CEREBRAL CRCULATON AND METABOLSM N PULMONARY EMPHYSEMA AND FBROSS WTH OBSERVATONS ON THE EFFECTS OF MLD EXERCSE1 By P SCHENBERG, BLACKBURN, M SASLAW, M RCH, AND G BAUM (From the Deprtment of Physiology, University of Mimi School of Medicine, the Deprtnt of Medicine, Vetern's Administrtion Hospitl, Corl Gbles, Fl, nd the Ntion Children's Crdic Hospitl, Mimi, Fl) (Submitted for publiction' November 21, 1952; ccepted Februry 11, 1953) Chronic pulmonry disese, prticulrly emphysem nd fibrosis, my result in vrible ltertions in blood oxygen nd crbon dioxide tensions, depending upon the severity of the disese Chnges in crbon dioxide nd oxygen tensions hve been shown to hve profound influence on cerebrl circultion in cute experiments on norml subjects (1) Recently Ptterson, Heymn, nd Duke (2) demonstrted tht cerebrl blood flow ws incresed bove norml in group of subjects with severe chronic pulmonry emphysem, most of whom hd cor pulmonle nd were in congestive hert filure Their studies re-emphsized the importnce of the influence of blood crbon dioxide nd oxygen tensions on cerebrl blood flow, even though the ltertions in the tensions of these gses were chronic Their ptients ll hd dvnced' pulmonry disese, however, nd it ws felt tht it would be of interest to study the effects of less severe pulmonry disese, nd less profound nd more vrible ltertions in blood gs tensions, on the cerebrl physiology Most of these ptients were studied before nd during moderte exercise, since mentl sttus chnges re known to occur in some ptients with chronic pulmonry disese during exertion METHODS Cerebrl blood flow studies were crried out by mens of modifiction (3) of the originl nitrous oxide technique (4) on 9 of 22 subjects with chronic pulmonry disese The originl nitrous oxide technique with intermittent smpling ws used in the other 13 ptients Twenty of the ptients hd chronic pulmonry emphysem of vrying severity, confirmed by history, physicl exmintion, rdiogrphic nd fluoroscopic studies, nd, in most cses, 1 This investigtion ws supported by reserch grnts (H-832 nd H-832C) from the Ntionl Hert nstitute of the Ntionl nstitutes of Helth, Public Helth Service by n estimtion of mximl brething cpcity, vitl cpcity, nd ir velocity index (5) Two ptients hd pulmonry fibrosis without evidence of significnt obstructive phenomen in the lungs, nd this ws confirmed by the finding of norml ir velocity index in these two subjects (S A nd J G, Tble ) Electrocrdiogrms were mde on ll subjects but one (G W), nd showed confirmtory evidences of cor pulmonle in 1 of the subjects Eight of the subjects with cor pulmonle showed evidences of hert filure (though only one, C A, ws in severe filure) t the time of dmission The dignosis of cor pulmonle in these ptients ws mde by clinicl findings, electrocrdiogrphic chnges, nd chest fluoroscopy (evidences of enlrgement of the right ventriculr outflow trct) The ptients were not studied until clinicl evidences of congestive filure hd disppered on pproprite mngement, nd none of the ptients ws studied during the cute stges of the illnesses which precipitted their dmission, usully bronchiolr or pulmonry infections n this wy n effort ws mde to study ech ptient in resonbly stble stte, so tht the possible effects of infection or hert filure would not interfere with n ccurte interprettion of the results The ptients were clssified for severity of pulmonry involvement ccording to the criteri set forth by Bldwin, Cournnd, nd Richrds (6, 7) The ptients were fsting but no restrictions were plced on smoking prior to the procedure n 12 of the subjects fter the initil blood flow procedure ws performed, exercise