982
`
`JACC Vol. 243. No. 4 October M94982-8 MARC J. SEMIGRAN, MD, BAR B. TAYLOR THOMPSON, MD, WARREN M. MRHAEL A. FIFER, MD, FACC &tin,
`
`Mwsachusetls
`
`decreased witb nitreprussid I patient who did not have vascular resistance with nit of the 16 patients, incladia~ te dec~a~ In pM~rn~~a~ but did with nitric oxide, been used to identify patients at acceptable risk for transplan- tation, but the effectiveness of these agents in predicting the reversibility of pulmonary vasoconstriction is limited by their systemic hypotensive effects. Nitric oxide, an endothelium-derived relaxing factor (7) produced from L-arginine by endothelial nitric oxide syntbase (8) has an in viva half-life of 111 to 130 ms (9). Inhaled nitric oxide has been shown to reverse pulmonary vasoconstriction in hypoxic lambs (10) and pediatric patients with congenital heart disease complicated by pulmonary hypertension (11). In adults with pulmonary hypertension due to the adult respiratory distress syndrome, inhaled nitric oxide decreases pulmonary vascular resistance without altering systemic arterial pressure (l&13). It has been demonstrated that in patients with pulmo- nary vascular disease; inhaled nitric oxide also causes a reduc- tion in pulmonary vascular resistance (14,15), accompanied by an improvement in right ventricular performance, as indicated by an increase in stroke volume despite a decrease in right ventricular end-diastolic pressure (14). To assess the potential role of inhaled nitric oxide in identifying reversible pulmonary vasoconstriction in patients with severe heart failure referred for heart transplantation, we compared its effects on transpulmonary pressure gradient, pulmonary vascular resistance and systemic arterial pressure with those of intravenous nitroprusside.
`
`As heart transplantation has evolved as a treatment for refractory heart failure, it has been recognized that early postoperative right heart failure is a common occurrence associated with substantial morbidity and mortality (l-3). Elevations of transpulmonaty pressure gradient and pulmo- nary vascular resistance are common in patients with chronic left heart failure, and their persistence through the peritrans- ptantation period can lead to right ventricular failure, partic- ularly if prolonged ischemia has occurred during harvesting and transportation of the donor organ. Severe, fixed elevation of transpuhuonary pressure gradient or pulmonaty vascular resistance is therefore considered a contraindication to ortho. topic heart transplantation. The immediate response of the pulmonary circulation to intravenous vasodilators, such as nitroprusside (4) amrinone (5) and prostaglandin E, (6), has
`
`From the Cardiac and Pulmonary Units, Departments uf Medicine, Respi-
`ratory Therapy and Anesthesia, Massachusetts General Hospital and Harvard
`Medical Schuo!, Boston, Mass;\chusetts. This study was supported in part by
`Grant Hf.43297 to Dr. Zapol from the National Heart, Lung, and Blood
`institute. N-&mal fnstitutrs of Health, Bethesda, Maryland. ft was presented in
`art at the 42nd Annual scientific Win
`of the American College of Cardiol-
`ogy, Anaheim, California. March, 1993.
`h(anusaipl received January 281%
`
`rev&d manuscript received April 14,
`
`1
`
`Michael A. Firer, Cardiac Unit, Massachu-
`setts Qmsal Hospital, WACC 478 15 Parkman Street, Boston, Massachusetts
`02114.
`
`81998 by the American Colkge of Cardiology
`
`0735-1097/94i$7.00
`
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`
`Ex. 2034-0001
`
`: Dr.
