Presentazione di PowerPoint

1
GLI INOTROPI IN RIANIMAZIONE quali usare, come
usarli come associarli USE OF INOTROPES IN THE
CRITICAL CARE SETTING
Giorgio Tulli M.D. Department of Anaesthesia and
Intensive Care Hospital San Giovanni di
Dio Florence
2
USE OF INOTROPES IN THE CRITICAL CARE SETTING

• In the critical care setting, positive inotropic
  agents are widely used for a range of problems
  including
• - cardiac arrest
• - cardiogenic shock
• - chronic and acute heart failure
• - septic shock
• The general therapeutic aims for all of these
  syndromes are
• - treating the underlying disorder
• - providing sufficient hemodynamic support to
  achieve
• adequate blood pressure and coronary
  perfusion and to
• relieve symptoms
• - preventing secondary complications
  affecting organs
• including the heart, brain, kidneys, lungs,
  gut , metabolism
• and Immune Response

3

• Person collapses
• Possible cardiac arrest
• Assess responsiveness

Comprehensive ECC Algorithm Circulation 2000
102 (suppl)

• Begin Primary ABCD Survey
• (Begin BLS Algorithm)
• Activate emergency response system
• Call for defibrillator
• A assess breathing (open airway, look,listen and
  feel

• B give 2 slow breaths
• C asess pulse, if no pulse
• C start chest compressions
• D attach monitor/defibrillator when available

• CPR continues
• Assess rhythm

Non VF/VT
VF/VT
Non-VF/VT (asystole or PEA)
Attempt defibrillation (up to 3 shocks if VF
persists)
Secondary ABCD Survey
CPR up to 3 minutes

• Breathing confirn and secure airway device
• Circulation gain intravenous access give
  adrenergic agent
• consider antiarrhythmics, buffer
  agents, pacing
• Non VF/VT patients EPINEPHRINE 1 mg IV, repeat
  every 3 to 5 minutes
• VF/VT patients Vasopressin 40 u IV , single
  dose, 1 time only or
• Epinephrine 1 mgIV,
  repeat every 3 to 5 minutes
• Airway attempt to place airway device
• Differential Diagnosis search for and treat
  reversible causes

CPR for 1 minute
5 H Hypovolemia,Hypoxia, Hydrogen ion
(acidosis), HyperHypokalemia, Hypothermia 5 T
Tablets (drug OD, accidents), Tamponade, cardiac,
Tension pneumothorax. Thrombosis,coronary,
pulmonary
4
CARDIAC ARREST

• Epinephrine (1.0 mg iv, or 2 mg to 3 mg by
  intrabronchial administration) repeated if
  necessary every 3 to 5 min , or Vasopressin 40 U
  iv , single dose, 1 time only
• Dopamine and dobutamine may be used after stable
  hemodynamics are established
• High dose epinephrine may increase coronary
  perfusion pressure and improve ROSC but it may
  exacerbate postresuscitation myocardial
  dysfunction.
• It is not recommended for routine use but can be
  considered if
• 1 mg-doses fail (Class Indeterminate .
  Interpretation Class IIb acceptable but not
  recommended weak supporting evidence)
• Vasopressin Class IIb acceptable , fair
  supporting evidence as an alternative to
  epinephrine for the treatment of adult shock
  refractory VF, but up today we lack sufficient
  data to support an active recommendation (Class
  Indeterminate not recommended not forbidden)

5
THE GOLDEN HOUR WHERE TIME IS MYOCARDIUM
Myocardial dysfunction
Systolic
Diastolic
LVEDP Pulmonary congestion
Cardiac output Stroke volume
Hypoxemia
Systemic perfusion
Hypotension
ISCHEMIA
Progressive myocardial dysfunction
Coronary perfusion pressure
Compensatory Vasoconstriction Fluid retention
DEATH
THE DOWNWARD SPIRAL IN CARDIOGENIC SHOCK
6
CARDIOGENIC SHOCK

• Dopamine (high dose 10µg/kg/min) if MAP
• 80
• to 90 mmHg
• Dobutamine may be added if blood pressure values
  are stabilized above these thresholds
• If cardiogenic shock persists despite dopamine,
  intra-aortic balloon counterpulsation and
  norepinephrine may be added to the regimen

7
Positive inotropic stimulation

• Catecholamines continue to be the pharmacologic
  mainstay of inotropic support for patients with
  acute left ventricular failure
• Catecholamines have predictable pharmacodynamics
  and a favorable pharmacokinetic profile
• Catecholamines allow rapid titration of effects
  and undesiderable side effects dissipate within
  minutes after cessation of infusion
• When catecholamines are combined, each substance
  can be titrated according to the desired effects
• The ideal catecholamine to treat patients with
  low cardiac output and an ideal combination of
  catecholamines for use in a critically ill
  patient with a dysfunctional heart remains to be
  determined

8
Positive inotropic stimulation

• Patients suffering from congestive cardiomyopathy
  showed elevated noradrenaline plasma levels as a
  result of noradrenaline spillover and decreased
  clearance
• Catecholamine administration is associated with
• a marked reduction in left ventricular
• ß-adrenoreceptor density and an increase in
  inhibitory G protein in the failing human
  myocardium
• It is time to reorient our inotropic therapy ?

