MANAGEMENT OF SEPSIS AND
Dr. Ankur Gupta
• Rapid diagnosis (within the first 6 hours) and
expeditious treatment are critical, since early,
goal directed therapy can be very effective.
• Multiple approaches are necessary in the
treatment of sepsis and shock.
• It is important to select patients for each given
therapy with great care, because the efficacy
of treatment — as well as the likelihood and
type of adverse results — will vary, depending
on the patient.
• Major cause of morbidity and mortality
• Sepsis ranks in the top 10 causes of death.
• Mortality in Septic Shock ranges from 40 to
• Mortality rate is proportional to the number
of organ systems that fail.
• Less defined in developing countries.
• Increasing incidence of severe sepsis in the USA is
attributable to the aging of the population, the
increasing longevity of patients with chronic
diseases, and the relatively high frequency with
which sepsis develops in patients with AIDS.
• Widespread use of antimicrobial agents,
glucocorticoids, indwelling catheters and
mechanical devices, and mechanical ventilation
also plays a role.
• Bacteremia - Presence of bacteria in blood, as
evidenced by positive blood cultures.
• Septicemia - Presence of microbes or their toxins in
• Systemic Inflammatory Response syndrome(SIRS) Two or more of the following conditions:
(1) fever (oral temperature >38C) or hypothermia (<36C);
(2) tachypnea (>24 breaths/min);
(3) tachycardia (heart rate > 90 beats/min);
(4) leukocytosis (>12,000/L), leukopenia (<4,000/L), or 10%
bands; may have a noninfectious etiology
• Sepsis - SIRS that has a proven or suspected
• Severe sepsis (similar to“sepsis syndrome”)
Sepsis with one or more signs of organ
1. Cardiovascular: Arterial systolic blood pressure
≤ 90 mmHg or mean arterial pressure ≤ 70 mmHg
that responds to administration of intravenous
2. Renal: Urine output < 0.5 mL/kg per hour for 1 h
despite adequate fluid resuscitation
• 3. Respiratory: PaO₂ /FIO₂ ≤ 250 or, if the lung is the
only dysfunctional organ, ≤ 200
• 4. Hematologic: Platelet count < 80,000/L or 50%
decrease in platelet count from highest value
recorded over previous 3 days
• 5. Unexplained metabolic acidosis: A pH ≤ 7.30 or a
base deficit ≥ 5.0 mEq/L and a plasma lactate level >
1.5 times upper limit of normal for reporting lab.
Septic shock - Sepsis with hypotension
(arterial blood pressure < 90 mmHg systolic, or
40 mmHg less than patient’s normal blood
pressure) for at least 1 h despite adequate
Need for vasopressors to maintain systolic
blood pressure ≥ 90 mmHg or mean arterial
pressure ≥ 70 mmHg
• Refractory septic shock - Septic shock that
lasts for 1 h and does not respond to fluid or
• Multiple-organ Dysfunction Syndrome (MODS)
Dysfunction of more than one organ, requiring
intervention to maintain homeostasis
• cornerstone of emergency management of
sepsis is early, goal-directed therapy, plus
lung-protective ventilation, broad-spectrum
Early, Goal-directed Therapy
• decreased mortality at 28 and 60 days as well
as the duration of hospitalization.
• mechanisms of the benefit of EGDT are
unknown but may include reversal of tissue
hypoxia and a decrease in inflammation and
EGDT – River`s trial
• Crystalloids were administered to maintain CVP
at 8 to 12 mm Hg.
• Vasopressors were added if the MAP was less
than 65 mm Hg.
• If central venous oxygen saturation was less than
70%, erythrocytes were transfused to maintain a
hematocrit of more than 30%.
• Dobutamine was added if the CVP, MAP, and
hematocrit were optimized yet venous oxygen
saturation remained below 70%.
Surviving Sepsis Campaign:
International guidelines - SSC
• Initial resuscitation (first 6 hrs) – hypotension
or elevated serum lactate 4 mmol/L.
Resuscitate using crystalloids or colloids
• Resuscitation goals
– CVP 8–12 mm Hg
– Mean arterial pressure ≥ 65 mm Hg.
– Urine output ≥ 0.5 mL/kg/hr.
– Central venous (superior vena cava) oxygen
saturation ≥ 70% or mixed venous ≥ 65%.
Vasopressors - SSCG
• Maintain MAP > 65 mm Hg.
