shock & inotropes in neonates - dr padmesh

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