Full text of DOI:10.1007/BF03018946

552
Clinical Reports
Treatment of pulmonary
hypertension during
surgery with nitric oxide
and vasodilators
Zu Yi Jiang MD,*
Tudor Costachescu MD,*
Marc Derouin MD,†
Gilbert Blaise MD*
Purpose: To describe the effects of the combination of several therapies on the pulmonary circulation and car-
diac function in a patient with severe pulmonary hypertension.
Clinical features: We report the case of a female patient with chronic secondary pulmonary hypertension and
cardiac failure who underwent right hemicolectomy under general anesthesia. Insertion of a pulmonary artery
catheter before the operation revealed pulmonary artery pressure (PAP) of 55/24 mmHg which was lowered
moderately by 40 parts per million (ppm) inhNO. During surgery, the patient presented an episode of atrial fib-
rillation with a slow, irregular heart rate of 45-50 min–1 and variable systemic pressure. A dipyridamole DPD (0.2
mg·kg–1) bolus stabilized systemic pressure and increased heart rate and cardiac output. However, PAP did not
change. Nitroglycerine infusion was started at 10 mg·hr–1 shortly after the initiation of DPD. The patient respond-
ed favourably to combined inhNO, intravenous DPD and NTG therapy with a marked and sustained reduction
of PAP and a systemic hemodynamic stability.
Conclusion: We conclude that: 1) in combination with inhNO, DPD does not augment the inhNO-induced
decrease in PAP; 2) DPD improves the hemodynamic profile and elevates cardiac output; 3) therapeutic combi-
nation (inhaled NO, NTG, DPD) has a potent effect on pulmonary pressure in cardiac failure patients.
Objectif : Décrire les effets d’une combinaison de thérapies sur la circulation pulmonaire et la fonction cardiaque
chez une patiente qui présente une sévère hypertension pulmonaire.
Éléments cliniques : Il s’agit d’une patiente, atteinte d’hypertension pulmonaire secondaire chronique et d’in-
suffisance cardiaque, qui a subi une hémicolectomie droite sous anesthésie générale. L’insertion préopératoire
d’un cathéter dans l’artère pulmonaire a révélé une pression artérielle pulmonaire (PAP) de 55/24 mmHg, mo-
dérément abaissée par 40 parties par million (ppm) de NOinh. Pendant l’opération, la patiente a présenté un
épisode de fibrillation auriculaire accompagné d’une fréquence cardiaque lente et irrégulière de 45-50 min–1 et
une pression générale variable. Un bolus de dipyridamole (DPD 0,2 mg·kg–1) a permis de stabiliser la pression
générale et d’augmenter la fréquence et le débit cardiaques. La PAP n’a toutefois pas changé. Une perfusion de
–1
nitroglycérine a été amorcée avec 10 mg·h peu après le début du DPD. La patiente a bien réagi à la thérapie
combinée de NOinh, de DPD intraveineux et de NTG, ce qui a entraîné une réduction marquée et soutenue
de la PAP et une stabilité hémodynamique générale.
Conclusion : Nous en concluons que : 1) en combinaison avec le NOinh, le DPD n’accentue pas la baisse de PAP
induite par le NOinh 2) le DPD améliore les caractéristiques hémodynamiques et augmente le débit cardiaque 3) la
NTG stimule la vasodilatation pulmonaire induite par le NOinh chez les patients atteints d’insuffisance cardiaque.
From the Département d’Anesthésie-Réanimation, Faculté de Médecine, Centre hospitalier de l’Université de Montréal, Hôpital Notre-
Dame,* Montréal and Centre hospitalier Régional,† Rimouski, Québec, Canada.
Address correspondence to: Gilbert Blaise MD, Département d’Anesthésie-Réanimation, CHUM-Hôpital Notre- Dame, 1560, rue
Sherbrooke est, Montréal, Qc H2L 4M1, Canada. Phone: 514-281-6000, Ext 5397; Fax: 514-896-4615; E-mail: blaisegil@videotron.ca
Accepted for publication February 4, 2000.
