Digoxin is used to treat heart failure and atrial fibrillation. It works by inhibiting the sodium-potassium pump in cardiac cells, increasing intracellular calcium levels and strengthening heart muscle contractions. The optimal serum concentration is 0.5-0.9 ng/mL. Adverse effects include nausea, vomiting, arrhythmias, and can be caused by electrolyte imbalances or drug interactions. Digoxin is primarily excreted unchanged in urine and its half-life is increased in renal impairment. It is indicated to treat heart failure with reduced ejection fraction or atrial fibrillation with a rapid ventricular response.

1. ‫الرحيم‬ ‫الرحمن‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
PEDIATRIC WAD MEDANI TEACHING HOSPITAL
UNIT: PROF AHMED ALNOUR
DR HISHAM ALUMDA
DR ABDALSALAM
PHARMACOLOGICAL BASIS AND PEDIATRICS USES OF
DIGOXIN
Presented by Dr ; Mogahed.I.H.Hussein

2. OBJECTIVES
• Understanding normal physiological mechanisms implicated in cardiac
muscle contraction and relaxation.
• Know the mechanisms by which digoxin alter cardiac contractility
• Know the pharmacokinetics of the drug
• Know the uses of digoxin and its potential adverse effects

9. Mechanism of Action
 Digoxin’s primary mechanism of action is the ability to
inhibit membrane-bound alpha subunits of sodium-
potassium ATPase (sodium pump), mainly but not
exclusively located in the human myocardium.
 This inhibition promotes sodium-calcium exchange, which
increases the intracellular calcium concentration that is
available to the contractile proteins, resulting in an increase
in the force of myocardial contraction.2,3

10. Mechanism of Action
 In the human myocardium, there is no evidence of up-
regulation of the sodium pump during chronic digoxin
therapy.4
 The inhibition of the sodium pump may also improve
baroreceptor sensitivity in HF and may explain some of the
neurohormonal effects of digoxin.5
 Digoxin also has important parasympathetic effects,
particularly on the atrioventricular node.

11. Mechanism of Action
 In patients with reduced systolic function and abnormal
central hemodynamics who are in sinus rhythm, digoxin
improves left ventricular ejection fraction (LVEF) and reduces
pulmonary capillary wedge pressure while increasing
cardiac output both at rest and during exercise.

12. Mechanism of Action
 In HF, however, when hemodynamics are normalized first
with diuretics and vasodilators, no further improvement in
pulmonary capillary wedge pressure or cardiac output is
achieved after the acute administration of digoxin.6,7
 The improvement in hemodynamics is sustained during
chronic therapy.8

14. Hemodynamic Effects
 Digitalis administration does not alter cardiac output in
normal subjects, although it does cause significant increase
in contractility.
 This lack of effect on cardiac output is likely due to an
increase in systemic vascular resistance produced by digitalis
that prevents the increase in contractility from translating
into increased cardiac output.

15. Neurohormonal Effects
 (1) Baroreceptor function: In low-output HF models, there is
attenuation of carotid sinus baroreceptor discharge
sensitivity. Administration of digoxin produces improvement
in baroreceptor function that results in decreased activation
of the sympathetic nervous system.5
 (2) Vagomimetic effect: Digoxin at therapeutic doses
increases vagal tone (ie, decreases sinoatrial and
atrioventricular conduction).10

16. Neurohormonal Effects
 (3) Sympathoinhibitory effects: Digoxin has a direct
sympathoinhibitory effect that does not appear to be
related to an increase in the cardiac output produced by the
drug. Although dobutamine and digoxin cause a similar
increase in cardiac output in HF, only the latter decreases
sympathetic nerve discharge.11
 (4) Circulating neurohormones: Therapeutic doses of
digoxin decrease the serum norepinephrine concentrations
and plasma renin activity.12

17. Neurohormonal Effects
 (5) Dose related effects on neurohormones: A low dose of digoxin
that has no effect on cardiac contractility or hemodynamics
decreases cardiac norepinephrine spillover in severe
HF.13 Increasing the dose within therapeutic range continues to
improve the hemodynamics without further improvement of the
neurohormonal profile.14
 (6) Antifibrotic effects: Patients with HF often have chronically high
levels of aldosterone. Aldosterone stimulation of the sodium
pump may lead to perivascular fibrosis that experimentally may
be prevented by digoxin administration.15

18. Electrophysiological Effects
 Therapeutic doses of digoxin have a predominantly
parasympathomimetic action on atrial myocardium, slowing
conduction, and prolonging atrioventricular node refractory
period.
 There are practically no electrophysiological effects on the
Purkinje system. Although digoxin intoxication may produce
lethal arrhythmias, therapeutic doses do not appear to
increase arrhythmias in the absence of ischemia.16

19. Electrophysiological Effects
 ventricular response. Irrespective of the indication, a low
dose of 0.125 mg should be used. Digoxin should be
avoided or used with extreme caution in the very elderly or
in patients with severe conduction abnormalities, acute
coronary syndromes, or renal failure.

