Sepsis seminar final

MANAGEMENT OF
SEPSIS IN ICU
MODERATOR
Dr Rajnish Gupta
Prepared by
Dr Rishi Gopalakrishnan

• A satisfactory clinical definition of sepsis has been
eluding since the ancient Greeks first coined the term!!
• Hippocrates claimed that sepsis was the process by which
flesh rots, swamps generate foul airs, and wounds fester.
Majno G. The ancient riddle of sigma eta psi iota sigma (sepsis). J Infect Dis1991;163:937-945
Background

Definitions
According to The Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3)
By Society of Critical Care Medicine and the European Society
of Intensive Care Medicine
• Sepsis is defined as life-threatening organ dysfunction caused
by a dysregulated host response to infection
• Septic shock is a subset of sepsis in which underlying
circulatory and cellular metabolic abnormalities are profound
enough to substantially increase mortality.
Singer M et al. The Third International Consensus Definitions for Sepsis and Septic
Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10

CLINICAL CRITERIA
• Sepsis: Suspected or documented infection and an acute
increase of ≥ 2 SOFA points
• Septic Shock: a clinical construct of sepsis with persisting
hypotension requiring vasopressors to maintain
MAP≥65mmHg and having a serum lactate level>2 mmol/L
(18mg/dL) despite adequate volume resuscitation.

International Sepsis Definitions
Conference 2001
The Third International Consensus
Definitions for Sepsis and Septic Shock
(Sepsis-3) 2016
Sepsis is defined as presence of infection
with systemic manifestations of infection
Sepsis is defined as life-threatening
organ dysfunction caused by a
dysregulated host response to infection
Severe sepsis is defined as sepsis plus
sepsis-induced organ dysfunction or
tissue hypoperfusion
Definition Redundant
Septic shock is defined as sepsis-
induced hypotension persisting despite
adequate fluid resuscitation.
Septic shock should be defined as a
subset of sepsis in which particularly
profound circulatory, cellular, and
metabolic abnormalities are associated
with a greater risk of mortality than with
sepsis alone

qSOFA (Quick SOFA) Criteria
• Respiratory rate ≥22/min
• Altered mentation
• Systolic blood pressure ≤100mmHg
Patients with suspected infection who are likely to have a
prolonged ICU stay or to die in the hospital can be promptly
identified at the bedside with qSOFA

• qSOFA uses 3 clinical variables, has no laboratory tests, and has
a predictive validity outside of the ICU that is statistically
greater than the SOFA score
• The qSOFA and SOFA scores also had acceptable agreement in
the majority of encounters
• SOFA has superior predictive validity in the ICU
• The qSOFA score had statistically worse predictive validity in
the ICU, likely related to the confounding effects of ongoing
organ support
Seymour CW et al; Assessment of Clinical Criteria for Sepsis: For the Third International
Consensus Definitions for Sepsis and Septic Shock JAMA. 2016 Feb 23;315(8):762-74.

SIRS (Systemic Inflammatory Response Syndrome)
• Two or more of:
Temperature >38°C or <36°C
Heart rate >90/min
Respiratory rate >20/min or PaCO2 <32mmHg (4.3 kPa)
White blood cell count >12 000/mm3 or <4000/mm3 or >10%
immature bands
Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of
innovative therapies in sepsis. Chest. 1992 Jun;101(6):1644-55

SEPSIS-3 endorsed by
• American Thoracic Society
• European Respiratory Society
• Academy of Medical Royal Colleges (UK)
• American Association of Critical Care Nurses
• European Resuscitation Council
• European Society of Emergency Medicine
• Indian Society of Critical Care Medicine
• Japanese Society of Intensive Care Medicice

Global estimates of 31.5 million sepsis and 19.4 million severe
sepsis cases, with potentially 5.3 million deaths annually
Global Incidence (based on data from 1995-2015)
• 437 per 100,000 person-years for sepsis
• 270 per 100,000 person-years for severe sepsis
Hospital mortality was 17% for sepsis and 26% for severe
sepsis during this period
Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and Mortality of Hospital-
treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med 2016; 193:259.
Epidemiology

• The incidence of sepsis varies among the different racial
and ethnic groups, but appears to be highest among
African-American males
• The incidence is also greatest during the winter, probably
due to the increased prevalence of respiratory infections
• Older patients ≥65 years of age account for the majority
(60 to 85 percent) of all episodes of sepsis
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States
from 1979 through 2000. N Engl J Med 2003; 348:1546.
Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Crit Care
Med 2007; 35:410.

In a study of 5,478 ICU admissions in 4 ICUs in India from
2006 to 2009 -
• The incidence of severe sepsis was 16.45% of all
admissions.
• ICU mortality of severe sepsis was 59.26%.
• Hospital mortality and 28-day mortality of severe sepsis
were 65.2% and 64.6%, respectively.
Todi, S. et al. Epidemiology of severe sepsis in India: an update. Critical Care, 14(Suppl 1)
2010 P382.

• Median duration of stay in the ICU for the severe sepsis
cohort who survived was 13 days
• Culture positivity was found in 61.6%.
• The lung was the predominant source of sepsis (57.45%).
• Gram-negative organisms were responsible for 72.45% of
cases and Gram-positive for 13.13%.
Todi, S. et al. Epidemiology of severe sepsis in India: an update. Critical Care, 14(Suppl 1)
2010 P382.

• Mortality rate is proportional to the number
of organ systems that fail
100%100%100%96%93%95%80%3
68%64%56%62%66%67%52%2
41%42%40%35%34%31%22%1
#OSF D1 D2 D3 D4 D5 D6 D7
Ann Surg. 1985;202(6):685-93.

Pathobiology
• Sepsis is a multifaceted host response to an infecting
pathogen that may be significantly amplified by
endogenous factors
• Sepsis is now recognized to involve early activation of
both pro- and anti-inflammatory responses, along with
major modifications in non-immunologic pathways such
as cardiovascular, neuronal, autonomic, hormonal,
bioenergetic, metabolic and coagulation, all of which
have prognostic significance.
• Organ dysfunction, even when severe, is not associated
with substantial cell death
Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock
(Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10

Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug
29;369(9):840-51

1- strong recommendation
• they recommend
2- weak recommendation
• they suggest
A- high quality : RCTs
B- intermediate : Downgraded RCTs or upgraded observational studies
C- low : Well-done observational studies with control RCTs
D- very low : Downgraded controlled studies or expert opinion based
on other evidence.