9
ß2-AR
Sarcolemmal Ca2 pump
ß1-AR
L
L
VDCC
Na/H exchanger
Ca2channel
Gs
AC
Gi -
Gs
Gq -
P
P
P
P
PLC
ATP
cAMP
ß-ARK GRK2/3
DAG
PKA
IP3R
MITO
IP3
PKC
SR
Ras Raf MEK ERK
FKBP
P
P
Ca2
Ca2
K
RYR
Ca2
CaM
Ca2
SERCA2
P PLB
CaMKs
Ca2
MLCV2
cTnl
Nucleus transcription
P
Sarcomers
P
Na/Ca2 exchanger
Na/Kpump
ß-ADRENERGIC SIGNALLING CASCADES IN CARDIOMYOCYTES
10
ß1-AR
Agonist
Adenyl Cyclase (AC)
as
ATP
a
Gs protein
PDE
ß
?
GTP
cAMP
AMP
GDP
PKA Protein kinase A
PKA phosphorylates and activates several cellular
structures
GTP
Protein Kinase A (PKA) activation by Cyclic
Adenosine Monophosphate(cAMP)

• Voltage dependent L type Ca2channel
• Na/H exchange channels
• Na/K pumps
• Ca2 release channels

11
Ca2
L
ß
?
AC
ß
?
a
a
AC
ATP
P
cAMP
Receptor resensitization
PKA
CaM
ß-ARK GRK2/3
Arrestin
Clathrin Clathrin Clathrin
P P P
endosome
Receptor degradation
Receptor internalization
ß-1 Adrenergic receptor internalization,
resensitization or degradation
In healthy human cardiomyocytes, ß1-ARs
constitute approximately 70 to 80 of the ß-ARs
In case of elevated sympathetic drive (eg,
cardiac insufficiency, shock states), ß1-Ars are
downregulated. ?2-ARs do not decrease but show
some loss of contractile response to agonist
stimulation as a result of the upregulation of
ß-ARK and Gi proteins
12
LPS
IL-1
LPS/LBP
TLR4
(Toll receptor)
THE HEART EXPRESSES TLRs
CD14
MD-2
IL-6
TF
TIRAP/MAL
Tollip
MyD88
IRAK-1
IRAK-2
Beta2 adrenergic agonists Ibuprofen Vitamin
C Inhibit IkB degradation
TNFa
TRAF-6
Beta2 receptor
ECSIT
MAP kinase
Beta2 adrenergic agonists Beta2
cathecolamines promote the generation of
IL-10 by the cAMP protein kinaseA pathways
TRIKA 1/2
NIK IKKs
IL-8
nucleus
IkB/NF-kB
Bcl-2
IL-10
Proposed signaling pathways in endothelial cells
on exposure to LPS. Knowledge of the inherent
specificity of various signaling intermediates
for LPS should enable the targeted design of
pharmacologic intervention strategies that will
inhibit the toxic effects of LPS without
paralyzing host immunity
13
ß3-ARs negative inotropic effect by activating a
NO-dependent paths
(b) Failing Heart
(a) Non-failing Heart
ß3
0.25
ß3
-
ai
-
ai
eNOS
eNOS
NO.
NO.
contractility


cAMP
cAMP
AC
AC
aS
aS
ß1
ß2
72
upregulated
ß1
ß2
downregulated
28
Postulated changes in ß-adrenergic receptor
signaling in cardiomyocytes from non failing to
failing myocardium
14
NO
ß1ß2
ß3
M3
stretch
T-tubule
caveolae
AC
Gi
Gs
Gi


L-Arg
Cav-3

eNOS
-
O2 NADPH
NITRIC OXIDE (NO) signaling into
the cardio- myocyte

iNOS
CAM

PKA PKB AMPK
toxic peroxynitrite
-
HbO2 MetHb
O-2 ONOO-
NO
PKC
-
GC

-
Reduction of MVO2
cGMP
-
cAMP
PDE2 (PDE3)
PKG
I
III

PKA
P
II
-
TnI
ARC
SR
IV
Negative inotropic effect
P
SERCA
RyRC
Ca2

Positive lusotropic effect
Ca2
VOC
Positive inotropic effect
P
ATPase
TnC
TnI
15
INOTROPES MECHANISMS OF ACTION
Meccanismo dazione degli inotropi positivi

Dobutamine
Digoxin
K
Ca2
beta-receptor
Gi
Na/Ca2ex.
Gs
Na/Kexchanger
Na
Ca2
ATP
Narises
cAMP (active)
rise in intracellular calcium
PDE
Milrinone PDE III inhibitor
AMP (inactive)
16
MECHANISM OF CONTRACTION relaxation phase
Il meccanismo contrattile fase di rilasciamento
LEVOSIMENDAN Calcium sensitisation for enhanced
cardiac contractility

Actin
Tropomyosin
Ca2
Myosin head (S1 fragment)
cTnC
ATP pocket
TnI
RLC
TnT
ELC
17
Il meccanismo contrattile fase di contrazione
MECHANISM OF CONTRACTION contraction phase
LEVOSIMENDAN Calcium sensitisation for enhanced
cardiac contractility

Ca2
cTnC
TnI
TnT
Ca2
Actin
Actin
Tm
TnT
Tm
Myosin head
Tm
cTnC
TnI
TnI
Actin
Actin
Tm
cTnC
TnT
Myosin head
Tm
Tm
TnT
Ca2
TnI
Calcium sensitisation leads to enhanced systolic
contraction of myofilaments, but allow normal
diastolic relaxation (inotropic and lusitropic
effect of Levosimendan)
cTnC
Ca2
Warber K.D. and Potter J.D., in The Heart and
Cardiovascular System, H.A. Fozzard et al., eds.,
Raven Press, New York, pp.779-788, 1986
18
Calcium ion
Calcium ion
LEVOSIMENDAN
Troponin C
Troponin C
ACTIN
ACTIN
Tropomyosin
Tropomyosin
MYOSIN
MYOSIN
In contrast to the positive inotropes, calcium
sensitisers such as Levosimendan increase the
contractile force generated for a given amount of
free calcium in the cytoplasm, binding to
Troponin C and increasing the sensitivity of the
contractile proteins to calcium without
increasing the influx of calcium into the
myocytes. Levosimendan binds during the first
part of systole rather during diastole
19
VASODILATATION
LEVOSIMENDAN
Potassium
K
K
K
K
K
K
KATP channel
K
Levosimendan has also been shown to increase
Coronary and Systemic Vasodilatation. This effect
is mediated by the opening of Adenosine
Triphosphate Dependent Potassium (KATP)
channels by the action of Levosimendan on muscle
tissue, reducing the preload and afterload of
the myocardium, improving oxygen supply to the
myocardium and renal blood flow
20
Some differences between IV inotropic agents
Tachyphylaxis ?
NO
YES
NO
21
(?dP/dtmax)
(?MvO2)
?efficiency (SW/MvO2)
Senzaki H et al Circulation 2000 101 1040-8
22
Cardiac VO2 study (PET scans in healthy
volunteers)
Dobutamine (n6)
Levosimendan (n5)
Ukkonen H et al Eur Heart J 1998 Suppl A547
23
Anti-stunning effect of LEVOSIMENDAN(dose
dependent)
segment shortening
LEVOSIMENDAN
control
stunning
Jamali IN et al Anest Analg 1997 8523-29
24
WHAT IS ACUTE HEART FAILURE
B-type natriuretic peptide (BNP) levels increase
with the severity of heart failure. BNP predicts
short term mortality after acute heart
failure (1654 pg/ml 50 risk of death, ROC
curve 0.88 to 0.92)
EXACERBATION OF CHRONIC HEART FAILURE (often with
LV dysfunction) 90
DE NOVO CARDIAC INJURY 10
DECOMPENSATED HEART FAILURE
25
Comparison of decompensated heart failure with
myocardial infarction
Felker GM et al Am Heart J 2003 145S18-25
26
The Killip classification of heart failure and
the mortality rates associated with the different
classes
Greenberg B et al Eur J Heart Failure 2003
513-21
27

