This document discusses neonatal shock, including its pathophysiology, terminology, history of inotropic drugs, and clinical uses of various inotropic agents. It covers topics such as the unique features of the preterm cardiovascular system, oxygen delivery principles, shock etiologies like hypovolemia and myocardial dysfunction, and the mechanisms and receptors targeted by drugs like dopamine, dobutamine, epinephrine, norepinephrine, milrinone, vasopressin, and corticosteroids. Clinical scenarios where different agents may be beneficial or have limitations are also summarized.

1. Dr Padmesh
Dept of Neonatology, Institute of Child
Health, Chennai

2. • 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

4. • BRIEF HISTORY:
• 1785 - Digitalis -William Withering – Drospy
• 1799 - John Ferriar - Cardiac effects of Digitalis
Digitalis purpurea (Common Foxglove)

5. • BRIEF HISTORY:
• Ancient Egyptians – ‘Squill’

6. • BRIEF HISTORY:
SANJIVANI: ‘LIFE RESTORING HERB’

8. • 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

10. • Shock is
“a state of cellular energy failure resulting from an
inability of tissue oxygen delivery
to satisfy tissue oxygen demand”
(Singer, 2008)

11. • 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]

12. • 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.Preload
2.Afterload
3.Contractility

13. • PRINCIPLES OF OXYGEN DELIVERY:
• Oxygen consumption
VO2 = Cardiac Output (CO) × (CaO2 −CvO2)
where
CvO2 is the mixed venous oxygen content.

14. • Relationship between oxygen consumption and
delivery.

15. • PER MOL GLUCOSE
• Aerobic metabolism: 38 mol ATP produced.
• Anaerobic metabolism: 2 mol ATP and 2 mol
lactate produced.

16. Pathogenesis of neonatal shock
• ETIOLOGICAL FACTORS:
– Hypovolemia
– Myocardial Dysfunction
– Abnormal Peripheral Vasoregulation

17. • Hypovolemia
• Hypovolemia may be
– absolute (loss of intravascular volume),
– relative (increased venous capacitance), or
– combined (septic shock).

18. • Hypovolemia
Hypovolemia
Decreased Preload Decreased O2 carrying
capacity
Decreased CO
Shock
Oxygen delivery DO2 = Cardiac Output (CO) × arterial O2 content (CaO2)

19. Pathogenesis of neonatal shock
• ETIOLOGICAL FACTORS:
– Hypovolemia
– Myocardial Dysfunction
– Abnormal Peripheral Vasoregulation

20. • Myocardial Dysfunction:
• Post-asphyxia
• Extreme preterm
• Septic shock
• Viral myocarditis Myocardial dysfunction
Decreased Cardiac Output
Decreased Oxygen delivery
to tissues

21. • Physiological considerations in preterm infants :
Myocardium contains only
30% contractile tissue
• Preterm heart Under-developed Sarcoplasmic
reticulum & T-tubules
Less contractile & functioning
near its physiological capacity

22. • Physiological considerations in preterm infants :
• Limited sympathetic innervation to preterm
myocardium.
INCREASING GESTATION
INNERVATION &
PROLIFERATION
OF
ADRENO
RECEPTORS

23. Pathogenesis of neonatal shock
• ETIOLOGICAL FACTORS:
– Hypovolemia
– Myocardial Dysfunction
– Abnormal Peripheral Vasoregulation

24. • Physiological considerations in preterm infants :
• Early gestations: Less β1 receptors, but many
active α1 receptors.
β1
α1
Peripheral
vasoconstriction
Afterload augmentation

26. • 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).

27. • Selective vaso constriction/ vaso dilation:
Decreased perfusion / oxygen delivery
Vital organs Non vital organs
Vasodilation Vasoconstrict

28. • 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)

29. • 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

31. • Adrenergic receptors relevant to vasopressor
activity:
–alpha-1
–beta-1
–beta-2
–dopamine receptors

35. Mechanisms of cardiomyocyte contraction.
Gs- and
Gi-protein
coupled
signal transduction

36. IP3-coupled
signal
transduction
Mechanisms of cardiomyocyte contraction.

37. Stimulating alpha or beta or dopaminergic receptors
on cell membrane of myocardial cells
Increased intracellular calcium availability
Increased actin–myosin bridge formation
Contractility

39. • UNIQUE FEATURES OF INOTROPES:
–One drug, many receptors
–Dose-response curve
–Direct versus reflex actions
–Tachyphylaxis

42. • DOPAMINE
• Endogenous sympathomimetic amine.
• Direct action on α-, β-, and dopaminergic
receptors.
• Also potentiates release of norepinephrine.
(50% of action)

43. 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;

44. • 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

45. • 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.