`

`
`JACC Vol. 24, No. 4 October 1994:949-8 I_ EMODYNAMK EFFECTS OF lNMALED NlTRlC OXIDE 983
`
`1 Siw DCM 1v 0.17
`
`49/M
`
`DCM
`
`111
`
`0.25
`
`2
`3
`
`Outcome
`
`Died, not listed for transplantation
`Transplantation performed
`Transplantation performed
`Died 4 weeks after transplantation
`(renal, hepatic failure)
`Transplantation performed
`Awaiting transplant
`Awaiting transplant
`Awaiting
`transplant
`Transplantation performed
`Transplantation performed
`Transplantation performed
`CABG
`Awaiting transplant
`Died awaiting transplant
`Awaiting transplant
`Awaiting transplant
`
`.77/M DCM IV 0.12
`
`4 50/M
`
`CAD
`
`IV
`
`5
`6
`7
`8
`9
`IO
`II
`12
`I3
`I4
`15
`I6
`Mean
`SEM
`
`S4lM CAD IV
`
`CAD
`CAD
`CAD
`DCM
`HCMIDCM
`DC
`CA
`DCM
`DCM
`DCM
`DCM
`
`111
`111
`111
`111
`IV
`111
`111
`111
`SV
`111
`III
`
`37/M
`SO/M
`W/M
`S2iM
`57/F
`49/M
`t13ik4
`4VM
`45/M
`S’NF
`53/M
`Sf
`2
`
`0.23
`
`0.13
`0.18
`0.15
`0.17
`0.10
`o.Kl
`0.
`t1.14
`II.27
`11SlY
`0.10
`0.17
`0. I6
`0.02
`
`= dilated cardiomyopathy; Diagn =
`CABS = coronary artery bypass grafting: CAD = curmutry artery disease; KM
`diagnosis; F = female; HCM = hypertrophic cardiomyopathy: LVEF = left ventricular ejection fraction; M = male;
`NYHA
`class = New York Heart Association functional class: PI = patient.
`
`included
`
`13 men and 3 I 2 years) with chronic New Yor A.ssociation class III or IV heart failure who were referred to the Massachusetts General Hospital for consideration of heart transplantation (Table 1). The cause of heart failure was dilated cardiomyopathy in nine patients, coronary artery dis- ease in six and progression of hypertrophic cardiomyopathy to ventricular dilation and systolic dysfunction in one patient. No patient had a history of primary pulmonary disease, and the results of pulmonary function testing were consistent with chronic left heart failure, showing a mild restrictive pattern and a mild decrease in diffusion capacity (16). All patients were treated with digoxin, diuretic drugs and vasodilators, and three (Patients 1,9 and 15) were treated with amiodarone for atrial or ventricular arrhythmias. Radionuclide left ventricular ejec- tion fraction was 0.16 f 0.02 (range 0.09 to 0.27). Patients 1,2 and 14 had chronic atrial fibrillation, and Patient 15 had a ventricular paced rhythm; the remaining 12 patients were in sinus rhythm. The study protocol was approved by the Sub- committee on Human Studies of the Massachusetts General Hospital, and written informed consent was obtained from all patients. emodynamic measurements. Digoxin, diuretic drugs and vasodilators were discontinued 12 to 24 h before catheteriza- tion, and amiodarone therapy was continued. No premedica- tion was administered. Right heart catheterization was per- formed by way of the internal jugular vein with a triple-lumen balloon-tipped catheter. Systemic arterial pressure was mea- sured from a radial artery cannula or from the side arm of a femoral artery introducer. The following hemodynamic variables were recorded: heart rate, right atrial pressure, pulmonary artery pressure, pulmo- nary capillary wedge pressure and systemic arterial pressure. Cardiac output was determined by the Pick oxygen technique. Q,xygen consumption was measured with an consumption