• Evidence for congestion
• (elevated filling pressure)
• Orthopnoea
• High jugular venous pressure
• Oedema
• Ascites
• Rales (uncommon)
• Abdominojugular reflex

PROFILES OF ADVANCED HEART FAILURE

• Evidence for low
• perfusion
• Narrow pulse pressure
• Cool forearms legs
• May be sleepy
• ACE inhibitor related
• symptomatic hypotension
• . Declining sodium levels
• Worsening renal function

CONGESTION AT REST ?
NO
YES
NO -5
Warm and Wet B
Warm and Dry A
-70
-20
-5 YES
Cold and Dry L
Cold and Wet C
28
GOALS OF MANAGING ACUTELY DECOMPENSATED CHRONIC
DYSFUNCTION

• Alleviate symptoms of congestion and oedema
• Reduce the work of breathing !!!
• Improve haemodynamic profile
• (without causing myocardial injury)
• Increase cardiac output without increasing
  oxygen requirements, restore perfusion to vital
  organs, support blood pressure!!!
• Preserve renal function
• Increase patient survival

29
THE FIVE ITEMS FOR TREATMENT OF ACUTELY
DECOMPENSATED CHF OR DE NOVO AHF

• Oxygen therapy, CPAP, BIPAP
• If ADCHF diuretics, keep ß blockers
• Additional i.v. nitrates
• Cardiac enhancing drugs
• - i.v. inotropic agents
• - calcium sensitizers
• Intra-aortic balloon pump, LV assist device

30
WHICH AGENT SHOULD I USE?

• ß-adrenergic agents dobutamine
• 
  dopamine
• Phosphodiesterase inhibitors milrinone
• 
  amrinone
• Calcium sensitisers
  LEVOSIMENDAN

31
Dobutamine or nitroprusside i.v. therapy in
severe heart failure
RESULTS
Capomolla S et al Eur J Heart Fail 2001 3 601-10
32
OPTIME-CHF study

• 951 pts (NYHA III/IV, mean LVEF 23)
• Randomly assigned to milrinone/placebo for 24 hrs
• Milrinone resulted in

• Higher 60 day mortality 10.3M vs 8.9P (p0.4)
• More hypotension requiring Rx 10.7 vs 3.2
• Trend to more arrhythmias, Myocardial Infarction

Short term i.v. MILRINONE for acute exacerbation
of CHF
Cuffe MS et al, JAMA 2002 2871541-7
33
Myocardial supply-demand balanceRest or
Stress?Are we operating on the wrong philosophy?
Cardiac work
NITRATES ß-BLOCKERS Ca SENSITIZERS
?-AGONISTS Cardiac glycosides PDE
inhibitors Diuretics
DEMAND
SUPPLY
Cardiac work
34
SHOULD WE BE DE-STRESSING THE DECOMPENSATED
HEART RATHER THAN FLOGGING IT FURTHER?
ERGO.THE USE OF INOTROPES AND DIURETICS ARE
(USUALLY) IRRATIONAL !
35
DECOMPENSATED HEART FAILURE
POOR VENTRICULAR FUNCTION

• Compensatory changes
• Vasoconstriction
• Tachycardia

Poor cardiac output Reduced tissue perfusion
FUROSEMIDE ?
36
FUROSEMIDE- the harm!

• FALL IN CARDIAC OUTPUT
• RISE IN SYSTEMIC VASCULAR RESISTANCES
• TRANSIENT RISE IN BLOOD PRESSURE
• VARIABLE CHANGE IN HEART RATE
• INCREASE IN CARDIAC WORK
• INCREASED PLASMA CATECHOLAMINES

Dikshit K et al, N Engl J Med
19732881087-90 Lal S et al, Br Heart J 1969
31 711-7 Francis GS et al, Ann Intern Med
1985 103 1-6 Bayliss J et al, Br Heart J
1987 57 17-22
37
WHY IS ADRENERGIC ACTIVATION NOT SO GOOD?

