Pulmonary hypertension in thoracic surgical patients

Alan F. Ross and Kenichi Ueda

Department of Anesthesia, University of Iowa Hospitals
and Clinics, Iowa City, Iowa, USA
Correspondence to Alan F. Ross, MD, Associate
Professor, Department of Anesthesia, University of
Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
E-mail: alan-ross@uiowa.edu
Current Opinion in Anaesthesiology 2010,
23:2533

Purpose of review
Literature about thoracic surgery in patients with pulmonary hypertension is scarce.
Perceived high risk has appropriately discouraged any unnecessary operation.
However, the medical therapy for pulmonary hypertension has made great advances
during the last decade. It is likely that future advances in survival and possibly the need
for diagnostic procedures will increase the anesthesiologists exposure to such
patients. Understanding the unique physiology as well as new therapeutic agents will
facilitate safe care for these challenging patients.
Recent findings
Since 1998, there have been three World Heath Organization symposiums on
pulmonary hypertension. The most recent meeting in 2008 at Dana Point included
revisions of the classification scheme and updates on new trials and therapies. New
drugs have been utilized in cardiac, lung, or liver transplant operations to treat pulmonary
hypertension. It is also recognized that one-lung ventilation presents unique problems
for the patient with pulmonary hypertension. Inhalation use of the new pulmonary
vasodilator drugs represents a new frontier for intraoperative pharmacology.
Summary
Here, the various types of pulmonary hypertension, physiologic changes, and new drug
therapies are reviewed. Clinical experience with patients with pulmonary hypertension
undergoing both nonthoracic and thoracic procedures is also reviewed. By identifying
potential problem areas and application of new pharmacology, an approach to the
patient with pulmonary hypertension is synthesized.
Keywords
bosentan, epoprostenol, inhaled pulmonary vasodilators, pulmonary arterial
hypertension, sildenafil
Curr Opin Anaesthesiol 23:2533
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907

Introduction
There recently have been significant advances in understanding and new drug therapy for pulmonary hypertension. Anesthesiologists have had little exposure to these
patients because the risk of surgery has been prohibitive.
With new therapies and better survival, more patients
may experience surgical operation. Better understanding
of the disease process, new drugs, and areas of potential
problems will help to make this encounter safe and
successful.

Pulmonary hypertension update

Pulmonary hypertension is a heterogeneous group of
disorders [1]. Organization has evolved considerably
since the first World Health Organization (WHO) symposium on pulmonary hypertension in Geneva in 1975.
Pulmonary hypertension was initially described as
primary (no known cause) or secondary (identified
0952-7907 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

cause). The major classification of pulmonary hypertension into five separate groups occurred at the second
WHO symposium in Evian, France, in 1998. This
Clinical Classification underwent minor revisions at
WHO symposiums at Venice in 2003 and most recently
at Dana Point in 2008 (Fig. 1) [2,3]. The most current
Dana Point classification is presented in Fig. 1 [3].
Terminology requires specific definitions [4]. Pulmonary hypertension describes all of the disorders in the
Clinical Classification scheme and is defined by a
mean pulmonary artery pressure (mPAP) greater than
25 mmHg at rest or greater than 30 mmHg with exercise.
Pulmonary arterial hypertension (PAH) refers to the
major group 1 disorders. PAH has the additional requirement that pulmonary artery capillary wedge (PCWP)
pressure is 15 mmHg or less. PAH has also been
described as requiring pulmonary vascular resistance
(PVR) to be at least 2 or 3 Wood Units [5]. The
distinction between pulmonary hypertension and PAH
DOI:10.1097/ACO.0b013e328334cb59

