1. Pathophysiology and Management of Sepsis
Keith Wille, MD
2016 CRRT Highlights
Hyderabad, India

2. Outline Epidemiology Definition Pathophysiology Management
Future Directions

3. Case Presentation
A 49 yo woman presents to the ED with nausea, occasional vomiting, fever, and flank pain. She notes mild dysuria, decreased urine output, and urinary frequency.
She has a history of diabetes. Her blood pressure is 80/40, pulse 110, respiratory 24, temp 39.7 C
Labs – WBC 6.4 (68% PMN, 2% Ba, 21% L), Cr 2.1 mg/dL, Plt 97,000

4. Questions
While you are planning your evaluation and treatment, you consider …
Does this patient have sepsis?
Does she meet criteria by the 2016 definition?
What interventions should be considered, and how fast should they be started?

5. Epidemiology Adults Pediatric 571,000 /year in the US Mortality
Severe Sepsis: 15-30%
Septic Shock: 20-60%
Pediatric
40,000/year in the US
Mortality
Severe Sepsis: 4-7%
Septic Shock: 13-34%
10th Leading Cause of Death
Wang et. Al 2007, Critical Care Medicine,
Noah, 2014 Clinical Pediatric Emergency Medicine

6. Prospective ICU data collection, 10 days in May 2012 at 730 centers in 84 countries
Patients with sepsis were at greater risk for in-hospital death (OR 1.29, [95% CI: ])
ICU and hospital mortality rates in septic patients were 25.8% and 35.3%, respectively.
Varied between :
11.9% and 19.3% (Oceania) to
39.5% and 47.2% (Africa)
Summary
Background Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce,
but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit
of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality.
Methods 730 participating centres in 84 countries prospectively collected data on all adult (>16 years) patients admitted to
their ICU between May 8 and May 18, 2012, except those admitted for fewer than 24 h for routine postoperative
monitoring. Participation was voluntary. Data were collected daily for a maximum of 28 days in the ICU and patients
were followed up for outcome data until death or hospital discharge. In-hospital death was analysed using multilevel
logistic regression with three levels: patient, hospital, and country.
Findings patients were included from ICUs in Europe (5445 patients; 54·1%), Asia (1928; 19·2%), the
Americas (1723; 17·1%), Oceania (439; 4·4%), the Middle East (393; 3·9%), and Africa (141; 1·4%). Overall,
2973 patients (29·5%) had sepsis on admission or during the ICU stay. ICU mortality rates were 16·2% (95% CI
15·5–16·9) across the whole population and 25·8% (24·2–27·4) in patients with sepsis. Hospital mortality rates were
22·4% (21·6–23·2) in the whole population and 35·3% (33·5–37·1) in patients with sepsis. Using a multilevel
analysis, the unconditional model suggested signifi cant between-country variations (var=0·19, p=0·002) and betweenhospital
variations (var=0·43, p<0·0001) in the individual risk of in-hospital death. There was a stepwise increase in
the adjusted risk of in-hospital death according to decrease in global national income.
Interpretation This large database highlights that sepsis remains a major health problem worldwide, associated with
high mortality rates in all countries. Our fi ndings also show a signifi cant association between the risk of death and the
global national income and suggest that ICU organisation has an important eff ect on risk of death.
Funding None.

7. Increased Incidence of Sepsis
The incidence of sepsis has been increasing
1.5 – 8.7%/ year
Possible contributing factors
Use of antibiotics leading to microbial resistance
More invasive procedures
Increasing use of immunosuppression
Increasing age of population
Martin. NEJM 2003

8. Microbiology Spectrum (EPIC II Study)
(n=14,000; 1265 ICUs in 75 countries; May 2007)

9. Changing Definition of Sepsis

10. Sepsis as a Disease Continuum
Infection or Trauma
SIRS
Sepsis
Severe Sepsis
Adult Criteria
A clinical response arising from a nonspecific insult, including  2 of the following:
Temperature  38oC, or  36oC
HR  90 beats/min
Respirations  20/min
WBC count 12,000/mm3, or 4,000/mm3,
or >10% bands
Sepsis with
1 sign of
organ dysfunction
Septic Shock
SIRS with a presumed
or confirmed infectious
process
Associated with biochemical changes:
Increased: IL-6, adrenomedullin, (s)CD14, sELAM-1, MIP-1a, CRP
Crit Care Med 1992;20:
Crit Care Med 2003;31(4):
It has become clear recently that SIRS alone does not add to the risk of death (Alberti. AJRCCM : 77) – see next slide.
SIRS = Systemic Inflammatory Response Syndrome
Bone Chest. 1992;101:1644.

