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Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital

Mechanisms of Action and Use of Inotropes and Vasopressors in the Neonate. Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Children Hospital Los Angeles Keck School of Medicine University of Southern California

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Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital

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  1. Mechanisms of Action and Use of Inotropes and Vasopressors in the Neonate Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Children Hospital Los Angeles Keck School of Medicine University of Southern California Los Angeles, CA

  2. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesBlood Pressure Range Is Gestational- and Postnatal-Age Dependent Lower Limit of the 80% Confidence Interval of BP in Neonates ( First 3 Postnatal Days)* 37-43 weeks 33-36 weeks Mean Blood Pressure (mm Hg) 27-32 weeks 23-26 weeks 0 12 24 36 48 60 72 Age (h) * = 90% of neonates will have a mean BP value at or above the lower limit of the confidence interval Nuntnarumit et al, Clin Perinatol; 1999

  3. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesClinical Presentations Requiring Different Approach to Treatment • Hypotensive ELBW neonate (<28 weeks) during the first postnatal day • Hypotensive ELBW/LBW neonate with a hemodynamically significant PDA (during the first week) • Hypotensive preterm or term neonate with perinatal depression • Hypotensive ELBW/LBW neonate with relative adrenal insufficiency and vasopressor/inotrope resistance • Any hypotensive neonate with systemic inflammatory response (sepsis, NEC)

  4. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Pressors, Lusitropes, Intorpes and Steroids Used in Neonates Dopamine Dobutamine Epinephrine Norepinephrine Vasopressin Isuprenaline Phosphodiesterase III Inhibitors (Milrinone, Amrinone) Hydrocortisone or Dexamethasone

  5. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesNeonatal Shock Impaired Regulation of Vascular Tone(with or without myocardial dysfunction)

  6. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesDopamine Cardiovascular Effects

  7. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesMechanisms of Action of Dopamine • * = DOB’s efficacy is independent of affinity for ARs • ** = DA also has serotoninergic actions on the periphery • Adrenergic, Dopaminergic and Vasopressin Receptors • 1/2  b2 a1 b1/2 DA1/DA2 V1a • Vascular Vascular Cardiac Cardiac Vascular/Cardiac Vascular Phenylephrine ++++ 0 + 0 0 0 Norepinephrine ++++ 0/+ ++ ++++ 0 0 Epinephrine ++++ ++ ++ ++++ 0 0 Dopamine++ ++++ ++ ++ +++ ++++ 0 Dobutamine+ +/0 ++ ++ ++++ 0 0 Isuprenaline 0 +++ +++ ++++ 0 0 Vasopressin 0 0 0 0 0 ++++ PDE-III Inhibitors 0 0 0 0 0 0 PDE-V Inhibitors 0 0 0 0 0 0

  8. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effects of Dopamine Infusion on Healthy Human Subjects DA1b1a Maximal Effect (%) DA1 receptor = Renal blood flow b1 receptor = Cardiac index & heart rate a receptor = Systemic vascular resistance index and arterial pressure Dopamine Dose (µg/kg/min) D’Orio et al, Arch Int Physiol Biochim; 1986

  9. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesFactors Affecting the Hemodynamic Response to Dopamine and Other Sympathomimetic Amins • Developmentally regulated level of expression of adrenergic receptors and intracellular signaling systems • Down-regulation of the adrenergic receptors and intracellular signaling systems in critical illness • Developmentally regulated maturity of the myocardium • Dysregulated release of local vasodilators (endogenous nitric oxide, vasodilatory prostaglandins, etc)

  10. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Dose-response Curves of Dopamine on Heart Rate and Blood Pressure in Preterm Neonates Systolic and Diastolic Blood Pressure Dose-response Curves in Hypotensive Preterm Neonates Heart Rate Dose-response Curve in Hypotensive Preterm Neonates 0 2 4 8 (µg/kg/min) 0 2 4 8 (µg/kg/min) Seri et al, Eur J Pediatr; 1984

  11. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of Dopamine on Blood Pressure, Central Venous Pressure, Heart Rate and TcpO2 in Preterm Neonates (2) Seri et al, Eur J Pediatr, 1984

  12. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of Dopamine on Blood Pressure, Central Venous Pressure, Heart Rate and TcpO2 in Preterm Neonates (2) Seri et al, Eur J Pediatr, 1984

  13. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesEstimation of Renal Blood Flow in ELBW neonates

  14. Dopamine-Induced Increase in Doppler Velocity Profile in the Renal Artery in a Preterm Neonate

  15. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesPulsatility and Resistance Indeces • Pulsatility Index = Peak Systolic Velocity - End Diastolic Velocity / Mean Velocity (PI = PSFV - EDFV / MFV) • Resistance Index (RI) = Peak Systolic Velocity - End Diastolic Velocity / Peak Systolic Velocity [PSFV - EDFV / PSFV] x 100