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26 Thoracic anesthesia

Figure 1 Classification of pulmonary hypertension, Dana Point

2008

1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic PAH
1.2. Heritable
1.2.1 BMPR2
1.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)
1.2.3 Unknown
1.3. Drug- and toxin-induced
1.4. Associated with
1.4.1. Connective tissue diseases
1.4.2. HIV infection
1.4.3. Portal hypertension
1.4.4. Congenital heart diseases
1.4.5. Schistosomiasis
1.4.6. Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of the newborn
1. Pulmonary veno-occlusive disease (PVOD) and/or
pulmonary capillary hemangiomatosis (PCH)
2. Pulmonary hypertension owing to left heart disease
2.1. Systolic dysfunction
2.2. Diastolic dysfunction
2.3. Valvular disease
3. Pulmonary hypertension owing to lung diseases and/or hypoxia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4. Sleep-disordered breathing
3.5. Alveolar hypoventilation disorders
3.6. Chronic exposure to high altitude
3.7. Developmental abnormalities
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
5. Pulmonary hypertension with unclear multifactorial mechanisms
5.1. Hematologic disorders: myeloproliferative disorders, splenectomy
5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell
histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid
disorders
5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure
on dialysis

can be illustrated by rearrangement of the expression for

PVR:
PVR mPAP  LAP  CO
mPAP LAP P
An increased mPAP could be due to an elevated left atrial
pressure (LAP), increased PVR or increased cardiac
output (CO). Usually PCWP is clinically used for LAP.
Pulmonary hypertension disorders from increased LAP
constitute group 2 conditions associated with left-sided
heart disorders.
Also the terms primary and secondary pulmonary
hypertension are no longer used in the classification
scheme, although literature usage continues. Pulmonary
hypertension with no identified cause is now termed
idiopathic pulmonary artery hypertension (IPAH) and
is classified in group 1. Pulmonary hypertension for which
a cause is identified includes many disorders. Those in
group 1 are termed associated pulmonary artery hypertension (APAH). Other secondary disorders differ significantly and establish the separate groups 25 [6].

Group 1 is PAH and disorders share the feature of lesions

localized to small, muscular pulmonary arterioles and a
clinical responsiveness to pulmonary vasodilator therapy
such as epoprostenol. Interestingly, PAH from a congenital heart lesion has a significantly better long-term
survival than other group 1 disorders [7,8].
Group 2 represents disorders of the left heart that cause
elevated pulmonary venous pressure. Therapy for group
2 pulmonary hypertension targets the left heart disorder
(e.g. valvuloplasty for mitral stenosis) rather than pulmonary vasodilator therapy [9]. Pulmonary vasodilator
therapy in circumstances of elevated pulmonary venous
pressure may result in pulmonary edema. This risk
depends on elevated pulmonary venous pressure, not
the specific pulmonary hypertension classification group.
A dramatic example was reported for a patient with venoocclusive disease (group 1) [10].
Group 3 represents disorders of the lung [chronic obstructive pulmonary disease (COPD), interstitial lung disease]
or conditions of hypoxemia (sleep apnea, high-altitude
exposure). The common feature is reduced arterial blood
oxygen. Therapy is directed to improve saturation, such
as supplemental oxygen [11,12].
Group 4 represents patients with chronic thrombotic or
pulmonary embolic disease. Anticoagulation is a mainstay
therapy for this group. Surgical pulmonary endarterectomy has been performed for chronic, proximal organized
clot, whereas vasodilator therapy has been used for peripheral lesions [13,14].
Group 5 is that of unclear, multifunctional causes and
includes pulmonary hypertension from diverse causes
such as splenectomy, thyroid disease, renal dialysis and
sarcoidosis.

Assessment for pulmonary hypertension

Symptoms of pulmonary hypertension are insidious. The
NIH Registry found that 2 years elapsed from the time of
initial symptom onset to the diagnosis of pulmonary
hypertension. Initial symptoms such as dyspnea (80%)
and fatigue (19%) may be attributed to other lung or heart
disorders rather than pulmonary hypertension. Less frequent initial symptoms included syncope or near syncope
(13%) and Raynauds phenomenon (10%). Angina related
to right ventricular hypertrophy (RVH) likely represents
advanced disease. Two-thirds of patients were female
with mean age of 36  15 years [1517].
ECG findings include RVH (87%) and right axis deviation (79%), but a normal ECG does not rule out severe
pulmonary hypertension. Chest radiographic findings
include central pulmonary artery dilation, loss (pruning)

