Adrenergic Agents

Home , Dobutamine, Midodrine, Relcovaptan, Selepressin, Vasotocin

(atrium) Increased contraction Increased heart rate b Vasodilation (ventricle) a Vasoconstriction EFFECTS OF ADRENERGIC AGENTS ON ARTERIAL PRESSURE

Arterial pressure = cardiac output x vascular tone a ADRENERGIC AGENTS

THE GOOD THE BAD

Increased blood flow / DO2 Vasodilation (systemic & pulmonary) b Increased spanchnic perfusion Tachycardia Isoproterenol Increased myocardial O2 demand (ischemia) Arterial hypotension

Increased blood pressure Increased brain perfusion (CPP) a Increased tissue perfusion pressure Peripheral vasoconstriction Phenylephrine Decreased cardiac output / DO2 Decreased renal / splanchnic perfusion b Adrenergic agents a

PRELOAD HEART RATE

CONTRACTILITY AFTERLOAD ADRENERGIC AGENTS

Isoproterenol Dopexamine b Dobutamine

Phenylephrine a DOBUTAMINE increases cardiac output has little influence on pressures (decreases vascular resistances) Systemic Arterial pressure - CVP Vascular = Resistance Cardiac output

A decrease in arterial pressure under dobutamine administration suggests some degree of hypovolemia Avoid early dobutamine administration in hypotensive patients (norepinephrine may be safer initially) ADRENERGIC AGENTS inotropes Isoproterenol Dopexamine b Dobutamine Dopamine Epinephrine Norepinephrine Phenylephrine a vasopressors ADRENERGIC AGENTS

+++

+ PRESSURE 0 norepinephrine dobutamine - (noradrenaline) dopamine isoproterenol epinephrine +++ phenylephrine (adrenaline) HEART RATE + FLOW 0 a b - VASOACTIVE DRUGS IN THE ICU

WHAT ABOUT REGIONAL BLOOD FLOW ? EFFECTS OF ISOPROTERENOL ON HEPATIC ARTERY BLOOD FLOW

After RICHARDSON et al. mL/min.100g Br J Pharmac 57:581;1976 100 80 60 40 20 0 BASELINE ISOPROTERENOL 0.02-0.05 mcg/min REGIONAL EFFECTS OF DOBUTAMINE IN ENDOTOXIC SHOCK

D De Backer, H Zhang, P Manikis et JL Vincent J Surg Res 65: 93-100, 1996

21 pentobarbital-anesthetized dogs endotoxin 2 mg/kg + saline infusion

- 7 control - 7 dobutamine 5 mcg/kg/min - 7 dobutamine 10 mcg/kg/min REGIONAL EFFECTS OF DOBUTAMINE IN ENDOTOXIC SHOCK mL/min.kg D De Backer, H Zhang, P Manikis et JL Vincent J Surg Res 65: 93-100, 1996 600 CARDIAC INDEX *+ + 500 * *+ * DOBU 5 400 + * DOBU 10 *+ *+ * 300

200 * CONTROL ** 100 **

BASE ENDO FLUIDS FLUIDS + INTERVENTION *p < 0.05 vs FLUIDS + p < 0.05 vs CTRL MEAN ± SEM REGIONAL EFFECTS OF DOBUTAMINE IN ENDOTOXIC SHOCK D De Backer, H Zhang, P Manikis et JL Vincent mL/min J Surg Res 65: 93-100, 1996 250 LIVER DO2 + + 200 * * * *+ DOBU 5 150 * + DOBU 10 100 + CONTROL 50 * ** 0

BASE ENDO FLUIDS FLUIDS + INTERVENTION * p < 0.05 vs FLUIDS + p < 0.05 vs CTRL MEAN ± SEM DOBUTAMINE IMPROVES GASTROINTESTINAL MUCOSAL BLOOD FLOW IN A PORCINE MODEL OF ENDOTOXIC SHOCK