46. • 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)

47. • 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)

48. • USES OF DOPAMINE: IN SEPTIC SHOCK:
• BENEFITS: Increased
– Myocardial contractility
– Mean arterial pressure (high dose)
– Systemic vascular resistance (high dose)

50. • 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

51. • 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.

52. J Perinatol 2006;26:S8–13;

53. • 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.

54. • USES OF DOBUTAMINE: IN TRANSITION PERIOD:
• BENEFITS:
Increased
– Myocardial contractility (Cardiac output)
– Oxygenation
Decreased
– Pulmonary vascular resistance
• LIMITATIONS:
– Decreased Peripheral vascular tone
– No increase in MAP

55. • 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

56. • 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

58. • 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

59. J Perinatol 2006;26:S8–13;

60. • EPINEPHRINE:
• Net hemodynamic effects:
– Increase in blood pressure
– Increase in cardiac output & systemic blood flow
– Increase in CBF in hypotensive preterm neonates.

61. • EPINEPHRINE:
• Side effects:
– tachycardia, arrhythmias, peripheral ischemia, lactic
acidosis, and hyperglycemia.
heart  Tachycardia
– β2 stimulation of
Liver  Lactic acidosis,
Hyperglycemia

62. • 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

63. • 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)

64. • 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

66. • 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.

67. • Norepinephrine:
• Standard of care for treatment of vasodilatory
septic shock in adults and children.

68. • 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)

69. • USES OF NOR EPINEPHRINE: IN PPHN:
• BENEFITS:
Increased
-MAP (in high dose)
-Systemic vascular resistance (in high dose)
-Left ventricular output
Decreased
-FiO2 requirement
-Pulmonary to systemic pressure ratio
• LIMITATIONS:
-Peripheral ischemia (>3.3 mg/kg/min)
-Acidosis (>3.3 mg/kg/min)

71. • Selective Phosphodiesterase type 3 inhibitor.
• Inotropic, inodilator, and lusitropic.

72. Decreased breakdown of CAMP  Ca influx into myocardial cells 
inotropy

73. • Milrinone increases cardiac output without an
increase in myocardial oxygen demand.
• Decreases afterload by decreasing systemic
vascular resistance.
Large vol of distribution
• Unique Pharmacology
Long t1/2 (1.5 to 3.5 hr)

74. • 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.

75. • USES OF MILRINONE: IN PPHN:
• BENEFITS:
Increased
-Myocardial contractility
-Oxygenation
Decreased
-Ductal shunting
-iNO requirement
-Lactic acid
• LIMITATIONS:
-Decreased MAP

77. • 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.

78. • 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.

79. • AVP increases vascular tone and produces
coronary and pulmonary vasodilation.
Increases blood pressure and cardiac output with
a decreased catecholamine requirement.

80. • USES OF VASOPRESSIN: IN PPHN:
• BENEFITS:
Increased
-Mean arterial pressure
-Systemic vascular resistance
Decreased
-Pulmonary vascular resistance
-Oxygenation index
-iNO requirement

81. • 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)

83. • Relative or absolute adrenal insufficiency +/-
• Secondary to
– decreased cortisol stores
– decreased ability to produce cortisol in response to
stress.

84. • Corticosteroids :
• Decrease breakdown of catecholamines,
• Modifies cAMP  Increases Ca levels in
myocardial cells
• Upregulate adrenergic receptors.
• Decreases capillary leak
INCREASES BLOOD PRESSURE

86. • Corticosteroids :
• Adverse effects:
– hyperglycemia,
– gastric irritation, and
– fluid retention.
• Long-term exposure:
– Osteopenia
– Inhibits immune function
– Inhibits somatic growth.

88. PDA with low SAP or DAP
• First line: Shunt limitation strategies, ductal closure
• Second line: Positive inotropic agent:
e.g.,dobutamine

89. 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

90. HIE
• First line: Positive inotropic agent:e.g.,dobutamine
• Second line: Positive inotropic agent:
eg:epinephrine
• Hydrocortisone if refractory

91. 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