VARIABILITY OF THE PULMONARY VASCULAR RESPONSE TO HYPOXIA AND RELATION TO GAS EXCHANGE IN DOGS*
JAMES B. FORREST AND ANGELICA FARGAS-BABJAK
17.25-32.2 kg) were anaesthetized with intravenous pentobarbitone (dose 30mg/kg) and intubated with a cuffed tracheal tube. Muscle paralysis was induced with pancuronium bromide (dose 0.06mg/kg) and mechanical ventilation started with intermittent positive pressure from a Harvard respirator. Tidal volume and respiratory frequency were set using the Radford nomogram and maintained at constant levels throughout the experiment. Supplemental doses of anaesthetic and musc]r relaxant were given as required. Catheters were placed in the left femoral artery for blood pressure monitoring, the right femoral artery for arterial blood gas sampling, and in the left femoral vein for administration of drugs and for venous sampling of haemoglobin and haematocrit. A number 7 triple-lumen SwanGanz catheter was inserted through the right femoral vein into the pulmonary artery for continuous measurement of pulmonary artery pressure (Ppa), and intermittent measurement of pulmonary wedge pressure (Pwp). Cardiac output (t~) was measured by the thermodilution method using an Edwards cardiac output computer (9510-A). Samples of pulmonary arterial blood were obtained for estimation of mixed venous blood gases and pH. The electrocardiogram was recorded. Rectal temperature was measured by thermistor probe (Yellow Springs Lab. Inc.), airway pressure, (AWP) by a needle inserted into the tracheal tube, and continuous breath to breath oxygen and carbon dioxide concentrations by Beckman OM-II oxygen analyser and LB-2 gas analyser. Mixed expired carbon dioxide concentrations were measured intermittently using a mixing box inMATERIALS AND METHODS serted in the expiratory line. All pressures were measured by Statham transducers (P37b) and toTwelve adult mongrel dogs (weight range gether with the electrocardiogram and respired gas concentrations were recorded on HewlettJames B. Forrest, MB., Ch.B., Ph.D., EEA.R.C.S., Associate Professor, and Angelica Fargas-Babjak, Packard (HP 2201) and Beckman Dynograph M.D., Resident in Anaesthesia. Departments of Anaes- (Type R411) pen recorders. A thermostatically thesia and Medicine, McMaster University Health Sci- controlled warming blanket prevented cooling ences Centre, Hamilton, Ontario, Canada, LSS 4J9. during the experiment. *Supported by the Canadian Medical Research Air was used as the inspired gas initially in all Council, Grant # MA 5880. Presented in part at the Canadian Anaesthetists' Society Meeting, June 20-23, experiments and then supplemented with oxygen if required to achieve more than 98 per cent arte1977. 479 Canad. Anaesth. Soc. J., vol. 25, no. 6, November 1978 IN 1904, the French physiologist Plumier 1 provided the first documented evidence that decreased inspired oxygen caused pulmonary hypertension. Since then, numerous workers have studied the effect of acute hypoxia on pulmonary vascular resistance 2-~ and it is now well established that it is the alveolar oxygen tension and not that of the systemic arterial blood which is the main determinant of the pulmonary vascular pressor response to hypoxia. 7-'~ On the other hand, the level of arterial oxygen saturation is largely determined by the relationship between ventilation and perfusion" which is in turn determined by the pulmonary vascular response to local hypoxia. While this response is present in all species so far tested, 9 the magnitude of the increase in pulmonary vascular resistance (PVR) for a given level of alveolar hypox ia varies greatly between species. 12 Further, in single species, the hypoxic pressor response shows considerable variation when related to arterial oxygen tensions, as for instance in the published reports for the dog. 3'6"13-17 Since the role of the PVR response to hypoxia would seem to be to minimize arterial oxygen desaturation, any individual variation in the response could indicate differences in the adaptation of the gas exchange apparatus of the lungs to a given hypoxic stimulus. The purpose of this study was to determine whether the PVR response to hypoxia is uniquely related to arterial oxygen saturation in individual animals. Mechanically ventilated anaesthetized dogs were used so that the PVR response could be studied uninfluenced by changes in ventilation.
480
C A N A D I A N A N A E S T H E T I S T S ' SOCIETY J O U R N A L
rial oxygen saturation. Thereafter the same airoxygen mixture was used in any one animal during recovery periods. The mean control inspired oxygen concentration was 28 per cent. This is subsequently referred to as normoxia in so far as a11erial blood was fully saturated in the control and recovery periods. Hypoxia was induced by switching to a mixture of oxygen in nitrogen to give inspired oxygen concentrations of S, 11, 16, or 20 per cent. After an initial control period lasting 60 minutes, during which baseline values of all parameters were obtained by serial estimation, the animals were subjected to a five-minute period of hypoxia followed by a 30-minute recovery period. Five minutes of hypoxia in each case was sufficient time for all measured parameters to achieve equilibrium. Each animal was exposed to the five levels of inspired oxygen during any one experiment and each experiment was repeated at least once in 9 of the 12 dogs. In the remaining three dogs, up to three levels of FIoz were repeated (cf. (n-l) in Table I!). The order in which the various levels o f hypoxia were administered was varied between animals to allow comparison of the effects of repeated exposure. Mixed venous and arterial blood ~ases and pH measurements were made in an Instrumentation Laboratory pH/gas analyser by the microelectrode technique. Samples were collected anaerobically in heparinized glass syringes. Calibration by tonometry was done throughout each experiment at regular intervals. Oxygen saturation (s) was calculated using the measured PO: corrected for temperature and pH from the Rossing and Cain ~s equation for dog blood thus: log (s/l-s) = 2.5198 log Po2 + 1.1804 (pH-7.0) 0.0472 - 2.362 I. Pulmonary vascular resistance (PVR) was calculated from PVR = (Ppa Pwp)/0 expressed as mmHg 1-j min. Additional calculated parameters were dead space]tidal volume ratio (VDIVT), pulmonary shunt fraction ((~s/Qt) and the alveolar to arterial oxygen gradie nt P(A-a)o2.
Statistical Attalysis Data were analysed by Student's paired t test. Linear regression analysis was done by analysis of variance of paired values. In the case of PVR and Ppa against Pao~, these included quadratic regression analysis. Statistical significance was taken as P = 0.05 orless. Highly significant refers to values where P = 0.01 or less.
A
e: 8
o----o :
:
E
"~' :.
PVR
6 i
-I 1g
L
l
[
I
1
I
D
nl
I~
CONTROL PERIOO F ] G U a E I, The mean values + I SDare shown f0eall dogs for cardiac output (open circles) and for pulmonary vascular resistance (closed circles) for each control period between hypoxic episodes.
RESULTS
Controls: effect of repeated expos,re There was a small (12 per cent) decrease in the mean control (~ after repeated hypoxia while mean control Ppa increased by about three per cent; thus PVR increased with successive hypoxic episodes by about 20 pet" cent after the fourth episode compared to initial values, but as with O this was not significant (Figure I). Individual animals in each case followed the same trend. No change was found for Pwp, AW P, heart rate or mean systemic blood pressure, during these control periods.
Group mean values The mean values of all control periods for the 12 dogs are given in Table I and compared to the pooled mean hypoxic values, Hypoxia in all cases increased Ppa to a mean for the group which was 43 per cent above control values. Similarly, PVR was increased by about 56 per cent, while (~ was decreased by only two per cent. There was a small increase in systemic arterial B P o f eight per cent in the hypoxic group. Arterial pH increased from a mean control value of 7.38 to 7.41 (H § decrease from 41,69 to 38.9 nmol 1-1) while Paco2 was reduced from 36.96 to 34.94 mm Hg (4.92 to 4.65 kPa), with hypoxia, while mean values for Pao~ were 98.2 and 45.65 mm Hg (13.06 and 6.07 kPa) respectively. The slightly lower Paco~ was
FORREST & FARGASoBABJAK" PULMONARY VASCULAR RESPONSE
481
TABLE I
Variable
Control + 1 SD
I-lypoxia • 1 SD
P
Pulmonary vascular resistance
kPa, l-J.min (ram Hg.I-].min)
0.29 + 0.03 (2.15 _.+ 0,21)
0,45 +_ 0.21 (3.35 + 1.59)
0.0005
Pulmonary artery pressure
kPa (ram Hg)
1,69 _+ 0.43 (12.70 + 3.25)
2,42 • 0.83 (18.16 • 6.27)
0. 8005
Cardiac output
l.min -1
3.90 + 0.64
3.83 • 1.01
N,S,
Mean arterial pressure
kPa (ram Hg)
20,02 • 3.43 (150.55 + 25,78)
21.57 _+ 3.87 (162.17 _+ 29,10)
N,S.
Mean airway pressure
kPa (ram Hg)
0.52 +_ 0.16 (3.91 Z 1.24)
0.53 • 0.17 (3.99 ___ 1.29)
N,S,
Arterial pH
nmol.I, H + (pH units)
42.00 _ 3.00 (7.38 _+ 0.03)
39.00 4- 3.00 (7.41 • 0.03)
N,S.
Arterial oxygen tension
kPa (tort)
13.06 + 1.95 (98.20 + 14.63)
6.07 + 2.39 (45.65 _+ 18.00)
0.0005
Arterial carbon dioxide tension
kPa (tort)
4.92 _+ 0.50 (36.96 4- 3.77)
4.65 + 0.59 (34.95 __. 4.44)
N.S.
