- Email: [email protected]
Vasodilators or vasoconstrictors prevent hypoxic pulmonary vasoconstriction
Vasodilators
or Vasoconstrictors Prevent Hypoxic Pulmonary Vasoconstriction I. Mayers,
T. Hurst, T. To, and D. Johnson
Prostaglandins modulate pulmonary vascular resistance (PM) and hypoxic pulmonary vasoconstriction (HPV). We studied the effects of a prostaglandin vasodilator (PGI,) and vasoconstrictor (PGE,) in the pulmonary circulation and compared these effects to the nonprostaglandin vasodilator sodium nitroprusside (SNP) and vasoconstrictor norepinephrine (NE) during 35% and 3% 0, ventilation. Pulmonary vascular resistance was divided into arterial, middle (Rm), and venous segmental resistances in 20 isolated left lower canine lobes using a stop-flow technique. Pulmonary vascular resistance was also analyzed as the slope and intercept (P,,,) of the pressure-flow relationship. We found that only PGI, specifically prevented the increase in Rm and P,,,, due to hypoxia. Sodium nitro-
prusside predominantly decreased venous segment resistance and, even in the presence of SNP, hypoxia significantly (P < .05) increased Rm (0.0179 k 0.0075 cm H,O/mL/min) compared with control ventilation (0.0078 -C 0.0043 cm H,O/mL/min). Both PGE, and NE increased PVR primarily by increasing the venous segmental resistance. After the addition of PGE, or NE, hypoxic ventilation did not result in further increases of Rm or P,,,. We conclude that PGI, but not SNP selectively inhibits HPV and that neither PGE, nor NE further augment HPV. The direct effect of these drugs on the pulmonary circulation and their resultant changes in systemic oxygen delivery must be considered prior to their use in the clinical setting. Copyright 0 1991 by W.B. seunders Company
I
oxygenation.” Finally, increasing the mixed venous oxygen tension may increase venous admixture by partial inhibition of hypoxic pulmonary vasoconstriction (HPV)“; this, in turn, may adversely affect systemic oxygenation. In our current experiments, we wished to assess the independent pulmonary vascular effects of the prostaglandin vasoconstrictor PGEz and the prostaglandin vasodilator PG12. We compared these effects with those of a nonprostaglandin vasodilator (nitroprusside) and a nonprostaglandin vasoconstrictor (norepinephrine). From these studies, we could extrapolate the effects on the pulmonary vasculature to a setting where HPV might be important in maintaining systemic oxygenation at a safe level. We evaluated pulmonary vascular resistance (PVR) using an isolated canine left lower lobe that allowed us to partition resistance into arterial, middle, and venous segmental resistances’“.” and to generate a pressure-flow (P-Q) relationship of the vasculature.15,1h We could therefore more precisely characterize the interactions of the test drugs with hypoxia. We could also ___-_
T HAS BEEN suggested that improving pulmonary hypertension by reducing pulmonary artery pressures may be beneficial in the setting of acute pulmonary injury.‘,’ However, the role of vasodilator therapy is as yet not fully defined. Although vasodilators may decrease pulmonary artery hypertension, they may also adversely affect venous admixture and systemic oxygenation.3m5 The use of PGI,, an endogenous prostaglandin vasodilator with cytoprotective properties, has been recently evaluated in the setting of acute respiratory distress syndrome.6 In human trials in acute respiratory distress syndrome, PGI, has been shown to maintain systemic oxygenation despite worsened ventilation/perfusion matching.7 However, in indomethacin-pretreated dogs, pulmonary vasodilation with PGIz increased pulmonary blood flow to the hypoxic lung and decreased systemic oxygenation without affecting mixed venous oxygen tension.’ In a similar model, PGE,, a vasoconstricting prostaglandin, reduced pulmonary blood flow to the hypoxic lung and improved systemic oxygenation.9 Understanding the effects of prostaglandins on the pulmonary vasculature are confounded if cardiac output and mixed venous oxygen tension change in an uncontrolled manner.’ Changes in pulmonary vascular pressures may affect venous admixture and systemic oxygenation by changing pulmonary vascular recruitment.” In addition, increases in cardiac output increase intrapulmonary shunt fraction, thereby affecting systemic Journalof
Crifical
Care, Vol6,
No 3 (September),
1991: pp 125-135
From the Depanments of Medicine and Anaesthesra, University of Saskatchewan, Saskatoon, Saskatchewan Canada. Received February I, 1991; accepted April 24, 1991. Supported by grants from the Saskatchewan Health Research Board and the Canadian Heart and Stroke Foundation. Address reprint requests to D. Johnson, MDCM, FRCP(C), Box 95, Royal University Hospital, Saskatoon, Saskatchewan S7N 0x0, Canada. Copyright o 1991 by W.B. Saunders Company 0883-944119110603-0003$05.0010
125
126
MAYERS
simultaneously control lobar perfusion pressures and mixed venous oxygen tension to ensure that our results were not influenced by independent changes in flow or by independent changes in venous admixture. METHODS
Animal Preparation These studies were carried out with approval of the University Animal Care Committee. The surgical preparation of the isolated lobe has been described in detail elsewhere.” In brief, 20 mongrel dogs (weight, 20 to 26 kg) were anesthetized (thiopental 25 mgikg), intubated, and ventilated (Harvard ventilator; Harvard Apparatus Co, Millis, MA) at a tidal volume (VT) of 20 mL/kg with room air. A catheter was inserted into the abdominal aorta via the femoral artery, which was subsequently used for phlebotomy and for drug administration. The left upper lobe was surgically removed to facilitate exposure of the left lower lobe and was saved for subsequent gravimetric determinations of edema. The left lower lobe artery and vein were dissected and cannulated. A no. 6 cuffed tracheal tube was inserted into the lobar bronchus through a bronchotomy. After the cannulae were inserted and the lobe isolated, the animals were killed by injection of 10 mL of supersaturated KC1 solution. The cannulated lobe was left in situ within the thoracic cavity and was connected to an extra corporeal circuit. The lobe was perfused with 400 mL phlebotomized autologous blood diluted to 500 mL with heparin (1,000 U) and normal saline. Pulmonary venous blood passively drained into a venous reservoir and was pumped by a roller pump through a heat exchanger, filter, and bubble deoxygenator (95% N,, 5% CO,) and was then returned to the arterial reservoir. The lobar bronchus was ventilated independently of the remainder of the lung by a second Harvard ventilator (VT = 150 to 200 mL). Lobar arterial pressure (Pa) and venous pressure (Pv) were set by adjusting the heights of the respective reservoirs. The Pa and Pv were measured at pressure ports near the arterial and venous cannulae, respectively. Airway pressure was measured with an air phase transducer connected by low compliance tubing to a port near the endobronchial tube. Before commencing the experimental protocol, at least 20 minutes were allowed for the preparation to stabilize, as assessed by a constant lobar blood flow (Q,) over a 5-minute period. Heparin (1,000 U) and 50% dextrose (1 mL) were added to the circuit every 30 minutes. At the conclusion of the experiments, the left lower lobe was removed and saved for gravimetric determinations of edema.
Calculations Using methodology similar to that described by Hakim et al,” total PVR (Rtot) was divided into arterial segment resistance (Ra), middle segment resistance (Rm), and venous segment resistance (Rv). We calculated the distribution of resistances using the pressure changes following a venous or arterial occlusion.” After an arterial occlusion there is an initial rapid decrease in pressure (APa) followed by a slow decrease in pressure. Similarly, after venous
ET AL
occlusion there is a rapid increase in venous pressure (APv) followed by a slow increase in pressure. Rtot was calculated as (Pa - Pv)/Q,. Ra and Rv were calculated as APa/& and APvIQ,, respectively. Rm was calculated as Rtot (Ra + Rv). We obtained the lobar pressure-flow (P-Q) relationship with the lobe under zone 2 conditions for flow (Pv, < -10 cm H,O; alveolar pressure, 0). To determine the P-Q relationship of the lobe under any given condition, we altered the level of the arterial reservoir to generate differing levels of pressure and then measured the resultant flows. The paired pressure and flow values were fit to a straight line by linear regression. The straight line was extrapolated to zero flow and the zero-flow pressure intercept was assumed to be the mean critical closing pressure (PCR,r) of the pulmonary vasculature. The slope of the P-Q relationship was also calculated by linear regression. The incremental resistance to flow was determined as the inverse of the slope of the P-Q relationship (l/slope). Venous admixture (Q,,/Q,) of the lobe was calculated from the following equation: QvJQ, = (Cc’O, - CaO,)/ (Cc’O, - CvO,), where Cx 0, refers to the content of oxygen in blood, c’ is end capillary blood, v is pulmonary venous blood, and a is pulmonary arterial blood. Oxygen contents were calculated from derived oxygen saturations’8 and hemoglobin concentrations. Alveolar PO, was calculated using the alveolar gas equation, while pulmonary arterial and venous values of PO, (PaO, and PvO,, respectively) were directly measured. Hemoglobin, in turn, was estimated as one third of the measured hematocrit. The wet weights of the left upper and left lower lobes were measured. Both lobes were then air dried and weighed until their weights varied by less than 1 g over 3 days. The ratio of the wet to dry weights of the left upper and lower lobes was then calculated. In addition, we calculated the ratio of the wet to dry weight of the left lower lobe divided by the wet to dry weight of the left upper lobe for each animal.