11. Problems with the Previous Definitions
SIRS-based
Up to 50% of hospital ward patients may have SIRS, and so screening for sepsis is impractical
Confusion between the terms infection, sepsis, and severe sepsis
Different criteria for sepsis resulted in different published rates and outcomes
Background: In 1992, the first consensus definition of severe
sepsis was published. Subsequent epidemiologic estimates were
collected using administrative data, but ongoing discrepancies
in the definition of severe sepsis produced large differences in
estimates.
Objectives: We seek to describe the variations in incidence and
mortality of severe sepsis in the United States using four methods
of database abstraction. We hypothesized that different methodologies
of capturing cases of severe sepsis would result in disparate
estimates of incidence and mortality.
Design, Setting, Participants: Using a nationally representative
sample, four previously published methods (Angus et al, Martin et al,
Dombrovskiy et al, and Wang et al) were used to gather cases
of severe sepsis over a 6-year period (2004–2009). In addition,
the use of new International Statistical Classification of Diseases,
9th Edition (ICD-9), sepsis codes was compared with previous
methods.
Measurements: Annual national incidence and in-hospital mortality
of severe sepsis.
Results: The average annual incidence varied by as much as
3.5-fold depending on method used and ranged from 894,013
(300/100,000 population) to 3,110,630 (1,031/100,000) using
the methods of Dombrovskiy et al and Wang et al, respectively.
Average annual increase in the incidence of severe sepsis was
similar (13.0% to 13.3%) across all methods. In-hospital mortality
ranged from 14.7% to 29.9% using abstraction methods of
Wang et al and Dombrovskiy et al. Using all methods, there was a
decrease in in-hospital mortality across the 6-year period (35.2%
to 25.6% [Dombrovskiy et al] and 17.8% to 12.1% [Wang et al]).
Use of ICD-9 sepsis codes more than doubled over the 6-year
period (158,722 – 489,632 [ severe sepsis], 131,719 –
303,615 [ septic shock]).
Conclusion: There is substantial variability in incidence and mortality
of severe sepsis depending on the method of database
abstraction used. A uniform, consistent method is needed for use
in national registries to facilitate accurate assessment of clinical
interventions and outcome comparisons between hospitals and
regions. (Crit Care Med 2013; 41:1167–1174)
BACKGROUND
The consensus definition of severe sepsis requires suspected or proven infection,
organ failure, and signs that meet two or more criteria for the systemic inflammatory
response syndrome (SIRS). We aimed to test the sensitivity, face validity, and
construct validity of this approach.
METHODS
We studied data from patients from 172 intensive care units in Australia and New
Zealand from 2000 through We identified patients with infection and organ
failure and categorized them according to whether they had signs meeting two or
more SIRS criteria (SIRS-positive severe sepsis) or less than two SIRS criteria (SIRSnegative
severe sepsis). We compared their characteristics and outcomes and assessed
them for the presence of a step increase in the risk of death at a threshold
of two SIRS criteria.
RESULTS
Of 1,171,797 patients, a total of 109,663 had infection and organ failure. Among
these, 96,385 patients (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%)
had SIRS-negative severe sepsis. Over a period of 14 years, these groups had similar
characteristics and changes in mortality (SIRS-positive group: from 36.1% [829 of
2296 patients] to 18.3% [2037 of 11,119], P<0.001; SIRS-negative group: from 27.7%
[100 of 361] to 9.3% [122 of 1315], P<0.001). Moreover, this pattern remained
similar after adjustment for baseline characteristics (odds ratio in the SIRS-positive
group, 0.96; 95% confidence interval [CI], 0.96 to 0.97; odds ratio in the SIRSnegative
group, 0.96; 95% CI, 0.94 to 0.98; P = 0.12 for between-group difference).
In the adjusted analysis, mortality increased linearly with each additional SIRS
criterion (odds ratio for each additional criterion, 1.13; 95% CI, 1.11 to 1.15;
P<0.001) without any transitional increase in risk at a threshold of two SIRS criteria.
CONCLUSIONS
The need for two or more SIRS criteria to define severe sepsis excluded one in eight
otherwise similar patients with infection, organ failure, and substantial mortality
and failed to define a transition point in the risk of death. (Funded by the Australian
and New Zealand Intensive Care Research Centre.)