End tidal carbon dioxide
per cent
5.46 _.+ 0.08
5.31 • 0.08
N.S.
Mixed expired carbon dioxide Pulmonary shunt fraction
per cent per cent
2,66 + 0.01 3.51 _.+ O. 98
2.60 + 0.01 t .09 _+ O. 79
N.S. 0.0005
Alveolar-arterial oxygen
kPa 9(torr)
7.45 + 0.82 (56,04 _+ 6.15)
2.13 _+ 1.56 (16.00 + 11.76)
0.0005
49,62 + 6.65
47.83 + 9,28
N.S.
percent
42.96 + 5.39
45.77 + 5.00
N,S.
Dead space/tidal volume ratio Haematocrit
N.S. = not significant where P > 0.05. reflected in a three per cent reduction in end e x p i r e d fractional carbon dioxide c o n c e n t r a t i o n s a n d a two per cent reduction in m i x e d expired carbon dioxide. T h e m e a n values for s h u n t fiaction ( 0 s / 0 t ) s h o w e d a large reduction in the hypoxic g r o u p o f 70 per cent c o m p a r e d to controls, with a similar reduction found for P(A-a)o2. N o significant c h a n g e w a s found for VD/VT, A W P or Pwp with hypoxia. Pulmonary Vascular Resistance All animals s h o w e d i n c r e a s e d Ppa and P V R with hypoxia but the m a g n i t u d e o f t h e s e inc r e a s e s varied greatly b e t w e e n animals. Figure 2 s h o w s the individual PVR values plotted against Paoz. In all c a s e s , little c h a n g e o c c u r r e d in P V R until Pao~ w a s r e d u c e d to less than 7 0 r a m Hg; h o w e v e r , no significant statistical correlations could be found for t h e s e curvilinear r e s p o n s e s . T h e rise in PVR and also Ppa w a s d e l a y e d in all c a s e s for o n e to two m i n u t e s after switching to the hypoxic inspired g a s m i x t u r e and, in general, the s h o r t e s t delays occurred with the lowest Fto~ v a l u e s o f 0.08. T h e increase in P V R r e a c h e d a plateau after four m i n u t e s in 52 hypoxic r u n s a n d
after three m i n u t e s in eight h y p o x i c runs. In all c a s e s t h e s e plateau v a l u e s o f P V R were unc h a n g e d after five m i n u t e s . All reported hypoxic v a l u e s refer to m e a s u r e m e n t s d o n e at five minutes. W h e n PVR w a s plotted against p e r c e n t o x y g e n saturation (%02 sat.), significant inverse linear relationships were f o u n d for all dogs (Figure 3 a n d T a b l e II). In individual a n i m a l s t h e s e lineal" PVR/%O2 sat, r e s p o n s e s were highly r e p r o d u c e able in each c a s e , with the e x c e p t i o n o f dog n u m b e r five, w h e r e P V R r e s p o n s e s were repeated tbr only two levels o f FIoz. H o w e v e r , with d o g 5 t h e s e P V R v a l u e s at e q u i v a l e n t Fie2 were very nearly identical. O n the o t h e r h a n d , c o m pari son b e t w e e n a n i m a l s clearly s h o w s great variability, T h e v a l u e s for slope, intercept, correlation coefficient a n d significant level are given for e a c h d o g in Table I1. T h e slopes of t h e s e P V R / % Oz sat. r e s p o n s e s r a n g e d from - 0 . 0 1 3 to - 0 . 1 4 4 but 83 per cent of these were less t h a n - 0 . 0 6 and 42 per cent were b e t w e e n - 0 , 0 4 and - 0 . 0 6 . T h u s it w a s possible to categorize dogs a s (a) low res p e n d e r s having a slope o f less t h a n - 0 . 0 4 (41 per cent), (b) m e d i u m r e s p o n d e r s having a slope be-
482
CANADIAN
ANAESTHETISTS'
SOCIETY
JOURNAL
TABLE II
Dog
n
PVR/% O2 sat. bR [
1 2 3 4 5 6 7 8 9 10 11 12
12 10 8 7 6 7 9 9 9 9 9 9
-0.144 -0,019 -0.057 -0,023 -0.019 --0,044 -0.048 -0.013 -0.055 -0,064 -0.037 -0.056
16.3 3.5 6.7 3.7 3.7 5.8 5.8 3.0 8,8 8.4 7.9 8.2
PPa/7~ Oz sat. 1
r
bp
0.951" 0.964* 0.842* 0,851~" 0,815:~ 0,948* 0.834* 0.598~ 0.846~" 0.972* 0. 779~t 0.845*
-0,561 -0.]25 -0.362 -0,108 -0.040 -0,091 -0,230 -0.076 -0.229 -0.224 -0.038 -0.I95
70.7 27.0 45.0 22,6 ]6.5 17.6 32.5 18.7 38.2 31.7 19.8 33.6
r 0.952* 0,564~: 0.597 N.S, 0,844t 0.493 N.S. 0,849~ 0.969* 0,788~" 0.940* 0,942* 0.592 N.S, 0.847*
ba, bp = slope, I = intercept, r = correlation coefficient (Y = bX + 1). * = significant at P -- 0,001. t -- significant at P = 0.01. ~; = significant at P = 0.05. NS = not significant where P > 0.05. c
lm/R
E
8 PVR
-r E E -
"" Z
9
9.. ",.~.o >
E E _
t
6
.~.. "
a
9
f
-
|
.':
~
.
9
9
2
" ,. 9
,
>
~ 9
z O
20
S
.----"1~ . "~'---'~ 6
I
I
I
I
I
40
60
80
100
120
P802 I
I
I
| 40
I
I ~)
I
I 80
1
} 100
140
ARTERIAL OXYGEN TENSION ( tort )
FIGURE 2. Pulmonary vascular resistance is plotted as mean values for individual runs against arterial oxygen tension. The two curves shown were drawn through the data from two dogs, but in no case were curves statistically significant at the 5 per cent probability level.
t w e e n - 0 . 0 4 a n d - 0 , 0 6 (42 p e r cent), o r (c) high r e s p o n d e r s h a v i n g a slope g r e a t e r than - 0 . 0 6 (17 per cent). T h e m e a n slope for all d o g s w a s - 0 . 0 4 8 with a m e a n correlation coefficient of 0,822. Similar i n v e r s e linear relationships were o b t a i n e d for Ppa against per cent o x y g e n saturation but the overall level o f significance w a s lower than for P V R (Table I1). T h e m e a n slope for P p a / % 02 sat. w a s - 0 , 1 9 0 for a m e a n correlation coefficient o f 0.781. T h e predictive value o f the slope o f Ppal%O2 sat. (bp) for the slope o f PVR]%O~ sat. (ha) w a s t e s t e d by an a n a l y s i s o f v a r i a n c e o f
ARTERIAL O X Y G E N S A T U R A T I O N ( % 1
FIGURE 3. Pulmonary vascular resistance is plotted against arterial oxygen saturation. The regression line for each dog is shown, In all cases these are highly significant and reproduceable (see text, of Table 11).
paired slope v a l u e s and w a s found to be highly significant (P < 0.001) s u c h that ba 0.25 br 0,001 (where r = 0.909). T h e high d e g r e e o f significance o f the a b o v e relationship w a s u n d o u b t edly due to the fact that cardiac o u t p u t and P w p were relatively u n c h a n g e d d u r i n g h y p o x i c e x p o sures. T h i s result indicates that it w a s possible with a high predictive a c c u r a c y to e s t i m a t e the c h a n g e in P V R from the Ppa r e s p o n s e . F u r t h e r the u s e o f a single control and a single h y p o x i c v a l u e o f Ppa did not r e d u c e the a c c u r a c y o f this prediction to a n y significant e x t e n t since individual r e s p o n s e s were highly r e p r o d u c e a b l e .
FORREST
& FARGAS-BABJAK:
PULMONARY
VASCULAR
483
RESPONSE
o.~ ---
z E E
~A-aD 2
] i
-!
F, i
~ o.~
i
o
~ oo~ i
o
i
o
.
..,/-
o
~ >
'I 0
I
I ~0 ARTERIAL
~"
1 40
OXYGEN
t
I 6C
I
SATURATION
I 80
I
I 1~
t % )
FlCURe 5. Pulmonary shunt fraction (closed circles) and alveolar to arterial oxygen gradienl (open circles) are plotted against arterial oxygen saturation as mean values for individual runs. The solid curve is drawn through the Qsl(~tvalues while the broken curve is drawn through the P(A-a)o~values. FIGURE 4. Frequency distributions for change in cardiac output, pulmonary artery pressure and in pulmonary vascular resistance are shown for the pooled data. The units on the abscissa are equivalent and are the fractional changes compared with control.
Sequential hypoxic exposures In order to compare the effects of repeated and sequential hypoxic exposures, the values for Ppa and PVR were expressed as a change compared with the immediately preceding value at normoxia thus: change = (value at 5 min hypoxia control value)/control value. In both cases highly significant and reproduceabte inverse linear relationships were again found for all dogs. The slopes of these were only slightly lower than the slope values shown in Table II. In general the correlation coefficients for these slopes were also slightly lower, but none of these differences between the values calculated as change compared to control and the absolute values were significantly different at the one per cent probability level. Thus the PVR and Ppa responses which were found were not significantly altered by the number or the sequence of hypoxic exposures.
