Download A Thotharam HIV related pulmonaryhypertension in

22June 2012
No.20
HIV related pulmonary hypertension
in the obstetric patient
A. Thotharam
Commentator: S. Maharaj
Moderator: M. Mudely
Department of Anaesthetics
CONTENTS
INTRODUCTION ................................................................................................... 3
DEFINITION .......................................................................................................... 3
HAEMODYNAMICS .............................................................................................. 5
CLASSIFICATION ................................................................................................ 5
Venice .................................................................................................................. 6
Dana Point ........................................................................................................... 7
PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH HUMAN
IMMUNODEFICIENCY VIRUS (HIV)..................................................................... 8
Prevalence ........................................................................................................... 8
Pathogenesis ....................................................................................................... 8
HIV-related factors ........................................................................................... 9
Other viral factors ............................................................................................ 9
Host factors...................................................................................................... 9
Clinical presentation ......................................................................................... 10
Diagnosis ........................................................................................................... 10
Natural history ................................................................................................... 12
Therapy .............................................................................................................. 13
ANAESTHETIC MANAGEMENT ........................................................................ 16
Pre operative assessment ................................................................................ 16
Delivery .............................................................................................................. 17
Vaginal delivery ............................................................................................. 17
Caesarean section ......................................................................................... 17
Regional Anaesthesia ................................................................................... 17
General ........................................................................................................... 18
Peri-operative monitoring ................................................................................. 19
Post partum ....................................................................................................... 19
Has there been an improvement in mortality over the last decade? ............. 20
CONCLUSION .................................................................................................... 21
REFERENCES.................................................................................................... 22
Page 2 of 26
INTRODUCTION
HIV, PULMONARY HYPERTENSION AND PREGNANCY
: A FATAL TRIAD
Pulmonary hypertension(PH) is a pathophysiological state characterized by
elevated mean pulmonary arterial pressure and is found in a number of clinical
conditions.31 It is a life threatening condition with poor prognosis if left untreated.
Human immunodeficiency virus–related pulmonary hypertension (HIV-PAH) exists
when pulmonary arterial hypertension (PAH) develops in patients who have
human immunodeficiency virus (HIV) infection and an alternative cause cannot be
recognized. 1-3
During pregnancy, physiologic cardiovascular and pulmonary changes worsen
existing pulmonary hypertension and right ventricular dysfunction. Pulmonary
hypertension is tolerated poorly in the parturient.4,5 Additional haemodynamic
changes occur with labour, especially during uterine contractions. After placental
extraction cardiac output and systemic vascular resistance increase dramatically.
Therefore physiologic changes during pregnancy, during delivery and the
postpartum period are critical for patients with severe PH.4-5
Deterioration in pregnancy typically occurs in the second trimester with symptoms
of fatigue, dyspnoea, chest pain, when most pregnancy-induced haemodynamic
changes have occurred4. During labour, uterine contractions add 500 ml of blood
to the circulation. The pain and effort of labour increases right atrial pressure and
cardiac output4,5, which may result in right heart failure and even death.
Women with PAH are advised against pregnancy and a termination of pregnancy
is considered if PH is identified early
in pregnancy. When pulmonary
hypertension is diagnosed late in pregnancy, the pregnancy is allowed to continue
and an elective delivery is usually planned.
Improved medical care of patients with PH has increased their life expectancy and
has resulted in more women of childbearing age considering pregnancy. 5
DEFINITION
The definition of pulmonary hypertension is based upon right heart catheterization
measurements. PH is defined as a mean pulmonary artery pressure greater than
or equal to 25mmHg at rest6,7 associated with a pulmonary capillary wedge
pressure lower than 12mmHg . A mean pulmonary artery pressure of 8 to 20
mmHg at rest is considered normal, while the significance of a mean pulmonary
artery pressure of between 21 to 24 mmHg at rest is unclear.9 Patients presenting
with pulmonary artery pressures in this range need further evaluation in
epidemiological studies.
Page 3 of 26
Two previous definitions that were acknowledged are no longer used. They
include a mean pulmonary artery pressure greater than 30 mmHg with exercise
(this is similarly measured by right heart catheterization)7 and a systolic pulmonary
artery pressure
greater than 40mmHg (derived
from
Doppler
8
echocardiography) . The latter corresponds to a tricuspid regurgitant velocity of
3.0 to 3.5 m/sec.