22. Pharmacokinetics
 Sixty to 80 percent of digoxin is absorbed from the tablets
and over 90% from the capsules in 1 to 3 hours.
 This is followed by a 6- to 8-hour tissue distribution phase.
In some patients, oral digoxin is partial inactivated by
colonic bacteria; as a result, certain antibiotics may increase
digoxin absorption.
 Only 16% of the absorbed digoxin is metabolized, whereas
the rest is excreted unchanged in the urine.

23. Pharmacokinetics
 The half-life of digoxin is 36 to 48 hours in patients with
normal renal function and 3.5 to 5 days in anuric patients.
 Digoxin is not removed by exchange transfusions or
peritoneal dialysis or hemodialysis, or during
cardiopulmonary bypass. In patients with normal renal
function, an oral daily maintenance dose without a loading
dose results in a steady-state blood concentration in
approximately 7 days.

24. Digoxin Dose/ Serum Concentration
 Low dose digoxin, resulting in a serum concentration (SDC)
less than 1 ng/mL, has beneficial hemodynamic,
neurohormonal, and clinical effects.26,27
 Retrospective analysis of the DIG trial suggests that digoxin
has a bidirectional effect, with a possible decrease in
mortality when SDC is 0.5 to 0.9 ng/mL and an increase in
mortality when SDC is above 1 ng/mL.28

25. Digoxin Dose/ Serum Concentration
 Additional data from the DIG trial suggest that in patients
with normal renal function who are not receiving
medications that tend to increase SDC, a dose of 0.125 mg
daily will result in SDC of approximately 0.8 ng/mL.21
 Determination of SDC is not routinely necessary because it
is predictable based on dose used. Only the post-
distribution phase (12 to 24 hours after the dose) is useful to
evaluate whether the dose of digoxin is acceptable.29

26. Factors predisposing to digitalis toxicity:
Electrolytic disturbances
 Hypokalemia can precipitate serious arrhythmia.
 Reduction of serum potassium levels is most frequently
observed in patients receiving thiazide or loop diuretics, and
this usually can be prevented by use of a potassium-sparing
diuretic or supplementation with potassium chloride.
 Hypercalcemia and hypomagnesemia also predispose to
digitalis toxicity.

27. Drugs:
 Quinidine, verapamil, and amiodarone, to name a few, can
cause digoxin intoxication, both by displacing digoxin from
tissue protein-binding sites and by competing with digoxin
for renal excretion.
 As a consequence, digoxin plasma levels may increase by 70
to 100 percent, requiring dosage reduction. Potassium-
depleting diuretics, corticosteroids, and a variety of other
drugs can also increase digoxin toxicity .
 Hypothyroidism, hypoxia, renal failure, and myocarditis are
also predisposing factors to digoxin toxicity.

29. Digoxin Intoxication
 Traditionally divided into extra cardiac and cardiac
 ‘Definite’ Toxicity defined as
 Nausea/Vomiting with
 Cardiac effects with
 Resolution of side effects on discontinuation
 SDC not a necessary criterion – but SDC > 2.0 ng/ml
helpful

30. Extracardiac SEs
 Nonspecific but more common
 Gastrointestinal (60-80%)
 Nausea / Vomiting
 Anorexia, Abdominal Pain, Diarrhoea
 Malaise (30-40%)
 Lethargy, Fatigue

31.  Neurological (20-30%)
 Dizziness, Confusion
 Headache
 Visual changes (flashing lights, halos, colour disturbances
in green – yellow spectrum, blurred vision)

32. Cardiac SEs
 More specific but less common
 Almost any permutations and combinations of heart block,
brady- and tachydysrhythmias are possible.
 The only dysrhythmia not assumed to be due to Digoxin
toxicity – Mobitz Type 2 Heart block

33. Inverse check mark: Digoxin effect

35.  Digoxin toxicity signs
Inverse check mark
with proximal ST segment depressed
In leads other than those with tall R waves
With T wave not rising above baseline (Inverted T)
With shortened Qtc

37.  Note that
 Digoxin does not affect the QRS
 Maximal therapeautic effect of digoxin is usually present
befoe the ECG effects appear

38. Management
 If the evidence of toxicity is relatively minor with, for example,
symptoms of nausea, withdrawal of the drug is often the only
specific treatment required.
 If there is no evidence of serious cardiac problems, such as
heart block or significant dysrhythmias, then following the
withdrawal of the drug and the correction of electrolyte
imbalance, symptomatic measures will usually suffice.

39.  More serious evidence of toxicity, particularly with cardiac
involvement, dysrhythmias, is potentially life threatening, and
requires admission to hospital.
 Measures
 Hypokalemia correction - intravenous supplementation of no more
than 20 mmol/h of potassium, to reduce digitalis binding to Na/K
ATPase. More rapid infusion may lead to asystole.
 Heart blocks – Atropine and Temporary cardiac pacing

40. Malignant ventricular arrhythmias
Phenytoin (100 mg intravenously, repeated after 5
minutes if required) is a useful antidysrhythmic as it
opposes digitalis binding and may improve
atrioventricular conduction by its anticholinergic
properties.‘

41. Malignant ventricular arrhythmias
Ultrashort acting beta blockers – Esmolol
Cardioversion should be avoided wherever possible,
due to the risk of precipitating asystole, and when
necessary should be attempted using the lowest energy
possible.