monitor (Waters Associates). Derived hemody- namic variables were calculated using the following formulas: Cardiac index (liters/min per m”) = Cardiac output/Body surface area; Transpulmonary pressure gradient (mm Hg) = ivlean pulmonary artery pressure - Pulmonary capillary wedge pressure; Stroke volume index (ml/m2) = Cardiac index/Heart rate; Right ventricular stroke work index (g-m/m2) = (0.0136) (Mean pulmonary artery pressure - Right atrial pressure)(Stroke volume index); Left ventricular stroke work index (g-m/m’) = (O.O136)(Mean systemic arterial pressure - Pulmonary capillary wedge pressure)(Stroke volume index); Systemic vascular resis- tance (dynesscm-‘) = 8O(Mean systemic arterial pressure - Right atrial pressure)/Cardiac output; Pulmonary vascular resis- tance (dynesscm-“) = 80(Transpulmonary pressure gradient)/ Cardiac output. Nitric oxide delivery. Nitric oxide gas (800 ppm in nitrogen [NJ) (Airco) was mixed with room air with the use of a standard low flow blender (Bird Blender) and then titrated with 100% oxygen using standard high flow rotameters (Timeter Instruments) to achieve a mixture of >90% oxygen with 20,40 or 80 ppm nitric oxide and the remhinder Np The mixture was then introduced into a non-rebreathing circuit consisting of large-bore aerosol tubing and a modified con- tinuous positive airway pressure mask (Respironics Inc.). The inspired concentration of nitric oxide and nitrogen dioxide was measured by chemiluminescence (17) (model 141%
`
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`Ex. 2034-0002
`
`I7
`atients. The study group
`

`
`984
`
`SEMIORAN ET AL. HEMODYNAMIC EFFECTS OF INHALED NITRIC OXIDE JACC Vol. 24, No. 4 October 1994:952-8
`
`T&le 2 Acute Hcme@amic Effects of Oxygen, Inhaled Nitric Oxide and Nitroprusside
`
`Heart rate (bcats/min)
`h(ean systemic arterial pressure (mm Hg)
`Right atrial pressure (mm
`Mean putmonary artery pressure (mm
`Pdrnonaty capillary wedge pressure (mm Hg)
`Transpuhnonary pressure gradient (mm Hg)
`Cardiac in&x (IiWmin per m’)
`Stroke volume index (ml/m’)
`RV stroke work index (g-m/m’)
`LV struke work index (g-m/m”)
`Systemic vascular resistance (dynes%*m -s)
`Pulmonary vascular &stance
`(dynes-sem “)
`PVWSVR
`Oxygen saturation (a)
`
`Baseline
`
`93 + 6
`PAZ2
`922
`38 -c 3
`2523
`14 4 2
`2.1 t 0.2
`23 -c 2
`921
`19 ” 2
`1,648 + 1,493
`323 + 64
`0.19 L 003
`94 c 2
`
`02
`
`9026
`87 t 2
`10r2
`37 2 3
`26 t 2
`11 t
`I*
`2.1 c 0.1
`24 + 2
`921
`20 ” 2
`1,649 + 119
`256 + 4l*
`0. IS f 0.02
`9YzI I*
`
`NO (aa ppm)
`+02
`
`96 t 6
`89 z 2
`852
`39 ‘+ 2
`32 r 2*$
`7%-l**
`2.3 r 0.2
`24 I? 2
`IO c
`I9 22
`1,625 t
`I21
`I39 ?I I.$*$
`0.09 It 0.01 “I
`
`0,
`
`9926
`YO’2
`9t2
`38 t 4
`26 5 3
`II ?2*
`
`“._ 77+0? -
`._
`*_ 73 * P _ 7
`
`?I) _+ 2
`I .692 + 144
`264 C! 49”
`0. IS I? 0.03
`lot) 2 1*
`
`Nitroprussidc
`
`98 ‘t 7
`68 _c I’?$
`-I-+ I”?$
`19 5 3*+*
`9 ? 2*‘rl
`IO c I*?
`2.Y t 0.3’1%
`30 2 4
`72
`Ii
`23 rt 2*?
`1,121 t 14lW$
`I69 ? 31)4t$
`0.15 L o.ot
`YY”_ 1’
`
`*p < 0.05 wsus baseline. tp < O.(1S nitroprussidc versus nitric oxide (NO). $p < 0.05 versus previous period uloxygcn (0,). Data are prcscnted irs nlcnn value -C
`SEM. LV 1 left ventricular: PVR = pulmomuy vascular rcsistancc; RV = right ventricular; SVR = systemic v;rsWlar resistnncc.