Table 1.Haemodynamic definitions of pulmonary hypertension31
Definitions
Characteristics
Clinical groups
Pulmonary hypertension
MAP > 25 mmHg
All
Pre capillary PH
MAP > 25 mmHg
1. Pulmonary arterial
Hypertension
PWP <15mmHg
CO normal/reduced
3. PH due to lung
Disease
4. Chronic
thromboembolic PH
5. PH with unclear and/or
multifactorial
mechanisms
Post capillary PH
Mean PAP
2. PH due to left heart
>25 mmHg
Disease
PWP >15 mmHg
CO normal/reduced
TPG >12 mmHg
TPG <12 mmHg
MAP= Mean Arterial pressure, PWP= pulmonary wedge pressure, CO= cardiac
output, TPG= transpulmonary gradient, PH = pulmonary hypertension
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HAEMODYNAMICS
Haemodynamic variables that contribute to pulmonary arterial pressure can be
identified using a variation of Ohm’s Law.9
Change in pressure = flow x resistance
Ppa - Ppv = Q x PVR
Ppa =
(Q x PVR) + Ppv
Where Ppa is mean pulmonary arterial pressure, Ppv is mean pulmonary venous
pressure, Q = right sided cardiac output , PVR is pulmonary vascular resistance .
Ppv is estimated by the pulmonary capillary wedge pressure (PCWP).
Ppa = (Q x PVR) + PCWP
From this equation, it is apparent that mean pulmonary arterial pressure is
determined by the pulmonary vascular resistance, right sided cardiac output and
mean pulmonary venous pressure. The primary cause of significant PH is almost
always increased pulmonary vascular resistance as in the case with HIV
infection.9
Regardless of the cause of PH, a known series of events occur. The right ventricle
hypertrophies in response to the pressure. If severe enough, the right ventricle
dilates and cardiac output falls.9
CLASSIFICATION
Just as the definition of PH has changed, so has the classification. PH was
previously classified as either idiopathic pulmonary arterial hypertension (IPAH,
previously known as primary pulmonary hypertension) or secondary PH.
Nevertheless, it became apparent that some forms of secondary PH closely
resemble IPAH in their histopathological features , natural history and response to
treatment. In an attempt to organize PH on a mechanistic basis, the World Health
Organization (WHO) classified PH into five groups based on aetiology.31
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Venice
Table 1: Venice clinical classification of pulmonary hypertension (2003) 76
Group 1 PAH
1.Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH
1.2 Familial (FPAH)
1.3 Associated with APAH
1.3.1 Collagen vascular disease
1.3.2 Congenital systemic-to-pulmonary shunts
1.3.3 portal hypertension
1.3.4 HIV infection
1.3.5 Drug and toxins
1.3.6
Other (thyroid disorders, glycogen storage disease,
Gaucher
disease,
Haemorrhagic
telangiactasia,
haemoglobinopathies, myeloproliferative disorders,
splenectomy
1.4 Associated with significant venous or capillary involvement
1.4.1 Pulmonary veno-occlusive disease
1.4.2 Pulmonary capillary haemangiomatosis
1.5 Persistent pulmonary hypertension of the newborn
Group 2 PH
2. Pulmonary hypertension due to left heart disease
2.1 Left sided atrial or ventricular heart disease
2.2 left sided valvular heart disease
Group 3 PH
3. Pulmonary hypertension owing to lung disease &/or hypoxaemia
3.1 COPD
3.2 interstitial lung disease,
3.3 Sleep disordered breathing
3.5 Alveolar hypoventilation disorders ,
3.6 Chronic exposure to high altitude,
3.7 Developmental disorders
Group 4 PH
4.Chronic thromboembolic pulmonary hypertension
4.1 Thromboembolic obstruction of proximal pulmonary arteries
4.2 Thromboembolic obstruction of distal pulmonary arteries
4.3Nonthromboembolic pulmonary embolism (tumour,parasite,foreign
material)
Group 5 PH
5.Miscellaneous
Sarcoidosis, histiocytosis X, Lymphangiomatosis, compression of
pulmonary vessels(adenopathy, tumours, fibrosing mediastintis)
Page 6 of 26
Dana Point
Table 2: Dana Point classification of pulmonary hypertension based on aetiology
(2008)31
Group
1 PAH
1.Pulmonary arterial hypertension (PAH)10
1.1 Idiopathic PAH
1.2 Heritable PAH,
1.2.1 BMPR2
1.2.2 ALK1, endoglin (With or without hereditary
haemorrhagic
telangiactasia)
1.2.3 unknown
1.3 Drug and toxins
1.4 Associated with PAH (APAH)
1.4.1 connective tissue disease
1.4.2 HIV infection
1.4.3 portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.4.6 Chronic haemolytic anaemia
1.5 Persistent pulmonary hypertension of the newborn
1’ Pulmonary veno-occlusive disease and/or pulmonary capillary
haemoangiomatosis
Group 2 PH
2. Pulmonary hypertension due to left heart disease
2.1 systolic dysfunction,
2.2 diastolic dysfunction
2.3 valvular heart disease9
3. Pulmonary hypertension owing to lung disease &/or hypoxaemia
3.1 COPD
3.2 interstitial lung disease,
3.3 Other pulmonary diseases with mixed restrictive and obstructive
pattern
3.2 Sleep disordered breathing
3.3 Alveolar hypoventilation disorders ,
3.6 Chronic exposure to high altitude,
3.7 Developmental disorders
4. Chronic thromboembolic pulmonary hypertension
5.Pulmonary hypertension with unclear multifactorial mechanisms
5.1 Haematological disorders: myeloproliferative disorders, splenectomy
5.2
Systemic disorders: sarcoidosis, pulmonary Langerhans cell
histiocytosis, neurofibromatosis, vasculitis.