42. Digoxin-specific antibody fragments
Digoxin-specific fab antibody fragments (Digibind)
are the most effective treatment available. However,
this therapy is expensive and therefore should be
reserved for treatment of serious toxicity, especially
in the presence of malignant cardiac dysrhythmias.

43. Digoxin-specific antibody fragments
These antibodies have a high affinity and specificity for
cardiac glycosides and have been shown to reverse
digoxin toxicity and reduce the risk of death.
In several large studies, approximately 80% of patients
had complete resolution of all evidence of toxicity, 10%
improved whilst 0% showed no response.
They appear effective for all age groups and also in
patients with poor renal reserve (despite eventual renal
elimination).

44. Digoxin-specific antibody fragments
 Pharmacokinetics
 Half life 12-20 hrs
 Vd 0.4 L/kg
 After administration, SDC cannot be measured
without complete elimination from the body

45. Special Considerations in the Use of
Digoxin
Acute Heart Failure Syndrome
 In patients hospitalized for HF and systolic dysfunction, oral
or intravenous administration of digoxin will increase the
cardiac output, reduce pulmonary capillary wedge pressure
and heart rate, and improve the neurohormonal profile.7

46. Acute Heart Failure Syndrome
 These beneficial hemodynamic effects have not been
correlated with symptoms. Rapid intravenous administration
of digoxin as a bolus may result in worsening HF through an
early predominant vasoconstrictor effect.36

47. Special Considerations in the Use of
Digoxin
Advanced Heart Failure
 Digoxin may be particularly beneficial in patients with a LVEF
less than 25%, symptoms with minimal exertion or at rest,
and/or cardiomegaly on chest x-ray.21
Isolated Right-Sided Heart Failure
 Digoxin increases cardiac output and decreases
norepinephrine concentration in patients with right
ventricular failure due to cor pulmonale.37 There are no
clinical data supporting the use of digoxin for isolated right-
sided failure.

48. Digoxin in the Multidrug Approach of
Heart Failure
 Diuretics
 Because digoxin affects potassium homeostasis,
combination therapy with non-potassium sparing diuretics
may induce serious arrhythmias.
 In these patients, high normal concentration of potassium
and magnesium should be maintained. The arrhythmogenic
effects of digoxin may be lessened by potassium sparing
diuretics.

49. Beta-Blockers
 Although chronic beta-blocker therapy is highly beneficial in
HF, during its initiation, hemodynamic deterioration may
occur, particularly in patients with very severe HF.38
 Beta-blocker use may also increase the safety of digoxin
therapy, because experimentally they can abolish the
digoxin-induced life-threatening arrhythmias in ischemic
HF.39

50. Precautions in Using Digoxin
 Digoxin should not be used in patients with sinoatrial or
second/third degree atrioventricular block unless a
functioning pacemaker is present. Digoxin should also not
be used in Wolff-Parkinson-White syndrome, hypertrophic
or restrictive cardiomyopathy, and amyloid heart disease.

51. Precautions in Using Digoxin
 It should be used with caution in patients with impaired
renal function, electrolyte disorders, thyroid disorders, and
acute coronary syndromes.
 It is preferable to discontinue digoxin a few days before
electrical cardioversion. If cardioversion is performed in
patients receiving digoxin, potassium levels should be
corrected, and the lowest energy possible should be used.

52. Indications for Digoxin Therapy
 Digoxin is indicated in patients with HF and impaired systolic
function who are in sinus rhythm and continue to have signs
and symptoms despite standard therapy that includes
angiotensin-converting enzyme inhibitors and beta-
blockers.40

53. Indications for Digoxin Therapy
 Digoxin may be particularly useful in patient therapies.
Digoxin is indicated in patients with atrial fibrillation, with or
without HF, and a rapid with severe symptoms, LVEF less
than 25%, or cardiomegaly on chest x-ray.
 In patients with diastolic HF, digoxin should be used for atrial
fibrillation with a rapid ventricular response and/or severe
symptoms not responding after optimization of all other

54. Digoxin in children
Despite the lack of data regarding its use in
children, digoxin continues to be used by most
clinicians in the management of pediatric heart
failure.
Primary Myocardial disease HF is most
acceptable indication of Digoxin in Pediatric HF.

55. Digoxin in children
Left to right shunts and Valvular heart disease patients
are treated with digoxin only after they become
symptomatic.
Also, any HF due to digoxin responsive
Tachyarrhythmia is a strong indication – needs Rapid
digitalisation
Lower starting dose (½ to ¾ maintenance) is indicated
in acute phase of myocarditis, renal failure, and with
drugs which increase SDC.

56. SHOCK

57. OBJECTIVES
IN UNDERSTANDING SHOCK
 Know the general principles that aid well recognition of CVS pathology
 Understands the primary disturbances, compensatory responses,
decompensatory processes, and possible therapeutic interventions that
pertain to various abnormal cardiovascular situations:
 Identifies the primary disturbances that can account for cardiogenic,
hypovolemic, anaphylactic, septic, and neurogenic shock states.