Frequency distribution of PVR, Q and Ppa change Since PVR is a calculated parameter and depends on the net change of three variables (Ppa, Pwp and 0), the relative influence of each of these during each of the 60 hypoxic exposures has been
analysed. Figure 4 shows the resulting frequency distributions for change in PVR, t~ and Ppa. The change in Pwp has been omitted since this was unaltered by hypoxia. Clearly the change in Ppa accounts for almost all the change in PVR as seen by the close similarity of the lower two histograms and demonstrates the high degree of predictability of the slope bR from bp described above. The two negative values of change in PVR were obtained from one run in each of two dogs with severe hypoxia (Ftoz = 0.08).
Pulmonary shunt flow and alveolar[arterial oxygen difference There was little variation in Qs/Qt or in alveolar/arterial oxygen difference P(A-a)oz between dogs at equivalent levels o f % Oz sat. 0s/(~t at full saturation ranged from 5.5 to 6.5 per cent and decreased exponentially with altered oxygen saturation to reach a fairly constant level of 0.5 per cent below 70 per cent oxygen saturation (Figure 5). It is of interest that two dogs at severe hypoxia had negative values for Qs/I)t. Similarly the P(A-a)oz decreased exponentially but was fairly constant at 5 mm Hg below 70 per cent oxygen saturation. The P(A-a)oz curve was shifted (hatched line) to the left around the point of inflection (80 to 90 percent oxygen saturation) compared with the curve for t)s/t)t (solid line). One o f the negative t~s/0t values was associated with a negative P(A-a)o2.
484
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL DISCUSSfON
little affected by these differences in cardiac output. In the case of the individual dog PVR reAlveolar hypoxia constricts pulmonary arterial sponses, the curvilinear relationships we found vessels and results in increased pulmonary vascu- against Pao 2 contrasts with the highly significant lar resistance in both the isolated lung and in and reproduceable inverse linear correlations intact animals, z,4.~5,t9 While the exact mediator with arterial oxygen saturation. Thus we conof this response is not known, the possible mech- clude that the PVR response to hypoxia is unanisms have recently been reviewed in detail2 ,z~ iquely related to arterial oxygen saturation in inThe increase in resistance is now thought to re- dividual animals, and that the slope of the result from reduction in the calibre of small a,te,'ies sponse varies greatly from one animal to another. of less than 0.2 mm diameter through active con- Further, we have shown that the slope of the PVR striction 9"2~ and is thought to be essentially a re- response can be predicted with a high degree of sponse to local change in alveolar Po2. z2 How- accuracy in individual animals fi'om the slope of ever, the magnitude of the increase in resistance the Ppa response. At any given level of PAo2, the varies greatly between species ~2 and within the arterial oxygen saturation dePends on a number same species 6 for any given level of alveolar of factors; haemoglobin and haematocrit levels, hypoxia. The results which we have found blood pH and temperature, alveolar dead space, confirm the variability of the PVR response to shunt flow, venous admixture and matching of hypoxia in the dog as compared with the pub- ventilation and perfusion. All of these could aflished reports for the mean change 3'6'~3J4-~7 and fect the PVR response to hypoxia directly or indisupport the findings of Barer, e t al. r in isolated rectly. We did not find any change in temperature lungs of cats where curvilinear but not significant or dead space/tidal volume ratio and, although relationships were found for PVR against arterial the arterial pH, haemoglobin and haematocrit values were increased above control these were Po2. Hypoxia resulted in a 43 per cent increase in not sufficient to appreciably alter oxygen saturathe group mean Ppa and a -~6 per cent increase in tion calculated from the Rosslng and Cain mean PVR, while cardiac output was virtually equation I~ for dog blood. The most important unchanged. This compares with the study of Sac- factor determining arterial oxygen saturation is kner, e t a L 2~ where equivalent levels of hypoxia probably ventilation perfusion ratio, t' resulted in a 60 percent increase in PVR, and also Increasing Ppa by itself reduces the relative that of Malik & Kid 15 where PVR was increased topographical differences in pulmonary blood by about 50 per cent. Despite the close similarity flow in the dog lung 2~ but this results in only a between our study and those quoted, significant small improvement in gas exchange since differences exist. Our values for control (~ were P(A-a)o2 is normally low. Recent studies have some two times higher and, further, did not shown that local alveolar hypoxia results in redischange with hypoxia, whereas Malik & Kidd t~ tribution of blood flow away from hypoxic areas, found that Q increased by some 30 per cent, but at thus minimizing arterial oxygen desaturatlon z4,:-~ a slower rate than the rise in Ppa. and also that regional differences may exist in the This difference in the cardiac response is likely ability of the pulmonary vessels to respond by due to the use of the muscle relaxant pan- constriction to bypoxia. 26"27 It seems possible curonium bromide in our study. This drug is that similar differences may also exist between known to have inotropic as well as chronotropic animals in the overall responsiveness of the pulactions on the heart, resulting in a sustained ele- monary resistance vessels to alveolar hypoxia. vation of cardiac output. The fact that we did not Our findings tend to confirm this hypothesis and find any change in I~ with hypoxis suggests that further suggest that the net gas exchange effect in the cardiac response (increasing ~ with decreas- terms of arterial oxygen saturation is unique to ing PAo2) which Malik & Kidd ~s found may de- the individual. Clearly those animals having a low pend on the level of the resting or control Q. PVR response to hypoxia also have more marked Further, the cardiac response is higher in spon- arterial oxygen desaturation at equivalent levels taneously breathing animals ~. It is possible that of inspired and alveolar oxygen. In other words, the small degree of hypocapnia which we found high responders are able to maintain higher levels during hypoxia, despite controlled ventilation, of arterial oxygen saturation. could have further attenuated the cardiac reA number of possible factors are known to alter sponse, t-~ What is clear, however, is that the the tone and calibre of lung resistance vessels in magnitude of the PVR response to hypoxia is association with hypoxia. Release of bioactive
FORREST & FARGAS-BABJAK: PULMONARY VASCULAR RESPONSE
485
amines such as histamine, serotonin, and for dogs with lower responses to have higher catecholamines, zs adenosine, z9 prostaglandins, 3~ baseline perfusion pressures. Further studies are as well as increased conversion ofangiotensin I to necessary to determine the exact role of pulmoangiotensin 11,3~ have been reported and indi- nary vessel structure in the variability of the PVR vidual rates ofagonist release do occur. No single response to hypoxia. humoral mediator, however, has so far been SUMMARY clearly identified with the hypoxic response; nevertheless, some or all of the pulmonary vascuAnaesthetized and mechanically ventilated lar agonists quoted above probably at least modulate this response in vivo. 3z The presence of dogs were subjected to five minutes of alveolar erythrocytes within the pulmonary circulation hypoxia with F[oz ranging from 0.08 to 0.20 while has recently been shown to be essential for pulmonary artery pressure (Ppa), pulmonary maintenance of normal vascular tone and respon- wedge pressure (Pwp) and cardiac output (Q) siveness to stimulation by agonist, 33 while were measured. Hypoxia increased Ppa in all platelets as a possible source of adenosine com- dogs whereas Pwp and (~ did not change sigpounds, serotonin, and prostaglandins were not nificantly. Thus pulmonary vascular resistance essential for the pressor response during (PVR) increased by a mean for alt dogs of 56 per hypoxia. While variations in the amount of cent. There was great variation in the absolute mediator released in response to hypoxia is a increase in Ppa and PVR between animals and distinct possibility, this would account only for these were not statistically correlated with artedifference in the magnitude of the response and rial Po2, but highly significant and reproduceable does not explain the ]inearity of the PVR relation- inverse relationships were found for Ppa and ship with arterial oxygen saturation. The effi- PVR against arterial oxygen per cent saturation. cie ncy of active contraction in pulmonary vascu- The slopes of these responses varied between lar smooth muscle which results in the dogs fiom -0.013 to - 0 . 1 4 4 for PVR and from haemodynamic response also depends to a large -0.038 tO -0.561 for Ppa. The alve01ar-arterial extent on the physical properties of the vessel oxygen gradient and the pulmonary shunt fracwaits. Thickening of the media smooth muscle tion were reduced in a similar way with decreaslayer of pulmonary arterial vessels, such as oc- ing arterial oxygen per cent saturation, but dead curs with chronic hypoxia, is an adaptive process space/tidal volume ratio remained unchanged. to prolonged stimulation, and may result also in Thus the slope of PVR response to hypoxia against arterial oxygen per cent saturation is increased reactivity. The haemodynamic effects of such adaptive unique for individual animals. This may reflect structural changes have been described in detail functional and likely structural adaptations of the for resistance vessels in hypertension 34 in the pulmonary vascular smooth muscle. systemic circulation and it seems probable that R~SUM~ similar adaptations exist within the pulmonary circulation as well, even though the haemoDes chiens anesthEsigs et ventilEs mEcaniquedynamic effects may differ. The relatively high compliance of the pulmonary arterial vessels meat ont ErE soumis ~ des Episodes d'hypoxie would tend to maintain low perfusion pressures alvgolaire de cinq minutes en les exposant ~t des even in the presence of moderate vessel adapta- Fio2 de 0,08, de 0,11, de 0,16 et de 0,2; la pression tions. However, such adaptations could result in artErielle pulmonaire, la pression pulmonaire significant differences in vascular reactivity due coincge (wedge) et le debit cardiaque 6talent to variation in the total amount of smooth muscle mesurgs Iors de ces Episodes. L'hypoxie s'est traduite par une 6lgvation de la membrane, with associated vaso-active agonist receptor sites. Induction of pulmonary hyperten- pression de I'arti:re pulmonaire chez t o u s l e s sion with dextran infusion results in marked at- chiens, alors que [a pression pulmonaire coincEe tenuation of the pulmonary vascular response to et le debit cardiaque n ' o n t pas chang6 de fa~;on hypoxia in dogs, 3s but we were unable to find any significative. On a observe une ElEvation de la consistent relationship between the magnitude of resistance vasculaire pulmonaire chez tous les the PVR response to hypoxia expressed as the ehiens (616vafion moyenne de 56 pour cent). L'on slope against oxygen saturation or in the absolute a note de grandes variations dans ies augmentarise in Ppa or PVR, with the pre-existing control tions de pression artErielle pulmonaire et de rEsisPpa or PVR. Nevertheless, there was a tendency tance vasculaire pulmonaire, variations sans rela-
486
CANADIAN ANAESTHETISTS ~ SOCIETY JOURNAL
tion significative a v e c la Pao~; u n e relation inv e r s e h a u t e m e n t significative el e o n s t a n t e a c e p e n d a n t 6td t r o u v d e entre la pression de I'art~:re p u l m o n a i r e e t l a rdsistance vasculaire pulm o n a i r e e t l a saturation en oxyg/~ne du s a n g art6riel. Le gradient en oxyg/~ne alv6olo-artdriel et le s h u n t d i m i n u a i e n t avec la d 6 s a t u r a t i o n en o x y g / m e , m a i s le rapport e s p a c e m o r t / v o l u m e c o u r a n t d e m e u r a i t le m 6 m e . Doric, la c o u r b e rept'6sentant la modification de rdsistance vasculaire p u l m o n a i r e s e c o n d a i r e /t I ' h y p o x i e e n rapport h la saturation artdrielle en o x y g 6 n e e s t unique c h e z un animal donn6. Ceei peut rep r 6 s e n t e r des a d a p t a t i o n s fonctionnelles et poss i b l e m e n t s t r u c t u r a l e s d e la m u s c u l a t u r e vasculaire p u l m o n a i r e , ACKNOWLEDGEMENTS
T h e a u t h o r s gratefully a c k n o w l e d g e the assist a n c e of the D e p a r t m e n t of Biostatistics and E p i d e m i o l o g y , M c M a s t e r U n i v e r s i t y , for statistical a n a l y s i s , and to M i s s J o y c e B r a n d s e n for typing the m a n u s c r i p t . REFERENCES I. PLUMIER, P.L. La circulation pulmonaire chez le
2. 3. 4. 5. 6.
