6. G-Protein Adenyl cyclase
ATP cAMP
Increased heart
muscle
contractility
Adrenaline
MECHANISM OF ACTION – cAMP
Increase the cycling of Calcium in & out of cell
14. • Cardiac arrest efficacy due to increased CPP
• Anaphylaxis
• Cardiogenic shock
• Bronchospasm
• Low output after CPB
• Hypotension with spinal/epidural can be treated with 1-
4µg/min
• Added to local anaesthetics to prolong action
INDICATIONS & USES
15. • Shock/hypotension
Bolus iv - 0.03-0.2 µg/kg
Infusion 0.03-0.015 µg/kg/min adults
0.05-0.5 µg/kg/min children
• Cardiac arrest
0.5-1 mg iv bolus & 0.01mg/kg iv in children
• Anaphylaxis
DOSE
16. • Ventricular arrythmias
> 1 mcg/kg/30 min with halothane
> 3 mcg/kg/30 min with isoflurane
• 3 PVC in 50% of adults (ED50) at 1.25 MAC @ dose of
2.1 μg/kg with halothane,
6.7 μg/kg with isoflurane,
10.9 μg/kg with enflurane.
• Children tolerate larger doses than adults
• Hypocapnia potentiates, pretreatment with sodium thiopental attenuates arrythmias.
APPLIED – ADRENALINE IN ANESTHESIA
19. DOSE DEPENDENT EFFECT OF DOPAMINE
<3
mcg
3 - 10
mcg
> 10
mcg
↑Contractilit
y
Minimal change
in
HR and SVR
↑ Renal
BF
↑ Splanchnic
BF
Modest ↑
CO
↑ Renal
BF
↓Proximal Tub.
Na Absorbtion
↑ Splanchnic
BF
↑ HR,
Vasoconstricti
on
↑/ ↓ Renal BF
↓/↑ Splanchnic
BF
Dopamine selectively increases renal blood flow when administered at 1-3 mcg/kg/min.
No data to support the routine use of low dose dopamine to prevent or treat acute renal failure or mesenteric ischemia.
Dopamine receptors induce urine
May be detrimental for monitoring
Not renal protective
20. DOBUTAMINE
Frequently used in severe, medically refractory heart failure and
cardiogenic shock.
Should not be routinely used in sepsis because of the risk of hypotension.
25. Digoxin Digitoxin
Avg digitalization dose
Oral 0.75-1.50 mg 0.8-1.2 mg
Intravenous 0.5-1.0 mg 0.8-1.2 mg
Avg daily maintenance dose
Oral 0.125-0.500 mg 0.05-0.20 mg
Intravenous 0.25 mg 0.1 mg
Onset of effect
Oral 1.5-6.0 hrs 3-6 hrs
Intravenous 50-30 mins 30-120 mins
Absorption from the GIT 75% 90-100%
Plasma protein binding 25% 95%
Route of elimination Renal Hepatic
Enterohepatic circulation Minimal Marked
Elimination half-time 31-33 hrs 5-7 days
Therapeutic plasma
concentration
0.5-2.0 ng/ml 10-35 ng/ml
26. MILRINONE
Effects are similar to dobutamine but with a lower incidence of dysrhythmias.
Used to treat patients with impaired cardiac function and medically refractory HF.
Vasodilatory properties limit their use in hypotensive patients.
27. MILRINONE
Minimal ↑ in
O2 demand ↓ SVR
↓ PVR
Minimal ↑ HR
↑ CO
Diastolic
Relaxatio
n
• Effect receptor independent - effective
in receptor down regulation
• ↡SVR hypotension
• Uses -
↡CO, where BP not low + SVR ↑
Pulm HTN + acute RVF
Post op cardiac pts
• Major concern - Hypotension
SVT, junctional and ventricular tachyarrythmias
(↑ in hypokalemia)
28. AMRINONE VS MILRINONE
2
8
MILRINONE
• More widely used
• t1/2 2.3 hours
• Excreted - urine
• Dose adjustment in renal impairment
• Dose: Bolus 50 - 75 mcg/kg over 1 hr
Infusion 0.5 - 0.75 mcg/kg/min
AMRINONE
• t1/2- 5.8 hrs
• Thrombocytopenia (2.4%). Platelets
monitoring.
