Vasoactive_Inotropes

7/29/2019 Vasoactive_Inotropes

1/80

Inotropes/Vasoactive Drugs


2/80

Goals of todays talk

Put vasoactive drugs role into overall

treatment context

Discuss individual drugs

Proof of what is best

Consider the microcirculation


3/80


Put vasoactive drugs role into overall

treatment context


4/80

Cardiac output x x % Sat O2

Fe defDilutionalInflammatoryVitamin deficiencyAplastic

Sickle cellThalassaemiamet HbCO Hb

free Hb and NOPulmonary hypertensionHypercoagulability

PRVAcclimatisation

Effective blood volumeCapacitanceObstructionSeptal shiftIV fluid

volume

C.O.P.

ArrhythmiasIschaemiaValvular problemsSeptal shift

RAA adaptaionSepsisValvular problemsPulmonary embolismHypertensionShunts

AltitudeHyperbaric O2

Decreased respiratory drive

drug inducedCVAFatigue (asthma)Obstruction

Sleep apnoea syndromeDecreased consciousness

ShuntPneumoniaPulmonary oedema

Dead spacePulmonary embolismFat embolism

MixedCOPDAsthma

Pump failure

Afterload

Anaemia

Abnormal Hb

Hemolysis

Hyperviscosity

Inspired O2

Hypoventilation

Ventilation/

perfusionabnormalities

Heart rate

Hb

Preload


5/80

Cardiac output - what are our goals?

Adequate effective cardiac output

Adequate blood pressure (>65 mean)

Adequate macro and micro-circulation

Correcting general haemodynamics is a

pre-requisite but not necessarily enough


6/80

Adequate cardiac output?

Biochemistry

ScV02

Lactate

Base deficit

Advanced technology

Visualizing the micro-circulation


7/80

Do we have adequate bloodpressure?

Arbitrarily defined as a mean BP > 65

There is no proof that this is correct

It may need to be tailored to each

patient


8/80

So How Do We Reach Our Goals ?

.....and in what order?


9/80

3 sequential physiological

targets :(1) Intravenous fluids to achieve a central venous

pressure of between 8 and 12 mm Hg;

(2) Pressors to achieve a mean arterial pressure

of at least 65 mm Hg

(3)Dobutamine or red blood cell transfusions to

restore tissue oxygen delivery, as assessed by

central venous oxygen saturation using a target of

at least 70%.

ii 1 1

i ii

N i i

i i i

i i i 1 i 1

i i ii i i i i i i

i

i ii i i i i

.

i i i ii i i i i i i i

I

.

N

N

N N

N

N

i i i ii ii i

i

i ii i i i

i i ii i i i

Guidelines for Management of Severe Sepsis and Septic Shock

N S

for

N

CCM 2009;36(1):296-327

wrong!


10/80

How to reachphysiological targets :

(1) First question: is patient fluid responsive?

(2) Raise the B.P. with inotropes/vasopressors

(3) Is C.O. adequate (ex. ScvO2, lactate clearance

etc)

If not - Dobutamine/RBCs????(4) Resuscitate the microcirculation

ii 1 1

i ii

N i i

i i i

i i i 1 i 1

i i ii i i i i i i

i

i ii i i i i

.


I

.

N

N

N N

N

N

i i i ii ii i

i

i ii i i i

i i ii i i i


N

N

N

S

for

N

CCM 2009;36(1):296-327


11/80

FLUIDS

Use a fluid challenge technique while associatedwith a haemodynamic improvement. (1D)

Give fluid challenges of 1000 ml of crystalloidsor 300500 ml of colloids over 30 minutes.

Rate of fluid administration should be reduced ifcardiac filling pressures increase without

concurrent haemodynamic improvement. (1D)

NB. 50% of patients respond to fluid only!

ii 1 1

i ii

N i i

i i i

i i i 1 i 1

i i ii i i i i i i

i

i ii i i i i

.


I

.

N

N

N N

N

N

i i i ii ii i

i

i ii i i i

i i ii i i i


N S

for

N

CCM 2009;36(1):296-327


12/80

25

20

15

10

5

0

Rt Atrial Pressure (mm Hg)

Ca

rdi a

cO

utpu

t

-4 0 +4 +8

normal, unstimulated heart

normal, stimulated heart

Fill the heart

Optimize fluids first, .....then inotropes!

Remember only 50%will adequately respond to

fluid alone !


13/80

J Trauma 2008;64:9-14

These findings provide evidence that the early use of

vasopressors for hemodynamic support after hemorrhagic

shock may be deleterious, and should be used cautiously..

