1. From
Evidence-Based
Practice of Critical Care
Chapter 31
Grainne McDermott
Patrick J. Neligan

2. 1. SIRS – Condition characterized by signs of
systemic inflammation
2. Sepsis – SIRS because of an infection
3. Severe sepsis – Sepsis + one or more vital
organ dysfunction
4. Septic shock – Severe sepsis +
hypotension refractory to volume infusion
5. MODS – Abnormal fn in > one vital organ
6. MOF – Failure of > one vital organ

3. 1. Hemodynamic Derangement in Sepsis
2. Vasopressor Therapy in Sepsis
3. Individual Vasopressors
4. Author’s Recommendations

4. Early Sepsis
- clinically analogous to hypovolemic shock
1. Hypovolemia
2. Lactic acidosis
3. Increased oxygen extraction (Reduced
SvO₂)
GOAL-DIRECTED VOLUME RESUSCITATION
(E.G.D.T.- Surviving Sepsis Campaign)

5. Late-stage septic shock
1. Vasoplegia
- loss of sympathetic tone, increased NO
production, acute depletion of Vasopressin
2. Reduced Stroke Volume
- Circulating myocardial depressant factor
- biventricular failure, decreased
EF, myocardial edema & ischemia
- CO maintained by a increased HR

6. Late-stage septic shock
3. Microcirculatory failure
- dysregulation & maldistribution of blood
flow, AV shunting, capillary leak
4. Mitochondrial dysfunction
- tissue oxygen extraction is impaired
(Increased SvO₂ & serum lactate inspite of
adequate oxygen delivery to tissues)

7.  Renal injury
 Hepatic dysfunction
 Delirium
 ARDS
MULTI-ORGAN FAILURE

8.  Indication: Hypotension, unresponsive to
fluid therapy.
 The ideal pressor agent would restore
blood pressure while maintaining cardiac
output and preferentially perfuse the
midline structures of the body
(brain, heart, splanchnic organs, and
kidneys).

9.  Noradrenaline
 Dopamine
 Dobutamine
 Adrenaline
 Phenylephrine
 Vasopressin
 Others
like Milrinone, Enoximone &
Levosimendan

11. CARDIOVASCULAR • Tachyarrhythmias
• Ischemia: digital, cardiac, and mesenteric
• Thrombogenic effect
• Increased myocardial work yet decreased metabolic efficiency
• Increased oxygen expenditure
• Thermogenic effects
IMMUNOLOGIC • Cellular injury
• Increased generation of reactive oxygen species
• Increased cytokine generation; this later declines
• Reduced antioxidative defenses
• Increased superoxide radical production
• Promotion of bacterial growth
• Biofilm formation
• Monocyte dysfunction
• Increased risk for nosocomial infection
SPLANCHNIC HYPOPERFUSION • Mesenteric ischemia
• Ileus
• Malabsorption
• Stress ulceration
• Deranged liver function
METABOLIC (PARTICULARLY EPINEPHRINE) • Aerobic glycolysis, lactic acidosis
• Insulin resistance and hyperglycemia
• Enhanced lipolysis leading to hepatic steatosis
DOPAMINE SPECIFIC • Interference with pituitary function, particularly thyroid
• Dysregulation of prolactin metabolism and immunosuppression

12.  Presently the agent of choice in sepsis
 α1- and β1-adrenergic receptor agonist
 Increases organ perfusion by increasing
vascular tone & MAP
 2-12 μg/min upto 30 μg/min IV
 Does not increase heart rate
 Vs. Dopamine, studies have shown better
improvements in Oxygen delivery, perfusion &
consumption with Noradrenaline.

13.  Potent β1-adrenergic receptor agonist
 Increases Oxygen delivery and consumption by
increasing myocardial contractility, SV, CO
 2-20 μg/kg/min upto 40 μg/kg/min IV
 Less increase in HR than Dopamine
 Vs Dopamine & Adrenaline, better splanchnic
blood flow & reduction in lactate production

14.  α1- and β1-adrenergic receptor agonist
 Mixed inotrope & vasoconstrictor
 1-50 μg/kg/min IV
 Potent chronotrope & more arrhythmogenic
 Potent diuretic (neither saves nor damages the
kidneys)
 Complex neuroendocrine & immunosuppressive
effects

15. SOAP study - The authors divided patients
into those who received dopamine alone or
in combination, and those who never
received dopamine. The dopamine group
had higher ICU (42.9% versus 35.7%;
P = .02) and hospital (49.9% versus
41.7%; P = .01) mortality rates.