`
`Inc.) and that of oxygen by
`Instruments
`ThermoEnvironmental
`polarimetry
`(Hudson Oxygen Meter). The total gas flow rate
`was maintained at 45 liters/min, a level that reduced
`the nitric
`oxide residence
`time within
`the breathing circuit and, hence,
`the time for the oxidation of nitric oxide to nitrogen dioxide.
`Nitrogen dioxide was not measurable
`in the expired gas at any
`dose of nitric oxide. Exhaled gases were scavenged and dis-
`carded
`to the atmosphere. Blood methemoglobin
`levels were
`determined spectrophotometrically
`(18) at baseline and during
`the inhalation of 80 ppm nitric oxide.
`the
`Study
`All measurements were made with
`data
`patient supine and wearing a face mask. Hemodynamic
`were obtained during a baseline period with
`the patient
`inhaling room air; during
`inhalation of >90% oxygen; during
`inhalation of 20, 40 and 80 ppm nitric oxide
`in addition
`to
`>!#I% oxygen; during another period of >90% ovgen;
`and
`during
`the intravenous administration
`of nitroprusside
`in ad-
`dition
`to the inhalation of z+JO% oxygen. We administered
`>9O$G oxygen during nitroprusside
`infusion
`to avoid hypox-
`emia due to intrapulmonary
`shunting. To allow valid compar-
`isons among baseline, nitroprusside and nitric oxide periods,
`we administered >90% oxygen throughout
`the study protocol.
`The dosage of nitroprusside was titrated upward until a systolic
`arterial pressure of 85 mm Hg, a mean pulmonary
`artery
`pressure of 20 mm Hg or a maximal dose of 500 @min was
`achieved. Hemodynamic measurements were obtained 5 min
`after
`the dose of nitric oxide was altered or 5 min after
`the
`desired dose of nitroprusside was reached. The total duration
`of nitric oxide administration
`to each patient was -40 min.
`Statistics. Results are expressed as mean value
`-C SEM. A
`two-way analysis of variance with subsequent comparisons of
`group means by the Newman-Keuls
`test was used for compar-
`isons among the l.atment
`periods of room air, oxygen, 80 ppm
`nitric oxide with oxygen and nitroprusside with oxygen, as well
`as for evaluation of the dose response to 0 to 80 ppm of nitric
`oxide. Preoperative and postoperative hemodynamic variables
`
`transplantation were com-
`in those patients who underwent
`pared by paired Student
`testing. A linear regression was used
`to compare
`the changes
`in pulmonary
`vascular
`resistance
`produced by nitric oxide with those observed after transplan-
`tation. A p value < 0.05 was considered sigtlificant.
`
`Mrememts, Right atrial pressure was elevated
`as were mean pulmonary artery pressure at
`38 -C 3 mm Hg and pulmonary capillary wedge pressure at 25 2
`3 mm Hg (Table 2). Cardiac
`index was depressed at 2.1 Ir 0.2
`liters/min per m’. Pulmonary vascular resistance was elevated at
`323 t 64 dynesscm-“.
`
`Effects of > oxygen.
`
`inhalation of >90% oxy-
`During
`gen, arterial oxygen saturation
`increased
`from 94 Z!I 2%
`to
`99 I- i% (p < 0,05), transpulmonary pressure gradient decreased
`from 14 2 2 to I1 2 1 mm Hg (p < O.OS), and pulmonary vascular
`resistance decreased
`from 323 + 64 to 256 2 41 dynesscm-”
`(p < 0.05)
`(Table 2). There was no effect on mean systemic
`arterial pressure or systemic vascular resistance. There were no
`significant differences in hemodynamic variables between the two
`>90% oxygen periods.
`the Jddition of 80 ppm nitric
`oxide. With
`oxide to >90% oxygen, mean pulmonary artery pressure was
`unchanged, but pulmonary capillary wedge pressure increased
`from 26
`,C 2 to 32 2 2 mm Hg
`(p < 0.05)
`(Table 2).