  16. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of dopamine (2.5-15 µg/kg/min) on systemic BP and MCA PI Mean Blood Pressure Middle Cerebral Artery (MCA) PI (mm Hg) (PI = Pulsatility Index) * (23/23) (23/23) Control Dopamine Control Dopamine Seri et al, J Pediatr, 1998

  17. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of Dopamine on the Resistance Index in the MCA in Hypotensive Preterm and Term Neonates Seri et al, Pediatr Res; 1993

  18. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of dopamine (2.5-15 µg/kg/min) on systemic BP and RA PI Mean Blood Pressure Renal Artery (RA) PI (mm Hg) (PI = Pulsatility Index) (a) (b) * * (23/23) (23/23) Control Dopamine Control Dopamine Seri et al, J Pediatr, 1998

  19. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of dopamine (2.5-15 µg/kg/min) on renal artery PI in relation to the drug-induced BP changes Mean Blood Pressure Renal Artery PI (mm Hg) (PI = Pulsatility Index) * = P<0.05 vs Control * ^ * ^ = P<0.05 vs lower panel * = P<0.05 vs Control (15/23) (15/23) * = P<0.05 vs Control * (8/23) (8/23) Control Dopamine Control Dopamine Seri et al, J Pediatr, 1998

  20. The dopamine-induced increase in urine output (a) and the percent change in the renal artery PI versus baseline renal artery PI (b) y = 2.0511 - 13.453x R^2 = 0.551 (a) (b) Urine Output (mL/kg/h) % Change in Renal Artery PI * 23/23 20/23 Control Dopamine Baseline Renal Artery PI Study Periods Seri et al, J Pediatr; 133:728 1998

  21. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of dopamine (5 µg/kg/min) on systemic BP and right renal artery PI(b) following indomethacin administration Mean Blood Pressure Renal Artery PI (mm Hg) (PI = Pulsatility Index) (a) (b) * * (20/20) (20/20) (23/23) (23/23) Indo Indo+Dopamine Indo Indo+Dopamine Seri et al, J Perinatol, 2002

  22. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of dopamine (2.5-15 µg/kg/min) on systemic BP and superior mesenteric artery PI during 1st DOL (No Indo) and 2nd DOL (Indo) Superior Mesenteric Artery PI Superior Mesenteric Artery PI No Indomethacin Indomethacin (a) (b) * * (21/23) (18/20) Control Dopamine Indo Indo + Dopamine Seri et al, J Pediatr, 1998

  23. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Dose-dependent Effects of Dopamine in Preterm Neonates* • Vasodilation in kidneys, intestine, coronary arteries • Increase in GFR • Direct renal tubular effects • Positive inotropy • Endocrine effects Dopamine Receptors > 0.5 µg/kg/min DOPAMINE Alpha Receptors • Vasoconstriction • Positive inotropy • Metabolic effects > 2-4 µg/kg/min • Positive inotropy (direct and indirect) • Positive chronotropy • Peripheral vasodilation • Metabolic effects Beta Receptors > 4-8 µg/kg/min * Without adrenoreceptor down-regulation

  24. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesTreatment of Low Systemic Blood Flow(Dopamine versus Dobutamine) * +34% +35% * +2% -1% * = P < 0.05 vs Dopamine * = P < 0.05 vs Dopamine (Osborn et al J Pediatr 2002 140:183)

  25. Hemodynamic Actions of Sympathomimetic Agents and Steroids in NeonatesBlood Pressure and SVC flow in ELBW/LBW neonates during the first 24 hours * = SVC flow is used as surrogate of cerebral blood flow (Modified from Osborn et al Arch Dis Child; 2004)

  26. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRelationship of Cerebral FOE to BP and Left Ventricular Output in Preterm Neonates during the First Three Postnatal Days Kissack et al. Pediatr Res 2004; 55:400 Left Ventricular Output (mL/kg/min) Mean Blood Pressure (mm Hg) Cerebral Fractional Oxygen Extraction Left Ventricular Output (mL/kg/min) Mean Blood Pressure (mm Hg) Left Ventricular Output (mL/kg/min) Mean Blood Pressure (mm Hg) Lower pCO2 values correlate with higher cerebral FOE (i.e. decreased BF in the hemispheres)

  27. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesProposed BP Range for Autoregulation of CBF in Neonates >3 days old Adults Neonates Cerebral Blood Flow Cerebral Blood Flow Mean Blood Pressure (mm Hg) Mean Blood Pressure (mm Hg) (Arch Dis Child 1996; 74:F63; Clin Perinatol 1997; 24:531; Ment Retard Dev Disab Res Rev 1997; 3:3)