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Pulmonary hypertension in thoracic surgical patients Ross and Ueda 27

of peripheral vessels, and enlargement of the right ventricle [16]. Transthoracic echocardiography is a key
screening test. Doppler measurement of tricuspid regurgitation velocity can estimate a right ventricular systolic
pressure. Other echo findings include RV and left ventricular (LV) size and function, RV influence on LV filling
and presence of pericardial effusion [18]. Causes of
pulmonary hypertension such as left heart abnormalities
or intracardiac shunts may be noted. However, echocardiography is not a substitute for cardiac catheterization
[19]. Doppler echocardiography may underestimate RV
pressures. The error is more significant in severe pulmonary hypertension and may differ from catheterization
by 20%. Also, echocardiography can only provide estimates of PCWP and cardiac output [20]. New magnetic
resonance imaging techniques have the ability to assess
RV size, function and stroke volume as well as pulmonary
artery stiffness, which have been correlated to pulmonary
hypertension prognosis [21].
Cardiac catheterization is the gold standard for pulmonary hypertension diagnosis, assessment for acute vasodilator response, and prognosis [1,5]. Key measures are
right atrial pressure (RAP), PAP, PCWP, CO, mixed
venous oxygen saturation and resistance calculations
(PVR and SVR). If a wedge pressure cannot be appropriately measured, left heart catheterization is necessary.
Response to vasodilators predicts better outcome. Prognosis is worse with increased RAP, increased mean PAP,
and decreased CO and mixed venous O2 saturation
[22,23].

Therapy for pulmonary hypertension

Initial evaluation of PAH includes acute response to
short-acting vasodilator agents such as nitric oxide, adenosine, or epoprostenol. A positive response is defined as
a reduction in mPAP of at least 10 mmHg to achieve an
absolute value of mPAP of 40 or less with an increased or
unchanged cardiac output [4,19]. Responders may
benefit from calcium channel blocker (CCB) drugs. Verapamil is avoided because of decreased contractility.
However, only 13% of patients with IPAH respond to
acute vasodilator testing and only half of these experience long-term benefits from CCB. Other general
measures include diuretics, supplemental oxygen,
digoxin and anticoagulation [23,24].
Major advances have occurred by study of patients with
the uncommon disorder of IPAH. Damage or dysfunction of the vascular endothelium results in a disruption of
the normal balance between vasoconstriction and
dilation, cell proliferation and growth inhibition, and
thrombosis and anticoagulation [25]. New drug therapy
targets three pathways to address this imbalance
(Table 1).

The first group of drugs is prostaglandin (prostanoids)

type agents that cause pulmonary and systemic vasodilation and inhibit platelet aggregation. These drugs differ
significantly in half-life and route of administration (epoprostenol i.v., treprostinil subcutaneous, and iloprost
inhaled). Side effects are similar. Epoprostenol is the
first-line therapy for severely ill patients and has been
demonstrated to improve survival. Beraprost is an oral
agent and is available only in Japan and Korea [2730].
The second group of drugs is endothelin receptor
antagonists (ERAs) [31]. Endothelin causes vasoconstriction and cell proliferation via receptors on smooth muscle
cells. Endothelin receptor A (ETA) promotes vasoconstriction and cell proliferation, whereas receptor B (ETB) is
involved in clearance of endothelin as well as nitric oxide
release from the endothelium. Bosentan blocks ETA and
ETB receptors, whereas ambrisentan and sitaxsentan are
selective ETA antagonists. Adverse actions of ERAs
include: hepatotoxicity, anemia, teratogenicity, testicular
atrophy and male infertility [2830]. Ambrisentan is a
nonsulfonamide, and may have a more favorable adverse
profile [32]. Elevation of liver enzymes (defined as three
times the upper limit of normal) occurs with bosentan
(10%), sitaxsentan (4%), and ambrisentan (2%).
The third pathway for pulmonary hypertension therapy is
inhibition of phosphodiesterase 5 (PDE5) [2830]. The
vasodilation effects of nitric oxide are mediated by cyclic
guanosine monophosphate (cGMP) that is subsequently
hydrolyzed by phosphodiesterases. Because PDE5 is predominately located in lung tissue, inhibition causes selective pulmonary vasodilation. Sildenafil is approved for
PAH therapy, whereas longer acting tadalafil is currently
indicated only for erectile dysfunction [26,33]. Combination therapy with sildenafil may potentiate effectiveness
and limit side effects of other single agents [34].
Many studies of these drugs have used improvement in
the 6 min walk distance as demonstration of efficacy. A
critical assessment of these expensive therapies noted
that exercise training alone can achieve a more than 90 m
improvement [35,36]. A recent meta-analysis of 23
randomized controlled trials in patients with PAH
suggested a reduction in overall mortality compared with
control groups [37]. The above drugs primarily address
vasoconstriction processes in pulmonary hypertension.
Future therapies are likely to target vascular remodeling
responsible for structural increases in PVR [38]. New
biomarkers such as the N-terminal fragment of brain
naturetic peptide (NT-proBNP) will help assess disease
severity and treatment response [39]. Most recently, the
inflammatory marker C-reactive protein has been shown
to predict outcome and response to therapy in PAH
[40]. It is interesting that the statin agent rosuvastatin,
which lowers C-reactive protein, has been shown effec-