12. Definitions of sepsis and septic shock were last revised in 2001
Definitions of sepsis and septic shock were last revised in Since then , advances have been made into the sepsis pathobiology, management, and epidemiology.
A task force was convened by Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)
IMPORTANCE Definitions of sepsis and septic shock were last revised in Considerable
advances have since been made into the pathobiology (changes in organ function,
morphology, cell biology, biochemistry, immunology, and circulation), management, and
epidemiology of sepsis, suggesting the need for reexamination.
OBJECTIVE To evaluate and, as needed, update definitions for sepsis and septic shock.
PROCESS A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and
epidemiology was convened by the Society of Critical Care Medicine and the European
Society of Intensive Care Medicine. Definitions and clinical criteria were generated through
meetings, Delphi processes, analysis of electronic health record databases, and voting,
followed by circulation to international professional societies, requesting peer review and
endorsement (by 31 societies listed in the Acknowledgment).
KEY FINDINGS FROMEVIDENCE SYNTHESIS Limitations of previous definitions included an
excessive focus on inflammation, the misleading model that sepsis follows a continuum
through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic
inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are
currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in
reported incidence and observed mortality. The task force concluded the term severe sepsis
was redundant.
RECOMMENDATIONS Sepsis should be defined as life-threatening organ dysfunction caused
by a dysregulated host response to infection. For clinical operationalization, organ
dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ
Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital
mortality greater than 10%. 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. Patients with septic shock can be clinically
identified by a vasopressor requirement to maintain a mean arterial pressure of 65mmHg
or greater and serum lactate level greater than 2 mmol/L (>18mg/dL) in the absence of
hypovolemia. This combination is associated with hospital mortality rates greater than 40%.
In out-of-hospital, emergency department, or general hospital ward settings, adult patients
with suspected infection can be rapidly identified as being more likely to have poor outcomes
typical of sepsis if they have at least 2 of the following clinical criteria that together constitute
a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater,
altered mentation, or systolic blood pressure of 100mmHg or less.
CONCLUSIONS AND RELEVANCE These updated definitions and clinical criteria should replace
previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and
facilitate earlier recognition and more timely management of patients with sepsis or at risk of
developing sepsis.

13. Redefining Sepsis in 2016
Changes categories to sepsis and septic shock
qSOFA (Quick SOFA) as a new diagnostic screening tool, 2 of 3 indicators:
Alteration in mental status
Systolic blood pressure < 100 mm Hg *
Respirations > 22 breaths/min *
Septic Shock Defined:
Persisting hypotension requiring vasopressors to maintain MAP ≥ 65 mm Hg
Blood lactate >2 mmol/L despite adequate volume resuscitation
A task force of 19 leaders in the field of sepsis was convened by SCCM and the European Society of Intensive Care Medicine (ESICM)

14. Evolving Definitions of Sepsis

15. Redefining Sepsis in 2016 Concerns with New Definition
Delayed diagnosis
Retrospective data review
Consensus of 2 organizations
Under the new definition, expected mortality decreases
sepsis terminology used instead of severe sepsis.
Septic Shock (n=1,134)
Severe Sepsis (n=827)
Probability of Death
Sepsis (n=1,063)
Infection, no SIRS (n=584)
Decisions based on retrospective data
(sepsis terminology would be used instead of severe sepsis or septic shock).
This gives the potential appearance that the organization is treating patients poorly as the observed mortality is high in comparison to what is expected.
Days in Hospital
Alberti C et al. AJRCCM 2003; 168: 77-84

16. Identifying Sepsis
Outside the ICU, the qSOFA has similar predictive validity to more complex scores
In the ICU, the SOFA has greater predictive validity than qSOFA or SIRS
Sepsis Redefined. SCCM 2016; Mar 29;

17. Identifying Patients with Sepsis

18. Sequential Organ Failure Assessment (SOFA) Score Defines Sepsis-Related Organ Dysfunction

19. Take Home Points: Sepsis Criteria
Prompt outside the ICU to consider sepsis
Infection plus 2 or more qSOFA points
Clinical criteria for sepsis
Infection plus 2 or more SOFA points
(or change from baseline)

20. Take Home Points: Septic Shock
profound circulatory, cellular, and metabolic abnormalities
greater risk of mortality
Despite adequate fluid resuscitation
vasopressors needed to maintain MAP ≥65 mmHg
and
lactate >2 mmol/l
Both sepsis and septic shock are identified based on clinical criteria

21. Pathophysiology

22. Sepsis Immunology
Figure 1. Sepsis immunology. The graph illustrates the different pillars influencing the immune response during sepsis. During infection the immune response of every individual is shaped in a unique way by predisposing endogenous and exogenous factors making it more or less likely that sepsis occurs. Septic shock with increased levels of pro- inflammatory mediators as well as increased anti-inflammation leading to long-lasting immuno-suppression with reactivated viral or newly developed nosocomial secondary infections can result in death. In addition to these major events, exhaustion of immunocompetent cells and increased activation of immunosuppressive mechanisms impact the survival during the course of sepsis. If the infection can be controlled by the immune system and the regulatory processes during the course of sepsis are balanced the likelihood for survival increases. However, a better understanding of all four pillars is needed and will facilitate better and more individualized treatment strategies during sepsis. SNPs – Single Nucleotide Polymorphisms, IL – interleukin, TNF – tumor necrosis factor, HMGB1 – high mobility group box 1, NO – nitric oxide, ATF3 – activating transcription factor 3, ST2 – suppression of tumorigenicity 2, IFN-I – type-1-like interferon.

