cre Med., 5,280. Mckenzie, C. F., Hllisey, J., Clrk, D., Steinberg, S., nd Helrich, M. (1982). The effects of PEEP on trchel mechnics. Anesthesiology, 57, A478. Nunn, J. F., nd Hill, D. W. (1960). Respirtory ded spce nd rteril to end-tidl CO, teion difference in nesthetized mn. J. Appl. Physiol., 15, 383. Rossing, T. H., Slutsky, A. S., Lehr, J. L., Drinker, P. A., Kmm, R., nd Drzen, J. M. (1981). Tidl volume nd frequency dependence of crbon dioxide elimintion by high frequency ventiltion. N. Engl.J. Med., 305, Sri, A. F., Rossing, T. H., Solwy, J., nd Drzen, J. M. (1984). Lung infltion during high frequency ventiltion. Am. Rev. Respir. Dis., 129, 333. Severinghus, J. W., nd Stupfel, M. (1957). Alveolr dedspce s n index of distribution of blood flow in pulmonry cpillries. J. Appl. Physiol., 10, 335. Sykes, M. K., McNicol, M. W., nd Cmpbell, E. J. M. (1976). Respirtory Filure, 2nd Edn, p Oxford: Blckwell Scientific Publictio. Whirwm, J. G., Chkrbrti, M. K., Konrzewski, W. H., nd Askitopoulou, H. (1983). A new vlveless ll-purpose ventiltor. Clinicl evlution. Br. J. Anesth., 55, Willims, M. A., nd Ryford, C. M. (1956). Effect of vrition of tidl volume on size of physiologicl ded spce in dogs. J. Appl. Physiol., 9, 30.