Ventricular interaction in a canine model of acute pulmonary hypertension and its modulation by vasoactive drugs

Ventricular Interaction in a Canine Model of Acute Pulmonary Hypertension and its Modulation by Vasoactive Drugs James

E. Calvin,

Jr, Stephanie

Langlois,

and

Glenn

Garneys

To determine the effect of a pulmonary glass bead embolism (GBE) upon left ventricular filling, we studied 13 dogs (seven with pericardium open, six with pericardium closed) before and after embolizing the pulmonary artery with sufficient glass beads to triple the pulmonary artery pressure. Furthermore, we examined the nature of the ventricular interaction and the effect upon hemodynamics created by intravenous nitroglycerin, dobutamine and hydralazine. Each dog was implanted with segment length crystals directed in the septal free wall plane of both ventricles, Millar catheters (Millar, Houston) placed in the right ventricle, left ventricle, and pulmonary artery (PA), and a thermodilution catheter placed in the PA. GBE reduced left ventricular end diastolic length (LVEDL) and stroke work, and shifted the left ventricular diastolic pressure-segment relationship

(LVDPSR) upwards. The presence of a pericardium had little effect on the biventricular response to any of the test interventions. Nitroglycerin reduced right ventricular end diastolic length (RVEDL) and shifted the LVDPSR downwards. It did not increase LVEDL. Dobutamine increased left ventricular stroke work (LVSW) without altering LVEDL or the LVDPSR. Hydralazine did not change LVEDL, LVSW or shift LVDPSR. We conclude that GBE depresses left ventricular function by the Frank Starling mechanism and shifts the LVDPSR upwards. Because pericardiectomy did not prevent the decrease in LVEDL mediated by GBE. and nitroglycerin did not increase LVEDL despite decreasing RVEDL, a series interaction must dominate.

AINTENANCE of normal circulatory homeostasis depends upon an adequate stroke output from both ventricles in response to changes in their respective loading conditions. The anatomical arrangement of both chambers inside the pericardium dictates that the loading conditions of one ventricle can influence the passive filling of the other.‘** Specifically, in both isolated heart preparations and in animal models,‘*‘* loading the right ventricle with either volume expansion or pulmonary artery constriction shifts the left ventricular diastolic pressurevolume relationship upwards such that the ventricle behaves as if it were stiff. This results in elevated left ventricular filling pressures although left ventricular volumes may be normal or decreased. It has been suggested that similar shifts in the left ventricular diastolic pressurevolume relationship occur when glass bead embolism (GBE), caused by a microvascular injury, complicates acute respiratory failure.13 However, this conclusion has been inferred by comparing pulmonary capillary wedge pressures and left ventricular end diastolic volumes derived by radionuclide angiography.13 Direct measurement of the left ventricular diastolic pressurevolume relationship has not been undertaken. Confirmation of these potential effects has particular relevance in patients with acute lung injuries complicated by pulmonary hypertension so that forward output and oxygen transport can be optimized.

In this study we sought to examine the effects of pulmonary GBE, a model that produces one form of microvascular injury, upon the left ventricular diastolic pressure-segment relationship (LVDPSR). Furthermore, we sought to determine if commonly used agents might further influence this relationship. Nitroglycerin, because of its capacity to decrease right ventricular preload, would be anticipated to shift the relationship downwards and could possibly enhance left ventricular filling.” Dobutamine as an inotropic drug could shift the relationship further upwards because of its influence on the heart’s viscoelastic properties, M-‘* or downwards because of its known effect of reducing right ventricular filling pressure.” Because hydralazine has been shown in other models of acute pulmonary hypertension*’ to increase cardiac output and decrease pulmonary vascular resistance, we sought to determine if hydralazine might also shift left

M

Journal

of Crirical

Care, Vol 3 No 1 (March),

1988:

pp 43-55

0 1988 by Grune & Stratton,

Inc.

From the Ontario Heart and Stroke University of Ottawa Heart Institute. Supported by Medical Research 8141. Presented as recipient of the Young the Society of Critical Care Medicine in Washington DC, May 29, 1986. Address reprint requests to James sity of Ottawa Heart Institute. Ottawa Carling Avenue, Ottawa, Ontario, KI o I988 by Grune & Stratton, Inc. 0883-9441/88/0301-0006$05.00/0

Foundation and the Ottawa, Canada. Counril Grant #MAInvestigator Award of Annual Meetings, held E. Calvin, Jr, UniverCivic Hospital, 1053 Y 4E9. Canada.

43

44

CALVIN,

ventricular diastolic pressure-volume relationship. Finally, by studying two groups of dogs, one with the pericardium open and one with it closed, we anticipated being able to determine the pericardium’s role in the anticipated decrease in left ventricular preload secondary to GBE.” If the decrease in left ventricular preload observed with GBE was mediated by direct competition between both ventricles for space within the pericardium, we would anticipate that the injection of emboli would not decrease left ventricular preload if the pericardium was open. However, if a decrease in left ventricular preload was observed with the pericardium open, the decrease must be on the basis of a decreased left ventricular input secondary to decreased right ventricular output series effect. MATERIALS

AND

METHODS

Anesthesia and Ventilation Thirteen mongrel dogs were studied after premeditation with diphenhydramine hydrochloride (Benadryl) (4 mg/kg) and morphine (2 mg/kg), and anesthetized with a combination of chloralose (50 mg/kg IV) and morphine (2 mg/kg) as previously described.‘2*‘4 The dogs were ventilated with a Harvard model 607 volume cycled animal respirator (Ealing Scientific, Millis, MA) using 100% oxygen, as initial respiratory rate of 18 breaths per minute, and a tidal volume of 350 mL. The arterial oxygen saturation never fell below 85% and the PCO, was adjusted by increasing the respirator rate to keep it in a physiological range. If mild metabolic acidosis was observed, it was treated with bicarbonate to maintain the pH above 7.35.

Surgical Instrumentation We exposed the heart through a left lateral thoracotomy. To determine the influence of the pericardium upon both ventricles’ response to GBE, we studied seven dogs with their hearts outside the pericardium and six dogs with their hearts inside the pericardium. In the first set, we opened the pericardium widely and rested the heart in a pericardial cradle. In the second group, we cut the pericardium vertically across the origin of the great vessels for a length extending from 1 cm superior to the aorta to 2 cm below the inferior margin of the left atria1 appendage. This procedure allowed us to instrument the heart while leaving most of the pericardial sac intact. After instrumenting the heart (as described below), we returned it back into the pericardial sac and loosely sutured the incision from its inferior margin to the level of the inferior border of the great vessels.” We instrumented all hearts with two pairs of piezo-electric crystals inserted directly into the mid-walls of both ventricles. The ventricular crystals were directed along the septal-free wall plane with one of each pair of the crystals imbedded near the septum beside the left anterior descending artery, just

LANGLOIS.

