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
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
9.
10. • Shock is
“a state of cellular energy failure resulting from an
inability of tissue oxygen delivery
to satisfy tissue oxygen demand”
(Singer, 2008)
24. • Physiological considerations in preterm infants :
• Early gestations: Less β1 receptors, but many
active α1 receptors.
β1
α1
Peripheral
vasoconstriction
Afterload augmentation
25.
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).
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
37. Stimulating alpha or beta or dopaminergic receptors
on cell membrane of myocardial cells
Increased intracellular calcium availability
Increased actin–myosin bridge formation
Contractility
38.
39. • UNIQUE FEATURES OF INOTROPES:
–One drug, many receptors
–Dose-response curve
–Direct versus reflex actions
–Tachyphylaxis
40.
41.
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.
48. • USES OF DOPAMINE: IN SEPTIC SHOCK:
• BENEFITS: Increased
– Myocardial contractility
– Mean arterial pressure (high dose)
– Systemic vascular resistance (high dose)
49.
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.
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
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
65.
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.
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)
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.
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)
82.
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
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
Notas do Editor
1 g% of Hb is capable of carrying about 1.34 ml of O2.
0.003 is the solubility coefficient of oxygen in human plasma.
SaO2 = saturation of hemoglobin with oxygen
Preload = End-diastolic volume of the ventricle, and, up to a point, the greater the preload, the larger the stroke volume (the Frank-Starling relationship).
Afterload is the force the ventricle must generate against the systemic or pulmonary vascular resistance. As long as appropriate perfusion pressure is ensured, the lower the afterload, the better the cardiac output.
Contractility (the intrinsic ability to generate force per unit time)
Typically, cardiac output in neonates is considered heart rate–dependent, because the neonate’s ability to augment stroke volume is somewhat limited compared to children or adults.
CaO2 =arterial O2 content .
If cardiac output falls, VO2 may be maintained constant by capillary bed vasodilation and increased O2 extraction by the tissues.
Increased O2 extraction is manifested as a lower CvO2 and therefore greater CaO2 – CvO2 difference
Normally, DO2 and VO2 are well matched. O2 extraction approximately 25%.
If the SaO2 is 100%, SvO2 would be expected to be 75%.
If cardiac output falls, VO2 may be maintained constant by capillary bed vasodilation and recruitment and/or by increased O2 extraction by the tissues.
Increased O2 extraction is manifested as a lower CvO2 and therefore greater CaO2 – CvO2 difference.
FICK PRINCIPLE: uptake or release of a substance by any organ is the product of the arteriovenous (A-V) concentration difference of the substance and the blood flow to that organ.
1. 75% of circulating blood volume is on venous side of circulation at any given point in time, therefore increase in venous capacitance caused by venodilation relative hypovolemia.
2. Preload is augmented by the negative intrathoracic pressure generated at each spontaneous inspiration. Therefore positive intrathoracic pressure associated with positive pressure mechanical ventilation reduces venous return and hence preload and cardiac output.
1. Adult heart 60% of myocardium is muscular; early pretermsmyocardium contains only 30% contractile tissue.
2. Mechanisms of control of myocyte activity such as sarcoplasmic reticulum and t-tubule system are underdeveloped and there is an over representation of mitochondria which are relatively disorganized.
3. Neonatal myocardium is less contractile and is functioning near its physiological capacity.Therefore,ability to respond to additional stress placed by metabolic demands (e.g., infection,changing loading conditions) or inotropes may be limited.
Because the preterm myocardium is adapted to a low-resistance intrauterine environment, characterized by reduced contractile elements, and has a limited ability to respond to increased afterload .
The adrenergic system also differs in the immature neonate.
Balance of response to catecholamine stimulating agents is skewed towards peripheral vasoconstriction and afterload augmentation at the expense of cardiac output,which may not be desirable in some patients.These effects are most pronounced at the earliest gestation and diminish with maturation .
guanine nucleotide-binding proteins
adenylyl cyclase
cAMP stimulated protein kinase