Inotropes

1. ROLE OF INOTROPES IN
MANAGEMENT OF ACUTE HEART
FAILURE
BY – DR NISHANT TYAGI

2.  HEART FAILURE IS THE PRINCIPLE COMPLICATION
OF VIRTUALLY ALL FORMS OF HEART DISEASE
 PREVLANCE – 1-2% OF PERSONS AGED 45-54 YEARS ,
INCREASES TO 10% OF PERSONS AGED > 75 YEARS
 ACUTE HEART FAILURE CONTRIBUTES TO 5% OF ALL
ADMISSIONS IN THE EMERGENCY DEPARTMENT OF A
GENERAL HOSPITAL
 AVERAGE DAYS OF ADMISSION FOR ACUTE HF – 5.3
DAYS

3. GOLES OF PHARMACOLOGYCAL
THERAPY FOR HF
ACUTE HF
-STABILISATION
-RESTORE ORGAN
PERFUSION
-DECREASE FILLING
PRESSURES TO OPTIMAL
-BEGIN THE CONVERSION
TO CHRONIC THERAPY
CHRONIC HF
-INCREASE SURVIVAL
-DECREASE SYMPTOMS AND
DISABILITY
-IMPROVE FUNCTIONAL
CLASS

4. HEART FAILURE
SYSTOLICSYSTOLIC+DIASTOLIC DIASTOLIC
ACUTE HF ACUTE DECOMPENSATION IN CHRONIC HF
2.FULMINANT
MYOCARDITIS
1. ACUTE MI 1.INFECTION
2.DRUG DEFAUTER
3.INCREASED SALT
AND FLUID INTAKE
NATURAL
PROGRESSION
OF DISEASE

5. POSITIVE INOTROPIC AGENTS
 CARDIAC GLYCOSIDES – DIGOXIN
 ADRENERGIC AGONISTS
 PHOSPHODIESTERASE 3 INHIBITERS
 CALCIUM SENSITIZERS

7. B - RECEPTERS
 B1, B2, B3
 IN HEARTS OF HEALTHY PEOPLE B1 RECEPTERS
ARE 80 % OF THE TOTAL
 IN CHRONIC HF B1 RECEPTORS GET
DOWNREGULATED (DESENSITISATION BY UPTO
50-60%)
 IN CHF THE B2 RECEPTORS INCREASE IN
NUMBER AND BECOME ABOUT 40% OF THE
TOTAL B RECEPTORS
 FROM ACUTE SUPPORT STANDPOINT BOTH
RECEPTORS CAN BE USED IN SUPPORTING
CARDIAC FUNCTION IN A DECOMPENSATED
PATIENT

8. B- AGONISTS
 MOST POWERFUL WAY OF INCREASING
CONTRACTILITY IN HUMAN HEART
 ALL ARE ARRHYTHMOGENIC – DIRECTLY
INCREASE IN cAMP , INCREASING SKELETAL
MUSCLE DEPOSITION OF K , DECREASING
SERUM Mg LEVELS.
 ALL DEVELOP DESENSITIZATION SO SHOULD BE
USED IN LOW DOSES AND INTERMITTANTLY

10. DOBUTAMINE
ADVANTAGES
-INCREASES CARDIAC
OUTPUT
-DECREASES SVR SO
DECREASES
FUNCTIONAL MR
DISADVANTAGES
-ARRHYTHMIA
-TACHYCARDIA
-WEAK B AGONIST- IN
DECOMPENSATED
CHF,THOSE ON B
BLOCKERS
-DESENSITIZATION ON
CHRONIC USE
- ONLY MINIMAL ACTION
ON PAP, PAWP

11. FIRST TRIAL
AM H J 1999
 487 PATIENTS , CLASS 3 / 4 , AGE – 65y, 80 TOOK CONTINUOUS
DOBUTAMINE INFUSION WITH AVERAGE DOSE 9 mcg/kg/min
FOR 14 DAYS , UPTO 6m FOLLOW UP
 DOBUTAMINE WAS MOST IMPORTANT INDEPENDENT RISK
FACTORS FOR DEATH IN THE STUDY
 CONCLUSION- IV CONTINUOUS DOBUTAMINE INFUSION MAY
INCREASE RISK OF DEATH IN PATIENTS WITH ADVANCED HF
DOBUTAMINEDOBUTAMINE CONTROLCONTROL
ADVERSE EVENTS- WORSENINGADVERSE EVENTS- WORSENING
HF, SCD, MI, DEATHHF, SCD, MI, DEATH
85%85% 65%65%
MORTALITYMORTALITY 71%71% 37%37%