• IMPORTANT PROGNOSTIC FACTOR IN HEART FAILURE
• CAUSES INCREASED MvO2
• .may be initially compensatory but, longer term,
  results in
• energy-depleted state and cell injury
• STIMULATES ARRHYTHMIAS, TACHYCARDIAS
• ? CAUSES DIRECT MYOCARDIAL TOXICITY
• ? STIMULATES VENTRICULAR REMODELLING
• STIMULATES LIPOLYSIS
• ..resulting FFA utilisation less efficient for
  given level of MvO2

38
PATHOPHYSIOLOGY
POOR LEFT VENTRICULAR FUNCTION
Poor forward flow
Increased back pressure
INOTROPES
Organ dysfunction (oliguria, confusion,
fatigue) Metabolic acidosis
Pulmonary congestion
FUROSEMIDE
39
OUTCOME FROM INOTROPES

• SHORT TERM ENHANCEMENT OF CARDIAC OUTPUT
• LONG TERM FEEL BETTER.BUT DIE QUICKER

• Milrinone
• Vesnarinone
• Dobutamine

40
LEVOSIMENDAN SAVES LIVES

• There are data from RUSSLAN and LIDO studies
• This should be confirmed in theSURVIVEstudy700
  pts, levosimendan vs dobutamine, March
  03-December 2004
• LEVOSIMENDAN is
• Very effective in all types of AHF
• VERY SAFE
• No need for invasive monitoring
• When physicians gain experience, no need for ICU
  plus decrease in hospital stay

41
LIDO STUDY
Simdax Studio LIDO
CHANGE () IN HAEMODYNAMIC VARIABLES AT 24 HOURS
LIDO
Follath et al. Lancet 2002
42
Efficacy and safety of intravenous Levosimendan
compared with Dobutamine in severe low output
heart failure (the LIDO study) A randomized
double blind trial F.Follath, JGF Cleland, H Just
et al Lancet 2002 360196-202
MORTALITY 26 for levosimendan and 38 for
dobutamine
p0.029
43
RUSSLAN STUDY RISK OF MORTALITY 6 MONTHS
Simdax Studio RUSSLAN
Levosimendan significantly lowered death rates by
40 during the first 14 days after treatment
(p0.036)
RISCHIO DI MORTALITA A 6 MESI
SURVIVORS
DAYS
Patients with acute heart failure after an acute
myocardial infarction
Moiseyev V.S. European Heart Journal 2002
231422-1432
44
NYHA IV
NYHA III
NYHA II
NYHA I
HTx
LEVOSIMENDAN
ANTICOAGULANTS
DIGITALIS
SPIRONOLACTONE
DIURETICS
ß-BLOCKERS
ACE INHIBITORS (AT1-RB)
NO MEDICAL TREATMENT
45
Treatment algorithm of decompensated heart failure
Decompensated HF patient Oedema () Warm
extremities SBP 90mmHg
Decompensated HF patient Oedema () Cold
extremities SBP 90mmHg
Decompensated HF patient Oedema (-) Cold
extremities SBP 90mmHg
Decompensated HF patient Oedema() or (-) Cold
extremities SBP

Optimisation of therapy

Increase ACE I doses

IV diuretics

Vasodilators (nitroprusside,

nitroglycerin, neseritide)

Dobutamine Dopamine Norepinephrine
LEVOSIMENDAN

• Inadequate response
• Increasing BUN
• Persisting oedema
• Persisting dyspnoea

Add Levosimendan
46
THE EARLIEST , THE BETTER
1 week Follow up
D/C planning
ER team
Med-Surg team
Med-Surg team
ICU team
Family MD
ED
ICU
WARD
WARD
HOME
ICU Follow up clinic
Critical Care consult
Critical care consult
Expanded role of critical care focused on long
term outcomes
47
A PLACE FOR LEVOSIMENDAN IN THE E.D.?

• Binds to troponin C during systole
• Doesnt affect Ca2 concentration or release from
  
• sarcoplasmatic reticulum
• Increases contractility by increasing sensitivity
  of
• myofilaments to Ca2
• Increases CO without significant rise in MvO2

A NEW TREATMENT PARADIGM?
Oxygen Nitrates (s/l then i/v) Anxiolytic
(morphine) (non invasive) ventilation other
mechanical support LEVOSIMENDAN
NON-IMPROVEMENT?
NON-IMPROVEMENT?
12-24µg/kg (bolus 10 mins), continuous infusion
0.1µg/kg/min decreased to 0.05µg/kg/min or
increased to 0.2µg/kg/min
48
Myocardial depression in the patient with sepsis

• It has become evident over the past decade that
  myocardial depression plays a clear role in human
  septic shock
• Septic myocardial depression in humans has been
  seen to be characterized by reversible
  biventricular dilation , decreased systolic
  contractile function and decreased response to
  both fluid resuscitation and catecholamine
  stimulation, all in the presence of an overall
  hyperdynamic circulation (high cardiac output and
  low systemic vascular resistences)
• This phenomenon is linked to the presence of a
  circulating myocardial depressant factor which
  probably represents low concentrations of TNFa
  and IL-1ß, acting in synergy and not linked to
  global myocardial hypoperfusion
• These effects are mediated by mechanisms that
  include Nitric Oxide (NO) and cyclic GMP
  generation

49
Elevation of Troponin I in sepsis and septic shock

• Troponin is now the preferred marker for cardiac
  injury
• Since troponin proteins normally regulate myocyte
  contraction, leaking of troponin into
  circulation is indicative of cardiac wall stress
  and apoptosis
• Although troponin elevation has superior
  sensitivity and specificity for myocardial
  injury, it does not define the mechanism of
  cardiac injury
• Troponin levels are likewise elevated by other
  mechanism of cardiac injury Cardiac Troponin T
  (cTnT) is elevated in
• - Patients with contusion injuries of the
  heart
• Cardiac troponin I (cTnI) levels predict
• - Myocardial dysfunction due to septic
  cardiomyopathy
• (myocardial necrosis or reversible
  myocardial depression?)
• (What is the appropriate threshold
  concentration that would
• be indicative of patients at the
  highest risks?)
• - aneurysmal subarachnoid haemorrhage
• - anthracycline cardiotoxicity
• - myocarditis
• - early detection of rejection in heart
  transplant recipients

50
ORGAN FAILURE IN SEPSIS
SEVERE SEPSIS

• Peripheral vascular effects
• Vasodilatation
• Regional vasoconstriction
• Capillary shunting
• Microemboli
• Endothelial cell dysfunction

• Direct myocardial effects
• Reduced ejection fraction
• Increased EDVI and ESVI
• Reduced stroke work
• tipically in survivors and
• reversible (7-14 days)