Neviere et al, Crit Care Med 25: 1271-7, 1997

Effects of Norepinephrine on gastric mucosa Norepinephrine + dobutamine Epinephrine in patients with septic shock Duranteau et al, Crit Care Med 27: 893-900, 1999

CARDIAC INDEX, L/min.M² GMP (laser Doppler, U) 6 500

5 400

4 300 3 200 2

1 100

0 0 NE EPI NE EPI N = 12 NE+Dobu NE+Dobu MAP 74 mmHg ADRENERGIC AGENTS

If the primary aim Is to increase blood flow Isoproterenol Dopexamine b Dobutamine Dopamine Epinephrine Norepinephrine Phenylephrine a If the primary aim Is to increase pressure The history of shock therapy

DOPAMINE IN THE TREATMENT OF HYPOTENSION AND SHOCK

Mac Cannel et al N Engl J Med 275: 1389-98, 1966

ACUTE HEMODYNAMIC EFFECTS OF DOPAMINE IN PATIENTS WITH SHOCK Loeb NS et al Circulation 44: 163-73, 1971 DOPAMINE

increases urine and sodium output - in healthy humans McDonald et al, J Clin Invest 43: 1116-24, 1964 - in patients with cardiac failure Goldberg et al, N Engl J Med 269: 1060-4, 1963 DOPAMINE dopaminergic

b a

0 5 10 15 20 mcg/kg/min Blood flow distribution

Dopaminergic receptors = vasodilation

Brain

Skin Muscle RV LV

Heart Gut Kidney more dopaminergic receptors Renal vasodilatory action of dopamine in patients with heart failure Elkayam et al, Circulation 117: 200-205, 2008

% change from baseline Renal blood flow 70

50 40 Cardiac output 30

0 0 1 2 3 4 5 6 7 8 9 10 11 Dose, mcg/kg/min

Intravascular Doppler ? RENAL DOSES OF DOPAMINE ? RENAL DOSE DOPAMINE: FACT AND FICTION Ann Intern Med 115: 153, 1991 DOPAMINE AND THE KIDNEY: TEN YEARS ON Clin Sci 84: 357, 1993 RENAL EFFECTS OF DOPAMINE: CAN OUR DREAM EVER COME TRUE? Crit Care Med 22: 5, 1994 RENAL-DOSE DOPAMINE: A SIREN SONG? Lancet 344: 7, 1994 LOW-DOSE DOPAMINE: WILL THERE EVER BE A SCIENTIFIC RATIONALE ? Br J Anaesth 78: 350, 1997 RENAL DOSE DOPAMINE: LONG ON CONJECTURE, SHORT ON FACT Crit Care Med 28: 1657, 2000 RENAL SUPPORT IN CRITICALLY ILL PATIENTS: LOW DOSE DOPAMINE or LOW DOSE DOBUTAMINE ? Duke et al, Crit Care Med 22: 1919-25, 1994 Creatinine clearance, mL/min ADRENERGIC AGENTS EFFECTS OF ADRENERGIC AGENTS ON HEPATO-SPLANCHNIC CIRCULATION IN SEPTIC PATIENTS D De Backer, J Creteur, JL Vincent ShO2 Crit Care Med 31: 1659-67, 2003

dopamine low doses epi low doses norepi high doses epi high doses norepi ADRENERGIC AGENTS

CARDIAC INDEX L/min.m² 5,5

5 +++ HIGH DOSES 4,5 +++ 4 ***

3,5

3 LOW DOSES 2,5 DOPA NOREPI EPI

Crit Care Med 31: 1659-67, 2003 ADRENERGIC AGENTS

FRACTIONAL SPLANCHNIC BLOOD FLOW % 30

25 LOW DOSES

++ 10 HIGH DOSES

5 DOPA NOREPI EPI Crit Care Med 31: 1659-67, 2003 VASOPRESSOR AGENTS

DOPAMINE The good The bad

Increased blood flow Increased renal blood flow Risk of arrhythmias Increased splanchnic blood flow Immunosuppression Increased edema clearance (prolactin release) Improved muscle function