ws crried out in the supine position by mens of type of exercycle ttched to the foot of the tble nd supplied with vrible resistnce lods This proved to be n unstisfctory type of exercise, for in lmost every instnce the ptient's legs would become tired before dyspne ppered; mny subjects who were unble to wlk 5 yrds without considerble dyspne experienced little difficulty, even fter performing the supine exercise for 2 to 35 minutes The second blood flow ws done fter the ptient hd exercised for t lest 1 minutes nd the exercise ws continued until the finl blood smples were drwn n one subject (T K) this exercise ws sufficient to produce mild cynosis, but none complined of severe respirtory distress, nd none showed' evidences of mentl disturbnces following exercise Arteril nd venous oxygen contents were determined spectrophotometriclly, ccording to the method of Hickm 72
CEREBRAL CRCULATON N PULMONARY EMPHYSEMA 721 TABLE Clinicl nd pulmonry function dt Per cent norml Per cent miml norml Air brething vitl velocity Cluifi- Pt Age Dignosis nd comments cpcity cpcity index ction C M S A R C S G J G M E L S N S H J W G T B G W T K J H C A H McD G C W E R S N V C K L S 59 Bronchil sthm, severe; pulmonry emphysem; no filure 72 Tuberculosis, modertely dvnced, ctive; pulmonry fibrosis; no filure 56 Chronic bronchitis, pulmonry emphysem; cor pulmonle; no filure 58 Pulmonry emphysem; cor pulmonle; filure on dmission 55 Chronic bronchitis; pulmonry fibrosis; no filure 58 Pulmonry grnulomtosis; cor pulmonle; filure 4 Bronchil sthm, severe; pulmonry emphysem; no filure 63 Pulmonry emphysem; cor pulmonle; filure on dmission 54 ntrinsic sthm; pulmonry emphysem; no filure 53 Bronchil sthm; bronchiectsis; pulmonry emphysem; cor pulmonle; filure 5 Pulmonry emphysem; cor pulmonle; filure on dmission 41 Pulmonry emphysem; no filure 56 Bronchil sthm; pulmonry emphysem; cor pulmonle; no filure 25 Pulmonry emphysem nd fibrosis; cor pulmonle; filure 57 Pulmonry emphysem; cor pulmonle; filure on dmission 63 Bronchil sthm; pulmonry emphysem; no filure 54 Bronchil sthm; pulmonry emphysem; no filure 54 Pulmonry emphysem; no filure 47 Bronchil sthm; pulmonry emphysem; no filure 57 Pulmonry emphysem; cor pulmonle; filure on dmission 55 Bullous emphysem; no filure 74 Bronchil sthm; pulmonry emphysem; no filure 3 42 72 6 59 1 28 41 66 V 27 35 77 V 55 53 16 -- V 38 52 73 28 84 33 V 35 64 55 38 49 78 V 25 36 69 V - 43 36 -- V 24 56 44 V - 43 42 75 56 6 79 76 55 99 56 21 36 58 V -- nd Fryser (8) Blood smples for oxygen determintion were drwn before nd fter ech blood flow mesurement, nd the verge ws used s the finl vlue for rteril-cerebrl venous oxygen difference nd rteril oxygen sturtion Crbon dioxide determintions were crried out on the vn Slyke-Neill mnometric pprtus, s described by Peters nd vn Slyke (9) Arteril blood pressure ws recorded t hert level by the usculttory method t intervls of pproximtely two minutes, nd men pressure clculted from the formul: MP = distolic pressure + % pulse pressure The clculted men pressures checked closely with men pressures mesured directly by mens of mercury U-tube mnometer ph mesurements were mde with the Model R Cmbridge ph meter Blood ws drwn into heprin-coted syringes nd immeditely trnsferred to constnt temperture room t 33-34 C The syringes were llowed to stnd for three to six minutes to llow the temperture to fll from body temperture to the temperture of the room before redings were mde Buffers t ph 4 (cid phthlte) nd 699 (phosphte) were used to check the instrument for stndrdiztion The Rosenthl fctor ws used to correct the redings to 38 C (1) Arteril nd venous oxygen tensions were estimted from the ph nd the per cent oxyhemoglobin sturtion, using the dissocition curves of Dill The vlues for oxygen tension when oxyhemoglobin sturtion ws bove 9 per cent were obtined from chrt of interpolted vlues, using Dill's figures, since it ws impossible to red the curves ccurtely bove this point Crbon dioxide ten-