Experimental Protocol Following stabilization, baseline flow for each lobe was set by adjusting Pa to near 18 cm H,O and Pv to 5 cm H,O. Each lobe was first ventilated with a normoxic gas mixture (35% O,, 7% CO,, and 58% N,); this was the initial normoxic period (period N). The lobe was then ventilated with a hypoxic gas mixture (3% 0,, 7% CO,, and 90% NJ; this was the initial hypoxic period (period H). The lobe was again ventilated with the normoxic gas mixture and, after Q, had returned to baseline values, the lobes were randomized to one of four drug groups (n = 5 in each group). Each lobe received either nitroprusside (5 mg bolus followed by 8 pgikgimin infusion), norepinephrine (0.1 mg bolus followed by 1 ugikgimin infusion), PGI, (0.5 mg bolus followed by 0.6 pg/kglmin infusion), or PGE, (0.5 mg bolus followed by 0.6 bgikgimin infusion). Drug doses were arbitrarily chosen to augment (vasodilators) or diminish (vasoconstrictors) lobar flow by at least 25%. Nitroprusside and norepinephrine solutions were prepared daily just prior to their infusion. PGI, and PGE, (Sigma, St Louis, MO) were initially dissolved in a stock solution of 10% absolute ethanol in normal saline’” and diluted 20-fold in 5%
PROSTAGLANDINS
& HYPOXIC
PULMONARY
VASOCONSTRICTION
127
dextrose in water just prior to administration. The stock solutions of PGI, and PGEz were refrigerated at 4°C and used within I week of preparation. Following drug administration, the lobes were allowed to stabilize for 1.5minutes, by which time QL changed by less than 5% over the final 5 minutes. The lobes then received another paired period of normoxic and hypoxic ventilation. The ventdatory periods are N,,, and HsNp for the group receiving nitroprusside, N,, and H,, for the group receiving norepmephrme, N,,,, and H,,,Z for the group receiving PGI,, and NPGEzand HPcifi2for the group receiving PGE?. Therefore, each group received paired periods of normoxic and hypoxic ventilation prior to drug administration and paired periods of normoxic and hypoxic ventilation during drug administration. Venous and arterial occlusions were performed in triplicate at the end of each ventilatory period. All occlusions were obtained under zone 3 flow conditions after stopping the ventilator at end expiration. Prior to occlusions, blood was withdrawn from the venous and arterial cannula for blood gas and hematocrit determinations. Blood gases were analyzed for PO:, PCO,, and pH at 37°C (model 162-2, Corning Medical, Medfield, MA) using appropriately calibrated electrodes and were then corrected for blood reservoir temperature after calculating hemoglobin saturation from a standard nomograr+“’ We also obtained a P-Q plot at the end of each period following vascular occlusions. Zone 2 conditions were set (Pv < -10 cm H,O), then the P-6 relationship was obtained by lowering the inflow reservoir height in steps of 3 to 5 cm HZO. To allow time for flow to stabilize, 6, was measured at each driving pressure after stopping the ventilator at end expiration for 20 seconds. We obtained a minimum of six paired pressure-flow measurements to calculate a regression equation. Following these determinations, zone 3 conditions were reestablished by setting Pv back to 5 cm Hz0 and the next ventilatoIy period was commenced. In this way, we obtained measurements at the end of each ventilatory period. which included values of inflow pressures and Table
1. Hemodynamic
and Blood
their respective flows under zone 2 conditions along with vascular occlusions under zone 3 conditions.
Statistics Within each group, values of blood gases, inspired gases. and hemodynamics were compared between conditions using a one-way analysis of variance (ANOVA). When the F statistic showed a significant difference, these values were compared by multiple ttests. Sidak’s multiplicative inequality was used to correct the t-statistic for the number of comparisons made between groups.‘” A probability value less than .05 was considered to show asignificant difference. The slopes and intercepts of the P-Q linear relationships were compared using a restricted maximum likelihood analysis described by Feldman.” All values except for slopes and intercepts are shown as mean ? standard deviation. RESULTS
Hernodynamic and Blood Gas Values
Tables 1 through 4 illustrate the mean values for hemodynamic parameters and blood gases obtained during the paired periods of normoxic and hypoxic ventilation in the four experimental groups. There were no differences in PvC02, PaO,, pH, Pa, and Pv by ANOVA within individual groups comparing ventilatory periods. Values of PvO, decreased significantly between paired normoxic and hypoxic periods; however, between matched normoxic or hypoxic periods (ie, before and during drug administratio?), values of PvO, were similar. Values of Q, significantly decreased during hypoxic ventilation (period H) compared with normoxic ventilation (period N) in all four groups. With drug
Gas Variables
PVCO,
40 2 2
41 + 1
PH PVOT
7.30 + 0.04 125 t 25 40 + 7
7.31 + 0.03 33 2 3t 472 18
Pa0,
Pa
19%
PV a:
&3/l& Abbreviations:
PVCO,, venous
1
18i
3-tl 126 2 6t
IO 2 5
Pvo,, venous
Receiving
39 f
1
521 165 f 16
PCO, (mmHg);
in Groups
Pao,, arterial
I,
1
40 + 2
7.28 t 0.03 129 f 18 47 2 14
7.31 r 0.02 32 f 4t 32 2 7
19 2 1
19 + 1
621 211 -t 17*
521 209 i 17* -
102
PO, (mmHg);
Prostaglandin
3
PO, (mmHg);
pH, venous
pH; Pa, pulmonary
arterial pressure (cm H,O); Pv, pulmonary venous pressure (cm H,O); a,, lobarflow (mL/min); &a/6, venous admixture (%). Periods N and H refer to normoxic and hypoxic ventilatory periods, respectively, prior to drug administration. Periods Np,+ and H,,,,, and NsNp and hypoxic ventilatory periods in groups receiving PGI, or nitroprusside, respectively, after administration and H,,, refer to normoxic of drug. Periods N,,, and H,,,,, and N,, and H,, refer to normoxic and hypoxic ventilatory periods in groups receiving PGE, or norepinephrine, *Significant tsignificant *Significant
respectively, after administration of drug. group difference by ANOVA (P < .05). difference comparing paired normoxic and hypoxic difference
(P < .05) comparing
matched
periods
periods before
(N v H or NDnuc v H,,,,).
and after drug administration
(N v N,,,,
or H v H,,,,,).
128
MAYERS
Table
2. Hemodynamic
and Blood
Gas Variables
in Groups
Receiving
Sodium
ET AL
Nitroprusside
Period
PVCO, PH pvo,* Pao,
39 t 5
39 ? 8
39 2 5
7.30 * 0.02 34 5 4t
7.28 2 0.02 136 + 36
7.27 + 0.02 32 + 13t
42 + 14 17 + 1 4+1
39 of: 6 175 1 5kl
39-t 11 17 + 1
128 2 20t -
243 -c 28$ 7c9
17 It_ 1 4+1
PA
Pv
179~ 82
4x &A/&
See Table
38 2 5 7.26 -t 0.05 139 2 34 37 I10
1 for abbreviations
25 12
and footnote
explanations.
administration, values of Q, significantly increased in the groups receiving PGI, or nitroprusside during both normoxic and hypoxic ventilation. With the administration of PGE, or norepinephrine, values of Q, decreased significantly comparing matched normoxic or hypoxic periods (ie, comparing period N with N,, or period H with HNE). Because of the small arterial to venous gradient for PO, during hypoxic ventilation, values of Qva/Qt were calculated only during normoxic ventilation periods that were similar in each group. In addition, values of hematocrit were all near 22% and there were no differences between periods. Similarly, temperature was maintained near 37°C over all periods. Finally, the ratio of wet to dry weights of the left lower lobe divided by the ratio of wet to dry weights of the left upper lobe was also similar in all groups (ie, PGI, [1.16 + 0.121, nitroprusside [1.16 + 0.041, PGE, [1.17 + 0.141, and norepinephrine [1.23 + 0.121).
in each group comparing period N and period H (P < .05). Hypoxic ventilation also resulted in significant increases (P < .05) in values of Rv in
the two groups that later received PGI, and PGE,. Prior to drug administration, hypoxic ventilation caused Rm to increase by 120%, 201%, lOO%, and 240% in the PGI,, nitroprusside, PGE,, and norepinephrine groups, respectively. Figure 5 illustrates values of P,.,, and incremental resistance in the four groups. During hypoxic ventilation, P,,,, tended to increase compared with control ventilation prior to drug administration, but the changes in P,,,, did not reach statistical significance for any individual group (.l > P < .05). Only after combining the data from all four groups was P,,, significantly greater during hypoxic ventilation compared with normoxic ventilation. The changes in incremental resistance (1 I slope) during hypoxic ventilation were less consistent with incremental resistance actually decreasing in the group to receive PGE, during period H compared with period N (P < .05). PGI, Administration. Values of Rtot and Rm decreased during periods N,,,, and H,,,, compared with period N and period H (P < .05).
Pulmonary Vascular Resistance
The values for PVR and its subdivisions in each of the four groups are illustrated in Figs 1 through 4. Rtot and Rm increased significantly Table
3. Hemodynamic
5r1 218 + 20*
and Blood
Gas Variables
in Groups
Receiving
Prostaglandin
E,
Period N
Pvco,
H
38 f 4
PH PVO," Pao, f’A
7.27 2 125 2 40-t 21 r
Pv a,*
6+1 153 2 11
~VA/OT
See Table
1 for abbreviations
0.03 35 11 2
7.27 34 38 20
-t k * +
0.02 4t 8 1
451 105 -c 6t
11+5
and footnote
NPGEP
38 2 3
-
explanations.
39 + 3 7.26 120 32 19
k + + +
0.03 22 4 1
5+1 110 + 8$ 10 + 4
4X2
37 k 2 7.26 35 37 19
2 + 2 2
0.04 5t 12 1
5+1 111 zk 12*
PROSTAGLANDINS
& HYPOXIC
PULMONARY
Table 4. Hemodynamic
VASOCONSTRICTION
and Blood
129
Gas Variables
in Groups
Receiving
Norepinephrine
Period N
H
37 - 3 7.30 It 0.03
35 f 4 7.30 f 0.03
35 + 4 7.31 f 0.02
155 f 50
33 t 3t
36 + 9 17-c 1
43 + 6 1621
138 T 30 332 10
QLX
5+1 177 * 31
&Al&
12 + 15
421 124 f 27t -
PVCO, PH pvo** Pa0, PA
Pv
See Table 1 for abbreviations
and footnote
36 f 3 7.30 f 0.02 362
lot
382 13 17t1 4 .k 1
17&l 4-1-l 130 +- 30t
124~
34$ _-
at7
explanations.