16. A syndrome of dopamine-resistant septic
shock (DRSS) has been
described, defined as MAP less than
70mm Hg despite administration of
Dopamine @ 20μg/kg per minute.
In one study, the incidence of DRSS was
60%, and those patients had a mortality
rate of 78%, compared with 16% in the
dopamine-sensitive group.

17.  β1-,β2-, and α1-adrenergic receptor agonist
 The increase of MAP in sepsis is mainly from
an increase in cardiac output (SV)
 2-20 μg/min IV
 Drawbacks (1) it increases myocardial oxygen
demand, (2) it increases serum glucose and
lactate, (3) appears to have adverse effects
on splanchnic blood flow, redirecting blood
peripherally

18.  Pure α1-adrenergic receptor agonist
 In sepsis, less effective vasoconstrictor
than noradrenaline or adrenaline.
 40-60 μg/min upto 180 μg/min IV
 Least likely to cause tachycardia
 Compared to NA, it reduces splanchnic
blood flow, O₂ delivery & lactate uptake

19.  Hormone that is released in response to
decreased intravascular volume and
increased plasma osmolality.
 Directly acts on V1 receptors
 Causes vasoconstriction & also increases
the responsiveness of the vasculature to
catecholamines
 0.01- 0.04 units/min IV

20. Vasopressin has emerged as an additive
vasoconstrictor in septic patients who have
become resistant to catecholamines. There
appears to be a quantitative deficiency of
this hormone in sepsis, and admin of
vasopressin in addition to NA increases
splanchnic blood flow and urinary output.

21.  VASST trial -Vasopressin+steroids, when
compared with NA, was associated with
significantly decreased mortality (35.9% vs
44.7%). Conversely, in patients who did not
receive corticosteroids, vasopressin was
associated with increased mortality as
compared with NA(33.7% vs 21.3%).
 Thus a beneficial synergy, between
vasopressin and corticosteroids in patients
who had septic shock, was demonstrated.

22. Phosphodiesterase inhibitors
1. Milrinone
2. Enoximone
Calcium sensitizers
Levosimendan
There are currently inadequate data on
these agents to recommend their use in
septic shock.

23.  Itis essential that patients are fluid-
resuscitated before commencement of
vasopressor therapy.
 Few data are available suggesting the
primacy of one agent over another;
however, catecholamines continue to be
the agent group of first choice.

24. Norepinephrine is a potent vasoconstrictor
that maintains cardiac output and restores
midline blood flow. It is not metabolically
active, and this would appear beneficial.

25. Dobutamine is a potent inotrope that is a
useful adjunct to fluid resuscitation in early
sepsis. In late septic shock, dobutamine is
widely used in combination with
norepinephrine as an inotrope.

26. There is an absolute deficiency of
Vasopressin in septic shock, and
combination therapy with catecholamines
should be considered. Few data support
the use of vasopressin as first-line therapy.
Corticosteroids appear to have an additive
effect with vasopressin and may improve
outcomes.

27. Dopamine is a problematic agent. It has a
variety of nonhemodynamic effects that
may affect neurohormonal and immune
function. It is an unpredictable
vasoconstrictor; a significant cohort of
patients are dopamine resistant and
require changeover to epinephrine and
norepinephrine.

28. Epinephrine is a potent vasoconstrictor and
inotrope. When commenced, it causes an
early lactic acidosis secondary to aerobic
glycolysis and may reduce splanchnic
blood flow. The clinical significance of this
is unclear, and both of these effects appear
to be time limited.

29. Phenylephrine has little or no value in the
management of the patient in septic shock.
There are inadequate data available to
recommend the use of calcium sensitizers
or phosphodiesterase inhibitors in septic
shock.

30. Thank You for your attention.

31. Vasopressors
 Maintain MAP ≥ 65mmHg.(1C)
 Norepinephrine or dopamine centrally administered are the initial
vasopressors of choice.(1C)
 Epinephrine, phenylephrine or vasopressin should not be administered as
the initial vasopressor in septic shock.(2C)
 Vasopressin 0.03 units/min maybe subsequently added to norepinephrine
with anticipation of an effect equivalent to norepinephrine alone.
 Use epinephrine as the first alternative agent in septic shock when BP is
poorly responsive to norepinephrine or dopamine.(2B)
 Do not use low-dose dopamine for renal protection.(1A)
 In patients requiring vasopressors, insert an arterial catheter as soon as
practical.(1D)
Inotropic therapy
 Use dobutamine in patients with myocardial dysfunction as indicated by
elevated cardiac filling pressures and low cardiac output.(1C)
 Do not increase cardiac index to predetermined supranormal levels(1B)