`An increase
`in pulmonary capillary wedge pressure ~5 mm Hg was
`observed
`in 9 of the 16 patients (Patients 1 to 3,5 to 8, 10, 16).
`Transpulmonary
`pressure gradient decreased
`from 11 2 1 to
`7 +- 1 mm Hg (p < 0.05), and pulmonary vascular resistance
`decreased
`from 256 + 41 to 139 I!I 14 dynesscan-”
`(p e 0.05,
`Fig. 1A). Cardiac output, mean systemic arterial pressure and
`systemic vascular
`resistance were unchanged. The
`ratio of
`pulmonary vascular resistance
`to systemic vascular resistance
`
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`
`Ex. 2034-0003
`
`to2
`Hg)
`Hg)
`1 921
`992 I*
`pmtucol.
`t
`Effects of nitric
`

`
`i l@we 2. Relation between dose of nitric oxide
`
`and
`and pulmonary capillary wedge pressure
`vascular rcsistancc
`Data are exprcsscd as mean value 5 SEM.
`‘rp c 0.05
`versus oxygen alone. #p < 0.05 versus 20 and 40 ppm nitric
`PPM = parts per
`
`resistance
`1. A,
`the addition of 80 ppm nitric oxide in each of
`(PVR) during oxygen itdministrarion and after
`the 16 patients. B, Pulmonary vascular
`and with
`maximal dose al nitroprnsside
`in each uf
`resistance during oxygen administrA_m
`the I6 patients.
`
`mm Hg
`
`The mean value ( and SEM are also shown. decreased from 0,15 t 0.02 to 0.09 t 0.01 with nitric oxide (p ==I 0.01). The effects of nitric oxide dosage on pulmonary vascular resistance and pulmonary capillary wedge pressure are shown in Figure 2, A and B, respectively. The maximal reduction of pulmonary vascular resistance was seen at 80 ppm, although an effect was observed with doses of 20 and 40 ppm. Pulmonary capillav wedge pressure increased with a dose of 20 ppm of nitric oxide; there was no further significant increase with doses of 40 or 80 ppm. Effects uf nilropmsside. With the addition of nitroprusside (214 t, 43 Fg!min) to >90% oxygen, mean pulmonary artery pressure decreased from 38 f 4 to 19 2 3 mm Hg (p -C O.Ol), and pulmonary capillary wedge pressure decreased from 26 4 3 to 9 2 2 mm Hg (p -=c 0.01) (Table 2). Transpulmonary pressure gradient did not change, but cardiac index increased frown 2.2 2 0.2 to 2-Y It 0.3 litcrs/min per n? (p < 0.05), and pulmonary vascular resistance decreased from 264 4 49 to 169 2 30 dynesscm ” ’ (p -C 0.05) (Fig. 1B). Mean systemic arterial pressure decreased from 90 + 2 to 68 + I
`
`change. Comparison of the erects of nitric oxide and nitruprusside, Kight atrial, mean pulmonary artery and pulmonary capillary wedge pressure were all lower during administration of nitro- prusside than during administration of nitric oxide. However, both transpulmonary pressure gradient and pulmonary vascu- lar resistance decreased to a greater extent with nitric oxide than with nitroprusside. Mean systemic arterial pressure was lower with nitroprusside, as was systemic vascular resistance. The ratio of pulmonary vascular resistance to systemic vascular resistance was lower with nitric oxide than with nitroprusside. Side effects. No side effects were observed during nitric
`
`(p < 0.01). The dosage of nitroprusside was limited to <SOtI pgfmin by a decrease in systemic arterial pressure in 7 of the 16 patients (Patients I,5 and 10 to 14). The ratio of pulmonaq vascular resistance to
`
`resistance
`
`did not
`
`systemic
`
`vascular
`
`oxide or
`
`nitroprusside administration. Despite the increased pulillo~dry capillary wedge pressure with nitric oxide, arterial oxygen saturation remained >95% in all patienrs, in part
`
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`
`Ex. 2034-0004
`
`pulmonary
`(PVR) IA)
`(PCWP) (B).