Management of Sepsis
• Initial Resuscitation and Infection Issues
• Hemodynamic Support and Adjunctive Therapy
• Supportive therapy
Surviving sepsis campaign: International guidelines for management of severe
sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637

Initial Resuscitation and
Infection Issues
• Initial Resuscitation
• Screening for Sepsis and Performance Improvement
• Diagnosis
• Antimicrobial Therapy
• Source Control
• Infection Prevention

• During the first 6 hrs of resuscitation, the goals of initial
resuscitation of sepsis-induced hypoperfusion (grade 1C):
a) CVP 8–12 mm Hg
b) MAP ≥ 65 mm Hg
c) Urine output ≥ 0.5 mL/kg/hr
d) Superior vena cava oxygenation saturation (Scvo2) or
mixed venous oxygen saturation (Svo2) 70% or 65%,
respectively.
This strategy is called early goal-directed therapy

• In mechanically ventilated patients or those with known
preexisting decreased ventricular compliance, a higher
target CVP of 12 to 15 mm Hg should be achieved to
account for the impediment in filling
• In patients with elevated lactate levels targeting
resuscitation to normalize lactate (grade 2C)

• TO BE COMPLETED WITHIN 3 HOURS:
1) Measure lactate level
2) Obtain blood cultures prior to administration of antibiotics
3) Administer broad spectrum antibiotics
4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/L
The Surviving Sepsis Campaign's Revised Sepsis Bundles 2015

TO BE COMPLETED WITHIN 6 HOURS OF TIME OF
PRESENTATION:
• 5. Apply vasopressors (for septic shock) to maintain MAP ≥65mmHg
• 6. In the event of persistent hypotension, MAP < 65 mm Hg or if initial
lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion
and document findings.
• 7. Re-measure lactate if initial lactate elevated.
Old bundle no. 6:
In the event of persistent arterial hypotension despite volume
resuscitation (septic shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):-
Measure central venous pressure (CVP)
Measure central venous oxygen saturation (ScvO2)

DOCUMENT REASSESSMENT OF VOLUME STATUS
AND TISSUE PERFUSION WITH: EITHER
• Repeat focused exam (after initial fluid resuscitation) by
licensed independent practitioner including vital signs,
cardiopulmonary, capillary refill, pulse, and skin findings.
OR TWO OF THE FOLLOWING:
• Measure CVP
• Measure ScvO2
• Bedside cardiovascular ultrasound
• Dynamic assessment of fluid responsiveness with passive
leg raise or fluid challenge

• Following trials do not demonstrate superiority of use of a
central venous catheter (CVC) to monitor CVP and ScvO2 in
all patients with septic shock who have received timely
antibiotics and fluid resuscitation compared with controls or in
all patients with lactate >4 mmol/L.
ProCESS Investigators, Yealy DM, Kellum JA, Juang DT, et al. A randomized trial of protocol-
based care for early septic shock. N Engl J Med 2014; 370(18):1683-1693
The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for
patients with early septic shock. N Engl J Med 2014
Mouncey PR, Osborn TM, Power GS, et al for the ProMISe trial investigators. Trial of early,
goal-directed resuscitation for septic shock. N Engl J Med 2015

Indian data from the Management of Sepsis in Asia’s Intensive
Care Units (MOSAICS) study. (17 ICUs in 162 patients)
• Hospital mortality was 38.3% (62/162).
• Compliance rates for the entire resuscitation and management
bundles were 6.8% (11/162) and 8% (13/162) respectively.
There was a trend to improving survival with bundle
compliance.
• Compliance with the resuscitation and management bundles
was associated with mortality rates of 18.2% and 19%,
respectively, while mortality rates with noncompliance were
39.7% and 41.1%.
• While mortality from severe sepsis is high, compliance to the
resuscitation and management bundles is generally poor in
ICUs in India
Divatia, J. Management of sepsis in Indian ICUs: Indian data from the MOSAICS
study. Critical Care, 16(Suppl 3) 2012 P90

Emanuel Rivers et al study in 2001
• Of 263 enrolled patients, 130 were randomly assigned to
early goal-directed therapy and 133 to standard therapy
• In-hospital mortality was 30.5% in the group assigned to
early goal-directed therapy, as compared with 46.5% in
the group assigned to standard therapy
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the
treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377

Gu W-J, Bakker J, Liu J-C did a meta analysis of RCTs
consisting of 13 trials involving 2,525 adult patients in 2014
• It showed that GDT significantly reduced overall mortality
Wira CR, Dodge K, Sather J, Dziura J did a Meta-analysis of
25 studies (15 manuscripts, 10 abstracts) with n=9597)
• The mortality rate for patients receiving protocolized
hemodynamic optimization (n=6031) was 25.8% contrasted to
41.6% in control groups (n=3566, p<0.0001).
Gu WJ et al. The effect of goal-directed therapy on mortality in patients with sepsis - earlier is better: a
meta-analysis of randomized controlled trials. Crit Care. 2014 Oct 20;18(5):570.
Wira CR et al. Meta-analysis of protocolized goal-directed hemodynamic optimization for the management of
severe sepsis and septic shock in the Emergency Department. West J Emerg Med. 2014 Feb;15(1):51-9

Protocolized Care for Early Septic Shock(ProCESS) study
• 1341 patients were enrolled of whom 439 were randomly
assigned to protocol-based EGDT, 446 to protocol-based
standard therapy, and 456 to usual care
• After 60 days, mortality in the protocol-based EGDT group
was 21.0%, in the protocol-based standard-therapy group was
18.2%, and in the usual-care group mortality was 18.9%
• There were no significant differences in 90-day mortality, 1-
year mortality, or the need for organ support
• Conclusion of study was that Protocol-based resuscitation of
patients in whom septic shock was diagnosed in the
emergency department did not improve outcomes.
ProCESS Investigators, Yealy DM, Kellum JA, Juang DT, et al. A randomized trial of
protocol-based care for early septic shock. N Engl J Med 2014; 370(18):1683-1693

The Australasian Resuscitation in Sepsis Evaluation
(ARISE) study
• 1600 enrolled patients, 796 were assigned to the EGDT
group and 804 to the usual-care group
• At 90 days mortality was 18.6% in the EGDT group and
18.8% in the usual-care group
• In critically ill patients presenting to the emergency
department with early septic shock, EGDT did not reduce
all-cause mortality at 90 days
The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed
resuscitation for patients with early septic shock. N Engl J Med 2014

