The term inotropic state is most commonly used in reference to various drugs that affect the strength of contraction of heart muscle (myocardial contractility). However, it can also refer to pathological conditions. For example, enlarged heart muscle (ventricular hypertrophy) can increase inotropic state, whereas dead heart muscle (myocardial infarction) can decrease it.
Rational choice of inotropes and vasopressors in intensive care unitSaneesh P J
The presentation introduces commonly used interpose and vasopressors; their classification; and how to choose the drug in ICU. Clinical scenarios - cariogenic shock; neurocritical care; septic shock and anaphylactic shock are elaborated.
A simple presentation on hypokalemia. The most common electrolyte disorder in the Critical Care practice.The presentation is based on a mortality and morbidity case report and discussion. It covers all the basic aspects of understanding the causes of hypokalemia in ICU and its management. Target audience are residents ICU and ER but all health care workers can benefit.
Erector spinae plane block is a relatively novel approach to pain management for a variety of surgical procedures. ESP block is a challenging anesthesia and analgesia technique that needs more research.
Geriatric anesthesia with special consideration Petrus IitulaPetrus Iitula
With age, comes changes in normal physiological functions of the body and different diseases are picked up in certain population groups as we age. all this factors predisposes the geriatric population to certain complications once under anesthesia. Hence anesthetic preparation for the geriatric patients is needed to avoid mortality and morbidity in this population.
The term inotropic state is most commonly used in reference to various drugs that affect the strength of contraction of heart muscle (myocardial contractility). However, it can also refer to pathological conditions. For example, enlarged heart muscle (ventricular hypertrophy) can increase inotropic state, whereas dead heart muscle (myocardial infarction) can decrease it.
Rational choice of inotropes and vasopressors in intensive care unitSaneesh P J
The presentation introduces commonly used interpose and vasopressors; their classification; and how to choose the drug in ICU. Clinical scenarios - cariogenic shock; neurocritical care; septic shock and anaphylactic shock are elaborated.
A simple presentation on hypokalemia. The most common electrolyte disorder in the Critical Care practice.The presentation is based on a mortality and morbidity case report and discussion. It covers all the basic aspects of understanding the causes of hypokalemia in ICU and its management. Target audience are residents ICU and ER but all health care workers can benefit.
Erector spinae plane block is a relatively novel approach to pain management for a variety of surgical procedures. ESP block is a challenging anesthesia and analgesia technique that needs more research.
Geriatric anesthesia with special consideration Petrus IitulaPetrus Iitula
With age, comes changes in normal physiological functions of the body and different diseases are picked up in certain population groups as we age. all this factors predisposes the geriatric population to certain complications once under anesthesia. Hence anesthetic preparation for the geriatric patients is needed to avoid mortality and morbidity in this population.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
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ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
1. INOTROPES aNdINOTROPES aNd
vaSOPRESSORS INvaSOPRESSORS IN
caRdIOgENIc ShOckcaRdIOgENIc ShOck
Dr. Anwar Yusr
Critical Care Consultant
University of Science and Technology
Hospital - Sana'a
USTH
2. Cardiogenic Shock
• Cardiogenic shock is defined as:
– SBP <90 mmHg for at least 30 minutes.
– which is secondary to myocardial dysfunction.
–Cardiac index (CI) < 2.2 l/min/m2.
– PCWP > 18 mmHg.
• It is associated with signs of tissue hypoperfusion:-
– decreased urine output: < 0.5ml/kg/hr.
– altered mental status: Confusion.
– peripheral vasoconstriction – sweaty, cold, pale.
– Capillary filling time >2 sec.
3. PATIENT WITH AHF
Bedside assessment to identify
haemodynamic profile
CONGESTION?
YES (95% of AHF patients) NO (5% of AHF patients)
“Wet” “Dry”
POOR PERFUSION?
NO
“Wet” & “Warm”
NO
“Dry” & “Warm”
YES
“Dry” & “Cold”
YES
“Wet” & “Cold”
Adapted from 2016 ESC HF Guildeines
4. “Wet” & “Cold”
Systolic blood pressure < 90 mmHg?
YES NO
Inotropic agent.
Consider vasopressor in
refractory cases.
Diuretic (when perfusion
corrected).
Consider mechanical
circulatory support if no
response to drugs.