`oxide.
`million hy volume.
`Pulmonary vascular
`the
`

`
`986 SEMIGRAN ET AL.
`
`HEMODYNAMIC EFFEC’l5 OF INHALED NITRIC OXIDE
`
`lO@O
`
`JACC Vol. 24, No. 4
`October 1994:982-B
`
`rr 3. Pubnonery vascular reristancc (PVR) at the time of initial
`evaluation
`(PRE) and 1 week postopcrativcly
`(1 WK POST)
`in the
`tients who have undergone heart wuwplantation. The mean
`and SEM are also shown.
`
`because of concomitant administr;ltion of XH.l% oxygen. Mct-
`hemoglobin
`Ievvcls did not increase
`to >1.5%
`in any patient
`during nitric oxide administration.
`Clfnfenl
`In 13 of the 16 patients studied, pulmo-
`nary vascular resistance decreased
`to <200 dynesscm-’
`with
`both nitroprusside
`and nitric oxide.
`In Patients 1 and 14,
`neither
`agent
`lowered
`pulmonaty
`vascular
`resistance
`to
`<200 dynessunnms. These patients were
`thought not to be
`suitable
`transplant
`recipients on the basis of these data, and
`they died of progressive heart failure. Patient 9, whose pulmo-
`with
`nary vascular resistance decreased
`to 240 dynesscm-’
`nitroprusside and to 200 dynes-srm’-s with nitric oxide, under-
`went successful transplantation;
`his pulmonary vascular rcsis-
`tance was 146 dynes-s-cm-” 1 week postoperatively.
`In all, seven study patients have undergone
`transplanta-
`tion. Pulmonary vascular
`resistance decreased
`from 328
`-c
`104 dynes%*m-s
`preoperatively
`to 157 z!z 18 dyness-cm+
`1
`(p C 0.05)
`week after transplantation
`(Fig. 3). There was no
`change 4 weeks after transplantation. The decrease
`in pulmonary vascular resistance observed during
`inhalation of
`fJ0 ppm nitric oxide predicted
`the decrease measured 1 week
`after transplantation
`(Fig. 4A), as did the decrease
`in pulmo-
`nary vascular resistance observed with nitroprusside
`(Fig. 4B).
`‘Lvo patients
`(Patients
`10 and
`ll), who had
`the highest
`preoperative
`pulmonary
`vascular
`resistance among
`those
`undergoing
`transplantation, were treated
`for early postopera-
`tive right heart failure with
`intravenous prostaglandin E, for
`the 1st 48 and 30 h, respectively. There were no deaths due to
`postoperative
`right heart failure,
`
`iscussion
`is
`failure
`Elevation of left atrial pressure
`in chronic heart
`associated with an obligatory
`increase
`in pulmonary
`artery
`pressure
`to maintain a pressure gradient
`for forward
`flow
`in
`the pulmonary circulation.
`Further elevation of pulmonary
`artery pressure results from pulmonary vasoconstriction. The
`
`dl 0 0
`
`20
`
`40
`
`80
`
`80
`
`100
`
`% DECREASE IN PVR WllM NRROPRUSSIDE @we 4.
`Correlation between
`in pulmonary vascular
`the decrease
`resistance (PVR) observed during
`inhalation of nitric oxide (A) or
`infusion of nitroprussidc (B) and that seen
`week postoperatively
`in
`the seven patients who have undergone heart transplantation. PPM =
`parts per million by volume.
`
`to pa-
`is of importance
`presence of pulmonary hypertension
`tients undergoing heart
`transplantation
`because
`it is a risk
`factor for premature death in the postoperative period (1). The
`right ventricle of the donor heart undergoes
`ischemic
`injury
`during the harvesting and implantation
`procedures, making
`it
`particularly vulnerable
`to acute dysfunction and failure when
`confronted with an increase
`in afterload
`(19). Thus, patients
`with a fixed elevation of pulmonary
`vascuilar resistance are
`generally
`excluded as candidates
`for heart
`transplantation
`because of a high early postoperative mortality
`rate (2,3,20).