Dr. David Plurad.-Annual meeting of the American Association for the Surgery of Trauma- 2010.

In critically injured patients, early treatment withvasopressors was associated with more than an11-fold increase in risk of death

B t!!!


14/80

Critical Care 2010, 14:R142

But!!!

Why preload?

Early administration of norepinephrine in severely hypotensive

septic-shock patients increased cardiac output through anincrease in cardiac preload and cardiac contractility


15/80

Preload

Why determine if fluid responsive ?

Starling curve

EVLWCardiacoutput

/Lungwater


16/80

arterial flow

Residual Volume

Mobilisable Volume

Because......Vasopressors are 5 X more potent on thevenous (capacity) side then on the arterial

(resistance) side

Venoconstriction

arterial flow

Residual Volume

Mobilisable VolumeMCP=


17/80

Lactate Clearance As a Sign of Resuscitation

JAMA, February 24, 2010Vol 303, No. 8! 739

third resuscitation target either a ScvO2% ...or a lactate

clearance of at least 10%

look for change in peripheral venous lactate concentrationfrom 2 blood specimens

a simpler and more generalizable method to monitor theadequacy of tissue oxygen delivery


18/80

VASOPRESSORS/INOTROPES

Maintain MAP 65mmHg.(1C)

Noradrenaline or dopamine centrally administered are

the initial vasopressors of choice.(1C)

Use Adrenaline as the first alternative agent in septicshock when blood pressure is poorly responsive to

noradrenaline or dopamine.(2B)

Use dobutamine in patients with normal bloodpressure, elevated cardiac filling pressures and low

cardiac output (1C)

ii 1 1

i ii

N i i

i i i

i i i 1 i 1

i i ii i i i i i i

i

i ii i i i i

.

i i i i

i i i i i i i i

I

.

N

N

N N

N

N

i i i ii ii i

i

i ii i i i

i i ii i i i


N S

for

N

CCM 2009;36(1):296-327


19/80

ii 1 1

i ii

N i i

i i i

i i i 1 i 1

i i ii i i i i i i

i

i ii i i i i

.

i i i i

i i i i i i i i

I

.

N

N

N N

N

N

i i i ii ii i

i

i ii i i i

i i ii i i i


N S

for

N As many people die of sepsis as ofmyocardial infarction

We should adopt the same door toneedlesense ofurgency as with fibrinolysis inSTEMI

Delay = lives lost!

CCM 2009;36(1):296-327

There is not a moment to lose


20/80


Discuss individual drugs


21/80

Vasoactive agents- general comments

Consider direct receptor effects

Overall effects are complex due to reflexresponses

Ex. Noradrenaline causes tachycardia but

vasoconstriction causes a reflex bradycardia Low doses of vasoconstrictors mainly increase

venous return by venoconstricting

f /


22/80

Kinase

cGMP

Ca2+Calciumstores

Vasoconstriction

Myosin

Myosinphosphatase

Myosin

Vasodilatation

P

Kinase

Nitricoxide

P

Atrialnatriuretic

peptide

Plasmamembrane

Norepinephrine

Ca2+

Angiotensin II

Cytoplasm

+

+

+

++

+ + + ++

N Engl J Med, Vol. 345, No. 8 August 23, 2001

Physiology of vasoconstriction/vasodilatation


23/80

CV role of adrenergic receptors

-> arterial/venoconstriction -> raises SVR/increasedvenous return

NB. venous side more sensitive to low dose

1 -> increases inotropy and heart rate

2 -> increased flow to skeletal muscles -> decreasedperipheral resistance

Dopamine

DA 1 -> coronary, renal and mesenteric arterialrelaxation

DA2 -> inhibit noradrenaline release

D ff t


24/80

DobutamineBeta 1 > Beta 2 > alpha

inotropicVasodilatory

Dopamine

alpha

high dosealpha

alpha 1 - constriction

DA2peripheral vasodilation

Opie 1998

Drug effects

Beta 1 (Beta 2)

inotropic

NoradrenalineBeta 1 > alpha > Beta 2

+

inotropicincreased BP

AdrenalineBeta 1 = Beta 2 > alpha

-

inotropicDilator/constrictor

DA1

increased renal blood flow

(low dose)

l d t t t h k


25/80

Drugs commonly used to treat shock


26/80

Alpha and Beta adrenergic effects of vasoactivecatecholamines

Isoprenaline

Dopexamine

Dobutamine

Dopamine

Adrenaline

Noradrenaline

Phenylephrine

Pressure

Flow


27/80

Individual vasoactivedrugs

Eff cts f s cti c t ch l mi s


28/80

Effects of vasoactive catecholamines onpressure and flow

PE Noradr Dopa Adr Dobut Dopex Isopren

Flow

Pressure

Noradrenaline


29/80

Noradrenaline

Receptors : potent agonist, less 1, no 2

Vascular effects :