AND

GARNEYS

below the first diagonal branch. The other one of each pair was imbedded on the respective ventricle approximately 1.5 cm from its mate. In this way, changes in the septal-free wall dimensions that are the most sensitive to changes that develop when acute pulmonary hypertension occurss”‘could be inferred from segment length changes. The crystals were driven electrically by a four-channel sonomicrometer (Triton Corporation, model 120, San Diego, Calif). We advanced a 7F Millar microtipped pressure transducer (Millar Instruments Co. model PC480 Houston, Tex) into the pulmonary artery through a stab wound in the right ventricular outflow tract. Similar pressure transducers were advanced into the right and left ventricles from cutdowns on the right external jugular vein and carotid artery, respectively. In the dogs with a resutured pericardium, we made the stab wound through a 4 mm slit in the pericardium. We attached all pressure transducers to a Validyne model CD19 solid state bridge amplifiers (Validyne Engineering, Northridge, CA) as previously described.‘2,‘4 Ventricular and pulmonary artery pressure signals were recorded and digitized directly at a rate of 200 samples onto an Apple Ile computer using an 8 channel analog to digital converter (A2 Devices, Alameda, Calif). Aortic pressure was recorded directly on paper using a Gould TA-600 thermal array recorder (Gould, Cleveland). In the seven experiments where the pericardium was left open, the segment length signals were recorded on paper. In the six experiments where the pericardium was closed, the segment length signals were digitized directly onto the computer. Routine hemodynamic variables including pulmonary artery pressure, left and right ventricular end diastolic and peak systolic pressures, and right ventricular end systolic pressures were obtained from the digitized data and the aortic pressure was obtained from the paper chart. Right ventricular end systole was taken at the time of the pulmonary artery incisura. Average values were obtained over ten seconds of recording for each intervention and used for subsequent analysis. Flow-derived stroke work, systemic vascular, and pulmonary vascular resistance were calculated using standard formulae.12 Arterial and mixed venous PO, were also obtained for each intervention.

Protocol Each experiment was commenced 15 to 20 minutes after the surgical instrumentation had been completed. All recordings were made over ten seconds during a held-end expiration at which time the ventilator was restarted. After baseline values had been obtained, 3 to 10 gm of 150 micron glass beads (Sigma Co., St. Louis, MO) were injected in serial doses sufficient to at least triple the pulmonary diastolic pressure and increase the heart rate by 20%. These end points were chosen from our previous experiments’2.‘4 which showed that this corresponded to a moderate lung injury that was stable enough to allow repeated measurements. Measurements were repeated at this end point. Each drug was infused until at least one of the following end points was reached (1) 30% increase in cardiac output; (2) 30% increase in heart rate; (3) 30% decrease in blood pressure.

VENTRICULAR

INTERACTION

45

First, an intravenous infusion of nitroglycerin was begun and titrated over several minutes. In general, the heart rate criterion was obtained first at an average dose of 200 mcg/min. Measurements were then obtained, and the infusion was subsequently stopped. After 15 to 20 minutes another control measurement (Cl) was obtained. At this point an intravenous infusion of dobutamine was begun at an average dose of 5 mcg/kg/min which was sufficient to meet the above described hemodynamic endpoints. The infusion was then stopped and a further control measurement (C2) was obtained after 15 to 20 minutes before starting an infusion of intravenous hydralazine (average dose 5 mcg/ kg/min). After meeting the above endpoints, the final measurements were made. Hydralazine was always given last because of its prolonged effects. In one experiment dobutamine was given first.

Statistical

(where the independent variable equals one if present; it is equal to zero if absent) of any of the test variables. Heart rate was included to determine the influence of any reflex changes in contractility. Diastolic function was analysed using the diastolic portions of at least two beats. The data was fitted to a multiple linear regression model similar to that previously described by Glantz6.z2 where left ventricular pressure is the dependent variable and the independent variables include right ventricular diastolic pressure, left ventricular diastolic segment length, heart rate, and the presence of any of the test conditions such that LVP

+ b X,G) where LVEDL, dobutamine; H, and b, regression This regression stroke work upon this relationship

+ bwm

+ b, &I(:)

&.VEDL + br+ Xr.d:) + bm XHR

end diastolic length; N, nitroglycerin; D, hydralazine; HR, heart rate; a,, intercept; coefficient. model describes the basic dependence of LVEDL (preload) and determines whether is significantly altered by the presence Table

PaDP (mmHg) B GEE

1. Pooled

Hemodynamic

+ b,, X,,

RESULTS

Pericardial Infruence

Summary statistics are shown in Table 1 and Table 2 and are expressed as mean t standard

and Blood

Gas Results

co ( 1 /min)

of All 13 Experiments

PVR (dynes _ set = cm 7

SVR (dynes = set = cm-7

HR

MAP (mmHg)

sv Iml)

11 *3 32 t 11

88 + 21 133-t23

96 r 13 89i 16

32 + 6 26 + 8

2.85 3.28

t .?4 + .97

171 f 81 645 + 296

3099 2315

N Cl D

28 + 11 25 k 9 27 -t 8

149+24 121 * 25 130 zk 48

77 * 18 9Ok 16 99-t 15

23 r 5 27 + 5 35 + 9

3.41 3.17 4.39

+ .97 t .64 + 1.42

535 452 407

k 282 + 243 t 223

c2 H ANOVA

22 i- 7 24 i: 8

116 t 23 162 t 20

89 +- 19 78? 16

25 + 5 25 + 5

2.97 4.01

* .66 k 1.15

423 392

+ 162 + 183

A.B.E

AD

Arc

B.C.D

Abbreviations: 8, baseline; hydralazine; PaDP, pulmonary

+ b hr Xhr

XN + b D XI, + b, .&I

where LVP, left ventricular pressure; aor intercept; b, regression coefficient; rvp, right ventricular pressure; Iv, left ventricular diastolic segment length; hr, heart rate; GBE, glass bead embolism; N, nitroglycerin; D, dobutamine; and H, hydralazine. The value of each of the intervention variables was zero if the intervention was absent and one if it were present, such that the amount of shifting of the left ventricular diastolic pressure-segment length relationship attributable to an intervention equals the amount of its regression coefficient. Because a test intervention might affect left ventricular compliance by its concommitant effects upon right ventricular diastolic pressure, the regression was also performed without including right ventricular pressure as a dependent variable. This allowed us to determine whether interventions had direct effects upon the left ventricular pressure-segment length relationship. In two animals the atria were paced during baseline and after GBE at a rate of 150 beats/min. This allowed an independent analysis of the effects of heart rate.