NOREPINEPHRINE

Strong vasopressor effect Risk of vasoconstriction SOAP Vasoactive drugs in circulatory shock

ICU mortality

All shock Septic shock (N =1058) (N = 462)

Dopamine 42.9 % 52.5 %

No dopamine 35.7 % 44.1 % p = 0.02 p = 0.08

Crit Care Med 34: 589-97, 2006 ICU mortality SOAP (multivariable analysis)

OR (95 % C.I.) p Mean SOFA score 1.52 (1.39 - 1.67) < 0.001 Mean fluid balance 1.39 (1.19 - 1.63) < 0.001 Age 1.03 (1.01 - 1.04) 0.001 Cancer 3.54 (1.72 - 7.30) 0.001 Dopamine administration 2.05 (1.25 - 3.37) 0.005 Medical admission 1.83 (1.12 - 2.99) 0.016

septic shock CritCrit Care Care Med Med 34:34: 589589-97,-97, 20062006

Dopamine vs norepinephrine in shock states De Backer et al, N Engl J Med 362: 779-89, 2010

30 Norepinephrine better

10 No difference

Z 0 50 100 150 200 -10

-20

-30 Dopamine better

-40 V

Sequential Trial (1600 patients) Dopamine vs norepinephrine in shock states De Backer et al, N Engl J Med 362: 779-89, 2010 RISK OF DEATH – NOREPINEPHRINE vs. DOPAMINE Conclusions: In a large population-based sample of patients with septic shock in the US, use of dopamine as initial vasopressor was associated with increased mortality among multiple clinical subgroups.

VASOACTIVE DRUGS IN THE ICU

Abandon dopamine Dopamine vs norepinephrine in shock states De Backer et al, N Engl J Med 362: 779-89, 2010

Early termination (arrhythmia) No of patients 50 5% 45 40 P < 0.001 35 30 25 20 15 1% 10 5 0

DOPAMINEAll centers NOREPINEPHRINE n = 1677 ADRENERGIC AGENTS

Isoproterenol Dopexamine b Dobutamine ? Dopamine Epinephrine Norepinephrine Phenylephrine a ADRENERGIC AGENTS EFFECTS OF ADRENERGIC AGENTS ON HEPATO-SPLANCHNIC CIRCULATION IN SEPTIC PATIENTS D De Backer, J Creteur, JL Vincent ShO2 Crit Care Med 31: 1659-67, 2003

dopamine low doses epi low doses norepi high doses epi high doses norepi ADRENERGIC AGENTS CARDIAC INDEX L/min.m² 5,5

5 +++ HIGH DOSES 4,5 +++ 4 ***

3,5

3 LOW DOSES 2,5 DOPA NOREPI EPI

Crit Care Med 31: 1659-67, 2003 ADRENERGIC AGENTS FRACTIONAL SPLANCHNIC BLOOD FLOW % 30

25 LOW DOSES

++ 10 HIGH DOSES

5 DOPA NOREPI EPI

Crit Care Med 31: 1659-67, 2003 EPINEPHRINE Epinephrine vs norepinephrine + dobutamine? Annane et al, Lancet 370: 676- 84, 2007

Norepinephrine Epinephrine + (N = 161) dobutamine (N = 169) SOFA score 12 12 Source = lung (%) 46 48 Mech. ventilation (%) 95 94 Blood lactate (mEq/L) 4.0 4.6 30 day mortality (%) 40.0 34.3 ICU mortality (%) 46.6 44.4 Hospital mortality (%) 52.2 48.5 JLV/USI 5/97

The CATS study 2016

Propensity-score matched 2018

Higher lactate levels How I treat shock

EPINEPHRINE SHOULD BE AVOIDED

Tachyarrhythmias Reduced hepato-splanchnic blood flow Increased blood lactate levels 27 835 patients with septic shock in 26 hospitals

Increased hospital mortality 35.9% vs 39.6%, p=0.03

"The decreased use of norepinephrine during periods of shortage was associated with an increase in use of phenylephrine." BASELINE SHORTAGE Nepi

