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Dr PadmeshDept of Neonatology, Institute of Child
Health, Chennai
INOTROPES
• TOPICS FOR DISCUSSION:
• 1. BRIEF HISTORY• 2. TERMINOLOGIES • 3. PATHOPHYSIOLOGY OF SHOCK IN NEWBORNS &
UNIQUE FEATURES IN PRETERMS• 4. RECEPTOR PHYSIOLOGY• 5. PHARMACOLOGY OF INDIVIDUAL DRUGS AND
CLINICAL SCENARIOS
BRIEF HISTORY
• BRIEF HISTORY:
• 1785 - Digitalis -William Withering – Drospy• 1799 - John Ferriar - Cardiac effects of Digitalis
Digitalis purpurea (Common Foxglove)
• BRIEF HISTORY:
• Ancient Egyptians – ‘Squill’
• BRIEF HISTORY:
SANJIVANI: ‘LIFE RESTORING HERB’
TERMINOLOGIES
• DEFINITIONS & TERMINOLOGIES:
• INOTROPY: myocardial contractility
• CHRONOTROPY: heart rate (firing of sinu atrial node)
• LUSITROPY: relaxation of myocardium
• DROMOTROPY: conduction velocity of atrioventricular node
• BATHMOTROPY: increases degree of excitability
• VASOPRESSOR: increases vascular tone
PATHOPHYSIOLOGY OF SHOCKIN NEONATES
• Shock is “a state of cellular energy failure resulting from an inability of tissue oxygen delivery to satisfy tissue oxygen demand”
(Singer, 2008)
• PRINCIPLES OF OXYGEN DELIVERY:
• Oxygen delivery DO2 = Cardiac Output (CO) × arterial O2 content (CaO2)
where CO = HR × stroke volume (SV)
& CaO2 = [1.34 × Hb × SaO2] + [0.003 × PaO2]
.
• PRINCIPLES OF OXYGEN DELIVERY:
• Oxygen delivery DO2 = Cardiac Output (CO) × arterial O2 content (CaO2)
where CO = HR × stroke volume (SV)
& CaO2 = [1.34 × Hb × SaO2] + [0.003 × PaO2]
1.Preload2.Afterload3.Contractility
.
• PRINCIPLES OF OXYGEN DELIVERY:
• Oxygen consumption VO2 = Cardiac Output (CO) × (CaO2 −CvO2)
where CvO2 is the mixed venous oxygen content.
.
• Relationship between oxygen consumption and delivery.
• PER MOL GLUCOSE
• Aerobic metabolism: 38 mol ATP produced.
• Anaerobic metabolism: 2 mol ATP and 2 mol lactate produced.
Pathogenesis of neonatal shock• ETIOLOGICAL FACTORS:– Hypovolemia– Myocardial Dysfunction– Abnormal Peripheral Vasoregulation
• Hypovolemia• Hypovolemia may be – absolute (loss of intravascular volume), – relative (increased venous capacitance), or – combined (septic shock).
• Hypovolemia Hypovolemia
Decreased Preload Decreased O2 carrying capacity
Decreased CO
Shock
Oxygen delivery DO2 = Cardiac Output (CO) × arterial O2 content (CaO2)
Pathogenesis of neonatal shock• ETIOLOGICAL FACTORS:– Hypovolemia– Myocardial Dysfunction– Abnormal Peripheral Vasoregulation
• Myocardial Dysfunction:
• Post-asphyxia• Extreme preterm • Septic shock• Viral myocarditis Myocardial dysfunction
Decreased Cardiac Output
Decreased Oxygen delivery to tissues
• Physiological considerations in preterm infants :
Myocardium contains only 30% contractile tissue
• Preterm heart Under-developed Sarcoplasmicreticulum & T-tubules
Less contractile & functioning near its physiological capacity
• Physiological considerations in preterm infants :
• Limited sympathetic innervation to preterm myocardium.
INCREASING GESTATION
INNERVATION & PROLIFERATIONOF ADRENO RECEPTORS
Pathogenesis of neonatal shock• ETIOLOGICAL FACTORS:– Hypovolemia– Myocardial Dysfunction– Abnormal Peripheral Vasoregulation
• Physiological considerations in preterm infants :• Early gestations: Less β1 receptors, but many
active α1 receptors.