Values of Rtot, Rm, or Rv were similar between periods N,,,, and HPG12.P,,,, was significantly lower (P < .05) during period H,,,, compared with period H, while incremental resistance was significantly lower (P < .OS) during period NPGI,[sub] compared with period N. NitropmssideAdministration. Values of Rtot and Rv during periods N,,, and H,,, were 020
HNF
NNE
r
000LI
significantly decreased compared with periods N and H, respectively (P < .OS). Nitroprusside administration also resulted in a significant decrease in values of Rm during period H,,,, (P < .05) but not during period N,,, compared with periods H and N, respectively. However, values of Rm were still significantly greater during period H,,, compared with period N,,,,.
*+ i IfI
0.20
i
2 0.15 E \ E 2 ,"OlO
-
Norepinephrine
N
H
N NE
H NE
Nltroprusslde
-
E 2 2
0.05
-
_J
0.00
I
Period
PGE,
PGI,
* Fig 1. The changes in Rtot in each experimental group are illustrated. The results are shown as mean values + standard deviations. *, Significant difference (P < .05) between paired normoxie and hypoxic ventilation periods; +, significant difference comparing matched periods before and after drug administration (N v N,,,, or H Y H,,,).
i
=“010
!J ;;
i
i
LG 0.05
0 00
;
i
MAYERS
130
0 05
0.05
Norepinephrine
ET AL
Nitroprusside r
0 04 z E 1003
E 2 r”
0.02
E 2 B 0.01
0.00
1
I
I
t-4
I
H SE Period
J
0.00
SE
0 07
N
1 5 0
004
;
0.06 -2 ‘5 0 05 1 E 2 0.04
N
v m 002 !z
d
0.02 0.01
0.01 I
N
I
H
I
NFW
I
’
0.00
HP,,,
Period
and Norepinephrine
,
N
I
H
I
NPGI,
I
%c,2
Period
The increase in Rm from period N,,, to period H,,, was 130%, while the increase from period N to period H was 201%. Values of 1 /slope and P cRITwere similar during all ventilatory periods. PGE,
Fig 2. The changes in Ra in each experimental group are illustrated. The results are shown as mean values f standard deviations. l , Significant difference (P < .05) between paired normoxie and hypoxic ventilation periods; +, significant difference comparing matched periods before and after drug administration (N v N,,, or H v H,,).
d E 0.03 2.
0.03
0.00
H SW
PGI,
0.06 005
N SW
0.07
PGE,
2 2
H Period
Administration.
The pattern of changes in resistance were similar during either PGE, or norepinephrine administration. Values of Rtot and Rv increased during periods N,, and N,,,, compared with their respective normoxic ventilation periods (period N) before drug administration. Values of Rtot, Ra, or Rv were similar comparing period H,, with period H or period H,,,, with period H. However, values of Rm decreased significantly during periods H,, and H,,,, compared with values during hypoxic ventilation before drug administration. Values of l/slope and PC,,, were similar during all ventilatory periods with administration of either norepinephrine or PGE,.
DISCUSSION
Experimental Model
We characterized the pulmonary vascular response to selective vasodilators and vasoconstrictors during hypoxic and control ventilation using both the segmental distribution of resistance and the lobar P-Q relationship. The P-Q relationship can be used to divide the pressure losses across the lobar vasculature into a pressure loss proportional to flow (sIope of the P-Q relationship) and a pressure loss independent of flow (zero-flow intercept). The zero-flow intercept or mean critical closing pressure has been described as a resistance that is dependent on vascular tone,‘* while the inverse of slope can be described as the incremental resistance to flow. We also measured the segmental distribution of resistances to more fully describe the interactions of the drugs with hypoxia. We have
PROSTAGLANDINS
& HYPOXIC
PULMONARY
VASOCONSTRICTION
0 08 0 07
0 08
Norepinephrine
r
i
- 006E > E 005\ 0 xN 0.04
E
2
+
003-
*
.I
c CT 002 0 01 I
000
i
I-
+
n
N NE
H NE
-.
Period
008 l
007
007
+
<005ON zc 004E
z E 0.06
-~
‘\ E 0.05
~-
2 d
-
+ 0.04
E
0003E 'x
-
PGI,
i
2 E 0061
Fig 3. The changes in Rm in each experimental group are illustrated. The results are shown as mean values 2 standard deviations. l , Significant difference (P i .05) between paired normoxie and hypoxic ventilation periods; f, significant difference comparing matched periods before and after drug administration (N v N,,,, or H v H,,,,).
008
PGE,
0.03 E
002-
0.02
f 001
0001
2e:
I
N
’ H
previously described our measurements of the segmental distribution of resistance in detail.” Our model varied from that of Hakim et a1’3’4in that they fixed flow and allowed driving pressure to vary with resistance. We do not believe that this difference in methodology was significant since the subdivisions of resistance are similar if measured using either a constant driving pressure or a constant flow system.23 We prospectively maintained our arterial and venous pressures in a low physiologic range to minimize hydrostatic alveolar edema, and therefore obtained relatively low lobar flow rates. However, we maintained the flows within a range in which incremental resistance was constant and were therefore confident that the low lobar flows did not confound interpretation of our results. Thus, we believe that with this methodology, our results are comparable to those of other investigators.‘3-‘” We prospectively controlled parameters that
NFGE,
Period
%x2
0.00
i
N
H
iA .NPGu
L. _ ~_. %x2
Period
might independently affect PVR and thereby confound our results. The lobar perfusion pressure was similar during all ventilatory periods in each group; therefore, neither changes in vascular recruitment nor vascular distension would influence our measurements.‘” Similarly, PaOz was maintained constant by the bubble deoxygenator and would not independently influence PVR.” Other factors that might influence resistance, such as pH, hematocrit, and temperature, were also similar between ventilatory periods. We elected to maintain pH in a slightly acidotic range to potentially augment the strength of the hypoxic vascular response.” PvOz was similar comparing the two control ventilation periods as well as comparing the two hypoxic ventilation periods in each group. We maintained PvO, high enough during all control periods (> 100 mm Hg in every animal) such that PvO, should not have independently influenced resistance. There was a trend for the
MAYERS
132
Norepinephrine
zE 2 2 xN 9 0.08
< z
EO04-
0.02
000
I ’
-
0.08
-
Nitroprusside
3
0.06
&
0.10
ET AL
I N
4 H
I N NE
I
H NE
0.06
-
2 XN g 0.04
-
s > lx
0.02
-
’ 0.00
I
1 N
I HSNP
PGI,
0.10
PGE,
0.08
I NSNP
Period
Period
0.08
1:
2 1E E 2
I H
zE
0.06
XN
h
T
E 0.04 -55
&0.02
0.02
I
0.00 1
,
I
1
I
N
H Period
NPGE2
HP,,,
’
0.00
I
wet/dry weight of the left lower lobe to be greater than the wet/dry weight of the upper lobe (ratio of lower to upper lobe, > 1). Therefore, there may have been slight edema accumulation in all groups, but the degree of edema sufficient to alter the distribution of segmental resistances requires free reflux of edema fluid into the airways?5 We did not observe free reflux of edema fluid during the experiment. Furthermore, the arterial to venous oxygen gradient was similar between both control ventilatory periods within groups. Finally, our anesthetic agent (pentobarbital) has been previously shown not to effect PVR.26 We are therefore confident that any differences we found in PVR were a direct consequence of the specific drug administered. EjTects of Hypoxia
We evaluated the pulmonary vascular response to hypoxia in all groups prior to drug
I
I
N
H
Period
I
I
NPGU
HPG,2
Fig 4. The changes in Rv in each experimental group are illustrated. The results are shown as mean values + standard deviations. l , Significant difference (P < ,051 between paired normoxie and hypoxicventiiation periods; +, significant difference comparing matched periods before and after drug administration (N Y N,, or H v H,,,).