Phenylephrine

Dopa Vasopressin Adré VASOACTIVE DRUGS IN THE ICU

Current recommendations

1- Norepinephrine is the vasopressor agent of choice Norepinephrine Advantages ▪ Natural agent ▪ Short half-life ▪ Easy titration ▪ Wide experience Potential disadvantages ▪ Adverse effects on regional blood flow ▪ Immunomodulatory effects ▪ Increased catabolism

VASOACTIVE AGENTS IN SEPTIC SHOCK

Dopamine Epinephrine Dopexamine Milrinone Prostaglandin E1 Levosimendan Angiotensin Nitroglycerin Metaraminol Pentoxifyllin Mephentermine Calcium Dobutamine Vasopressin PDE inhibitors Norepinephrine Hydralazine N-acetylcysteine Magnesium Terlipressin Phenylephrine Prostacyclin L-NMMA Calcium antagonists Enoximone Isoproterenol IV Vasopressor IV Vasopressor Only Variables + Midodrine p (n= 140) (n= 135)

IV vasopressor 3.8 2.9 < .001 duration, days

IV vasopressor 21 (15) 7 (5.2) .007 reinstitution, No. (%)

Change in creatinine, 0.8 ± 1.6 0.5 ± 1.3 .048 mg/dL

ICU LOS, 9.4 ± 6.7 7.5 ± 5.9 .017 days

ICU mortality 26 (18.6%) 15 (11.1%) .08 Gutron 2018 Activation of the renin–angiotensin–aldosterone system (RAAS)

Angiotensinogen

renin

Angiotensin I Endothelial cell dysfunction ACE Adrenergic ACE inhibitors Angiotensin II Vasopressin

a V1 AT 1 AT 2

Aldosterone Giapreza VASOPRESSIN

NOT JUST ANOTHER VASOPRESSOR AGENT….

Dopamine Norepinephrine Phenylephrine Metaraminol Mephentermine (LNMMA) Vasopressin …. ENDOCRINE SUPPORT

✓ Corticosteroids ✓ Glucose control ✓ Vasopressin MANAGEMENT OF SEPSIS

HEMODYNAMIC INFECTION STABILIZATION CONTROL MODULATION OF THE SEPSIS RESPONSE

IV fluids Vasoactive Antibiotics Source agents APC control Gamma-globulins ? Vasopressin ? Hydrocortisone ? Extracorporeal systems ? VASOPRESSIN

Use in variceal bleeding

Use in Vasopressor hepato-renal effects Antidiuretic syndrome effects Use in CPR Use in distributive shock

1900 2000 VASOPRESSIN Vasopressin deficiency contributes to the vasodilation of septic shock Landry et al, Circulation 95: 1122-5, 1997 vasopressin, pg/mL 25

10 relative 5 vasopressin Normal deficiency 0 SEPTIC CARDIOGENIC SHOCK VASOPRESSIN

POTENTIAL BENEFICIAL EFFECTS Increased vascular tone Increased urine output Less edema formation

POTENTIAL SIDE EFFECTS Excessive vasoconstriction / Decreased organ perfusion Hepato-splanchnic ischemia / Altered liver tests Myocardial ischemia / Arrhythmias Cutaneous lesions Pulmonary hypertension Platelet aggregation VASOPRESSIN SHEEP EXPERIMENTS sheep anesthetized with fentanyl-midazolam cecal ligation and perforation IV saline to keep PAOP at baseline levels MAP < 75 mmHg

control

norepinephrine

norepinephrine + vasopressin 0.01 U/min

vasopressin 0.02 U/min

Time, hours Sun et al, Am J Respir Crit Care Med 168: 481-6, 2003 VASOPRESSIN

Mean arterial pressure

140 CL VP 120 *° *° *° *° *° NE VPNE 100

80 * VPNE vs CL

MAP (mmHg) MAP 60 ° VP vs CL $ NE vs CL 40 + VPNE vs NE $ $ $ $ #+ #+ # VP vs NE 20 01 56 1011 1516 2021 2526 30 31 TIME,Time hours (h) Cumulative Urine VASOPRESSIN 6000 Output Cumulative fluid 10000 4000 Infusion 7500 2000 5000