12. DICE : INTERMITTANT 6 MONTHS LOW
DOSE DOBUTAMINE INFUSION IN SEVERE
HEART FAILURE
AM HEART J, 1999
 38 PATIENS, Av AGE-65y, Av CLASS 3 / 4, Av CI- 1.9L/m2/min, Av
EF-22%, DOSE-2.5 mcg/kg/min FOR 48 Hours / WEEK FOR 6
MONTHS
 PATIENTS WERE STABLE FOR ATLEAST 48 HOURS AND
RANDOMLY ASSSIGNED TO TAKE EITHER DOBU INFUSION OR
STANDERED CHF MEDICINES
 CONCLUSION- INTERMITTANT DOBUTAMINE COULD BE AN
ALTERNATIVE FOR SELECTED PATIENTS WITH SEVERE HF
WHEN CONVENTIONAL THERAPIES HAVE FAILED AS IT
INCREASES FUNCTIONAL CLASS AND REDUCES NO. OF
HOSPITALIZATIONS
DOBUTAMINEDOBUTAMINE CONTROLCONTROL
NO. OF HOSPITALISATIONS FOR HFNO. OF HOSPITALISATIONS FOR HF 77 1111
> 1 HOSPITALISATIONS FOR HF> 1 HOSPITALISATIONS FOR HF 00 44
CLASSCLASS 2.52.5 33
DEATHSDEATHS 55 33

13. DOPAMINE RELEASES NE THROUGH TYRAMINE LIKE EFFECT , POTENT
NEURONAL UPTAKE INHIBITOR OF NE
 IN ADVANCED HF, PATIENTS OFTEN HAVE DEPLETED NE
STORES, DOPAMINE IS LESS EFFECTIVE THAN ALL OTHER
DIRECTLY ACTING AGENTS
 IN DOSE <5 mcg/kg/min ACTS SELECTIVLY ON POSTSYNAPTIC
D1 AND PRESYNAPTIC D2 RECEPTERS TO CAUSE INCREASE
IN RENAL BLOOD FLOW AND GFR BUT THIS
RENOPROTECTIVE ACTION HAS NEVER BEEN PROVEN
 HAS EXTREMLY LOW EFFINITY FOR ALL THREE B1 B2 AND
ALPHA RECEPTERS
 CAUSES MORE TACHYCARDIA AND ARRHYTHMIA THAN
DOBUTAMINE BECAUSE IT DIRECTLY RESEASES NE , SO NOT
USED IN HF
 PROLINGED INFUSION HAS BEEN ACCUSED OF INDUCING
HYPOXEMIA, IMPAIRED VENTILATORY RESPONSE AND GAS
EXCHANGE, WORSENING SPLANCHNIC OXYGENATION AND
IMPARED GI ENDOCRINAL AND IMMUNOLOGIC FUNCTION
 USED IN CONDITIONS WHERE HF IS ASSOCIATED WITH LOW
SVR LIKE SEPSIS, ITROGENIC OVERVASODILATION

14. NOREPINEPHRINE
 NOT A GOOD INOTROPE BUT POWERFUL
VASOCONSTRICTOR
 CHIEFLY STIMULATES THE ALPHA RECEPTORS
 USED WHERE SHOCK IS ACCOMPNIED BY
PEREPHERAL VASODILATION – WARM SHOCK
 IT IS SOMETIMES COMBINED WITH PDE –
INHIBITERS TO AVOID PEREPHERAL
VASODILATATION
 CONTRAINDICATED IF THE SYSTEMIC
VASCULAR RESISTANCE IS HIGH

15. EPINEPHRINE
 EXCELLENT POSITIVE INOTROPIC ,
CHRONOTROPIC ACTION PLUS INCREASES SVR
 EXCELLENT INOTROPE FOR TRANSPLANTED
HEART
 DRUG OF CHOICE IN CARDIAC ARREST
 CALCIUM IS OFTEN ADDED TO INFUSION TO
PRODUCE SINERGESTIC EFFECT

