A presentation in sepsis with recent updates.

1. SEPSIS
DR. NAVIN ADHIKARI
INTERNAL MEDICINE, NAMS RESIDENT

2. DEFINITIONS
 Infection is the invasion of normally sterile tissue by
organisms.
 Bacteremia is the presence of viable bacteria in the blood as
evident by blood culture.
 Sepsis is life-threatening organ dysfunction caused by a
dysregulated host response to infection.
 Septic shock is subset of sepsis in which underlying
circulatory and cellular/metabolic abnormalities lead to
substantially increased mortality risk as compared to sepsis.

3. DEFINITIONS
 Severe sepsis refers to sepsis-induced tissue
hypoperfusion or organ dysfunction with thought to be
due to the infection. ( Removed from Sepsis 3)
 Systemic inflammatory response syndrome (SIRS) is
the clinical syndrome that results from a dysregulated
inflammatory response to a insult, such as an
autoimmune disorder, pancreatitis, vasculitis,
thromboembolism, burns, or surgery.

4. MULTIPLE ORGAN DYSFUNCTION SYNDROME
 Multiple organ dysfunction syndrome (MODS) refers to progressive
organ dysfunction in an acutely ill patient, such that homeostasis
cannot be maintained without intervention. It is severe end of the
severity both SIRS and sepsis.
 Primary MODS is the well-defined insult in which organ dysfunction
occurs early and can be directly attributable to the insult itself (eg,
renal failure due to rhabdomyolysis)
 Secondary MODS is organ failure that is not in direct response to the
insult itself, but is a consequence of the host’s response (eg, acute
respiratory distress syndrome in patients with pancreatitis)

5. SIRS CRITERIA
SIRS criteria include 1 point for each of the following
(score range, 0–4):
 Temperature >38°C (>100.4°F) <36 C
 Tachypnoea breath >20 breaths per min
 Tachycardia with heart rate >90 beats per min
 Leukocytosis with white blood cell count >12,000/μL;
leukopenia <4000 or bands > 10 %
 More than two and suspected infection is Sepsis.

6. SIRS PITFALLS
 Issues not addressed by SIRS in Sepsis
 More than just rampant inflammation
 Key role of immuno suppression
 Contribution of non-immune mechanisms
 Possible adaptive nature of organ dysfunction-hibernation
 Ability to predict death is poor
 May be cased by other non infective pathologies that can
mimics sepsis

7. SEPSIS MIMICS
 Pancreatitis
 Drug reactions
 Widespread vasculitis – catastrophic antiphospholipid
syndrome, Goodpasture’s syndrome
 Autoimmune diseases – inflammatory bowel disease,
rheumatoid arthritis, systemic lupus erythematosus
 Malignancy – carcinoid syndrome
 Haematological conditions – haemophagocytic syndrome,
diffuse lymphoma, thrombotic thrombocytopenic purpura

8. SOFA
 SOFA is Sequential Organ Failure Assessment, is also known as
Sepsis Assossiated Organ Failure Assessment.
 The SOFA scoring system is composed of scores from six organ
systems, graded from 0 to 4 according to the degree of dysfunction
1. Respiratory-the ratio of arterial oxygen tension to fraction of
inspired oxygen (PaO2/FiO2)
2. Hepatic-the bilirubin level
3. CNS - GCS scale
4. CVS - the amount of vasoactive medication necessary to prevent
hypotension
5. Coagulation - the platelet concentration
6. Renal - the serum creatinine or urine output

9. CALCULATION OF SOFA SCORE

10. SOFA CONT..
 The SOFA score ranges from 0 to 24 points, with up to 4
points accrued across six organ systems.
 The SOFA score is widely studied in the ICU among
patients with infection, sepsis, and shock.
 With ≥2 new SOFA points, the infected patient is
considered septic and may be at ≥10% risk of in-hospital
death.

11. qSOFA
 The qSOFA score ranges from 0 to 3 points, with 1 point
each
 Hypotension – systolic blood pressure < 100 mmHg
 Altered mental status – Glasgow Coma Scale score ≤ 14
 Tachypnoea – respiratory rate ≥ 22 breaths/min
 Sepsis can also be diagnosed by suspected infection and
any two of above.
 Predictive validity similar to full SOFA score outside the
ICU
 Used in the emergency and wards for early detection of
Sepsis

12. qSOFA Continued
 Does not contain the lab parameter
 Can be used by the paramedics and nursing staff as well
 easy to measure repeatedly

14. DEFINITION AND CRITERIA COMPARISION
OF SEPSIS 1/2 AND 3

15. Sepsis
• SIRS
• (+) suspected
infection
Severe Sepsis
• Organ
dysfunction
Septic Shock
• Hypotension
despite adequate
fluid resuscitation
Sepsis
• SIRS
• (+) suspected
infection
Severe Sepsis
• Organ
dysfunction
Septic Shock
• Hypotension
despite adequate
fluid resuscitation
SEPSIS 1 AND 2
SEPSIS 3
SEPSIS