• ProMISe Trial (Protocolized Management in Sepsis) :
Patients were randomly assigned to receive either EGDT (a
6-hour resuscitation protocol) or usual care.
• Enrolled 1260 patients, with 630 assigned to EGDT and 630
to usual care.
• 90 days mortality was 29.5% in the EGDT group and 29.2%
in the usual-care group
• Increased treatment intensity in the EGDT group was
indicated by increased use of intravenous fluids, vasoactive
drugs, and red-cell transfusions and reflected by
significantly worse organ-failure scores, more days
receiving advanced cardiovascular support, and longer stays
in the ICU.
Mouncey PR, Osborn TM, Power GS, et al for the ProMISe trial investigators. Trial of
early, goal-directed resuscitation for septic shock. N Engl J Med 2015

• On average, EGDT increased costs, and the probability
that it was cost-effective was below 20%.
• CONCLUSIONS : In patients with septic shock who
were identified early and received intravenous antibiotics
and adequate fluid resuscitation, hemodynamic
management according to a strict EGDT protocol did not
lead to an improvement in outcome.
Mouncey PR, Osborn TM, Power GS, et al for the ProMISe trial investigators. Trial of
early, goal-directed resuscitation for septic shock. N Engl J Med 2015

• A systematic review and meta-analysis of early goal-directed
therapy was published in 2015
• They included 11 randomised clinical trials evaluating
EGDT versus usual care or an alternative non-EGDT
resuscitation strategy among more than 5000 patients with
septic shock.
• Across the five studies of patients presenting to the ED with
septic shock, EGDT was not associated with decreased
mortality compared with usual care
• EGDT was associated with increased admission to ICU
Angus DC et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the
ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015
Sep;41(9):1549-60.

Screening for Sepsis and
Performance Improvement
1. routine screening of potentially infected seriously ill patients
for severe sepsis to increase the early identification of sepsis and
allow implementation of early sepsis therapy (grade 1C).
• Reducing the time to diagnosis of severe sepsis is thought to be
a critical component of reducing mortality from sepsis-related
multiple organ dysfunction(MODS).
2. Hospital–based performance improvement efforts in severe
sepsis (UG).

Diagnosis:
• 1. Cultures before antimicrobial therapy if no significant
delay (> 45 mins) (grade1C).
• At least 2 sets of blood cultures (both aerobic and
anaerobic bottles) be obtained with at least 1 drawn
percutaneously and 1 drawn through each vascular access
device, unless the device was recently (<48 hrs) inserted
(grade 1C).
• Cultures of other sites should also be obtained before
antimicrobial therapy (grade 1C), such as urine,
cerebrospinal fluid, wounds, respiratory secretions, or
other body fluids that may be the source of infection.

• Imaging studies performed promptly to confirm a
potential source of infection (UG).
• Consideration of patient risk for transport and invasive
procedures.
• Bedside studies, such as ultrasound, may avoid patient
transport

• The Gram staining in particular for respiratory tract
specimens.
• Rapid influenza antigen testing during periods of
increased influenza activity in the community is also
recommended
• 1,3 beta-D-glucan assay (grade 2B), mannan and anti-
mannan antibody assays (2C), if available and invasive
candidiasis is suspected.

The potential role of biomarkers (PCT, CRP)
• Undefined role for diagnosis of infection in patients
presenting with severe sepsis
• No recommendation given to distinguish between severe
infection and other acute inflammatory states
• It has not been demonstrated to help in discriminating the
acute inflammatory pattern of sepsis from other causes of
generalized inflammation (eg, postoperative, other forms
of shock)

Antimicrobial Therapy:
• 1. within the first hour of recognition of septic shock (grade
1B) and severe sepsis without septic shock (grade 1C) as the
goal of therapy.
• 2a. Initial empiric therapy against all likely pathogens
(bacterial and/or fungal or viral (grade 1B).
• 2b. regimen should be reassessed daily for potential de-
escalation (grade 1B).
• 3. Use of low PCT levels or similar biomarkers in the
discontinuation of empiric antibiotics in patients who initially
appeared septic, but have no subsequent evidence of infection
(grade 2C)

Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical
care. Journal of antimicrobial chemotherapy. 2011 Apr 1;66(suppl 2):ii33-40.

• 4a. Combination empirical therapy
- for neutropenic patients with severe sepsis (grade 2B) and
- for patients with difficult-to-treat, multi drugresistant bacterial
pathogens such as Acinetobacter and Pseudomonas spp. (grade
2B).
• For patients with severe infections associated with respiratory
failure and septic shock, combination therapy with an extended
spectrum beta-lactam and either an aminoglycoside or a
fluoroquinolone is suggested for P. aeruginosa bacteremia
(grade 2B).
• A combination of beta-lactam and macrolide for patients with
septic shock from bacteremic Streptococcus pneumoniae
infections (grade 2B).

• TB septicaemia is a rare but important condition in our
setting
• It occurs exclusively in immunocompromised patients
although there are few reports in immunoocompetent
individuals also
• It can lead to septic shock with MODS termed as sepsis
tuberculosa gravissima
• Without proper anti tubercular treatment, its invariably
fatal
Severe Tuberculosis Sepsis in an Immunocompetent Patient Bridges, Debbie A. et al.
The American Journal of Medicine 2006, Volume 119 , Issue 3 , e11 - e14

• 4b. Empiric combination therapy not more than 3–5 days.
De-escalation as soon as the susceptibility profile is known
(grade 2B).
• 5. Duration of therapy typically 7–10 days;
longer courses may be appropriate in patients with,
slow clinical response,
undrainable foci of infection,
bacteremia with S. aureus;
some fungal and viral infections or
immunologic deficiencies, including neutropenia(grade 2C).

• 6. Antiviral therapy initiated as early as possible in
patients with severe sepsis or septic shock of viral origin
(grade 2C).
• 7. Antimicrobials should not be used in severe
inflammatory states determined to be of noninfectious
cause (UG).

• E. Source Control
• 1. Source control be sought and diagnosed or
excluded as rapidly as possible, and
- intervention be undertaken within the first 12 hr, if
feasible (grade 1C).
• 2. When infected peripancreatic necrosis is identified,
definitive intervention is best delayed until adequate
demarcation of viable and nonviable tissues has occurred
(grade 2B).