722 P SCHENBERG, BLACKBURN, M SASLAW, M RCH, AND G BAUM _ "f)co,in co ei M lho ento N N NO - m ~~~~* -W; c>*soo "co 51 S> fg_ tc_ eo O Cco _ or_++ou _ N *+e U~~~~~) _ if) oo -c'n 's oo b O C4 n~ t-os it-coo- q* ( - C4 n t c o- - - '*-No' - E) t- f 'o C " :<o<+ - o ub A ~~~~~~~~cot enon een ls ;g- 7 U- g b 6 m i _ c el v b~~~~~~9c owsy st P" om e e "t" m oo%o- > + A U L + N1e moo Mc N o A co% ~ nc -W4 -i %m A if) ON NO )No in o 42 b de4 w&n"oo O ) oil o O > v + O> O O _ e 1 1 ;X* b N~ %Os% scs% O % s s % \ co 56 ow M"S 1>W 1n11' 1o1 1 co %Z i < % %O%O% % m 4 co o-io t + fi ft X*tt t 1*ee o *PX l C o m- Uso t( n o- o _ Y z v_soooooc Y 5O 1 e n1 1bm\ en \ _ e '%'- % wiui ir; t ~ ~~~ + 8)\ ~~ U )U ) +U )+S ) u to in'o o o o o ooo >o O - O t,: q no odq "Wn OXq oo o q_ ue+ e1l1 g>1 g g co O _e6 6 o *6 e- ococm 6 - C~~~~(4 o cn ' X Z9-oo co oco_o_seo_ in C4 _ o ~~~~~~~~~~~~~~~~~~~~~~ co 1,4~~~ 144C4 Uot%fo)oo roo4oo t' n ' ) _ 2 - -'- --- - - - - - -- ci A1~1f1~t~f)4 141-14m~~~ 'C i o W N f)'r)sf)'' n131 %f) en " w- ) 4r' 1 44 co t44' " o '4o C4 co not Nro XOwOs in uo thtrc _ t~~~* * qwnc s3ri % 6 ** * r co~~~~~ (;o XX,,3X32=>Q->2 t ft f ; 'W
CEREBRAL CRCULATON N sions were estimted from the nomogrms of Peters nd vn Slyke (9) RESULTS Comprison with norml subjects A clinicl summtion of the ptients is given in Tble, nd the results of the studies re given in detil in Tble The ptients rnged in ge from 25 to 74 yers, with n verge of 55 yers They were compred with group of 32 norml subjects who rnged in ge from 38 to 79 yers, verging 56 yers (11) t ws felt necessry to compre the subjects with others in similr ge group, s definite chnges in cerebrl circultion nd metbolism ccompny dvncing ge ( 11 ) There ws no significnt ltertion in cerebrl blood flow, rteril-cerebrl venous 2 difference, cerebrl 2 consumption, or cerebrl vsculr resistnce (Tble ) The blood gs tensions indicte tht the chemicl effects of pulmonry disese in most of these ptients were not extensive Only five of the ptients hd vlues for pco2 of 5 mm Hg or bove; PULMONARY EMPHYSEMA however, pco2 determintions were not obtified in the three ptients with the lowest rteril 2 sturtion nd tensions becuse of technicl error Were these figures vilble, it is possible tht much higher men for 723 pco2 would hve been obtined, but even so the men vlue for cerebrl blood flow is within, norml limits Arteril ph did not differ significntly from the norml, nd men per cent rteril oxygen sturtion ws 913, both indictions tht this group represents reltively mild, or t lest well-compensted pulmonry disese f the subjects re divided into two groups ccording to clinicl severity of their disese, by contrsting those subjects in group nd with those in groups nd V, there re no significnt differences observed in cerebrl blood flow, cerebrl oxygen consumption, nd rteril ph between the two groups Since the clinicl clssifiction is itself prtilly dependent upon rteril PO2 nd pco2 vlues, the vlue for PO2 is significntly lower nd tht for pco2 higher in the second so % so do C _ 6 i : 6% Uo l A U 4o 4 U v 4 11 )5 4 45 SO 5S 6 Arteril PCO2 (mm HS) FG 1 CORRELATON BETWEEN ARTERAL PCO2 AND CBF r=63 p <OO1