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Oral

Oral

Tadalafil

Oral

Ambrisentan (Letairis)

Sildenafil (Revatio), (Viagra)

Oral

Oral

Beraprost

Sitaxsentan (Thelin)

Aerosol inhalation,
and continuous i.v.

Iloprost (Ventavis)

Oral

Subcutaneous or i.v.
Inhalation use is
investigational

Treprostinil (Remodulin)

Bosentan (Tracleer)

Continuous i.v. with

indwelling catheter
and infusion pump

Epoprostenol (Flolan)

Route

FDA approved 2002 (subcutaneous),

2004 (i.v.), stable prostanoid, premixed
drug available, greater infection rate,
more gram-negative bacteremia, may
potentiate other antihypertensive drugs
FDA approved 2004.
Potentiates antihypertensive drugs

Start 1.25 ng/kg/min

Usual dose <40 ng/kg/min
(2x epoprostenol dose)
t1/2 3 h

Once a day dosing

Investigational doses: 2.5, 10, 20,
or 40 mg/day [26]

20 mg t.i.d.
Approved by FDA
t1/2 34 h

1, 2.5, 5 or 10 mg/day
Start dose 5 mg/day
Increase to 10 mg/day

100 mg/day

Start 62.5 mg b.i.d., 125 mg b.i.d.

after 4 weeks
t1/2 5 h

Start 20 mg q.i.d., increase

if tolerated
t1/2 3540 min

Not FDA approved for the United States

RCTs showed early improvement
(36 months), but not improvement
at 12 months
Nonselective endothelin receptor antagonist
ETA ETB prevents and reverses vascular
remodeling and RVH
Requires regular tests: LFTs q month,
Hct q 3 months
Regular pregnancy tests
May require increase in warfarin dose
Approved in Europe, Canada, Australia
Not FDA approved in US
Selective ETA receptor antagonist
Increases INR, so decrease warfarin
dose to 80%
FDA approved 2007
Selective ETA receptor antagonism
Adverse characteristics similar to bosentan
Monthly LFTs, pregnancy tests
periodic Hct, interferes with hormonal
contraceptives
FDA approved for IPAH in 2005
Inhibitor of phosphodiesterase 5 to
increase cGMP levels
Potentiates antihypertensive drugs
Contraindicated if also use organic nitrates
Longer-acting PDE5 inhibitor
FDA approved only for erectile dysfunction
Investigational for PAH

FDA approved 1995, IPAH and

APAH scleroderma, pulmonary
vasodilator, antiplatelet aggregation
Probable inotropic effects
Improved survival for IPAH
Daily sterile reconstitution, ice packs
for drug stability

Start 2 ng/kg/min,
increase based
on symptoms/side effects.
Optimal 2540 ng/kg/min
t1/2 3 min