CAN J ANESTH 2000 / 47: 6 / pp 552–555

Jiang et al.: NITRIC OXIDE A N D PULMONARY HYPERTENSION
553
NHALED nitric oxide (inhNO) causes potent
and selective pulmonary vasodilatation in
diverse clinical conditions associated with pul-
On arrival, she was anticoagulated with heparin
until the day of surgery. Electrocardiography revealed
atrial fibrillation with a ventricular rate of 60-65 min–1,
complete right bundle-branch block and right ventric-
ular hypertrophy. Chest X-ray showed moderate
enlargement of the right heart with signs of pul-
monary hypertension. Transesophageal echocardiog-
raphy presented a 6 mm patent foramen ovale
associated with considerable bidirectional shunt. The
left ventricular ejection fraction was estimated to be
40% with severe biventricular diastolic dysfunction.
The left atrium was dilated with moderate mitral
regurgitation. The right heart was markedly dilated
and hypokinetic. No arteriostenosis was observed by
coronary angiography.
monary hypertension.1 However, some
I
patients with persistent pulmonary hypertension
respond incompletely2 or require prolonged therapy.
Dipyridamole (DPD) is also used to treat pulmonary
hypertension; 3,4 as it inhibits phosphodiesterase V and
cyclic guanosine 3’,5’ monophosphate (cGMP) degra-
dation. Concomitant therapy may be of some benefit
in patients who respond inadequately to inhNO alone.
Nitroglycerine (NTG) is another drug that is often
given to control pulmonary hypertension, but sys-
temic side-effects5 limits its application. We report the
clinical effect of DPD and NTG on the response to
inhNO in a patient with chronic secondary pulmonary
hypertension and cardiac failure who underwent sig-
moid resection under general anesthesia.
Surgical procedure
After receiving 2 mg ativan as premedication, anesthe-
sia was induced with 68 µg sufentanil, 100 mg propo-
fol and 80 mg rocuronium, and maintained by
continuous infusion of 130 µg·kg–1·min–1 propofol,
0.5 µg·kg– 1·min– 1 sufentanil and intermittent vecuro-
nium for muscle relaxation. The trachea was intubat-
ed and the lungs ventilated with oxygen 100%,
adjusted to keep partial pressures of arterial carbon
dioxide (PaCO2) in the low range (35 mmHg).
Inhaled nitric oxide (40 parts per million ppm) was
injected cyclically into an inspiratory line by NO injec-
Case report
A 48-yr-old woman with sigmoid adenocarcinoma was
scheduled for a right hemicolectomy. She also suffered
from severe secondary pulmonary hypertension and
cardiac failure. When she was 30 yr old, she had a ven-
tricular septal defect repaired to correct a major left-
to-right shunt and marked pulmonary artery
hypertension of 125/55 mmHg. Despite aggressive
treatment with digitalis, a calcium channel blocker and
an anticoagulant after surgical closure of the ventricu-
lar-septal defect, she developed atrial fibrillation with
an intraventricular conduction defect and maintained
high pulmonary pressure. In the past year, the patient
complained of abdominal pain and intermittent con-
stipation. She underwent double contrast radiography
and colonoscopy which revealed a 3.5 cm diameter
adenocarcinoma in the ascending colon. She was
scheduled for laparotomy in a community hospital.
One hour after the induction of anesthesia, she had an
acute episode of pulmonary hypertension with severe
hypoxemia (pulse oximetry: 56%) and systemic
hypotension (80/40 mmHg). Anesthesia and surgery
were stopped immediately and the patient was trans-
ferred to our university hospital as it has the technol-
ogy to deliver inhNO.
tor, with NO and nitrogen dioxide (NO ) concentra-
2
tion being monitored via an electrochemical NO and
NO2 analyser. An arterial cannula and pulmonary
artery flotation catheter were inserted for continuous
monitoring of systemic and pulmonary pressures.
