Acute management of pulmonary hypertension

Acute management of
pulmonary hypertension
Mardi Gomberg-Maitland, MD, MSc
Director, Pulmonary Hypertension
University of Chicago

Why all the fuss?
• We DON’T have the luxury of TIME
• Small changes in clinical status that
normally you may think are not important,
ARE and these patients CRASH
QUICKLY
• When we miss them, we may be too late!

PAH Classification 2003
• Idiopathic (IPAH)
• Familial (FPAH)
• Pulmonary hypertension associated with (APAH)
– Collagen vascular disease
– Congenital systemic to pulmonary shunts
– Portal hypertension
– Drugs/toxins
– HIV infection
• Persistent pulmonary hypertension of the newborn
• PAH with venous/capillary involvement (PVOD, PCH)
Simonneau G et al. J Am Coll Cardiol. 2004;43(12 Suppl 1):5S-12S.
Rich S. Executive Summary from the World Symposium-PPH 1998; World Health Organization.

Non-PAH
• Pulmonary hypertension (PH) with left heart disease
– Atrial or ventricular
–Valvular
• PH with lung disease/hypoxemia
– Chronic obstructive pulmonary disease (COPD)
– Interstitial lung disease
– Sleep-disordered breathing
– Developmental abnormalities
• PH due to chronic thrombotic and/or embolic disease
Simonneau G et al. J Am Coll Cardiol. 2004;43(12 Suppl 1):5S-12S.
Rich S. Executive Summary from the World Symposium-PPH 1998; World Health Organization.

Vascular Homeostasis
(Balanced Equilibrium)
Stimulators Inhibitors
Smooth
Muscle Cell
Growth Apoptosis
Endothelial
Cell

Imbalance of Vascular Growth
Stimulators
Proliferation
in PAH
Smooth
muscle cell
Endothelial
cell
Inhibitors
Apoptosis

Pulmonary Artery Smooth Muscle Cell
(Permissive Genotype)
Phenotypic switch
Hypertensive pulmonary artery
Smooth muscle cell
Hypertensive pulmonary
endothelial cell
Risk factors

Pathology of PAH
• Neomuscularization of arterioles
• Medial hypertrophy
• Concentric laminar intimal fibrosis

• Thrombin deposition
Pathology of PAH

Plexiform Lesions
Endothelial Cell Proliferation
Yeager ME et al. Circ Res. 2001;88:E2-E11. Taraseviciene-Stewart L et al. FASEB J. 2001;15:427-438.

Is There a Reason to Suspect PAH?
Clinical History (Symptoms, Risk Factors), Exam, CXR,
and ECG
• Dyspnea
• Angina
• Syncope
• Edema
• Raynaud’s disease

Definitions
Normal PAP 18-25 / 6-10 mmHg
with mean 12-16 mmHg
Pulmonary hypertension= mean >20mmHg
Pulmonary vascular resistance (PVR)
(mean PA-wedge)/CO (normal

World Health
Organization Classification
Class I: No limitations
Class II: Slight limitation of physical activity,
ordinary activity causes dyspnea, fatigue,
chest pain, or near syncope
Class III: Marked limitation, less than ordinary
activity
Class IV: Inability to perform activity without
symptoms, signs of right heart failure,
dyspnea, and/or fatigue at rest; discomfort
increases with any physical activity
Rich S. Executive Summary from the World Symposium-PPH 1998; World Health Organization.

PAH Prognosis: Functional Class
Correlates With Survival
Class I and Class II: 6 years
Class III: 2.6 years
Class IV: 6 months
Based on NIH registry
D'Alonzo GE et al. Ann Int Med. 1991;115:343-349.

CO
PAP
PVR
PAH: Hemodynamics over Time
Pre-symptomatic/
Compensating
Symptomatic/
Decompensating
Time (variable)
Declining/
Decompensated
Symptom Threshold
R Heart
Failure/Death

Is There a Reason to Suspect PAH?
Clinical History (Symptoms, Risk Factors), Exam, CXR,
and ECG
• Presence of PH
– Loud P2 – RV lift
– Systolic murmur (TR)
– Diastolic murmur (PR)
–RV S4 gallop
McGoon M, et at. Chest. 2004;126:14S-34S.
• Presence of RV
failure
– JVD with V wave
–RV S3 gallop
– Hepatomegaly
– Edema
– Ascites

Is There a Reason to Suspect PAH?
Clinical History (Symptoms, Risk Factors), Exam,
CXR, and ECG
RV Enlargement
into Retrosternal Clear
Space
Courtesy of: Michael McGoon, MD
Peripheral
Hypovascularity
(Pruning)
Prominent Hilar
Pulmonary Arteries