23. Pathophysiology of Sepsis
Excessive pro- and anti-inflammatory cytokines
TNF, IL-6, IL-8, IL-10,
Kinins, Thrombins
Heat shock proteins
Cell activation
Immunosuppression
Oxidant stress
Apoptosis
Disordered coagulation, micro-thrombosis
Endothelial / epithelial dysfunction
Microcirculatory dysfunction
Inappropriate cell repair
Multiple Organ Dysfunction Syndrome (MODS)

24. Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis
Altered Consciousness
Confusion
Psychosis
Tachycardia
Hypotension
Altered CVP
Altered PAOP
Myocardial depression
Tachypnea
PaO2 <70 mm Hg
SaO2 <90%
PaO2/FiO2 300
Oliguria
Anuria
 Creatinine
Following identification of a patient with sepsis, the clinician must assess the patient for the presence of acute organ dysfunction (severe sepsis). The presence of acute organ dysfunction is often recognized clinically by the patient’s presenting signs and symptoms. However, in some instances laboratory data or results of invasive monitoring will confirm the diagnosis of organ dysfunction.
The illustration of the patient on this slide has arrows pointing to various organs that might provide clues to the presence of organ dysfunction. Indications of organ dysfunction include:
Central nervous system: altered consciousness, confusion, psychosis, delirium
Respiratory system: tachypnea, hypoxemia, oxygen saturation <90%, decreased ratio of arterial oxygen vs inspired oxygen
Liver: jaundice, increased liver enzymes, hypoalbuminemia, increased prothrombin time
Cardiovascular: tachycardia, hypotension, altered central venous pressure, altered pulmonary artery occlusive pressure
Kidney: oliguria, anuria, increased creatinine
Hematological: thrombocytopenia, abnormal coagulation tests, decreased levels of Protein C, increased D-dimers
Balk RA. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit Care Clin 2000;16:
Jaundice
 Enzymes
 Albumin  PT
 Platelets
 PT/APTT
 Protein C
 D-dimer
Immunesuppression
Immobility
Catabolism
Myopathy
Balk Crit Care Clin 2000;16:337

25. Organ System Dysfunction
Organ failure has a cumulative effect on mortality.
Organs failure frequency:
Lungs (18%)
Kidneys (15%)
CV (7%)
Hematologic (6%)
Early recognition influences outcome.
Number of Organ Failures
Angus Crit Care Med 2001
Martin NEJM 2003

26. Changes in Understanding of Sepsis Pathophysiology
More than just unimpeded inflammation
Key role of immunosuppression
Contribution of non-immune mechanisms
Possible adaptive nature of organ dysfunction – hibernation
Re-appraisal of the nature of septic shock
Abstract
Background: Despite increased understanding of the pathophysiology of septic acute
kidney injury (AKI), treatment options are limited, and mortality remains high. Summary:
Septic AKI is triggered by pathogen-associated molecular patterns from bacteria and damage-
associated molecular patterns released from or exposed on damaged cells. Downstream
effects include glomerular and peritubular endothelial dysfunction, downregulation
of tubular reabsorptive work, cell-cycle arrest, regulated cell death and destruction
of damaged cell organelles. In the laboratory, pharmacological modulation of some of
these pathways prevents AKI or enhances recovery from AKI, yet no data exist to support
the utility of such AKI therapy in man. However, avoiding systemic and renal venous congestion,
hypotension and fluid overload attenuates AKI in critically ill septic patients. Key
Message: While therapies aiming at modulating the sepsis-induced cellular response are
discovered and tested, hemodynamic optimization remains critical in patients with or at
risk of AKI.

27. Management
Bundles
Fluids
Pressors
Antibiotics
Adjunctive measures

28. Pathway of Care Rapid Recognition Rapid Initiation of Treatment
3 Hour Bundle
6 Hour Bundle
Reassessment parameters
Critical Monitoring and Targeted Therapies

29. Treatment Initiation 3 Hour Bundle
Serum Lactate
Broad Spectrum
Antibiotics
(* within 1 hr by SSC)
Blood Cultures
Fluid Resuscitation
30 ml/kg Crystalloid
Serum lactate measured
Blood culture obtained prior to antibiotics
Broad-spectrum antibiotics within 3 hour of presentation to the ED, or within 1 hour in currently hospitalized patients
Deliver an initial minimum of 30 ml/kg of crystalloid if hypotensive or elevated lactate > 4 mmol/L