Analysis

= a, + bCsE Xo&

X,,

+ boss XGBE + h

Average values were obtained for each intervention and were used for subsequent statistical analysis. A two-way analysis of variance was performed initially, to determine the influence of the pericardium on each variable. A repeated measures one-way analysis of variance was then used to determine if there was a significant difference among the set of seven measurements that were obtained. A NewmanKeuls test was then applied to determine among which groups the differences occurred. The influence of test conditions upon left ventricular function was analysed using a forward stepwise multiple linear regression model, such that LVSW was the dependent variable and was influenced by independent variables such that LVSW

= a, + b,,

CD

A.E

PaO, (T0rr)

pa2 (Twrl

+ 1136 k 789

343 + 108 116 + 77

55 + 4 48 ? 10

2273 2567 2362

+ 816 t 648 i 717

89 i 56 83 + 37 94 k 46

45 + 5 44 t 6 52 t 9

2739 1962

+ 690 5 439

78 t 19 103 t 30

45 r 5 53 i 11

A.C.D

CD

A.D

Cl, control; N, nitroglycerin; C2, control after nitroglycerin; D, dobutamine; C3, control after dobutamine; H, artery diastolic pressure: HR. heart rate: MAP, mean artery pressure: SV, stroke volume; CO, cardiac output;

PVR, pulmonary vascular resistance: SVR, systemic vascular resistance. ANOVA, analysis of variance results where: A, a significant difference between GBE and control, P < .05; B, a significant difference between Nitroglycerin and GEE, P < .05; C, a significant difference between Dobutamine and Cl, P < .05; D, a significant difference between Hydralazine and C2, P < .05; E, a significant difference between GBE and either

Cl or C2. P < .05.

46

CALVIN,

Table LVEDL

(mm)

2.

Ventricular

Function

Results

(Pooled

Results,

LANGLOIS,

AND

GARNEYS

n = 13)

LVEDP lmmklg)

LVSW

RVEDL

RVEDP

RVSW

RVESP

(am-m)

lmml

(mm)

(gm-m)

lmml

(mm)

12 + 3

57 * 13

15.1

* 4.4

6+1

16 f 7

42+ 17 36 + 13 45 2 12 73 + 23

15.9 14.8 15.2

+ 4.6 k 4.5 + 4.2

9c3 7+1 7+2

12 k 3.1 13.1 + 3.5

15.1

+ 3.8

8?4

42 t 13 45 + 20

14.7

+ 4.1

9?5

14.2

z+ 3.7 8

B GBE

12.3

r 4.1

11.7

f 4.1

12 + 3

N Cl

11.5 12.0

+ 3.8 + 3.9

10 + 3 11 k3

D

12.1

k 3.9

13 k 3

c2 H ANOVA

11.9 11.7

+ 3.9 + 3.9 A

11+3 11+2 B

AC

9 + 10

4.2 8.6

+ 1.3 + 3.1

7.6 7.9 11.8

k 3.2 + 3.1 + 5.6

6.2 7.5

k 3.7 * 4.3 AS

36 t

16

RVESL

31 + 15 27 f 14

12.1 12.5

40 k 21 23 + 8

11.6 12.3

28k

12.1

13

k 3.4 + 3.5 k 3.0 + 3.1 * 3.3

A.8

AC

Abbreviations: 8, baseline; GBE, glass bead embolism; N. nitroglycerin; Cl, control; C2, control after nitroglycerin; D, dobutamine; H, hydralazine; RVEDL, right ventricular end diastolic length, RVEDP = right ventricular end diastolic pressure; RVESL = right ventricular end systolic length, RVESP = right ventricular end systolic pressure. ANOVA, analysis of variance results where A, a significant difference between GBE and control, P < .05; 8, a significant difference between P < .05; D, a significant difference between H and C2, P -c .05.

deviation. Two-way analysis of variance revealed that the presence or absence of the pericardium did not have any effect upon the hemodynamic variables. Hence, the results are pooled from all 13 experiments. The pericardium’s lack of a role in modulating any interaction between the two ventricular chambers is demonstrated by the fact that GBE increased right ventricular end diastolic segment length 7% in dogs with and 4% (P not significant) in dogs without a pericardium, and decreased left ventricular end diastolic length 4% with and 6% (P not significant) without a pericardium. Furthermore, stroke volume decreased to 81% of baseline in dogs with and 86% of baseline values in dogs without a pericardium (P not significant). The degree of injury was similar in both groups as the pulmonary diastolic pressure after embolization and before drug interventions was identical (3 1 + 14 mmHg with and 32 + 7 mmHg without pericardium). Efects of GBE

Glass bead embolism increased pulmonary diastolic pressure to 300% of baseline values initially, and decreased arterial oxygen saturation to 30% of baseline values (Table 1). The pulmonary diastolic pressure decreased to 200% of the baseline values during each of the control periods prior to dobutamine and hydralazine (Cl and C2, respectively). Despite this increase in pulmonary diastolic pressure, cardiac output and mean arterial blood pressure did not change. Stroke volume decreased to 8 1% of baseline values (P < .05) after GBE, but was compensated for by an increase in heart rate to 15 1% of

N and GBE, P < .05; C, a significant

difference

between

D and Cl,

baseline. Pulmonary vascular resistance increased to 400% of baseline initially. There was a significant decrease in pulmonary vascular resistance in each of the subsequent control periods (Cl and C2), but pulmonary vascular resistance still remained 200% above baseline in each of the subsequent control periods. Glass bead embolism doubled right ventricular end systolic pressure (Table 2). Glass bead embolism doubled right ventricular stroke work (RVSW) (P < .05) (Table 2) and it remained elevated for each of the subsequent control periods. Glass bead embolism also increased right ventricular end diastolic length (RVEDL) slightly but this was not significant (Table 2). However, it did increase right ventricular end systolic length (P < .05) although this effect was not sustained in the control periods. In contrast, GBE reduced left ventricular stroke work (LVSW) to 73% of baseline and this effect was maintained in the control periods (Table 2). It also decreased LVEDL. Hence, left ventricular performance was decreased largely by a preload mediated mechanism. The dependence of LVSW upon left ventricular preload is again emphasized in both Fig 1 and Table 3. Fig 1 demonstrates the relationship between LVSW and LVEDL in one of our experiments. In general, the relationship is linear although dobutamine appears to increase LVSW independent of preload. In Table 3, multiple linear regression analysis of data from all experiments again confirms the dependence of LVSW upon preload in all experiments, but also demonstrates a slight negative effect exerted by GBE upon LVSW in

