Pulmonary Vasodilator Treatments in the ICU Setting Lara Shekerdemian Circulation 1979 Ann Thorac Surg 27 Anesth Analg 211 1
Factors in the ICU Management of Pulmonary Hypertension After Cardiopulmonary Bypass The lungs: ventilation The endothelium & smooth muscle: vasodilators Ca ++ RV LV The heart: RV supportive measures Hypoxia K + K + Endothelium-Dependent Pathways Change in PVR (%) cgmp pmol/ml Pre Post Pre Post Circulation 1993 2
Endothelin-1 and Post-operative PHT 14 12 Tissue cgmp (pmol/g) Circulation 2 Komai J Thorac Cardiovasc Surg 1993 Endothelin-1 (fmol/ml) 1 8 6 4 2.2.4.6.8 1. 1.2 Pp/Ps Pulmonary Vasodilators in the ICU Route of Administration of Pulmonary Vasodilators Targeting the endothelium NO-cGMP pathway PGI2 pathway ET-1 pathway Considerations Delivery Selectivity Cost Systemic PVR SVR Shunt PaO2 Inhaled PVR SVR Shunt PaO2 3
The Nitric Oxide Pathway U-46619 Study Drug Vessel Lumen Nitric Oxide Pathway V'/Q' Matching (%) Endothelial Cells Smooth Muscle L-arginine NOS Citrulline Nitric Oxide Nitric Oxide GTP sgcy cgmp Eur Respir J 1997 Inhaled Nitric Oxide after Cardiac Surgery mmhg 5 4 3 2 1 PAP ppm 2 ppm ino 16 12 U/m 2 8 4 ppm PVRI ino 2 ppm 1 children after surgery for CHD Median age 6 months 42% reduction in PVR Cochrane Database Syst Rev 25 Miller, JTCVS 1994 4
5 66 3 2 Pulmonary Pressure 45 4 35 3 Systemic Pressure 62 58 54 5 PaO2 2 1 PAP/SAP 1 25 Base PCycl line ino ino + PC 46 Ann Thorac Surg 1995 Base line PCycl ino ino + PC Baseline ino 2ppm Ann Thorac Surg 1996 Baseline ino 2ppm Problems with Inhaled Nitric Oxide: Cost (and availability) Nitric Oxide Hours (FY8-FY1) Problems with Nitric Oxide: Rebound Expenses (all ICUs) PA Pressure (mmhg) mpap (mmhg) ino at 2ppm Time (mins) Ivy J Thorac Cardiovasc Surg 1998 5
Alternatives to Nitric Oxide 5 Text 4 PAP Sys Cdyn (ml/cm/h2o) 7 6 3 2.6.5.4.3.2 NO on NO off No On Prostacyclin - systemic / inhaled Sildenafil - enteral / parenteral Endothelin receptor antagonists - systemic The Prostacyclin Pathway Aerosolized Iloprost Vessel Lumen Prostacyclin Pathway Endothelial Cells COX Arachidonic Acid PgH2 Prostacycl. synthase PgI2 Smooth Muscle ATP PgI2 AC camp 6
15 children 5 post-op CHD 1 pre-op Equivalent potency Conclusion: In medical setting with limited access to the nitric oxide, inhaled iloprost is consider to be an effective alternative treatment for postoperative PHC in children undergoing congenital heart surgery. Circulation 21 Int J Cardiol 28 Augmenting the Nitric Oxide Pathway 4 Vessel Lumen Endothelial Cells Smooth Muscle Nitric Oxide Pathway L-arginine NOS Nitric Oxide Nitric Oxide GTP Citrulline sgcy cgmp Infants at risk of PHT Pulmonary vasodilation Systemic vasodilation Increased intrapulmonary shunt Not intolerable but need for caution PVR Systolic BP PaO2 3 2 7 6 5 15 12 9 min Intensive Care Med 24 2 min 4 min ino then sild sild then ino 7
Placebo Sildenafil 8 Time to Extubation i-v Sildenafil in patients with Post-op PHT (PAP>1/2 Systemic) PA Systolic Pressure 6 4 2 66 pulmonary hypertensive infants receiving ino Closure of septal defects / Cavopulm shunts Time to ICU Discharge Time to Hospital Discharge Intensive Care Med 211 Transpulm Gradient 15 1 5 Pre-Sildenafil Max Dose Sild Stepwise dose increase 5-7 days Well tolerated No desaturation or rebound Eur J Cardiothorac Surg 21 The Management of Rebound ino 4ppm Cardiac Index P<.1 P<.1 PA Pressure Left PVR Plasma cgmp.4 on.3 off.2 6 12 24 26 ino 4ppm 15 on off 1 5 In Healthy Lungs Acute increase in PVR on stopping ino Inhaled NO reduces endothelial NOS activity Text Acute reduction in cgmp on stopping ino Anaesthesia 211 6 12 24 26 Time (hrs) Black J Appl Physiol 1999 8
Sildenafil Duration of Ventilation P =.18 % Change in PA pressure 1hr after stopping ino ICU Length of Stay P <.1 P =.4 SILDENAFIL PLACEBO SILDENAFIL PLACEBO SILDENAFIL PLACEBO Am J Respir Crit Care Med 26 Less selective than ino? greater selectivity for pulmonary vasculature in the presence of PHT Has been investigated in aerosolized form Useful in prevention of rebound PA Press Urea Ornithine P<.5 OTC NOS Arginase Arginine Aspartate P<.5 Citrulline NO PVR Arginosuccinate Single dose on CPB 2nd dose 4hrs post-op +/- 48hr infusion Safe, well tolerated?efficacy Am J Physiol Lung Cell Mol Physiol 29 JTCVS 27 9
Endothelin-1 Pathway Vessel Lumen Endothelial Cells Endothelin Pathway Pre-pro endothelin ECE Proendothelin PA Pressure (mmhg) 3 25 2 Smooth Muscle Endothelin 1 A B Pulmonary/Systemic Pressure.5.4.3 Baseline Oxygen BQ123 ino JTCVS 22 Bosentan 5 PA pressure Oxygenation Index 4 3 In large parts of the Bosentan world, particularly 2 in developing Placebo countries, ino and ECMO are not readily available 1 due to high costs and lack of a sufficient infrastructure 2 4 6 12 24 36 J Perinatol 211 1
Pulmonary Vasodilators in the Intensive care Unit Acute severe crises less common in many regions, with early surgery, pre-emptive management More 'insidious' post-operative PHT is still a problem Increasing interest in alternatives to ino Cost, availability, rebound Selectivity needs to be considered Pulmonary Vs systemic Ventilated Vs non-ventilated regions Presence / absence of lung injury Careful use of systemic agents early after surgery Whittenberger J Appl Physiol 196 To Be Discussed The scope of the problem Pathophysiology of pulmonary hypertension in the ICU Management in CHD Acute intervention Alternatives to ino 1. Sensitivity.9.8.7.6.5.4.3.2.1. 1..9.8.7.6.5.4.3.2 Specificity.1. Pediatr Crit Care Med 22 11