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Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Childre

Pathophysiology and Treatment of Neonatal Shock. 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.

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Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Childre

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  1. Pathophysiology and Treatment of Neonatal Shock 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. Pathophysiology and Treatment of Neonatal ShockDefinition of Hypotension and Normal Blood Pressure • Hypotension is best defined by the absence of adequate perfusion pressure to vital organs • Normal (autoregulatory) blood pressure range: • developmentally regulated (gestational- and postnatal-age dependent) • may be affected by the underlying pathophysiology • not known in the neonate

  3. Pathophysiology and Treatment of Neonatal ShockBlood 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

  4. Pathophysiology and Treatment of Neonatal ShockPhases of Neonatal Shock Compensated phase  Heart rate;  Urine output; but no change in blood pressure; blood flow “maldistributed” to vital organs (brain, heart, adrenal glands) Uncompensated phase  Heart rate;  Urine output;  Blood pressure; blood flow decreases in all organs, tissue hypoperfusion and acidemia develop Irreversible phase Irreversible cellular damage

  5. Pathophysiology and Treatment of Neonatal ShockNeonatal Shock Blood pressure (BP) is an acceptable measure of tissue perfusion in the neonate with uncompensated shock as long as the normal range of BP is known By definition, BP is a poor measure of tissue perfusion in compensated shock As vital organ assignment appears to be developmentally regulated, in the ELBW neonate during the first 24 hours of extrauterine life normal BP does not necessarily indicate normal brain blood flow

  6. Pathophysiology and Treatment of Neonatal ShockFactors Influencing Treatment Gestational age Postnatal age Underlying pathophysiology and severity of illness Etiology/type/phase of shock Pharmacodynamics and pharmakokinetics of vasoactive agent(s) Presence or absence of inflammatory response syndrome, adrenal insufficiency, state of adrenergic receptor expression

  7. Pathophysiology and Treatment of Neonatal ShockEtiology of Neonatal Shock Hypovolemic shock: Inadequate circulating blood volume 2. Cardiogenic shock: Myocardial dysfunction 3.Distributive shock: Failure of vasoregulation with or without dysfunction of the immature myocardium

  8. Pathophysiology and Treatment of Neonatal Shock Pressors, Lusitropes, Intorpes and Steroids Used in Neonates Dopamine Dobutamine Epinephrine Norepinephrine Vasopressin Isuprenaline Phosphodiesterase III Inhibitors (Milrinone, Amrinone) Hydrocortisone or Dexamethasone

  9. Pathophysiology and Treatment of Neonatal ShockClinical 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)

  10. Pathophysiology and Treatment of Neonatal ShockEstimation of Renal Blood Flow in ELBW neonates

  11. Pathophysiology and Treatment of Neonatal ShockApproaches to Organ Blood Flow measurements: SVC Blood Flow Measurement of SVC Blood Flow in ELBW neonates during the first DOL Evans et al; Arch Dis Child 2000; 82: F182

  12. Pathophysiology and Treatment of Neonatal ShockEvaluating Blood Flow in the Fetus

  13. Pathophysiology and Treatment of Neonatal ShockEvaluating Brain Development by fMRI in the Neonate Sensory-Motor Pathways: Contra-lateral, Bi-lateral & Thalamus 39/42w GA/PCA male 26/39w GA/PCA female 40/43w GA/PCA male 39/42w GA/PCA male (a,b): Contra-lateral sensory-motor (c): Bi-lateral deactivation, (d): Bilateral deactivation in thalamus

  14. Pathophysiology and Treatment of Neonatal ShockNeonatal Shock Hypovolemia

  15. Pathophysiology and Treatment of Neonatal ShockPrimary Etiology: HypovolemiaRelationship Between BP and Blood Volume in Preterm Neonates Mean BP Systolic BP Mean BP Blood Pressure (mm Hg) Blood Volume (mL/kg) Blood Volume (mL/kg) Blood Volume (mL/kg) Barr et al, J Pediatr; 1977 Bauer et al, Arch Dis Child; 1993 Wright et al, Arch Dis Child; 1994

  16. Pathophysiology and Treatment of Neonatal ShockPrimary Etiology: Hypovolemia Randomized Controlled Trial of Colloid and Crystalloid Infusions in Hypotensive Preterm Infants 5% Albumin (n=32)  59% required pressor support Normal Saline (n=31) 58% required pressor support Mean Blood Pressure (mm Hg) MAP x FiO2 (cm H2O) Mean Blood Pressure (mm Hg) MAP x FiO2 (cm H2O) 2 8 24 48 2 8 24 48 Time (hours) Time (hours) So et al, Arch Dis Child; 1997

  17. Pathophysiology and Treatment of Neonatal ShockPrimary Etiology: Hypovolemia Randomized Controlled Trial of Colloid and Crystalloid Infusions in Hypotensive Neonates Preterm Neonates Term Neonates ^ * Blood Pressure * ^ Oca et al, J Perinatol; 23:473; 2003

  18. Pathophysiology and Treatment of Neonatal ShockNeonatal Shock Impaired Regulation of Vascular Tone(with or without myocardial dysfunction)

  19. Pathophysiology and Treatment of Neonatal Shock Dopamine

  20. Pathophysiology and Treatment of Neonatal ShockMechanisms 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

  21. Pathophysiology and Treatment of Neonatal Shock 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

  22. Pathophysiology and Treatment of Neonatal ShockFactors 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)

  23. Pathophysiology and Treatment of Neonatal Shock Effect of Dopamine on Blood Pressure, Central Venous Pressure, Heart Rate and TcpO2 in Preterm Neonates Seri et al, Eur J Pediatr, 1984