58. OBJECTIVES
 Lists the compensatory processes that may arise during various
types of circulatory shock.
 Identifies the decompensatory processes that may arise during
shock and describes how these lead to irreversible shock states
 Defines circulatory shock.

60. General Principles
• PA, mean arterial pressure;
• CO, cardiac output;
• TPR, total peripheral resistance;
• SV, stroke volume;

61. General Principles
• HR, heart rate
• ESV, end-systolic volume
• EDV, end-diastolic volume
• PcV' central venous pressure

62. General Principles
• NE, norepinephrine
• ACh, acetylcholine
• P P' arterial pulse pressure
• CA, arterial compliance
• SA, sinoatrial.

63. General Principles
• PA =COxTPR
• CO=SVxHR
• SV=EDV-ESV
• Ejection fraction = SV/EDV

64. General Principles

65. General Principles
NO & MUSCLE RELAXATION

66. General Principles
SMOOTH MUSCLE R&C

67. General Principles
SMOOTH MUSCLE R&C

68. General Principles
IMMUNOLOGICAL RESPONSE THAT LEAD
TO SHOCK

69. General Principles
Requirements for Effective Operation
• For effective efficient ventricular pumping action, the heart must
be functioning properly in five basic respects:
1. The contractions of individual cardiac muscle cells must occur at
regular intervals and be synchronized (not arrhythmic).
2. The valves must open fully (not stenotic).

70. General Principles
Requirements for Effective Operation
3- The valves must not leak (not insufficient or regurgitant).
4- The muscle contractions must be forceful (not foiling).
5- The ventricles must fill adequately during diastole.

72. Demand Supply

73.  Demand  Supply

74. Introduction
• A state of circulatory "shock" exists whenever there is a
generalized, severe reduction in blood supply to the body tissues
and the metabolic needs of the tissues are not met.
• Even with all cardiovascular compensatory mechanisms activated,
arterial pressure is usually (though not always) low in shock.

75. Introduction
• In severe shock states of any etiology, inadequate brain
blood flow leads to loss of consciousness often with sudden
onset (called syncope).
• The approach to understanding the causes and selecting an
appropriate treatment depends on determination of the
underlying primary disturbance.

76. Introduction
• Recall that arterial pressure is determined by cardiac output
and total peripheral resistance, so any loss in blood pressure
is a result of a decrease in either one or both of these
variables

77. Primary Disturbances
• In general, the shock state is precipitated by one of three
cardiovascular crises:
(1) severely depressed myocardial functional ability.
(2) grossly inadequate cardiac filling due to low mean
circulatory filling pressure.

78. Primary Disturbances
(3) profound systemic vasodilation either due to the abnormal
presence of powerful vasodilators or due to the absence of
neurogenic tone normally supplied by the sympathetic nervous
system.
The consequences of these primary disturbances are represented in
the five categories of shock summarized in the next Figure .

79. Primary Disturbances
Cardiogenic shock
• Cardiogenic shock occurs whenever cardiac pumping ability
is compromised (eg, as a result of severe arrhythmias, abrupt
valve malfunction, coronary occlusions, or myocardial
infarction).
• The direct consequence of any of these abnormalities is a
significant fall in cardiac output.

80. Primary Disturbances
Hypovolemic shock
• Accompanies significant hemorrhage (usually greater than 20% of
blood volume), or fluid loss from severe burns, chronic diarrhea, or
prolonged vomiting.
• These situations can induce shock by depleting body fluids and
thus circulating blood volume.
• The direct consequence of hypovolemia is inadequate cardiac
filling and reduced stroke volume.

81. Primary Disturbances
Hypovolemic shock
• There are some situations that may result in reduced cardiac filling
that are not related to hypovolemia.
• For example, cardiac tamponade, associated with fluid
accumulation in the pericardial sac, prevents adequate diastolic
filling as does the occurrence of a pulmonary embolus (a clot
mobilized from systemic veins lodging in a pulmonary vessel).

82. Primary Disturbances
Anaphylactic shock
• Anaphylactic shock occurs as a result of a severe allergic reaction to an
antigen to which the patient has developed a sensitivity (eg, insect bites,
antibiotics, and certain foods).

83. Primary Disturbances
Anaphylactic shock
• This immunological event, also called an "immediate hypersensitivity
reaction," is mediated by several substances (such as histamine,
prostaglandins, leukotrienes, and bradykinin) that, by multiple
mechanisms, results in substantial arteriolar vasodilation, increases in
microvascular permeability, and loss of peripheral venous tone.
• These combine to reduce both total peripheral resistance and cardiac
output

84. Primary Disturbances
Septic shock
• Septic shock is also caused by profound vasodilation but
specifically from substances released into the circulating
blood by infective agents. One of the most common is
endotoxin, a lipopolysaccharide released from bacteria.