724 1P SCHRENBERG, BLACKBURN, M SASLAW,, -M RCH, AND G BAUM S1 d S SO C ~~~~~~~~~~~~ A C 4 * 3 L 41 5 55 6 65 7 75 8 Arteril poz (mm Hg) group thn in the first When considering ll the ptients together, however, there is n dequte correltion between rteril pco, nd cerebrl blood flow nd no correltion between rteril PO nd cerebrl blood flow (Figures 1 nd 2) There TABLE Efects of mild exercise on cerebrl metbolic functions (men vlues in 12 subjects) FG 2 CORRELATON BETWEEN ARTERAL PO, AND CBF r-3 Before During exercise exercise p vlue Art p2 78 74 >5 CBF 528 583 >2 Art 2 content 172 17 >5 Venous O, content 18 11 >5 A-V O 648 588 >1 Art C2 content 535 531 >5 Venous CO, content 547 542 >5 Art ph 738 734 <2* Art pco2 458 492 >2 Venous pco, 51 511 >5 Per cent rt 2 st 917 898 >2 Per cent venous 2 st 575 586 >5 Venous p2 3217 337 >(A5 CMRO2 323 318 >5 MAP 97 112 <1* CVR 185 188 >5 * Denotes sttisticlly significnt chnge is lso no correltion between cerebrl blood flow nd clinicl severity of the ventiltory defect s expressed by reduction in percentge norml mximl brething cpcity Effects of exercise The effects of exercise on the 12 subjects in whom it ws studied re summrized in Tble The only sttisticlly significnt chnges were the drop in rteril ph from 738 to 734 nd the increse in nien rteril pressure 't is of interest tht the nly tswo subjects who showed considerble rise in cerebrl blood flow during exercise lso hd sizble increse in pco, (S A nd T K, Tble Ul), lthough two other subjects showed some increse in pco, without ccompnying significnt elevtion of cerebrl blood flow There is no evidence of even trend towrd n increse in cerebrl blood flow or decrese in rteril-cerebrl venous 2 difference during exercise, for-the c1*nges were quite vrible, nd only one ptient (T K) ws ctully responsible for the pprent chnge in the men vlues of these functions Cerebrl oxygen consumption nd cerebrl vsculr resistnce were
CEREBRAL CRCULATON N PULMONARY EMPHYSEMA not ltered by exercise, lthough there ws firly consistent increse in men rteril pressure There ws no consistent chnge in per cent rteril 2 sturtion or rteril PO2' the only striking reduction in either occurring in T K This is further evidence of the reltive mildness of this type of exercise or the reltive lck of severity of pulmonry disese in these ptients, or both Pulmonry fibrosis The two ptients with pulmonry fibrosis showed no differences in cerebrl metbolic functions from the ptients with emphysem ntermittent vs continuous smpling techniques There ws no significnt difference in ny of the cerebrl metbolic functions in the nine subjects studied by the continuous smpling technique s compred to the 13 studied by the originl intermittent smpling technique, s seen in Tble V, nd for tht reson both groups were combined for finl sttisticl nlysis in this study The studies were done by both techniques s prt of plnned observtions to determine the possible TABLE V Comprison of intermittent nd continuous smpling techniques (men vlues) ntermittent Continuous (13 subjects) (9 subjects) CBF 57 51 CMRO2 33 35 CVR 169 189 All p vlues >3 reson for the differences in m-en vlues in norml subjects s reported by Kety nd Schmidt (4), Scheinberg nd Sted (3) nd Ptterson, Heymn, nd Nichols (12) n this group of subjects, t lest, there is no significnt difference between results obtined by the two techniques Electroencephlogrms Electroencephlogrms performed on eight of the subjects were ll within norml limits DSCUSSON 725 The dt reported here cnnot be compred with the observtions on cerebrl circultory functions in pulmonry emphysem reported by Pt- 36 3A 1 24 1M 1 1 h L 's 4 4 4s5 o 4 " 6 AvtrW pcozl ol!mw_ FG 3 CORRELATON BETWEEN CVR AND ARTERAL PCO, r=51 5 > p >OO1