Findings On Electrocardiography
RAD
RAE
RAD, RAE, RVH with strain
RVH RV strain

RV
RA
Echocardiography
LV
LA
RV
LV
Apical 4 chamber Parasternal Short Axis

4 Most Common Causes Acute SOB
• Cardiogenic shock/Right heart failure
• Infection
• Arrythmia
• Thromboembolism

Vitals/Physical Exam: Important
• May be in cardiogenic shock with warm extremities
(NOT cold and clammy)!
• Signals for low cardiac output:
- change in mentation
- syncope
- drop in urine output
- drop in oxygen saturation (pulse ox)
- relative drop in blood pressure
- nausea/emesis, abdominal pain

The Downward Spiral
HYPOTENSION RVEDP
REDUCED RV CORONARY BLOOD FLOW
RV ISCHEMIA
CARDIAC OUTPUT

Hemodynamic and biochemical correlates of
RV failure from pulmonary hypertension
Coronary
driving
pressure
(mmHg)
Lactate/
pyruvate
Control
65
17.6
Vlahakes G, et al. Circulation 1981;63:87
RV
hypertension
44
13.9
Failure
23
56.8
Phenylephrine
78
19.5

Acute Management
Low Output:
- drop in blood pressure: inotropes: low dose
dopamine, phenylephrine (less tachycardia)goal
systemic vasoconstriction
**goal SBP higher than with left heart disease
>100 mmHG**
- fluid bolus not routine especially if left heart
disease as this can cause PULMONARY
EDEMA

Acute Management
Anasarca:
High dose diuretics: lasix drips at
high rates with metolazone
**OK to lose 5-6 L net/day (if BP low
in this setting will use inotropes with lasix
drip)

Infection
Hypotension, tachycardia, fever all are not
well tolerated
Need to culture and start antibiotics
sometimes empirically, and may need
inotropes
THESE PATIENTS HAVE NO RESERVE!

Atrial Arrhythmia
Retrograde P waves

Treatment of Atrial Arrhythmias
Routine treatment is calcium channel
blocker or beta blocker IV but if
suspect PAH do echocardiography
first because these drugs can cause
acute cardiogenic shock in PAH!

Atrial Arrhythmia
Despite the presence of right atrial
enlargement, most commonly atrial
arrhythmias present in late disease unless
if secondary to congenital heart disease
(especially post repair).
Acute Treatment: IV amiodarone,
IV digoxin, IV dofetilide,
DC cardioversion

Chronic Treatment:
Atrial Arrhythmia
Medical: oral amiodarone, oral dofetilide,
? Sotalol
Electrophysiology procedures:
1. Ablation: flutter, atrial tachycardia, AVNRT,
accessory pathways, atrial fibrillation
2. PPM with AV nodal ablation
3. Atrial remodeling

Main Points : Atrial Arrhythmia
• Aggressive treatment needed as
arrhythmia is not well tolerated in PAH
• ECHO acutely if unsure if PAH
• Acute treatment with amiodarone,
digoxin, dofetilide,DC cardioversion
• Chronic treatment with medication/EP
procedures

• Patients have high vagal tone therefore
pain control is important
• Use atropine
Bradycardia

Ventilation Perfusion Lung Scan
Primary
Pulmonary
Hypertension
Chronic
Pulmonary
Embolism

CT Scan

Mosaic Perfusion

Pulmonary Arterial Hypertension (PAH):
Therapy
• General measures
– Diuretics, oxygen
– Digoxin
• Anticoagulants (ACs) (evidence ±)
• Vasodilators/antiproliferative
– Calcium channel blockers (CCBs)
– Prostacyclins
– Endothelin receptor antagonists (ERAs)
– Phosphodiesterase 5 (PDE 5) inhibitors
– Investigational agents
• Atrial septostomy
• Lung transplant

Digoxin
Oxygen
General Treatment Options
• May increase contractility in right heart
failure
• May reduce sympathetic activation
• Symptomatic relief
• Maintain O2 saturation ≥91% if
desaturation is present at rest, sleep, or
with ambulation

Diuretics
General Treatment Options
• Reduce peripheral edema, intravascular
volume, and venous pressure
• Avoid excessive diuresis
• Monitor electrolyte balance
• Combination of loop diuretic and
metolazone or spironolactone may be
beneficial

Digoxin and Oxygen
• If renal failure remember digoxin
toxicity
• Oxygen- symptomatic relief
Maintain saturation>91% at rest, with
exercise, with sleep, in the hospital

Anticoagulation
• Recommended for patients with PAH
• May prolong survival by preventing thrombin
induced vascular proliferation
• not likely to affect symptoms
• Suggested INR 2.0-3.0
• *THEREFORE OK TO STOP AS THIS IS
CHRONIC THERAPY- prefer Vitamin K to FFP
due to volume load

%
Survival
Rich S et al. N Engl J Med.
1992;327:76-81.
Effect of High-Dose CCBs on
100
90
80
70
60
50
40
Survival in PPH
Months
0 12 24 36 48 60
Responders
Nonresponders
NIH Registry Cohort
NIH Registry Patients
treated at UIC

Calcium Channel Blockers
• If responders, these patients are on
higher doses than you are used toamlodipine
10 mg twice daily,
diltiazem 360 mg twice daily
• Don’t worry that this will drop their
blood pressure- give the medication
pre procedure.