16. INOTROPIC DEPENDENCE
 MANIFESTED AS SYMPTOMATIC HYPOTENSION,
RECURRENT CONGESTIVE SYMPTOMS, OR WORSENING
RENAL FUNCTION EARLY AFTER DISCONTINUATION OF
INOTROPIC THERAPY
 SHOULD NOT BE DECLARED UNTIL MULTIPLE
INTERVENTIONS AND WEANING ATTEMPTS HAVE BEEN
MADE IN MOST CASES REQUIRING 2-3 WEEKS
 CONTINUOUS INOTROPIC THERAPY IS USED AS A BRIDGE
TO ARRIVAL AT A DESTINATION SUCH AS
TRANSPLANTATION, VAD OR DEATH

17. PHOSPHODIESESTERASE
INHIBITORS
ADVANTAGES
 POST RECEPTER
MECHANISM SO
INDIPENDENT OF
DOWNREGULATED B
RECEPTER , PT. ON B
BLOCKERS
 DECREASES IN PAP IS
GREATER THAN
DOBUTAMINE
DISADVANTAGES
 MORE ARRHYTHMIA ,
MORE DEATH,
HYPOTENSION
 MILRINONE HAS 80%
RENAL EXCRETION
SO DOSE IS TO BE
REDUCED IN RENAL
INSUFFICIENCY
 THROMBOCYTOPENIA
WITH AMRINONE
 HALF LIFE OF 80hous

18. OPTIME-CHF TRIAL: OUTCOME OF A
PROSPECTIVE TRIAL OF IV
MILRINONE FOR EXACERBATIONS
OF CHF
 AIM – WEATHER IV MILRINONE ADDED TO STANDERED
MEDICATION REDUCES HOSPITAL STAY IN 60 DAYS FOR HF
PATIENTS NOT REQUIRING INOTROPES
 951 PT. Av CLASS ¾,Av AGE 63YEARS,Av EF-23%,WERE
RANDOMISED TO TAKE EITHER IV MILRINONE(477) OR
PLACEBO FOR 15h. 70% WERE ON ACE I , 90% OON DIURETICS,
20% ON B BLOCKERS ,FOLLOW UP 60 DAYS ,
 CONCLUSION- PATIENTS WHO DO NOT REQUIRE INOTROPES
DO NOT BENEFIT FROM MILRINONE
MILRINONE(477)MILRINONE(477) CONTROLCONTROL
NO OF DAYS IN HOSPITALNO OF DAYS IN HOSPITAL SAMESAME SAMESAME
QUALITY OF LIFEQUALITY OF LIFE SAMESAME SAMESAME
MORTALITYMORTALITY SAMESAME SAMESAME
COMPLICATIONSCOMPLICATIONS 13%13% 2%2%

19. CALCIUM SENSITIZERS -
LEVOSIMENDAN
 CURRENTLY LICENSED IN 10 EUROPEAN COUNTRIES
 INCREASES CNTRACTILITY BY BINDING TO TROPONIN
C THUS SENSITIZING THE CONTRACTILE PROTEIN TO
INTRACELLULAR Ca
 INDUCES PERIPHERAL AND CORONARY
VASODILATION BY OPENING ATP SENSITIVE K
CHANNELS
 WELL ABSORBED ORALLY ALSO

20. CALCIUM SENSITIZERS -
LEVOSIMENDAN
ADVANTAGES
 NO INCREASE IN HR
 NO INCREASE IN
ARRHYTHMIA
 INDIPENDENT OF B
BLOCKER USE,
DOWNREGULATED B
RECEPTER
 VASODILATER –
DECREASES PRE AND
AFTERLOAD
DISADVANTAGES
 HYPOTENSION
 HEADACHE