726 P SCHENBERG, BLACKBURN, M SASLAW, M RCH, AND G BAUM 9' _ so * 7 4 56 9 4 5 75 so 55 9 9S %Oxygen Sturt,ion 1 FG 4 CORREATON BETWEEN PER CENT OXYGEN SATURATON AND CBF r 3 = terson, Heymn, nd Duke (2), since most of our subjects suffered less pulmonry disbility thn did theirs n both groups of subjects there ws dequte correltion between cerebrl blood flow nd pco2, nd cerebrl vsculr resistnce nd pco2 n our subjects the p vlues for these correltions were < 1 nd between 1 nd 5, respectively (Figures 1 nd 3) We found no correltion, however, between po2 nd cerebrl blood flow or between per cent rteril 2 sturtion nd cerebrl blood flow (Figures 2 nd 4), nd we re unble to explin this discrepncy Our ptients were not studied until the effects of the cute illnesses which precipitted dmission to the hospitl hd subsided nd the ptients were resonbly stble Ptterson, Heymn, nd Duke mke no sttement concerning whether this precution ws observed in their group n ddition five of the nine ptients they reported hd evidence of congestive hert filure due to cor pulmonle Since this type of filure reportedly is ccompnied' frequently by n incresed crdic output (13), there is possibility tht the filure itself rther thn pulmonry emphysem my be responsible for the elevted cerebrl blood flow in these subjects Two of their subjects hd low nd norml crdic indices (T-1824 dye), however, mking such n explntion dubious without further investigtion The correltion between cerebrl blood flow nd pco2 in our subjects confirms previous observtions on the effects of inspired CO, on cerebrl circultion (1), nd the norml men vlue for cerebrl blood flow obtined in this group is comptible with n essentilly norml men vlue for pco2 The bsence of correltion between cerebrl blood flow nd rteril PO2 is surprising, s is the pprent bsence of effect of decresed men vlue for rteril PO2 in the whole group Previous observtions (1) hve indicted tht decrese in PO2 is fir stimulus for producing cerebrl vsodilttion in norml subjects; perhps the bsence of this phenomenon in the group of subjects reported here indictes the development of tolernce nd diminished response to the cerebrl vsodilting effect of low oxygen environ-
CEREBRAL CRCULATON N PULMONARY EMPHYSEMA ment if the oxygen deprivtion is chronic rther thn cute Little ws lerned bout the effects of exercise in this study, except tht ptients with only modertely severe functionl pulmonry disbility hve remrkble tolernce to this type of exercise One might nticipte n increse ini cerebrl blood flow to ccompny rise in rteril pco2 in those ptients whose limittion of ventiltory cpcity prevents compenstory hyperventiltion, nd such seemed to be the cse in the two subjects who showed the most striking chemicl responses to exercise t is of interest tht the reduction in rteril ph during exercise ws not ssocited with chnge in cerebrl blood flow This is further evidence tht ltertion in rteril ph per se is not the importnt fctor in the regultion of cerebrl blood flow (14) Since none of our subjects developed signs of mentl confusion during this reltively mild exertion, one of the purposes of this study, which ws to investigte the physiologicl bsis for the confusion which occurs during physicl exertion in mny such ptients, ws not chieved These studies verify the previously estblished reltionship between rteril pco2 nd cerebrl blood flow nd demonstrte reltive lck of importnce of individul chnges in rteril ph, rteril PO2' nd rteril CO2 content in the regultion of cerebrl circultion They lso demonstrte tht cerebrl vsculr nd metbolic functions in chronic pulmonry diseses re unrelted to the severity of the clinicl nd spirometric disturbnce, but re rther relted to ltertion in