In the perioperative period, pulmonary artery pres-
sure (PAP) decreased from 55/24 to 41/18 mmHg
following inhNO. During the surgical procedure, the
patient presented rapid atrial fibrillation with a slow,
irregular heart rate of 45-50·min–1 and fluctuation of
systemic pressure from 80/30 to 145/70 mmHg. A
DPD bolus (0.2 mg·kg–1) was injected to augment
inhNO-induced pulmonary vasodilatation. Heart rate
increased to its preoperative level, systemic pressure
stabilised at 135/70 mmHg and cardiac output
increased from 5.1 to 5.8 L·min–1. However, pul-
TABLE Cardiac indices before and during inhaled nitric oxide (inhNO), infusion of dipyridamole (DPD) and nitroglycerine (NTG)
Before inhNO
After inhNO
InhNO+DPD
InhNO+DPD+NTG
Heart rate (beat·min– 1)
Systemic AP (mmHg)
70-100
120/70
55/24
5,1
45-50
80/30-145/70
41/18
not recorded
98%
70-100
135/70
41/18
5,8
55-60
115/60
26/7
5,8
Pulmonary AP (mmHg)
Cardiac output (litre·min– 1)
SaO (FIo2 =100%)
98%
99%
99%
2

554
CANADIAN JOURNAL OF ANESTHESIA
monary pressure did not change. A NTG infusion was
then started at a rate of 10 mg·hr–1; this combined
treatment effectively reduced PAP from 41/18 to
26/7 mmHg and systemic pressure from 135/70 to
115/60 mmHg (Table).
monary vasodilatation in primary pulmonary hyperten-
sion,1 1 in pulmonary hypertension resulting from con-
genital heart disease,1 2 in the adult respiratory distress
syndrome1 3 and in patients after cardiac surgery.1 4
However, some patients may show partial2 or no clini-
cal responses to inhNO therapy. The vasodilator effect
of DPD is mediated by: 1) inhibiting cGMP degrada-
tion in vascular smooth muscle9 via suppression of
phosphodiesterase V to cause pulmonary vasodilation;
2) blockade of adenosine cellular reuptake, leading to
adenosine accumulation in interstitial spaces around the
arterioles, which results in dilation of the coronary, sys-
temic and pulmonary vasculature.1 5 Ovine models of
pulmonary hypertension have shown that the effect of
DPD on pulmonary vasodilation is not influenced by
adenosine receptor blockade.16 This observation has
established that cGMP-specific phosphodiesterase inhi-
bition is the main mechanism by which DPDs reduce
pulmonary vasodilation.
Surgery was completed successfully. The patient
was then transferred to the intensive care unit (ICU)
where inhNO was discontinued two days later.
However, she experienced an episode of pulmonary
hypertension and acute hypoxemia. Inhaled nitric
oxide was restarted with immediate improvement of
oxygenation and pulmonary pressure. Nitric oxide
administration was continued for a week as she devel-
oped postoperative pneumonia. Her pulmonary status
improved and she was weaned progressively from
inhNO without further problem. The trachea was
extubated on the eighth postoperative day. She was
discharged on the 15th day post-surgery in good con-
dition, and six-month follow-up was satisfactory.
Fullerton et al.9 reported DPD-induced augmenta-
tion of pulmonary vasodilatation in 10 postoperative
cardiac patients treated with inhNO. On the opposite,
except for two subjects with pulmonary hypertension
resulting from longstanding left atrial hypertension,
Ziegler et al.3 found no increase of pulmonary vasodi-
latation with DPD in eight patients given inhNO.
In the present case, DPD did not alter PAP during
inhNO treatment but improved the hemodynamic
profile by stabilizing systemic pressure, increasing
heart rate and cardiac output. It is not surprising that
the vasodilating effect of DPD is not specific to the
pulmonary circulation, since cGMP modulation of
vascular tone is located in both pulmonary and sys-
temic vessels.3 It is unclear whether the action of DPD
on the pulmonary circulation could be augmented
through an increase of initial doses in patients with
chronic heart failure. Kinsella et al.4 have described
their successful experience with combined treatment
of a neonate after extracorporeal membrane oxygena-
tion; their DPD dose was 0.6 mg·kg– 1. Ivy et al.1 who
reported the hemodynamic effects of DPD (0.6
mg·kg– 1) and inhNO (20 ppm) in 13 pediatric
patients with pulmonary hypertension, found that
DPD augmented the NO-induced fall in the pul-
monary vascular resistance index in 50% of these sub-
jects. Thus, a positive clinical response to DPD in
terms of the potentiated effect of inhNO may depend
on its dose and on underlying cardiac function.