• 3. In a severely septic patient, the effective intervention
associated with the least physiologic insult should be
used
- (eg, percutaneous rather than surgical drainage of an abscess) (UG).
• 4. If intravascular access devices are a possible source,
they should be removed promptly after other vascular
access has been established (UG).

• F. Infection Prevention
• 1a. Selective oral decontamination and selective digestive
decontamination to reduce the incidence of VAP;
• 1b. Oral chlorhexidine gluconate to reduce the risk of
VAP in ICU patients with severe sepsis (grade 2B).

• Careful infection control practices
- hand washing
- expert nursing care, catheter care
- barrier precautions
- airway management
- elevation of the head of the bed
- subglottic suctioning

• G. Fluid Therapy of Severe Sepsis
• 1. Crystalloids as the initial fluid of choice (grade 1B).
• 2. Hydroxyethyl starch for fluid resuscitation is not recommended
(grade 1B).
• 3. Albumin in suggested when substantial amounts of crystalloids are
required(grade 2C).
• A meta-analysis of 56 randomized trials found no overall difference
in mortality between crystalloids and artificial colloids (modified
gelatins, HES, dextran) when used for initial fluid resuscitation
Perel P, Roberts I: Colloids versus crystalloids for fluid resuscitation in critically ill
patients. Cochrane Database Syst Rev 2011

• 4. Initial fluid challenge - 30 mL/kg of crystalloids (a
portion of this may be albumin equivalent).
• 5.Fluid administration is continued as long as there is
hemodynamic improvement either based on
- dynamic (eg, change in pulse pressure, stroke volume
variation) or
- static (eg, arterial pressure, heart rate) variables (UG).

Vasopressors
• 1. Target of MAP is 65 mm Hg (grade 1C).
• 2. Norepinephrine as the first choice vasopressor (grade 1B).
• 3. Epinephrine (added to and substituted for norepinephrine)
when an additional agent is needed (grade 2B).
• 4. Vasopressin 0.03 units/minute can be added to
norepinephrine (NE) with intent of either raising MAP or
decreasing NE dosage (UG).

• 5. Low dose vasopressin is not recommended as the
single initial vasopressor.
-vasopressin doses higher than 0.03-0.04
units/minute should be reserved for salvage therapy
(UG).
• 6. 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 circumstances where
(a) norepinephrine is associated with serious arrhythmias,
(b) persistent low BP or high cardiac output or
(c) as salvage therapy when combined inotrope/vasopressor
drugs and low dose vasopressin have failed to achieve 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 if resources are available (UG).

Inotropic Therapy
• 1. A trial of dobutamine infusion up to 20 micrograms/kg/min
be administered or added to vasopressor (if in use) in the
presence of
(a) myocardial dysfunction or
(b) ongoing signs of hypoperfusion, despite achieving
adequate intravascular volume and adequate MAP (grade 1C).
• 2. Not recommended to increase cardiac index to predetermined
supranormal levels (grade 1B).
Cardiac Index CI = CO/BSA.

Corticosteroids
• 1. Intravenous hydrocortisone is not needed to treat adult
septic shock patients if adequate fluid resuscitation and
vasopressor therapy are able to restore hemodynamic stability.
• In case this is not achievable, intravenous hydrocortisone at a
dose of 200 mg per day (grade 2C).
Annane D, Sébille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862–871

• One French multicenter RCT of patients in vasopressor-
unresponsive septic shock (hypotension despite fluid
resuscitation and vasopressors for more than 60 mins),
low dose steroid use showed
- significant shock reversal and
- reduction of mortality rate in patients with relative
adrenal insufficiency (defined as post ACTH cortisol
increase ≤ 9 μg/dL)
• A large, European multicenter trial (CORTICUS) that
enrolled patients without sustained shock and had a lower
risk of death than the French trial, failed to show a
mortality benefit with steroid therapy
Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group: Hydrocortisone
therapy for patients with septic shock. N Engl J Med 2008; 358:111–124)

• Annane et al analyzed the results of 12 studies and calculated a
significant reduction in 28-day mortality with prolonged low-dose
steroid treatment in adult septic shock patients (RR, 0.84; 95% CI,
0.72−0.97; p = 0.02)
(Annane D, Bellissant E, Bollaert PE, et al: Corticosteroids in the treatment of
severe sepsis and septic shock in adults: A systematic review. JAMA 2009;
301:2362–2375)
• Sligl and colleagues meta-analysis, revealed no statistically
significant difference in mortality (RR, 1.00; 95% CI, 0.84−1.18).
(Sligl WI, Milner DA Jr, Sundar S, et al: Safety and efficacy of corticosteroids
for the treatment of septic shock: A systematic review and meta-analysis. Clin
Infect Dis 2009; 49:93–101)
• Both reviews, however, confirmed the improved shock reversal
by using low-dose hydrocortisone.

• 2. ACTH stimulation test is not to be used to identify adults
with septic shock who should receive hydrocortisone (grade
2B).
• for septic shock patients who suffer from relative adrenal
insufficiency (no adequate stress response), random cortisol
levels have not been demonstrated to be useful.
• An inappropriately low random cortisol level (< 18 μg/dL)
in a patient with shock would be considered an indication
for steroid therapy.

• 3. Taper steroid dose when vasopressors are no longer
required (grade 2D).
- There has been no comparative study between a fixed-
duration and clinically guided regimen or between tapering and
abrupt cessation of steroids.
• 4. Corticosteroids not be administered for the treatment of
sepsis in the absence of shock (grade 1D).
• 5. When low-dose hydrocortisone is given, it is suggested
using continuous infusion rather than repetitive bolus
injections (grade 2D), in view of side effects like
hyperglycemia and hypernatremia with the latter.

Supportive Therapy of
Severe Sepsis
• Blood Product Administration
• 1. Once tissue hypoperfusion has resolved and in the
absence of myocardial ischemia, severe hypoxemia,
acute hemorrhage, or ischemic heart disease, red blood
transfusion is recommended when Hb <7.0 g/dL to
target a hemoglobin concentration of 7.0 –9.0 g/dL in
adults (grade 1B).
• 2. Erythropoietin is not recommened as a specific
treatment of anemia associated with severe sepsis
(grade 1B).