30. Early Goal Directed Therapy
Single Center Study (US)
263 Patients
Severe Sepsis/Septic Shock
Mortality reduction of 12.6%
NNT = 8
Limitations
Difficult to parse out the individual impact of each intervention
Use of invasive central venous monitoring
difficult to demonstrate benefit
Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy
Collaborative Group. Early goal-directed therapy in the treatment of severe
sepsis and septic shock. N Engl J Med Nov 8;345(19):
Objectives: To determine “whether early goal-directed therapy before admission to
the intensive care unit effectively reduces the incidence of multiorgan dysfunction,
mortality, and the use of health care resources among patients with severe sepsis or
septic shock.” (p. 1369)
Methods: this prospective randomized study was conducted at Henry Ford Hospital,
a large urban academic center, between March 1997 and March Adult patients
presenting to the emergency department with two criteria for the systemic
inflammatory response syndrome and either a systolic blood pressure of 90 mmHg or
less after a fluid challenge, or blood lactate of 4 mmol per liter or more were eligible
for inclusion. Patients were randomized to either early goal directed therapy
(EGDT) or standard therapy.
All patients in both groups underwent arterial in central venous catheterization.
Patients in the standard therapy group treated at the discretion of the treating
physicians according to a protocol that aimed at maintaining central venous pressure
(CVP) between 8 and 12 mmHg, mean arterial pressure (MAP) ≥ 65 mmHg, and
urine output ≥ 0.5 mL/kg/hr. These patients were admitted for inpatient care as soon
as possible.
Patients in the EGDT group were treated according to protocol for at least six hours
in the emergency department prior to admission. This protocol consisted of a 500 mL
bolus of fluid every 30 minutes to achieve a CVP of 8 to 12 mmHg. Vasopressors
were given to maintain a MAP of at least 65 mmHg, when necessary. Vasodilators
were given to maintain a MAP of less than 90 mmHg, when necessary. All patients
underwent continuous central venous oxygen saturation (ScvO2) monitoring. If the
ScvO2 was less than 70%, packed red blood cells were transfused to maintain a
hematocrit of at least 30%; if the ScvO2 was still less than 70% dobutamine was
infused at 2.5 µg per kilogram of body weight and titrated until the oxygen saturation
was 70% or higher.
The primary outcome was in-hospital mortality. Secondary outcomes included organ
dysfunction scores (APACHE II, SAPS II, and MODS), treatments administered, and
the consumption of healthcare resources (duration of vasopressor therapy and
mechanical ventilation and hospital length of stay). A total of 263 patients were
randomized, open 236 completed the initial six-hour study period. There were 133
subjects in the standard therapy group and 130 subjects in the EGDT group.
Limitations:
1. The intervention being assessed was a bundle, including many separate
interventions (ScvO2 monitoring, CVP monitoring, aggressive blood transfusion,
and the use of inotropic infusions). It is unclear which component(s) led to the
observed reduction in mortality.
2. The study was not blinded, and there is a very real risk of performance bias as a
result.
3. Patients in the EGDT received significant more IV fluids in the 6-hour treatment
window, which potentially could have resulted in the observed reduction in
mortality.
4. The protocol required central venous access and arterial cannulation in all
patients in both study arms. This is contrary to standard practice in many
institutions, where central venous and arterial access is reserved for patients
requiring vasopressors.
5. The study evaluated a treatment protocol with multiple components. It is difficult
to ascertain the actual benefit of each individual component.
Bottom Line:
This large, randomized trial conducted at a large academic institution in the US
demonstrated a significant reduction in mortality with the use of early-goal directed
therapy in severe sepsis and septic shock. The use of a treatment protocol as the
intervention makes it difficult to ascertain which individual components contributed
to the efficacy of the protocol. Patients in the EGDT group received nearly 1.5 more
liters of fluid in the first six hours than the usual care group, which may have had a
significant impact on the reduction in mortality. More recent studies have shown no
benefit to EGDT in these patients, likely due to the more aggressive management
utilized in sepsis currently.

31. Recent EGDT Trials

32. NO DIFFERENCE between UC and EGDT groups
Abstract
Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency
department. In the presence of standard or usual care, the prevailing mortality was over %. In response, a
systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed
therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the
publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized
controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated
into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and
disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS,
ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the
elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A
review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed
therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential
for an appropriate interpretation of these trials and their conclusions. Nguyen et al. Critical Care (2016) 20:160
NO DIFFERENCE between UC and EGDT groups
Standard of care changed during subsequent trials
Better recognition and earlier intervention of sepsis care

33. Fluid Administraton in the EGD Trials
KEY POINTS
Fluid resuscitation to correct hypovolemia and support organ perfusion is central to current
management of severe sepsis and septic shock.
Recent randomized trials have not confirmed a benefit for targeting invasive physiologic parameters;
the ideal fluid volume and end points in sepsis resuscitation remain unknown.
Increased fluid balance is associated with increased mortality in early and late sepsis; whether conservative
fluid management can improve sepsis outcomes requires further study.
Hydroxyethyl starch increases risk of acute kidney injury and may increase mortality in patients with
sepsis.
Whether albumin or physiologically balanced crystalloids improve clinical outcomes in sepsis
remains the focus of ongoing study.