`Pulmonary hypertension caused by either an elevation
`
`in
`
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`
`Ex. 2034-0005
`
`)
`outcome.
`I
`I
`

`
`JACC Vol. 24, No. 4
`October 199.1:982-8
`
`NEMODYNAMiC
`
`EFFECTS OF INWSD
`
`NITRIC OXIDE
`
`syst
`
`contrast. those whose pulmonary vascular resistance could not be reduced to ~200 dynepscm-’ or could be so re at the expense of systemic ~~ypoteas~o~ bad a 3-mon ity of
`
`41%
`
`Bn
`
`decreasing
`
`systemic arterial pressure in patients M~~der~oi~~8 evasuation for heart transplantation, but the degree of baseline pu9monary vasoconstriction of patients in this study was not in the range cons E circulations. Nitric oxide, an cndothelium-derived relaxation factor, causes vascular smooth muscle cell relaxation by acti- vating guanylate cyclasc, leadiag to an increase in ~ntracel~ulaF cyclic guanosine monophosphate (GMP) and reduction of intracellular calcium concentration (24,25). Because nitric oxide is rapidly bound to (26) and inactivated by (27) hemo- globin, inhaled nitric oxide might be expect be a selective pulmonary vasodilator. Previous studies in ic sheep (IO). patients with primary pulmonary vclscular disease (15) and patients with pulmonary hypertension that was secondary to congenital heart disease (91) or chronic obstructive lung disease (28) or that persisted after cardiopulmonary bypass (29,30) have shown significant reductions in pulmonary vascu- lar resistance, without alterations in systemic arterial pressure,
`
`in response
`
`to nitric
`
`oxide
`
`ic
`
`~~~~sta~~e
`
`n, while having a be tr~c~~ar
`performance
`through
`nitropmsside adminis.
`afterload reduction of the left ventricle, may have limited the dose of
`to the p~~rn~~a~
`the ratio of pulmo- nary vascular
`reSiStanCe
`to
`
`Ths,
`
`left
`
`have been increases in
`
`oxide
`
`in our study, this expla- nation is uniikeiy. 3) Left ventricular diastolic function may have been impaired without a change in Icft ventricular end-diastolic volume. It
`
`seems unlil<ely that
`
`Whatever
`
`such molecules
`
`(34).
`
`implications.
`
`our
`study, 13 of 16 patients had this level of pulmonV vasodilation without systemic hypotension with either p:‘~ic
`
`hypotension.
`
`in
`
`987 ssure or arteriolar vasoconstr~ctio~ his observation 91 utilize vasodilators such as nitro at patients whose pulmo- nary vascular resistance decreased to S-200 dynespcmm5 dur- ing nitroprusside infusion before transplantation had a mor- tality rate of oniy 4% at 3 months after tra~sp9a~tat~o~.