VENTRICULAR

47

INTERACTION

.D .D

7c

$1

;i

cardiac output to 138% of C 1 values largely by increasing stroke volume 130% of Cl values (P < .05). Dobutamine increased arterial oxygen tension to 113% of Cl and mixed venous arterial oxygen tension to 118% of C 1 values. It did not change RVEDL but it decreased end systolic length 7% (P < .07) and increased RVSW to 150% of Cl values (Fig 1). It did not change LVEDL, but increased LVSW to 162% of Cl values (Table 2). Table 3 again confirms that dobutamine had a significant positive effect upon LVSW independent of any preload change. The Efects of Hydralazine

Fig 1. The relationship between the LVSW from one experiment. In general, the relationship one. Dobutamine shifts the relationship upwards.

and LVEDL is a linear

Compared to its control, hydralazine did not change pulmonary diastolic pressure or pulmonary vascular resistance (Table 1). However, it did increase cardiac output to 135% of C2 values, and heart rate to 139% of C2 values. It did not change stroke volume. The increase in cardiac output was associated with a 30% reduction in systemic vascular resistance (P < .05) and 12% reduction in mean arterial blood pressure (P < .05). Furthermore, hydralazine increased arterial oxygen tension to 125% of C2 values and mixed venous oxygen tension to 118%. Compared to C2, hydralazine did not change either RVEDL or end systolic length or RVSW (Table 2). Finally, hydralazine did not change LVEDL or LVSW (Table 2).

addition to the observed effect mediated by a decrease in left ventricular preload. Heart rate had little effect upon this relationship. Eflects of Nitroglycerin

Nitroglycerin decreased pulmonary diastolic pressure and pulmonary vascular resistance slightly but did not change cardiac output, or arterial oxygen tension (Table 1). It reduced RVEDL and end systolic length (Table 2), consistent with its venodilator effects but did not change RVSW (Table 2). It had no effect upon LVEDL or LVSW although it decreased both right and left ventricular end diastolic pressure compared to the values obtained after GBE (Table 2).

Diastolic Function After Glass Bead Embolism and Its Modulation by Drug Therapy

Glass bead embolism increased right ventricular end diastolic pressure by 3 mmHg compared to baseline values (Table 2, P < .05 for closed pericardia experiments). Of the drugs tested, only nitroglycerin decreased right ventricular end diastolic pressure (Table 2) although this effect was small. Nitroglycerin also decreased left ventricular end diastolic pressure.

The Effects of Dobutamine

Dobutamine did not change pulmonary diastolic pressure or pulmonary vascular resistance (Table 1). It increased right ventricular end systolic pressure 150% of its control (C2), and mean arterial blood pressure (110% of Cl values P < .05, Table 2). Furthermore, it increased Table Equation

LVSW

Regression

GEE

.06 - 10.94’

A R2

Coefficient SE constant Multiple

3.

Analysis N

.Ol

5.17

(pooled

data, D

.27 29.56 b

n = 91 J H

HR

-

-

LVEDL

.ll 1.74b

-

4.73

.43

39.70 R

.66

Abbreviations: A R*, amount of total variance explained a, P < .05, coefficient >O; b. P < ,001, coefficient >O.

by the variable;

N, nitroglycerin;

D, dobutamine;

Ii, hydralazine;

HR. heart rate;

48

CALVIN,

52.5

-

Control

.........’

Pulmonary Hypertensmn

LANGLOIS,

AND

GARNEYS

- - -. Nitroglycerrne - - - Dobutamme

Y -5 0 5 z 2 P

-.-.-

Hvdralazme

30.0 22.5 15.0

8.0

8.5

9.0

9.5

LV Segment

Figure 2 demonstrates a family of left ventricular diastolic pressure-segment length curves for one of the experiments. Glass bead embolism shifted the curve upwards and to the left compared to baseline. This pattern was observed in five of the six dogs in whom it was studied (intact pericardium). None of the drugs significantly shifted the curve or changed its slope in this example. Furthermore, no drug was able to restore LVEDL to preembolization values. Multivariate analysis on all dogs confirmed these observations. The results are summarized in Tables 4 and 5. The right ventricular diastolic pressure was responsible for the majority of the explained variance of left ventricular diastolic pressure (50-86%) which is similar to results previously reported6*” (Table 3). Left ventricular Table

4.

Multivariate

10.0

10.5

Length(mm)

Analysis

of Left

Fig 2. Left ventricular diastolic pressure-segment length relationship during GEE in one experiment. Glass bead embolism shifts the relationship upwards and to the left. None of the drugs used shifted the relationship to pre-GBE values and none of the drugs restored left ventricular end diastolic segment length to control values.

segment length explained only a small portion of the variance (0% to 12%). Both of these dependent variables had regression coefficients (b,, = .69 + .37,P< .005andb,, = 3.32 + 3.17, P -C .OS) greater than zero. The addition of an extra geometry term (the second power of left ventricular segment length) did not explain the variance any further. Because of this observation and the high correlation it had with the first power of left ventricular segment length, the second power was discarded from further analysis. Heart rate was not an important variable. It explained 0% to 2% of the variance (mean 0.6%) and did not have a significant regression coefficient in any of the experiments. Hence, it was dropped for analysis. As shown in Fig 3, even at controlled heart rates, a significant shift upwards Ventricular

Pressure-Segment

Relationship

R’ Explained by Independent Variables Experiment

n

Total R’ %

RVP

LV Segment Length

1 2 3

257 221 294

81 81 67

54 c.27) 53 (.99) 50 c.3 1)

2 (2.04) 11 (5.05) 12 (9.00)

4 5 6

291 317 392

88 94 70

81 t.92) 86 C.12) 56 t.54)

0 (.66) l(1.17) 8 (1.99)

ii

.69

3.32

1.33

SD P

.37 .05

3.17 .Ol

3.35 NS

Numbers in parentheses represent coefficients. Abbreviations: N, nitroglycerin: D. dobutamine;

GBE 14 (6.50) 16 (2.77) 4 (3.11) 1 l.49) 4 (- 1.5) 2 (2.16)

Absence of numbers indicates that H, hydralazine; RVP, right ventricular

N 1 (&1.12) 0 (-) 1 c--j 5 (1.29) l(1.07) 2 (-1.80)

D 7 t.931 0 (.88)

3 t-1 1 (- 1.02)

0 (-) 0 (-) 0 t.551 O(-1.11)

0 1 2 2

~ .09 1.20

.21 .76

NS

NS

regression coefficients pressure.

ii

% refers

are not different to the coefficients.

t-1 t.52) (1.93) (- 1.33) ,017 1.17 NS from

zero.