Start 2.5 mg, 69x/day

Increase to 5 mg/69x/day
t1/2 30 min

Characteristics

Dosagea

Headache, myalgia, flushing

Blurred vision (25%) [26]

Headache, flushing, dyspepsia,

epistaxis, nasal congestion,
visual disturbance

Leg edema, more in patients

>65 years, nasal congestion
Testicular atrophy
Nonsulfonamide drug, less liver toxicity
Elevated liver aminotransferases in 2%

Adverse characteristics similar

to bosentan
Elevated liver aminotransferases in 4%

Syncope, flushing, mild anemia, edema,

interferes with hormonal contraceptives,
teratogenicity, testicular atrophy
Male infertility
Elevated liver aminotransferases in 10%
Yearly cost $36 000

Cough 38%, headache 30%, flushing 27%,

jaw pain 12%
Serious side effects: syncope 5%, tachycardia
2% pneumonia
Increased bleeding if taking anticoagulant drug
Headache 70%, flushing 55%,
jaw pain 2550%

Headache, jaw pain, flushing,

nausea, diarrhea, skin rash,
musculoskeletal pain
High output heart failure with overdose
Catheter problems: infection
thrombosis, severe rebound
if dose interruption
Yearly cost $75 000
Site pain and erythema in 85%
Headache, diarrhea, rash, nausea
Bleeding risk if taking anticoagulant drug
Yearly cost $89 000

Adverse/side effects

This table collates information from multiple sources about drug therapy for pulmonary hypertension. Note abbreviations: ng, nanogram; mg, microgram; mg, milligram.
For preparation of this table, starting drug dosages were those published in [4].

PDE5 inhibitors

Endothelin receptor
antagonists

Prostanoids

Drug

Table 1 New drug therapy for pulmonary hypertension

28 Thoracic anesthesia

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Pulmonary hypertension in thoracic surgical patients Ross and Ueda 29

tive in preventing pulmonary hypertension in an animal

model [41].

Pulmonary hypertension and surgery

Retrospective reviews are available for patients with
pulmonary hypertension undergoing noncardiac surgery.
In contrast, there are only case reports of thoracic operations in patients with pulmonary hypertension.
Noncardiac surgery and pulmonary hypertension

Three retrospective reviews of noncardiac surgery in

patients with pulmonary hypertension found that uncomplicated, lower risk surgical procedures were tolerated
satisfactorily if performed in centers of expertise However,
even if the intraoperative course was stable, significant
adverse events could occur in the postoperative period.
In 1999, Ammash et al. [42] described noncardiac surgery
(no thoracic procedures) outcomes for 24 patients with
Eisenmenger syndrome. Half of the cases were done at the
authors tertiary medical facility and half were from smaller
hospitals. Preoperative saturations were 6392% (mean
81%) and hematocrits ranged from 41.9 to 73.5% (mean
53.8%). RV dysfunction was moderate or severe in over
half the cases. Most anesthetic patients were general and
most patients were extubated immediately after operation.
One death occurred in a patient who underwent a prolonged (over 8 h) spinal fusion for disabling scoliosis.
Another death from an outside institution followed an
appendectomy. Overall the mortality was 7% [42].
In 2005, Ramakrishna et al. [43] reported their 12-year
retrospective experience of 145 patients with severe
pulmonary hypertension who underwent noncardiac
surgery, including some thoracic procedures. Types of
pulmonary hypertension included: IPAH (20%), APAH
(35%), lung disease (19%), and chronic thrombo-embolic
pulmonary hypertension (8%). The average right ventricular systolic pressure (RVSP) was 68  21 mmHg. Early
perioperative mortality rate was 7%. Respiratory failure
(60%) and RV failure (50%) were frequent contributing
factors to mortality. Causes of morbidity were respiratory
failure (28%), dysrhythmia (12%), and congestive heart
failure (11%). Thoracic surgery cases showed the highest
morbidity at 61.5%. Markers for early morbidity included
greater than 3 h of anesthesia and intraoperative vasopressor support. Cases done with neuraxial or other
regional anesthesia were excluded [43].
In 2007, Lai et al. [44] reported outcomes of noncardiac
surgery in 62 patients with severe pulmonary hypertension mostly associated with left-sided heart disease.
The average RVSP was 78.8  9.4 mmHg. General
anesthesia (propofol, midazolam, sevoflurane, isoflurane,
and desflurane) was used for over half of the cases and