Discussion
The management of patients with pulmonary hyper-
tension and cardiac failure during surgery is complex.
Minor stimuli, such as insertion of a peripheral cannu-
la, endotracheal suction and surgical stress, can cause
arrhythmias and increase pulmonary vascular resis-
tance. General anesthesia can produce unpredictable
reductions in pulmonary blood flow,6 especially in the
presence of chronic cardiac failure.
Recently, pulmonary endothelial damage was
demonstrated to be an early histological finding in
children with congenital heart disease and pulmonary
hypertension.7 It appears that longterm left-to-right
shunt through a VSD results in a persistent increase of
pulmonary flow, leading to pulmonary endothelial
injury. In addition, the endothelial injury coupled
with excessive release of locally active mediators pro-
duces vascular structural changes such as smooth mus-
cle hypertrophy, intimal fibrosis, irregularity of elastic
fibres, vessel wall infiltration with erythrocytes and
inflammatory cells. This process is characterized by an
inexorable cycle of endothelial dysfunction with
decreased production of endothelium-derived
vasodilators or an increase of vasoconstrictors.8
Inhaled nitric oxide is now regarded as a very potent
pulmonary vasodilator that effectively reduces PAP and
pulmonary vascular resistance by stimulating guanylate
cyclase in pulmonary vascular smooth muscle to pro-
duce cGMP and cause vascular smooth muscle relax-
ation.9 Cyclic guanosine 3’,5’ monophosphate
production in vascular smooth muscle cells is countered
by its degradation by cGMP-specific phosphodiesteras-
es.1 0 Recently, inhNO was confirmed to induce pul-
Nitroglycerine is a NO donor that has the same
mechanism of action as inhNO via the cGMP pathway,
but its effect is produced only after intracellular NO
release.17 Intravenous NTG alone has been shown to
reduce pulmonary pressure and pulmonary vascular

Jiang et al.: NITRIC OXIDE A N D PULMONARY HYPERTENSION
555
6 O’Hare R, McLoughlin C, Milligan K, McNamee D,
resistance effectively while increasing cardiac indices in
patients with severe pulmonary hypertension.6 The
addition of NTG (10 mg·kg– 1) to our patient’s ongoing
inhNO and intravenous DPD regimen effectively
decreased PAP from 41/18 to 26/7 mmHg with
recovery of preoperative systemic pressure. This result
suggested that NTG not only potentiated the inhNO-
induced pulmonary vasodilation, but also modulated
left ventricular afterload since it releases NO and acti-
vates guanylyl cyclase in both the pulmonary and sys-
temic circulations.1 8 Why was the addition of a small
NTG dose more effective in reducing pulmonary
hypertension than the combination of inhNO and
DPD? Several explanations can be offered: (1) The
inhNO dose was not high enough to stimulate cGMP
production maximally, (2) NTG dilated some peripher-
al pulmonary vessels where inhNO was not present.
Furthermore, NTG had more pronounced beneficial
effects on the heart than inhNO. It decreased left ven-
tricular afterload and improved ventricular relaxation as
well as diastolic distensibility19 by increasing cGMP in
the systemic circulation and myocardium.
From these findings, we speculate that DPD may
enhance the response to inhNO therapy in some
patients with chronic pulmonary hypertension and
cardiac failure, and this effect is dependent on a suit-
able dose. We conclude that to control chronic pul-
monary hypertension effectively in patients with
cardiac failure, an improvement of hemodynamic pro-
file is required. This appears to be achieved more read-
ily by the use of combined therapy with inhNO,
intravenous DPD and NTG during surgery.
Sidhu H. Anaesthesia for Caesarean section in the pres-
ence of severe primary pulmonary hypertension. Br J
Anaesth 1998; 81: 790–2.
7 Haworth SG. Pulmonary vascular remodelling in neona-
tal pulmonary hypertension. Chest 1988; 93: 133S–8S.
