Role of Vassopressor

and Inotropic in Sepsis

Putu Agus Surya Panji
TEAM ICU
 Mechanisms contribute to vasodilatory shock in
inflammatory states

1.Excessive Nitrite Oxide (NO) production

2.Membrane hyperpolarization
3.Corticosteroid insufficiency
4.Low plasma level of vasopressin
5.Inactivation of catecholamines
 Septic Shock
Initial interventions:
•Reversing the underlying If Not Successful
cause
•Intravenous fluids.

Catecholamines (dopamine,
epinephrine and/or
norepinephrine) ! to
support systemic circulation.

6Wheeler AD, Turchiano J, Tobias JD. A case of refractory intraoperative hypotension treated with vasopressin infusion. J Clin Anesth. 2008;20(2):
139-142.
 Septic Shock
Cardiovascular Dysfunction ! 40 – 70 % mortality

Catecholamines : primary vasopressors

Vasopressin : an alternative agent

6Wheeler AD, Turchiano J, Tobias JD. A case of refractory intraoperative hypotension treated with vasopressin infusion. J Clin Anesth. 2008;20(2):
139-142.
 Vasodilatory Shock in Inflammatory States

cytokine-induced Nitric Oxide

⇧expression of inducible (NO) """
nitric oxide synthase A potent
(iNOS) endogenous
vasodilator

14D. W. Landry and J. A. Oliver, “Mechanisms of disease: the pathogenesis of vasodilatory shock,” The New England Journal of Medicine, vol. 345, no. 8,
pp. 588–595, 2001.
15B. Levy, S. Collin,N. Sennoun et al., “Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside,” Intensive Care Medicine, vol.

36, no. 12, pp. 2019–2029, 2010

 Refractory Shock

Inflammatory Response

Systemic
hypoperfusion

Inappropriate
vasodilatation + Persistent
hypotension
12J. S. Hochman, “Cardiogenic
shock complicating acutemyocardial infarction: expanding the paradigm,” Circulation, vol. 107, no. 24, pp. 2998–3002, 2003.
13C. Thiemermann, C. Szab´o, J. A. Mitchell, and
J. R. Vane, “Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in
hemorrhagic shock is mediated by nitric oxide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 1, pp.
267–271, 1993.
 Hypotension Refractory 

in Septic Shock

SEPTIC SHOCK PATIENTS

sop re ssi n Catec

u s v a
Endoge no adren holamine
levels # ergic
recep -1
α
tors #

Development of hypotension
refractory to standard
catecholamine vasopressors.
10LandryDW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25: 1279-82.
12Patel
BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002; 96:
576-82.
 Other mechanisms :
•Inappropriately low plasma levels of vasopressin,
oxidation, & inactivation of catecholamines

Altogether these mechanisms ! loss of vascular tone &

hyporesponsiveness to vasopressors which are the main
characteristics of
REFRACTORY SHOCK
14D. W. Landry and J. A. Oliver, “Mechanisms of disease: the pathogenesis of vasodilatory shock,” The New England Journal of Medicine, vol. 345, no. 8,
pp. 588–595, 2001.
15B. Levy, S. Collin,N. Sennoun et al., “Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside,” Intensive Care Medicine, vol.