0 2500 1 6 11Time16 (h)21 26 31 0 Time (h) 1 6 11 16 21 26 31 Sun et al, Am J Respir Crit Care Med 168: 481, 2003 9000mL Fluid Balance

6000

3000

0 1 6 11 Time16 (h)21 26 31 Sun et al, Am J Respir Crit Care Med 168: 481, 2003 VASOPRESSIN On this subacute model of septic shock secondary to peritonitis in sheep vasopressin infusion (limited doses) alone or in combination with norepinephrine results in - greater arterial pressure but no change in cardiac output - lower mesenteric blood flow - lower blood lactate concentrations - greater urine output and less edema formation - prolonged survival

Sun et al, Am J Respir Crit Care Med 168: 481-6, 2003 VASOPRESSIN RECEPTORS PHARMACOLOGIC INTERVENTIONS

Agonists Antagonists Non-selective vasopressin conivaptan

Selective V1a Phe2-85 Orn8-Vasotocin relcovaptan (POV) OPC 21268 selepressin

V2 desmopressin satavaptan tolvaptan mozavaptan lixivaptan Phe2-85 Orn8-Vasotocin (POV) Selective V1a agonist

POV = Phe2-Orn -Vasotocin

Selepressin Control

Vasopressin

Selepressin / sham Sham Selepressin Vasopressin Control Late intervention Early intervention

Selepressin Selepressin

Selepressin Late intervention Early intervention

Selepressin

Selepressin Late intervention Early intervention

Selepressin

Selepressin Interpretation

Early selepressin administration may protect the microvasculature and limit edema formation 2017 Increased the number of days alive and free of mechanical ventilation

Proportion of DAF ventilation by Day 7 *

Mean, 60% confidence limits *: p=0.01 vs. placebo Conclusions Selepressin infusion in septic shock patients • dose-dependently reduced NE requirements • appeared to shorten the duration of shock • decreased cumulative fluid balance and relative fluid overload • appeared to decrease the duration of mechanical ventilation • appeared to be safe and well tolerated (at a dose up to 2.5 ng/kg/min) Selepressin for septic shock Phase II / III Adaptive design Sepsis-ACT

Type of study Placebo-controlled, double-blinded RCT

Population Hemodynamic Patients with septic shock pattern?

Primary end-point 30 day mechanical ventilation & vasopressor free days vasopressin

norepinephrine VASOPRESSIN to maintain blood flow VASOPRESSIN + DOBUTAMINE - Martikainen et al, Acta Anaesth Scand 48: 935-43, 2004 - Albanese et al, Shock 33: 1897-902, 2005 - Ertmer et al, Crit Care 10: R144, 2006

VASOPRESSIN + LEVOSIMENDAN - Rehberg, Ertmer, Vincent et al, Crit Care Med 38: 2016-23, 2010 - Yang JJ, Crit Care Med 39: 921, 2011 2019

N=868 Vasopressin ? ? ? Relatively late to limit the doses of norepinephrine ? Early ? for endothelial protection (to limit edema formation) ? ? ? ? VASOPRESSIN

POTENTIAL BENEFICIAL EFFECTS Increased vascular tone Increased urine output ? Less edema formation

VASOPRESSIN

POTENTIAL BENEFICIAL EFFECTS Increased vascular tone Increased urine output Less edema formation

0.10 U/min

No ! 0.05 U/min Maybe ?

Increased vascular tone Decreased cardiac output Increased urine output Excessive vasoconstriction Less edema formation Impaired hepato-splanchnic perfusion Reduced coronary blood flow Pulmonary hypertension HYPERKINETIC STATE How I treat shock

NO ROUTINE ADMINISTRATION OF VASOPRESSIN

Only in SOME cases of distributive shock with a hyperdynamic state Angiotensin II

ATHOS-3

efficacysafety

mortality There is no evidence of a reduction in mortality....