7.
8. 9. 10.
chien. Arch. Internat. de Physiol. I: 176-213 (1904). EULEr, V.S. YON & LILJESTRAND, G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol. Scand. 12:301-320 (1946). Lr, wts, B.M. & GOaLIN, R. Effects of hypoxia on pulmonary circulation of the dog. Am. J. Physiol. 170:574-587 (1952). LLOVO, T.C., Jr. Effect of alveolar hypoxia on pulmonary vascular resistance. J. Appl. Physiol. /9: 1086--1094 (1964). S'raoum R.C. & CONN, H.L., JR. Pulmonary vas. cular effects of moderate and severe hypoxia in the dog. Am. J. Physiol. 179:119-122 (1954). TUCKEr, A. & REEVES, J.T. Non-sustained pulmonary vasoconstriction during acute hypo• in anaesthetized dogs. Am. J. Physiol. 228:756-761 (1975). BarEr, G.R., H o w a r o , P., & SHAW, J.W. Stimulus-response curves for the pulmonary vas. cular bed to hypoxia and hypercapnia. J. Physiol. (Load.) 2 / / : 139-155 (1970). F~SHm~,N, A.P. Respiratory gases in the regulation of the pulmonary circulation. Physiol. Rev. 41: 214-280(1961). FtSHMAN, A,P. Hypoxia on the pulmonarycirculation. How and where it acts. Circulation Res. 38: 221-231 (1976). HAuot=, A. Hypoxia and pulmonary vascular resistance. The relative effects of pulmonary arterial and alveolar Po~. Acta Physiol. Scand. 76:121-130 (1969).
I ]. WEST, J.B. Regional differences in gas exchange in the lungoferect man. J. Appl. Physiol. 17:893-898 (1962). 12. GROVER, R.F., VOGEL, K.H., AVERILL, K.H., & BLOUnT, G-S., Jr. Pulmonary hypertension. Individual and species variability relative to vascular reactivity. Am. Heart J. 66:1-3 (1963). 13. BERRY, W.B., McLAUGHLII~, J.S., CLARK, W.D,) & MORROW, A.G. The effects of acute hypoxia on pressure, flow and resistance in the pulmonary vascular bed. Surgery 58:404-411 (1965). 14. DALu I., MICHEL, C.C., RAMSAY, D.J., & WAALER, B.A. Conditions governing the pulmonary vascular response to ventilation hypoxia and hypoxaemia in the dog. J. Physiol. (Load,) 196: 351-379 (1968). 15. MALta, A.B. & KIDD, S.L. Time course of pulmonary vascular response in dogs. Am. J. Physiol. 224:1-6 (1973). 16. THILENIUS, D.G. & DERENZO, C. Hypoxic pulmonary vasoconstriction in unanaesthetized dogs with constant arterial Pcoz and pH. Clin. Sci. 37: 731-737 (1969). 17. THILENXUS, D.G. & DERENZO, C. Effects of acutely induced changes in arterial pH on pulmonary vascular resistance during normoxia and hypoxia in awake dogs. Clin. Sci. 42:277-287 (1975). 18. RossINO, R.G. & CAIN, S.M. A nomogram relating Po~, pH, temperature, and haemoglobin saturation in the dog. J. Appl. Physiol. 21 : 195-201 (1966). 19. MILES, P.H. & StlEPHERO, J.T. Relationship between pH, Po2 and Pco2 on the pulmonary vascular bed of the cat. Am. ]. Physiol. 21.5:1170-1176 ( 1968L 20. BER~OFSKY, E.H. Mechanisms underlying vasomotor regulation of regional pulmonary blood flow in normal and diseased states. Am. J. Med. 57: 378-394 (1974). 21. SACKNER, M . A . , WILL, D.H., & DoBoIs, A,B. The site of pulmonary vasomotor activity during hypoxia or serotonin administration. J, Clin. Invest. 45:112-121 (1966). 22. GRANT, B.J.B., DAVieS, E.E., JONES, H.A., & HUGHES, J.M.B. Local regulation of pulmonary blood flow and ventilation perfusion ratios in the coati-mundi. J. Appl. Physiol. 40:216-228 (1976). 23. WEST, J.B., DOLt.ERe, C.T., & NaIMARK, A. Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J. Appl. Physiol, 19:713-724 (196a).
24. ARRORELlus,M., Jr., UuA, B., & Zauner, C.W. The relative effect of hypoxia and gravity on pulmonary blood flow. Respiration 31:369-380 (1974). 25. KATO, M. & STAUg, N.C. Response of small pulmonary arteries to unilobar hypoxia and hypercapnia. Circulation Res. 19:426-440 (1966). 26. HALES, C.A., AnLUWALIA, B., & K.AZEML H. Strength of pulmonary vascular response to regional hypoxia. J. Appl. Physiol. 38:1083-1087 (1975). 27. MALONEY, J.E., ALCORN, D., CANNATA, J., WALKER, A., ~/. R|TCHIE, B.C. Regional vascular response to hypoxia in the lungs of anaesthetized sheep. Austral. J. Exp. Biol. Med. Sci..52:801-812 (1974).
FORREST & FARGAS-BABJAK: PULMONARY VASCULAR RESPONSE
487
32. TUCKER, A., HOFFMAN, E. A., & Wcm, E K. Histamine receptor antagonism does not inhibit hypoxic pulmonary vasoconstriction in dogs. Chest 71 : 261-262 (1977). 33. McMuaTI:tY, I.F., HOOKWAY, B.W., & ROOS, S. Red blood cells play a crucial role in maintaining vascular reactivity to hypoxia in isolated rat lungs. Chest 7t: 253-2.55 (1977). 34. FOLKOW, B. Haemodynamic consequences of adaptive structural changes of the resistance vessels in hypertension. Clin. Sci. 41 : l - 12 (1971). 35. BENUMOF, J.L. & WAHRENBROCK.E.A. Blunted hypoxic pulmonary vasoconstriction by increased 3[, BERKOV, S. Hypoxic pulmonary vasoconstriction lung vascular pressures. J. Appl. Physiol. 38: in the rat. The necessary role of angiotensin II. 846-850 (197.5). Circulation Res. 35:256-261 (1974).
28. HAUOE, A. & MELMON, K.L. Role of histamine in hypoxic pulmonary hypertension in the rat. 11. D~pletion of histamine, serotonin and catecholamines. Circulation Res. 22:371-392 (1968). 29. MENTZER, R.M., JR., RUB[O, R., & BEa~qE, R.M. Release of adenosine by hypoxic canine lung tissue and its possible role in the pulmonary circulation. Am. J. Physiol. 229:1625-t631 (1975). 30. KADOWlTZ, P.J.. JOINER, P.D., & HYMAN, A.L. Physiological and pharmacological roles of prostaglandlns. Ann. Rcv. Pharmacol. 15:285-306 (1975).