  24. Neonatal Shock: Blood PressureDopamine Therapy 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

  25. Pathophysiology and Treatment of Neonatal Shock 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

  26. Pathophysiology and Treatment of Neonatal Shock Effect of Dopamine on the Resistance Index in the MCA in Hypotensive Preterm and Term Neonates Seri et al, Pediatr Res; 1993

  27. Pathophysiology and Treatment of Neonatal Shock Changes in HbD (CBF), MAP and SaO2 in a 1-day-old 28-week GA preterm infant. Subsequent HU/S remained normal Changes in HbD (CBF), MAP and SaO2 in a 1-day-old 27-week GA preterm infant. Subsequent HU/S revealed PVL Changes in HbD (cerebral intravascular oxygenation; HbO2-Hb) correlate with changes in CBF (Tsuji et al; Pediatrics 2000; 106:625)

  28. Pathophysiology and Treatment of Neonatal Shock 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

  29. Pathophysiology and Treatment of Neonatal Shock 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

  30. Pathophysiology and Treatment of Neonatal Shock 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

  31. Pathophysiology and Treatment of Neonatal ShockTreatment 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)

  32. Pathophysiology and Treatment of Neonatal ShockMean Blood 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)

  33. Pathophysiology and Treatment of Neonatal ShockRelationship 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)

  34. Pathophysiology and Treatment of Neonatal ShockProposed 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)

  35. Pathophysiology and Treatment of Neonatal ShockNeonatal Shock Impaired Regulation of Vascular Tone(with or without myocardial dysfunction)

  36. Pathophysiology and Treatment of Neonatal Shock Epinephrine

  37. Pathophysiology and Treatment of Neonatal ShockMechanisms of Action ofEpinephrine • * = 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

  38. Pathophysiology and Treatment of Neonatal Shock Effect of the Addition of Epinephrine to Dopamine/Dobutamine on BP and Urine Output in Preterm Neonates with Shock Mean Blood Pressure Urine Output N=11 N=11 * * = P<0.05 vs Control * * mL/kg/hour mm Hg * = P<0.05 vs Control DA/DB + EPI (6 h) DA/DB + EPI (1 h) DA/DB + EPI (6 h) DA/DB DA(DB) Tan, Evans, Seri; Pediatr Res; 1999

  39. Pathophysiology and Treatment of Neonatal ShockNeonatal Shock Impaired Regulation of Vascular Tone(with or without myocardial dysfunction)

  40. Pathophysiology and Treatment of Neonatal ShockNeonatal Septic or Vasodilatory Shock Vasopressin

  41. Pathophysiology and Treatment of Neonatal ShockMechanisms of Action ofVasopressin • * = 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

  42. Pathophysiology and Treatment of Neonatal ShockSeptic ShockVasodilation (low systemic vascular resistance) Down-regulation of cardiovascular adrenergic receptors and signaling pathways (decreased sensitivity to catecholamines) Relative or absolute adrenal insufficiency (decreased sensitivity to catecholamines) Increased nitric oxide synthesis Nitric oxide-independent activation of soluble guanylate cyclase (increased production of CO, OH- by bacterial endotoxin) Vasopressin deficiency Activation of KATP and KCa channels

  43. Pathophysiology and Treatment of Neonatal ShockNeonatal Septic or Vasodilatory ShockVasopressin (1) Mechanisms of Action V1a receptor stimulation Baroreceptor inactivation in sepsis/autonomic failure enhances vasopressin-induced vasoconstriction Potentiation of vasopressor effects of catecholamines Direct inactivation of KATP channels in vascular smooth muscle AVP blunts NO- and ANP-induced increases in cGMP AVP inhibits the function of iNOS Organ-specific heterogeinity of vascular responsiveness: at low doses, AVP stimulates oxytocin receptor-induced endothelial production of NO in the brain and coronary arteries

  44. Pathophysiology and Treatment of Neonatal ShockNeonatal Septic or Vasodilatory ShockVasopressin (1) • Experience with vasopressin in critically ill neonates: • Small number of newborns with vasodilatory shock following cardiac surgery • (Rosenzweig et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 1999; 100:II-182)

  45. Pathophysiology and Treatment of Neonatal ShockNeonatal Shock Myocardial Dysfunction

  46. Pathophysiology and Treatment of Neonatal Shock Dobutamine

  47. Pathophysiology and Treatment of Neonatal ShockMechanisms of Action ofDobutamine • * = 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

  48. Pathophysiology and Treatment of Neonatal ShockTreatment ofHypotension (1)(Dopamine versus Dobutamine) Gestational Age = 27 (23-33) Weeks • * Control Dopamine Dobutamine * Mean Blood Pressure (mm Hg) n = 20 n = 20 Control Control Dopamine Dobutamine [5 (5-10) µg/kg/min] [10 (5-15) µg/kg/min] • * = P<0.05 vs Control = P<0.05 vs Dobutamine (Greenough and Emery, 1993)

  49. Pathophysiology and Treatment of Neonatal Shock Cardiovascular Effects of Dopamine and Dobutamine in Preterm Neonates with Gestational Age < 32 Weeks Left Ventricular Output (ml/kg/min) Systemic Vascular Resistance (dynes/sec/cm5/m2) Mean Blood Pressure (mm Hg) • • * • * * * *= P<0.05 vs Control •= P<0.05 vs Dopamine * = P<0.05 vs Control •= P<0.05 vs Dobutamine * = P<0.05 vs Control •= P<0.05 vs Dobutamine C DA DB N=20 Dopamine = 12 µg/kg/min Dobutamine = 17 µg/kg/min Roze et al, Arch Dis Child; 1993

  50. Pathophysiology and Treatment of Neonatal ShockUse of Lusitropes in Neonatal Shock Milrinone

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