Microvascular insufficiency Tissue hypoxia
Severe fall in Systemic Vascular Resistance
Multiorgan failure
Severe myocardial depression
51
LPS and other bacterial components
Endothelium
Monocytes
Neutrophils
Cytokines TNFa-IL-1ß
Oxygen radicals
Lipid mediators
NO
Increased TF and PAI-1
Complement
Chemotaxis, lysosomal enzymes
Procoagulant effect
Microvascular occlusion
Vascular instability Cardiac Dysfunction
Coagulopathy
Fever
Vasodilatation
Capillary leak
SEPSIS AND MULTIPLE ORGAN FAILURE
52
HEMODYNAMIC CHANGES IN SEVERE SEPSIS
COSV x HR, SVR (MAP-CVP)/CO x 79.92 DO2
CI x arterial oxygen x 10, VO2 CI x (arterial
venous oxygen) x 10
53
Cardiovascular support basic principles

• Patients with septic shock should be treated in
  an intensive care unit, with continuous ECG
  monitoring and monitoring of arterial oxygenation
• Arterial cannulation should be performed in
  patients with shock to provide a more accurate
  measurement of intra arterial pressure and to
  allow beat to beat analysis so that decisions
  regarding therapy can be based on immediate and
  reproducible blood pressure information
• Resuscitation should be titrated to clinical end
  points of arterial pressure, HR, urine output,
  skin perfusion and mental status, and indices of
  tissue perfusion such as blood lactate
  concentrations and SvO2
• Assessment of cardiac filling pressures may
  require central venous or pulmonary artery
  catheterization. PAC also allows for assessment
  of pulmonary arterial pressures, CO measurement,
  and measurement of SvO2

54
Hemodynamic support in septic shockIntensive
Care Medicine (2001) 27S80-S92
55
FLUID RESUSCITATION IN SEPTIC SHOCK

• What is the endpoint of fluid resuscitation in
  septic shock?
• Answer (a) adequate tissue perfusion , grade
  E
• Does fluid resuscitation increase cardiac output
  in septic shock patients?
• Answer yes, grade C
• Should fluid infusion be the initial step in the
  cardiovascular support of septic shock patients?
• Answer yes , grade D
• Can the use of pulmonary artery catheter guided
  therapy improve outcome from septic shock?
• Answer uncertain, grade D

Intensive Care Medicine 2001 27 S80-S92
56
CHOICE OF FLUID IN SEPTIC SHOCK

• Is resuscitation with colloids or crystalloids
  associated with similar outcomes in septic shock?
• Answer uncertain, grade C
• Should albumin be avoided in resuscitation from
  septic shock
• Answer uncertain , grade C
• Can one recommend a minimum hemoglobin
  concentration in severe sepsis?
• Answer yes, 7-8 g/dl, grade B
• Can one recommend a minimum hemoglobin
  concentration in septic shock?
• Answer uncertain , grade E

Intensive Care Medicine 2001 27 S80-S92
57
VASOPRESSOR THERAPY IN SEPTIC SHOCK

• Does adrenergic support improve outcome from
  septic shock?
• Answer yes, grade E
• Is the combination of norepinephrine and
  dobutamine superior to dopamine in the treatment
  of septic shock?
• Answer uncertain , grade C
• Among adrenergic agents, are dopamine or
  norepinephrine the first line agents to correct
  hypotension in septic shock?
• Answer yes, grade E
• Should low dose dopamine be routinely
  administered for renal protection?
• Answer no, grade D

Intensive Care Medicine 200127S80-S92
58
INOTROPIC THERAPY IN SEPTIC SHOCKTHE SUPRANORMAL
APPROACH

• Is dobutamine the pharmacological agent of choice
  to increase cardiac output in the treatment of
  septic shock?
• Answer yes, grade D
• Are hyperkinetic patterns associated with better
  outcome in septic shock patients?
• Answer yes, grade C

Intensive Care Medicine 2001 27 S80-S92
59
Haemodynamic alteration in septic shock
Elevated O2 requirements
Alterated extraction
O2 CONSUPTION (VO2)
Decreased contractility
O2 TRANSPORT (DO2)
Systemic QO2 Cardiac Index x (Hb x SaO2 x
1.34) ( PaO2 x 0.003)/100
Jv Kpc ( Pc Pi ) - Jc ( pc - pi)
60
THE EARLIEST , THE BETTER
1 week Follow up
D/C planning
ER team
Med-Surg team
Med-Surg team
ICU team
Family MD
ED
ICU
WARD
WARD
HOME
ICU Follow up clinic
Critical Care consult
Critical care consult
Expanded role of critical care focused on long
term outcomes
61
Supplemental oxygen /- Endotracheal intubation
and Mechanical ventilation
Rivers E et al EGDT in the treatment of severe
sepsis and septic shock N Engl J Med 2001,
3451368-1377
Central venous and Arterial catheterization
Sedation,paralysis (if intubated) Or both
crystalloid
CVP
colloid
8-12 mmHg
MAP
Vasoactive agents
90mmHg
65 andScvO2
70
Transfusion of red cells Until hematocrit30
70
Inotropic agents
Goals achieved
NO
YES
ICU admission
62
Therapeutic interventions standard therapy
versus EGDT
A negative or positive value indicates how the
control group therapy compares with the treatment
group. a P0.03, e P0.04. EGDT early goal directed
therapy
63
Outcome measures percentage change or
improvement, baseline to 72 hours
Baseline to 72 hours surviving to hospital
discharge

64
Why was there no difference in mechanical
ventilation or vasopressor use between the
standard treatment and EGDT groups during the
first 6 hours, but a large difference in fluid
transfusions and, expecially, in dobutamine
administration?