spinal anesthesia in about one-third. No particular anesthetic agent or technique was judged superior to another.
Reversible, intraoperative hypotension occurred in
approximately 20% of both pulmonary hypertension
and control cases. One episode of reversible bradycardia
occurred in a patient with pulmonary hypertension.
Despite the stable intraoperative courses, early postoperative morbidity was 24% and in-hospital mortality
was 9.7%. Causes of morbidity were delayed extubation
(21%), heart failure (9.7%) and major arrhythmia (3.2%).
This series included four thoracic procedures: wedge
resection, lobectomy, open lung biopsy, and esophagectomy, but further details were not provided [44].
Thoracic surgery and pulmonary hypertension

In contrast to the above noncardiac surgeries, lung biopsy

is normally a minor thoracic procedure. However, for
patients with pulmonary hypertension, this procedure
can have major complications. Kreider et al. [45], in
2007, reported their results of video-assisted thoracic
lung biopsy in interstitial lung disease. Preoperative
testing determined that eight patients had a pulmonary
artery systolic pressure (PASP) greater than 40 mmHg. In
this pulmonary hypertension subgroup, four patients
(50%) experienced morbidity and two patients died
(25%) [45].
A number of lung biopsy case reports illustrate specific
problems [4650] (Table 2). Anesthetic techniques were
general with or without epidural. In three of the reports
[all thorascopic with one-lung ventilation (OLV)], significant bleeding occurred [4648]. In one case, the onset
of severe bleeding coincided with a progressive rise in
pulmonary pressures at the end of the operation. The
authors considered that endoscopic staples were not
designed for elevated pressures of pulmonary hypertension [48]. In another case, severe bleeding was not noted
until the next day [47]. Both cases required thoracotomy
to control the bleeding. Of note is that each of these
reports also described significantly increased pulmonary
artery pressures during OLV. In contrast, two case reports
of open lung biopsy without OLV reported no sequelae
except elevated pulmonary artery pressure postoperatively [49,50].

Peri-operative management for patients with

pulmonary hypertension requiring thoracic
surgery
There is no clear evidence that any agent or technique is
preferable for patients with pulmonary hypertension.
Even drugs without myocardial-depressant properties
may be poorly tolerated if the patient is dependent on
the sympathetic nervous system to maintain resting
hemodynamics [51]. Regional anesthesia with thoracic
epidural (TEA) is also controversial. TEA could limit

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Open lung biopsy

Open lung biopsy

PPHb

PPHb

31 years, female [49]

25 years, male [50]

PAP 153/76
CVP 26
preop nifedipine
PAP 163/68
CVP 29
preop nifedipine

Thoracoscopic
lung biopsy
Pulmonary hypertension secondarya
to Sjogren syndrome
43 years, female [48]

PAP 85/47
no change with O2,
ATP, or PGI2
PAP 65/30
decreased with O2
Thoracoscopic
lung biopsy
VSD
14 years, female [47]

surgical stimulus and prevent an acute pulmonary hypertension crisis. Alternatively, TEA could block cardiac
sympathetic nerves and thus reduce cardiac function
[52]. Whatever technique is chosen, provision for immediate and continuous support of the circulation should be
available.
ASD, atrial septal defect; GA, general anesthesia; iNO, inhaled nitric oxide; mPAP, mean pulmonary artery pressure; OLV, one-lung ventilation; VSD, ventricular septal defect.
a
Secondary pulmonary hypertension is an older terminology. Current terminology would be APAH associated pulmonary arterial hypertension.
b
PPH in these references indicates primary pulmonary hypertension. Current terminology would be IPAH indicating no known cause.