• Stop if PLT < 50,000/c mm
• Dose: Bolus 1-3mg/kg over 1 hour
infusion at 5 - 15 mcg/kg/min
29. LEVOSIMENDAN
IV Loading dose - 12 mcg/kg over 10 minutes infusion of 0.1 to 0.2
mcg/kg/min
Dissolve 0.3 mg/kg in 50ml of 5% dextrose and run at 12 ml/hr for 10 minutes
and then reduce infusion to 1–2 ml/hr
30. Bollen Pinto et al., Current Opinion in Anesthesiology 2008,
21:168–177
MECHANISM OF ACTION OF LEVOSIMENDAN ON CARDIOVASCULAR FUNCTIONS
31. LEVOSIMENDAN
3
1
• Adverse effects:
AF – More common than dobutamine
Ventricular arrythmias - less common than dobutamine
Mild hypokalemia
• T1/2 1.5 – 2h
• Active metabolite OR-1896 T1/2 of 70 - 80 hours
• Measurable in serum even 14 days after stopping infusion
Hemodynamic effects persists for days after stopping
• Concern - hypotension
• Excretion: Urine+faeces
32. COMPARISON LEVOSIMENDAN, MILRINONE, DOBUTAMINE
Feature Levosimendan Milrinone Dobutamine
Class Calcium channel Phosphodiesterase-III Catecholamine(β-
sensitizer inhibitor adrenergic agent)
↑intracellular Ca No Yes Yes
concentrations
Vasodilator Coronary and Peripheral Mild peripheral
systemic
↑Myocardial O₂ No No Yes
demand
Arrhythmogenic Rare and may be due Ventricular and Ventricular ectopic
potential to QTc prolongation supraventricular activity; less
arrhythmias arrhythmogenic than
milrinone
Adverse events Headache, Ventricular Tachycardia and
hypotension irregularities, increased SBP on
hypotension, headache overdosage
33. VASOPRESSIN
Physiologic states - Minimum role in maintenance of BP ;
Main role - Maintaining plasma volume/serum osmolarity
Dose > 0.03units/min coronary, mesenteric ischemia, skin necrosis.
Avoid > 0.04units/min unless severe refractory shock.
34. VASOPRESSIN
3
4
• T1/2 of 10-20 mins use IV infusion
• Normal level : 4-20 pg/ml
• Relative deficiency in sepsis – Seen in 1/3rd patients
• Adult studies , as shock state continues, levels drop. This relative/absolute
deficiency - Basis of use in shock
• Pediatric data: Inconsistent
35. VASOPRESSIN
3
5
• Patients in shock found to be highly sensitive. Even small dose, which would
have no effect in normotensive, healthy subject can significantly increase BP
in a patient with shock.
• Advantages as a pressor agent over classical agents:
No chronotropy (Useful in high HRs)
Effective even in acidosis
Has own receptor system - Effective in receptor downregulation
Potentiates NE (unknown mechanisms)
36. INFUSION PREPARATION OF VASOACTIVE DRUGS
3
6
• 6 x BW (kg) – (in mg) to mix in 100 ml of solvent gives
1ml/hr = 1 mcg/kg/min
• 3 x BW (kg) - (in mg) to mix in 50 ml of solvent gives
1ml/hr = 1 mcg/kg/min
38. COMPLICATIONS
HYPOPERFUSION – dusky tips of fingers/toes, limb ischemia
AKI – adequate volume resuscitation, protect kidneys by MAP >60mmHg, avoid
excessive vasoconstrictors.
DYSRRHYTHMIAS – sinus tachy, AF, AVNRT, ventricular tachycardia
MI – myocardial O2 concumption + insuffient diastolic filling time
LOCAL EXTRAVASATION – into surrounding CT skin necrosis
HYPERGLYCEMIA – х insulin. ( NE >> EN / DA )
39. CORRECTABLE FACTORS
• ACIDOSIS - ↡ Sensitivity to calcium
↡ No. Of receptors
↡ cAMP levels (In animal models, overcome by increasing dose)
• HYPOXIA - same effect on all drugs, Effect more pronouncd (Not overcome by ↑dose)
• HYPOCALCEMIA
30
DECREASED EFFECTS OF INOTROPES
40. 4
0
PROLONGED USE
• Desensitisation
• Receptor down regulation
• ↡ Generation of new receptors
• Down regulation of adenylate
cyclase
• G- protein mediated methods
DECREASED EFFECTS OF INOTROPES
SEPSIS
• Endotoxins
• NO
• Interleukins
• Relative adrenal insufficiency
• Steroid replacement in resistant shock
NON CORRECTABLE FACTORS
44. SELECTION AND TITRATION
Choice of initial agent - suspected etiology.
If maximal doses of a first agent are inadequate, then a second drug should
be added to the first.
Utilize alternative receptor profiles - synergistic effect
Recognize potential adverse effects of each medication
In refractory septic shock, no control trial - utility of third agent.