34. Saline vs Albumin Fluid Evaluation (SAFE) Study
6997 patients
Multi-center DBPRCT
Saline vs 4% Albumin
Findings
No difference in:
ICU or hospital LOS
Days on MV or RRT
Mortality
No outcome difference in severe sepsis patients
Subgroup with Severe Sepsis (600 per group): No statistical difference in outcome

35. P=0.39
Fig. 2. Survival curves of 3 large studies of volume resuscitation with human albumin solutions in severe sepsiswith no adverse effects on renal function: SAFE [55] (A), EARSS [58] (B), and ALBIOS [14] (C). Copyright permission obtained from original sources.
Fluid administration is a key intervention in hemodynamic resuscitation. Timely expansion (or restoration) of
plasma volume may prevent tissue hypoxia and help to preserve organ function. In septic shock in particular,
delaying fluid resuscitation may be associated with mitochondrial dysfunction and may promote inflammation.
Ideally, infused fluids should remain in the plasma for a prolonged period. Colloids remain in the intravascular
space for longer periods than do crystalloids, although their hemodynamic effect is affected by the usual metabolismof
colloid substances; leakage through the endotheliumin conditions with increased permeability, such as
sepsis; and/or external losses, such as with hemorrhage and burns. Albumin has pleiotropic physiological activities
including antioxidant effects and positive effects on vessel wall integrity. Its administration facilitates
achievement of a negative fluid balance in hypoalbuminemia and in conditions associated with edema. Fluid resuscitation
with human albumin is less likely to cause nephrotoxicity than with artificial colloids, and albumin
infusion has the potential to preserve renal function in critically ill patients. These properties may be of clinical
relevance in circulatory shock, capillary leak, liver cirrhosis, and de-escalation after volume resuscitation. Sepsis
is a candidate condition in which human albumin infusion to preserve renal function should be substantiated.
SAFE EARRS ALBIOS

36. SAFE - Saline vs Albumin Fluid Evaluation
ALBIOS - Albumin Italian Outcome Sepsis
EARRS - European Antimicrobial Resistance Surveillance System

37. Higher chloride fluids were associated with an
Background: The objective of this systematic review and meta-analysis was to assess the relationship
between the chloride content of intravenous resuscitation fluids and patient outcomes in the perioperative
or intensive care setting.
Methods: Systematic searches were performed of PubMed/MEDLINE, Embase and Cochrane Library
(CENTRAL) databases in accordance with PRISMA guidelines. Randomized clinical trials, controlled
clinical trials and observational studies were included if they compared outcomes in acutely ill or surgical
patients receiving either high-chloride (ion concentration greater than 111 mmol/l up to and including
154 mmol/l) or lower-chloride (concentration 111 mmol/l or less) crystalloids for resuscitation. Endpoints
examined were mortality, measures of kidney function, serum chloride, hyperchloraemia/metabolic
acidosis, blood transfusion volume, mechanical ventilation time, and length of hospital and intensive
care unit stay. Risk ratios (RRs), mean differences (MDs) or standardized mean differences (SMDs) and
confidence intervals were calculated using fixed-effect modelling.
Results: The search identified 21 studies involving 6253 patients. High-chloride fluids did not affect
mortality but were associated with a significantly higher risk of acute kidney injury (RR 1⋅64, 95
per cent c.i. 1⋅27 to 2⋅13; P <0⋅001) and hyperchloraemia/metabolic acidosis (RR 2⋅87, 1⋅95 to 4⋅21;
P <0⋅001). High-chloride fluids were also associated with greater serum chloride (MD 3⋅70 (95 per cent
c.i. 3⋅36 to 4⋅04) mmol/l; P <0⋅001), blood transfusion volume (SMD 0⋅35, 0⋅07 to 0⋅63; P =0⋅014) and
mechanical ventilation time (SMD 0⋅15, 0⋅08 to 0⋅23; P <0⋅001). Sensitivity analyses excluding heavily
weighted studies resulted in non-statistically significant effects for acute kidney injury and mechanical
ventilation time.
Conclusion: A weak but significant association between higher chloride content fluids and unfavourable
outcomes was found, but mortality was unaffected by chloride content.
Paper accepted 14 August 2014
Published online 30 October 2014 inWiley Online Library ( DOI: /bjs.9651
Introduction
The administration of intravenous fluids for resuscitation
occurs routinely in the perioperative setting and in the
management of critically ill patients. There has been considerable
interest in defining optimal fluid resuscitation
strategies1, yet practice patterns and fluid selection vary
considerably2. While much attention has been directed at
the ‘colloid versus crystalloid’ debate, increasing evidence
suggests clinically important differences related to intravenous
fluid chloride content3–7.
Often referred
Higher chloride fluids were associated with an
increased AKI risk but not an increased mortality risk