`systemic vascular resistance did not change with nitroprusside, whereas it decreased by 40% with nitric oxide, demonstrating the selectivity of ~~baled nitric sure observed with doubtedly reflects an in- crease in left VentricM~ar end-diastolic pressure. Similarly, Haywood et al. (23) observed an increase in pulmonary ressure associated with a decrease in pulmo- ring infusion of adellosine in pa- here are several possible mecha- nisms for our observation: 9) There may
`and 28%, r er vas~~d~9ators have ate pulmonary vasoreactivity hypotension. ~rostag~a~di~ E, also caused ~i~~~~t~i~g systemic 9iy~ote~~s~on at dosages required for adequate pulmonary v~is(~di9at~o~ ia patients with heart failure (6). Adcnosine decreased pulmonary vascular resistance witbout
`ventricular end-systolic and end-diastolic volumes due to a negative inotropic effect of nitric oxide. The demonstration by Finkel et al. (32) that inhibitors of nitric oxide synthase reverse the ability of pro-inflammatory cytokines to decrease contrac- tility in hamster papillary muscle supports such a negative inotropic etiect. 2) Left ventricular preload may have increased in response to improved right ventricular pump function. These cllanges would be associated with an increase in left ventricular end-diastolic volume and pressure. Because strok.e volume was unaltered by nitric
`an agent that increases intracellular cyclic GMP and decreases intracellular calcium would have a direct adverse effect on myocardial relaxation. However, if inhalation of nitric oxide causes dila- tion and increased turgor of the coronary circulation, it could impair left ventricular compliance by this mechanism (33). Because nitric oxide is rapidly inactivated by hemoglobin (27), any effect of nitric oxide on the left ventricular myocardium or the coronary circulation must be mediated by a metabolite or carrier molecule that preserves its biologic effect: Evidence has been presented for the existence of
`the mechanism, the increase in left ventricular filling pressure seen during nitric oxide administration may limit its role to that of a diagnostic rather than a therapeutic agent in patients with severe heart failure. Clinical
`Although controversy remains with regard to the level of pretransplantation pulmonary vasocon- striction beyond which the risk of right heart failure after transplantation is excessive, the study of Costard-llckle and Fowler (4) has established an acceptably low risk in patients whose pulmonary vascular resistance is 1200 dynespcm ’ either at baseline or during administration of a dose : nitroprusside that does not induce systemic
`
`oxide donor (31), caused a decrease in pulmonary vascular resistance associated with an increase in cardiac output with- out a change in transpulmonary pressure gradient; although pulmonary artery pressure decreased with nitroprusside, there was a corresponding decrease in pulmonary capillary wedge pressure. Furthermore, nitroprusside had, as expected, systemic he- reducing mean
`
`oxide at dosages ranging from 20 to 80 ppm. The results of the present study extend to patients with chronic left heart failure the observation that nitric
`decreases pulmonary vascular resistance without reducing sys- temic vascular resistance or mean systemic arterial pressure. The major effect of nitric oxide was a decrease in transpulmo- nary pressure gradient associated with an increase
`pulmo- naly capillary wedge pressure without an equivalent increase in pulmonary artery pressure. In contrast, nitroprusside,
`
`in
`
`a nitric
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`Ex. 2034-0006
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`SEMlOM ET XL.
`vascular
`tered
`c~rc~lat~oa.
`

`
`SEMIGRAN ET AL.
`HEMODYNAMK EFFECR3 OF INHALED NITRIC OXIDE
`
`JACC Vol. 24, No. 4
`October 1994:98,?-8
`
`oxide or nitroprusside; 2 patients had pulnionary vasoconstric-
`tion that was not reversed by these agents; 1 patient (Patient 9)
`not achieve the specified degree of pulmonary vasodilation
`with nitroprusside because administration of this agent was
`limited by systemic hypotension. His pulmonary vascular resis-
`tance did decrease satisfactorily with nitric oxide; he under-
`went heart transplantation without postoperative right heart
`failure and had a subsequent early decrease in pulmonary
`vascular resistance. Nitric oxide may thus have an important
`role in identifying potential heart transplant recipients in
`whom reversal of pulmonary vasoconstriction by nonselective
`vasodilators such as nitroprusside is limited by systemic hypo
`tension. Further studies enrolling greater numbers of patients
`with pulmonsry vasoconstriction that reverses with nitric oxide
`who ultimately undergo heart transplantation are necessary to
`test this hypothesis. In the seven patients who have thus far
`received a heart transplant, the decrease in pulmonary vascular
`resistance observed with inhaled nitric oxide during their initial
`evaluation did predict the decrease observed after transplan-
`tation.
`Inhaled nitric oxide is a selective pulmonary
`Summary.
`ilator in patients with severe chronic heart failure. The
`V
`selectivity of inhaled nitric oxide for the pulmonary circulation
`offers a potential advantage over nonselective vasodilators
`such as nitroprusside in the identification of reversible pulmo-
`nary vasoconstriction in potential heart transplant recipients.
`Nitric oxide increases left ventricular filling pressure in pa-
`tients with severe heart failure by an unknown mechanism.
`
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