Dose dependant - arterial and venous

vasoconstriction

Cardiac effects :Moderate increase in stroke volume (10-15%)

Heart rate/tachycardia (variable due to reflexes)

Uses

Becoming the first line agent in septic shock

Combined vasodilation and cardiac dysfunction (ex.Sepsis/SIRS)

Noradrenaline continued


30/80

Noradrenaline-continued

Dose :

0.5 - 30 mcg/min - potent vasopressor

In septic patients noradrenaline

-> increased renal blood flow and urine output

Adverse effects :

increased myocardial O2 consumption

renal/splanchnic vasoconstriction --> renal ischaemia

esp. if hypovolaemic (use with care)

Adrenaline


31/80

Adrenaline

Potent and 1+2, =

1 -> venoconstriction -> increased venous return

2 -> increased flow to skeletal muscles -> decreased peripheral resistance

Doses :

Very low dose (0.01 - 0.05 mcg/kg/min) -> increased cardiac output

Higher doses -> receptors outweigh 2 vasodilation -> increase mean BP Cardiac effects

More potent effect on contractility than noradrenaline

Increased heart rate/tachycardia

Uses

When severe cardiac dysfunction is contributing to shock

Cardiac arrest

Anaphylactic shock

Adrenaline - continued


32/80

Adrenaline - continued

2nd line agent because :

decreased splanchnic/renal flowtachyarrhythmias

myocardial ischaemia

Potential problems

Care if on blockers -> unopposedactivity -> hypertension

Reduced splanchnic flow

Increased myocardial workload -> ischaemia

A i i V i


33/80

Produced in SupraOptic/Para Vent Nuclei. Granules stored in Posterior Pituitary

Mechanism of action :

V1 receptors :

Baroreceptor function - Vasoconstricts all blood vessels via non adrenergicreceptors

Blood levels ~ 10 - 200 pcg/mL

Relative deficiency in sepsis ( and other causes of refractory vasodilator shock)

Minimal pressor effect in normal subjects

Many who do not respond to catecholamines respond to Vasopressin

Useful for drop in BP during GA if patient on ACEI/Angio II blockers andunresponsive to catecholamines (3rd system controlling BP)

Arginine Vasopressin


34/80

Crit Care Med 2011 Vol. 39, No. 1


35/80

V2 receptors :

Controls osmolality - Primary function - 1% change --> secretion.Acts on collecting duct to produce concentrated urine

Vasodilatation

Increase in von Willebrands factor and VIIIc

(Urine osmolality 300 mOsm/kg - 1200 mOsm/kg)

Blood levels ~ 1-7 pcg/mL

V3 receptors :

In Anterior pituitary --> mediates release of ACTH

Arginine Vasopressin - cont

Role of Arginine Vasopressin in Septic Shock


36/80

Vasodilatory shock

Mediated by huge release of NO (also causesmyocardial depression)

Maybe resistance to NorAdrenaline

AVP stores eventually depleted in post.pituitary

AVP acts by :

inhibits iNO

Restores action of Noradrenaline

Role of Arginine Vasopressin in Septic Shock


37/80



38/80


A i i V i i S ti Sh k ( td)


39/80

Arginine Vasopressin in Septic Shock (contd)

Dose :

1 - 4 U/hr - effective since vasodilatory shock patients have blood levels ~ 3pcg/mL (should be > 10 X higher)

Increase BP by ~ 30%, also decreases NorAdr requirements by 70%

AVP increases GFR by constricting the efferent arteriole in the glomerulus

Adverse effects :

Excess vasoconstriction -> end organ ischaemia (inclu. myocardial

ischaemia, intestinal ischaemia)

Never more then 6U/hr--> splanchnic/coronary vasoconstriction(used in hepatic failure)

Decreased cardiac output due to increased afterload

N r dr li s Adr li


40/80

Noradrenaline vs Adrenaline

100HR

50

Noradrenaline Adrenaline

BP

180

60

120

TPR

10 mcg/min

0 15 0 15

Time(min)

Dopamine vs Dobutamine


41/80

These data demonstrate that dopamine at doses greater than 2 to 4 gper kg per minute exerts a vasoconstrictor effect and increases heartrate and left ventricular filling pressure.