Vasodilators.
Diuretics.
Consider inotropic agent
in refractory cases.
Adapted from 2016 ESC HF Guildeines
5. Therapeutic Targets
• Inotrope support is indicated when there is evidence of
tissue hypoperfusion despite fluid optimisation.
• Generally recommended therapeutic targets of
haemodynamic parameters are:
1. MAP 65-75 mmHg.
2. CI > 2.5 [l/min/m2].
3. SVR 800-1000 (dyne/s/m-5).
4. SVO2 > 65%.
5. CPI > 0.6 [w/m2). (MAP x cardiac index x 0.0022).
• All of which aim to improve organ perfusion with the
minimized use of vasoactive drugs and heart rate <110
bpm.
8. Dobutamine
• β1 >>>β2>>α1 (β1: β2 = 3:1).
• Inotropic (increase CO), Mild Chronotropic and
vasodilation: < 5micg/kg/min.
(At higher doses >15, peripheral effect becomes vasoconstriction).
Should be avoided if SBP < 80 mmHg.
Worsening ischemia due to (increase O2 consumption).
? Loss of efficacy in patients on chronic beta blocker
therapy/acidosis/hypoxia.
AF, Ventricular arrhythmias (rare).
Tolerance after 48h.
CONTRAINDICATION : Hypotension and HOCM.
9. DOPAMINE
<3 mcg 3 - 10 mcg > 10 mcg
↑Contractility
Minimal change in
HR and SVR
↑ Renal BF
↑ Splanchnic BF
Modest ↑ CO
↑ Renal BF
↓Proximal Tub.
Na Absorbtion
↑ Splanchnic BF
↑ HR,
Vasoconstriction
↑/ ↓ Renal BF
↓/↑ Splanchnic BF
Dose Dependent effect of Dopamine.
D > β1> α1>> β2.
Tachycardia, Tachyarrythmias, and Worsening ischemia.
10. NOREPINEPHRINE
α1>>β1> β2
Powerful vasopressor, modest
inotropic effects, Less chronotropic.
Predominantly a vasoconstrictor and
a weak inotrope.
As a vasopressor:
100-fold more potent than dopamine.
3 to 5 times more potent than
phenylephrine for raising MAP.
Cardiotoxic at high doses due to
apoptosis in experimental models.
( PKA mediated).
11. SOAP II trial
Norepinephrine is preferred over dopamine when blood pressure is low. (IIB/B)
Medical support with inotropes and vasopressor agents should be individualized
and guided by invasive hemodynamic monitoring. Use of dopamine in
this setting may be associated with excess hazard.
De Backer et al. NEJM 2010;369:779-789
2012 ESC Guidelines for the management of acute myocardial infarction in patients presenting with
STEMI
Comparison of norepinephrine and dopamine in the
treatment of shock (SOAP-II trial)
13. Adrenaline Independent Predictor of
Survival curves for use of adrenaline
Mortality
Propensity score: age, gender, medical history (myocardial infarction, coronary artery bypass graft surgery, hypertension, renal insufficiency), acute
coronary syndrome as the etiology of cardiogenic shock, resuscitation prior to inclusion and initial presentation (confusion, blood lactate, creatinine,
systolic blood pressure, sinus rhythm, and left ventricular ejection fraction).
Tarvasmaki T et al. Crit Care Med 2016;20:208
14. Adrenaline Use Related to Deterioration in
Cardiac and Renal Biomarkers in CS
Tarvasmaki T et al. Crit Care Med 2016;20:208
Adrenaline use associated with markedly worse evolution of cardiac and renal biomarker levels over the
initial 96 hours; likely due to an increase in myocardial oxygen consumption, excessive vasoconstriction
and/or direct organ toxic damage due to intense adrenergic stimulation.
15. Epinephrine vs Norepinephrine in AMI Related CS
Levy B. et al. J Am Coll Cardiol. 2018;72(2):173–82
similar effects on arterial pressure and cardiac
index but a higher incidence of refractory
shock with epinephrine.
19. Milrinone- Clinical application
The main use is in reducing RV afterload and in
advanced non-ischaemic cardiomyopathies.
Theoretical advantages compared to β agonists :
- Chronotropic effect is less than β agonists.
- Less tachycardia for AF patients.
- Better efficacy for those on chronic BB therapy.