gseous exchnge in the lungs, nd specificlly to crbon dioxide retention SUMMARY 1 Cerebrl blood flow, oxygen consumption, nd vsculr resistnce were mesured in 22 ptients with chronic pulmonry disese of moderte functionl severity, nd compred with group of norml controls of the sme verge ge The effects of mild exercise were studied in 12 of the ptients 2 There ws no significnt difference in cerebrl blood flow s mesured by the intermittent smpling technique in 13 of these subjects s compred to the continuous smpling technique in the remining nine subjects 3 Men vlues for cerebrl blood flow, cerebrl A-V 2 difference, cerebrl oxygen consumption, nd cerebrl vsculr resistnce did not differ significntly from the norml control subjects 4 The correltion between cerebrl blood flow nd rteril pco2 ws good, wheres no correltion ws found between cerebrl blood flow nd rteril POi or per cent rteril 2 sturtion 5 The effects of exercise on cerebrl metbolic functions in these ptients were vrible nd without significnt trend A reduction in rteril ph during exercise did not influence cerebrt blood flow 6 These studies re-emphsize the importnt reltionship between rteril pco2 nd cerebrl blood flow nd demonstrte the reltive unimportnce of the clinicl' nd spirometric severity clssifiction on cerebrl blood flow in chronic pulmonry disese ACKNOWLEDGMENT The uthors grtefully cknowledge the technicl ssistnce of Mrs Jnet Fetner REFERENCES 727 1 Kety, S S, nd Schmidt, C F, The effects of ltered rteril tensions of crbon dioxide nd oxygen on cerebrl blood flow nd cerebrl oxygen consumption of norml young men J Clin nvest, 1948, 27, 484 2 Ptterson, J L, Jr, Heymn, A, nd Duke, T W, Cerebrl circultion nd metbolism in chronic pulmonry emphysem With observtions on the effects of inhltion of oxygen Am J Med, 1952, 12, 382 3 Scheinberg, P, nd Sted, E A, Jr, The cerebrl blood flow in norml mle subjects s mesured by the nitrous oxide technique Norml vlues for blood flow, oxygen utiliztion, glucose utiliztion nd peripherl resistnce, with observtions on the effect of tilting nd nxiety J Clin nvest, 1949, 28, 1163 4 Kety, S S, nd Schmidt, C F, The nitrous oxide methods for the determintion of cerebrl blood flow in mn: Theory, procedure nd norml vlues J Clin nvest, 1948, 27, 476 5 Gensler, E G, Air velocity index A numericl expression of the functionlly effective portion of ventiltion Am Rev Tuberc, 195, 62, 17
728 P SCHENBERG, BLACKBURN, M SASLAW, M RCH, AND G BAUM 6 Bldwin, E de F, Cournnd, A, nd Richrds, D W, Jr, Pulmonry insufficiency Physiologicl clssifiction, clinicl methods of nlysis, stndrd vlues in norml subjects Medicine, 1948, 27, 243 7 Bldwin, E de F, Cournnd, A, nd Richrds, D W, Jr, Pulmonry insufficiency A study of 122 cses of chronic pulmonry emphysem Medicine, 1949, 28, 21 8 Hickm, J B, nd Fryser, R, A spectrophotometric method for determining blood oxygen J Biol Chem, 1949, 18, 457 9 Peters, J P, nd vn Slyke, D D, Quntittive Clinicl Chemistry, Vol, Methods Willims & Wilkins, Bltimore, 1932 1 Rosenthl, T B, The effect of temperture on the ph of blood nd plsm in vitro J Biol Chem, 1948, 173, 25 11 Scheinberg, P, Blckburn,, Rich, M, nd Sslw, M, The effects of ging on cerebrl circultion nd metbolism n mnuscript 12 Ptterson, J L, Jr, Heymn, A, nd Nichols, F T, Jr, Cerebrl blood flow nd oxygen consumption in neurosyphilis J Clin nvest, 195, 29, 1327 13 Hrvey, R M, Ferrer,, Richrds, D W, Jr, nd Cournnd, A, nfluence of chronic pulmonry disese on the hert nd circultion Am J Med, 1951, 1, 719 14 Schieve, J F, nd Wilson, W P, The chnges in cerebrl vsculr tone in experimentl metbolic lklosis nd cidosis J Clin nvest, 1952, 31, 659