85. Primary Disturbances
Septic shock
• This substance induces the formation of a nitric oxide synthase (called
inducible nitric oxide synthase to distinguish it from the normally present
comtitutive nitric oxide synthase) in endothelial cells, vascular smooth
muscle, and macrophages that then produce large amounts of the potent
vasodilator nitric oxide.
• The term distributive shock is sometimes used to describe both the
anaphylactic and septic shock states.

86. Primary Disturbances
Neurogenic shock
• Neurogenic shock is produced by loss of vascular tone due to
inhibition of the normal tonic activity of the sympathetic
vasoconstrictor nerves and often occurs with deep general
anesthesia or in reflex response to deep pain associated with
traumatic injuries.

87. Primary Disturbances
Neurogenic shock
• It may also be accompanied by an increase in vagal activity, which
significantly slows the cardiac beating rate.
• This type of shock is often referred to a vasovagal syncope. The
transient syncope evoked by strong emotions is a mild form of
neurogenic shock and is usually quickly reversible.

89. Primary Disturbances
• As shown in the top half of previous Figure, the common primary
disturbances in all forms of shock are decreased cardiac output
and/or total peripheral resistance leading to decreased mean
arterial pressure.
• Generally, the reduction in arterial pressure is substantial, and so
therefore, is the influence on the cardiovascular centers from
reduced arterial baroreceptor discharge rate.

90. Primary Disturbances
• In addition, in the case of hypovolemic, anaphylactic, and
septic shock, diminished activity of the cardiopulmonary
baroreceptors due to a decrease in central venous pressure
and/or volume acts on the medullary cardiovascular centers
to stimulate sympathetic output.

91. Primary Disturbances
• In the case of cardiogenic shock, central venous pressure will
increase; and in the case of neurogenic shock, central venous
pressure cannot be predicted because both cardiac output and
venous return are likely to be depressed.
• Thus, in these instances, it is not clear how the
cardiopulmonary baroreceptors affect autonomic output

92. Primary Disturbances

94. Compensatory Mechanisms
• Compensatory Mechanisms in general, the various forms of
shock evoke the compensatory responses in the autonomic
nervous system that we would expect from a fall m blood
pressure.

95. Compensatory Mechanisms
• Two primary exceptions to this statement include
(I) neurogenic shock, where reflex responses may be absent or lead
to further depression of blood pressure
(II) certain instances of cardiogenic shock associated with
inferoposterior myocardial infarctions, which elicit a reflex
bradycardia and decrease sympathetic drive (the Bezold-Jarisch
reflex).

96. Compensatory Mechanisms
• These increases in sympathetic activity and decreases in
parasympathetic activity are indicated in the bottom half of the
previous Figure.
• Cardiac and peripheral vascular compensatory responses to shock,
however, may be much more intense than those that accompany
more ordinary cardiovascular disturbances.

97. Compensatory Mechanisms
• Many of the commonly recognized symptoms of shock (eg, pallor, cold
clammy skin, rapid heart rate, muscle weakness, and venous constriction)
are a result of greatly increased sympathetic nerve activity.
• When the immediate compensatory processes are inadequate, the
individual may also show signs of abnormally low arterial pressure and
reduced cerebral perfusion, such as dizziness, confusion, or loss of
consciousness.

98. Compensatory Mechanisms
• Additional compensatory processes initiated during the shock state may
include the following:
1. Rapid and shallow breathing occurs, which promotes venous return to the
heart by action of the respiratory pump.
2. Increased renin release from the kidney as a result of sympathetic stimulation
promotes the formation of the hormone, angiotensin II, which is a potent
vasoconstrictor and participates in the increase in total peripheral resistance even
in mild shock states.

99. Compensatory Mechanisms
3. Increased circulating levels of vasopressin (also known as antidiuretic
hormone) from the posterior pituitary gland contribute to the increase in
total peripheral resistance. This hormone is released in response to
decreased firing of the cardiopulmonary and arterial baroreceptors.
4. Increased circulating levels of epinephrine from the adrenal medulla in
response to sympathetic stimulation contribute to systemic vasoconstriction.

100. Compensatory Mechanisms
5. Reduced capillary hydrostatic pressure resulting from intense arteriolar
constriction, promotes fluid movement from the interstitial space into the
vascular space.
6. Increased glycogenolysis in the liver induced by epinephrine and
norepinephrine results in a release of glucose and a rise in blood (and interstitial)
glucose levels and, more importantly, a rise in extracellular osmolarity by as
many as 20 mOsm. This will induce a shift of fluid from the intracellular space
into the extracellular (including intravascular) space.

101. Compensatory Mechanisms
• The latter two processes result in a sort of "autotransfusion"
that can move as much as a liter of fluid into the vascular
space in the first hour after the onset of the shock episode.
• This fluid shift accounts for the reduction in hematocrit that is
commonly observed in hemorrhagic shock.

102. Compensatory Mechanisms
• The extent of fluid shift may be limited by a reduction in
colloid osmotic pressure.
• In addition to the immediate compensatory responses, fluid
retention mechanisms are evoked by hypovolemic states that
affect the situation in the long term.