• Norepinephrine and dopamine centrally
administered are the initial vasopressors of
• Use epinephrine as the first alternative agent.
• Do not use low-dose dopamine for renal
• I.V. infusion of low-dose vasopressin (0.03 to
0.04 U per minute) has been reported to
increase BP, urinary output, and creatinine
clearance, permitting a dramatic decrease in
• Side effects –
– intestinal ischemia,
– decreased cardiac output,
– skin necrosis,
– cardiac arrest
• lung-protective ventilation (TV of 6 ml/kg or as
low as 4 ml if the plateau pressure exceeds 30
cm H2O) decreases mortality and is beneficial
in septic acute lung injury.
• Advantages –
– decrease the mortality rate (from 40 to 31%),
– lessen organ dysfunction,
– lower levels of cytokines.
• PEEP – no significant difference in mortality
• Patients receiving ventilation require
appropriate but not excessive sedation.
• Titrating sedation and interrupting sedation
daily until patients are awake decrease the
risks associated with sedation.
• Neuromuscular blocking agents should be
• Diagnosis - Obtain appropriate cultures before
– Obtain two or more BCs
– One or more BCs should be percutaneous
– One BC from each vascular access device in place
> 48 hrs .
– Culture other sites as clinically indicated
ANTIBIOTICS - SSCG
• Begin intravenous antibiotics as early as
possible and always within the first hour of
recognizing severe sepsis and septic shock.
• Reassess antimicrobial regimen daily to
optimize efficacy, prevent resistance, avoid
toxicity, and minimize costs.
• Immunocompetent adult –
– ceftriaxone (2 g q24h) or ticarcillin-clavulanate
(3.1 g q4–6h) or piperacillin-tazobactam (3.375 g
– imipenem-cilastatin (0.5 g q6h) or meropene (1 g
q8h) or cefepime (2 g q12h).
– Gentamicin or tobramycin (5–7 mg/kg q24h).
– Ciprofloxacin (400 mg q12h) or levofloxacin (500–
750 mg q12h) plus clindamycin (600 mg q8h).
• Neutropenia (500 neutrophils/L) –
– imipenem-cilastatin (0.5 g q6h) or meropenem (1
g q8h) or cefepime (2 g q8h).
– ticarcillin-clavulanate (3.1 g q4h) or piperacillintazobactam (3.375 g q4h) plus tobramycin (5–7
• Splenectomy –
– Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h).
– vancomycin (15 mg/kg q12h) plus ciprofloxacin
(400 mg q12h) or levofloxacin (750 mg q12h) or
aztreonam (2 g q8h).
• AIDS –
– Cefepime (2 g q8h), ticarcillin-clavulanate (3.1 g
q4h), or piperacillin tazobactam (3.375 g q4h) plus
tobramycin (5–7 mg/kg q24h).
– ciprofloxacin (400 mg q12h) or levofloxacin (750
mg q12h) plus vancomycin (15 mg/kg q12h) plus
ACTIVATED PROTEIN C
• Therapy with APC (24 μg / kg / hr for 96 hours)
has been reported to decrease mortality and
to ameliorate organ dysfunction in patients
with severe sepsis.
• Approved for administration to patients with
severe sepsis and an increased risk of death.
• Absolute decrease in the mortality rate of
ACTIVATED PROTEIN C
• Contraindications – PROWESS trial
– Recent trauma or surgery (within 12 hours),
– Active hemorrhage,
– Concurrent therapeutic anticoagulation,
– Thrombocytopenia (defined as a platelet count of
less than 30,000 per cubic millimeter),
– Recent stroke
ACTIVATED PROTEIN C
• Mechanism of action –
– increase protein C.
– decrease markers of thrombin generation.
– prevents hypotension.
ANEMIA IN SEPSIS
• Mediators of sepsis (TNF-α and interleukin-1β)
decrease the expression of the erythropoietin
gene and protein.
• Rivers et al. used a hematocrit of 30% and Hebert
et al. compared hemoglobin values of 70 and 100
g per liter as a threshold for transfusion.
• SSCG - Give RBC`s when Hb decreases to 7.0 g/dL
(70 g/L) to target a Hb of 7.0–9.0 g/dL in adults .
• SSCG –
– Consider i.v. hydrocortisone for adult septic shock
when hypotension responds poorly to adequate
fluid resuscitation and vasopressors.