• With a goal oriented protocol, patients are
  stratified based on hemodynamic derangments.
• Using measurements of ScvO2, it is possible to
  identify patients with profound global myocardial
  dysfunction who are hence at risk of impaired
  perfusion. These patients, almost 15 of those in
  the EGDT group, received dobutamine during the
  first 6 hours because myocardial suppression was
  diagnosed.
• Once myocardial dysfunction is corrected (and
  compliance improved), these patients become more
  suitable for volume loading, so this group
  received almost 3.5 liters more fluids in the
  first 6 hours than the control patients.
• In spite of more volume loading, the EGDT group
  received less mechanical ventilation over the
  subsequent 72 hours than in the standard
  treatment group

65
Why was cardiovascular collapse a significant
cause of death in the control group?

• Cryptic shock (shock with normal vital signs) is
  a frequent occurrence in early severe sepsis and
  septic shock.
• Despite resuscitation to the goals for mean
  arterial blood pressure and CVP , almost 40 of
  control patients continued to exhibit global
  tissue hypoxia (decreased ScvO2 and increased
  lactate levels) in these patients, there was a
  twofold increase in hemodynamic deterioration,
  requiring more mechanical ventilation, pulmonary
  artery catheterization and vasopressor use in the
  subsequent 72 hours

66
How do severe sepsis and septic shock differ
hemodynamically in the early stages compared with
that classically described in the ICU?

• Patients presenting with early sepsis and septic
  shock are characterized by hypovolemia (lowCVP),
  normal to increased blood pressures, and
  decreased cardiac output (decreased central
  venous oxygen saturation and low cardiac index).
  This is in contrast to ICU patients who are
  euvolemic, have high ScvO2, and have elevated
  cardiac indices

67
What are the most important ways in which EGDT
can improve outcomes?

• The key factors are early detection of high risk
  patients in cryptic shock, early reversal of
  hemodynamic perturbations and global tissue
  hypoxia, prevention of acute cardiovascular
  collapse, and the possibility of preventing the
  inflammatory aspects of global tissue hypoxia
  that accompany the inflammation or infection

68
Charing Cross renal rescue protocol

• 1 Precondition- NORMOVOLEMIA
• GTN 2mg/h maintained throughout protocol
• (low dose30 to40µg/min, predominantly
  produce venodilatation
• high doses 150 to 500µg/min lead to
  arteriolar dilatation)
• Colloid challenge
• CVP/PCWP against SV and clinical
  endpoints
• Warm peripheries
• 2 Precondition-PATIENT RELATED NORMOTENSION
• Norepinephrine to achieve normal systolic
  blood pressure
• (as soon as normovolemic), Dobutamine if
  an inotropic support
• is necessary after echocardiogram
• 3 Offload work of the mTAL
• Furosemide 10 mg bolus, followed by 1-4
  mg/h
• (when 1 and 2 have been achieved)

69
MECHANISMS OF VASODILATORY SHOCK
Sepsis or tissue hypoxia with lactic acidosis
ATP, H , Lactate in vascular smooth muscle
Vasopressin secretion
Nitric oxide synthase
Nitric oxide
Vasopressin stores
Open KCa
Open KATP
cGMP
Cytoplasmic Ca2
Plasma vasopressin
Phosphorilated myosin
VASODILATATION
N Engl J Med 2001,345588-595
70
VASOPRESSIN INFUSION IN SEPTIC SHOCK

• Relative depletion of circulating vasopressin has
  been identified in established septic shock, and
  there is increasing interest in the
  administration of low dose exogenous vasopressin
  as an alternative vasopressor agent
• It has been showed immediate and sustained
  increases in mean arterial pressure during low
  dose (0.04 U/min)vasopressin infusion in septic
  shock refractory to traditional vasopressor
  agents. Urine output increased, and no
  significant changes in cardiac function , heart
  rate, oxygenation, metabolic parameters, or serum
  levels of atrial natriuretic peptide,
  aldosterone, angiotensin II or renin were noted
  (Crit Care Med 200129487-493)
• In a double blind trial comparing 4 hour infusion
  of vasopressin and norepinephrine in patients
  with severe septic shock, it has been showed that
  all patients maintained stable mean arterial
  pressure and cardiac index , gastric mucosal
  carbon dioxide tension and electrocardiographic
  ST segments. In contrast to patients receiving
  norepinephrine infusions, patients receiving
  vasopressin demostrated increased urine output
  and creatinine clearance (Anesthesiology 2002
  96576-582)
• A single injection of terlipressin, a long acting
  vasopressin analog,into patients with
  norepinephrine resistant septic shock produced a
  significant increase in blood pressure that
  lasted for at least 5 hours (Lancet
  20023591209-1210)

71
VASOPRESSIN AND ITS ANALOGS

• Vasopressin levels are low in advanced stages of
  vasodilatory shock
• A significant body of evidence from small
  randomized controlled trials, prospective cohort
  studies, and retrospective case series,
  indicates beneficial hemodynamic effects of low
  dose replacement therapy with vasopressin or its
  analog
• Despite reversal of catecholamine resistance, no
  obvious improvement in outcome can be derived
  from the available data, due to the small sample
  size of the two RCTs
• The currently available data on the side effects
  of vasopressin treatment for septic shock
  expecially regarding the splanchnic circulation
  are very limited, detrimental changes in
  splanchnic perfusion, metabolism, cannot be
  predicted by markers of global tissue oxygenation
• It has to be recommended judicious use of these
  compounds ideally inside RCTs and with adequate
  monitoring of regional perfusion

72
Administration of low dose dopamine by
continuous intravenous infusion (2µg/Kg/min/) to
critically ill patients at risk of renal failure
does not confer clinically significant
protection from renal dysfunction Low dose
dopamine in patients with early renal
dysfunction A placebo controlled randomized
trial (ANZICS clinical trials group) Lancet
2000 3562139-43
Low dose of dopamine is thought to be
harmless. That is not true.
DOPAMINE
suppress respiratory drive, pulmonary shunt
increase cardiac output increase myocardial
VO2
trigger myocardial ischaemia, induce
hypokalemia
arrhytmias hypophosphatemia

predispose to gut ischemia disrupt metabolic,
immunological homoeostasis (action on T cells
function) and suppression of the release of
prolactin (TSHsuppressed,GH stimulated)
There is no justification for using renal dose
dopamine in the critically ill
73
A
Corticosteroid insufficiency during acute illness
B
C
Normal nonstressed function of the
hypothalamic- pituitary-adrenal axis
Normal function of the hypothalamic-pituitary- adr
enal axis during illness
Central nervous system disease, corticosteroids