21. RUSSLAN TRIAL – RANDOMISED STUDY ON SAFETY AND
EFFECTIVENESS OF LEVOSIMENDAN IN PATIENTS WITH
LVF DUE TO AMI ; EURO HEART J 2002
 PLACEBO CONTROLLED, DOUBLE BLIND , 504 PATIENTS WITYHIN 5 DAYS OF
MI(MEAN 2 DAYS) , WITH EVIDENCE OF HF ON X-RAY AND CLINICAL NEED OF
INOTROPES, RANDOMISED TO 5 GROUPS .
1 CONTROL AND 4 WERE GIVEN 10min BOLUS FOLLOWED BY CONTINUOUS
INFUSION OF LEVOSIMENDAN FOR 6 h 0.1, 0.2, 0.3 ,0.4mcg/kg/min RESPECTIVLY
,BASELINE CHARACTERISTICS AND CONCOMITANT MEDICATIONS WERE SIMILAR
IN ALL GROUPS , 6 m FOLLOW UP
LEVOSIMENDANLEVOSIMENDAN CONTROLCONTROL P VALUEP VALUE
RISK OFRISK OF
HYPO TENSION /ISCHAEMIAHYPO TENSION /ISCHAEMIA
13.4%13.4% 10.8%10.8% 0.4560.456
MORTALITY IN 6 hrs.MORTALITY IN 6 hrs. 2%2% 5.9%5.9% 0.0330.033
MORTALITY IN 24 hrs.MORTALITY IN 24 hrs. 4%4% 8.8%8.8% 0.0440.044
MORTALITY IN 14 DAYMORTALITY IN 14 DAY 11.7%11.7% 19.6%19.6% 0.0310.031
MORTALITY IN 6 MONTHSMORTALITY IN 6 MONTHS 22.6%22.6% 31.4%31.4% 0.0530.053
 FIRST TRIAL THAT DEMONSTRATED A DECREASE OF MORTALITY IN POST INFARCT PATIENTSFIRST TRIAL THAT DEMONSTRATED A DECREASE OF MORTALITY IN POST INFARCT PATIENTS
BYBY
THE ADMINISTRATION OF A POSITIVE INOTROPIC AGENT.THE ADMINISTRATION OF A POSITIVE INOTROPIC AGENT.
CONCLUSION:LEVOSIMENDAN SIGNIFICANTLY REDUCED IN HOSPITAL MORTALITY ,DIDN’TCONCLUSION:LEVOSIMENDAN SIGNIFICANTLY REDUCED IN HOSPITAL MORTALITY ,DIDN’T
INCREASE SIGNIFICANT HYPOTENSION/ISCHAEMIA AND WAS ASSOCIATED WITH A LONGINCREASE SIGNIFICANT HYPOTENSION/ISCHAEMIA AND WAS ASSOCIATED WITH A LONG
TERM SURVIVAL BENEFIT LASTING UPTO 180 DAYS IN PATIENTS WITH LVF COMPLICATINGTERM SURVIVAL BENEFIT LASTING UPTO 180 DAYS IN PATIENTS WITH LVF COMPLICATING
AMI.AMI.

22. LIDO : LEVOSIMENDAN INFUSION VERSUS
DOBUTAMINE STUDY; LANCET 2002
 PROSPECTIVE , MULTICENTER , RANDOMISED TRIAL, 203 PT, Av EF <
35%, Av CI < 2.5 L/min, Av PCWP > 15 mmHG, DOUBLE BLIND,
LEVOSIMENDAN 24 mcg/Kg BOLUS OVER 10MIN THEN 0.1-0.2
mcg/Kg/min AND DOBUTAMINE 5-10 mcg/Kg/min FOR 24h, 6 m FOLLOW
UP , OTHER MEDICATIONS WERE SAME IN BOTH GROUPS
 EXCLUSION – ACTIVE CAD, VALVULAR HD , HCM ,RCMP,
CIRCULATORY SHOCK, ONGOING ARRRHYTHMIALEVOSIMENDANLEVOSIMENDAN DOBUTAMINEDOBUTAMINE P VALUEP VALUE
IMPROVEMENT IN DYSNOEAIMPROVEMENT IN DYSNOEA 68%68% 59%59%
IMPROVEMENT IN FATIGUEIMPROVEMENT IN FATIGUE 63%63% 47%47%
MORTALITY AT 1 mMORTALITY AT 1 m 8%8% 17%17% 0.0490.049
MORTALITY IN 6MMORTALITY IN 6M 26%26% 38%38%
RHYTHM DISTERBANCESRHYTHM DISTERBANCES 4%4% 13%13% 0.0230.023
CORONARY EVENTSCORONARY EVENTS 0%0% 7%7% 0.0130.013
HEADACHEHEADACHE 14%14% 5%5%
CONCLUSION – IV LEVOSIMENDAN WAS BETTER TOLERATED AND HAD FEWER SIDE
EFFECTS AND OFFERED A SURVIVAL ADVANTAGE OF MORE THAN 30% IN 6m AS
COMPARED TO IV DOBUTAMINE
LIMITATIONS- SMALL SAMPLE SIZE, USE IN CRDIOGENIC SHOCK NOT EVALUATED