5.3 Metabolic disorders: glycogen storage disease,Gauchers disease .
5.4 Others: tumoural obstruction, fibrosing mediastinitis,chronic renal
failure on dialysis
Group 3 PH
Group 4 PH
Group 5 PH
Page 7 of 26
PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH HUMAN
IMMUNODEFICIENCY VIRUS (HIV)
HIV infection is an independent risk factor for pulmonary hypertension (PAH)11-13,
which may occur irrespective of the mode or stage of HIV infection, and degree of
immunodeficiency1, 14 . Mortality in patients with PAH-HIV is usually related to
pulmonary vascular disease rather than other complications of HIV infection. PAH
is considered and independent predictor of death.1, 14, 15
Prevalence
The initial prevalence of PAH in HIV patients was found to be 0.1–0.5%15-17 with
an estimated incidence of 0.1% per year. This is 6-12 times greater than the
prevalence of PAH in individuals without HIV infection .
The largest study was a prospective cohort study of 7648 consecutive patients
(done in France- 2004 to 2005) with HIV which found a prevalence of HIV PAH of
0.5%17. Studies likely underestimate the true prevalence of HIV-PAH because the
disease often exists prior to the onset of symptoms and diagnosis. Asymptomatic
disease is not included in the prevalence estimate.
It was suggested that the use of highly active antiretroviral therapy could decrease
the rate of PAH associated with HIV infection18, but a population study recently
conducted in France contradicts this hypothesis because the calculated
minimal prevalence of HIV-related PAH was 0.46%, very similar to before the
highly active antiretroviral therapy era.17
Pathogenesis
The pathogenesis of HIV-related PAH remains unclear. Both host and viral
factors are likely to play important roles. 1 The contributions of viral and host
factors are difficult to distinguish as many patients with HIV infection have coexisting conditions that are associated with PAH (eg Hepatitis B/ Hepatitis C
infection)1
Plexiform lesions are the hallmark histopathologic finding in patients with severe
PAH including HIV PAH.9 Plexiform lesions are characterized by abnormal
endothelial cells, intima disruption , medial hypertrophy , thrombosis and luminal
obliteration with recanalization19. HIV infection probably does not directly cause
the plexiform lesions since HIV is not known to infect endothelial cells. However
HIV infection may affect the same pathways that produce plexiform lesions in
other types of PAH. Supporting this theory,the plexiform lesions of HIV-PAH are
indistinguishable from the lesions seen in patients who have idiopathic PAH
(IPAH) 20,21.
Page 8 of 26
 HIV-related factors
HIV proteins may contribute to the development of HIV-PAH, as suggested
by the data that follows:73
 gp 120- gp 120 is an HIV surface protein that facilitates the binding of HIV to
CD4 –positive T lymphocytes. It stimulates in vitro secretion of endothelin-1,
a molecule which is known to contribute to IPAH by causing vasoconstriction
as well as smooth muscle cell proliferation22. Endothelin-1 may contribute
similarly to HIV-PAH . This theory is supported by the observation that
circulating monocytes from patients with HIV infection have increased
endothelin-1 gene expression.73
 Tat- Tat is an HIV transactivator that is essential for viral replication . It
downregulates a molecule (BMPR2- Bone morphogenic protein receptor
type II) whose function is to induce apotosis in a variety of cell types 23. A
deficiency of BMPR2 function will allow excess endothelial cell growth and
proliferation in response to injury, which may contribute to PAH 24,25.
 Nef- Nef is an HIV adaptor protein that is essential for the maintenance of
high levels of HIV RNA. Nef predominates in the alveolar mononuclear cells
and the endothelial cells of patients who have HIV-PAH 19. In animals ,
infection with Nef-positive virus induces plexiform lesions , whereas infection
with a Nef-negative virus does not.73 Hence this data suggest that Nef may
contribute to formation of these plexiform lesions in patients with HIV-PAH.