0 2 4 6 8 10

Dobutamine

Dopamine

mcg/kg/min

12

WedgePressure

32

22

TPR

1600

1200

1400

90

70

80

HR

50Stroke

Volume30

Circulation 58:466475, 1978

Dopamine vs. Dobutamine

AVP (contd)


42/80

AVP (contd)

Dose

0.05 U/min Maybe ?

Increased BPIncreased diuresis

0.10 U/min

No !

Increased BPDecreased COAltered splanchnic perfusionPulmonary hypertension



43/80

Terlipressin

2 X as potent at V1 receptor

1/2 life 4-6 hrs cf. to 6 min for AVP

Therefore difficult to titrate

Steroids

In retrospective study- seem to significantly enhancethe effects of AVP


Dobutamine


44/80

Dobutamine

Receptors : 1 > 2

Vascular effects : 2, vasodilation

Cardiac effects - lower doses

Increased cardiac output - strong inotrope

Increased heart rate

Effect on BP variable

Uses

Cardiogenic shock

Refractory shock from sepsis

Potential problems

Tachydysrhythmias

Hypotension from 2 effects

Dopamine


45/80

op Precursor of Nor and adrenaline

Receptors : , 1 > 2, dopaminergic

Effects - dose dependant (but lots of overlap) :

vasodilation of renal/mesenteric

5-10 mcg/kg/min - 1 receptor -> inotropic/chronotropic

>10 mcg/kg/min - receptor -> arterial vasoconstriction

Uses

Shock from sepsis or SIRS

No longer used in renal doses

Potential problems

Dysrhythmias

Raises Pulmonary arterial pressure


46/80


Proof of what is best


47/80

In sepsis - does it matter

which one we use?

Studies evaluating vasoactive drugs in


48/80

Studies evaluating vasoactive drugs inseptic shock

SOAP II


49/80

SOAP II

100

80

60

20

40

00 4 8 12 16 20 28

++)"$)#(-)

+'NorepinephrineDopamine

821858

617611

553546

504494

467452

432426

394386

24

412407

Norepinephrine

Dopamine

P=0.07 by log-rank test

...no significant difference in the rate of death betweenpatients treated with dopamine or with norepinephrine,

...dopamine was associated with a more adverse events.

N Engl J Med 2010;362:779-89.

European trial:


50/80

pAdrenaline vs Noradrenaline + Dobutamine

Hypothesis : Adrenaline may be better than Nor + Dobutamine based on more

activity Study design : randomised trial of patients with septic shock

Subjects : 330 randomised

Adrenaline 161

Nor +/- Dobutamine 169

Outcome

No reduction in 28 day mortality

No differences in adverse effects

Conclusion : No significant difference

Lancet 2007 Aug 25;370:676-84


51/80

So, why the confusion?

Beware if:


52/80

A trial does not meet its primary endpoint

There is a secondary endpoint that is statisticallysignificant (P


53/80

ii 1 1

i ii

N i i

i i i

i i i 1 i 1

i i ii i i i i i i

i

i ii i i i i

.


I

.

N

N

N N

N

N

i i i ii ii i

i

i ii i i i

i i ii i i i


N S

for

N

CCM 2009;36(1):296-327

There is no high-quality

primary evidence torecommend one

catecholamine overanother

Untoward Effects of Catecholamines


54/80


Overt effects

Tachyarrhythmias

Local ischaemia

Especially if inadequately filled

Lancet Vol 370 Aug 25, 2007; 636-637



55/80


Covert effects

Stimulation ofbacterial growth and virulence

Increase biofilm formation

Reduce metabolic efficiencyEnhance fatty acid metabolism

Modify immune-cell populations

Some pro-inflammatory

Some ant-inflammatory

Lancet Vol 370 Aug 25, 2007; 636-637

f


56/80


Consider the microcirculation

h d t


57/80

Do we have adequate

microcirculatory flow?This seems to be the new frontier

Shock and the microcirculation


58/80

Shock and the microcirculation

Shock is defined in terms of a critically low blood pressure

Physiological definition - the inability of the

circulation to sustain the cellular respiration needed

to maintain normal organ function We use surrogate global hemodynamic variables to

diagnose and treat:

upstream (e.x., blood pressure, U.O.)

downstream (e.x., SvO2, lactate)

o we have adequate microcirculatory flow?