  28. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesDopamine Renal Effects

  29. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of Dopamine in Preterm InfantsEvidence for a Direct Tubular Effect (1) No significant changes in blood pressure in 30 normotensive preterm infants * = P<0.05 vs Control * * * * % Percent of Control (0.5-2 mg/kg/min) Tulassay, Seri et al, Int J Pediatr Nephrol; 1983

  30. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of Dopamine in Preterm InfantsEvidence for a Direct Tubular Effect (2) ** * = P<0.05 vs Control ** ** % ** Percent of Control Seri et al, Pediatr Res; 1993

  31. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of Dopamine in Preterm InfantsIndirect Evidence for Increased Medullary Blood Flow No significant changes in blood pressure in 30 normotensive preterm infants * * = P<0.05 vs Control * * * % Percent of Control * (0.5-2 mg/kg/min) Tulassay, Seri et al, Int J Pediatr Nephrol; 1983

  32. 6 10 9 5 8 7 4 6 3 5 4 2 3 2 1 1 0 0 Control DA LY DA+S-SP Control DA LY DA+S-SP Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Changes in Renal and Duodenal Blood Flow during Infusion of Dopamine, LY (a DA2 Receptor Agonist) and DA + S-SP (DA2 Receptor Blocker) Duodenal Blood Flow Renal Blood Flow * = P<0.05 vs Control * = P<0.05 vs Control * * * * Duodenal Blood Flow (ml/g tissue/min) Renal Blood Flow (ml/g tissue/min) Seri et al, Acta Physiol Scand; 1987

  33. SFP - FFP = PUFAA SFP FFP CORTEX PUFAA AA EA Glomerulus MEDULLA SFP =stop-flow pressure FFP =free-flow pressure PUFAA =glomerular capillary ultrafiltration pressure Micropuncture: Assessment of Single Nephron GFR

  34. 80 60 40 20 0 0 2 4 6 8 20 30 Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of Dopamine on Single Nephron GFR in Rats % Dopamine (1 µg/kg/min) SNGFR (% Increase vs Control) Time (minutes) Seri et al, Am J Physiol; 1989

  35. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of DopamineMechanism of the Increase in Glomerular Filtration Rate (1) SFP - FFP = PUFAA * * = P<0.05 vs Control * Pressure (mm Hg) Stop-Flow Free-Flow Glomerular Pressure Pressure Ultrafiltration Pressure Control Dopamine Seri et al, Am J Physiol; 1989

  36. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of DopamineMechanism of the Increase in Glomerular Filtration Rate (2) IN VITRO Dopamine Control Afferent and efferent vasodilation PT PT AA EA AA EA IN VIVO Dopamine Dopamine PT Afferent vasodilation renin - angiotensin efferent vasodilation AA EA

  37. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Effect of Dopamine on Plasma Renin Activity and Aldosterone Concentration in Preterm Neonates Plasma Renin Activity Plasma Aldosterone Concentration (ng/mL/h) (pg/mL) * * = P<0.05 vs Control Sulyok, Seri et al, Eur J Pediatr; 1985

  38. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of Dopamine in Preterm InfantsEvidence for Glomerular and Direct Tubular Effects (1) % * * = P<0.05 vs Control * * * Percent of Control (0.5-2 mg/kg/min) Seri et al, Pediatr Res; 1993

  39. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of Dopamine in Preterm InfantsEvidence for Inhibition of the Sodium Pump (1) Effect of L-Dopa (10-4 M, ) and Vehicle ( ) on Ouabain-Sensitive O2-Consumption Rate (QO2) at Different Sodium Concentrations in the Medium in the Presence of Nystatin in Rat Renal Proximal Tubule Cells Inset:Lineweaver-Burk plot of data. L-Dopa decreases Vmax and K0.5 to the same extent indicating that dopamine acts as an uncompetitive inhibitor of the Na+, K+-ATPase enzyme. Seri et al, AJP, 1998

  40. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in NeonatesRenal Effects of Dopamine in Preterm InfantsEvidence for Inhibition of the Sodium Pump (2) Effect of L-Dopa (10-4 M) and Ouabain (10-2 M) on Net K+ Fluxes Rat Renal Proximal Tubule Cells 2 1 Seri et al, AJP, 1998 Rate of cellular K+ loss induced by dopamine (1) and ouabain (2)