38. double cross-over trial 4 ICUs in NZ No difference in outcome Caveats
Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit:  The SPLIT Randomized Clinical Trial
JAMA. 2015;314(16): doi: /jama
N=2262
DB randomized,
double cross-over trial
4 ICUs in NZ
No difference in outcome
Caveats
- exposure to study fluid was modest (2L)
- population was low to
moderate risk for AKI
Importance  Saline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality.
Objective  To determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU).
Design and Setting  Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients.
Participants  All patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed.
Interventions  Participating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration.
Main Outcomes and Measures  The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality.
Results  In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, −2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, −0.1% [95% CI, −1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, −1.0% [95% CI, −3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40).
Conclusions and Relevance  Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality.
Trial Registration  clinicaltrials.gov Identifier: ACTRN
Cumulative Incidence of Patients Requiring Renal Replacement Therapy
Until Day 90 After Enrollment
JAMA. 2015;314(16):

39. 6 Hour Bundle
Vasopressors for MAP less than 65 mmHg after fluid resuscitation
Reassess volume status and tissues perfusion if persistent hypotension (MAP < 65) after initial fluid resuscitation or lactate > 4 mmol/L
Remeasure lactate if initial level elevated
Vasopressors Reassess volume status Remeasure serum lactate

40. Outcome: kidney failure defined by AKIN group stage 3 definition
Factorial 2X2 RCT at
18 Adult ICUs in the UK
N=409
Median age, 66 years
Male, 58.2%
Outcome: kidney failure
defined by AKIN group
stage 3 definition
IMPORTANCE:
Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.
OBJECTIVE:
To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.
DESIGN, SETTING, AND PARTICIPANTS:
A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.
INTERVENTIONS:
Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).
MAIN OUTCOMES AND MEASURES:
The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.
RESULTS:
A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]).
CONCLUSIONS AND RELEVANCE:
Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.
TRIAL REGISTRATION:
clinicaltrials.gov Identifier: ISRCTN
Kidney Failure Free Days

41. IMPORTANCE:
Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.
OBJECTIVE:
To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.
DESIGN, SETTING, AND PARTICIPANTS:
A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.
INTERVENTIONS:
Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).
MAIN OUTCOMES AND MEASURES:
The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.
RESULTS:
A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]).
CONCLUSIONS AND RELEVANCE:
Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.
TRIAL REGISTRATION:
clinicaltrials.gov Identifier: ISRCTN
There was less use of renal replacement therapy in the vasopressin group than in the
norepinephrine group (25.4% vs 35.3%; difference, -9.9% [95% CI, -19.3% to -0.6%]).

42. Control the Source of Infection
Technique Examples
Drainage Abscess Empyema
Debridement Necrotizing fasciitis Mediastinitis
Device removal Infected vascular catheter or urinary catheter
Definitive control Cholecystectomy Amputation

43. Adjunctive Issues Sedation/Analgesia/NM blockade
Protocols improve outcome
Mechanical Ventilation
Low tidal volume strategy (ARDSnet)
Corticosteroids
fluid refractory, pressor resistant, or adrenal insufficiency
Renal replacement therapy
Prophylaxis
Deep vein thrombosis
Stress ulcer
Nutrition support
Early engagement with physical therapy
Protocols improve ou
Key points
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated
host response to infection.
A specific protocol termed, ‘‘early goal-directed therapy,’’ has not been shown to
improve survival in sepsis compared with ‘‘usual care.’’
Although this specific protocol is not beneficial if applied to all patients with
sepsis, key tenets of sepsis management, including early fluid resuscitation, cultures,
antibiotic therapy, lactate measurement, and vasopressors (if indicated),
are indicated in all septic patients.
Compliance with 3- and 6-hour bundles of sepsis management is associated with
improved outcomes in septic patients.tcome for sedation/analgesia and glucose control.
Surviving Sepsis Guidelines 2012