– Hydrocortisone is preferred to dexamethasone.
– Hydrocortisone dose should be 300 mg/day .
– Do not use corticosteroids to treat sepsis in the
absence of shock
• Important adverse effects in patients with
– Decreased numbers of lymphocytes,
– Immunosuppression (leading to nosocomial
infection and impaired wound healing ),
– Loss of intestinal epithelial cells.
HYPERGLYCEMIA AND INTENSIVE
• Hyperglycemia - acts as a procoagulant,
induces apoptosis, impairs neutrophil
function, increases the risk of infection,
impairs wound healing.
• Insulin - control hyperglycemia and improve
lipid levels , has anti inflammatory,
anticoagulant, and anti apoptotic actions.
HYPERGLYCEMIA AND INTENSIVE
• The appropriate target glucose range and insulin
dose in patients with sepsis are unknown.
• SSCG - Aim to keep blood glucose 150 mg/dL (8.3
• Although intensive insulin therapy appears to be
beneficial in surgical patients, the lack of efficacy
in medical patients, indicates clinical equipoise
and the need for a randomized, controlled trial in
patients with Sepsis.
RENAL DYSFUNCTION AND DIALYSIS
• ARF is associated with increased morbidity, mortality.
• Continuous renal-replacement therapy decreases the
incidence of adverse biomarkers, but there is little
evidence that it changes outcomes.
• Low-dose dopamine (2 to 4 μg / kg / min) neither
decreases the need for renal support nor improves
survival and, consequently, is not recommended.
• Lactic acidosis is a common complication of septic
shock; however, sodium bicarbonate improves neither
hemodynamics nor the response to vasopressor
Deep vein thrombosis prophylaxis SSCG
• Use either low-dose UFH or LMWH, unless
• Use a mechanical prophylactic device, such as
compression stockings or an intermittent
compression device, when heparin is
Stress ulcer prophylaxis - SSCG
• Provide stress ulcer prophylaxis using H2
blocker or proton pump inhibitor.
• Enteral nutrition is important because it is
generally safer and more effective than total
• However, total parenteral nutrition may be
required in patients who have had abdominal
sepsis, surgery, or trauma.
• Anti lipopolysaccharide therapy was
• Therapies that block proinflammatory
cytokines have failed.
• Excessively immunosuppressive , Ibuprofen,
platelet-activating factor acetylhydrolase,
bradykinin antagonists, and other therapies
have not improved survival among patients
POTENTIAL NEW THERAPIES
• Interferon gamma improved macrophage
function and increased survival in one study.
• Inhibition of apoptosis (e.g., with anticaspases)
improved survival in an animal model.
• Lipid emulsion (which binds and neutralizes
lipopolysaccharide) is being evaluated in a phase
• Superantigens and mannose.
• Inhibition of tissue factor, a proximal target,
might mitigate excessive procoagulant activity.
• Strategies to boost immunity could improve the
outcome of sepsis when applied early in sepsis
• Approximately 20 to 35% of patients with
severe sepsis and 40 to 60% of patients with
septic shock die within 30 days.
• Septic shock is also a strong predictor of
short- and long-term mortality.
• Case-fatality rates are similar for culturepositive and culture-negative severe sepsis.
• Optimal management of sepsis requires early,
goal directed therapy; lung-protective ventilation;
antibiotics; and possibly activated protein C.
• corticosteroids, vasopressin, and intensive insulin
therapy requires further study.
• Later in the course of sepsis, appropriate
management necessitates organ support and
prevention of nosocomial infection.
• Studies focused on novel targets, mechanisms of
action, and combination therapy may improve
• Sepsis resuscitation bundle – (within 6 hrs )
– Measure s.lactate.
– Obtain blood culture prior starting antibiotics.
– Give BS ABT within 3 hrs of ED admission/1 hr of
non ED admission.
– Treat hypotension and/or elevated lactate with
fluids (20 ml/kg crystalloids).
– Apply vasopressors for ongoing hypotension.
– Maintain adequate CVP (>8) and ScvO2 (>70%).
• Sepsis management bundle – (within 24 hrs of
presentation), in accordance with ICU policy.
– Give low dose steroids for septic shock.
– Give rhAPC.
– Maintain glucose control lower limit of normal ,
but < 180 mg/dl.
– Maintain inspiratory plateau pressure < 30 cm H₂0
for ventillated patients.