VENTRICULAR

Table

5.

INTERACTION

Multivariate

49

Analysis

of Left

Ventricular

Pressure

is Excluded

Segment

Relation

as an Independent

When

Right

Ventricular

Diastolic

Pressure

Variable

R2 Explained by Independent Variables Total R’ %

Experiment

LV Segment Length

14 (7.27) l(1.02)

5 I- 1.54) l (-1.07)

55 69

44 (11.85) 47 (2.74)

11 (5.24) 13 (2.93)

0 (-) 6 (-1.61)

71 62

61 (4.49) 52 (3.23)

1 (- 1.48) 4 (2.82)

5.76 4.06

P

represent

N, Nitroglycerin:

coefficients. D, Dobutamine;

0 I.811 3 t-2.60)

2.97 3.07 .05

.02 in parentheses

Abbreviations:

N

2 (2.38) 41 (9.84)

x SD

Numbers

GBE

69 63

Absence

- 1.00 1.23 NS

of numbers

H, Hydralazine.

was observed after GBE in the two experiments where the atria were paced at 150 beats/min during both baseline and GBE. The other independent variables were responsible for only a small portion of the explained variance in any individual experiment, and none had significant regression coefficients when results were summarized for all experiments. This suggests that any shifts that were observed during pulmonary hypertension were explained by changes in right ventricular loading conditions. When right ventricular diastolic pressure was excluded as an independent variable (Table 4) the dependence of left ventricular diastolic pressure upon left ventricular diastolic segment length was evident (regression coefficient = 5.76 -+ 4.06, P < .02). However, GBE shifted this relationship upwards in five of the six dogs

Fig 3. The left ventricular diastolic pressure-segment length relationship during acute pulmonary hypertension in one experiment. Ventricular pacing allowed the relationship to be compared to the baseline relationship at a fixed heart rate.

indicates

2 refers

that regression

D

H

48 (1.60)

0 (-)

0 (-) 0 (6)

20 t-5.80) O(b)

l(G) 7 (2.61) 2 I-- 1.7)

2 (p.70) 2 (1.98) l(-1.38)

.51 1.84 NS coefficients

-.75 2.70 NS are not different

from

zero.

to the coefficients,

by a mean value of 3 mmHg. Interestingly, the mean increase in right ventricular end diastolic pressure in the closed pericardia experiments after GBE was also 3 mmHg. Nitroglycerin created very small effects shifting the curve downwards in four of the six dogs by a mean value of 1 mmHg. Neither dobutamine nor hydralazine had any consistent effects. Dobutamine shifted the curve upwards in two, downwards in one, and had no effect in three dogs. Hydralazine shifted the curve downwards in two, upwards in two, and had no effect in two dogs. DISCUSSION

Several investigators’-” have reported significant ventricular interactions during acute pulmonary hypertension and have suggested its importance in explaining the disturbed left ventricular function that is sometimes associated with pulmonary hypertension. Pulmonary hypertension has usually been modelled by banding the pulmonary artery. However, this type of injury is not representative of the injury occurring in the microvasculature with acute respiratory failure.14 We have previously looked at the left ventricular diastolic pressure volume relationship after GBE, a model of acute pulmonary microvascular injury that has a different vascular load from pulmonary artery constriction.‘3 It is also associated with pulmonary edema, making it physiologically more similar to acute respiratory failure. In our first report, we determined that GBE decreased left ventricular preload and stroke work independent of heart rate changes.” We also compared, in our first report, the dia-

50

stolic pressure-area relationship at different levels of right ventricular preload during both normal conditions and after GBE. Multiple linear regression analysis determined the dependency of left ventricular diastolic pressure upon right ventricular pressure with very little independent effect from GBE. However, right ventricular diastolic pressure was constantly being altered by volume loading as part of the experimental protocol. As a result, the independent effects of the acute right ventricular pressure overload produced by GBE upon right diastolic pressure was not readily apparent. Furthermore, the influence of the pericardium on the heart’s response to pulmonary hypertension was not evaluated in this early study. Because the pericardium’s restraining effects create competition between both ventricles for space, its role also needed further elucidation. This present study then represents the first attempt in a model of pulmonary hypertension produced by a microvascular injury to characterize left ventricular diastolic function by analysing the left ventricular diastolic pressure-volume relationship directly. Our results confirm that during the modest elevation of pulmonary artery pressure observed in this model there was a decrease in left ventricular end diastolic segment length and stroke work as we previously observed. Furthermore, we demonstrated that the left ventricular diastolic pressure-segment length relationship shifted upwards by approximately 3 mmHg (increased left ventricular diastolic pressure for a given left ventricular diastolic volume), suggestive of impaired left ventricular diastolic function. In contrast to our previous study, we allowed right ventricular diastolic pressures to vary on their own in response to the altered afterload conditions. Hence, the results of this study reflect the normal response to acute pulmonary hypertension produced by GBE without the influence of external volume loading being superimposed upon the injury. These observations, attributable to GBE, are secondary to the combination of both a series interaction produced by decreased right ventricular stroke output, and a direct interaction produced by the competition of both ventricles for space within the confines of the pericardium. The former interaction (series) refers to the fact that the left ventricular input is composed of the right

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ventricular output. Should the stroke volume of the right ventricle decrease, left ventricular preload, as measured by left ventricular end diastolic pressure or left ventricular end diastolic volume, would also decrease because of decreased pulmonary venous return. This is best demonstrated by analysing the effects produced by occluding the vena cavae.9 Such a maneuver reduces both right ventricular size and output. As a result, left ventricular end diastolic volume, end diastolic pressure, and stroke output are reduced with all left ventricular end diastolic dimensions reduced symmetrically. In contrast, direct ventricular interaction is caused by the right ventricle dilating, and by so doing, shifting the interventricular septum leftwards’-” or by simply reducing the space available to the left ventricle with the pericardium.12 In contrast to a series interaction, this results in an increase in left ventricular end diastolic pressure. Both forms of interaction are present in this study. However, the relative importance of these two interactions can be inferred from two observations that we have made in this study. First, the pericardium had little influence on the left ventricular response to GBE. We found that the absence of a pericardium did not prevent the decrease in left ventricular preload and stroke work observed during GBE. This suggests the predominance of a series interaction over a direct interaction. If the latter were dominant, an open pericardium would have resulted in a smaller decrease in left ventricular preload caused by acute pulmonary hypertension, because the competition between both ventricles for the available space would have been removed (Fig 4). Hence, the series interaction appears to dominate, although a direct interaction mediated by the septum may still be present. However, this observation is made with the realization that in this study right ventricular filling pressures, although they had increased by 3 mmHg, were not excessively high when a direct interaction may have had more influence. Similarly, Molaug and his co-workers23 also found that the pericardium did not restrain the ventricles during selective pressure loading, because as one ventricle dilated, the other shrunk regardless of the presence of the pericardium. In their study, as well as ours, the relative increase in right ventricular size was matched by the decrease in left ventricular size,