- Lusitropic and vasodilatory effects (esp. pulmonary).
Loading dose: 50 mcg/kg administered over 10 minutes
followed by 0.375 mcg/kg/minute.
(However more expensive, hypotension and prolonged action).
22. Pollesello P, Papp Z. J Cardiovasc Pharmacol 2007;50:257-63
Molecular targets, mechanisms of action
and pharmacological effects of levosimendan
Molecular
targets
Mechanisms of
action
Pharmacological
effects
Therapeutic
effects
Selective binding
to the calcium-
saturated form of
cardiac troponin C
Calcium sensitization
of contractile proteins
Positive inotropy Increased ejection fraction
Anti-stunning
Opening of KATP
channels on
smooth muscle
cells in vasculature
Membrane hyper-
polarization.
Vasodilation in all vascular
beds (also coronary and
peripheral circulation).
Lower pre- and afterload
Anti-ischaemic Tissue
perfusion.
Opening of KATP
mitochandria
channels in
cardiomyocytes
Protection of
mitochondria in
ischaemia-reperfusion
Pre-conditioning Anti-
apoptotic
Cardioprotection Anti-
ischaemic Long-term
benefits
23. Levosimendan - Pharmacology
• Loading :Loading : 12-24µg/kg over 10 min.12-24µg/kg over 10 min.
• Infusion:Infusion: 0.05-0.2µg/kg/min.0.05-0.2µg/kg/min.
• Active metabolite – OR-1896 (half life of 80 hours) –
responsible for prolonged action upto several days
after stopping infusion.
Side effects
• Hypotension 4%–10% of patients, depending on
the dose and use of a bolus.
• Headache.
• Arrhythmias: ventricular extra-systoles, and sinus
tachycardia, occurred mainly or exclusively at
higher doses.
24.
25. LEVOSIMENDAN - Evidence
• Significant mortality benefit for critically ill
patients with heart failure and patients
undergoing cardiac surgery.
(Metanalysis from 11 controlled trials (2009)
• Improves mortality after coronary
revascularisation compared to standard therapy.
(Critical Care 2011)
Only intravenous positive inotrope that has had a
mortality benefit consistently.
Uniform physiological benefits for coronary, renal
and G.I systems.
“ALL THESE DATA SUPPORT THE USE OF LEVOSIMENDAN
IN POST MI CARDIOGENIC SHOCK PATIENTS FOR ITS
CALCIUM SENSITIZING , INOTROPIC AND ANTI
MYOCARDIAL STUNNING PROPERTIES”
26. COMPARISON BETWEEN LEVOSIMENDAN,
MILRINONE AND 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 potential
Ventricular and Ventricular ectopic
to QTc prolongation supraventricular activity; less
arrhythmias arrhythmogenic than
milrinone
Adverse events Headache, Ventricular Tachycardia and
hypotension irregularities, increased SBP on
hypotension,
headache
overdosage
27.
28. Risks of Inotropes and Vasopressors in CS
Van Diepen S. J Am Coll Cardiol. 2018;72(2):183
29. What Do The ESC Guidelines 2016 Say?
Recommendations for inotropic agents and vasopressors in patients
with cardiogenic shock
Short-term, i.v. infusion of inotropic agents may be
considered in patients with hypotension (SBP <90 mmHg)
and/or signs/symptoms of hypoperfusion despite
adequate filling status, to increase cardiac output, increase
blood pressure, improve peripheral perfusion and maintain
end-organ function.
IIb C
An intravenous infusion of levosimendan or a PDE III
inhibitor may be considered to reverse the effect of beta-
blockade if beta-blockade is thought to be contributing to
hypotension with subsequent hypoperfusion.
IIb C
Inotropic agents are not recommended unless the patient is
symptomatically hypotensive or hypoperfused because of
safety concern.
III A
556,
557
30. What Do The ESC Guidelines Say?
Recommendations for inotropic agents and vasopressors in patients
with cardiogenic shock
A vasopressor (norepinephrine preferably) may be
considered in patients who have cardiogenic shock, despite
treatment with another inotrope, to increase blood pressure
and vital organ perfusion.
IIb B
558
It is recommended to monitor ECG and blood pressure when
using inotropic agents and vasopressors, as they can cause
arrhythmia, myocardial ischaemia, and in the case of
levosimendan and PDE III inhibitors also hypotension.