  41. Hemodynamic Actions of Pressors, Lusitropes and Inotropes in Neonates Renal Effects of Dopamine in Preterm Infants Cellular Mechanisms of the Dopamine-Induced Na+-K+,ATPase Inhibition DOPAMINE + DA Gp 1 PLC AC Gs - Gi DA + 2 + DOPAMINE PKC AC = Adenylate cyclase DA1 = Dopamine1 receptor DA2 = Dopamine2 receptor DARPP32 = Dopamine and cAMP regulated phosphoprotein Gi = AC inhibitory G protein Gp = PLC stimulatory G protein Gs = AC stimulatory G protein PKA = Protein Kinase A PKC = Protein Kinase C PLA2 = Phospholipase A2 PLC = Phospholipase C PP-1 = Protein phosphatase-1 + PKA + cAMP + + DARPP 32 PLA2 - PP-1 3 Na+ + PK-A/C - - -   P i Aperia, Bertorello & Seri, 1987; Seri et al, 1988; Meister et al, 1989; Seri et al, 1990; Ibara et al, 1993 - 2 K+

  42. . K+ K+ K+ K+ X X K+ K+ Na+ Na+ Na+ Na+ Na+ Na+ X Na+ H+ X K+ X K+ Na+ Na+ Pi X K+ Na+ X K+ Na+ Na+ CORTEX K+ Na+ H2O ADH K+ Na+ Dopamine Inhibits: Na+,K+-ATPase, Na+/H+ exchanger, Na+/Pi cotransporter, ADH-sensitive H2O channel Dopamine Increases: RBF, GFR The net effect of dopamine:  Na+, Pi , HCO-3, H2O excretion, concentrating capacitity X K+ Na+ MEDULLA X K+ H2O ADH Na+

  43. Dose-dependent Effects of Dopamine in Preterm Infants* • Vasodilation in kidneys, intestine, coronary arteries • Increase in GFR • Direct renal tubular effects • Positive inotropy • Endocrine effects Dopamine Receptors > 0.5 µg/kg/min DOPAMINE Alpha Receptors • Vasoconstriction • Positive inotropy • Metabolic effects > 2-4 µg/kg/min • Positive inotropy (direct and indirect) • Positive chronotropy • Peripheral vasodilation • Metabolic effects Beta Receptors > 4-8 µg/kg/min * Without adrenoreceptor down-regulation

  44. Neonatal Shock: Blood Pressure Decreased Sensitivity of the Cardiovascular System to Catecholamines (1) In critical illness, down-regulation of the cardiovascular adrenergic receptors and signaling pathways occurs

  45. Neonatal Shock: Blood Pressure Down-Regulation of Adrenergic Receptors Ligand ? Minutes Phosphorytlation & Sequestration + Minutes of mM agonist exposure + Rapidly reversible (minutes) Down-Regulation + Hours of agonist exposure + Decreased mRNA stability + Decreased transcription + Reversal of down-regulation requires new protein synthesis G s AC Hours G s COOH Ligand P P Phosphorylation (PKA, bARK) P COOH P Lysosome Sequestration ? AC = Adenylate Cyclase bAR = b Adrenoreceptor bARK = b Adrenoreceptor Kinase Gs = Stimulatory G protein PKA = Protein Kinase A Minutes Down-Regulation Hausdorff, Garon, & Lefkowitz; 1990

  46. Primary Etiology: C. Impaired Vascular Tone Regulation± Myocardial Dysfunction Treatment Hydrocortisone

  47. Neonatal Shock: Blood Pressure Effects of Steroids on Down-Regulation of Adrenoreceptors and Signaling Pathways • Genomic Effects of Steroids: • Increase in the rate of a- and b-adrenoreceptor and adenylate cyclase gene transcription • Increased density of a- and b-adrenoreceptors and enhanced expression of adenylate cyclase • Inhibition of iNOS gene activation and cytokine/ chemokine production • (Ann Rev Physiol 53:497; 1991)

  48. Neonatal Shock: Blood Pressure Decreased Sensitivity of the Cardiovascular System to Catecholamines (2) Relative or absolute adrenal insufficiency of the critically ill preterm and term neonate Watterberg et al; Pediatrics 1999

  49. Neonatal Shock: Blood Pressure Effect of hydrocortisone on mean blood pressure at 2 and 4 hours after the first dose of the drug Mean Blood Pressure N=23 * = P<0.05 vs Control mm Hg * * Pre-HC HC [2 h] HC [4 h] Seri et al; Pediatrics 2001

  50. Neonatal Shock: Blood Pressure Effects of Steroids on Cardiovascular Function Non-Genomic Effects of Steroids : 1. Inhibition of catechol-0-methyltransferase (COMT) and norepinephrine reuptake (Circ Res 24:383, 1969) • 2. Increase in intracellular calcium availability: • physiologic concentrations of aldosterone and pharmacologic doses of • cortisol via the PLC-PKC pathway (J Mol Med 73:439,1995) • glucocorticoid-induced calmodulin-dependent activation of calcium • channels (J Steroid Bioch Mol Biol 55:185, 1995) 3. Improved capillary integritydue to decreased cytokine/chemokine production (J Clin Invest 68:13, 1981)

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