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INTERACTION

Pedcardium

Anticipated

affect

Fig 4. The role of the pericardium during pulmonary hypertension induced by GEE. If direct compression of the left ventricle by the right ventricle (A) was the dominant mechanism of ventricular interaction during pulmonary hypertension, then prior removal of the pericardium should prevent the decrease in left ventricular size that does occur (B). In the present study, pulmonary hypertension decreased left ventricular size even when the pericardium wes absent suggesting that a series interaction must dominate.

suggesting that total pericardial volume did not increase during this degree of acute pressure overload of the right ventricle. Second, nitroglycerin decreased RVEDL and shifted the left ventricular pressure-segment length relation downwards in at least four of six dogs (approximately 1 mmHg). Although these two effects might have increased left ventricular preload by making more space available within the pericardium and by improving left ventricular diastolic function, they did not (Fig 5). This is most likely because right ventricular stroke volA. Pm-nitroglycerin

Fig 5. The significance of nitroglycerin in determining the dominant interaction between right ventricle and left ventricle. If the right ventricle compresses the left ventricle within the pericardium (A). then the decrease in right ventricular size observed with nitroglycerin should be accompanied by an increase in left ventricular size (6). Because the anticipated increase in left ventricular size did not occur when right ventricular sire decreased. a series interaction must dominate.

ume also fell secondary to decreased right ventricular preload (series effect). Again, both forms of interaction were present with nitroglycerin. However, the series effects upon stroke volume and biventricular preload outweighed the potential benefits of improved left ventricular diastolic function. Thus, it is apparent that series effects represent the major interaction between both ventricles in as much as flow is concerned. A direct effect or interaction between both ventricles appears to have more influence upon filling pressures. Determining the relative importance of the mechanism of ventricular interaction in this model is of more than academic interest. The observation that the series component is dominant has practical implications for therapy of such patients. Agents that act by primarily decreasing right ventricular preload by venodilatation will not necessarily increase left ventricular preload even though the left ventricular pressure volume relationship is shifted downwards. This is demonstrated in a study by Sibbald et al which found that isosorbide dinitrate (Isordil) did not improve oxygen transport in a group of 16 patients with acute hypoxemic respiratory failure24 despite lowering left ventricular filling pressures and right ventricular preload. Furthermore, our results suggest that pericardiectomy (removing the pericardium’s restraining effect) in such patients may not increase left ventricular filling, either, unless right ventricular stroke output also increases. Because in our study stroke output was not better maintained in those animals when the pericardium was left open, caution about the potential use of pericardiectomy as a treatment should be exercised. The fact that the left ventricular pressuresegment length relationship was shifted downwards by nitroglycerin does confirm a hemodynamic advantage, however. Subsequent volume loading should result in an increase in left ventricular preload and stroke volume without excessive elevation of left ventricular end diastolic pressure. Hence, volume loading in combination with nitroglycerin could be expected to increase cardiac output without increasing hydrostatic capillary pressures in the lung. Although nitroglycerin did, in fact, shift the left ventricular diastolic pressure-segment length relationship downwards, it decreased pulmonary

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vascular resistance insignificantly. Although nitroglycerin has been shown in some patients with pulmonary hypertension to decrease pulmonary vascular resistance,25 it has been shown to have variable results in another experimental model of microvascular injury. Pearl et al*‘j demonstrated a 43% reduction in pulmonary vascular resistance after oleic acid was infused in dogs. In the same model, Benoit et al*’ found an increase in pulmonary vascular resistance despite lowering both pulmonary artery pressure and arterial BP. In both of these experiments, the level of pulmonary vascular resistance after oleic acid infusion was less than that observed in this study, and cardiac output after oleic acid infusion decreased. In our study, pulmonary artery pressure was markedly elevated after GBE and decreased with nitroglycerin. However, cardiac output was elevated prior to the administration of nitroglycerin. This may partially explain why we did not observe a decrease in pulmonary vascular resistance with nitroglycerin. Dobutamine had very little effect on the diastolic pressure-segment length relationship. This is likely because dobutamine did not decrease right ventricular size and it did not change heart rate. The former effect would have shifted the pressure volume relationship downwards had it occurred. An increase in heart rate, if it had occurred, might have shifted the relationship upwards because the heart’s viscoelastic properties would have been affected by elevated filling rates.‘6-‘8 Dobutamine acted primarily as an inotropic agent in this model, as demonstrated by increased stroke work and end systolic pressure at similar end diastolic and end systolic lengths (Fig 6). It was the most successful of the three drugs at increasing stroke work, stroke volume, and cardiac output without changing either right or left ventricular preload. In addition, dobutamine had the beneficial effect of increasing both mixed venous and arterial oxygen tension. These last two effects are obviously important in the management of pulmonary hypertension in association with hypoxemic respiratory failure. Finally, it is likely that dobutamine did not increase left ventricular preload in our study because it also increased contractility of the left ventricle thereby increasing stroke volume by reducing left ventricular end systolic volume.

CALVIN,

lo

11

12

LANGLOIS,

13

RV SEGMENT (mm)

14

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15

LENGTH

Fig 6. Right ventricular pressure segment loops predobutamine and during dobutamine infusion based on mean values. Dobutemine results in an increased end systolic pressure and decreased end systolic length, suggesting an inotropic effect. l-1, dobutamine; I----). pre-dobutamine.

Therefore, enhancing preload reserve was not necessary as a compensatory mechanism to increase stroke volume. These results are similar to a recent report by Molloy et al who determined in eight patients with acute hypoxemic respiratory failure that dobutamine is an excellent inotropic drug that reduces filling pressures, increases cardiac output, and decreases heart volumes.** Our results with hydralazine were similar to Ghigone et al*’ except that it did not decrease pulmonary vascular resistance. It acted primarily as a systemic vasodilator in this study. The increase in cardiac output we observed was almost exclusively by increasing heart rate. One major difference between this study and those of Ghigone and others29-‘3 is that the cardiac output was not reduced prior to the administration of hydralazine in this study, and the pulmonary vascular resistance was not markedly elevated. Hence, the pulmonary vasodilator effects were somewhat blunted. Significant heart rate effects were observed in this study. In designing the protocol, we felt that allowing the heart rate to vary would provide insight into clinical situations because heart rate changes are often present. However, we attempted to assess heart rate effects by our statistical analysis. The main criticism of this approach is that heart rate effects could have mediated preload changes, enhanced contractili-