 Other viral factors
Another co-infection in patients with HIV is Human Herpes virus or HHV8
which is the virus responsible for Kaposi’s sarcoma . The endothelial
abnormalities in patients with Kaposi’s sarcoma closely resemble the
plexiform lesions that are characteristically found in HIV-PAH.26 Whether
Human Herpes Virus 8 has a role in the pathogenesis of HIV-PAH is not
been fully elucidated.
 Host factors
Patients with a certain human leukocyte antigen (HLA) may also be
predisposed to HIV-PAH. In a case-control study , the frequency of HLA
class II DR52 and DR6 was higher in patients with HIV-PAH when compared
with healthy subjects and a racially diverse group of patients with HIV
infection who did not have PAH.27
A number of host cytokines are much higher in patients with HIV infection .
These cytokines may play a role in the development of HIV-PAH. Such
cytokines include interleukin-6, IL1 beta, tumour necrosis factor alpha and
platelet derived growth factor which can induce a procoagulant state,
increase the expression of endothelial adhesion molecules and increase the
accumulation of inflammatory cells in the pulmonary arteries28 ,29.
Page 9 of 26
These cytokines are unlikely thought to be the sole cause of HIV-PAH
because they are elevated in all patients with HIV infection, only a fraction of
whom develop HIV-PAH.73
Clinical presentation
HIV-related PAH shares a similar clinical presentation with IPAH.
These findings may not be as straight forward to recognise as being due to PH if
the PH is due to another underlying condition like HIV infection as the
presentation of the underlying disease may obscure those of PH.1
History
Patients with PH initially experience exertional dyspnoea, lethargy, and fatigue
,which are a result of inability to increase cardiac output with exercise 30.
Symptoms at rest are reported in advanced cases. As PH advances and right
ventricular failure develops, exertional chest pain, exertional syncope and
peripheral oedema may develop. In many circumstances, angina occurs due to
subendocardial hypoperfusion which is due to increased right ventricular wall
stress and myocardial oxygen demand.
Physical examination
The initial physical finding of PH is usually increased intensity of the pulmonary
component of the second heart sound. This second heart sound may even be
palpable. The second heart sound is narrowly split or may be single in patients
with preserved right ventricular function. Splitting of the second heart sound
widens as the right ventricle fails or if a right bundle branch block develops.
Auscultation of the heart may also reveal a systolic ejection murmur and in more
severe disease, a diastolic pulmonary regurgitant murmur(pulmonary
insufficiency) .The right sided regurgitant murmurs and gallops are augmented
with inspiration.
Right ventricular failure results in systemic venous hypertension. This can lead to
a variety of findings such as elevated jugular venous pressure, a right ventricular
third heart sound as well as a prominent ‘V’ wave in the jugular venous pulse if
tricuspid regurgitation is present. Inaddition hepatomegaly, a pulsatile liver,
peripheral oedema, ascites and pleural effusions may be present.
Diagnosis
Diagnosis of Human immunodeficiency virus-induced PAH requires confirmation
of PAH, confirmation of HIV infection and exclusion of other causes of pulmonary
hypertension.
Tests used in the diagnosis include:
Page 10 of 26
Chest radiograph
Abnormal findings encompass: central pulmonary arterial dilatation, which
contrasts with “pruning” of the peripheral blood vessels.
Right atrial and right ventricular hypertrophy may be appreciated in
advanced cases.
The chest radiograph allows associated lung diseases or pulmonary
venous hypertension caused by left heart disease to be excluded. The
severity of PH does not co-incide with the extent of radiographic
abnormalities.31
Electrocardiogram
This may offer indicative or supportive evidence of PH by showing RV
hypertrophy, strain and right atrial dilatation. RV hypertrophy on ECG is
present in 87% and right axis deviation in 79% of patients with IPAH30. The
absence of these findings does not exclude the presence of PH neither will it
eliminate severehaemodynamic abnormalities.
The ECG has insufficient sensitivity(55%) and specificity (70%) to be a
screening tool for detecting significant PH. Ventricular arrhythmias are rare.
Supraventricular arrhythmias may be present in advanced stages, in
particular atrial flutter, but also atrial fibrillation, which almost invariably
leads to further clinical deterioration.32
Myat Tun Lin Nyo et al, Case report, CVJA 2012
ECG trace of a parturient with HIV-PAH :sinus tachycardia,right ventricular hypertrophy,right axis deviation , T
inversionV1-V4
Page 11 of 26
wave
Echocardiography
This is the screening method of choice. Anatomic and functional data
including ventricular function , valvular abnormalities and intracardiac shunts
can be assessed. Echo may show RVH, dilatation of the right heart
chamber with impairment of left ventricular filling and paradoxical motion of
the interventricular septum. Doppler studies provide an estimate of
pulmonary artery systolic pressure by measuring peak velocity of the jet of
tricuspid regurgitation or by directly measuring systolic flow velocity across
pulmonary valve. 73
Confirm PAH
Right heart catheterization is necessary to confirm PAH, which occurs when
the following criteria are met.33
 Mean pulmonary artery pressure >25 mmHg at rest.
