Pulmonary Hypertension
Respiratory Critical Care Conference, September 2016 Peter Leary, MD MSc Division of Pulmonary & Critical Care Medicine University of Washington School of Medicine
Take home points 1.
Pulmonary hypertension is not one disease but many Appropriate treatment requires appropriate diagnosis
2. Treatment for pulmonary arterial hypertension is focused on diuresis and afterload reduction The current proliferation of drugs for PAH leaves many unanswered questions but a structured goal-directed approach is possible 3. There has been progress in pulmonary arterial hypertension, but there is more work to be done Novel targets and approaches are needed
The spectrum of diseases with high pulmonary pressures
The Physiology
mPAP= PVR * CO + PCWP
mPAP= mean pulmonary artery pressure; pcwp= pulmonary capillary wedge pressure; PVR=pulmonary vascular resistance CO= cardiac output
A violet by any other name... still isn’t a rose • High pressure • Primary versus Secondary • WHO Classification Scheme
Pulmonary hypertension heterogeneity Group 1 • Idiopathic, heritable, toxic, Pulmonary Arterial Htn • Associated (HIV, CREST, etc) Group 2 Left Heart Disease
• Systolic, diastolic, valvular
Group 3 • Hypoxemia: Sleep Disorders Alveolar Hypoxia/Lung • Capillary Bed Loss: ILD/COPD Group 4 Thromboembolic
• CTEPH, Tumor embolism
Group 5 Miscellaneous
• Sarcoid, LAM, Vasculitis, • metabolic disease Galie N, JACC (2013), McLaughlin V, JACC (2015)
WHO Group 1 – Pulmonary Arterial Hypertension Endothelial thickening
I n situ thrombosis
Plexiform lesions & smooth muscle hypertrophy
Normal
Mild/Moderate
Severe
Zwicke DL. Advances in Pulmonary Hypertension (2011)
WHO Group 2 – Pulmonary Venous Hypertension
PV Compliance
• Increased wall stress • Activation of vascular stretch receptors
Decreased pulmonary vascular compliance PVR
Kulik TJ. Pulm Circ (2014), Tedford RJ. Circulation (2012)
WHO Group 2 LVAD placement Mitral or VSD intervention 10 20 30 40
PVR post-intervention
VSD closure Mitral valve surgery
Wedge Pressure (mmHg)
Pre-LVAD 30 days
2
4
6
8
PVR (wood units)
Kulik TJ, Pulm Circ (2014); 125: 289-97 & Masri SC – ASAIO in press
0
PVR pre-intervention Pre-LVAD 30 days
WHO Group 3 – Parenchymal Lung Disease & Hypoxia Normal lung
Schematic of emphysema
Pulmonary Fibrosis
Emphysema
WHO Group 4 – Chronic Thromboembolic Disease
. Kim N, Adv Pulm Htn (2013)
WHO Group 5 – Miscellaneous
Causes of pulmonary hypertension
. Strange G et al. Heart 2012;98:1806-1811.
Natural History and Evaluation of WHO Group 1-Pulmonary Arterial Hypertension
Symptoms at Diagnosis Symptoms Dyspnea Fatigue Angina* Near Syncope Syncope* Leg Edema* Palpitations
Initial Symptom (%) At Diagnosis (%) 60 98 19 73 7 47 5 41 8 36 3 37 5 33
* = symptoms of advanced disease, also includes dyspnea at rest
Hegewald MJ, Markewitz B, Elliott CG. Int J Clin Pract Suppl. 2007 Sep;(156):5-14. Review.
Delays in diagnosis? Historical Epoch Kennedy Era
Time from 1st Symptom to diagnosis ~1.8 years
Reagan Era
~1.3 years
Bush Era
~1.1 years
EKG
Right Axis Deviation
RVH: R-wave >7 boxes in V1 (with right axis and ‘large’ S-waves in v5/6)
Big RA: P-wave >2 boxes high in II
S1Q3T3
Right Heart Strain: Flipped lateral leads and ↓ ST
EKG is abnormal in ~ 80% of patients at dx Hegewald MJ, Markewitz B, Elliott CG. Int J Clin Pract Suppl. 2007 Sep;(156):5-14. Review.
Chest X-ray
CXR is abnormal in ~ 90% of patients at dx
Chest CT Ao PA
PA/Ao Diameter >1 to identify PH
• Sensitivity 0.70 • Specificity 0.92 Ng CS et al. J Thorac Imaging. 1999 Oct;14(4):270-8.