JAMES B. FORREST AND ANGELICA FARGAS-BABJAK
17.25-32.2 kg) were anaesthetized with intravenous pentobarbitone (dose 30mg/kg) and intubated with a cuffed tracheal tube. Muscle paralysis was induced with pancuronium bromide (dose 0.06mg/kg) and mechanical ventilation started with intermittent positive pressure from a Harvard respirator. Tidal volume and respiratory frequency were set using the Radford nomogram and maintained at constant levels throughout the experiment. Supplemental doses of anaesthetic and musc]r relaxant were given as required. Catheters were placed in the left femoral artery for blood pressure monitoring, the right femoral artery for arterial blood gas sampling, and in the left femoral vein for administration of drugs and for venous sampling of haemoglobin and haematocrit. A number 7 triple-lumen SwanGanz catheter was inserted through the right femoral vein into the pulmonary artery for continuous measurement of pulmonary artery pressure (Ppa), and intermittent measurement of pulmonary wedge pressure (Pwp). Cardiac output (t~) was measured by the thermodilution method using an Edwards cardiac output computer (9510-A). Samples of pulmonary arterial blood were obtained for estimation of mixed venous blood gases and pH. The electrocardiogram was recorded. Rectal temperature was measured by thermistor probe (Yellow Springs Lab. Inc.), airway pressure, (AWP) by a needle inserted into the tracheal tube, and continuous breath to breath oxygen and carbon dioxide concentrations by Beckman OM-II oxygen analyser and LB-2 gas analyser. Mixed expired carbon dioxide concentrations were measured intermittently using a mixing box inMATERIALS AND METHODS serted in the expiratory line. All pressures were measured by Statham transducers (P37b) and toTwelve adult mongrel dogs (weight range gether with the electrocardiogram and respired gas concentrations were recorded on HewlettJames B. Forrest, MB., Ch.B., Ph.D., EEA.R.C.S., Associate Professor, and Angelica Fargas-Babjak, Packard (HP 2201) and Beckman Dynograph M.D., Resident in Anaesthesia. Departments of Anaes- (Type R411) pen recorders. A thermostatically thesia and Medicine, McMaster University Health Sci- controlled warming blanket prevented cooling ences Centre, Hamilton, Ontario, Canada, LSS 4J9. during the experiment. *Supported by the Canadian Medical Research Air was used as the inspired gas initially in all Council, Grant # MA 5880. Presented in part at the Canadian Anaesthetists' Society Meeting, June 20-23, experiments and then supplemented with oxygen if required to achieve more than 98 per cent arte1977. 479 Canad. Anaesth. Soc. J., vol. 25, no. 6, November 1978 IN 1904, the French physiologist Plumier 1 provided the first documented evidence that decreased inspired oxygen caused pulmonary hypertension. Since then, numerous workers have studied the effect of acute hypoxia on pulmonary vascular resistance 2-~ and it is now well established that it is the alveolar oxygen tension and not that of the systemic arterial blood which is the main determinant of the pulmonary vascular pressor response to hypoxia. 7-'~ On the other hand, the level of arterial oxygen saturation is largely determined by the relationship between ventilation and perfusion" which is in turn determined by the pulmonary vascular response to local hypoxia. While this response is present in all species so far tested, 9 the magnitude of the increase in pulmonary vascular resistance (PVR) for a given level of alveolar hypox ia varies greatly between species. 12 Further, in single species, the hypoxic pressor response shows considerable variation when related to arterial oxygen tensions, as for instance in the published reports for the dog. 3'6"13-17 Since the role of the PVR response to hypoxia would seem to be to minimize arterial oxygen desaturation, any individual variation in the response could indicate differences in the adaptation of the gas exchange apparatus of the lungs to a given hypoxic stimulus. The purpose of this study was to determine whether the PVR response to hypoxia is uniquely related to arterial oxygen saturation in individual animals. Mechanically ventilated anaesthetized dogs were used so that the PVR response could be studied uninfluenced by changes in ventilation.
480
C A N A D I A N A N A E S T H E T I S T S ' SOCIETY J O U R N A L
rial oxygen saturation. Thereafter the same airoxygen mixture was used in any one animal during recovery periods. The mean control inspired oxygen concentration was 28 per cent. This is subsequently referred to as normoxia in so far as a11erial blood was fully saturated in the control and recovery periods. Hypoxia was induced by switching to a mixture of oxygen in nitrogen to give inspired oxygen concentrations of S, 11, 16, or 20 per cent. After an initial control period lasting 60 minutes, during which baseline values of all parameters were obtained by serial estimation, the animals were subjected to a five-minute period of hypoxia followed by a 30-minute recovery period. Five minutes of hypoxia in each case was sufficient time for all measured parameters to achieve equilibrium. Each animal was exposed to the five levels of inspired oxygen during any one experiment and each experiment was repeated at least once in 9 of the 12 dogs. In the remaining three dogs, up to three levels of FIoz were repeated (cf. (n-l) in Table I!). The order in which the various levels o f hypoxia were administered was varied between animals to allow comparison of the effects of repeated exposure. Mixed venous and arterial blood ~ases and pH measurements were made in an Instrumentation Laboratory pH/gas analyser by the microelectrode technique. Samples were collected anaerobically in heparinized glass syringes. Calibration by tonometry was done throughout each experiment at regular intervals. Oxygen saturation (s) was calculated using the measured PO: corrected for temperature and pH from the Rossing and Cain ~s equation for dog blood thus: log (s/l-s) = 2.5198 log Po2 + 1.1804 (pH-7.0) 0.0472 - 2.362 I. Pulmonary vascular resistance (PVR) was calculated from PVR = (Ppa Pwp)/0 expressed as mmHg 1-j min. Additional calculated parameters were dead space]tidal volume ratio (VDIVT), pulmonary shunt fraction ((~s/Qt) and the alveolar to arterial oxygen gradie nt P(A-a)o2.
Statistical Attalysis Data were analysed by Student's paired t test. Linear regression analysis was done by analysis of variance of paired values. In the case of PVR and Ppa against Pao~, these included quadratic regression analysis. Statistical significance was taken as P = 0.05 orless. Highly significant refers to values where P = 0.01 or less.
A
e: 8
o----o :
:
E
"~' :.
PVR
6 i
-I 1g
L
l
[
I
1
I
D
nl
I~
CONTROL PERIOO F ] G U a E I, The mean values + I SDare shown f0eall dogs for cardiac output (open circles) and for pulmonary vascular resistance (closed circles) for each control period between hypoxic episodes.
RESULTS
Controls: effect of repeated expos,re There was a small (12 per cent) decrease in the mean control (~ after repeated hypoxia while mean control Ppa increased by about three per cent; thus PVR increased with successive hypoxic episodes by about 20 pet" cent after the fourth episode compared to initial values, but as with O this was not significant (Figure I). Individual animals in each case followed the same trend. No change was found for Pwp, AW P, heart rate or mean systemic blood pressure, during these control periods.
Group mean values The mean values of all control periods for the 12 dogs are given in Table I and compared to the pooled mean hypoxic values, Hypoxia in all cases increased Ppa to a mean for the group which was 43 per cent above control values. Similarly, PVR was increased by about 56 per cent, while (~ was decreased by only two per cent. There was a small increase in systemic arterial B P o f eight per cent in the hypoxic group. Arterial pH increased from a mean control value of 7.38 to 7.41 (H § decrease from 41,69 to 38.9 nmol 1-1) while Paco2 was reduced from 36.96 to 34.94 mm Hg (4.92 to 4.65 kPa), with hypoxia, while mean values for Pao~ were 98.2 and 45.65 mm Hg (13.06 and 6.07 kPa) respectively. The slightly lower Paco~ was
FORREST & FARGASoBABJAK" PULMONARY VASCULAR RESPONSE
481
TABLE I
Variable
Control + 1 SD
I-lypoxia • 1 SD
P
Pulmonary vascular resistance
kPa, l-J.min (ram Hg.I-].min)
0.29 + 0.03 (2.15 _.+ 0,21)
0,45 +_ 0.21 (3.35 + 1.59)
0.0005
Pulmonary artery pressure
kPa (ram Hg)
1,69 _+ 0.43 (12.70 + 3.25)
2,42 • 0.83 (18.16 • 6.27)
0. 8005
Cardiac output
l.min -1
3.90 + 0.64
3.83 • 1.01
N,S,
Mean arterial pressure
kPa (ram Hg)
20,02 • 3.43 (150.55 + 25,78)
21.57 _+ 3.87 (162.17 _+ 29,10)
N,S.
Mean airway pressure
kPa (ram Hg)
0.52 +_ 0.16 (3.91 Z 1.24)
0.53 • 0.17 (3.99 ___ 1.29)
N,S,
Arterial pH
nmol.I, H + (pH units)
42.00 _ 3.00 (7.38 _+ 0.03)
39.00 4- 3.00 (7.41 • 0.03)
N,S.
Arterial oxygen tension
kPa (tort)
13.06 + 1.95 (98.20 + 14.63)
6.07 + 2.39 (45.65 _+ 18.00)
0.0005
Arterial carbon dioxide tension
kPa (tort)
4.92 _+ 0.50 (36.96 4- 3.77)
4.65 + 0.59 (34.95 __. 4.44)
N.S.
End tidal carbon dioxide
per cent
5.46 _.+ 0.08
5.31 • 0.08
N.S.