 Pulmonary capillary wedge pressure < 15mmHg
Supportive data include an elevated pulmonary vascular resistance and
transpulmonary gradient. The transpulmonary gradient is defined as the
difference between the mean pulmonary arterial pressure and the
pulmonary capillary wedge pressure.
Confirm HIV
This is done by detecting antibodies to the virus.
Exclude alternatives
Groups 2, 3, 4, and 5 PH (Dana Point classification) must be excluded
before a patient who has HIV infection and pulmonary arterial hypertension
can be diagnosed with HIV-PAH. Hence further diagnostic testing such as
echocardiography, chest radiography, computed tomography, pulmonary
function testing,
polysomnography, ventilation-perfusion scanning or
pulmonary angiography, autoantibody testing or spirometry should be
carried out. 73
Natural history
Mortality appears to be high in patients with HIV related pulmonary arterial
hypertension

A systematic review of 131 patients with HIV-PAH found that 50% of patients
died during a median follow up of eight months1. The median duration from
the diagnosis of HIV-PAH until death was six months. The data however
needs to be interpreted with caution as not all the patients received the same
management in these studies and many studies included patients who were
managed before Highly Active Anti-Retroviral Therapy (HAART) became
common.
Page 12 of 26



An observational study of 35 patients with HIV-PAH found that 23 patients
died (66%) with a median survival duration of 2.7 years after diagnosis34. HIV
infection was accountable for 52 % of deaths, with 32% due to PAH or
undetermined (16%)
An observational study of 82 patients with HIV-PAH demonstrated a one, two
and three year mortality rate of 27, 40 and 53% respectively14.
A more recent series of 77 patients with HIV-PAH in the modern therapeutic
era suggests that mortality has improved35. The one and three year survival
rates were 88 and 72 % respectively, which shows an improvement from
previous studies. All of these patients received HAART and 50 patients (65%)
received advanced therapy for their PAH.
Therapy
The treatment discussed here is unique to HIV-PAH however the
treatment of HIV-related PAH is less well established in comparison
with other forms of PAH. The treatment of PAH can be divided into primary
therapy and advanced therapy. Primary therapy is aimed at factors contributing to
the PAH and consequences of the PAH. Advanced therapy includes treatment
with agents with more complex mechanisms of action including vasodilatation and
decreased vascular growth. Primary and advanced therapy for HIV-PAH are
essentially very similar to that of the other types of PAH.
 Antiretroviral therapy
HAART is effective at suppressing HIV replication and restoring immune
function in patients who meet the criteria for treatment. However its initiation for
the sole purpose of treating HIV-PAH is not indicated due to conflicting data
regarding its effectiveness.73 In one retrospective cohort study of 35 patients
with HIV-PAH, results were compared among patients who received
combination antiretrovirals (ARVs) (n=14) , a single nucleoside analogue
reverse transcriptase inhibitor (n=12) or no ARV (n=9)34. Only the patients
treated with combinationARVs had an improvement in haemodynamics, as
assessed by Doppler echocardiography. In addition there seemed to be fewer
PAH associated deaths among patients who received combination ARVs.
However, the patients receiving combination therapy were also receiving PAHdirected therapy (epoprostenol) , hence the results need to be reviewed with
concern.
Another cohort study of 82 patients with HIV-PAH found that survival
deteriorated when patients received HAART without advanced therapy with
epoprostenol.14
Bruno et al performed a retrospective review to determine variables affecting
survival in patients with HIV-PAH on HAART. They concluded that HAART was
unable to improve haemodynamic variables in these patients.35
From a South African perspective a randomized controlled trial of HAART vs
placebo needs to be performed to establish whether HAART is effective in
decreasing the incidence of HIV-PAH.
Page 13 of 26
 Calcium channel blockers
These agents are not recommended for the treatment of HIV-PAH because
efficacy has not been documented and unbearable adverse effects can develop
12
.These comprise considerable hypotension as a result of
systemic
vasodilation and decreased right ventricular filling.
 Diuretics
Are can be included in therapy if fluid retention exists35. They should be used
with concern to prevent a drop in cardiac output( due to decreased right and/or
left ventricular preload), arrhythmias induced by hypokalaemia, and metabolic
acidosis.
 Anticoagulation is not routinely recommended in HIV- PAH alone,because of
an increased risk of bleeding, anticipated compliance issues, and drug
interactions6,66.In essence : each patients treatment should be individually tailor
made.