• 3. FFP not be used to correct clotting abnormalities in the
absence of bleeding or planned invasive procedures (grade
2D).
• 4. Antithrombin is not recommended for the treatment of
severe sepsis and septic shock (grade 1B).
• High-dose antithrombin was associated with an increased
risk of bleeding when administered with heparin.
Warren BL, Eid A, Singer P, et al; KyberSept Trial Study Group: Caring for the critically ill patient. High-dose
antithrombin III in severe sepsis: A randomized controlled trial. JAMA 2001; 286:1869–1878

• 5. In patients with severe sepsis, administer platelets prophylactically
- when <10,000/mm3 in the absence of apparent bleeding.
- when < 20,000/mm3, with significant risk of bleeding.
• Higher platelet counts (≥50,000/mm3) are advised for active
bleeding, surgery, or invasive procedures (grade 2D).
• Factors considered to increase the risk of bleeding in patients with
severe sepsis include
-temperature >38°C,
- recent minor hemorrhage,
- rapid decrease in platelet count, and
- other coagulation abnormalities.

• Immunoglobulins : Not suggested in adult patients with
severe sepsis or septic shock (grade 2B).
• One larger multicenter RCT (n = 624) in adult patients
found no benefit for IVIG.
Werdan K, Pilz G, Bujdoso O, et al; Score-based immunoglobulin G therapy of patients with sepsis: The
SBITS study. Crit Care Med 2007; 35:2693–2701

• Selenium: Not suggested for the treatment of severe sepsis
(grade 2C).
• Only one large clinical trial has examined the effect on
mortality rates, and no significant impact was reported on
the intent-to-treat population with severe SIRS, sepsis, or
septic shock
Angstwurm MW, Engelmann L, Zimmermann T, et al: Selenium in intensive Care (SIC): Results
of a prospective randomized, placebo controlled, multiple-center study in patients with severe
SIRS, sepsis, and septic shock. Crit Care Med 2007; 35:118–126

Recombinant Activated Protein C (rhAPC) :
• PROWESS trial (1,690 patients) in 2001 showed a
significant decrease in mortality in severe sepsis patients
• PROWESS SHOCK trial (1,696 patients) showed no benefit
in patients with septic shock (mortality 26.4% for rhAPC,
24.2% placebo) with a relative risk of 1.09 and a p value of
0.31
• The drug has been withdrawn from the market since then
Bernard GR et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS)
study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J
Med. 2001 Mar 8;344(10):699-709
Ranieri VM et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic
shock. N Engl J Med. 2012 May 31;366(22):2055-64

Mechanical Ventilation of Sepsis-Induced ARDS
• 1. Target a tidal volume of 6 mL/kg predicted body weight in
patients with sepsis-induced ARDS (grade 1A vs. 12 mL/kg).
• 2. Initial upper limit goal for plateau pressures is ≤30 cm H2O
(grade 1B).
• ARDS Network trial (volume- and pressure-limited strategy)
showed an absolute 9% decrease in all-cause mortality in
patients with ARDS ventilated with tidal volumes of 6 mL/kg
compared with 12 mL/kg of predicted body weight (PBW),
and aiming for a plateau pressure ≤ 30 cm H2O.
Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with
traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med
2000; 342:1301–1308

• 3. PEEP be applied to avoid alveolar collapse at end
expiration (atelectotrauma) (grade 1B).
• 4. Strategies based on higher rather than lower levels of
PEEP be used for patients with sepsis- induced moderate or
severe ARDS (grade 2C).
• A meta-analysis using individual patient data showed no
benefit high PEEP in all patients with ARDS
- however, patients with moderate or severe ARDS (Pao2/Fio2
ratio ≤ 200 mm Hg) had decreased mortality with higher PEEP,
whereas those with mild ARDS did not.
Briel M, Meade M, Mercat A, et al: Higher vs lower PEEP in patients with ALI and
ARDS: Systematic review and meta-analysis. JAMA 2010; 303:865–873

• 5. Recruitment maneuvers be used in sepsis patients with
severe refractory hypoxemia (grade 2C).
• Blood pressure and oxygenation should be monitored and
recruitment manoeuvres discontinued if deterioration in
these variables is observed.
• 6. Prone positioning be used in sepsis-induced ARDS
patients with a Pao2/Fio2 ratio ≤ 100 mm Hg (grade 2B).
• Several studies in patients with hypoxemic respiratory
failure or ARDS have shown that most patients respond to
the prone position with improved oxygenation, but none of
them demonstrated a mortality benefit.
Fan E, Wilcox ME, Brower RG, et al: Recruitment maneuvers for acute lung injury: A
systematic review. Am J Respir Crit Care Med 2008; 178:1156–1163

• One meta-analysis suggested potential benefits for prone
positioning in patients with profound hypoxemia and
Pao2/Fio2 ratio ≤ 100 mm Hg, but not in those with less
severe hypoxemia.
• Other methods to treat refractory hypoxemia, including
high-frequency oscillatory ventilation(HFOV),
airway pressure release ventilation(APRV)
extracorporeal membrane oxygenation(ECMO).
Sud S, Friedrich JO, Taccone P, et al: Prone ventilation reduces mortality in patients with acute respiratory
failure and severe hypoxemia: Systematic review and meta-analysis. Intensive Care Med 2010; 36:585–599

• 7. Mechanically ventilated sepsis patients be maintained
with the head of the bed elevated to 30-45 degrees to limit
aspiration risk and to prevent the development of VAP
(grade 1B).
• 8. NIV be used in whom the benefits of NIV have been
carefully considered and are thought to outweigh the risks
(grade 2B).
• A low threshold for airway intubation should be maintained.

• 9. Weaning protocol be in place and spontaneous breathing
trials given when they satisfy the following criteria:
a)arousable;
b) hemodynamically stable (without vasopressor
agents);
c) no new potentially serious conditions;
d) low ventilator and end-expiratory pressure
requirements; and
e) low Fio2 requirements which can be met safely
delivered with a face mask or nasal cannula.
• If the spontaneous breathing trial is successful, consideration
should be given for extubation (grade 1A).

• 10. Routine use of the pulmonary artery catheter for patients
with sepsis-induced ARDS is not recommended(grade 1A).
• 11. A conservative rather than liberal fluid strategy for
patients with established sepsis-induced ARDS who do not
have evidence of tissue hypoperfusion (grade 1C).
• Fluid-conservative strategy to minimize fluid infusion and
weight gain based on either a central venous catheter (CVP
< 4 mm Hg) or a PA catheter (pulmonary artery wedge
pressure < 8 mm Hg) led to fewer days of mechanical
ventilation and reduced length of ICU stay.
National Heart, Lung and Blood Institute ARDS Clinical Trials Network; Wiedemann HP et al: Comparison
of two fluid management strategies in ALI. N Engl J Med 2006; 354:2564–2575

• 12. In the absence of specific indications such as
bronchospasm and hyperkalemia, beta 2-agonists are not
recommended for treatment of sepsis-induced ARDS
(grade 1B).