17. RISK FACTORS
 Intensive care unit admission – Approximately 50 percent of
intensive care unit (ICU) patients have a nosocomial infection .
 Bacteremia – Patients with bacteremia often develop systemic
consequences of infection..
 Advanced age (≥65 years) – is an independent predictor of
mortality due to sepsis.
 Immunosuppression – Comorbidities that depress host-defense
(eg, neoplasms, renal failure, hepatic failure, AIDS, asplenism)
and immunosuppressant medications.
 Diabetes and cancer – Diabetes and some cancers may alter the
immune system, result in an elevated risk for developing sepsis, and
increase the risk of nosocomial sepsis.

18. RISK FACTORS CONT..
 Community acquired pneumonia
 Previous hospitalization
 Genetic factors – genetic factors can increase the risk of
infection.

19. PATHOGENESIS
1. Initiation of the inflammatory response
2. Propagation of the inflammatory response
3. Activation of the coagulation system
4. Organ damage from sepsis
5. Increase in Lactate level
6. The anti-inflammatory cascade

20. PATHOGENESIS

21. HYPERLACTEMIA
 Not specific to Sepsis.
 Can occur in other shock and condition

22. HYPERLACTEMIA IN SEPSIS
 Lactate is powerful marker of illness severity
 Hyperlactatemia more frequently caused by impaired
tissue oxygen use rather than by impaired oxygen
delivery.
 Acidemia only observed in the presence of renal
dysfunction.
 Clinical significance – patients with impaired oxygen
delivery benefit from goal directed therapy. However,
the majority of patients with good O2 delivery but
impaired cellular O2 use may have worse outcome after
aggressive fluid replacement.

23. ETIOLOGY
 Causative agents vary significantly depending on the
region, hospital size, season, transplantation, oncology, or
haemodialysis units).
 Bacteria (gram-positive and gram-negative) are
identified as the causative organism in approximately
90% of cases.
 Mainly caused by Enterobacteriaceae, especially
Escherichia coli and Klebsiella pneumoniae, and by
Pseudomonas aeruginosa.
 Also caused by Staphylococcus aureus, coagulase
negative staphylococci, enterococci, and streptococci

24. ETIOLOGY
 The significant number of organism isolates that are now
resistant to antibiotics.
 The leading fungal pathogen causing sepsis is Candida.
 MRSA is also increasingly prevalent in the community.
 Over the last decades, vancomycin -resistant enterococci
(VREs) have emerged, with >10% of enterococci being
VREs.

25. SITE OF INFECTION
 The respiratory tract accounted for 44 - 60%.
 The bloodstream 20%
 Abdomen 26%
 Skin 14%
 Urinary system 12 - 20 %.
 In 20% to 30% of patients, a definite source of infection
is not found.

26. CLINICAL MANIFESTIONS
 Clinical manifestations of sepsis are quite variable,
depending on the initial site of infection, the offending
pathogen, the pattern of acute organ dysfunction, the
underlying health of the patient. (eg, cough and
shortness of breath of pneumonia, pain and purulent
exudate in a surgical wound may suggest an underlying
abscess).
 Two of the most commonly affected organ systems in
sepsis are the respiratory and cardiovascular systems.
 Respiratory compromise classically manifests as features
of acute respiratory distress syndrome (ARDS).

27. CLINICAL MANIFESTIONS CONT..
 Cardiovascular compromise typically presents as features
hypotension.
 Features of Acute kidney Injury like oliguria, azotemia
 Central nervous system dysfunction presents as coma or
delirium.
 Many other abnormalities occur in sepsis, including ileus,
features of thrombocytopenia and disseminated
intravascular coagulation, adrenal dysfunction, and
sick euthyroid syndrome.

28. MANAGEMENT
Surviving Sepsis Campaign: International Guidelines for
Management of Sepsis and Septic Shock: 2016
The initial SSC guidelines were first published in 2004 ,
and revised in 2008 and 2012 . The latest is of 2016 with
1hr bundle treatment on 2018.

29. INITIAL RESUSCITATION
 Sepsis and septic shock are medical emergencies, and
treatment and resuscitation begin immediately.
 At least 30 mL/Kg of IV crystalloid fluid within first 3 hours.
 After initial resuscitation, additional fluids guided by
frequent reassessment .
 MAP >65 mm Hg
 Further hemodynamic assessment (such as assessing cardiac
function e.g bedside echocardiography) to determine the type
of shock if the clinical examination does not lead to a clear
diagnosis.
 Guiding resuscitation to normalize lactate in patients with
elevated lactate levels as a marker of tissue hypoperfusion.