Mixed expired carbon dioxide Pulmonary shunt fraction
per cent per cent
2,66 + 0.01 3.51 _.+ O. 98
2.60 + 0.01 t .09 _+ O. 79
N.S. 0.0005
Alveolar-arterial oxygen
kPa 9(torr)
7.45 + 0.82 (56,04 _+ 6.15)
2.13 _+ 1.56 (16.00 + 11.76)
0.0005
49,62 + 6.65
47.83 + 9,28
N.S.
percent
42.96 + 5.39
45.77 + 5.00
N,S.
Dead space/tidal volume ratio Haematocrit
N.S. = not significant where P > 0.05. reflected in a three per cent reduction in end e x p i r e d fractional carbon dioxide c o n c e n t r a t i o n s a n d a two per cent reduction in m i x e d expired carbon dioxide. T h e m e a n values for s h u n t fiaction ( 0 s / 0 t ) s h o w e d a large reduction in the hypoxic g r o u p o f 70 per cent c o m p a r e d to controls, with a similar reduction found for P(A-a)o2. N o significant c h a n g e w a s found for VD/VT, A W P or Pwp with hypoxia. Pulmonary Vascular Resistance All animals s h o w e d i n c r e a s e d Ppa and P V R with hypoxia but the m a g n i t u d e o f t h e s e inc r e a s e s varied greatly b e t w e e n animals. Figure 2 s h o w s the individual PVR values plotted against Paoz. In all c a s e s , little c h a n g e o c c u r r e d in P V R until Pao~ w a s r e d u c e d to less than 7 0 r a m Hg; h o w e v e r , no significant statistical correlations could be found for t h e s e curvilinear r e s p o n s e s . T h e rise in PVR and also Ppa w a s d e l a y e d in all c a s e s for o n e to two m i n u t e s after switching to the hypoxic inspired g a s m i x t u r e and, in general, the s h o r t e s t delays occurred with the lowest Fto~ v a l u e s o f 0.08. T h e increase in P V R r e a c h e d a plateau after four m i n u t e s in 52 hypoxic r u n s a n d
after three m i n u t e s in eight h y p o x i c runs. In all c a s e s t h e s e plateau v a l u e s o f P V R were unc h a n g e d after five m i n u t e s . All reported hypoxic v a l u e s refer to m e a s u r e m e n t s d o n e at five minutes. W h e n PVR w a s plotted against p e r c e n t o x y g e n saturation (%02 sat.), significant inverse linear relationships were f o u n d for all dogs (Figure 3 a n d T a b l e II). In individual a n i m a l s t h e s e lineal" PVR/%O2 sat, r e s p o n s e s were highly r e p r o d u c e able in each c a s e , with the e x c e p t i o n o f dog n u m b e r five, w h e r e P V R r e s p o n s e s were repeated tbr only two levels o f FIoz. H o w e v e r , with d o g 5 t h e s e P V R v a l u e s at e q u i v a l e n t Fie2 were very nearly identical. O n the o t h e r h a n d , c o m pari son b e t w e e n a n i m a l s clearly s h o w s great variability, T h e v a l u e s for slope, intercept, correlation coefficient a n d significant level are given for e a c h d o g in Table I1. T h e slopes of t h e s e P V R / % Oz sat. r e s p o n s e s r a n g e d from - 0 . 0 1 3 to - 0 . 1 4 4 but 83 per cent of these were less t h a n - 0 . 0 6 and 42 per cent were b e t w e e n - 0 , 0 4 and - 0 . 0 6 . T h u s it w a s possible to categorize dogs a s (a) low res p e n d e r s having a slope o f less t h a n - 0 . 0 4 (41 per cent), (b) m e d i u m r e s p o n d e r s having a slope be-
482
CANADIAN
ANAESTHETISTS'
SOCIETY
JOURNAL
TABLE II
Dog
n
PVR/% O2 sat. bR [
1 2 3 4 5 6 7 8 9 10 11 12
12 10 8 7 6 7 9 9 9 9 9 9
-0.144 -0,019 -0.057 -0,023 -0.019 --0,044 -0.048 -0.013 -0.055 -0,064 -0.037 -0.056
16.3 3.5 6.7 3.7 3.7 5.8 5.8 3.0 8,8 8.4 7.9 8.2
PPa/7~ Oz sat. 1
r
bp
0.951" 0.964* 0.842* 0,851~" 0,815:~ 0,948* 0.834* 0.598~ 0.846~" 0.972* 0. 779~t 0.845*
-0,561 -0.]25 -0.362 -0,108 -0.040 -0,091 -0,230 -0.076 -0.229 -0.224 -0.038 -0.I95
70.7 27.0 45.0 22,6 ]6.5 17.6 32.5 18.7 38.2 31.7 19.8 33.6
r 0.952* 0,564~: 0.597 N.S, 0,844t 0.493 N.S. 0,849~ 0.969* 0,788~" 0.940* 0,942* 0.592 N.S, 0.847*
ba, bp = slope, I = intercept, r = correlation coefficient (Y = bX + 1). * = significant at P -- 0,001. t -- significant at P = 0.01. ~; = significant at P = 0.05. NS = not significant where P > 0.05. c
lm/R
E
8 PVR
-r E E -
"" Z
9
9.. ",.~.o >
E E _
t
6
.~.. "
a
9
f
-
|
.':
~
.
9
9
2
" ,. 9
,
>
~ 9
z O
20
S
.----"1~ . "~'---'~ 6
I
I
I
I
I
40
60
80
100
120
P802 I
I
I
| 40
I
I ~)
I
I 80
1
} 100
140
ARTERIAL OXYGEN TENSION ( tort )
FIGURE 2. Pulmonary vascular resistance is plotted as mean values for individual runs against arterial oxygen tension. The two curves shown were drawn through the data from two dogs, but in no case were curves statistically significant at the 5 per cent probability level.
t w e e n - 0 . 0 4 a n d - 0 , 0 6 (42 p e r cent), o r (c) high r e s p o n d e r s h a v i n g a slope g r e a t e r than - 0 . 0 6 (17 per cent). T h e m e a n slope for all d o g s w a s - 0 . 0 4 8 with a m e a n correlation coefficient of 0,822. Similar i n v e r s e linear relationships were o b t a i n e d for Ppa against per cent o x y g e n saturation but the overall level o f significance w a s lower than for P V R (Table I1). T h e m e a n slope for P p a / % 02 sat. w a s - 0 , 1 9 0 for a m e a n correlation coefficient o f 0.781. T h e predictive value o f the slope o f Ppal%O2 sat. (bp) for the slope o f PVR]%O~ sat. (ha) w a s t e s t e d by an a n a l y s i s o f v a r i a n c e o f
ARTERIAL O X Y G E N S A T U R A T I O N ( % 1
FIGURE 3. Pulmonary vascular resistance is plotted against arterial oxygen saturation. The regression line for each dog is shown, In all cases these are highly significant and reproduceable (see text, of Table 11).
paired slope v a l u e s and w a s found to be highly significant (P < 0.001) s u c h that ba 0.25 br 0,001 (where r = 0.909). T h e high d e g r e e o f significance o f the a b o v e relationship w a s u n d o u b t edly due to the fact that cardiac o u t p u t and P w p were relatively u n c h a n g e d d u r i n g h y p o x i c e x p o sures. T h i s result indicates that it w a s possible with a high predictive a c c u r a c y to e s t i m a t e the c h a n g e in P V R from the Ppa r e s p o n s e . F u r t h e r the u s e o f a single control and a single h y p o x i c v a l u e o f Ppa did not r e d u c e the a c c u r a c y o f this prediction to a n y significant e x t e n t since individual r e s p o n s e s were highly r e p r o d u c e a b l e .
FORREST
& FARGAS-BABJAK:
PULMONARY
VASCULAR
483
RESPONSE
o.~ ---
z E E
~A-aD 2
] i
-!
F, i
~ o.~
i
o
~ oo~ i
o
i
o
.
..,/-
o
~ >
'I 0
I
I ~0 ARTERIAL
~"
1 40
OXYGEN
t
I 6C
I
SATURATION
I 80
I
I 1~
t % )
FlCURe 5. Pulmonary shunt fraction (closed circles) and alveolar to arterial oxygen gradienl (open circles) are plotted against arterial oxygen saturation as mean values for individual runs. The solid curve is drawn through the Qsl(~tvalues while the broken curve is drawn through the P(A-a)o~values. FIGURE 4. Frequency distributions for change in cardiac output, pulmonary artery pressure and in pulmonary vascular resistance are shown for the pooled data. The units on the abscissa are equivalent and are the fractional changes compared with control.
Sequential hypoxic exposures In order to compare the effects of repeated and sequential hypoxic exposures, the values for Ppa and PVR were expressed as a change compared with the immediately preceding value at normoxia thus: change = (value at 5 min hypoxia control value)/control value. In both cases highly significant and reproduceabte inverse linear relationships were again found for all dogs. The slopes of these were only slightly lower than the slope values shown in Table II. In general the correlation coefficients for these slopes were also slightly lower, but none of these differences between the values calculated as change compared to control and the absolute values were significantly different at the one per cent probability level. Thus the PVR and Ppa responses which were found were not significantly altered by the number or the sequence of hypoxic exposures.
