Pulmonary Hypertension

Pulmonary Hypertension Respiratory Critical Care Conference, September 2016 Peter Leary, MD MSc Division of Pulmonary & Critical Care Medicine Univer...
Author: Joan Randall
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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