Epoprostenol (Flolan)
*short half life- no more than 6 minutes!
*can’t switch lines without priming with
epoprostenol
*medication needs to be kept cold- ice
packs frozen solid- MAKE SURE
CHANGE ICE PACKS q6-8 HOURS

Cumulative Survival
1
0.8
0.6
0.4
0.2
0
Long-Term Outcome in IPAH With
Months
Sitbon O, et al. J Am Coll Cardiol. 2002;40:780-788.
Epoprostenol
IV epoprostenol
(n=178)
p

Required Supplies for
Epoprostenol Administration
• Supply of epoprostenol
• Glycine Buffer Diluent
• Portable Infusion Pump (2)
• Medication cassettes 50 or 100ml
• IV extension sets with 0.22 micron
filter to connect to subclavian
catheter
• Insulated carrying pouch
• Cold Packs
• 9 volt batteries for pumps
• Normal Saline for injection
• Antimicrobial Soap
• Povidone-Iodine Solution
• 70% Alcohol
• Dressing Change Kits
• Betadine prep pads
• Alcohol Prep pads
• Needles (18 and 23 gauge)
• Syringes (3ml, 10ml, 60ml Luer
Lok®)
• Other, as needed

*patients know more than all of us! LEARN from them
*cassette changes need to be ON TIME! Efficacy decreases
past 24 hours- in hospital 24 hour cassette always not 8
hour option
*change tubing every 3 days
Epoprostenol:
*need to go through a stable line if Hickman catheter is not
working- PICC line/central line
*CADD pump- any questions call PH TEAM

Prostacyclin Problems:
Leaking Hickman
Need to have stable line to for flolan/remodulin
and then can repair catheter!
Place central access and CALL PH TEAM to
prime line

Treprostinil Sodium Injection
Usage/Administration/Delivery System
• Administered via
continuous infusion using
an ambulatory pump
designed for
subcutaneous infusions
• Administered via a selfinserted
subcutaneous
catheter

Treprostinil (Remodulin)
*longer half life- 4.6 hours- larger
*medication stable at room temperature- no ice
packs
*now IV therapy available- half life 4.4 hours
*change medication q 48hrs

Inhaled Iloprost
• Approved by FDA in December 2004 for class III,
IV PAH
• Duration of hemodynamic effect only 90 minutes
• Requires frequent administration; at least 6x/day
at 10 to 15 minutes
• Trials in Europe: Improved FC, 6MW, Hemodynamics
vs. placebo
• Has favorable effects on gas exchange in pulmonary
fibrosis
• Patient will bring device to ER
Olschewski H, et al. N Engl J Med. 2002;347:322-329.

• Oral
Endothelin Antagonists (ERAs)
• “Nonselective” ERA/ERB
• Bosentan*
• “Selective” ERA
• Sitaxsentan †
• Ambrisentan †
*FDA approved
† Investigational/in development

ERAs
• Patients are to take their own bosentan
(Tracleer). First month 62.5 twice daily
then uptitrated to 125mg twice daily. It is
available at U of C pharmacy if needed
• If patients have liver failure, medication is
discontinued.
• No known rebound if miss dose.

L-Arginine
Potential of PDE-5 Inhibitors
as a Treatment for PAH
• PDE-5 located in pulmonary circulation
• PDE-5 responsible for cGMP hydrolysis in the lung
• cGMP appears to regulate pulmonary vascular tone and growth
• PDE-5 inhibitor raises cGMP levels
eNOS
Nitric
oxide
PDE-5I
Wharton J et al. Am J Respir Crit Care Med. 2005;172:105-113.
cGMP Lowers
PA
PDE-5 pressure
GMP

PDE-5 Inhibitors
• These patients are on higher doses than
you are used to- sildenafil 80 mg three
times daily
• May drop blood pressure, call us if
hypotensive before holding- but like
calcium blockers if on chronic therapy
unlikely acute drop if all else stable
• May be rebound effect- don’t hold

PH Cardinal Rules
1. PH PATIENTS HAVE LITTLE
CARDIOVASCULAR RESERVE
2. CALL US! There are no unimportant
questions!
3. CALL US! There are no unimportant
questions!