Frequency distribution of PVR, Q and Ppa change Since PVR is a calculated parameter and depends on the net change of three variables (Ppa, Pwp and 0), the relative influence of each of these during each of the 60 hypoxic exposures has been
analysed. Figure 4 shows the resulting frequency distributions for change in PVR, t~ and Ppa. The change in Pwp has been omitted since this was unaltered by hypoxia. Clearly the change in Ppa accounts for almost all the change in PVR as seen by the close similarity of the lower two histograms and demonstrates the high degree of predictability of the slope bR from bp described above. The two negative values of change in PVR were obtained from one run in each of two dogs with severe hypoxia (Ftoz = 0.08).
Pulmonary shunt flow and alveolar[arterial oxygen difference There was little variation in Qs/Qt or in alveolar/arterial oxygen difference P(A-a)oz between dogs at equivalent levels o f % Oz sat. 0s/(~t at full saturation ranged from 5.5 to 6.5 per cent and decreased exponentially with altered oxygen saturation to reach a fairly constant level of 0.5 per cent below 70 per cent oxygen saturation (Figure 5). It is of interest that two dogs at severe hypoxia had negative values for Qs/I)t. Similarly the P(A-a)oz decreased exponentially but was fairly constant at 5 mm Hg below 70 per cent oxygen saturation. The P(A-a)oz curve was shifted (hatched line) to the left around the point of inflection (80 to 90 percent oxygen saturation) compared with the curve for t)s/t)t (solid line). One o f the negative t~s/0t values was associated with a negative P(A-a)o2.
484
CANADIAN ANAESTHETISTS' SOCIETY JOURNAL DISCUSSfON
little affected by these differences in cardiac output. In the case of the individual dog PVR reAlveolar hypoxia constricts pulmonary arterial sponses, the curvilinear relationships we found vessels and results in increased pulmonary vascu- against Pao 2 contrasts with the highly significant lar resistance in both the isolated lung and in and reproduceable inverse linear correlations intact animals, z,4.~5,t9 While the exact mediator with arterial oxygen saturation. Thus we conof this response is not known, the possible mech- clude that the PVR response to hypoxia is unanisms have recently been reviewed in detail2 ,z~ iquely related to arterial oxygen saturation in inThe increase in resistance is now thought to re- dividual animals, and that the slope of the result from reduction in the calibre of small a,te,'ies sponse varies greatly from one animal to another. of less than 0.2 mm diameter through active con- Further, we have shown that the slope of the PVR striction 9"2~ and is thought to be essentially a re- response can be predicted with a high degree of sponse to local change in alveolar Po2. z2 How- accuracy in individual animals fi'om the slope of ever, the magnitude of the increase in resistance the Ppa response. At any given level of PAo2, the varies greatly between species ~2 and within the arterial oxygen saturation dePends on a number same species 6 for any given level of alveolar of factors; haemoglobin and haematocrit levels, hypoxia. The results which we have found blood pH and temperature, alveolar dead space, confirm the variability of the PVR response to shunt flow, venous admixture and matching of hypoxia in the dog as compared with the pub- ventilation and perfusion. All of these could aflished reports for the mean change 3'6'~3J4-~7 and fect the PVR response to hypoxia directly or indisupport the findings of Barer, e t al. r in isolated rectly. We did not find any change in temperature lungs of cats where curvilinear but not significant or dead space/tidal volume ratio and, although relationships were found for PVR against arterial the arterial pH, haemoglobin and haematocrit values were increased above control these were Po2. Hypoxia resulted in a 43 per cent increase in not sufficient to appreciably alter oxygen saturathe group mean Ppa and a -~6 per cent increase in tion calculated from the Rosslng and Cain mean PVR, while cardiac output was virtually equation I~ for dog blood. The most important unchanged. This compares with the study of Sac- factor determining arterial oxygen saturation is kner, e t a L 2~ where equivalent levels of hypoxia probably ventilation perfusion ratio, t' resulted in a 60 percent increase in PVR, and also Increasing Ppa by itself reduces the relative that of Malik & Kid 15 where PVR was increased topographical differences in pulmonary blood by about 50 per cent. Despite the close similarity flow in the dog lung 2~ but this results in only a between our study and those quoted, significant small improvement in gas exchange since differences exist. Our values for control (~ were P(A-a)o2 is normally low. Recent studies have some two times higher and, further, did not shown that local alveolar hypoxia results in redischange with hypoxia, whereas Malik & Kidd t~ tribution of blood flow away from hypoxic areas, found that Q increased by some 30 per cent, but at thus minimizing arterial oxygen desaturatlon z4,:-~ a slower rate than the rise in Ppa. and also that regional differences may exist in the This difference in the cardiac response is likely ability of the pulmonary vessels to respond by due to the use of the muscle relaxant pan- constriction to bypoxia. 26"27 It seems possible curonium bromide in our study. This drug is that similar differences may also exist between known to have inotropic as well as chronotropic animals in the overall responsiveness of the pulactions on the heart, resulting in a sustained ele- monary resistance vessels to alveolar hypoxia. vation of cardiac output. The fact that we did not Our findings tend to confirm this hypothesis and find any change in I~ with hypoxis suggests that further suggest that the net gas exchange effect in the cardiac response (increasing ~ with decreas- terms of arterial oxygen saturation is unique to ing PAo2) which Malik & Kidd ~s found may de- the individual. Clearly those animals having a low pend on the level of the resting or control Q. PVR response to hypoxia also have more marked Further, the cardiac response is higher in spon- arterial oxygen desaturation at equivalent levels taneously breathing animals ~. It is possible that of inspired and alveolar oxygen. In other words, the small degree of hypocapnia which we found high responders are able to maintain higher levels during hypoxia, despite controlled ventilation, of arterial oxygen saturation. could have further attenuated the cardiac reA number of possible factors are known to alter sponse, t-~ What is clear, however, is that the the tone and calibre of lung resistance vessels in magnitude of the PVR response to hypoxia is association with hypoxia. Release of bioactive
FORREST & FARGAS-BABJAK: PULMONARY VASCULAR RESPONSE
485
amines such as histamine, serotonin, and for dogs with lower responses to have higher catecholamines, zs adenosine, z9 prostaglandins, 3~ baseline perfusion pressures. Further studies are as well as increased conversion ofangiotensin I to necessary to determine the exact role of pulmoangiotensin 11,3~ have been reported and indi- nary vessel structure in the variability of the PVR vidual rates ofagonist release do occur. No single response to hypoxia. humoral mediator, however, has so far been SUMMARY clearly identified with the hypoxic response; nevertheless, some or all of the pulmonary vascuAnaesthetized and mechanically ventilated lar agonists quoted above probably at least modulate this response in vivo. 3z The presence of dogs were subjected to five minutes of alveolar erythrocytes within the pulmonary circulation hypoxia with F[oz ranging from 0.08 to 0.20 while has recently been shown to be essential for pulmonary artery pressure (Ppa), pulmonary maintenance of normal vascular tone and respon- wedge pressure (Pwp) and cardiac output (Q) siveness to stimulation by agonist, 33 while were measured. Hypoxia increased Ppa in all platelets as a possible source of adenosine com- dogs whereas Pwp and (~ did not change sigpounds, serotonin, and prostaglandins were not nificantly. Thus pulmonary vascular resistance essential for the pressor response during (PVR) increased by a mean for alt dogs of 56 per hypoxia. While variations in the amount of cent. There was great variation in the absolute mediator released in response to hypoxia is a increase in Ppa and PVR between animals and distinct possibility, this would account only for these were not statistically correlated with artedifference in the magnitude of the response and rial Po2, but highly significant and reproduceable does not explain the ]inearity of the PVR relation- inverse relationships were found for Ppa and ship with arterial oxygen saturation. The effi- PVR against arterial oxygen per cent saturation. cie ncy of active contraction in pulmonary vascu- The slopes of these responses varied between lar smooth muscle which results in the dogs fiom -0.013 to - 0 . 1 4 4 for PVR and from haemodynamic response also depends to a large -0.038 tO -0.561 for Ppa. The alve01ar-arterial extent on the physical properties of the vessel oxygen gradient and the pulmonary shunt fracwaits. Thickening of the media smooth muscle tion were reduced in a similar way with decreaslayer of pulmonary arterial vessels, such as oc- ing arterial oxygen per cent saturation, but dead curs with chronic hypoxia, is an adaptive process space/tidal volume ratio remained unchanged. to prolonged stimulation, and may result also in Thus the slope of PVR response to hypoxia against arterial oxygen per cent saturation is increased reactivity. The haemodynamic effects of such adaptive unique for individual animals. This may reflect structural changes have been described in detail functional and likely structural adaptations of the for resistance vessels in hypertension 34 in the pulmonary vascular smooth muscle. systemic circulation and it seems probable that R~SUM~ similar adaptations exist within the pulmonary circulation as well, even though the haemoDes chiens anesthEsigs et ventilEs mEcaniquedynamic effects may differ. The relatively high compliance of the pulmonary arterial vessels meat ont ErE soumis ~ des Episodes d'hypoxie would tend to maintain low perfusion pressures alvgolaire de cinq minutes en les exposant ~t des even in the presence of moderate vessel adapta- Fio2 de 0,08, de 0,11, de 0,16 et de 0,2; la pression tions. However, such adaptations could result in artErielle pulmonaire, la pression pulmonaire significant differences in vascular reactivity due coincge (wedge) et le debit cardiaque 6talent to variation in the total amount of smooth muscle mesurgs Iors de ces Episodes. L'hypoxie s'est traduite par une 6lgvation de la membrane, with associated vaso-active agonist receptor sites. Induction of pulmonary hyperten- pression de I'arti:re pulmonaire chez t o u s l e s sion with dextran infusion results in marked at- chiens, alors que [a pression pulmonaire coincEe tenuation of the pulmonary vascular response to et le debit cardiaque n ' o n t pas chang6 de fa~;on hypoxia in dogs, 3s but we were unable to find any significative. On a observe une ElEvation de la consistent relationship between the magnitude of resistance vasculaire pulmonaire chez tous les the PVR response to hypoxia expressed as the ehiens (616vafion moyenne de 56 pour cent). L'on slope against oxygen saturation or in the absolute a note de grandes variations dans ies augmentarise in Ppa or PVR, with the pre-existing control tions de pression artErielle pulmonaire et de rEsisPpa or PVR. Nevertheless, there was a tendency tance vasculaire pulmonaire, variations sans rela-
486
CANADIAN ANAESTHETISTS ~ SOCIETY JOURNAL
tion significative a v e c la Pao~; u n e relation inv e r s e h a u t e m e n t significative el e o n s t a n t e a c e p e n d a n t 6td t r o u v d e entre la pression de I'art~:re p u l m o n a i r e e t l a rdsistance vasculaire pulm o n a i r e e t l a saturation en oxyg/~ne du s a n g art6riel. Le gradient en oxyg/~ne alv6olo-artdriel et le s h u n t d i m i n u a i e n t avec la d 6 s a t u r a t i o n en o x y g / m e , m a i s le rapport e s p a c e m o r t / v o l u m e c o u r a n t d e m e u r a i t le m 6 m e . Doric, la c o u r b e rept'6sentant la modification de rdsistance vasculaire p u l m o n a i r e s e c o n d a i r e /t I ' h y p o x i e e n rapport h la saturation artdrielle en o x y g 6 n e e s t unique c h e z un animal donn6. Ceei peut rep r 6 s e n t e r des a d a p t a t i o n s fonctionnelles et poss i b l e m e n t s t r u c t u r a l e s d e la m u s c u l a t u r e vasculaire p u l m o n a i r e , ACKNOWLEDGEMENTS
T h e a u t h o r s gratefully a c k n o w l e d g e the assist a n c e of the D e p a r t m e n t of Biostatistics and E p i d e m i o l o g y , M c M a s t e r U n i v e r s i t y , for statistical a n a l y s i s , and to M i s s J o y c e B r a n d s e n for typing the m a n u s c r i p t . REFERENCES I. PLUMIER, P.L. La circulation pulmonaire chez le
2. 3. 4. 5. 6.