30. INITIAL RESUSCITATION
 Reassessment should include a thorough clinical
examination and evaluation of available physiologic
variables (heart rate, blood pressure, arterial oxygen
saturation, respiratory rate, temperature, urine
output, and others, as available) as well as other
noninvasive or invasive monitoring, as available.
 These new guidelines do not include prescribed
resuscitative targets such as CVP or ScV02 to guide
resuscitation.

31. DIAGNOSIS
 Appropriate routine microbiologic cultures (including
blood) be obtained before starting antimicrobial
therapy in patients with suspected sepsis or septic shock
if doing so results in no substantial delay in the start of
antimicrobials.
 Appropriate routine microbiologic cultures always include
at least two sets of blood cultures (aerobic and
anaerobic).

32. ANTIMICROBIAL THERAPY
 Administration of IV antimicrobials within one hour for
both sepsis and septic shock.
 Empiric broad-spectrum therapy with one or more
antimicrobials to cover all likely pathogens (including
bacterial and potentially fungal or viral coverage)
 Empiric antimicrobial therapy be narrowed once
pathogen identification and sensitivities are established
and/or adequate clinical improvement is noted with
evidence of infection resolution.
 Daily assessment for de-escalation of antimicrobial
therapy in patients with sepsis and septic shock

34. SOURCE CONTROL
 Source control be identified or excluded as rapidly as
possible and intervention be implemented as soon as possible..
Like drainage of an abscess, debridement of infected necrotic
tissue, removal of a potentially infected device.
 Prompt removal of intravascular access devices that are a
possible source of sepsis or septic shock after other vascular
access has been established .
 Foci of infection readily amenable to source control include
intra-abdominal abscesses, gastrointestinal perforation,
ischemic bowel or volvulus, cholangitis, cholecystitis,
pyelonephritis associated with obstruction or abscess,
necrotizing soft tissue infection, other deep space infection
and implanted device infections.

35. FLUID THERAPY
 Crystalloids as the fluid of choice for initial
resuscitation.
 Balanced crystalloids or normal saline.
 Albumin in addition to crystalloids for initial
resuscitation and subsequent intravascular volume
replacement in patients when patients require substantial
amounts of crystalloids .
 No hydroxyethyl starches (HESs) for intravascular
volume replacement.
 Further fluid resuscitation should be discontinued when
there is no longer a physiological response.

36. VASOACTIVE MEDICATIONS
 Norepinephrine as the first-choice vasopressor.
 Vasopressin (up to 0.03 U/min) or epinephrine to
norepinephrine with the intent of raising MAP to target, or
adding vasopressin ( 0.03 U/min) to decrease norepinephrine
dosage.
 Dopamine as an alternative vasopressor agent to
norepinephrine only in highly selected patients (e.g., patients
with low risk of tachyarrhythmias and absolute or relative
bradycardia)
 Low-dose dopamine for renal protection
 Dobutamine in patients who show evidence of persistent
hypoperfusion despite adequate fluid loading and the use of
vasopressor agents.

37. CORTICOSTEROIDS
 No use of IV hydrocortisone to treat septic shock patients
if adequate fluid resuscitation and vasopressor therapy are
able to restore hemodynamic stability.
 If this is not achievable, IV hydrocortisone at a dose of
200mg per day is to be given.

38. BLOOD PRODUCTS
 RBC transfusion only when hemoglobin concentration
decreases to < 7.0 g/dL in adults in the absence of
extenuating circumstances, such as myocardial ischemia,
severe hypoxemia, or acute hemorrhage
 No erythropoietin
 Fresh frozen plasma to correct clotting abnormalities
 Administer platelets prophylactically if:
Platelets < 10,000/uL in absence of apparent bleeding
Platelets < 20,000/uL if risk of bleeding
Platelets < 50,000/uL if active bleeding, surgery
No use of Selenium or Immunoglobulins

39. MECHANICAL VENTILATION
 Target tidal volume 6 ml/kg predicted body weight.
 Head end of bed 30-45 ° elevated.
 Positive end-expiratory pressure (PEEP) should be used
to prevent alveoli collapse and the resulting barotrauma
from repeated inflation/collapse cycles.
 Prone Positioning: PaO2/FiO2 ratio ≤ 100 mm Hg
 In absence of specific indications (bronchospasms) , do
not use beta-2 agonists in sepsis induced ARDS
 Avoid NMBAs if possible but a short course(<48 hr) can
be used in early.

40. GLUCOSE CONTROL
 When two consecutive blood glucose levels are >
180mg/dL , insulin is started with target of upper blood
glucose level ≤ 180mg/dL .
 Blood glucose values be monitored every 1 to 2 hours
until glucose values and insulin infusion rates are stable,
then every 4 hours there after in patients receiving insulin
infusions.