administration. In each group, total resistance increased during hypoxic ventilation, with the greatest change in resistance occurring in the middle vascular segment. Venous segmental resistance also tended to increase in all groups to a lesser extent; this achieved statistical significance in the PGI, and PGE, groups. The middle segment increase in resistance in response to hypoxia has been previously described.14,‘5317Although we did not specifically repeat hypoxic challenges at the conclusion of our experiments, we have previously demonstrated that this model maintains HPV over a similar time period.” In these prior studies, at the beginning of the experiments, values of Rtot and Rm during normoxic ventilation were 0.048 + 0.016 and 0.006 +- 0.005 cm H,O/mL/ min, respectively. During hypoxic ventilation, Rtot and Rm increased to values of 0.060 -+ 0.014 and 0.025 + 0.008 cm H,O/mL/min, respectively, At the conclusion of these experi-
PROSTAGLANDINS
& HYPOXIC
PULMONARY
VASOCONSTRlCTlON
133
100
Nkroprussrde
,I/
,,'v
t
/
80 I
0 1 0
2
4
6
Pressure Fig 5. The changes in the extrapolated critical closing pressure (P,,) and the slopes of the P-6 relationship during each ventilatory period for all four groups are illustrated. Each line does not represent actual data but rather represents the calculated linear relationship between pressure and flow (see Methods). Open circles represent normoxic periods (period N), closed circles represent hypoxic periods (period H), open triangles represent normoxie periods during drug infusion (period NDRUC), and closed triangles represent hypoxic periods during drug infusion (period H DRUG1
8
(cm
10
12
14
0
H,O)
2
4
Pressure
6
8
(cm
i0
.1
H;,O)
100 -
PGE, 80 x E \ 2 5 g
60-
40
20 -
20
OL 0
2
4
6
Pressure
ments, values of Rtot and Rm during normoxic ventilation were 0.045 + 0.013 and 0.006 -+ 0.004 cm H,O/mL/min, respectively. During hypoxic ventilation, Rtot and Rm again increased to values of 0.056 + 0.015 and 0.022 + 0.01 cm HzO/mL/min, respectively. Thus, we were able to demonstrate that the strength of HPV was essentially unchanged over time in this model. As well, in these present experiments, there was still a partial response to hypoxia during nitroprusside infusion. Thus, it is unlikely that our results are simply due to the loss of HPV over time. A complementary model of the pulmonary vasculature divides the pressure drops across the vasculature into flow-dependent and -independent pressure drops.” The effects of hypoxia in our experiments are similar to those observed by Sylvester et all6 in the isolated pig lung. Hypoxia tended to increase the flow-independent pressure drop (PCRIT) but had minimal effects on the flow-dependent pressure drop
8
10
(cm
12
c
14
H,O)
(l/slope). These results suggest that hypoxia acts to increase the tone of the vessels that set the Starling resistor”.” and these vessels are located in the middle vascular segment in dogs. Specific Effects of Vasodilators
Our results are consistent with the previous findings that both nitroprusside’7.‘H and PGIz7.x.‘x act to decrease PVR during normoxic or hypoxic ventilation. We arbitrarily chose doses of both vasodilators sufficient to increase pulmonary blood flow by at least 25%. The administered dose of PGI,“,‘* and nitroprusside”.” was in the high range used by other investigators in intact animals. The absolute magnitude of the dilator response is augmented when the tone of the pulmonary circulation is increased.“.” The relatively large dose of vasodilators needed to significantly increase flow in our studies may be due to a relatively low resting PVR in our isolated lobes. During control ventilation, nitroprusside acted
MAYERS
134
primarily to reduce the venous segment resistance while PGI, decreased middle segment resistance. The effects of PGI, would be consistent with the hypothesis that a prostaglandin vasodilator acted to maintain the low resting PVR in the normal lung.1629 The difference between these vasodilators becomes most apparent during hypoxic ventilation. PGI, administration completely ablated the increase in middle resistance normally observed during hypoxic ventilation. Although nitroprusside also diminished the hypoxic pressor response, the middle segment resistance still increased. This qualitative difference between the two agents was also evident when the pulmonary P-Q relationship was analyzed. PGI,, but not nitroprusside, ablated the increase in P,,,, observed with hypoxic ventilation. Neither vasodilator in these experiments affected venous admixture in these otherwise normal lungs. During control ventilation, alveolar PO, would not have stimulated HPV.29-” Although both nitroprussideZ7X32and PGI,28 minimized HPV, PGI, appears to more specifically antagonize the effects of hypoxia. This suggests that in the clinical setting, PGI, vasodilation might result in worsened systemic oxygenation due to more effective prevention of HPV. Specific Effects of Vasoconstrictors We chose doses of both vasoconstrictors sufficient to decrease pulmonary blood flow by at least 25%. Our results during normoxic ventilation confirm that norepinephrine and PGE, increase PVR primarily by increasing venous segment resistance.‘3333334 In contrast to Murray et al,35 we were unable to demonstrate any significant increase in the incremental resistance with vasoconstriction. In our experiments, P GRIT tended to increase during control ventilation in the presence of both vasoconstrictors. Similar results have been demonstrated in experiments more analogous to ours using various vasoconstrictors, including PGF,, PGE,, and angiotensin II.29,36 During hypoxic ventilation,
ET AL
there were no further increases in total resistance or in any of the segmental resistances, suggesting that the vasculature was maximally constricted. However, individual components of resistance were not maximal; ie, middle segment resistance during hypoxic ventilation without the drugs was higher than middle segment resistance with the drugs. These findings suggest that an increase in downstream venous resistance prevents the increase in middle resistance associated with hypoxic ventilation. Changing the vascular compliance with the drugs might change the physical locus of the vascular segments. In effect, the venous segment might engulf the part of the middle segment that usually responds to hypoxia. This, however, does not explain why the region of vasculature cannot constrict with hypoxia, it merely shifts the lack of response to the venous segment. It is more likely that the pulmonary vasculature autoregulates to some extent and that in the face of a vasoconstricting stimulus, increased vasodilators are released. This is suggested by the findings that after cyclooxygenase blockade and inhibition of the prostaglandin vasodilator (PGI,), vasoconstrictors further augment HPV.* We have also previously described the release of vasodilating prostaglandins in response to a hypoxic stimulus.“’ In the clinical setting, if hypoxic vasoconstriction is maintaining systemic oxygenation, then the addition of a vasoconstrictor to augment systemic blood pressure may worsen oxygenation by the loss of regional HPV. In conclusion, we found that PGI, ablates HPV, whereas nitroprusside is only a partial inhibitor. Vasoconstrictors may also effect HPV by nonspecifically increasing vascular tone and preventing the localized regional pressor effect of hypoxia. ACKNOWLEDGMENT The authors thank the expert secretarial assistance of Kathleen Brown and the expert technical assistance of Terry Eckersley and Dumitru Lucaciu.
REFERENCES 1. Humphrey H, Hall J, Sznajder I, et al: Improved survival in ARDS patients associated with a reduction in pulmonary capillary wedge pressure. Chest 97:1176-1180, 1990 2. Bernard GR: Pulmonary edema. Chest 89594-600, 1986
3. Radermacher P, Huet Y, Pluskwa F, et al: Comparison of ketanserin and sodium nitroprusside in patients with severe ARDS. Anesthesiology 68:152-157,198s 4. Melot C, Lejeune P, Leeman M, et al: Prostaglandin E, in adult respiratory distress syndrome. Am Rev Respir Dis 139:106-110, 1989
PROSTAGLANDINS & HYPOXIC PULMONARY VASOCONSTRICTION 5. Radermacher P, Santak B, Becker H, et al: Prostaglandin E, and nitroglycerin reduce pulmonary capillary pressure but worsen VaiQ distribution in patients with ARDS. Anesthesiology 70:601-606, 1989 6. Demling RH: Role of prostaglandins in acute pulmonary microvascular injury. Ann N Y Acad Sci 384:517-534, 1982 7. Radermacher P, Santak B, Whist HJ, et al: Prostacyclin for the treatment of pulmonary hypertension in the adult respiratory distress syndrome: Effects on pulmonary capillary pressure and ventilator-perfusion distributions. Anesthesiology 72:238-244, 1990 8. Sprague RS, Stephenson AH, Lonigro AJ: Prostaglandin I, supports blood flow to hypoxic alveoli in anesthetized dogs. J Appl Physiol56:1246-1251, 1984 9. Sprague RS, Stephenson AH, Heitmann LJ, et al: Differential response of the pulmonary circulation to prostaglandins E2 and F, in the presence of unilateral alveolar hypoxia. J Pharmacol Exp Ther 229:38-43,1984 IO. Lynch JP: Influence of cardiac output on intrapulmonary shunt. J Appl Physiol46:315-321, 1979 11. Breen PH, Schumacker PT, Hedenstierna G, et al: How does increased cardiac output increase shunt in pulmonary edema’? J Appl Physiol53:1273-1280, 1982 12. Domino KB, Wetstein L, Glasser SA, et al: Influence of mixed venous oxygen tension (PvO,) on blood flow to atelectatic lung. Anesthesiology 59:428-434,1983 13. Hakim TS, Michel RP, Chang HK: Partitioning of pulmonary vascular resistance in dogs by arterial and venous occlusion. J Appl Physiol52:710-715,1982 14. Hakim TS, Michel RP, Minami H, et al: Site of pulmonary hypoxic vasoconstriction studied with arterial and venous occlusion. J Appl Physiol54:1298-1302, 1983 1.5. Rock P, Patterson GA, Permutt S, et al: Nature and distribution of vascular resistance in hypoxic pig lungs. J Appl Physiol59:1891-1901.1985 16. Sylvester JT, Mitzner W, NGeow Y, et al: Hypoxic constriction of alveolar and extra-alveolar vessels in isolated pig lung. J Appl Physiol54:1660-1666,1983 17. Johnson D, Mayers I, To T: The effects of halothane on hypoxic pulmonary vasoconstriction. Anesthesiology 72: 125133, 1990 1X. Hyman AL, Kadowitz PJ: Pulmonary vasodilator activity of prostacyclin (PGI,) in the cat. Circ Res 45:404409, 1Y7Y 19. Rossing RG, Cain SM: A nomogram relating PO,, pH, temperature and hemoglobin saturation in the dog. J Appl Physiol 21:195-201, 1966 20. Sokol RR, Rohlf FJ: Biometry. Statistical Tables. San Francisco, CA, Freeman, 1981, p 81