Reduced feedback
-
Hypothalamus
-
-
Stress cytokines
CTRH
CTRH
CTRH
Pituitary apoplexy, corticosteroids
Pitutary
-
-
-
-
ACTH
ACTH
ACTH
Cytokines, anesthetics antiinfective
agents corticosteroids hemorrage, infection
-
Adrenal
Decreased cortisol and decreased
corticosteroid binding globulin
Binding of cortisol to corticosteroid binding
globulin
Increased cortisol and decreased
corticosteroid binding globulin
Cytokines,local corticosteroid activation
Cytokines Glucocorticoid resistance
-

Increased action in tissue
Decreased action in tissue
Normal action in tissue
Activity of the Hypothalamic-Pitutary-Adrenal
Axis under Normal Conditions (A), during an
Appropriate Response to Stress (B) and during an
Inappropriate Response to Critical Illness ( C )
74
Potential effetcs of corticosteroids during
septic shock
Activation of IKB-a
Correction of a relative adrenocortical deficiency
Decreased trascription for proinflammatory
cytokines, Cox-2, ICAM-1, VCAM-1. Increased
transcription for IL-1-RA
Inhibition of NFk-b
Reversal of adrenergic receptor desensitization
deficiency
Inhibition of inducible iNOS
Hemodynamic improvement
Decrease in the dosage of catecholamines
75
Nonresolving acute respiratory distress syndrome
Critical illness (especially if features of
corticosteroids insufficiency are present
Randomly, timed measurement of cortisol level
THE SCHEME HAS BEEN EVALUATED FOR PATIENTS WITH
SEPTIC SHOCK Annane et al. JAMA
2000 2831038-1045 Annane et al JAMA
2002 288862-871

15-34µg/dl
34µg/dl
Increase in response to corticotropin test

9µg/dl
Functional hypoadrenalism unlikely
Hypoadrenalism likely
Initiate pharmacologic glucocorticoid therapy
Consider physiologic Corticosteroid replacement
Corticosteroid therapy Unlikely to be helpful
Investigation of adrenal corticosteroid function
in critically ill patients on the basis of
cortisol levels and response to the corticotropin
stimulation test. It must be borne in mind that
no cutoff value will be entirely reliable
76
Septic shock (cathecolamine dependency,
poor response to ACTH)
Mild illness or condition (nonfebrile cough or
cold Dental extraction with Local anesthetic)
Moderate illness or condition(fever, minor
trauma,minor surgery)
Severe illness or condition (major
surgery, trauma, critical illness
Increase dose to 15mg of prednisolone/day
or equivalent
Increase dose to 50mg of Hydrocortisone IM or IV
every 6 hr
50 mg of Hydrocortisone IV Every 6 hr with or
without 50µg of Fludrocortisone/ day
Return to normal dose 24 hr after resolution
Taper dose to normal by decreasing by 50 per day
Treat for 7 days
No change
Suggested corticosteroid replacement doses during
intercurrent and acute illness in patients with
proven or suspected adrenal insufficiency,
including those receiving corticosteroid therapy
77
DOBUTAMINE
DOPAMINE
Inotropic ß1ß2a
DA2
ß1(ß2)
DA1
Peripheral vasodilatation
low doses
ß1
a high doses
Inotropic ß1/ß2
DA1
a1constriction
Renal blood flow
inotropic
NOREPINEPHRINE
EPINEPHRINE
ß1ß2a
ß1aß2
receptor specific effects of physiologic and
pharmacologic catecholamines
78
Glycogen
COUNTER REGULATORY HORMONES (epinephrine,glucagon,
cortisol) CYTOKINES STRESS
SEPSIS an hypermetabolic hypercatabolic state
Glucose
Pyruvate
Alanine
Glycolysis
LIVER
Glucose Pyruvate
Glucose Lactate
Gluconeogenesis
glycogen
Alanine
Lactate
Alanine
Lactate pyruvate
Glycolysis
Glycerol
Amino acids
Proteinolysis
Lipolysis
79
EPINEPHRINEconcepts of hemodynamic treatment of
septic shock patients should not only aim at
hemodynamic parameters, but should also try to
limit additional drug induced metabolic
stimulation

• Epinephrine is the most potent catecholamine with
  respect to
• metabolic effects.
• VO2 and glucose production are enhanced and are
  accompanied by
• - Hyperglycemia
• - Hyperlactatemia, with decreased arterial pH,
  without adequate
• insulin response, due to suppression of
  insulin release

Epinephrine not only decreases hepatosplanchnic
blood flow and oxygen exchange , but also
compromises hepatosplanchnic lactate clearance,
increases the lactate/pyruvate ratios indicating
a transient modulation of cytosolic redox state
Clutter WE et al Regulation of glucose
metabolism by sympathochromaffin catecholamines.
Diabetes Metab Rev 1988 41-15 Meier-Hellmann
A et al Epinephrine impairs splanchnic perfusion
in septic Shock Crit Care Med 1997 25 399-404
Levy B et al Comparison of norepinephrine and
dobutamine to epinephrine for hemodynamics,
lactate metabolism and gastric tonometric
variables in septic shock A prospective
randomized study Intensive Care Med 1997
23282-7 Leverve XM From tissue perfusion to
metabolic marker assessing organ competition and
co-operation in critically ill patients?
Intensive Care Med 1999 25 890-2 Totaro Rj
and Raper RF Epinephrine induced lactic acidosis
following cardiopulmonary bypass Crit Care Med
1997 25 1693-9 Mackenzie SJ et al Adrenaline
treatment of septic shock Effects on
hemodynamics and oxygen transport. Intensive Care
Med 1991 17 36-9 Day NP et al The effects
of dopamine and adrenaline infusions on acid base
balance and systemic haemodynamics in severe
infection Lancet 1996 348219-23
80
PHENYLEPHRINE
Replacing norepinephrine with the pure a-agonist
phenylephrine not only selectively reduces
regional blood flow, but also impairs the
hepatosplanchnic metabolic performance as shown
by a decrease splanchnic lactate uptake rate,
despite no change in systemic hemodynamics or
gas exchange. Administration of pure a-agonists
may threaten the hepatosplanchnic metabolism
and, therefore, should be avoided
Reinelt H et al Impact of exogenous beta
adrenergic receptor stimulation on
hepatosplanchinic oxygen kinetics and metabolic
activity in septic Shock Crit Care Med 1999
27325-31
81
DOPAMINE
Whatever the impact of dopamine on splanchnic
perfusion may be, it failed to exert a beneficial
effect on regional PCO2 equilibrium, given as
either pHi or PCO2 gap, and in high doses,
dopamine even causes pHi to decrease. Therefore ,
beside its equivocal effects on splanchnic
perfusion, dopamine has no obvious positive
effect on splanchnic metabolism to justify
routine use