BUT Any POSITIVE RCT? (showing a reduction in mortality) 2019

Avoiding iatrogenicity

2018

Crit Care Med survival

angiotensin II

placebo

P = 0.018 2019

This variable responsiveness to vasopressors is similar to the clinical approach of anti-microbial sensitivity.

(...) propose the concept of “broad spectrum vasopressors” wherein patients with septic shock are started on multiple vasopressors with a different mechanism of action simultaneously while the vasopressor sensitivity is assessed.

Once the vasopressor sensitivities are assessed, then the vasopressors are ‘deescalated’ accordingly.

We believe that this concept may offer a new approach to the treatment of septic shock. VASOPLEGIA

Is not just

HYPOTENSION NOS inhibitor 546C88 in patients with septic shock Lopez et al, Crit Care Med 32: 21-30, 2004

70 TREATMENT PLACEBO 59 60 52 49 50 36 40 27 30 15 MORTALITY, % 20

0 Day 3 Day 14 Day 28

N = 797 patients NOS inhibitor 546C88 in patients with septic shock Lopez et al, Crit Care Med 32: 21-30, 2004

PLACEBO

% Survivors% 546C88 2019 MYOCARDIAL DEPRESSION IN SEPTIC SHOCK Poor response to fluid challenge

Increase in No increase cardiac filling pressures in cardiac output

Edema No improvement formation in tissue perfusion

Low SvO2 Poor myocardial function (without anemia) (echocardiography) DOBUTAMINE ADMINISTRATION IN SEPTIC SHOCK

Monitoring splanchnic perfusion : The dobutamine test Creteur et al, Am J Respir Crit Care Med 160: 839-45, 1999

(%) 2 20

10 DSvhO 0 p < 0.01 -10 D O B test D O B test + -

(DOB test + : PCO2gap decrease of at least 5mmHg) Monitoring splanchnic perfusion : The dobutamine test Creteur et al, Am J Respir Crit Care Med 160: 839-45, 1999

30 30 DOB test + DOB test -

20 20

10 10 PCO2gap (mmHg) PCO2gap (mmHg) N = 13 N = 23 0 0 DOB DOB DOB DOB 0 10 0 10 SvO2

75 % Vasopressors (primarily) 70 %

65 % Fluids 60 % Transfusion 55 % Dobutamine Early Goal-Directed Therapy EGDT

the ProCESS TRIAL ScvO2 71%

the ARISE TRIAL ScvO2 73%

the ProMISe TRIAL ScvO2 70% Rivers et al ScvO2 49 % In the recent trials Less severely ill Higher initial ScvO2 (already in the target range) Improved early resuscitation? Less commonly treated by mech. ventilation Lower mortality rate Not all needed ICU admission Higher patient selection Enrolment primarily during office hours (but greater benefit outside these hours?) 2018 SURVIVING SEPSIS CAMPAIGN

2016

VASOACTIVE AGENTS

We suggest using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents. Grade 2C

Crit Care Med 2017 Intensive Care Med 2017 THE CHALLENGES

Fluid challenge Vasopressor challenge

Dobutamine challenge

WHAT ABOUT THE MICROCIRCULATION? CARDIOVASCULAR ALTERATIONS IN SEPSIS

High SvO2 High CO

Endothelial Circulating dysfunction vasoactive Vasodilation substances

Microvascular Decreased cell obstruction deformability The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, Vincent JL. Crit Care Med 34:403-8, 2006

22 patients with septic shock (less than 48 h duration)

Dobutamine 5 mcg/kg/min

Orthogonal Polarization Spectral (OPS) imaging technique The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, Vincent JL. Crit Care Med 34:403-8, 2006

The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, Vincent JL. Crit Care Med 34:403-8, 2006