59/80

o e h ve eq e ro r l ory flo

At last we have new exciting tools allowing us to see the

microcirculation

Ex. Side stream Dark Field Spectroscopy

Microvascular perfusion


60/80

Intensive Care Med (2010) 36:20042018

New insights have established two main findings:

(1) the independent perfusion behavior of the microcirculation in

relation to classically measured systemic hemodynamic variables,

albeit within certain absolute limits of minimal perfusion pressure

(2) persistence of microcirculatory alterations are associated with

morbidity and mortalityirrespective ofcorrection ofsystemichemodynamics


Effect of Dobutamine on Microcirculation in patients with


61/80

septic shock are independent of its systemic effects


changescapillaryperfusion %

the decrease in lactate levels was

proportional to the improvement incapillary perfusion but not to changes in

cardiac index

Persistent microcirculatory alterations are associated with


62/80

organ failure and death in patients with septic shock

CCM 2004, 32:1825-1831

Despite similar hemodynamic and oxygenation profiles and use of vasopressors at the

end of shock, patients dying after the resolution of shock in multiple organ failure

had a lowerpercentage of perfused small vessels than survivors.

Vasoactive agents and microvascular perfusion


63/80

Vasoactive agents and microvascular perfusion


Additional exogenous vasoconstriction by means of a vasopressivedrug results in a reduced net perfusion pressure over the

microcirculation, despite increment ofsystemic blood pressure

Macro and micro factors involved in 02 transport


64/80


1. Convective transport of 02

(i.e. flow) depends on RBC flow,

Hct and 02 saturation

2. Diffusion - O2 transportfrom the capillary to the cell,

which is inversely related to

distance

p

02 transport depends on :

Shuttting down capillaries

worsens diffusion distance



65/80



Microcirculatory perfusion pressure

= pre-capillary inflow pressure - venular outflow pressure.

Most of the pressure drop occurs upstream in small arterioles

(resistance vessels) which regulate blood flow.

Mean capillary pressure is therefore much closer to venous

pressure than to arterial pressure

asoactive agents and microvascular perfusion...(cont.)


66/80

= distribution of red cells is related to the diameter of thedaughter vessels


g p

Vasoconstricted Vasodilated

Plasma skimming

Increasing arterial blood pressure with


67/80

Critical Care 2009, 13:R92

the increase in MAP (>75) with norepinephrine failed to improve sublingual

microcirculation, or any other variable related to perfusion

g pnorepinephrine does not improve microcirculatory

blood flow

So more is not necessarily better

Effect of adrenaline on microcirculatory blood flow


68/80

Crit Care Med 2006; 34[Suppl.]:S454S457

during cardiac arrest in animals

epinephrine resulted in a massive reduction ofmicrocirculatory blood flow

F

l ow

ind

ex

0

1

2

3

0 0.5 1 3 5 1 5 1 5Minutes

No Adrenaline

ROSCCPRVF

Adrenaline1

m g

Ad r

Microcirculation in cardiogenic shock


69/80


Inotropic agents, but not vasopressors, are advocated.

Intra-aortic balloon counter pulsation improved

microcirculatory blood flow in cardiogenic shock Additional NE dosage was inversely correlated with

microcirculatory blood flow

Microcirc lation in cardiogenic shock

Before Terlipressin


70/80

Before Terlipressin

MAP 58HR 98CVP 13UO 20 ml/hr

After Terlipressin


71/80

p

MAP 80HR 98CVP 12UO 110 ml/hr

Microvascular dysfunction


72/80

50 ICU patients resuscitated to adequate globalhaemodynamic endpoints

After successful resuscitation, peripheral

perfusion assessed: Capillary refill, Core-peripheral

temperature, Peripheral Flow Index

Compared lactate levels, on-going organ failure





73/80


M rov s l r ys o

Adequate global values with poor peripheral perfusionprobably a sign of compensatory mechanisms still present.

Microcirculation in cardiogenic shock


74/80

g


75/80

If still unresponsive to fluids and vasoactive


76/80

agents, dont forget :

Steroids

Replacement doses (


77/80

p pp

Haemodynamically stable?

Yes No

Volume responsive?

Yes No

Vasodilated?

Yes

Volume andvasopressors

No

Pump problem (ex. PE)ECHO?

add Inotrope

Volume

RECAP


78/80

Aim is an adequate effective cardiac output Time is of the essence

Get the sequence right

Fluid - get fluid responsiveness right

Pressors - get BP right

Dobutamine/RBCs - get effective CO right

Microcirculation - stay tuned!


79/80

Further reading

http://web.me.com/johnvogel2
http://web.me.com/johnvogel2http://web.me.com/johnvogel2


80/80

Questions ?

Vasoactive_Inotropes

Documents

Transcript of Vasoactive_Inotropes