β1
α1 Peripheral vasoconstriction Afterload augmentation
OTHER UNIQUE FEATURES IN NEONATES
• CO2-CBF reactivity > pressure flow reactivity.
• 1 mm Hg change in PaCO2 4% change in CBF,• 1 mm Hg change in blood pressure 1% change in
CBF only
• Hypocapnia PVL• Hypercapnia IVH
(Greisen, 2005; Müller et al, 2002).
• Selective vaso constriction/ vaso dilation:
Decreased perfusion / oxygen delivery
Vital organs Non vital organs
Vasodilation Vasoconstrict
• Vital organ assignment in preterms:
• Vessels of forebrain of dog pups vasoconstrict (nonvital organ) whereas vessels of hindbrain vasodilate in response to hypoxic exposure (Hernandez et al, 1982).
• CBF autoregulation appears in brainstem first and in only later in forebrain. (Ashwal et al, 1984)
• DOWN REGULATION OF ADRENERGIC RECEPTORS:
• Downregulation is the process by which a cell decreases the quantity of a cellular component.
• Adrenergic receptors: capable of desensitising or downregulating.
• May require higher doses of drug
RECEPTOR PHYSIOLOGY
• Adrenergic receptors relevant to vasopressor activity:– alpha-1–beta-1–beta-2–dopamine receptors
α1 – VASOCONSTRICTION
β1 – INOTROPY, CHRONOTROPY
β2 – VASODILATION
Dopamine – VASODILATION,VASOCONSTRICTION through NE
Mechanisms of cardiomyocyte contraction.
Gs- andGi-protein coupled signal transduction
β1, β2
IP3-coupled signal transduction
Mechanisms of cardiomyocyte contraction.α1
Stimulating alpha or beta or dopaminergic receptors on cell membrane of myocardial cells
Increased intracellular calcium availability
Increased actin–myosin bridge formation
Contractility
• UNIQUE FEATURES OF INOTROPES:
–One drug, many receptors –Dose-response curve –Direct versus reflex actions– Tachyphylaxis
PHARMACOLOGY OF INDIVIDUAL DRUGS
DOPAMINE
• DOPAMINE
• Endogenous sympathomimetic amine.
• Direct action on α-, β-, and dopaminergic receptors.
• Also potentiates release of norepinephrine. (50% of action)
In neonates with escalating dopamine infusion, the pattern of receptor stimulation is first dopaminergic, then a-adrenergic, and finally b-adrenergic
J Perinatol 2006;26:S8–13;
• Effective dose varies among neonates:
• Decreased metabolism of drug
Lower doses may have increased action
• Immature sympathetic innervation
Blunted norepinephrine release
Relative resistance to dopamine
• Lack of response to conventional doses (2–20 mg/kg/min) in critically ill neonates:– Receptor downregulation– Relative adrenal insufficiency– Blunted NE release
• Case series in neonates not responding to conventional doses suggest that dopamine at doses of 30 to 50 mg/kg/ min increased blood pressure and urine output.
• USES OF DOPAMINE: IN TRANSITION PERIOD:• BENEFITS: Increased– Myocardial contractility– Mean arterial pressure (high dose)– Systemic vascular resistance (high dose)– Cerebral blood flow– Tissue oxygenation
• LIMITATIONS:– Increased systemic vascular resistance may impair
cardiac contractility (high dose)
• USES OF DOPAMINE: IN PPHN:• BENEFITS: Increased– Myocardial contractility– Mean arterial pressure (high dose)– Systemic vascular resistance (high dose)
• LIMITATIONS:– Increased Pulmonary arterial pressure (all doses)
• USES OF DOPAMINE: IN SEPTIC SHOCK:• BENEFITS: Increased– Myocardial contractility– Mean arterial pressure (high dose)– Systemic vascular resistance (high dose)
DOBUTAMINE
• DOBUTAMINE:• Synthetic sympathomimetic amine.• Acts directly on α- and β-receptors without the
release of norepinephrine.
• Relative affinity for:– β1-cardioreceptors myocardial contractility, – β2-receptors vasodilation of peripheral vasculature
• Dobutamine has asymmetric carbon atom, with the two enantiomers having different affinity for adrenergic receptors.
• Negative isomer a1-agonist Increases myocardial contractility and SVR.