I C
540,
559
-563
In such cases intra-arterial blood pressure measurement may
be considered. IIb? C
31. 31
Emergency Management of Complicated STEMIEmergency Management of Complicated STEMI
Administer
• Fluids
• Blood transfusions
• Cause-specific
interventions
Consider vasopressors
Arrhythmia
Bradycardia Tachycardia
Systolic BP
Greater than 100 mm Hg
Systolic BP
70 to 100 mm Hg
NO signs/symptoms
of shock
Systolic BP
70 to 100 mm Hg
Signs/symptoms
of shock
Systolic BP
less than 70 mm Hg
Signs/symptoms of shock
Dobutamine
2 to 20
mcg/kg per
minute IV
Low Output -
Cardiogenic Shock
Nitroglycerin
10 to 20 mcg/min IV
Dopamine
5 to 15
mcg/kg per
minute IV
Norepinephrine
0.5 to 30 mcg/min IV
Hypovolemia
Administer
• Furosemide IV 0.5 to 1.0 mg/kg
• Morphine IV 2 to 4 mg
• Oxygen/intubation as needed
• Nitroglycerin SL, then 10 to 20 mcg/min IV if SBP
greater than 100 mm Hg
• Dopamine 5 to 15 mcg/kg per minute IV if SBP 70 to
100 mm Hg and signs/symptoms of shock present
• Dobutamine 2 to 20 mcg/kg per minute IV if SBP 70
to 100 mm Hg and no signs/symptoms of shock
FirstlineofactionSecondlineofactionThirdlineofaction
See Section 7.7
in the ACC/AHA Guidelines for
Patients With ST-Elevation
Myocardial Infarction
Check Blood Pressure
Clinical signs: Shock, hypoperfusion, congestive heart failure, acute pulmonary edema
Most likely major underlying disturbance?
Further diagnostic/therapeutic considerations (should be considered in
nonhypovolemic shock)
Diagnostic Therapeutic
♥ Pulmonary artery catheter ♥ Intra-aortic balloon pump
♥ Echocardiography ♥ Reperfusion/revascularization
♥ Angiography for MI/ischemia
♥ Additional diagnostic studies
Acute Pulmonary Edema
Check Blood Pressure
Systolic BP
Greater than 100 mm Hg
and not less than 30 mm Hg
below baseline
ACE Inhibitors
Short-acting agent such as
captopril (1 to 6.25 mg)
Circulation 2000;102(suppl I):I-172-I-216.
35. Inotropic mechanisms and drugs (Hasenfuss & Teerlink, EHJ 2011)
Inotropic mechanism Drugs Comments (MSN)
Sodium-Potassium ATPase
inh.
Digoxin Mild inotrope, diastolic dysfunction, vagal, arrythmias
B-adrenoreceptor stimulation Dobutamine, Dopamine HR increase, arrythmias
A and B adrenoreceptor
stimulation
Adrenaline,
Noradrenaline
Vasoconstriction, HR and arrythmias
PDE inhibition Enoximone, milrinone HR inc, Vasodilatation, some inotropic effect,
arrythmias
Calcium sensitation Levosimendan Mild inotrope, calcium sensitisation, impr.
mitochonrial function, vasodilatation, HR may
increase, hypotension related to arrythmias
Acto-myosin cross-bridge
activation
Omecamtiv mecarpil Prolongs contractile phase, further evidence needed
SERCA activation Gene transfer Applied in chronic HF
SERCA activation +
vasodilatation
Nitroxyl donor, CLX-
1020
No study results posted at clinicaltrials.cov
Ryanodine receptor
stabilization
S44121 No studies registered
Sodium-potassium cross-
bridge activation + SERCA
activation
Istaroxime Istaroxime decreases PCWP, increases SBP, and
decreases diastolic stiffness in patients with acute
heart failure syndrome. Program ongoing, some study
withdrawals
Energetic modulation Etoximir, pyruvate No studies registered
36. New inotropic agents
Hasenfuss, et al. Eur Heart J 2011;32:1838-
1845
Istaroxime:
Inotropic effect ∼inhibition of Na-K
ATPase
Lusitropic effect ∼stimulation of SERCA 2a.