103. Compensatory Mechanisms
• The production and release of the antidiuretic hormone (vasopressin)
from the posterior pituitary promote water retention by the kidneys.
• Furthermore, activation of the renin-angiotensin-aldosterone pathway
promotes renal sodium retention {via aldosterone) and the thirst
sensation and drinking behavior {via angiotensin II). These processes
contribute to the replenishment of extracellular fluid volume within a few
days of the shock episode.

104. Decompensatory Processes
• Often the strong compensatory responses during shock evoked by
the intense sympathetic activation are capable of preventing
drastic reductions in arterial pressure.
• However, because the compensatory mechanisms involve
overwhelming arteriolar vasoconstriction, perfusion of tissues other
than the heart and the brain may be inadequate despite nearly
normal arterial pressure.

105. Decompensatory Processes
• For example, blood flow through vital organs such as the liver,
gastrointestinal tract, and kidneys may be reduced nearly to zero by intense
sympathetic activation.
• The possibility of permanent renal, hepatic, or GI tract ischemic damage is a
very real concern even in seemingly mild shock situations.
• Patients who have apparently recovered from a state of shock may die several
days later because of renal failure, uremia, or sepsis due to bacterial
penetration of the weakened mucosal barrier in the GI tract.

106. Decompensatory Processes
• The immediate danger with shock is that it may enter the progressive stage, wherein the general
cardiovascular situation progressively degenerates, or, worse yet, enter the irreversible stage,
where no intervention can halt the ultimate collapse of cardiovascular system that results in death.
The mechanisms behind progressive and irreversible shock are not completely understood.
• However, it is clear from the mechanisms shown in the next Figure, that bodily homeostasis can
progressively deteriorate with prolonged reductions in organ blood flow.
• These homeostatic disturbances, in turn, adversely affect various components of the cardiovascular
system so that arterial pressure and organ blood flow are further reduced.

107. Decompensatory Processes
• Note that the events shown in the Figure are decompensatory mechanisms.
• Reduced arterial pressure leads to alterations that further reduce arterial
pressure rather than correct it {ie, a positive feedback process).
• These decompensatory mechanisms that are occurring at the tissue level to
lower blood pressure are eventually further compounded by a reduction in
sympathetic drive and a change from vasoconstriction to vasodilation with a
further lowering of blood pressure.

108. Decompensatory Processes
• The factors that lead to this unexpected reduction in sympathetic drive
from the medullary cardiovascular centers are not clearly understood.
• If the shock state is severe enough and/or has persisted long enough to
enter the progressive stage, the self-reinforcing decompensatory
mechanisms progressively drive arterial pressure down. Unless corrective
measures are taken quickly, death will ultimately result.

109. Decompensatory Processes

110. Decompensatory Processes

111. KEY CONCEPTS
 Circulatory shock is defined as a generalized, severe
reduction in tissue blood flow so that metabolic needs are
not met.
 The primary disturbances that can lead to shock can be
categorized as those that directly interfere with pump
function, those that interfere with ventricular filling, or those
that cause sustained vascular dilation.

112. KEY CONCEPTS
 Shock is usually accompanied by a compensatory increase in
sympathetic activity aimed at maintaining arterial pressure
via augmented cardiac output and vascular resistance.
 Decompensatory processes precipitated by the shock state
are generally caused by inadequate tissue blood flow, loss of
local homeostasis, and tissue damage leading to a
progressive and irreversible fall in arterial pressure.

113. MANAGMENT
 The most common error in treating shock is underestimating
the severity of the condition.
 If compensated shock is suspected, treat promptly and
aggressively to prevent progression to hypovolemic shock.
 All patients require a secure vascular access, oxygen therapy,
and cardiopulmonary monitoring.

114. MANAGMENT
 The goals of initial management are to restore normal mental
status, heart rate and blood pressure, good peripheral
perfusion, and adequate urine output.

115. ED
1. Position: allow a conscious patient to assume a position of
comfort.
2. Oxygen: give 100% supplemental oxygen by nonrebreather
mask to spontaneously breathing patients. Consider the use of
noninvasive positive-pressure ventilation (BiPAP, CPAP) as an
alternative to intubation in selected cases (awake and
cooperative patients).

116. ED
3. Assisted ventilation: if there is evidence of airway
compromise, assist ventilation with either a bag-mask device or
tracheal intubation.

117. ED
4. Intravenous access: establish two large-bore peripheral IV
lines or place a central catheter.
If venous access is not possible or delayed, use an IO needle.
In critically ill or injured patients, do not spend more than 1–2
minutes attempting to establish peripheral vascular access. The
effort may be resumed after the IO line is secured.

118. ED
5. Fluid: infuse a fluid bolus of 20 mL/kg of isotonic crystalloid
(lactated Ringer’s or normal saline) as rapidly as possible.
Several boluses may be required; large volumes of fluid for
resuscitation in previously healthy children do not increase the
risk of developing acute respiratory distress syndrome or
cerebral edema.
Trauma victims may require blood (10 mL/kg) to replace
ongoing losses; use cross-matched, type-specific or O-negative
blood.