 Advanced therapy
Advanced therapy includes management with prostanoids, endothelin receptor
antagonists and phosphodiesterase 5 inhibitors. It is usually used for patients
who show continuing PH and a WHO functional class II,III or IV despite
adequate primary therapy.
 Both intravenous and inhaled epoprostenol improve haemodynamics and
symptoms in patients with HIV-PAH.14,37-39 Prostanoids may be used pre/post
partum as they are considered teratogenic74 and have negative effects on
uterine blood flow75.
 Intravenous epoprostenol was evaluated in an uncontrolled clinical trial of 6
patients. Acute infusion of epoprostenol decreased the mPAP (mean Pulmonary
artery pressure by 8.5mmHg) and PVR (pulmonary vascular resistance - mean
216 dyn/sec per cm-5) while increasing the cardiac output (mean 2L/min) and
increasing cardiac index (mean 1.1L/min) 39. Repeat catheterization of five
patients after one year of IV epoprostenol therapy showed greater
haemodynamic function. Ongoing haemodynamic benefit was seen after two
years in three patients and after four years in two patients. Furthermore the
New York Heart Association functional class improved in all of these patients.
 Epoprostenol must be infused via an infusion pump and a central venous
catheter. Dose : 1-2 ng/kg per min and increased by 1-2 ng/kg every one to two
days as tolerated. Maximum dose has not been established. Doses as high as
150-200 ng/kg per min have been used. Complications include jaw pain,
diarrhoea, arthralgias, thrombosis, pump malfunction, central venous catheter
infection can also occur.
Page 14 of 26
 Inhaled epoprostenol was evaluated in two patients with HIV-PAH38. Seven
months of inhaled epoprostenol showed improved walking distance, NYHA
functional class, mPAP, and PVR.
 Trepostinil- can be given intravenously or subcutaneously. Intravenous route is
preferred as it is associated with less pain on injection. Treprostinil may improve
the symptoms and haemodynamics of HIV-PAH. This was shown in an
uncontrolled clinical trial in which three patients with HIV-PAH were treated with
trepostinil40. The six minute walk distance and NYHA functional class improved
at one year in all patients. In addition the systolic pulmonary artery pressure
(estimated by echo) improved in two of these patients.
 Iloprost- Is an inhaled prostanoid that may improve the symptoms and
haemodynamics of patients with HIV-PAH. Another uncontrolled clinical trial
demonstrated that the eight patients treated with iloprost ,had acute
improvement of the pulmonary vascular resistance and cardiac index.41 Among
the four patients who continued with long term iloprost the six minute walking
distance increased and the haemodynamic improvement persisted.41
There are case studies successfully describing the use of iloprost for PAH in
pregnancy49 albeit its association with teratogenicity50.
 Bosentan- is an oral non selective endothelial receptor antagonist that blocks
endothelin-1, a vasoconstrictor and smooth muscle mitogen. Bosentan also
may improve the symptoms and haemodynamics of patients with HIV-PAH.
However, endothelial receptor antagonists are contraindicated in pregnancy as
they are teratogenic42
 Sildenafil - Is a phosphodiesterase (PDE5) inhibitor thereby increasing cyclic
GMP, and prolonging the vasodilatory effects of nitric oxide. Sildenafil appears
to improve symptoms and haemodynamics in patients with HIV-PAH, according
to many case reports43-46. Clinical trials have shown that oral sildenafil is
effective in the treatment of both acute and chronic pulmonary hypertension 47 48
Drug interactions however occur between sildenafil and protease inhibitors.
Protease inhibitors can increase levels of sildenafil and sildenafil can decrease
levels of protease inhibitors.43
 Nitric oxide(NO) – May be used as an inhaled gas. It is a selective pulmonary
vasodilator and acts by stimulating soluble guanylate cyclase and increasing
cyclic guanosine monophosphate. Inhaled NO is currently cumbersome,
expensive, and needs a sophisticated system because it is administered only
during the initial part of the inspiration phase. Patient mobility is also limited.
Rebound pulmonary hypertension may occur with withdrawal.
The experiences with NO in pregnancy are limited to few case studies.
Page 15 of 26
ANAESTHETIC MANAGEMENT
Pre operative assessment
 Preoperative assessment consists of the history, physical examination, and
laboratory studies.
 Assessment of risk and coexisting diseases during preoperative
evaluation should focus on the patient’s status, anaesthesia, CD4 cell count,
the coexistence of opportunistic infections ,malignancies, concurrent treatments
with antiretroviral or anti-opportunistic drugs. This will allow a good prediction
for the peri-operative risk of the HIV-patient to be construed.
 Advanced HIV infection, when accompanied with opportunistic infections or
malignancies, may complicate the perioperative course and management. The
CD4 count/mortality relationship is useful in risk assessment.
 Physical examination must include a comprehensive neurological exam
together with the other systems, including a difficult airway.