Echo
Systolic PAP of 40mmHg on echo to identify PAH
• Sensitivit y 0.76 • Specificit y 0.58
Rich J et al, Chest 139(5): 988-993, 2011 Janda S et al. Heart doi:10.1136/hrt.2010.212084
Right heart catheterization Absolutely needed before you make the diagnosis and start therapy After you make the diagnosis the following tests if not already done should all be considered on the merits to treat the disease appropriately: Chest CT, PFTs, Echocardiogram, VQ Scan, ANA, RF, anti-ccp, ANCA, anti-scl70, anti-ro, anti-la, anti-ds dna, HIV, toxicology screen, a history, Liver function tests, sleep study, ova and parasites, schistosomiasis serology
Natural History : PAH
CO
PAP PVR
NYHA
I
II
III Time
IV
Treatment for WHO Group 1Pulmonary Arterial Hypertension
The “Big 3” Pathways in PAH
3 Drugs
3 Drugs
3 Drugs Humbert M N Engl J Med (2004)
PAH Drug Development Timeline Treprostinil (IV) Treprostinil (SQ) Bosentan (PO) BREATHE Epoprostenol (IV)
1995
2001
2002
RTS Epoprostenol (IV) Macitentan (PO) SERAPHIN Ambrisentan (PO) ARIES Riociguat (PO) PATENT Sildenafil (PO) Tadalafil (PO) CHEST SUPER PHIRST
2004
Iloprost (inhaled) AIR
2005
2007
2009
Treprostinil (inhaled)
2010
2012
2013
2014
Treprostinil (PO) FREEDOM Selexipag (PO) GRIPHON
Research progress Survival 1 year
3 year
5 year
Historical Controls
68%
48%
34%
Bosentan
~90%
~75%
Flolan/ Remodulin
~85%
~70%
~60%
Gomberg-Maitland et al, JACC 2011; 57: 1053-61.
How and when to treat PAH confirmed by expert center
Treatment naive patient
CCB Therapy
Vasoreactive
Low Risk
Oral Monotherapy
General measures Supportive therapy
Acute vasoreactivity test (I-PAH, H-PAH, D-PAH only) Non-vasoreactive (or not IPAH/HPAH/DPAH)
Oral Combo Therapy
High Risk
Parenteral Therapy
Inadequate response
Double/triple sequential therapy OR lung transplant
. Galie N, ESC/ERS 2015 Guidelines
Supportive therapy & General Measures! “In most but not all cases RV failure (in PAH) is associated with fluid overload and a negative fluid balance is a key to successful therapy.” –Marius Hoeper • Approach chronic right heart failure conceptually like left heart failure (BNP, diuresis, salt avoidance, etc) • Oxygen for sitting or ambulatory saturation 100) Hoeper et al, AJRCCM, 184: 1114-24, 2011
A note on diuretics Some evidence that furosemide isn’t the best choice....
Meta-analyses of unblinded but randomized evidence in 471 participants with torsemide relative to furosemide:
RR for heart failure readmission: 0.41 (p15 Ve/VCO2 65%
RA 8-14 mmHg CI 2.0-2.4 SvO2 60-65%
RA >14 mmHg CI 50%, Riociguat (n=21) improved stroke volume Non-operative chronic thromboembolic pulmonary hypertension Lewis et al, Circulation 2007; 116: 1555-62; Guazzi et al, Circ-HF 2011; 4: 8-17;
Comorbidity Management- Bleeding Bleeding -
Beware volume overload with PRBC transfusion and consider diuresis with each unit
-
Platelets and FFP both of which have high concentrations of thomboxane A2 (a pulmonary vasoconstrictor) may lead to profound pulmonary vasoconstriction
Dezube et al, Adv in PH, 12: 24-30, 2013
Comorbidity Management- PE Thrombolysis should be considered if no contraindications - The MOPETT Trial suggests improved hemodynamics with no significant bleeding if ½ dose TPA is used (e.g. 50mg if weight is over 50kg with 10mg pushed over the first minute and 40mg infused over 2 hours)
Sharifi, et al, Am J Cardiol, 111(2): 273-77, 2013
Comorbidity Management- Ventillation TRY NOT TO INTUBATE! If you do intubate: PVR may be lowest at functional residual capacity - Therefore, low tidal volume ventilation may be appropriate for all patients with PAH
The rest of the ARDS playbook may not be as good -
PEEP increases PVR and should be minimized Permissive hypercapnia can increase PVR by more than 50% and mPAP by more than 30%
Dezube et al, Adv in PH, 12: 24-30, 2013