• Maynard ND et al Liver function and splanchnic
  ischemia in critically ill patients Chest 1997
• 111180-7 -
• Meier Hellmann A et al The effects of low dose
  dopamine on splanchnic blood flow and oxygen
• uptake in patients with septic shock
  Intensive Care Med 1997 2331-7 -
• Neviere R et al The contrasting effects of
  dobutamine and dopamine on gastric mucosal
  perfusion in
• septic patients.Am J Respir Crit Care Med
  19961541684-8
• Marik PE and Mohedin M The contrasting effects
  of dopamine and norepinephrine on systemic and
• splanchnic oxygen utilisation in hyperdynamic
  sepsi JAMA 1994 272 1354-7

82
DOBUTAMINE
Dobutamine has been widely used to influence
systemic oxygen delivery (DO2) and to detect
systemic and regional pathological VO2/DO2
relationships. In patients with septic shock ,
dobutamine infusion increased regional blood flow
with concomitant increases in DO2 and ShvO2,
whereas VO2 remained unchanged, and endogenous
glucose production decreased. The effect of
dobutamine on splanchnic perfusion and metabolism
has been determined using intramucosal pHi or the
arterial gastric mucosal PCO2 gap. The effect of
dobutamine on the arterial gastric mucosal
PCO2gap might serve as a diagnostic tool to
reveal patients with splanchnic hypoperfusion.
Adding dobutamine to norepinephrine in volume
resuscitated patients increased CO and
concomitantly decreased the arterial gastric
mucosal PCO2 gap as a consequence of improved
gastric mucosal perfusion, but failed to show an
influence on hepatic metabolism as determined by
indocyanine green elimination. Compared with
epinephrine alone, the use of dobutamine together
with norepinephrine may be equally effective in
maintaining hemodynamic stability in septic
patients without deteriorating parameters of
systemic and regional metabolism
Schaffartzik W et al Intensive Care Med 2000
261740-6 - De Backer D Intensive Care Med
2000 26 1719-22 - Reinelt H et al
Anesthesiology 1997 86818-24 - Levy B et al
Crit Care Med 1997 251649-54 - Levy B et al
Intensive Care Med 1999 25942-8 Creteur J
et al Am J Respir Crit Care Med 1999 160 839-45
- Joly LM et al Am J Respir Crit Care Med
1999 1601983-6 - Ensinger H et al
Anesthesiology 1999 911587-95
83
Metabolic consequences of sepsis.Metab
olic support during sepsis

• Stress and critical illness are associated with
  hypermetabolism characterized by insulin
  resistance resulting from increased counter
  regulatory hormone concentrations
• Sepsis aggravates this metabolic stress due to
  cytokine release
• Hypermetabolism is affiliated with increased
  oxygen demands from both mitochondrial oxygen
  utilization and oxygen radical formation,
  particularly in the liver
• The hallmark of this metabolic stress is
  hyperglycemia despite increased oxygen uptake
• Hyperlactatemia may occur without evidence of
  tissue ischemia and is mainly due to impaired
  lactate clearance

• Avoid hyperglycemia (blood glucose even
• Limit exogenous insulin treatment up to
  approximately 4-6 IUL to prevent hepatic
  steatosis
• Adapt calorific support andor consider replacing
  glucose by non glucose carbohydrates
• Use lipid emulsions to reduce CO2 load
  (triglyceride levels
• Avoid epinephrine and pure a-agonists

84
SEPSIS INDUCED HYPOTENSION
Flow diagram for guidance in management decision
in Septic Shock
250-1000ml boluses of crystalloids each
over 5-15 minutes basilar crackles on lung
auscultation or increase in pulseoximetry O2
saturation
Begin fluid resuscitation (crystalloid preferred)
NO
YES
Blood pressure acceptable
Establish re-evaluation interval
Consider CVP or PAC monitoring
CI 3.0
Continue fluid resuscitation until subtle
evidence of intravascular volume overload or
CVP 8-14 mmHg or PAOP 14-18mmHg or SBP 90mmHg
or MAP 60-65 mmHg
YES or unknown
NO
Vasopressor (norepinephrine Preferred)
targeting SBP 90mmHg or MAP 60-65mmHg
and Dobutamine targeting CI 3.0
Vasopressor (norepinephrine Preferred
targeting SBP 90 mmHg or MAP 60-65 mmHg
SBP 90mmHg or MAP 60-65 mmHg
YES
NO
SBP90mmHg or MAP 60-65 mmHg
YES
NO

• Consider CVP or PAC
• monitoring, if not already in place
• Add second vasopressor agent
• Consider vasopressin .01-.04 U/min

Establish re- evaluation interval

• Consider drotrecogin
• alpha therapy
• Consider steroid therapy

Establish re-evaluation interval and
regularly attempt to wean vasopressor to maintain
blood pressure target
85
Evidence evaluation from published (and
unpublished) studies can be classified using a
five level scoring system
NNT 10 , NNT 17, RCT in progress,
studies in progress