• Positive isomer β1 and β2 agonist increase myocardial contractility, heart rate, conduction velocity and decreases SVR.
J Perinatol 2006;26:S8–13;
• Dobutamine is used primarily for treatment of decreased myocardial contractility and low cardiac output.
• Dobutamine may be the drug of choice during the transition period in premature neonates due to its ability to improve contractility of the immature myocardium and decrease afterload.
• In general, dobutamine is more effective than dopamine in increasing cardiac output in neonates with myocardial dysfunction.
• USES OF DOBUTAMINE: IN TRANSITION PERIOD:• BENEFITS: Increased– Myocardial contractility (Cardiac output)– OxygenationDecreased– Pulmonary vascular resistance
• LIMITATIONS:– Decreased Peripheral vascular tone– No increase in MAP
• USES OF DOBUTAMINE: IN PPHN:• BENEFITS: Increased– Myocardial contractility (Cardiac output)– Renal perfusion– Cerebral blood flow
• LIMITATIONS:– Decreased Peripheral vascular tone– No change in MAP
• USES OF DOBUTAMINE: IN SEPTIC SHOCK:• (only use in conjunction with another inotrope
in warm shock)
• BENEFITS: Increased– Myocardial contractility (Cardiac output)
• LIMITATIONS:– Decreased Systemic vascular resistance
EPINEPHRINE
• EPINEPHRINE:• Endogenous catecholamine
• Stimulates α1,2- and β1,2-receptors.
• Low doses (0.01–0.1 mcg/kg/min) β1,2 effect increase in myocardial contractility with associated peripheral vasodilation.
• High-dose (>0.1 mcg/kg/min) α receptor effect increased systemic vascular resistance
J Perinatol 2006;26:S8–13;
• EPINEPHRINE:• Net hemodynamic effects:– Increase in blood pressure– Increase in cardiac output & systemic blood flow– Increase in CBF in hypotensive preterm neonates.
• EPINEPHRINE:• Side effects:– tachycardia, arrhythmias, peripheral ischemia, lactic
acidosis, and hyperglycemia.
heart Tachycardia– β2 stimulation of
Liver Lactic acidosis, Hyperglycemia
• USES OF EPINEPHRINE: IN TRANSITION PERIOD:• BENEFITS: Increased– Myocardial contractility– Mean arterial pressure (high dose)– Systemic vascular resistance (high dose)– Cerebral blood flow
• LIMITATIONS:Increased– Heart rate– Plasma lactate– Blood glucose
• USES OF EPINEPHRINE: IN SEPTIC SHOCK:
• BENEFITS: Increased– Myocardial contractility (Cardiac output)– MAP (in high dose)– Systemic vascular resistance (in high dose)
• LIMITATIONS:– Lactic acidosis– Peripheral ischemia (in high dose)– Mesenteric ischemia (in high dose)
• USES OF EPINEPHRINE: IN PPHN:
• BENEFITS: Increased– Myocardial contractility (Cardiac output)– MAP (in high dose)– Systemic vascular resistance (in high dose)
• LIMITATIONS: No change in
- Pulmonary vascular resistance- Pulmonary artery pressure
NOR EPINEPHRINE
• Norepinephrine:• Endogenous catecholamine.• Activation of α1,2- and β1-receptors• Increases systemic vascular resistance & cardiac
output.
• Increases cardiac output by increasing contractility via β1-receptors, although this effect is less pronounced due to potent α -mediated vasoconstriction.
• Norepinephrine:• Standard of care for treatment of vasodilatory
septic shock in adults and children.
• USES OF NOR EPINEPHRINE: IN SEPTIC SHOCK:
• BENEFITS: Increased– Myocardial contractility (Cardiac output)– MAP (in high dose)– Systemic vascular resistance (in high dose)– Tissue perfusion
• LIMITATIONS:-Increased myocardial oxygen consumption-Increase in systemic vascular resistance may impair
cardiac contractility (high dose)
• USES OF NOR EPINEPHRINE: IN PPHN:
• BENEFITS: Increased
-MAP (in high dose)-Systemic vascular resistance (in high dose)-Left ventricular outputDecreased -FiO2 requirement-Pulmonary to systemic pressure ratio
• LIMITATIONS:-Peripheral ischemia (>3.3 mg/kg/min)-Acidosis (>3.3 mg/kg/min)
MILRINONE
• Selective Phosphodiesterase type 3 inhibitor.