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ty, and shifted the left ventricular diastolic pressure-segment relationship upwards. We do agree that a heart rate effect could have contributed to the decrease in left ventricular preload and prevented an increase in right ventricular preload after GBE by limiting the time for the ventricles to fill. However, it should be pointed out that similar increases in heart rate are observed with patients with acute lung injuries and therefore allowing the rate to vary is clinically relevant. To determine if heart rate effects were mediating any reflex change in contractility, we included it in our multiple linear regression model for LVSW. Multiple linear regression analysis confirmed the dependence of LVSW upon left ventricular preload without any contribution from heart rate effects and failed to show any enhancement of contractility after GBE. This confirms our previous observations.‘* Because we observed that GBE had a slight negative inotropic effect overall (Table 4) (however, significant variability was observed between dogs) and decreased BP, it is much more likely that the heart rate effect was secondary to the decrease in LVEDL (relative hypovolemia) or depressed contractility, or both, rather than a primary mediator of the overall effects we have described. Although heart rate effects could also influence diastolic function by altering the filling rate, our analysis of the left ventricular diastolic pressure-segment length relationship took heart rate effects into consideration. In both our statistical analysis and by controlling heart rate by atria1 pacing in two dogs, we failed to reveal any significant effect upon left ventricular diastolic function by altering heart rate. It is possible heart rate effects could have offset shifts in this relationship produced by the direct action of the drugs tested. However, we believed that the net effect upon left ventricular diastolic function is the clinically relevant one, and this is what our results identified. It is clear that heart rate effects did not adversely affect left ventricular diastolic function and that the upward shift in the relationship after GBE was equivalent to the change in right ventricular end diastolic pressure, strongly suggesting the major mechanism for the shift was a ventricular interaction. The alterations in both lung function and pulmonary hemodynamics in this model cannot

53

be explained wholly on the basis of the vascular obstruction created by the beads themselves. Malik and Van der Zee34 have previously shown that the use of heparin, which inhibits pulmonary intravascular coagulation, prevents the pulmonary edema formation and impaired gas exchange observed after embolization, compared to untreated dogs. Furthermore, pretreatment with heparin increases the number of glass beads required to reach a given level of pulmonary artery pressure and pulmonary vascular resistance. Flick et a13’ also showed that depletion of white blood cells by either ethanine hydrochloride or colchicine inhibits the formation of pulmonary edema in sheep that are infused with glass beads. Both of these sets of data suggest that the injury created by glass bead infusion is more complex than just the obvious obstructive effects of the beads themselves and that humoral factors are important mediators for increased permeability and, to some extent, the increase in pulmonary vascular resistance. We have demonstrated in this experiment that there were no signs of deterioration throughout the experiment. Although arterial oxygen tension decreased significantly after the glass bead infusion, there was no further decrease observed in the control periods prior to the administration of drugs. Furthermore, cardiac output, stroke volume, and RVSW were well maintained in the control periods after embolization. The only significant change in the control periods after embolization was a significant decrease in the pulmonary vascular resistance and pulmonary artery diastolic pressure. This suggests that the model was not deteriorating, but improving. Although this spontaneous improvement suggests a reversible component, it does raise difficulties in interpreting the response to drugs. It was for this reason that effects attributable to any of the drugs were only reported when they occurred relative to the respective control period. During the intervening control periods, we demonstrated a return of heart rate and BP effects back to pre-drug levels. However, even with this caution, we cannot completely rule out drug interactions. The drugs could not be randomized primarily because hydralazine had to be given last because of its sustained effect. In one dog, dobutamine was given prior to nitroglycerin to determine whether the effects attributable to

54

CALVIN,

dobutamine and nitroglycerin were related to the order of their administration. In this dog the inotropic effects of dobutamine and vasodilator effects of nitroglycerin were confirmed. Previously we have demonstrated that this model simulates adult respiratory distress syndrome physiologically, since it results in a lung injury characterized by an increase in lung water measured by wet/dry weight ratios, an inflammatory response, reduced lung compliance, and pulmonary hypertension.14 For these reasons, it is useful to study the mechanisms of the lung injury and the ensuing interaction. However, it is a very unique model of microvascular injury because the degree of pulmonary hypertension is more severe than others.29*33Hence, caution should be expressed when extrapolating our results to the clinical situation, since it is an artificial model. The use of a single pair of segment-length crystals primarily measures regional ventricular function. Slinker and Glantz36 have recently analysed the use of dimension or segmental length crystals to estimate volume changes, and found their use satisfactory as long as high frequency information was not required. Their use introduces a source of error when used to calculate derivatives or filling rates. However, static dimensions or segment lengths are reliable estimates of volume. Present knowledge of left ventricular geometry during acute pulmonary hypertension’-” suggests that the septal-free wall minor axis is the dimension most sensitive to the volume changes that occur with right ventricular pressure overload. In fact, the base-apex dimension and anteroposterior dimension change minimally if at all. Hence, volume estimates are better correlated with changes in the septal-free wall dimension during right ventricular pressure overload. We have used a segment length directed specifically in the septal-free wall plan to estimate right and left ventricular volume changes. We have found that pulmonary hypertension produced GBE results in similar changes

LANGLOIS.

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GARNEYS

in left ventricular septal-free wall segment lengths as it does in septal-free wall dimensions.‘* In summary, our results have confirmed by direct measurement that shifts in left ventricular diastolic pressure-segment length relationships do occur with acute pulmonary hypertension induced by GBE. We have also confirmed that GBE decreases left ventricular preload as measured by end diastolic segment length. This results in an apparent depression of left ventricular function mostly on the basis of the FrankStarling mechanism. Therapy aimed at improving left ventricular filling (preload) and reducing left ventricular compliance would be useful. Of the drugs tested, only nitroglycerin improved left ventricular compliance but left ventricular preload did not increase as a result. This suggests that improving left ventricular compliance alone may not necessarily improve oxygen transport largely because of a series interaction between both ventricles. However, we speculate that volume loading in combination with nitroglycerin may increase left ventricular preload without excessively elevating pulmonary hydrostatic pressures. Hydralazine’s effects in this study were disappointing, but other studies do suggest it has a role in improving oxygen transport in patients with lung injuries. However, our study did not show any improvement in left ventricular compliance with hydralazine. In contrast, dobutamine improved stroke volume, cardiac output, and arterial oxygen tension by its inotropic effect. Therefore, despite the theoretical advantage of improving left ventricular distensibility with some vasodilators in this setting, it appears that inotropic agents as single agents may theoretically be more effective in improving oxygen transport in critically ill patients. ACKNOWLEDGMENTS The authors wish to thank Vera Temple and Keith Sheldrick for their technical assistance, and Teresa Wood for her typing assistance.