135 21. Feldman HA: Families of lines: Random effects in linear regression analysis. J Appl Physiol64:1721-1732,1988 22. Graham R, Skoog C, Oppenheimer L. et al: Critical closure in canine pulmonary vasculature. Circ Res 50:566572, 1982 23. Townsley MI, Korthus RJ, Taylor AE: Effects of arachidonate on permeability and resistance distribution in canine lungs. J Appl Physiol58:206-210, 1985 24. Brimioulle S, Lejeune P, Vachiery JL, et al: Effects of acidosis and alkalosis on hypoxic pulmonary vasoconstriction in dogs. Am J Physiol258:347-353, 1990 25. Wang CG, Hakim RS, Michel RP, et al: Segmental pulmonary vascular resistance in progressive hydrostatic and permeability edema. J Appl Physiol59:242-254, 1985 26. Bjertnaes LJ: Hypoxia induced vasoconstriction in isolated perfused lungs exposed to injectable or inhalational anaesthetics. Acta Anaesthesiol Stand 21:133-147, 1977 27. Kadowitz PJ, Nandiwada P, Gruetter CA, et al: Pulmonary vasodilator responses to nitroprusside and nitroglycerin in the dog. J Clin Invest 67:893-902, 1981 28. Colley PS, Cheney FW, Hlastala MP: Ventilationperfusion and gas exchange effects of sodium nitroprusside in dogs with normal and edematous lungs. Anesthesiology 50:489-495,1979 29. Gerber JG, Voelkel N, Nies AS, et al: Moderation of hypoxic vasoconstriction by infused or arachidonic acid: Role of PGI,. J Appl Physiol49:107-112, 1980 30. Naeije R, Melot C, Mols P, et al: Effects of vasodilators on hypoxic pulmonary vasoconstriction in normal man. Chest 82:404-409,tYEZ 31. Voelkel NF: Mechanisms of hypoxic pulmonary vasoconstriction. Am Rev Respir Dis 133:1186-l 195, 1986 32. Bixler TJ, Gott VL, Garchren TJ: Reversal of experimental pulmonary hypertension with sodium nitroprusside. J Thorac Cardiovasc Surg 81:537-545, 1981 33. Dawson CA: Role of pulmonary vasomotion in physiology of the lung. Physiol Rev 64:544-616, 1984 34. Kadowitz PJ, Joiner PD, Hyman AL: Effect of prostaglandin E, in pulmonary vascular resistance on intact dog. swine and lamb. Eur J Pharmacol31:72-80, 1975 35. Murray PA, Lodato RF, Michael JR: Neural antagonists modulate pulmonary pressure-flow plots in conscious dogs. J Appl Physiol60:1900-1907, 1986 36. Harabiu AL, Peake MD, Sylvester JT: Effect of severe hypoxia in the pulmonary vascular response to vasoconstrictor agents. J Appl Physiol50:561-565, 1981 37. Johnson D, Mayers I, Hurst T: Halothane inhibits hypoxic pulmonary vasoconstriction in the presence of cycle-oxygenase blockade. Can J Anaesth 37287.295. 1990
or Vasoconstrictors Prevent Hypoxic Pulmonary Vasoconstriction I. Mayers,
T. Hurst, T. To, and D. Johnson
Prostaglandins modulate pulmonary vascular resistance (PM) and hypoxic pulmonary vasoconstriction (HPV). We studied the effects of a prostaglandin vasodilator (PGI,) and vasoconstrictor (PGE,) in the pulmonary circulation and compared these effects to the nonprostaglandin vasodilator sodium nitroprusside (SNP) and vasoconstrictor norepinephrine (NE) during 35% and 3% 0, ventilation. Pulmonary vascular resistance was divided into arterial, middle (Rm), and venous segmental resistances in 20 isolated left lower canine lobes using a stop-flow technique. Pulmonary vascular resistance was also analyzed as the slope and intercept (P,,,) of the pressure-flow relationship. We found that only PGI, specifically prevented the increase in Rm and P,,,, due to hypoxia. Sodium nitro-
prusside predominantly decreased venous segment resistance and, even in the presence of SNP, hypoxia significantly (P < .05) increased Rm (0.0179 k 0.0075 cm H,O/mL/min) compared with control ventilation (0.0078 -C 0.0043 cm H,O/mL/min). Both PGE, and NE increased PVR primarily by increasing the venous segmental resistance. After the addition of PGE, or NE, hypoxic ventilation did not result in further increases of Rm or P,,,. We conclude that PGI, but not SNP selectively inhibits HPV and that neither PGE, nor NE further augment HPV. The direct effect of these drugs on the pulmonary circulation and their resultant changes in systemic oxygen delivery must be considered prior to their use in the clinical setting. Copyright 0 1991 by W.B. seunders Company
I
oxygenation.” Finally, increasing the mixed venous oxygen tension may increase venous admixture by partial inhibition of hypoxic pulmonary vasoconstriction (HPV)“; this, in turn, may adversely affect systemic oxygenation. In our current experiments, we wished to assess the independent pulmonary vascular effects of the prostaglandin vasoconstrictor PGEz and the prostaglandin vasodilator PG12. We compared these effects with those of a nonprostaglandin vasodilator (nitroprusside) and a nonprostaglandin vasoconstrictor (norepinephrine). From these studies, we could extrapolate the effects on the pulmonary vasculature to a setting where HPV might be important in maintaining systemic oxygenation at a safe level. We evaluated pulmonary vascular resistance (PVR) using an isolated canine left lower lobe that allowed us to partition resistance into arterial, middle, and venous segmental resistances’“.” and to generate a pressure-flow (P-Q) relationship of the vasculature.15,1h We could therefore more precisely characterize the interactions of the test drugs with hypoxia. We could also ___-_
T HAS BEEN suggested that improving pulmonary hypertension by reducing pulmonary artery pressures may be beneficial in the setting of acute pulmonary injury.‘,’ However, the role of vasodilator therapy is as yet not fully defined. Although vasodilators may decrease pulmonary artery hypertension, they may also adversely affect venous admixture and systemic oxygenation.3m5 The use of PGI,, an endogenous prostaglandin vasodilator with cytoprotective properties, has been recently evaluated in the setting of acute respiratory distress syndrome.6 In human trials in acute respiratory distress syndrome, PGI, has been shown to maintain systemic oxygenation despite worsened ventilation/perfusion matching.7 However, in indomethacin-pretreated dogs, pulmonary vasodilation with PGIz increased pulmonary blood flow to the hypoxic lung and decreased systemic oxygenation without affecting mixed venous oxygen tension.’ In a similar model, PGE,, a vasoconstricting prostaglandin, reduced pulmonary blood flow to the hypoxic lung and improved systemic oxygenation.9 Understanding the effects of prostaglandins on the pulmonary vasculature are confounded if cardiac output and mixed venous oxygen tension change in an uncontrolled manner.’ Changes in pulmonary vascular pressures may affect venous admixture and systemic oxygenation by changing pulmonary vascular recruitment.” In addition, increases in cardiac output increase intrapulmonary shunt fraction, thereby affecting systemic Journalof
Crifical
Care, Vol6,
No 3 (September),
1991: pp 125-135
From the Depanments of Medicine and Anaesthesra, University of Saskatchewan, Saskatoon, Saskatchewan Canada. Received February I, 1991; accepted April 24, 1991. Supported by grants from the Saskatchewan Health Research Board and the Canadian Heart and Stroke Foundation. Address reprint requests to D. Johnson, MDCM, FRCP(C), Box 95, Royal University Hospital, Saskatoon, Saskatchewan S7N 0x0, Canada. Copyright o 1991 by W.B. Saunders Company 0883-944119110603-0003$05.0010
125
126
MAYERS
simultaneously control lobar perfusion pressures and mixed venous oxygen tension to ensure that our results were not influenced by independent changes in flow or by independent changes in venous admixture. METHODS
Animal Preparation These studies were carried out with approval of the University Animal Care Committee. The surgical preparation of the isolated lobe has been described in detail elsewhere.” In brief, 20 mongrel dogs (weight, 20 to 26 kg) were anesthetized (thiopental 25 mgikg), intubated, and ventilated (Harvard ventilator; Harvard Apparatus Co, Millis, MA) at a tidal volume (VT) of 20 mL/kg with room air. A catheter was inserted into the abdominal aorta via the femoral artery, which was subsequently used for phlebotomy and for drug administration. The left upper lobe was surgically removed to facilitate exposure of the left lower lobe and was saved for subsequent gravimetric determinations of edema. The left lower lobe artery and vein were dissected and cannulated. A no. 6 cuffed tracheal tube was inserted into the lobar bronchus through a bronchotomy. After the cannulae were inserted and the lobe isolated, the animals were killed by injection of 10 mL of supersaturated KC1 solution. The cannulated lobe was left in situ within the thoracic cavity and was connected to an extra corporeal circuit. The lobe was perfused with 400 mL phlebotomized autologous blood diluted to 500 mL with heparin (1,000 U) and normal saline. Pulmonary venous blood passively drained into a venous reservoir and was pumped by a roller pump through a heat exchanger, filter, and bubble deoxygenator (95% N,, 5% CO,) and was then returned to the arterial reservoir. The lobar bronchus was ventilated independently of the remainder of the lung by a second Harvard ventilator (VT = 150 to 200 mL). Lobar arterial pressure (Pa) and venous pressure (Pv) were set by adjusting the heights of the respective reservoirs. The Pa and Pv were measured at pressure ports near the arterial and venous cannulae, respectively. Airway pressure was measured with an air phase transducer connected by low compliance tubing to a port near the endobronchial tube. Before commencing the experimental protocol, at least 20 minutes were allowed for the preparation to stabilize, as assessed by a constant lobar blood flow (Q,) over a 5-minute period. Heparin (1,000 U) and 50% dextrose (1 mL) were added to the circuit every 30 minutes. At the conclusion of the experiments, the left lower lobe was removed and saved for gravimetric determinations of edema.