41. BICARBONATE THERAPY
 NOT to be used if pH ≥ 7.15
 Used after calculating deficit
 Shouldn't be corrected rapidly

42. STRESS ULCER PROPHYLAXIS
 Used in those who have risk factors for gastrointestinal
(GI) bleeding .
 PPIs or histamine-2 receptor antagononist can be used.

43. DVT PROPHYLAXIS
 Daily LMWH (Inj. Enoxaparin 40 mg SC OD)
 If CrCl < 30 ml/min, use Dalteparin or another form of
LMWH that has low degree of renal metabolism.
 Mechanical prophylaxis should be used in addition to
pharmacological prophylaxis and in patients for whom
pharmacological prophylaxis is contraindicated.

44. NUTRITION
 Oral or enteral feeding as tolerated within the first 48
hours of diagnosis
 Low dose feeding(upto 500 calories/day) in 1st week,
advancing only as tolerated.
 Use IV glucose and enteral nutrition rather than TPN
alone in first 7 days

45. SSC GUIDELINE DIFFERENCE IN 2012 AND
2016
 These new guidelines 2016 do not include prescribed
resuscitative targets such as CVP or ScV02 to guide
resuscitation. (No Early goal Directed Therapy).This is
in contrast to the prior guidelines that advocated for
achieving a CVP of 8–12 mm.
 The initial dobutamine dose is no longer specified in
the 2016 guidelines. In the 2016 update, phenylephrine is
no longer recommended for treatment of septic shock
outside of research protocols.
 No suggestion that the least invasive technique be
employed to achieve source control in 2016.

46. HOUR-1 BUNDLE 2018 UPDATE
INITIAL RESUSCITATION FOR
SEPSIS AND SEPTIC SHOCK
 1) Measure lactate level.*
 2) Obtain blood cultures before administering antibiotics.
 3) Administer broad-spectrum antibiotics.
 4) Begin rapid administration of 30mL/kg crystalloid for
 hypotension or lactate ≥4 mmol/L.
 5) Apply vasopressors if hypotensive during or after fluid
 resuscitation to maintain a mean arterial pressure ≥ 65 mm
Hg.
 *Remeasure lactate if initial lactate elevated (> 2 mmol/L).

48. META- ANALYSIS
 Early Goal-Directed Therapy for Septic Shock— A Patient-Level
Meta-Analysis
A study of 3723 patients at 138 hospitals in seven countries.
Mortality at 90 days was similar for EGDT (462 of 1852 patients
[24.9%]) and usual care (475 of 1871 patients [25.4%]); the
adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14;
P=0.68). EGDT was associated with greater mean (±SD) use of
intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and
cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than
was usual care; other outcomes did not differ significantly, although
average costs were higher with EGDT. Subgroup analyses showed no
benefit from EGDT for patients with worse shock (higher serum
lactate level, combined hypotension and hyperlactatemia, or higher
predicted risk of death) or for hospitals with a lower propensity to
use vasopressors or fluids during usual resuscitation.

50. EARLY GOAL DIRECTED THERAPY

51. Protocol based EGDT Vs Protocal Standard
Care vs usual care
 Of 1341 patients, of whom 439 were randomly assigned to
protocol-based EGDT, 446 to protocol-based standard
therapy, and 456 to usual care.
 Resuscitation strategies differed significantly with respect to the
monitoring of central venous pressure and oxygen and the use of
intravenous fluids, vasopressors, inotropes, and blood
transfusions. By 60 days, there were 92 deaths in the protocol-
based EGDT group (21.0%), 81 in the protocol-based
standard-therapy group (18.2%), and 86 in the usual-care
group (18.9%).
 There were no significant differences in 90-day mortality, 1-year
mortality, or the need for organ support.
 Conclusions: In a multicenter trial conducted in the tertiary care
setting, protocol-based resuscitation of patients in whom septic
shock was diagnosed in the emergency department did not
improve outcomes.

55. POTENTIAL THERAPY UNDER TRIAL
 Toll-like receptor antagonists and neutralizing antibodies
 Interferon gamma polyclonal intravenous immunoglobulin
 Hemoperfusion through adsorptive materials or
membranes
 Plasma exchange
 Whole blood exchange
 Anticoagulants
 Naloxone
 Statins
 Short-acting beta blocker esmolol

56. REFERANCES
 HARRISONS PRINCIPLE OF INTERNAL MEDICINE
20 EDITION
 DAVIDSON’S PRINCIPLE AND PRACTICE OF
MEDICINE 23 EDITION
 SURVIVING SEPSIS CAMPAIGN GUIDELINES 2016
 UPTODATE