REFERENCES 1. Elzinga G, Van Grondelle R, Westerhoff NC, et al: Ventricular interference. Am J Physiol226:941-947, 1974 2. Janicki JS, Weber KT: Factors influencing the diastolic pressure-volume relation of the cardiac ventricles. Fed Proc 39:133-140, 1980 3. Taylor RR, Cove11 JW, Sonnenblick EH, et al: Dependence of ventricular distensibility on filling of the opposite ventricle. Am J Physiol 213:711-718, 1967

4. Kelly DT, Spotnitz HM, Beiser BD, et al: Effects of chronic right ventricular volume and pressure loading on left ventricular performance. Circulation 44:403-412, 1971 5. Bemis CE, Serur JR, Borkenhager D, et al: Influence of right ventricular filling pressure or left ventricular pressure and dimension. Circ Res 34:498-504, 1974 6. Glantz SA, Misbach GA, Moores WY, et al: The pericardium substantially affects the left ventricular diastolic

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pressure volume relationship in the dog. Circ Res 42:433-441, 1978 7. Stool WE, Mullins CB, Leshin SJ, et al: Dimensional changes of the left ventricle during acute pulmonary arterial hypertension in dogs. Am J Cardiol 33:868-875, 1974 8. Visner MS, Arentzen MJ, O’Connor EV, et al: Alterations in left ventricular three-dimensional geometry and systolic function during acute right ventricular hypertension in the conscious dog. Circulation 67:353-365, 1983 9. Olsen CO, Tyson GS, Maier GW, et al: Dynamic ventricular interaction in the conscious dog. Circ Res 52:85104, 1983 10. Badke FR: Left ventricular dimensions and function during right ventricular pressure overload. Am J Physiol 242:H61 l-618, 1982 Il. Kingma I, Tyberg JV, Smith ER, et al: Effects of diastolic transseptal pressure gradient on ventricular septal position and motion. Circ 68: 1304- 13 14, 1983 12. Calvin JE, Baer RW, Glantz SA: Pulmonary injury depresses cardiac systolic function through the Starling mechanism. Am J Physiol25l:H722-H733, 1986 13. Sibbald WJ, Driedger AA, Myers ML, et al: Biventricular function in the adult respiratory distress syndrome. Chest 84:126-134, 1983 14. Calvin JE, Baer RW, Glantz SA: Pulmonary artery constriction produces a greater right ventricular dynamic afterload than lung microvascular injury in the open chest dog. Circ Res 56:40-56, 1985 15. Ludbrook PA, Byrne JD, McKnight RC: Influence of right ventricular hemodynamics on left ventricular diastolic pressure-volume relations in man. Circ 59:21-31, 1979 16. Templeton GH, Wildenthal K, Willerson JT, et al: influence of acute myocardial depression on left ventricular stiffness and its elastic and viscous components. J Clin Invest 56:278-285, 1975 17. Rankin JS, Arentzen CE, Anderson RW, et al: Viscoelastic properties of the diastolic left ventricle in the conscious dog. Circ Res 41:37-45, 1977 18. Horowitz LD, Bishop VS: Left ventricular pressurediameter relationships in the conscious dog. Cardiovasc Res 6:163-171, 1972 19. Klein NA, Siskin SJ, Frishman WH, et al: Hemodynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure. Am J Cardiol 48: I70- 175, 198 I 20. Ghigone M, Girling L, Prewitt RM: Effects of hydralazine on cardiopulmonary function in canine low pressure pulmonary edema. Anesthesiology 59:187-190, 1983 21. Tyson GS, Maier GW, Olson CO, et al: Pericardial influences on ventricular filling in the conscious dog: An analysis based on pericardial pressure. Circ Res 54: 173- 184, 1984

55 22. Glantz SA: Computing indices of diastolic stiffness has been counter productive. Fed Proc 39: l62- 168, 1980 23. Molaug M, Stokland 0, Ilebekk A, et al: Myocardial function of the interventricular septum: Effects of right and left ventricular pressure loading before and after pericardiotomy in dogs. Circ Res 49:52-61, 1981 24. Sibbald WJ, Short AIK, Driedger AA, et al: The immediate effects of isosorbide dinitrate on right ventricular function in patients with acute hypoxemic respiratory failure: A combined invasive and radionuclide study. Am Rev Resp Dis 131:862-868, 1985 25. Pearl RG, Rosenthal MH, Schroeder JS, et al: Acute hemodynamic effects of nitroglycerin in pulmonary hypertension Ann Intern Med 99:9- 13, 1983 26. Pearl RG, Rosenthal MH, Ashton JPA: Pulmonary vasodilator effects of nitroglycerin and sodium nitroprusside in canine oleic acid-induced pulmonary hypertension. Anesthesiology 58:514-518, 1983 27. Benoit A, Ducas J, Girling L, et al: Acute cardiopulmonary effects of nitroglycerin in canine oleic acid pulmonary edema. Anesthesiology 62:754-758, 1985 28. Molloy DW, Ducas J, Dobson K, et al: Hemodynamic management in clinical acute hypoxemic respiratory failure: Dopamine vs Dobutamine. Chest 89:636-640, 1986 29. Rubin LJ, Handel F, Peter RH: The effects of oral hydralazine on right ventricular end diastolic pressure in patients with right ventricular failure. Circ 65:1369-l 373. 1982 30. Miller MJ, Chappell TR, Cook W, et al: Effects of oral hydralazine on gas exchange in patients with car pulmonale. Am J Med 75:937-942, 1983 31. Ducas J, Girling L, Schick U, et al: Pulmonary vascular effects of hydralazine in a canine model of pulmonary thromboembolism. Circ 73(5):1050-1057, 1986 32. Lee KY, Molloy DW, Slykerman L, et al: Effects of hydralazine and nitroprusside on cardiopulmonary function when a decrease in cardiac output complicates a short term increase in pulmonary vascular resistance. Circ 68(6):1299l303,1983 33. Packer M: Vasodilator therapy for primary pulmonary hypertension. Ann Int Med 103:258-270, 1985 34. Malik AB, Van Der Zee H: Mechanisms of pulmonary edema induced by microembolization in dogs. Circ Res 42172-79. 1978 35. Flick MR, Azriel P, Staub NC: Leukocytes are required for increased lung microvascular permeability after microembolization in sheep. Circ Res 48:344-35 I, 198 1 36. Slinker BK, Glantz SA: The accuracy of inferring left ventricular volume change from dimensions depends on the frequency of informtion needed to answer a given question. Circ Res 56:161-174, 1985