 The laboratory work-up should include complete blood count .Check for toxic
effects or possible interaction of antiretrovirals ( anaemia/ thrombocytopaenia),
clotting functions, and glucose, liver (use of Bactrim), and renal function tests
(use of protease inhibitors). Verification of the immunological status, i.e., the
CD4 lymphocyte cell count and viral load during the previous 3 months, is
important. Chest radiograph and electrocardiogram should be performed in all
patients. Patients with a history or signs of cardiac or pulmonary dysfunction
should undergo a more thorough evaluation (blood gases, pulmonary function
tests, echocardiography, cardiac effort test, and radioactive cardiac scanning or
even cardiac catheterization.
 One must remember that these patients have often been subjected to
cardiotoxic antiretroviral drugs, may be in a hypercoagulable state, may have
accelerated coronary arteriosclerosis, and often have decreased left ventricular
contractility. They will require appropriate preoperative work-up and therapy
before any anaesthetic or surgical procedure.
 Another consideration is that acute or prolonged pre op treatment with NO or
inhaled prostacyclins may inhibit platelet aggregation hence pre op
thromboelastogram should ideally be performed to exclude clotting
abnormalities.
Page 16 of 26
Delivery
The optimal mode of delivery (vaginal vs. caesarean section) and anaesthetic
management in patients with PAH remains a matter of debate. Vaginal delivery,
however, is related to smaller shifts in blood volume, less clotting or bleeding
complications, and a lower risk of infection.67
 Vaginal delivery
Regional anaesthesia for vaginal delivery is an acceptable technique. Low dose
epidural analgesia is imperative.51,52. It has no deleterious haemodynamic effect
by itself and significantly lowers the adverse haemodynamic consequences of
labour53. However careful timing is important if patients are receiving
anticoagulation.
 Caesarean section
As mentioned, the choice of anaesthetic for these patients remains debatable.
Whatever the choice may be, the risk of right sided heart failure is markedly
increased. Elective caesarean section is often used 52,54,55,56, as it takes place
during the day to avoid the risk of emergency deliveries with the haemodynamic
instability that could occur under these conditions. Before anaesthesia , chronic
medical treatment already being given for pulmonary hypertension and right
sided heart failure should be continued. Patient positioning intraoperatively is
also very important.
 Regional Anaesthesia
Epidural anaesthesia has been used successfully for caesarean sections in
patients with HIV-PAH. There are now more case reports highlighting the
successful use of regional anaesthesia with positive outcome52,55,59,60 61.
Nevertheless the dense and extended block required for analgesia during
caesarean section may have haemodynamic consequences. Specifically single
shot spinal anaesthesia is considered a contraindication in these patients62,63. .
Hence, graded epidural anaesthesia is often regarded as the best regional
technique52,60,61. Some authors prefer using combined spinal-epidural
anaesthesia because it provides a superior sensory block than epidural
anaesthesia and is associated with an unlikely risk of hypotension when used in
very low doses, spinally.62,63
Regional anaesthesia also has the advantage of not interfering with the immune
system or with antiretroviral drugs. Contraindications however must be noted.
Several haemodynamic goals should be reached: maintain the pulmonary
pressure as low as possible and the systemic pressure within 15% above and
below the basal level (the systemic pressure should always be higher than the
pulmonary pressure). Avoid arrhythmias , tachycardia and maintain sinus
rhythm.
Page 17 of 26
 General
Some authors have described the use of general anesthesia with good maternal
outcome57,58.In these patients, pulmonary complications can exist due to
opportunistic infections. This may lead to respiratory distress and hypoxaemia,
worsened by a lowered functional residual capacity seen in pregnancy.
Although some authors have described the use of general anaesthesia with
good outcome57,58, others have reported higher pulmonary arterial pressure
during laryngoscopy and tracheal intubation , and the adverse effects of PEEP
may result in cardiac failure62,63.
Potent inhalational agents have the ability to drop systemic vascular resistance,
contractility, and heart rate, thereby producing hypotension and low cardiac
output. The
reduction in contractility and the increased incidence of
dysrhythmias that occur with halothane are poorly tolerated. Isoflurane,
sevoflurane, and desflurane have less effect on contractility and may result in
beneficial pulmonary vasodilation, but, the marked reductions in systemic
vascular resistance may result in systemic hypotension.69 In patients with
adequate functional reserve sevoflurane can be used as it is shorter-acting and
more readily titratable than isoflurane and unlike desflurane does not produced
tachycardia during rapid increases in concentration.69 Nitrous oxide increases
pulmonary resistance in patients with pulmonary hypertension and should be
avoided69.