44. Future Directions

45. ABSTRACT
Introduction: The incidence of sepsis, the systemic inflammatory response of the host to an
infectious insult, has steadily increased over past decades. This trend is expected to continue.
Sepsis is a leading cause of death and disability worldwide. Treatment relies on antibiotics
associated to source control and supportive care. Major progress has been made in the understanding
and overall management of sepsis. However, there is no specific treatment for sepsis.
Areas covered: We searched PubMed and the ClinicalTrials.gov site for English language reports
of phase II and III clinical trials pertaining to the field of sepsis. The current review provides a
summary of promising candidate treatments for sepsis. We broadly separated candidate drugs
into three distinct categories: Blood purification techniques, immunomodulatory drugs and
treatments targeting other systems including the heart, the endothelium or coagulation.
Expert opinion: Efforts to identify an efficient treatment for sepsis are hampered by the broad
definition of the syndrome associated with major heterogeneity between patients affected by
sepsis. The characterization of homogeneous groups of patients, through biological or clinical
markers is unfortunately lacking. Current research remains active. Candidate drugs for sepsis
include hemoperfusion with polymyxin B coated fibre devices, modulation of the immune system
with treatments such as hydrocortisone, intravenous immunoglobulins, mesenchymal stem cells,
GM-CSF or interferon gamma. Candidate drugs acting on the cardiovascular system include short
acting beta 1 blockers, levosimendan or selepressin. Finally, promising strategies, involving
monoclonal antibodies or protein antagonists, which selectively inhibit bacterial virulence factors
are being assessed at the bedside. A much awaited and needed specific treatment for sepsis will
hopefully soon emerge. EXPERT OPINION ON EMERGING DRUGS, 2016
VOL. 21, NO. 1, 27–37

46. ABSTRACT
Introduction: Sepsis is a heterogeneous syndrome characterized by both immune hyperactivity and
relative immune suppression. Biomarkers have the potential to improve recognition and management
of sepsis through three main applications: diagnosis, monitoring response to treatment, and stratifying
patients based on prognosis or underlying biological response.
Areas covered: This review focuses on specific examples of well-studied, evidence-supported biomarkers,
and discusses their role in clinical practice with special attention to antibiotic stewardship and
cost-effectiveness. Biomarkers were selected based on availability of robust prospective trials and metaanalyses
which supported their role as emerging tools to improve the clinical management of sepsis.
Expert commentary: Great strides have been made in candidate sepsis biomarker discovery and
testing, with the biomarkers in this review showing promise. Yet sepsis remains a dynamic illness
with a great degree of biological heterogeneity – heterogeneity which may be further resolved by
recently discovered gene expression-based endotypes in septic shock.

47. Purpose: The developing world carries the greatest burden of sepsis-related mortality, but success in managing
severe sepsis in resource-limited countries (RLCs) remains challenging. A “three delays” model has been developed
to describe factors influencing perinatal mortality in developing nations. This model has been validated across
differentWorld Health Organization regions and has provided the framework for policymakers to plan targeted
interventions. Here, we propose a three delays model for severe sepsis in RLCs.
Materials and Methods: A literature review was performed using the PubMed, Google Scholar, and Ovid databases.
Additional sources were found after review of the reference lists from retrieved articles.
Results:We propose a three delaysmodel for severe sepsis in adults in RLCs. The model highlights limitations in the
3 basic pillars of sepsis management: (1) sepsis recognition and diagnosis at the time of triage, (2) initial focused
resuscitation, and (3) postresuscitation clinical monitoring and reassessment.
Conclusions: Characterizing themajor barriers to effective treatment of severe sepsis in RLCs frames the problemin a
language common to global health circles, which may stimulate further research, streamline treatment, and reduce
sepsis-related mortality in the developing world.
© 2015 Elsevier Inc. All rights reserved.

48. Summary Early recognition and screening of sepsis
- qSOFA, serum lactate
Rapid resuscitation with IV fluids
Early source identification and management (broad spectrum IV antibiotics, control source of sepsis)
Vasopressors /Mechanical Ventilation / Critical Care management for persisting shock
Education of patient and family for at-risk conditions
(30mL/kg IVF bolus challenge)

49. Conclusions
Sepsis is a common problem and often demands treatment well before ICU admission
Several interventions now exist that improve survival in sepsis
Early recognition of sepsis and timely institution of therapy improve patient outcome

50. End

51. Acronyms Australasian Resuscitation In Sepsis Evaluation (ARISE)
Protocolised Management in Sepsis (ProMISe)
Protocol-based care for early septic shock ProCESS)

52. Clinical Criteria Identifying Patients With Sepsis and Septic Shock

53. Surviving Sepsis Campaign Bundles

54. Potential Therapeutic Targets in Septic AKI

55. Pathophysiology of Sepsis

56. Pathophysiology of Sepsis
Disorder Due to Uncontrolled Inflammation?
Increased inflamatory mediators like IL-1, TNF,
IL-6.
Based on animal studies.
In a study in children with meningococcemia, TNF levels directly correlated with mortality.
Clinical trials involving TNF anagonist, antiendotoxin antibodies, IL-1 receptor antagonists, cortocosteroids failed to show any benefits.
Patients with RA treated with TNF antagonist develop infectious complications.

57. Pathogenesis of Sepsis

58. Pathophysiology of Sepsis
Failure of Immune System to Eliminate
Microorganism?
Shift from inflammatory (ThI) to antiinflammatory response (Th2).
Anergy.
Apotosis of B cells, T cells, Dendritic cells.
Loss of macrophage expression of MHC Class I and co-stimulatory molecules.
Immunosuppressive effect of apoptotic cells.