Extubated in OR
PAP increased to190/78 postop

No complications

PAP increased to 135/76 mmHg

during OLV
Difficult hemostasis
Re-operation for postoperative
bleeding
Died from RV failure on postoperative day 8

mPAP increased to 78 mmHg

during OLV
Re-operation for postoperative bleeding

GA epidural, OLV
Induction: ketamine, fentanyl
Maintenance: propofol, fentanyl
iNO (20 ppm)
norepinephrine to 0.28 mg/kg/min
GA, OLV
Induction: propofol
Maintenance: sevoflurane, propofol, fentanyl
GA, OLV isoflurane, fentanyl
nitroprusside 0.13 mg/kg/min
multiple interruptions to re-inflate
lung because unstable course
GA epidural, DLV
Induction: fentanyl, thiopentone
Maintenance: isoflurane, fentanyl
GA, DLV
Induction: lidocaine, fentanyl thiopentone,
suxamethonium
Maintenance: isoflurane, atracurium
mPAP 59
PAP decreased with
epoprostenol
Thoracoscopic
lung biopsy
ASD Eisenmenger syndrome
38 years, female [46]

Surgical
procedure
Cause of pulmonary hypertension
Age, sex (reference)

Table 2 Case reports of pulmonary hypertension and thoracic surgery

Preoperative PAP
(mmHg)

Anesthesia management

Events/outcome

30 Thoracic anesthesia

Echocardiography and invasive monitoring may be essential to determine causes of hemodynamic instability.
Right-sided problems include decreased venous return,
RV distension, RV failure, and increased PVR. The
hypertrophied RV is preload dependent and may not
tolerate volume depletion such as bleeding. However,
over-aggressive volume loading is also detrimental. A
distended RV shifts the atrial and ventricular septums
toward the left, causing impeded left heart filling and
decreased systemic pressure and cardiac output [53]. RV
oxygen balance also is critical. With pulmonary hypertension and RV hypertrophy, right coronary artery flow
becomes more dependent on diastole [54]. With hypertrophy, coronary flow reserve may be depleted [55]. It is
key to maintain systemic blood pressure, and replace
significant blood loss. Vasopressor drugs with inotropic
properties such as norepinephrine are superior to alphaagonist agents such as phenylephrine [56,57]. Inotropic
support with dobutamine may also be useful [58].
Whereas vasopressin is commonly considered only to
cause systemic vasoconstriction, animal studies indicate
negative inotropic effects and increased PVR can occur,
particularly at higher doses [59,60].
A major issue for pulmonary hypertension and thoracic
surgery is OLV. For normal patients, OLV is tolerated
because hypoxic pulmonary vasoconstriction (HPV)
reduces pulmonary shunt and thus improves systemic
oxygenation. However, in patients with pulmonary hypertension, HPV during OLV may cause an intolerable
increase in PVR. There is considerable interest that
inhaled pulmonary vasodilators may attenuate this
disturbance (Table 3). Proposed benefits of inhaled
vasodilators are several. Inhalation provides higher concentrations in the pulmonary circulation and promotes
selective pulmonary rather than systemic vasodilation.
Inhaled agents maintain V/Q matching because the vasodilation effect occurs in the vicinity of well ventilated
regions of the lung. In contrast, intravenous vasodilators
may interfere with HPV in both lungs, resulting in an
increased pulmonary shunt and systemic hypoxemia.
However, study results require careful interpretation.
Several studies involve patients undergoing lung transplantation during which norepinephrine was simultaneously infused. In such circumstances, it is difficult
to ascertain the effect of the inhaled agent on the
systemic resistance. If the study was done during unilateral pulmonary artery clamping, assessment of the drug
effect on pulmonary shunt is also questionable.