 Decreased venous return compromises right ventricular preload and pulmonary
blood flow. When mechanically ventilating a patient, decreased venous return
can occur from positive intrathoracic pressure, such as positive-end-expiratory
pressure (PEEP). High PEEP also evokes alveolar overdistension and
compression of the capillary network in the alveolar wall and interstitium. This
increases PVR and decreases pulmonary blood flow . High PEEP can shift the
interventricuar septum producing paradoxical motion , causing right heart
dilatation and a smaller left ventricle chamber size72.
 Decreased systemic vascular resistance (as in post induction) may depress
systemic arterial pressure. Hypotension decreases coronary perfusion pressure
, which can result in myocardial ischaemia resulting in right sided heart failure.
 Drugs: Protease inhibitors inhibit CYP 450 thereby impairing metabolism of
fentanyl, amiodarone, quinidine. Nevirapine is an inducer of CYP 450 therefore
higher doses of anaesthetic drugs may be essential. Etomidate, atracurim,
remifentanil and desflurane are not dependent on CYP 450 hepatic metabolism
, and hence are the drugs of choice.
 Avoid ergometrine and nitrous oxide, as both increase PVR.
Page 18 of 26
 Many haemodynamic goals should be reached: keep pulmonary pressure low.
Systemic pressures must be within 15% of the starting pressures (the systemic
pressure should always be higher than the pulmonary pressure) and maintain
sinus rhythm.
 Avoidance of hypercarbia, hypoxia, hypothermia and acidosis is also
imperative. Also avoid increase in PVR, maintain RV preload, maintain LV
afterload, and right ventricular contractility.
 In case of persistent hypotension, the use of vasoconstrictors such as
phenylephrine and norepinephrine can augment coronary perfusion pressure
and avoid right ventricular ischemia. Norepinephrine also provides inotropic
support. Norepinephrine is metabolized by the pulmonary vascular endothelium.
Therefore, its metabolism is reduced in PPH, and its concentrations increase.68
Other agents such as dobutamine and milrinone, which increase cardiac output,
maintain systemic blood pressure, and decrease pulmonary vascular
resistance, are indicated69.
Peri-operative monitoring
Monitoring at delivery with electrocardiograpy, pulse oximetry, and invasive
arterial blood pressure monitoring is always advocated. However pulmonary
artery catheter insertion is debated due to the increased risk of pulmonary artery
rupture and thrombosis in pulmonary hypertension.62,64. Standard vascular access
includes a central venous line, and a large venous catheter for rapid fluid
administration.
Post partum
Oxytocin infusions must be slow as direct boluses can be fatal in high risk,
haemodynamically unstable patients65
The postpartum period is often the commonest period for acute PH
decompensation 58. Probable causes include a progressive increase in pulmonary
vascular tone , acute pulmonary vasospasm, cardiac arrhythmias, pulmonary
thromboembolism, heightened sympathetic tone and fluid shifts.
All precautions should be taken to avoid hypoxaemia, hypotension and
hypovolaemia, hypothermia and hypercarbia. Postoperative control of pain should
be efficient. Any therapy to decrease PVR and improve pulmonary blood flow
should be weaned with caution. Patients should be monitored in an intensive care
setting.
Page 19 of 26
Has there been an improvement in mortality over the last decade?
BEDARD ET AL , EUROPEAN HEART JOURNAL
(2009) 30 ; 256-265
Mortality rates among parturients with PAH remain high, although they seem to
have decreased in the last decade compared with previous era70,71 . Pregnancy
should, therefore, continue to be discouraged in patients with PAH.70,71
Page 20 of 26
CONCLUSION
HIV-PAH is a serious clinical problem associated with significant morbidity and
mortality. Despite the most modern treatment efforts, the maternal mortality as
around 36%70,71. Scheduled caesarean delivery during combined spinal-epidural
anaesthesia seems to be an attractive approach, but there is no evidence of
actual benefit.Hence pregnancy must still be discouraged in patients with severe
PH.
HIV-associated PAH has almost been exclusively studied in the US and European
countries, with just a few case reports from African countries. My experience or
observation
is that HIV–associated pulmonary hypertension is actually
underdiagnosed or misdiagnosed , with patients being investigated for other
conditions, hence a diagnosis of pulmonary hypertension is not an early one,
often with no treatment been advocated.
Although HAART has become widely accessible in developed countries, it is less
accessible in our government sector . However, early diagnosis, supportive
treatment, and HAART are steps that can considerably advance the quality of life
of patients with HIV related PAH. The optimal management of these potentially
fatal condition involves interaction with a multidisciplinary approach, with an
individually, tailor made anaesthetic plan for each patient.
So bear this condition in mind, the next time you come across a parturient with
signs and symptoms suggestive of HIV-PAH as the “evidence of absence, is not
absence of evidence”
Page 21 of 26
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