• Inotropic, inodilator, and lusitropic.
Decreased breakdown of CAMP Ca influx into myocardial cells inotropy
• Milrinone increases cardiac output without an increase in myocardial oxygen demand.
• Decreases afterload by decreasing systemic vascular resistance.
Large vol of distribution
• Unique PharmacologyLong t1/2 (1.5 to 3.5
hr)
• Milrinone augments the pulmonary vasodilation induced by nitric oxide.
• In observational clinical trials, milrinone decreases pulmonary artery pressures and oxygenation index without a significant effect on blood pressure.
• Use with caution in PPHN with associated hypotension.
• USES OF MILRINONE: IN PPHN:
• BENEFITS: Increased
-Myocardial contractility-OxygenationDecreased -Ductal shunting-iNO requirement-Lactic acid
• LIMITATIONS:-Decreased MAP
VASOPRESSIN
• Endogenous arginine-vasopressin (AVP): Neuropeptide
• Posterior Pituitary
• V1 receptors: vascular tone, platelet function, release of aldosterone and cortisol.
• V2 receptors: Fluid balance and vascular tone.
• Primary physiologic role: extracellular osmolality.• Vascular effects of vasopressin: stimulation of G
protein–coupled V1a and V2 receptors.• V1a receptor (IP3) Vasoconstriction• V2 receptors (cAMP) Vasodilation
• Vasoconstrictive effects of vasopressin dominate when used as an infusion.
• AVP increases vascular tone and produces coronary and pulmonary vasodilation.
Increases blood pressure and cardiac output with
a decreased catecholamine requirement.
• USES OF VASOPRESSIN: IN PPHN:
• BENEFITS: Increased
-Mean arterial pressure-Systemic vascular resistance
Decreased-Pulmonary vascular resistance-Oxygenation index-iNO requirement
• USES OF VASOPRESSIN: IN SEPTIC SHOCK:
• BENEFITS: Increased
-Mean arterial pressure-Systemic vascular resistance
Decreased-Catecholamine requirement
• LIMITATIONS: Increase in systemic vascular resistance
may impair cardiac contractility (high dose)
CORTICOSTEROIDS IN SHOCK
• Relative or absolute adrenal insufficiency +/-
• Secondary to – decreased cortisol stores– decreased ability to produce cortisol in response to
stress.
• Corticosteroids :• Decrease breakdown of catecholamines, • Modifies cAMP Increases Ca levels in
myocardial cells • Upregulate adrenergic receptors. • Decreases capillary leak
INCREASES BLOOD PRESSURE
• Corticosteroids :• Adverse effects: – hyperglycemia, – gastric irritation, and – fluid retention.
• Long-term exposure:– Osteopenia– Inhibits immune function – Inhibits somatic growth.
SUMMARY
PDA with low SAP or DAP
• First line: Shunt limitation strategies, ductal closure • Second line: Positive inotropic agent:
e.g.,dobutamine
SEPSIS/ NNEC • Warm shock: Low DAP, tachycardia: – First line: Volume(crystalloid,blood products)
Vasopressor agents: e.g.,dopamine – Second line: Vasopressoragents :e.g.,vasopressin,
norepinephrine• Cold shock: Low SAP or severe/ combined
hypotension:– First line: Volume expansion (crystalloid or blood
products), Positive inotropic agent: e.g:epinephrine – Second line: Hydrocortisone
HIE• First line: Positive inotropic agent:e.g.,dobutamine • Second line: Positive inotropic agent:
eg:epinephrine • Hydrocortisone if refractory
PPHN• Normal LV and RV systolic function:– First line: Sedation,muscle relaxation,optimum ventilation,
pulmonary vasodilators e.g.,iNO – Second line: If normal MAP and DAP: Milrinone
If low MAP and DAP: Vasopressin If restrictive or no DA: Prostaglandin
• LV and/or RV systolic dysfunction:– Sedation & muscle relaxation – Pulmonary vasodilator(iNO) – If normal or high MAP/DAP: Milrinone– If low MAP/DAP: Dobutamine – Second line: If low MAP/DAP: Vasopressin
Thank you