36, no. 12, pp. 2019–2029, 2010

Surviving Sepsis Campaign
2012



“Guidelines for Management of Severe
Sepsis and Septic Shock”
HEMODYNAMIC SUPPORT
AND ADJUNCTIVE THERAPY
 H. VASOPRESSORS
1. We recommend that vasopressor therapy initially target
a MAP of 65 mmHg (grade 1C)
2. We recommend norepinephrine as the first-choice vasopressor (grade
1B)
3. We suggest epinephrine (added to and potentially substituted for
norepinephrine) when an additional is needed to maintain adequate
blood pressure (grade 2B)
4. Vasopressin (up to 0,03 U/min) can be added to norepinephrine with the
intent of raising MAP to target or decreasing norepinephrine dossage
(UG)
5. Low dose vasopressin is not recommended as the single initial
vasopressor for treatment of sepsis induced hypotension, and
vasopressin doses higher than 0,03-0,04 U/min should be reserved for
salvage therapy (failure to achieve an adequate MAP with other
agents( (UG)
 VASOPRESSORS cont
6. We suggest dopamine as an alternative vasopressor
agent to norepinephrine only in highly selected patients
(eg, patients with low risk of tachyarrhythmias and
absolute or relative bradycardia) (grade 2C)
7. Phenylephrine is not recommended in the treatment of
septic shock except in the following circumstances: (a)
norepinephrine is associated with serious arrhytmias, (b)
cardiac output is known to be high and blood pressure
persistently low, or (c) as salvage therapy when combined
inotrope/vasopressor drugs and low-dose vasopressin
have failed to achieve the MAP target (grade 1C)
8. Low dose dopamine should not be used for renal
protection (grade 1A)
9. All patients requiring vasopressors have an arterial
catheter placed as soon as practical is resources are
available (UG)
Apply vasopressors (for hypotension that
does not respond to initial fluid
resuscitation) to maintain a mean arterial
pressure (MAP)≥65 mm Hg
Gunakan dopamin atau epinefrin (adrenalin) pada pasien dengan
hipoperfusi jaringan yang menetap meski sudah mendapatkan
resusitasi cairan bebas (liberal) (LoE: C)

Pada pasien yang membutuhkan dopamin atau epinefrin

(adrenalin), ukur tekanan darah arteri dan denyut jantung dengan
sering (LoE: D)

Berikan hidrokortison intravena (hingga mencapai 300 mg/hari)

atau prednisolon (hingga 75 mg/hari) bagi pasien-pasien dewasa
yang membutuhkan peningkatan dosis epinefrin (adrenalin) atau
dopamin (LoE: B).

Pertimbangkan penggunaan dosis ekuivalen hidrokortison atau

prednisolon pada anak-anak dengan syok berat (LoE: C)
 1. High Dose Epinephrine
2. Norepinephrine
3. HighSYSTEMIC
HOW TO INCREASE Dose Dopamine
VASCULAR RESISTANCE ?
! Receptor alfa (α1 arteri)
So…which vasopressor is the
best?
 DOPAMINE
OR
NOREPINEPHRINE ?
 ADVANTAGE DISADVANTAGE

DOPAMINE ↑ CO ↑ Heart rate and can produce

Preferentially distribute blood flow to the splanchnic tachyarrhythmias.
and renal vasculature by its additional Dopamine may also suppress
dopaminergic properties
pituitary function, particularly
Dopamine may have beneficial effects on prolactin secretion
diaphragmatic function
↑ Resorption of edema fluid
NOREPINEPHRINE Norepinephrine is a more potent Concerns with the use of
vasoconstrictor, through its potent α-1 norepinephrine are the potential
stimulation with moderate β-1 and minimal risks of excessive
β-2 activity. vasoconstriction and decreased
organ perfusion.
Norepinephrine was found to be more effective
than dopamine in restoring hemodynamic However, the combination of
stability and even sometimes urine output in norepinephrine with dobutamine
patients with sepsis. may counteract this effect
Screat and Ccreat during
norepinephrine (NE)
therapy. * p 0.01
compared with
baseline values.
Urine Output (ml/hr)

Time after infusion (hr)

Effect of norepinephrine on

the outcome of septic shock 



Martin C, Viviand X, Leone M, et al.

Crit Care Med 2000; 28:2758-2765
Martin et al.
Findings:
NE had significantly lower
hospital mortality (62% vs
82%) p<.001
 Vasopressin and Sepsis

Septic Shock !
generalised vasodilation & myocardial depression

Patients with vasodilated septic Hypothesised :

shock: the pressor response to There is relative deficiency of
catecholamines may markedly endogenous vasopressin ! lack of
reduced vascular responsiveness

16Marik P, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilisation in hyperdynamic sepsis.
JAMA;1994:272:1354-1357
17Levy B, Bollaert P, Charpentier C et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism and

gastric tonometric variables in septic shock: a prospective, randomised study. Intens Care Med. 1997;23:282-287
18Chernow B, Roth B. Pharmacologic manipulation of the peripheral vasculature in shock. Clinical and experimental approaches. Circ Shock