119. ED
Trauma patients who remain hypotensive after fluid
resuscitation may require immediate operative intervention.
6. Reassess: after each intervention, look for improvement in
vital signs, skin perfusion, and level of consciousness. Insert a
Foley catheter and monitor urine output; the goal is 1–2
mL/kg/h or 30 mL/h in adolescents.

120. ED
7.Inotropic infusion: if the patient remains hypotensive after
initial fluid resuscitation of 40–60 mL/kg, an inotropic agent, or
a combination of several agents, may be necessary to stabilize
blood pressure .
Titrate the dose to the desired effect. Monitor the patient
carefully and switch to a less potent agent once the blood
pressure has improved.

121. ED
8.Septic shock: administer antibiotic therapy as soon as
possible.
Send the appropriate cultures, but do not delay therapy if
cultures are not readily obtained.

122. ED
Empiric antibiotics include vancomycin plus cefotaxime or
ceftriaxone for the possibility of resistant Streptococcus
pneumoniae and methicillin-resistant Staphylococcus aureus.
Consider adding acyclovir for HSV in neonates and cefepime for
Pseudomonas aeruginosa in immunocompromised patients.

123. ED
9.Anaphylactic shock: management involves early recognition of
symptoms of anaphylaxis and anticipating need for advanced
airway techniques .

124. Cardiogenic shock
10. Give fluid boluses judiciously, at volumes of 5–10 mL/kg, to
patients with a history of cardiomyopathy or congenital heart
disease. Reassess frequently for signs of cardiac failure.
Give patients in congestive heart failure supplemental oxygen,
diuretics (furosemide 1 mg/kg), and inotropic agents
(dobutamine, dopamine), and consult with a pediatric
cardiologist.

125. Cardiogenic shock
Treat pediatric dysrhythmias according to the PALS Guidelines .
a. Asystole and PEA: epinephrine
b. Symptomatic bradycardia: epinephrine and atropine
c. Supraventricular tachycardia :
i. Stable: adenosine ii. Unstable: synchronized cardioversion
(0.5–1 J/kg)

126. Cardiogenic shock
d. Ventricular tachycardia (with pulses)
i. Stable: amiodarone or procainamide (not concurrently) or
lidocaine
ii. Unstable: synchronized cardioversion (0.5–1 J/kg)

127. Cardiogenic shock
e. Ventricular fibrillation and pulseless ventricular tachycardia:
CPR followed by defibrillation, one shock,(2J/kg)and immediate
resumption of CPR, epinephrine, and/or amiodarone, and/or
lidocaine.
Alternate drugs with defibrillation (4J/kg: single shock each
time).

128. Cardiogenic shock
Always resume CPR immediately after shock for 2 minutes or 5
cycles of 30:2 or 10 cycles of 15:2, then reassess rhythm.
Once defibrillation isS successful, many patients will required
additional CPR before they regain a perfusing rhythm.

131. References
 ↵ Withering W. An account of the foxglove and some of its medical uses, with practical remarks
on dropsy, and other diseases. In Willins FA, Keys TE, eds. Classics of Cardiology. Volume I. New
York, NY: Henry Schuman, Dover Publications; 1941: 231–252.
 ↵ Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations
of toxicity: part I. Prog Cardiovasc Dis. 1984; 26: 495–530.
 ↵ Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations
of toxicity: part II. Prog Cardiovasc Dis. 1984; 26: 413–458.
 ↵ Schmidt TA, Allen PD, Colucci WS, et al. No adaptation to digitalization as evaluated by
digitalis receptor (Na/K-ATPase) quantification in explanted hearts from donors without heart
disease and from digitalized recipients with end-stage heart failure. Am J Cardiol. 1992; 70: 110–
114.
 ↵ Wang W, Chen JS, Zucker IH. Carotid sinus baroreceptor sensitivity in experimental heart
failure.Circulation. 1990; 81: 1959–1966.

132. References
 ↵ Gheorghiade M, St. Clair J, St. Clair C, et al. Hemodynamic effects of intravenous digoxin in
patients with severe heart failure initially treated with diuretics and vasodilators. J Am Coll
Cardiol. 1987; 9: 849–857.
 ↵ Gheorghiade M, Hall V, Lakier J, et al. Comparative hemodynamic and neurohormonal effects
of intravenous captopril and digoxin and their combinations in patients with severe heart
failure. J Am Coll Cardiol. 1989; 13: 134–142.
 ↵ Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis therapy improves left ventricular
function in heart failure. N Engl J Med. 1980; 303: 1443–1448.
 ↵ Lynch JJ, Kitzen JM, Hoff PT, et al. Reduction in digitalis-associated post-infarction mortality
with nadolol in conscious dogs. Am Heart J. 1988; 115: 67–76.
 ↵ HFSA Guidelines Heart Failure Society of America (HFSA) practice guidelines. HFSA guidelines
for management of patients with heart failure caused by left ventricular systolic
dysfunction:pharmacological approaches. J Card Fail. 1999; 5: 357–382.