Sedation, Analgesia, and
Neuromuscular Blockade in Sepsis
• 1. Continuous or intermittent sedation be minimized in
mechanically ventilated sepsis patients, targeting specific titration
endpoints (grade 1B).
• Limiting the use of sedation in critically ill ventilated patients can
reduce the duration of mechanical ventilation and ICU and hospital
lengths of stay
Marx WH, DeMaintenon NL, Mooney KF, et al: Cost reduction and outcome improvement
in the intensive care unit. J Trauma 1999; 46:625–9
MacLaren R, Plamondon JM, Ramsay KB, et al: A prospective evaluation of empiric versus
protocol-based sedation and analgesia. Pharmacotherapy 2000; 20:662–672
Brook AD, Ahrens TS, Schaiff R, et al: Effect of a nursing-implemented sedation protocol on
the duration of mechanical ventilation. Crit Care Med 1999; 27:2609–2615

• Awakening and Breathing Controlled trial : a paired
spontaneous awakening trial combined with a
spontaneous breathing trial decreased the duration of
mechanical ventilation, length of ICU, and hospital stay,
and 1-year mortality.
Girard TD, Kress JP, Fuchs BD, et al: Efficacy and safety of a paired sedation and ventilator
weaning protocol for mechanically ventilated patients in intensive care (Awakening and
Breathing Controlled trial): A randomised controlled trial. Lancet 2008; 371:126–134

• 2. Neuromuscular blocking agents (NMBAs) be avoided
if possible in sepsis without ARDS due to the risk of
prolonged neuromuscular blockade following
discontinuation.
• If NMBAs must be maintained, either intermittent bolus
as required or continuous infusion with train-of-four
monitoring of the depth of blockade should be used
(grade 1C).
• 3. A short course of NMBA of not greater than 48 hours
for patients with early sepsis-induced ARDS and a
Pao2/Fio2 < 150 mm Hg is suggested (grade 2C).

• No evidence exists that neuromuscular blockade in sepsis
with ARDS reduces mortality or major morbidity.
• No studies have been published that specifically address the
use of NMBAs in septic patients.
• The most common indication for NMBA use in the ICU is to
facilitate mechanical ventilation.
• When appropriately used, NMBAs may improve chest wall
compliance, prevent respiratory dyssynchrony, and reduce
peak airway pressures.

• NMBAs not be administered unless there is a clear
indication for neuromuscular blockade that cannot be safely
achieved with appropriate sedation and analgesia.
Murray MJ, Cowen J, DeBlock H, et al; Task Force of the American College of Critical Care Medicine
(ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System
Pharmacists, American College of Chest Physicians: Clinical practice guidelines for sustained
neuromuscular blockade in the adult critically ill patient. Crit Care Med 2002; 30:142–156

• Rudis et al randomized 77 critically ill ICU patients
requiring neuromuscular blockade to receive dosing of
vecuronium based on train-of-four stimulation(test group) or
on clinical assessment (control group).
-The peripheral nerve stimulation group received less
drug and recovered neuromuscular function and spontaneous
ventilation faster than the control group.
Rudis MI, Sikora CA, Angus E, et al: A prospective, randomized, controlled evaluation of peripheral nerve
stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients. Crit
Care Med 1997;25:575–583

Glucose Control
• 1. A protocolized approach recommended in blood glucose
management in ICU patients with severe sepsis, commencing
insulin dosing when 2 consecutive blood glucose levels are
>180 mg/dL.
• Many RCTs studied mixed populations of surgical and medical
ICU patients and found that intensive insulin therapy did not
significantly decrease mortality, whereas the NICE-SUGAR
trial demonstrated an increased mortality.
• All studies reported a much higher incidence of severe
hypoglycemia (glucose ≤ 40 mg/dL) (6%−29%) with intensive
insulin therapy.
• Several meta-analyses confirmed that intensive insulin therapy
was not associated with a mortality benefit in surgical,
medical, or mixed ICU patients.

• Target an upper blood glucose level ≤180 mg/dL rather than
an upper target blood glucose ≤ 110 mg/dL (grade 1A).
• The trigger to start an insulin protocol for blood glucose
levels > 180 mg/dL with an upper target blood glucose level
< 180 mg/dL derives from the NICE-SUGAR study.
• . NICE-SUGAR trial is the largest, most compelling study to date on
glucose control in ICU patients.
The NICE-SUGAR Study Investigators: Intensive versus conventional glucose
control in critically ill patients. N Engl J Med 2009; 360:1283–1297

• 2. Blood glucose values be monitored every 1–2 hrs until
glucose values and insulin infusion rates are stable and then
every 4 hrs thereafter (grade 1C).
• Several studies have suggested that the variability in glucose
levels over time is an important determinant of mortality.
• Hyperglycemia and glucose variability seem to be
unassociated with increased mortality rates in diabetic
patients compared to nondiabetic patients.
Krinsley JS: Glycemic variability and mortality in critically ill patients: The impact
of diabetes J Diabetes Sci Technol 2009; 3:1292–1301
Egi M, Bellomo R, Stachowski E, et al: Blood glucose concentration and outcome of
critical illness: The impact of diabetes. Crit Care Med 2008; 36:2249–2255

• 3. Glucose levels obtained with point-of-care testing of
capillary blood be interpreted with caution, as such
measurements may not accurately estimate arterial blood
or plasma glucose values (UG).

Renal Replacement Therapy
• 1. Continuous renal replacement therapies and intermittent
hemodialysis are equivalent in patients with severe sepsis
and acute renal failure (grade 2B).
• 2. Use continuous therapies to facilitate management of
fluid balance in hemodynamically unstable septic patients
(grade 2D).
• A typical dose for continuous renal replacement therapy is
20 to 25 mL/kg/h of effluent generation

Bicarbonate Therapy
• Sodium bicarbonate not suggested for the purpose of
improving hemodynamics or reducing vasopressor
requirements in patients with hypoperfusion-induced
lactic acidemia with pH ≥7.15 (grade 2B).