23. COMPARISON
DOBUTAMINEDOBUTAMINE MILRINONEMILRINONE LEVOSIMENDANLEVOSIMENDAN
VASODILATORVASODILATOR MILDMILD
PEREPHERALPEREPHERAL
PEREPHERALPEREPHERAL CORONARY ANDCORONARY AND
SYSTEMICSYSTEMIC
INCREASE ININCREASE IN
INTRACELLULAR CaINTRACELLULAR Ca
YESYES YESYES NONO
INCREASE IN CARDIACINCREASE IN CARDIAC
O2 DEMANDO2 DEMAND
YESYES NONO NONO
RISK OF ARRHYTHMIARISK OF ARRHYTHMIA LESS THANLESS THAN
MILRINONEMILRINONE
VENTRICULARVENTRICULAR
12%,SUPRAVEN12%,SUPRAVEN
TRICULAR 4%TRICULAR 4%
NO EVIDENCENO EVIDENCE
ADVERCE EFFCTSADVERCE EFFCTS TACHYCARDIATACHYCARDIA ARRHYTHMIA,ARRHYTHMIA,
HYPOTENSIONHYPOTENSION
HEADACHE,HYPHEADACHE,HYP
OTENSIONOTENSION

24. CONCLUSIONS
 ROLE OF INOTROPES IN DECOMPENSATED HF IS CRUSIAL,
ALTHOUGH CONTROVERTIAL
 DOPAMINE HAS BEEN LARGELY REPLASED BY
DOBUTAMINE IN CLINICAL PRACTICE , WHILE THE
CLINICAL VALUE OF ITS RENAL DOSE IS NO LONGER
SUPPORTED
 IMPLEMENTATION OF B BLOCKERS AS STANDARD
TREATMENT OF HF MAKES ADRENERGICS UNFAVOURABLE
FOR INOTROPIC SUPPORT IN THESE PATIENTS
 ADRENIRGIC AGONISTS AND PDE-I IMPROVE
HEMODYNAMIC STATUS AND QUALITY OF LIFE “ IN
EXCHANGE ” FOR REDUCED SURVIVAL
 INCREASED cAMP THAT RESULT IN INCREASED Ca RELEASE
FROM SR HAS BEEN CONSIDERED COMMON ETIOLOGY FOR
PROARRHYTHMIA
 Ca SENSITIZERS ARE A NOVEL CATEGORY OF AGENTS AS
THEY SEEM TO LACK PROARRHYTHMIC ACTIVITY AS THEY
DO NOT INCREASE INTRACELLULAR Ca LEVELS, AND THEY

25. FUTURE
 INCREASING EFFICIENCY OF GENE TRANSFER
TECHNIQUES HAS ALLOWED IMPROVED
CONTRACTILITY AND SURVIVAL AFTER VIRAL
TRANSFECTION OF SL Ca ATP ase INTO SMALL
ANIMAL MODELS

26. SYSTOLIC HF
TAKE HOME MESSAGE
SBP <70mm Hg
(LOW CO,INCREASED PAWP)
SBP >90mmHg
(LOW CO, INCREASED PAWP&SVR
SBP 70-90mm Hg
NO EVIDENCE
OF CRITICAL
HYPOPERFUSION
EVIDENCE
OFCRITICAL
HYPOPERFUSION-
BRAIN INJURY
LACTIC ACIDOSIS
DOPAMINE
EPINEPHRINE WITH OR
WITHOUT NOREPINEPHRINE
DOBUTAMINE
ISCHEMIC
NON ISCHEMIC
1LEVOSIMENDAN
2.MILRINONE
3.DOBUTAMINE
ON B BLOCKER NOT ON B BLOCKER
1 LEVOSIMENDAN/MILRINONE
2 DOBUTAMINE
DOBUTAMINE/MILRINONE
CARDIAC
ARREST
INITIAL TRIAL OF ONLY
VASODILATERS AND DIURETICS

27. THANK YOU