•↑ systolic blood pressure.
•↓ heart rate.
Myosin activators
(e.g. Omecamtiv mecarbil):
•↑ rate of effective myosin cross-bridge
formation.
→ ↑ duration of myocyte contraction.
•No effect on cAMP or calcium.
37. OMECANTIV
MECARBIL
Cardiac Specific Myosin
Activator.
•Stimulate myosin-ATPase
Accelerates the rate of actin-
dependent phosphate release from
the actin-myosin crossbridge
Promotes transition to the force
producing on-state of the cross
bridge
More cross-bridges activated per
unit time
Increased contractile force
38. Omecamtiv Mecarbil
[cardiac myosin activators]
Cleland JG, Teerlink JR, Senior R, et al.
The effects of the cardiac myosin activator, omecamtiv mecarbil, on
cardiac function in systolic heart failure: A double-blind, placebo-
controlled, crossover, dose-ranging phase 2 trial.
Lancet 2011
•Double blind, placebo controlled, dose ranging trial
•Infusions: 2 vs. 24 vs. 72 hr
•Plasma drug concentration measured at the end of each infusion
•Safety and tolerability assessed
•45 patients
38
Noveltherapies
Plasma concentration dependent effects
↑ ventricular ejection time with no change in dp/dt
Small ↓ in heart rate
Reduction in end-systolic and end-diastolic volumes
↑ cardiac ischemia
ATOMIC-AHF trial underway
39. 70%
60%
50%
40%
30%
20%
10%
0%
Tilarginine 48%
42%
Placebo
Tilarginine: Placebo
RR: 1.14
95% CI: 0.92-1.41
P=0.24
0 5 10 15 20 25 30
Days from randomization
JAMA. 2007;297(15):1657-1666.
30day-Mortality
Effect of Tilarginine Acetate in Patients With Acute
Myocardial Infarction and Cardiogenic Shock
The TRIUMPH Randomized Controlled Trial
40. Cyclosporine
Cyclosporine is another new drug which has been
proposed for reduction of re-perfusion injury in
cases of large size AMI complicated with CS. The
CLOTILDE trial (Cyclosporine in Acute Myocardial
Infarction Complicated by Cardiogenic Shock,
NCT01901471), tested the hypothesis that
administration of cyclosporine during the
reperfusion phase of AMI would reduce the
infarct size by 20-40%, reduce the risk of multi-
organ failure and improve the clinical status of
these patients.
41. GLUCAGON
• Increases cardiac output by approximately 20%,
which is associated with a decrease in
peripheral vascular resistance with less
myocardial oxygen demand when compared
with norepinephrine.
• Administer this agent to patients with
cardiogenic shock who do not respond to
conventional therapy or cannot tolerate other
agents because of the development of
significant arrhythmias or hematologic toxicity.
42. GENE THERAPY
• To increase sarcoplasmic reticulum calcium
pump activity by stimulating the calcium
pumps.
• Most approaches are related to reduced SR
calcium uptake, however, abnormal SR leak
has also been considered.
• It has been shown in isolated myocytes that
overexpression of the RyR-regulatory protein
FKBP12.6 increases SR calcium content and
fractional shortening.
43. Summary
Treatment of cardiogenic shock relies mainly on
Revasuclarization and mechanical support.
INOTROPES INDICATED Only if symptoms and signs of
congestion and hypoperfusion are present.
INOTROPES May be useful as initial therapy bridging
to MCS + definitive therapy (Revasc, LVAD, transplant).
Inotropes and pressors are associated with either no
benefit or worse outcomes.
Use the lowest dose able to achieve desired targets
(resolution of hypoperfusion and end organ damage)
and for the shortest possible time.
No RCT demonstrating clear clinical benefit for any
drug, Inotrope of choice based on local expertise.
44. Summary
In spite of this, virtually all cardiogenic shock patients
receive treatment with catecholamines usually a
combination of inotrope and vasopressor.
Accumulating evidence favors norepinephrine over
dopamine.
Adrenaline (and dopamine) use seem to be associated
with increased mortality.
PDE III inhibitors or levosimendan should be favoured
in patients on beta-blockers and levosimendan in
patients with decompensated chronic heart failure or
for postoperative cardiac stunning.
Positive long-term effects of levosimendan on mortality
are still controversial.