45. Norepinephrine - first choice ( Grade 1B)
Add / substitute epinephrine when additional drug is needed (Strong
recommendation; Grade 1B).
Vasopressin 0.03 units/min may be added. Reduce NE – salvage therapy (Weak
recommendation; Grade 2A) Low dose vasopressin not recommended
Dopamine only in highly selected patients at very low risk of arrhythmias or low
heart rate (Weak recommendation; Grade 2C).
Dobutamine infusion in low cardiac output or hypoperfusion, even after adequate
intravascular volume (Strong recommendation; Grade 1C)
• Steroids – role. HC ~ 200mg/day, continuous infusion.
• Phenylephrine: only when NE is a/w serious arrythmias, Cardiac output is high as BP persistently low,
Salvage therapy.
SURVIVING SEPSIS – 2018
Target MAP ≥ 65 mm Hg
46.
47. SOFA SCOREVARIABLES Out of 6 variables, only CVS is treatment
dependent – to inotropes/vasopressors.
52. SOAP II TRIAL
All patients with shock were randomized for first-line
vasopressor therapy
Dopamine: n=858
Norepinephrine: n=821
Over 60%of patients with septic shock
Primary outcome was 28daymortality
N Engl J Med 2010;362:779-89
55. CLINICALIMPACT
• Significantly more atrial fibrillation when dopamine used as primary vasopressor
• Dopamine and norepinephrine previously considered equivalent for sepsis patients
• Most recent surviving sepsis guidelines removed dopamine as primary vasopressor
56. Addition of corticosteroid to low dose vasopressin was associated with decreased mortality
and organ dysfunction as compared to norepi and corticosteroid.
Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock, Crit
Care Med. 2009; 37; 811-818.
64. LEVOSIMENDAN TRIALS
LIDO, CASINO, SURVIVE trials: Compared LM with dobutamine
REVIVE, RUSSLAN trials: Evaluated LM in a placebo controlled, in low-output heart failure of
different etiologies
All demonstrated hemodynamic benefits with greater increase in CO in LM group
REVIVE and SURVIVE trials could not demonstrate survival benefits
META-ANALYSIS of 45 adult studies with 5480 patients - Significant mortality benefit - 6%
absolute risk reduction
Follath F,Cleland JG, Just H, et al. Efficacyand safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study):arandomised double-blind trial. Lancet.2002;360:196–
202
MebazaaA, Nieminen MS,Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure:the SURVIVERandomized Trial. JAMA.2007;297:1883–1891
Packer M, Leier CV
.Survival in congestive heart failure during treatment with drugs with positive inotropic actions.Circulation. 1987;75(Suppl 4):55–63 MoiseyevVS,Poder P
,Andrejevs N, et al. Safetyand efficacyof a
novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. Arandomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J.2002; 23:1422–32
46
65. LEVOSIMENDAN TRIALS
6
5
• LeoPARDS study: Effect of LM in sepsis. (Multicentre UK trial underway)
• LM compared with milrinone.
• Majority in postoperative LCOS situations.
• Pediatric studies - retrospective case series, 4 RCTs conducted.
• Showed improvement in hemodynamics, reduction in lactate, reduction in need for
conventional inotrope use and ability to wean catecholamines.
• Mortality benefit - Not proven. More data needed to further establish role
Egan JR, Clarke AJ,Williams S, et al. Levosimendan for low cardiac output: apediatric experience. JInt CareMed. 2006;21:183–7
NamachivayamP
,Crossland DS, ButtWW,et al. Earlyexperience with Levosimendan in children with ventricular dysfunction. Pediatr Crit CareMed. 2006;7:445–448
Magliola R, Moreno G,V
assallo JC, et al. Levosimendan, anew inotropic drug: experience in children with acute heart failure.ArchArgent Pediatr. 2009;107:139–145
66. Angiotensin II added to high dose
norepinephrine infusion (>0.2mcg/kg/min)
is associated with an improvement in blood
pressure at hour 3 of therapy vs. placebo
without an increase in adverse effects,
however more studies are still required to
determine patient oriented outcomes
67. IN PAEDIATRICS
The PLS TASK FORCE agreed that the adult findings could not be extrapolated
to the pediatric population because infants and children have different
physiological responses to vasoactive drugs (varying according to age even
within the age range of infants and children), particularly when compared with
adult physiological responses.
68. Pediatric Life Support: 2020 International Consensus on
Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Science With Treatment Recommendations
Ian K. Maconochie, Richard Aickin, Mary Fran Hazinski, Dianne L. Atkins, Robert
Bingham, Thomaz Bittencourt Couto, Anne-Marie Guerguerian, Vinay M. Nadkarni,
Kee-Chong…and On behalf of the Pediatric Life Support Collaborators
69. VASOACTIVE DRUGS FOR SEPTIC SHOCK (PLS 1604: SCOPREV)
ScopRev - use of vasoactive drugs in pediatric septic shock, excluding other
forms of distributive shock.