8 Gaine SP, Rubin LJ. Primary pulmonary hypertension.
Lancet 1998; 352: 719–25.
9 Fullerton DA, Jaggers J, Piedalue F, Grover FL,
McIntyre RC Jr. Effective control of refractory pul-
monary hypertension after cardiac operations. J Thorac
Cardiovasc Surg 1997; 113: 363–8.
10 Thomas MK, Francis SH, Corbin JD. Characterization
of a purified bovine lung cGMP-binding cGMP phos-
phodiesterase. J Biol Chem 1990; 265: 14964–70.
11 Hoehn T, Krause M, Hentschel R. High-frequency ven-
tilation augments the effect of inhaled nitric oxide in
persistent pulmonary hypertension of the newborn.
Eur Respir J 1998; 11: 234–8.
12 Berner M, Beghetti M, Ricou B, Rouge JC, Prêtre R,
Friedli B. Relief of severe pulmonary hypertension after
closure of a large ventricular septal defect using low
dose inhaled nitric oxide. Intensive Care Med 1993;
19: 75–7.
13 Troncy E, Collet J-P, Shapiro S, et al. Inhaled nitric
oxide in acute respiratory distress syndrome. A pilot
randomized controlled study. Am J Respir Crit Care
Med 1998; 157: 1483–8.
14 Fullerton DA, Jones SD, Jaggers J, Piedalue F, Grover
FL, McIntyre RC Jr. Effective control of pulmonary
vascular resistance with inhaled nitric oxide after car-
diac operation. J Thorac Cardiovasc Surg 1996; 111:
753–63.
15 Cortigiani L, Baroni M, Picano E, et al. Acute hemody-
namic effects of endogenous adenosine in patients with
chronic heart failure. Am Heart J 1998; 136: 37–42.
16 Ziegler JW, Ivy DD, Fox JJ, Kinsella JP, Clarke WR,
Abman SH. Dipyridamole, a cGMP phosphodiesterase
inhibitor, causes pulmonary vasodilation in the ovine
fetus. Am J Physiol 1995; 269: H473–9.
17 Salvemini D, Pistelli A, Vane J. Conversion of glyceryl
trinitrate to nitric oxide in tolerant and non-tolerant
smooth muscle and endothelial cells. Br J Pharmacol
1993; 108: 162–9.
18 Troncy E, Jacob E, Peres da Silva E, et al. Comparison
of the effect of inhaled nitric oxide and intravenous
nitroglycerine on hypoxia-induced pulmonary hyper-
tension in pig. Eur J Anaesthesiol 1996; 13: 521–9.
19 Paulus WJ, Vantrimpont PJ, Shan AM. Acute effects of
nitric oxide on left ventricular relaxation and diastolic
distensibility in humans. Assessment by bicoronary
sodium nitroprusside infusion. Circulation 1994; 89:
2070–8.
References
1 Ivy DD, Ziegler JW, Kinsella JP, Wiggins JW, Abman
SH. Hemodynamic effects of dipyridamole and inhaled
nitric oxide in pediatric patients with pulmonary hyper-
tension. Chest 1998; 114: 17S.
2 Fullerton DA, McIntyre RC Jr. Inhaled nitric oxide:
therapeutic applications in cardiothoracic surgery. Ann
Thorac Surg 1996; 61: 1856–64.
3 Ziegler JW, Ivy DD, Wiggins JW, Kinsella JP, Clarke WR,
Abman SH. Effects of dipyridamole and inhaled nitric
oxide in pediatric patients with pulmonary hypertension.
Am J Respir Crit Care Med 1998; 158: 1388–95.
4 Kinsella JP, Torielli F, Ziegler JW, Ivy DD, Abman SH.
Dipyridamole augmentation of response to nitric oxide
(Letter). Lancet 1995; 346: 647–8.
5 Van Obbergh LJ, Charbonneau M, Blaise G.
Combination of inhaled nitric oxide with i.v nitroglyc-
erin or with a prostacyclin analogue in the treatment of
experimental pulmonary hypertension. Br J Anaesth
1996; 77: 227–31.