Calculations Using methodology similar to that described by Hakim et al,” total PVR (Rtot) was divided into arterial segment resistance (Ra), middle segment resistance (Rm), and venous segment resistance (Rv). We calculated the distribution of resistances using the pressure changes following a venous or arterial occlusion.” After an arterial occlusion there is an initial rapid decrease in pressure (APa) followed by a slow decrease in pressure. Similarly, after venous
ET AL
occlusion there is a rapid increase in venous pressure (APv) followed by a slow increase in pressure. Rtot was calculated as (Pa - Pv)/Q,. Ra and Rv were calculated as APa/& and APvIQ,, respectively. Rm was calculated as Rtot (Ra + Rv). We obtained the lobar pressure-flow (P-Q) relationship with the lobe under zone 2 conditions for flow (Pv, < -10 cm H,O; alveolar pressure, 0). To determine the P-Q relationship of the lobe under any given condition, we altered the level of the arterial reservoir to generate differing levels of pressure and then measured the resultant flows. The paired pressure and flow values were fit to a straight line by linear regression. The straight line was extrapolated to zero flow and the zero-flow pressure intercept was assumed to be the mean critical closing pressure (PCR,r) of the pulmonary vasculature. The slope of the P-Q relationship was also calculated by linear regression. The incremental resistance to flow was determined as the inverse of the slope of the P-Q relationship (l/slope). Venous admixture (Q,,/Q,) of the lobe was calculated from the following equation: QvJQ, = (Cc’O, - CaO,)/ (Cc’O, - CvO,), where Cx 0, refers to the content of oxygen in blood, c’ is end capillary blood, v is pulmonary venous blood, and a is pulmonary arterial blood. Oxygen contents were calculated from derived oxygen saturations’8 and hemoglobin concentrations. Alveolar PO, was calculated using the alveolar gas equation, while pulmonary arterial and venous values of PO, (PaO, and PvO,, respectively) were directly measured. Hemoglobin, in turn, was estimated as one third of the measured hematocrit. The wet weights of the left upper and left lower lobes were measured. Both lobes were then air dried and weighed until their weights varied by less than 1 g over 3 days. The ratio of the wet to dry weights of the left upper and lower lobes was then calculated. In addition, we calculated the ratio of the wet to dry weight of the left lower lobe divided by the wet to dry weight of the left upper lobe for each animal.
Experimental Protocol Following stabilization, baseline flow for each lobe was set by adjusting Pa to near 18 cm H,O and Pv to 5 cm H,O. Each lobe was first ventilated with a normoxic gas mixture (35% O,, 7% CO,, and 58% N,); this was the initial normoxic period (period N). The lobe was then ventilated with a hypoxic gas mixture (3% 0,, 7% CO,, and 90% NJ; this was the initial hypoxic period (period H). The lobe was again ventilated with the normoxic gas mixture and, after Q, had returned to baseline values, the lobes were randomized to one of four drug groups (n = 5 in each group). Each lobe received either nitroprusside (5 mg bolus followed by 8 pgikgimin infusion), norepinephrine (0.1 mg bolus followed by 1 ugikgimin infusion), PGI, (0.5 mg bolus followed by 0.6 pg/kglmin infusion), or PGE, (0.5 mg bolus followed by 0.6 bgikgimin infusion). Drug doses were arbitrarily chosen to augment (vasodilators) or diminish (vasoconstrictors) lobar flow by at least 25%. Nitroprusside and norepinephrine solutions were prepared daily just prior to their infusion. PGI, and PGE, (Sigma, St Louis, MO) were initially dissolved in a stock solution of 10% absolute ethanol in normal saline’” and diluted 20-fold in 5%
PROSTAGLANDINS
& HYPOXIC
PULMONARY
VASOCONSTRICTION
127
dextrose in water just prior to administration. The stock solutions of PGI, and PGEz were refrigerated at 4°C and used within I week of preparation. Following drug administration, the lobes were allowed to stabilize for 1.5minutes, by which time QL changed by less than 5% over the final 5 minutes. The lobes then received another paired period of normoxic and hypoxic ventilation. The ventdatory periods are N,,, and HsNp for the group receiving nitroprusside, N,, and H,, for the group receiving norepmephrme, N,,,, and H,,,Z for the group receiving PGI,, and NPGEzand HPcifi2for the group receiving PGE?. Therefore, each group received paired periods of normoxic and hypoxic ventilation prior to drug administration and paired periods of normoxic and hypoxic ventilation during drug administration. Venous and arterial occlusions were performed in triplicate at the end of each ventilatory period. All occlusions were obtained under zone 3 flow conditions after stopping the ventilator at end expiration. Prior to occlusions, blood was withdrawn from the venous and arterial cannula for blood gas and hematocrit determinations. Blood gases were analyzed for PO:, PCO,, and pH at 37°C (model 162-2, Corning Medical, Medfield, MA) using appropriately calibrated electrodes and were then corrected for blood reservoir temperature after calculating hemoglobin saturation from a standard nomograr+“’ We also obtained a P-Q plot at the end of each period following vascular occlusions. Zone 2 conditions were set (Pv < -10 cm H,O), then the P-6 relationship was obtained by lowering the inflow reservoir height in steps of 3 to 5 cm HZO. To allow time for flow to stabilize, 6, was measured at each driving pressure after stopping the ventilator at end expiration for 20 seconds. We obtained a minimum of six paired pressure-flow measurements to calculate a regression equation. Following these determinations, zone 3 conditions were reestablished by setting Pv back to 5 cm Hz0 and the next ventilatoIy period was commenced. In this way, we obtained measurements at the end of each ventilatory period. which included values of inflow pressures and Table
1. Hemodynamic
and Blood
their respective flows under zone 2 conditions along with vascular occlusions under zone 3 conditions.
Statistics Within each group, values of blood gases, inspired gases. and hemodynamics were compared between conditions using a one-way analysis of variance (ANOVA). When the F statistic showed a significant difference, these values were compared by multiple ttests. Sidak’s multiplicative inequality was used to correct the t-statistic for the number of comparisons made between groups.‘” A probability value less than .05 was considered to show asignificant difference. The slopes and intercepts of the P-Q linear relationships were compared using a restricted maximum likelihood analysis described by Feldman.” All values except for slopes and intercepts are shown as mean ? standard deviation. RESULTS
Hernodynamic and Blood Gas Values
Tables 1 through 4 illustrate the mean values for hemodynamic parameters and blood gases obtained during the paired periods of normoxic and hypoxic ventilation in the four experimental groups. There were no differences in PvC02, PaO,, pH, Pa, and Pv by ANOVA within individual groups comparing ventilatory periods. Values of PvO, decreased significantly between paired normoxic and hypoxic periods; however, between matched normoxic or hypoxic periods (ie, before and during drug administratio?), values of PvO, were similar. Values of Q, significantly decreased during hypoxic ventilation (period H) compared with normoxic ventilation (period N) in all four groups. With drug
Gas Variables
PVCO,
40 2 2
41 + 1
PH PVOT
7.30 + 0.04 125 t 25 40 + 7
7.31 + 0.03 33 2 3t 472 18
Pa0,
Pa
19%
PV a:
&3/l& Abbreviations:
PVCO,, venous
1
18i
3-tl 126 2 6t
IO 2 5
Pvo,, venous
Receiving
39 f
1
521 165 f 16
PCO, (mmHg);
in Groups
Pao,, arterial
I,
1
40 + 2
7.28 t 0.03 129 f 18 47 2 14
7.31 r 0.02 32 f 4t 32 2 7
19 2 1
19 + 1
621 211 -t 17*
521 209 i 17* -
102
PO, (mmHg);
Prostaglandin
3
PO, (mmHg);
pH, venous
pH; Pa, pulmonary
arterial pressure (cm H,O); Pv, pulmonary venous pressure (cm H,O); a,, lobarflow (mL/min); &a/6, venous admixture (%). Periods N and H refer to normoxic and hypoxic ventilatory periods, respectively, prior to drug administration. Periods Np,+ and H,,,,, and NsNp and hypoxic ventilatory periods in groups receiving PGI, or nitroprusside, respectively, after administration and H,,, refer to normoxic of drug. Periods N,,, and H,,,,, and N,, and H,, refer to normoxic and hypoxic ventilatory periods in groups receiving PGE, or norepinephrine, *Significant tsignificant *Significant
respectively, after administration of drug. group difference by ANOVA (P < .05). difference comparing paired normoxic and hypoxic difference
(P < .05) comparing
matched
periods
periods before
(N v H or NDnuc v H,,,,).
and after drug administration
(N v N,,,,
or H v H,,,,,).
128
MAYERS
Table
2. Hemodynamic
and Blood
Gas Variables
in Groups
Receiving
Sodium
ET AL
Nitroprusside
Period
PVCO, PH pvo,* Pao,
39 t 5
39 ? 8
39 2 5
7.30 * 0.02 34 5 4t
7.28 2 0.02 136 + 36
7.27 + 0.02 32 + 13t
42 + 14 17 + 1 4+1
39 of: 6 175 1 5kl
39-t 11 17 + 1
128 2 20t -
243 -c 28$ 7c9
17 It_ 1 4+1
PA
Pv
179~ 82
4x &A/&
See Table
38 2 5 7.26 -t 0.05 139 2 34 37 I10
1 for abbreviations
25 12
and footnote
explanations.
administration, values of Q, significantly increased in the groups receiving PGI, or nitroprusside during both normoxic and hypoxic ventilation. With the administration of PGE, or norepinephrine, values of Q, decreased significantly comparing matched normoxic or hypoxic periods (ie, comparing period N with N,, or period H with HNE). Because of the small arterial to venous gradient for PO, during hypoxic ventilation, values of Qva/Qt were calculated only during normoxic ventilation periods that were similar in each group. In addition, values of hematocrit were all near 22% and there were no differences between periods. Similarly, temperature was maintained near 37°C over all periods. Finally, the ratio of wet to dry weights of the left lower lobe divided by the ratio of wet to dry weights of the left upper lobe was also similar in all groups (ie, PGI, [1.16 + 0.121, nitroprusside [1.16 + 0.041, PGE, [1.17 + 0.141, and norepinephrine [1.23 + 0.121).
in each group comparing period N and period H (P < .05). Hypoxic ventilation also resulted in significant increases (P < .05) in values of Rv in
the two groups that later received PGI, and PGE,. Prior to drug administration, hypoxic ventilation caused Rm to increase by 120%, 201%, lOO%, and 240% in the PGI,, nitroprusside, PGE,, and norepinephrine groups, respectively. Figure 5 illustrates values of P,.,, and incremental resistance in the four groups. During hypoxic ventilation, P,,,, tended to increase compared with control ventilation prior to drug administration, but the changes in P,,,, did not reach statistical significance for any individual group (.l > P < .05). Only after combining the data from all four groups was P,,, significantly greater during hypoxic ventilation compared with normoxic ventilation. The changes in incremental resistance (1 I slope) during hypoxic ventilation were less consistent with incremental resistance actually decreasing in the group to receive PGE, during period H compared with period N (P < .05). PGI, Administration. Values of Rtot and Rm decreased during periods N,,,, and H,,,, compared with period N and period H (P < .05).