1986;18:141-155
 Arginin-Vasopressin system

Vasopressin or its synthetic analogs (terlipressin) stimulate

the V1 receptor that is found on vascular smooth muscle
resulting in vasoconstriction

Several studies have also demonstrated its effectiveness at

restoring arterial blood pressure when the SNS and RAAS
have been blocked

7Boccara G, Ouattara A, Godet G, et al. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in
patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology. 2003;98(6):1338-1344.
 Vasopressin
-a peptide hormone
synthesized by the The primary role:
hypothalamus Regulate Its release into the
-stored in the vesicles serum osmolarity & bloodstream when
of of posterior pituitary maintain cardiovascular there is an arterial
gland. homeostasis hypotension &
hypovolemia.

Vasopressin has been implicated in the treatment of

circulatory arrest of septic shock

7Boccara G, Ouattara A, Godet G, et al. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in
patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology. 2003;98(6):1338-1344.
 Vasopressin

endogenous vasopressin
release is an important
vasoconstrictor mechanism In common with other stress
in shock states hormones (f.e
catecholamines), hypotension
stimulates vasopressin release
via activation of aortic &
carotid baroreceptors.

8Padfield PL, Brown JJ, Lever AF, Moron JJ, Robertson JIS. Blood pressure in acute and chronic vasopressin excess. N Eng J Med. 1981;304:1067-1070
9Linder KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Georgieff M. Stress hormone response during and after cardiopulmonary
resuscitation. Anesthesiology 1992; 77:662-668
 Landry et al :
Patients in vasodilatory septic shock are deficient in
vasopressin because of a defect in the baroreflex-mediated
secretion of the hormone.

10Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25: 1279-82.
11Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25: 1279-82
Control of Arteriolar Smooth Muscle

Vasopressin
Site of action of vasopressin !
On Vasopressin receptor
V1 ! located on arterial smooth muscle
V2 ! are found in renal tubules

Kee VR, hemodynamic Pharmacology of Intravenous

vasopressor. Crit Care Nurse 2003, 23:79-82
Figure 19.14
 Vasopressin 0,03 unit/ minute can be
added to NE ! with intent to ↑ MAP
or decreasing NE dosage
 I. INOTROPIC THERAPY

1. A trial of dobutamin infusion up to 20

micrograms/kg/min be administered
or added to vasopressor (if in use) in
the presence of (a) myocardial
dysfunction as suggested by elevated
cardiac filling pressure and low
cardiac output, or (b) ongoing signs
of hypoperfusion, despite achieving
adequate intravascular volume and
adequate MAP (grade 1C)
2. Not using a strategy to increase
cardiac index to predetermined
supranormal levels (grade 1B)
 J. CORTICOSTEROIDS
1. Not using intravenous hydrocortisone to treat adult septic
shock patients is adequate fluid resuscitation and
vasopressor therapy are able to restore hemodynamic
stability (see goals for intial resuscitation). In case this is
not achieveable, we suggest intravenous hydrocortisone
alone at a dose of 200 mg per day (grade 2C)
2. Not using the ACTH Stimulation test to identify adults with
septic shock who should receive hydrocortisone (grade 2B)
3. In treated patients hydrocortisone tapered when
vasopressors are no longer required (grade 2D)
4. Corticosteroids not be administered for the treatment of
sepsis in the absence of shock (grade 1D)
5. When hydrocortisone is given, use continuous flow (grade
2D)
 CONCLUSION
• The optimal adrenergic support in shock is controversial.
Dopamine and norepinephrine are the most commonly used
agents to restore tissue perfusion pressure in these conditions.
• Timing of vasopressor dan inotropik treatment on septic shock
patients following EGDT protocol or base on invasive / non
invasive hemodinamic monitoring.
• The choice of vasopressor for septic shock patients is better
Norepinephrine compare with Dopamine and renal dose
dopamine is controversial
• Effects of Norepinephrine can be balanced with use of inodilator
(dobutamine)
Matur Suksma