133. References
 ↵ Gheorghiade M, Ferguson D. Digoxin: a neurohormonal modulator in heart
failure? Circulation. 1991;84: 2181–2186.
 ↵ Krum H, Bigger JT, Goldsmith RL, et al. Effect of long-term digoxin therapy on
autonomic function in patients with chronic heart failure. J Am Coll
Cardiol. 1995; 25: 289–294.
 ↵ Ferguson DW, Berg WJ, Sanders JS, et al. Sympathoinhibitory responses to digitalis
glycosides in heart failure patients: direct evidence from sympathetic neural
recordings. Circulation. 1989; 80: 65–77.
 ↵ van Veldhuisen DJ, Man in’t Veld AJ, Dunselman PHJM, et al. Double-blind placebo-
controlled study of ibopamine and digoxin in patients with mild to moderate heart
failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll
Cardiol. 1993; 22: 1564–1573.

134. References
 ↵ Newton GE, Tong JH, Schofield AM, et al. Digoxin reduces cardiac sympathetic activity in
severe congestive heart failure. J Am Coll Cardiol. 1996; 28: 155–161.
 ↵ Gheorghiade M, Hall VB, Jacobsen G, et al. Effects of increasing maintenance dose of digoxin
on left ventricular function and neurohormones in patients with chronic heart failure treated with
diuretics and angiotensin-converting enzyme inhibitors. Circulation. 1995; 92: 1801–1807.
 ↵ Sundaram S, Zampino M, Gheorghiade M. Is there still a place for digoxin in heart failure? In:
van Veldhuisen DJ, Pitt B, eds. Focus on Cardiovascular Diseases: Chronic Heart Failure.
Amsterdam, the Netherlands: Benecke NI; 2002: 219–254.
 ↵ Lown B, Graboys TB, Podrid PJ, et al. Effect of a digitalis drug on ventricular premature beats. N
Engl J Med. 1977; 296: 301–306.
 ↵ Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril
and digoxin in patients with mild to moderate heart failure. JAMA. 1988; 259: 539–544.

135. References
 ↵ DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their
combination in the treatment of patients with chronic heart failure. N Engl J
Med. 1989; 320: 677–683.
 ↵ Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic
heart failure treated with angiotensin-converting enzyme inhibitors. N Engl J Med. 1993; 329: 1–
7.
 ↵ Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin
withdrawal in patients with mild to moderate congestive heart failure: results of the PROVED
trial. J Am Coll Cardiol.1993; 22: 955–962.
 ↵ The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients
with heart failure. N Engl J Med. 1997; 336: 525–533.
 ↵ Redfors A. The effect of different digoxin doses on subjective symptoms and physical working
capacity in patients with atrial fibrillation. Acta Med Scand. 1971; 190: 307–320.

136. References
 ↵ Zarowitz BJ, Gheorghiade M. Optimal heart rate control for patients with chronic atrial fibrillation: are
pharmacologic choices truly changing? Am Heart J. 1992; 123: 1401–1403.
 ↵ Khand AU, Rankin AC, Martin W, et al. Carvedilol alone or in combination with digoxin for the management
of atrial fibrillation in patients with heart failure? J Am Coll Cardiol. 2003; 42: 1944–1951.
 ↵ Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm:
a randomized, double-blinded trial. Ann Intern Med. 1987; 106: 503–506.
 ↵ Slatton ML, Irani WN, Hall SA, et al. Does digoxin provide additional hemodynamic and autonomic benefit at
higher doses in patients with mild to moderate heart failure and normal sinus rhythm? J Am Coll
Cardiol. 1997; 29: 1206–1213.
 ↵ Adams KF Jr, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart
failure. J Am Coll Cardiol. 2002; 39: 946–953.
 ↵ Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with
heart failure. JAMA. 2003; 289: 871–878.
 ↵ Valdes R, Jortani S, Gheorghiade M. Standards of laboratory practice: cardiac drug monitoring. Clin
Chem. 1998; 44: 1096–1109.

137. References
 ↵ Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis. 2002; 44: 251–266.
 ↵ Antman EM, Wenger TL, Butler VP Jr, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific
Fab antibody fragments: final report of a multicenter study. Circulation.1990; 81: 1744–1752.
 ↵ Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J
Med. 2002; 347: 1403–1411.
 ↵ Eichhorn EJ, Gheorghiade M. Digoxin: new perspective on an old drug. N Engl J Med. 2002; 347:1394–1395.
 ↵ Rich MW, McSherry F, Williford WO et al. Effect of age on mortality, hospitalizations and response to digoxin in patients with heart
failure: the DIG study. J Am Coll Cardiol. 2001; 38: 806–813.
 ↵ Beller GA, Conroy J, Smith TW. Ischemia-induced alterations in myocardial Na/K-ATPase and cardiac glycoside binding. J Clin
Invest. 1976; 57: 341–350.
 ↵ Cohn JN, Tristani FE, Khatri IM. Cardiac and peripheral vascular effects of digitalis in clinical cardiogenic shock. Am Heart
J. 1969; 78: 318–330.
 ↵ Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary
hypertension. Chest. 1998; 114: 787–792.
 ↵ Hall SA, Cigarroa CG, Marcoux L et al. Time course of improvement in left ventricular function, mass, and geometry in patients
with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol. 1995; 25: 1154–1161.