K b1 receptor Na Ca b adrenergic agents

Adenylate cyclase Ca Digoxin

ATP Ca cAMP Phosphodiesterase

L-type Protein PDE3 channel kinase A inhibitors 5’AMP

Actin-myosin PDE inhibitors

adenylcyclase cAMP phosphodiesterase amrinone milrinone enoximone PDE inhibitors

Addition of enoximone to adrenergic agents in the management of severe heart failure Vincent et al, Crit Care Med 20: 1102-6, 1992

enoximone baseline 0.125 mg/kg

CI, L/min.M² 1.58 1.84 MAP, mmHg 74 76 K b1 receptor Na Ca b adrenergic agents

Adenylate cyclase Digoxin

ATP Ca cAMP Phosphodiesterase PDE3 L-type Protein channel kinase A inhibitors 5’AMP Levosimendan Ca

Actin-myosin K b1 receptor Na Ca b adrenergic agents

Adenylate cyclase Ca Digoxin

ATP Ca cAMP Phosphodiesterase

L-type Protein PDE3 channel kinase A inhibitors 5’AMP

Actin-myosin

Levosimendan Myofilament calcium sensitizer ( + some PDE inhibition ) Activates K+ATP channel in the membranes and cardiac mitochondria

Does NOT increase cAMP levels Does NOT increase intracellular calcium Decreases vascular tone Consequences Limited increases in MVO2 No effect on diastolic relaxation Vasodilation Some increase in heart rate (baroreflex) Cardioprotection Hemodynamic effects of levosimendan in healthy subjects Doorduin et al

Baseline PLACEBO Baseline LEVOSIMENDAN LEVOSIMENDAN

LEVOSIMENDAN

levosimendan placebo Mean SOFA score 6.68 vs. 6.06 Mortality 34.5% vs. 30.9%

• lower likelihood of successful weaning from mechanical ventilation • higher risk of supraventricular tachyarrhythmia Randomized, cross-over, double-blinded study, healthy volunteers

LEVOSIMENDAN

PLACEBO target = 40% of Pdimax levosimendan decreased neural activation (increased neuromechanical efficiency of the diaphragm) transdiaphragmatic twitch pressure 2017

Conclusions Current evidence is not sufficient to support levosimendan as superior to dobutamine or as an optimal adjunct in severe sepsis and septic shock. HEMODYNAMIC EFFECTS OF VASOACTIVE AGENTS Resistance (vascular tone)

vasopressors ARTERIAL PRESSURE vasodilators

inotropes

CARDIAC OUTPUT VASOACTIVE DRUGS IN THE ICU Current recommendations

1- Norepinephrine is the vasopressor agent of choice

2- Optimal blood pressure level must be individualized It is naive to select one blood pressure level for all individuals 3- Early vasopressor therapy may be necessary to avoid ANY hypotension 4- Vasopressor therapy should not mask hypovolemia 5- Inotropic therapy may be required to optimise blood flow

INDIVIDUALIZE therapy NO ARTERIAL HYPOTENSION

CARDIAC b-BLOCKING DIURETICS INDEX AGENTS ?? NITRATES

FLUID VASODILATORS CHALLENGE INOTROPES

PAOP ARTERIAL HYPOTENSION

CARDIAC FLUID VASOPRESSORS INDEX CHALLENGE

FLUID VASOPRESSORS CHALLENGE INOTROPES

PAOP Increased Increased vascular resistance PRESSURE cardiac work

Volume loading Vasoconstriction Adrenergic stimulation Exercice / pain

FLOW Myocardial failure Cirrhosis Hypovolemia Vasodilation Tamponade / pulm emb. Distributive shock

Decreased Decreased cardiac work vascular resistance Increased Increased vascular resistance PRESSURE cardiac work

PHENYLEPHRINE NOREPINEPHRINE

ANGIOTENSIN EPINEPHRINE VASOPRESSIN DOPAMINE NOS INHIBITOR DOBUTAMINE

FLOW FUROSEMIDE ISOPROTERENOL BETA-BLOCKING AGENTS VASODILATORS

Decreased Decreased cardiac work vascular resistance