7.
8. 9. 10.
chien. Arch. Internat. de Physiol. I: 176-213 (1904). EULEr, V.S. YON & LILJESTRAND, G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol. Scand. 12:301-320 (1946). Lr, wts, B.M. & GOaLIN, R. Effects of hypoxia on pulmonary circulation of the dog. Am. J. Physiol. 170:574-587 (1952). LLOVO, T.C., Jr. Effect of alveolar hypoxia on pulmonary vascular resistance. J. Appl. Physiol. /9: 1086--1094 (1964). S'raoum R.C. & CONN, H.L., JR. Pulmonary vas. cular effects of moderate and severe hypoxia in the dog. Am. J. Physiol. 179:119-122 (1954). TUCKEr, A. & REEVES, J.T. Non-sustained pulmonary vasoconstriction during acute hypo• in anaesthetized dogs. Am. J. Physiol. 228:756-761 (1975). BarEr, G.R., H o w a r o , P., & SHAW, J.W. Stimulus-response curves for the pulmonary vas. cular bed to hypoxia and hypercapnia. J. Physiol. (Load.) 2 / / : 139-155 (1970). F~SHm~,N, A.P. Respiratory gases in the regulation of the pulmonary circulation. Physiol. Rev. 41: 214-280(1961). FtSHMAN, A,P. Hypoxia on the pulmonarycirculation. How and where it acts. Circulation Res. 38: 221-231 (1976). HAuot=, A. Hypoxia and pulmonary vascular resistance. The relative effects of pulmonary arterial and alveolar Po~. Acta Physiol. Scand. 76:121-130 (1969).
I ]. WEST, J.B. Regional differences in gas exchange in the lungoferect man. J. Appl. Physiol. 17:893-898 (1962). 12. GROVER, R.F., VOGEL, K.H., AVERILL, K.H., & BLOUnT, G-S., Jr. Pulmonary hypertension. Individual and species variability relative to vascular reactivity. Am. Heart J. 66:1-3 (1963). 13. BERRY, W.B., McLAUGHLII~, J.S., CLARK, W.D,) & MORROW, A.G. The effects of acute hypoxia on pressure, flow and resistance in the pulmonary vascular bed. Surgery 58:404-411 (1965). 14. DALu I., MICHEL, C.C., RAMSAY, D.J., & WAALER, B.A. Conditions governing the pulmonary vascular response to ventilation hypoxia and hypoxaemia in the dog. J. Physiol. (Load,) 196: 351-379 (1968). 15. MALta, A.B. & KIDD, S.L. Time course of pulmonary vascular response in dogs. Am. J. Physiol. 224:1-6 (1973). 16. THILENIUS, D.G. & DERENZO, C. Hypoxic pulmonary vasoconstriction in unanaesthetized dogs with constant arterial Pcoz and pH. Clin. Sci. 37: 731-737 (1969). 17. THILENXUS, D.G. & DERENZO, C. Effects of acutely induced changes in arterial pH on pulmonary vascular resistance during normoxia and hypoxia in awake dogs. Clin. Sci. 42:277-287 (1975). 18. RossINO, R.G. & CAIN, S.M. A nomogram relating Po~, pH, temperature, and haemoglobin saturation in the dog. J. Appl. Physiol. 21 : 195-201 (1966). 19. MILES, P.H. & StlEPHERO, J.T. Relationship between pH, Po2 and Pco2 on the pulmonary vascular bed of the cat. Am. ]. Physiol. 21.5:1170-1176 ( 1968L 20. BER~OFSKY, E.H. Mechanisms underlying vasomotor regulation of regional pulmonary blood flow in normal and diseased states. Am. J. Med. 57: 378-394 (1974). 21. SACKNER, M . A . , WILL, D.H., & DoBoIs, A,B. The site of pulmonary vasomotor activity during hypoxia or serotonin administration. J, Clin. Invest. 45:112-121 (1966). 22. GRANT, B.J.B., DAVieS, E.E., JONES, H.A., & HUGHES, J.M.B. Local regulation of pulmonary blood flow and ventilation perfusion ratios in the coati-mundi. J. Appl. Physiol. 40:216-228 (1976). 23. WEST, J.B., DOLt.ERe, C.T., & NaIMARK, A. Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J. Appl. Physiol, 19:713-724 (196a).
24. ARRORELlus,M., Jr., UuA, B., & Zauner, C.W. The relative effect of hypoxia and gravity on pulmonary blood flow. Respiration 31:369-380 (1974). 25. KATO, M. & STAUg, N.C. Response of small pulmonary arteries to unilobar hypoxia and hypercapnia. Circulation Res. 19:426-440 (1966). 26. HALES, C.A., AnLUWALIA, B., & K.AZEML H. Strength of pulmonary vascular response to regional hypoxia. J. Appl. Physiol. 38:1083-1087 (1975). 27. MALONEY, J.E., ALCORN, D., CANNATA, J., WALKER, A., ~/. R|TCHIE, B.C. Regional vascular response to hypoxia in the lungs of anaesthetized sheep. Austral. J. Exp. Biol. Med. Sci..52:801-812 (1974).
FORREST & FARGAS-BABJAK: PULMONARY VASCULAR RESPONSE
487
32. TUCKER, A., HOFFMAN, E. A., & Wcm, E K. Histamine receptor antagonism does not inhibit hypoxic pulmonary vasoconstriction in dogs. Chest 71 : 261-262 (1977). 33. McMuaTI:tY, I.F., HOOKWAY, B.W., & ROOS, S. Red blood cells play a crucial role in maintaining vascular reactivity to hypoxia in isolated rat lungs. Chest 7t: 253-2.55 (1977). 34. FOLKOW, B. Haemodynamic consequences of adaptive structural changes of the resistance vessels in hypertension. Clin. Sci. 41 : l - 12 (1971). 35. BENUMOF, J.L. & WAHRENBROCK.E.A. Blunted hypoxic pulmonary vasoconstriction by increased 3[, BERKOV, S. Hypoxic pulmonary vasoconstriction lung vascular pressures. J. Appl. Physiol. 38: in the rat. The necessary role of angiotensin II. 846-850 (197.5). Circulation Res. 35:256-261 (1974).
28. HAUOE, A. & MELMON, K.L. Role of histamine in hypoxic pulmonary hypertension in the rat. 11. D~pletion of histamine, serotonin and catecholamines. Circulation Res. 22:371-392 (1968). 29. MENTZER, R.M., JR., RUB[O, R., & BEa~qE, R.M. Release of adenosine by hypoxic canine lung tissue and its possible role in the pulmonary circulation. Am. J. Physiol. 229:1625-t631 (1975). 30. KADOWlTZ, P.J.. JOINER, P.D., & HYMAN, A.L. Physiological and pharmacological roles of prostaglandlns. Ann. Rcv. Pharmacol. 15:285-306 (1975).