Pulmonary Vascular Resistance
The values for PVR and its subdivisions in each of the four groups are illustrated in Figs 1 through 4. Rtot and Rm increased significantly Table
3. Hemodynamic
5r1 218 + 20*
and Blood
Gas Variables
in Groups
Receiving
Prostaglandin
E,
Period N
Pvco,
H
38 f 4
PH PVO," Pao, f’A
7.27 2 125 2 40-t 21 r
Pv a,*
6+1 153 2 11
~VA/OT
See Table
1 for abbreviations
0.03 35 11 2
7.27 34 38 20
-t k * +
0.02 4t 8 1
451 105 -c 6t
11+5
and footnote
NPGEP
38 2 3
-
explanations.
39 + 3 7.26 120 32 19
k + + +
0.03 22 4 1
5+1 110 + 8$ 10 + 4
4X2
37 k 2 7.26 35 37 19
2 + 2 2
0.04 5t 12 1
5+1 111 zk 12*
PROSTAGLANDINS
& HYPOXIC
PULMONARY
Table 4. Hemodynamic
VASOCONSTRICTION
and Blood
129
Gas Variables
in Groups
Receiving
Norepinephrine
Period N
H
37 - 3 7.30 It 0.03
35 f 4 7.30 f 0.03
35 + 4 7.31 f 0.02
155 f 50
33 t 3t
36 + 9 17-c 1
43 + 6 1621
138 T 30 332 10
QLX
5+1 177 * 31
&Al&
12 + 15
421 124 f 27t -
PVCO, PH pvo** Pa0, PA
Pv
See Table 1 for abbreviations
and footnote
36 f 3 7.30 f 0.02 362
lot
382 13 17t1 4 .k 1
17&l 4-1-l 130 +- 30t
124~
34$ _-
at7
explanations.
Values of Rtot, Rm, or Rv were similar between periods N,,,, and HPG12.P,,,, was significantly lower (P < .05) during period H,,,, compared with period H, while incremental resistance was significantly lower (P < .OS) during period NPGI,[sub] compared with period N. NitropmssideAdministration. Values of Rtot and Rv during periods N,,, and H,,, were 020
HNF
NNE
r
000LI
significantly decreased compared with periods N and H, respectively (P < .OS). Nitroprusside administration also resulted in a significant decrease in values of Rm during period H,,,, (P < .05) but not during period N,,, compared with periods H and N, respectively. However, values of Rm were still significantly greater during period H,,, compared with period N,,,,.
*+ i IfI
0.20
i
2 0.15 E \ E 2 ,"OlO
-
Norepinephrine
N
H
N NE
H NE
Nltroprusslde
-
E 2 2
0.05
-
_J
0.00
I
Period
PGE,
PGI,
* Fig 1. The changes in Rtot in each experimental group are illustrated. The results are shown as mean values + standard deviations. *, Significant difference (P < .05) between paired normoxie and hypoxic ventilation periods; +, significant difference comparing matched periods before and after drug administration (N v N,,,, or H Y H,,,).
i
=“010
!J ;;
i
i
LG 0.05
0 00
;
i
MAYERS
130
0 05
0.05
Norepinephrine
ET AL
Nitroprusside r
0 04 z E 1003
E 2 r”
0.02
E 2 B 0.01
0.00
1
I
I
t-4
I
H SE Period
J
0.00
SE
0 07
N
1 5 0
004
;
0.06 -2 ‘5 0 05 1 E 2 0.04
N
v m 002 !z
d
0.02 0.01
0.01 I
N
I
H
I
NFW
I
’
0.00
HP,,,
Period
and Norepinephrine
,
N
I
H
I
NPGI,
I
%c,2
Period
The increase in Rm from period N,,, to period H,,, was 130%, while the increase from period N to period H was 201%. Values of 1 /slope and P cRITwere similar during all ventilatory periods. PGE,
Fig 2. The changes in Ra in each experimental group are illustrated. The results are shown as mean values f standard deviations. l , Significant difference (P < .05) between paired normoxie and hypoxic ventilation periods; +, significant difference comparing matched periods before and after drug administration (N v N,,, or H v H,,).
d E 0.03 2.
0.03
0.00
H SW
PGI,
0.06 005
N SW
0.07
PGE,
2 2
H Period
Administration.
The pattern of changes in resistance were similar during either PGE, or norepinephrine administration. Values of Rtot and Rv increased during periods N,, and N,,,, compared with their respective normoxic ventilation periods (period N) before drug administration. Values of Rtot, Ra, or Rv were similar comparing period H,, with period H or period H,,,, with period H. However, values of Rm decreased significantly during periods H,, and H,,,, compared with values during hypoxic ventilation before drug administration. Values of l/slope and PC,,, were similar during all ventilatory periods with administration of either norepinephrine or PGE,.
DISCUSSION
Experimental Model
We characterized the pulmonary vascular response to selective vasodilators and vasoconstrictors during hypoxic and control ventilation using both the segmental distribution of resistance and the lobar P-Q relationship. The P-Q relationship can be used to divide the pressure losses across the lobar vasculature into a pressure loss proportional to flow (sIope of the P-Q relationship) and a pressure loss independent of flow (zero-flow intercept). The zero-flow intercept or mean critical closing pressure has been described as a resistance that is dependent on vascular tone,‘* while the inverse of slope can be described as the incremental resistance to flow. We also measured the segmental distribution of resistances to more fully describe the interactions of the drugs with hypoxia. We have
PROSTAGLANDINS
& HYPOXIC
PULMONARY
VASOCONSTRICTION
0 08 0 07
0 08
Norepinephrine
r
i
- 006E > E 005\ 0 xN 0.04
E
2
+
003-
*
.I
c CT 002 0 01 I
000
i
I-
+
n
N NE
H NE
-.
Period
008 l
007
007
+
<005ON zc 004E
z E 0.06
-~
‘\ E 0.05
~-
2 d
-
+ 0.04
E
0003E 'x
-
PGI,
i
2 E 0061
Fig 3. The changes in Rm in each experimental group are illustrated. The results are shown as mean values 2 standard deviations. l , Significant difference (P i .05) between paired normoxie and hypoxic ventilation periods; f, significant difference comparing matched periods before and after drug administration (N v N,,,, or H v H,,,,).
008
PGE,
0.03 E
002-
0.02
f 001
0001
2e:
I
N
’ H
previously described our measurements of the segmental distribution of resistance in detail.” Our model varied from that of Hakim et a1’3’4in that they fixed flow and allowed driving pressure to vary with resistance. We do not believe that this difference in methodology was significant since the subdivisions of resistance are similar if measured using either a constant driving pressure or a constant flow system.23 We prospectively maintained our arterial and venous pressures in a low physiologic range to minimize hydrostatic alveolar edema, and therefore obtained relatively low lobar flow rates. However, we maintained the flows within a range in which incremental resistance was constant and were therefore confident that the low lobar flows did not confound interpretation of our results. Thus, we believe that with this methodology, our results are comparable to those of other investigators.‘3-‘” We prospectively controlled parameters that
NFGE,
Period
%x2
0.00
i
N
H
iA .NPGu
L. _ ~_. %x2
Period
might independently affect PVR and thereby confound our results. The lobar perfusion pressure was similar during all ventilatory periods in each group; therefore, neither changes in vascular recruitment nor vascular distension would influence our measurements.‘” Similarly, PaOz was maintained constant by the bubble deoxygenator and would not independently influence PVR.” Other factors that might influence resistance, such as pH, hematocrit, and temperature, were also similar between ventilatory periods. We elected to maintain pH in a slightly acidotic range to potentially augment the strength of the hypoxic vascular response.” PvOz was similar comparing the two control ventilation periods as well as comparing the two hypoxic ventilation periods in each group. We maintained PvO, high enough during all control periods (> 100 mm Hg in every animal) such that PvO, should not have independently influenced resistance. There was a trend for the
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Norepinephrine
zE 2 2 xN 9 0.08
< z
EO04-
0.02
000
I ’
-
0.08
-
Nitroprusside
3
0.06
&
0.10
ET AL
I N
4 H
I N NE
I
H NE
0.06
-
2 XN g 0.04
-
s > lx
0.02
-
’ 0.00
I
1 N
I HSNP
PGI,
0.10
PGE,
0.08
I NSNP
Period
Period
0.08
1:
2 1E E 2
I H
zE
0.06
XN
h
T
E 0.04 -55
&0.02
0.02
I
0.00 1
,
I
1
I
N
H Period
NPGE2
HP,,,
’
0.00
I
wet/dry weight of the left lower lobe to be greater than the wet/dry weight of the upper lobe (ratio of lower to upper lobe, > 1). Therefore, there may have been slight edema accumulation in all groups, but the degree of edema sufficient to alter the distribution of segmental resistances requires free reflux of edema fluid into the airways?5 We did not observe free reflux of edema fluid during the experiment. Furthermore, the arterial to venous oxygen gradient was similar between both control ventilatory periods within groups. Finally, our anesthetic agent (pentobarbital) has been previously shown not to effect PVR.26 We are therefore confident that any differences we found in PVR were a direct consequence of the specific drug administered. EjTects of Hypoxia
We evaluated the pulmonary vascular response to hypoxia in all groups prior to drug
I
I
N
H
Period
I
I
NPGU
HPG,2
Fig 4. The changes in Rv in each experimental group are illustrated. The results are shown as mean values + standard deviations. l , Significant difference (P < ,051 between paired normoxie and hypoxicventiiation periods; +, significant difference comparing matched periods before and after drug administration (N Y N,, or H v H,,,).