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Epoprostenol [68]
Milrinone
PDE inhibitor

Nitroprusside

Mitral valve surgery [80], animal model [81]

Lung transplant [76]

Treprostinil
Prostaglandin E1 (PGE1)
Nitroglycerin (NTG)
Nitric oxide donor

PEAa, ICU [71], animal study [72], animal

study [73]
Animal study [75]
Lung transplant [76]
Mitral valve surgery [77], mitral valve surgery
[78]
Animal study [79]
Iloprost

Epoprostenol
Prostaglandin
agents

A different issue is when pulmonary hypertension

patients are receiving chronic pulmonary vasodilator
agents. If these drugs inhibit HPV, OLV could result
in an increased pulmonary shunt and hypoxemia. For
example, in normal volunteers, sildenafil taken 1 h prior
to breathing a hypoxic gas mixture (11% O2) nearly
abolished the normal rise in pulmonary artery pressure
[82]. Because chronic pulmonary vasodilator agents cannot be discontinued, modification of lung ventilation
techniques (e.g. CPAP/O2 to nonventilated lung, limited
lobar bronchial blocker) may be necessary.
Table 3 is original with data collected from the individual cited references. OLV, one-lung ventilation.
a
PEA, pulmonary endarterectomy surgery.

iNO [62], milrinone

cardiac surgery [68]
Animal study [67]
Animal study [67], cardiac surgery [18]

Nitric oxide (iNO)

Nitric oxide

Thoracic [61], lung transplant [62]

Inhaled nitric oxide, aerosolized epoprostenol, and aerosolized prostaglandin E1 have been studied for effect
during OLV. Inhaled nitric oxide lowered PVR and
improved oxygenation during OLV in patients with
increased pulmonary artery pressures, but not in patients
who had normal pulmonary artery pressures [61,64].
Inhaled but not intravenous epoprostenol showed selective pulmonary vasodilator effect during OLV in an animal
model [67]. When inhaled or intravenous epoprostenol was
administered with inhaled nitric oxide during OLV, effects
on pulmonary artery pressure and oxygenation were
superior to inhaled nitric oxide alone [61]. Other vasodilator agents have been administered by inhalation
although not during OLV. In general, the inhalation route
seems to provide selective pulmonary vasodilation.

Inhaled iloprost more effective than

inhaled NTG [78]
Inhaled nitroprusside similar to inhaled
nitric oxide [79]

No effect on pulmonary artery pressures

in normal patients, OLV [63],
methemoglobinemia and
carboxyhemoglobinemia [65],
rebound pulmonary hypertension
when discontinue iNO, animal study [66]
Rebound pulmonary hypertension, animal
study [69], inhibition of platelet
aggregation, cardiac surgery [70]
Iloprost may be superior to iNO: animal
study [72], cardiac surgery [74]
Epoprostenol [62],
iloprost, PEAa [64]
Thoracic [61],
thoracic [63]

iNO, PEAa [64]

Other/adverse effects
Combination therapy with
Effective with OLV
Type cases with selective pulmonary
vasodilation effect
Inhaled pulmonary
vasodilator

Table 3 Peri-operative inhaled pulmonary vasodilators

Pulmonary hypertension in thoracic surgical patients Ross and Ueda 31

Finally, the postoperative period should be anticipated

for complications, even if the intraoperative course was
stable. Patients with pulmonary hypertension and thoracic surgery should be closely monitored postoperatively
in an ICU. Correct analgesia is essential after thoracic
surgery. Inadequate pain control could exacerbate pulmonary hypertension, whereas excess opioids have
potential for respiratory depression. TEA and thoracic
paravertebral block (TPB) are effective analgesia techniques [83]. Compared with TEA, TPB has less incidence of systemic hypotension [84]. The risk/benefit of
analgesia infusion devices must be carefully considered
because patients with pulmonary hypertension are not
likely to tolerate overdose [42].

Conclusion
Whereas the literature about surgery in patients with
pulmonary hypertension is scarce, the ongoing research
and advances in new drug therapies is abundant. It is
likely that anesthesiologists will have increased
exposure to patients with pulmonary hypertension. It
is also likely that novel use of inhaled vasodilator agents
will increase. At present, thoracic surgery with OLV
presents a significant obstacle to patients with pulmonary hypertension. Postoperative recovery is also a challenge. Opportunities exist for innovation in techniques
and pharmacology.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

32 Thoracic anesthesia

Acknowledgements
A.F.R. has received research support from Emphasis Medical,
Bronchus Technologies, and Aries.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
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of special interest
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