Deep Vein Thrombosis Prophylaxis
• 1. Patients with severe sepsis should receive daily
pharmacoprophylaxis against venous thromboembolism (VTE)
(grade 1B).
• LMWH is preferred (grade 1B versus twice daily UFH, grade 2C
versus three times daily UFH).
• Evidence supports three times daily UFH(5000 IU) compared to
two times daily UFH
• If creatinine clearance is <30 mL/min, use dalteparin (grade 1A)
or another form of LMWH with low degree of renal metabolism
(grade 2C) or UFH (grade 1A).
• 2. Patients with severe sepsis be treated with a combination of
pharmacologic therapy and intermittent pneumatic compression
devices whenever possible (grade 2C).
King CS, Holley AB, Jackson JL, et al: Twice vs three times daily heparin dosing for thromboembolism
prophylaxis in the general medical population: A meta analysis. Chest 2007; 131:507–516

• 3. Septic patients who have a contraindication for heparin
use (eg, thrombocytopenia, severe coagulopathy, active
bleeding, recent intracerebral hemorrhage) should not
receive pharmacoprophylaxis (grade 1B),
• They should receive mechanical prophylactic treatment,
such as graduated compression stockings or intermittent
compression devices (grade 2C), unless contraindicated.
• When the bleeding risk decreases start pharmacoprophylaxis
(grade 2C).

• H2 blocker or PPI recommended in severe sepsis/septic
shock with risk factors for bleeding (grade 1B).
• When stress ulcer prophylaxis is used, proton pump
inhibitors rather than H2RA (grade 2D)
• The rationale for considering only suppression of acid
production (and not sucralfate) is based on the study of
1,200 patients by Cook et al comparing H2 blockers and
sucralfate
• Patients without risk factors do not receive prophylaxis
(grade 2B).
Stress Ulcer Prophylaxis
Cook D, Guyatt G, Marshall J, et al: A comparison of sucralfate and ranitidine for the prevention of upper
gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N
Engl J Med 1998; 338:791–797

• Administer oral or enteral (if necessary) feedings, as
tolerated, rather than either complete fasting or provision of
only intravenous glucose within the first 48 hours after a
diagnosis of severe sepsis/septic shock (grade 2C).
• Avoid mandatory full caloric feeding in the first week but
rather suggest low dose feeding (eg, up to 500 calories per
day), advancing only as tolerated (grade 2B).
Nutrition

• 3. Use intravenous glucose and enteral nutrition rather
than total parenteral nutrition (TPN) alone or parenteral
nutrition in conjunction with enteral feeding in the first 7
days after a diagnosis of severe sepsis/septic shock (grade
2B).
• 4. Use nutrition with no specific immunomodulating
supplementation rather than nutrition providing specific
immunomodulating supplementation in patients with
severe sepsis (grade 2C).

Setting Goals of Care
• Discuss goals of care and prognosis with patients and
families (grade 1B).
• Incorporate goals of care into treatment and end-of-life care
planning, utilizing palliative care principles where
appropriate (grade 1B).
• Address goals of care as early as feasible, but no later than
within 72 hours of ICU admission (grade 2C).

Impact of SSC 2012
• A retrospective study in East Surrey hospital showed a
20% relative decrease in mortality after the second
publication of surviving sepsis guidelines.
• The original aim of the campaign was to reduce mortality
from sepsis by 25% in 5 years
• Overall the surviving sepsis campaign has had a
significantly beneficial effect on mortality rates in
patients with sepsis.
Melville J, Ranjan S, Morgan P. ICU mortality rates in patients with sepsis before and after
the Surviving Sepsis Campaign. Critical Care. 2015;19(Suppl 1):P15.

Newer biomarkers
Cesar Henriquez-Camacho and Juan Losa, “Biomarkers for Sepsis,” BioMed Research
International, vol. 2014, Article ID 547818, 6 pages, 2014

TREM (triggering receptor expressed on myeloid cells)
• Its expression on phagocytes is upregulated by exposure
to bacteria and fungi
• A meta-analysis of 11 studies (1795 patients included)
showed a pooled sensitivity and specificity of 79% and
80%
• In this meta-analysis, for a prevalence of 62% of sepsis,
the negative predictive value (NPV) was 0.7 and the
positive predictive value (PPV) is 0.86
• Plasma sTREM-1 had a moderate diagnostic performance
in differentiating sepsis from SIRS and was not sufficient
for sepsis diagnosis in systemic inflammatory patients
C. Bopp et al. “Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory response
syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation,” European
Journal of Anaesthesiology, vol. 26, no. 6, pp. 504–507, 2009

• The soluble form of urokinase-type plasminogen activator
receptor (suPAR) is a new biological marker of
immunologic activation
• High serum suPAR concentrations have also been found
to predict mortality in patients with active tuberculosis
and other diseases associated with an inflammatory
response
• Recently, two studies evaluating diagnostic accuracy of
suPAR have shown specificity from 64–77%
K. Donadello, S. Scolletta, F. S. Taccone et al., “Soluble urokinase-type plasminogen activator receptor as a
prognostic biomarker in critically ill patients,” Journal of Critical Care, vol. 24, no. 1, pp. 144–149, 2014.
A. Koch, S. Voigt, C. Kruschinski et al., “Circulating soluble urokinase plasminogen activator receptor is
stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically
ill patients,” Critical Care, vol. 15, no. 1, article R63, 2011

• Adrenomedullin (ADM) is a 52-amino-acid peptide with
immune modulating, metabolic, and vasodilator activity
• Pro-ADM is a biomarker of prognostic value and could
be used to identify more severe patients with pneumonia
and/or needing ICU care
• In a recent single prospective observational study
conducted in a Spanish adult intensive care unit (137
patients), pro-ADM showed a significant dose-response
trends to predict hospital mortality (OR = 3.00, 95% CI
1.06–8.46) compared to PCT and CRP. However, the
prognostic accuracy was better for severity scores than
for any biomarker
B. Suberviola et al; “Hospital mortality prognostication in sepsis using the new biomarkers suPAR and
proADM in a single determination on ICU admission,” Intensive Care Medicine, vol. 39, no. 11, pp. 1945–
1952, 2013.

• An Italian study comparing PCT and MR-pro-ADM in
200 septic patients, 90 patients with SIRS, and 30 healthy
individuals, the pro-ADM distinguished septic patients.
The combined use of PCT and MR-pro-ADM gave a
posttest probability of 0.998 in the cohort of all septic
patients. The combination of biomarkers may
substantially improve the early diagnosis of sepsis
S. Angeletti et al; “Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis
diagnosis,” Clinical Chemistry and Laboratory Medicine, vol. 51, no. 5, pp. 1059–1067, 2013.