administration. In each group, total resistance increased during hypoxic ventilation, with the greatest change in resistance occurring in the middle vascular segment. Venous segmental resistance also tended to increase in all groups to a lesser extent; this achieved statistical significance in the PGI, and PGE, groups. The middle segment increase in resistance in response to hypoxia has been previously described.14,‘5317Although we did not specifically repeat hypoxic challenges at the conclusion of our experiments, we have previously demonstrated that this model maintains HPV over a similar time period.” In these prior studies, at the beginning of the experiments, values of Rtot and Rm during normoxic ventilation were 0.048 + 0.016 and 0.006 +- 0.005 cm H,O/mL/ min, respectively. During hypoxic ventilation, Rtot and Rm increased to values of 0.060 -+ 0.014 and 0.025 + 0.008 cm H,O/mL/min, respectively, At the conclusion of these experi-
PROSTAGLANDINS
& HYPOXIC
PULMONARY
VASOCONSTRlCTlON
133
100
Nkroprussrde
,I/
,,'v
t
/
80 I
0 1 0
2
4
6
Pressure Fig 5. The changes in the extrapolated critical closing pressure (P,,) and the slopes of the P-6 relationship during each ventilatory period for all four groups are illustrated. Each line does not represent actual data but rather represents the calculated linear relationship between pressure and flow (see Methods). Open circles represent normoxic periods (period N), closed circles represent hypoxic periods (period H), open triangles represent normoxie periods during drug infusion (period NDRUC), and closed triangles represent hypoxic periods during drug infusion (period H DRUG1
8
(cm
10
12
14
0
H,O)
2
4
Pressure
6
8
(cm
i0
.1
H;,O)
100 -
PGE, 80 x E \ 2 5 g
60-
40
20 -
20
OL 0
2
4
6
Pressure
ments, values of Rtot and Rm during normoxic ventilation were 0.045 + 0.013 and 0.006 -+ 0.004 cm H,O/mL/min, respectively. During hypoxic ventilation, Rtot and Rm again increased to values of 0.056 + 0.015 and 0.022 + 0.01 cm HzO/mL/min, respectively. Thus, we were able to demonstrate that the strength of HPV was essentially unchanged over time in this model. As well, in these present experiments, there was still a partial response to hypoxia during nitroprusside infusion. Thus, it is unlikely that our results are simply due to the loss of HPV over time. A complementary model of the pulmonary vasculature divides the pressure drops across the vasculature into flow-dependent and -independent pressure drops.” The effects of hypoxia in our experiments are similar to those observed by Sylvester et all6 in the isolated pig lung. Hypoxia tended to increase the flow-independent pressure drop (PCRIT) but had minimal effects on the flow-dependent pressure drop
8
10
(cm
12
c
14
H,O)
(l/slope). These results suggest that hypoxia acts to increase the tone of the vessels that set the Starling resistor”.” and these vessels are located in the middle vascular segment in dogs. Specific Effects of Vasodilators
Our results are consistent with the previous findings that both nitroprusside’7.‘H and PGIz7.x.‘x act to decrease PVR during normoxic or hypoxic ventilation. We arbitrarily chose doses of both vasodilators sufficient to increase pulmonary blood flow by at least 25%. The administered dose of PGI,“,‘* and nitroprusside”.” was in the high range used by other investigators in intact animals. The absolute magnitude of the dilator response is augmented when the tone of the pulmonary circulation is increased.“.” The relatively large dose of vasodilators needed to significantly increase flow in our studies may be due to a relatively low resting PVR in our isolated lobes. During control ventilation, nitroprusside acted
MAYERS
134
primarily to reduce the venous segment resistance while PGI, decreased middle segment resistance. The effects of PGI, would be consistent with the hypothesis that a prostaglandin vasodilator acted to maintain the low resting PVR in the normal lung.1629 The difference between these vasodilators becomes most apparent during hypoxic ventilation. PGI, administration completely ablated the increase in middle resistance normally observed during hypoxic ventilation. Although nitroprusside also diminished the hypoxic pressor response, the middle segment resistance still increased. This qualitative difference between the two agents was also evident when the pulmonary P-Q relationship was analyzed. PGI,, but not nitroprusside, ablated the increase in P,,,, observed with hypoxic ventilation. Neither vasodilator in these experiments affected venous admixture in these otherwise normal lungs. During control ventilation, alveolar PO, would not have stimulated HPV.29-” Although both nitroprussideZ7X32and PGI,28 minimized HPV, PGI, appears to more specifically antagonize the effects of hypoxia. This suggests that in the clinical setting, PGI, vasodilation might result in worsened systemic oxygenation due to more effective prevention of HPV. Specific Effects of Vasoconstrictors We chose doses of both vasoconstrictors sufficient to decrease pulmonary blood flow by at least 25%. Our results during normoxic ventilation confirm that norepinephrine and PGE, increase PVR primarily by increasing venous segment resistance.‘3333334 In contrast to Murray et al,35 we were unable to demonstrate any significant increase in the incremental resistance with vasoconstriction. In our experiments, P GRIT tended to increase during control ventilation in the presence of both vasoconstrictors. Similar results have been demonstrated in experiments more analogous to ours using various vasoconstrictors, including PGF,, PGE,, and angiotensin II.29,36 During hypoxic ventilation,
ET AL
there were no further increases in total resistance or in any of the segmental resistances, suggesting that the vasculature was maximally constricted. However, individual components of resistance were not maximal; ie, middle segment resistance during hypoxic ventilation without the drugs was higher than middle segment resistance with the drugs. These findings suggest that an increase in downstream venous resistance prevents the increase in middle resistance associated with hypoxic ventilation. Changing the vascular compliance with the drugs might change the physical locus of the vascular segments. In effect, the venous segment might engulf the part of the middle segment that usually responds to hypoxia. This, however, does not explain why the region of vasculature cannot constrict with hypoxia, it merely shifts the lack of response to the venous segment. It is more likely that the pulmonary vasculature autoregulates to some extent and that in the face of a vasoconstricting stimulus, increased vasodilators are released. This is suggested by the findings that after cyclooxygenase blockade and inhibition of the prostaglandin vasodilator (PGI,), vasoconstrictors further augment HPV.* We have also previously described the release of vasodilating prostaglandins in response to a hypoxic stimulus.“’ In the clinical setting, if hypoxic vasoconstriction is maintaining systemic oxygenation, then the addition of a vasoconstrictor to augment systemic blood pressure may worsen oxygenation by the loss of regional HPV. In conclusion, we found that PGI, ablates HPV, whereas nitroprusside is only a partial inhibitor. Vasoconstrictors may also effect HPV by nonspecifically increasing vascular tone and preventing the localized regional pressor effect of hypoxia. ACKNOWLEDGMENT The authors thank the expert secretarial assistance of Kathleen Brown and the expert technical assistance of Terry Eckersley and Dumitru Lucaciu.
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135 21. Feldman HA: Families of lines: Random effects in linear regression analysis. J Appl Physiol64:1721-1732,1988 22. Graham R, Skoog C, Oppenheimer L. et al: Critical closure in canine pulmonary vasculature. Circ Res 50:566572, 1982 23. Townsley MI, Korthus RJ, Taylor AE: Effects of arachidonate on permeability and resistance distribution in canine lungs. J Appl Physiol58:206-210, 1985 24. Brimioulle S, Lejeune P, Vachiery JL, et al: Effects of acidosis and alkalosis on hypoxic pulmonary vasoconstriction in dogs. Am J Physiol258:347-353, 1990 25. Wang CG, Hakim RS, Michel RP, et al: Segmental pulmonary vascular resistance in progressive hydrostatic and permeability edema. J Appl Physiol59:242-254, 1985 26. Bjertnaes LJ: Hypoxia induced vasoconstriction in isolated perfused lungs exposed to injectable or inhalational anaesthetics. Acta Anaesthesiol Stand 21:133-147, 1977 27. Kadowitz PJ, Nandiwada P, Gruetter CA, et al: Pulmonary vasodilator responses to nitroprusside and nitroglycerin in the dog. J Clin Invest 67:893-902, 1981 28. Colley PS, Cheney FW, Hlastala MP: Ventilationperfusion and gas exchange effects of sodium nitroprusside in dogs with normal and edematous lungs. Anesthesiology 50:489-495,1979 29. Gerber JG, Voelkel N, Nies AS, et al: Moderation of hypoxic vasoconstriction by infused or arachidonic acid: Role of PGI,. J Appl Physiol49:107-112, 1980 30. Naeije R, Melot C, Mols P, et al: Effects of vasodilators on hypoxic pulmonary vasoconstriction in normal man. Chest 82:404-409,tYEZ 31. Voelkel NF: Mechanisms of hypoxic pulmonary vasoconstriction. Am Rev Respir Dis 133:1186-l 195, 1986 32. Bixler TJ, Gott VL, Garchren TJ: Reversal of experimental pulmonary hypertension with sodium nitroprusside. J Thorac Cardiovasc Surg 81:537-545, 1981 33. Dawson CA: Role of pulmonary vasomotion in physiology of the lung. Physiol Rev 64:544-616, 1984 34. Kadowitz PJ, Joiner PD, Hyman AL: Effect of prostaglandin E, in pulmonary vascular resistance on intact dog. swine and lamb. Eur J Pharmacol31:72-80, 1975 35. Murray PA, Lodato RF, Michael JR: Neural antagonists modulate pulmonary pressure-flow plots in conscious dogs. J Appl Physiol60:1900-1907, 1986 36. Harabiu AL, Peake MD, Sylvester JT: Effect of severe hypoxia in the pulmonary vascular response to vasoconstrictor agents. J Appl Physiol50:561-565, 1981 37. Johnson D, Mayers I, Hurst T: Halothane inhibits hypoxic pulmonary vasoconstriction in the presence of cycle-oxygenase blockade. Can J Anaesth 37287.295. 1990