Infants and children with septic shock, with and without myocardial
dysfunction.
Insufficient evidence to recommend a specific inotrope or vasopressor to
improve mortality in pediatric distributive shock.
Should be tailored to each patient’s physiology and adjusted to the
individual’s clinical responses.
70. VASOACTIVE DRUGS FOR SEPTIC SHOCK (PLS 1604: SCOPREV)
2 RELEVANT RCTS
60 children with septic shock in ER and ICU
Compared the effects of dopamine with those of
epinephrine.
The primary outcome - resolution of shock in the first
hour,
With epinephrine than dopamine (OR, 4.8; 95% CI, 1.3–
17.2; P=0.019).
On day 3, lower SOFA scores in epinephrine group (8
versus 12, P=0.05).
No difference in the adverse event rate, no
difference in mortality.
Double-blind RCT
120 children with refractory septic shock (despite 40
mL/kg fluid). Randomization - dopamine or epinephrine
primary outcome – 28 day mortality
secondary outcome - healthcare-associated infection.
Dopamine - increased death and infection than
epinephrine
Concern : Dose of epinephrine disproportionately
greater physiological effect than matched doses of
dopamine.
74. CARDIOGENIC SHOCK AND INOTROPES (PLS 418: EVUP)
The early addition of vasoactive drugs
Reasonable to use epinephrine, levosimendan, dopamine, dobutamine - infants
and children.
Milrinone - beneficial for prevention and treatment of low cardiac output
following cardiac surgery.
Insufficient data to support or refute the use of norepinephrine in pediatric
cardiogenic shock.
75. EPINEPHRINE TIME OF INITIAL DOSE AND DOSE INTERVAL DURING
CPR (PLS 1541: SYSREV)
We suggest that the initial dose of
epinephrine in pediatric patients with
nonshockable IHCA and OHCA be
administered as early in the
resuscitation as possible (weak
recommendation, very low-certainty
evidence).
76. INOTROPES IN RESUSCITATION
Pediatric arrests - noncardiac origin
Epinephrine
Vasoconstrictor effect as important as ionotropic effect to
increase coronary circulation during CPR
Makes myocardium responsive to defibrillation attempts
Vasopressin
Levels survivors >> nonsurvivors
Ability to ↑ BP - ↑ SVR and ↑ coronary, cerebral perfusion
AHA + ERC 2010 : 40 U as alternative to adrenaline
No definite recommendation for use in CPR
64
78. DRUGS FOR THE TREATMENT OF BRADYCARDIA:
ATROPINE VERSUS NO ATROPINE AND ATROPINE VERSUS EPINEPHRINE
(PLS NEW: EVUPS)
Infants and children with bradycardia for any reason
Epinephrine - bradycardia and poor perfusion that is unresponsive to ventilation and
oxygenation.
Atropine - bradycardia due to increased vagal tone or anti-cholinergic drug toxicity.
Insufficient evidence to support or refute routine use of atropine for pediatric cardiac
arrest.
80. POST CARDIAC SURGERY
8
0
LCOS: Cardiac index < 2.0 L/min/ m2
6-18 hours after a cardiopulmonary bypass surgery
Primary aim - Support myocardial contractility without increasing workload and
O2 consumption
Many prefer Dopamine 3-10 mcg/kg/min; but doses > 15 mcg/kg/min rarely
used - Vasoconstriction and tachycardia at very high doses
Alternatives : Dobutamine, Low-dose epinephrine
Milrinone: PRIMACORP study
81. Efficacyand safety of prophylactic use of milrinone in pediatric patients at highrisk of
developing LCOSafter cardiacsurgery
Concluded that prophylacticuse of high-dose milrinone after pediatric congenital heart
surgery reduces risk of LCOS
8
1
Milrinone: Important vasoactive agent for use in post-cardiac surgery in children
83. In hyperdynamic septic shock, norepinephrine - first-line agent.
Vasopressin - second-line agent to reduce need for other pressors.
In cardiogenic shock, norepinephrine is preferred initial agent. After
establishing adequate perfusion, Dobutamine added.
In anaphylactic shock, 1st line agent is Epinephrine followed by
Vasopressin as second line agent.
Epinephrine is the 1st line agent in hypotension after CABG.
In both neurogenic shock and anaesthesia-induced hypotension,
Phenylephrine is the 1st line agent.
TAKE HOME POINTS