• sCD14 subtype (sCD14-ST), or presepsin, is normally
present in very low concentrations in the serum of healthy
individuals and has been shown to be increased in
response to bacterial infections
• Presepsin has showed a significant prognostic value and
initial values were significantly correlated with in-
hospital mortality of patients affected by sepsis, severe
sepsis, or septic shock
S. Masson, P. Caironi, E. Spanuth et al., “Presepsin, (soluble CD14 subtype) and procalcitonin levels for
mortality prediction in sepsis: data from the Albumin Italian Outcome Sepsis trial,” Critical Care, vol. 18,
no. 1, article R6, 2014.
B. Liu, Y. X. Chen, Q. Yin, Y. Z. Zhao, and C. S. Li, “Diagnostic value and prognostic evaluation of
Presepsin for sepsis in an emergency department

• Recent studies have shown that the alteration of
natriuretic peptide and troponin levels strongly predicated
the prognosis in patients with sepsis or septic shock
• Higher serum level of myoglobin could predict more
severity and poor outcome for patients with sepsis
Cheng H, Fan WZ, Wang SC, et al. N-terminal pro-brain natriuretic peptide and cardiac
troponin I for the prognostic utility in elderly patients with severe sepsis or septic shock in
intensive care unit: A retrospective study. J Crit Care. 2015 Jun;30(3):654.e9-14
Yao L,Liu Z, Zhu J, et al, Higher serum level of myoglobin could predict more
severity and poor outcome for patients with sepsis, Am J Emerg Med (2016)

NEWER DRUGS
• Ulinastatin (or urinary trypsin inhibitor, UTI, bikunin) is an
acidic glycoprotein found in the human blood and urine
• Ulinastatin inhibits the processes of coagulation and
fibrinolysis, and promotes microperfusion.
• The action of Ulinastatin on the expression of various
immune regulatory cells, proinflammatory mediators and
HLA-DR in CD14+ monocytes suggests that it is expected to
improve prognosis of patients with severe sepsis
Karnad DR, Bhadade R, Verma P.K, Moulick ND, Daga MK, Chafekar ND, et al. Intravenous
administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized
controlled study. Intensive Care Med. Jun 2014; 40(6):830-8
Wu TJ, Zhang LN, Kang CC. Zhonghua Wei. The effect of ulinastatin on disbalance of inflammation
and immune status in patients with severe sepsis. Zhong Bing Ji Jiu Yi Xue. Apr 2013 ; 25(4):219-23

• Beta-blockade — Beta-blocker therapy may potentially
attenuate the deleterious effects of the sympathetic
adrenergic response that occurs during septic shock. One
open-label, single center trial randomized 154 patients with
septic shock to an esmolol infusion or standard therapy
Compared to patients on standard therapy, patients receiving
esmolol had improvements in the following variables at 96
hours:
• Greater decline from baseline HR (by 28 beats/min versus
6 beats/min)
• Higher left ventricular stroke work index (43 versus
31 mL/m2)
Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and
clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013; 310:1683.

• Reduced need for vasopressors (-0.11 mcg/kg/min versus
-0.01 mcg/kg/min)
• Reduced need for fluid replacement
therapy (4L/day versus 5.4 L/day)
• Improvements were also observed in secondary outcomes
that included metabolic variables (eg, lactate and pH),
markers of end organ function (eg, glomerular filtration
rate) and 28-day mortality (50 versus 81 percent).
Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and
clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013; 310:1683.

Opal SM, Dellinger RP, Vincent J-L, Masur H, Angus DC. The next generation of sepsis trials: What’s next
after the demise of recombinant human activated Protein C? Critical care medicine. 2014;42(7):1714-1721

Drugs being invstigated
• Naloxone
• Pentoxifylline
• GM-CSF
• Anti-endotoxin Vaccine
(In Phase II trials now)

• Eritoran (Synthetic lipid A antagonist)
(no reduction in 28 day mortality – ACCESS trial)
Opal SM et al; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-
TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.
JAMA. 2013 Mar 20;309(11):1154-62
• Human Lactoferrin (no reduction in 28 day mortality
and even maybe harmful)
Vincent JL et al; Talactoferrin in Severe Sepsis: Results From the Phase II/III Oral
talactoferrin in Severe sepsis Trial. Crit Care Med. 2015 Sep;43(9):1832-8
• Haemoperfusion through adsorptive materials like
polymixin B fibre column have shown reduced
mortality in some studies
Vincent JL, Laterre PF, Cohen J, et al. A pilot-controlled study of a polymyxin B-
immobilized hemoperfusion cartridge in patients with severe sepsis secondary to intra-
abdominal infection. Shock 2005; 23:400.

Rosuvastatin
• Statins reduce inflammation and have been shown to prevent ARDS
in murine models
• A study done by The National Heart, Lung, and Blood Institute ARDS
Clinical Trials Network showed that Rosuvastatin therapy did not
improve clinical outcomes in patients with sepsis-associated ARDS
and may have contributed to hepatic and renal organ dysfunction
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for
Sepsis-Associated Acute Respiratory Distress Syndrome.The New England journal of medicine.
2014;370(23):2191-2200. doi:10.1056/NEJMoa1401520.

• Sepsis is defined as life-threatening organ dysfunction
caused by a dysregulated host response to infection
• infection and an acute increase of ≥ 2 SOFA points
• Septic shock is a subset of sepsis in which underlying
circulatory and cellular metabolic abnormalities are
profound enough to substantially increase mortality
• a clinical construct of sepsis with persisting hypotension
requiring vasopressors to maintain MAP≥65mmHg and
having a serum lactate level>2 mmol/L (18mg/dL)
despite adequate volume resuscitation

• Although there are many conflicting studies on the use of
EGDT, it remains significant in our setting
• Early identification and prompt therapy of sepsis should
be the goal

• Hundreds of millions of dollars have been expended
enrolling over 30,000 patients in clinical trials to test and
develop new agents in sepsis.
• Yet, not a single agent has convincingly proven to be
consistently efficacious in clinical trials. There are no
new drugs on the market to show for all this effort
• This warrants that some new ideas need to be instituted in
drug discovery and evaluation process
• “The definition of insanity is repeating the same
experiment over and over again, expecting a different
result” - Albert Einstein

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