2.  To know definitions of SIRS, sepsis, septic
shock, MODS
 To learn basic pathophysiology
But first, a real case:

3.  86/ Malay/ Lady
 U/L HPT and IHD
 Presented to Hospital Tampin A&E on
29/4/2012
 C/O:
› Poor oral intake x 2/52
› Lethargy x 2/7
› Minimal URTI sx
› Previously ADL independent

4.  O/E:
› Alert, lethargic looking
› Dehydrated
› Temp 38.5
› Pulse 144
› Blood pressure 184/104
› Respirations 22
› Chest, CV, Abdominal
exam normal

5.  Laboratory:
› FBC: WCC 15.48 ( N 45, L 49) / Hb 14.4 / Plt 161
› RP: Urea 19.4 / Creat 131 / Na 147 / K 4.6
› UFEME: Leu 3+ / Nitrate neg /Blood moderate /
Ketone small
 CXR: Hyperinflated lungs
 ECG: T inversion leads II, III, avF, v5, v6

6.  Diagnosis:
› Sepsis 2’ UTI with
dehydration 2’ poor oral
intake
 Admitted to Ward 2
› Fluid therapy 3 pints over
24H
› Vital signs monitoring
› CBD
› Strict IO monitoring
› Blood c&s, Urine c&s
› IV Zinacef 750mg stat and
TDS
› Nasal prong 3L/min

7.  Day 2:
 AM rounds:
Condition same
Tolerating minimal fluid
Urine output >30ml/H
Spiking temperature
 PM rounds:
Patient appears weak. c/o chestpain started at 8pm
BP 96/63
P 130
ECG Sinus tachycardia. ST depression II, III, avF, v4-v6

8.  Treated as ACS
 Started on:
› S/L GTN 0.5mg stat, and PRN
› S/c clexane 60mg stat and OD
› T isordil 10mg BD
› T aspirin 300mg stat, 100mg OD
› KIV inotrope

9.  VBG:
uncompensated
metabolic acidosis
 RP:
Urea 20/ Creat 120/
Na 154 / K 4.3
 IVD changed to HSD5
 DIL issued to family
members

10.  Explained to family members
regarding patient’s ill
condition:
› Sepsis
› Kidney injury
› ACS
 In the event of cardiac arrest,
family not keen for active
resuscitation
 DNR issued

11.  Day 3:
› Fever settled
› Vital signs stable without inotrope
› Hydration improves, good urine output
› Seen by dietician and started on RT feeding
200cc/3hourly
› IVD 2 pints HS and 1 pint D5 over 24H

12.  Day 4 - Day 7:
› General condition improving
› Vital signs stable
› Hydration status normal, good urine output
› Completed IV Zinacef
› Completed S/c Clexane
› L hand thrombophlebitis
› On IV Ciprofloxacin 400mg BD
› Off IVD
› Cont RT feeding

13.  Day 8:
› Temp 38.7
› BP 136/74
› P 92
› RR 28 – 32
› Sp02 97 under RA
› L hand thrombophlebitis
› Chest: bibasal crepitations
› CXR: pneumonic changes L LZ
› Cont IV Ciprofloxacin 400mg BD

14.  Day 10:
› GCS E3V4M5
› Spiking temp 38
› Tolerating RT feeding
› BP 136/74. P 86. RR 28. Sp02 95-96 under RA
› Chest bibasal crepts
› Noted L LL swelling – upto calf and knee. Tender calf.
Feeble DPA and PTA
? L LL DVT

15.  Discussed with family members the need for transfer to
HTJS for US doppler
 Family members refused
 Consented for S/C Clexane
 DIL reinformed

16.  Day 11:
› General condition ill, gasping
› BP lowish 90/60
› P 113
› RR 28
› Sp02 95% under NP 3L/min
› Fluid resuscitation

17.  Day 12: (11/5/2012)
› Patient succumbed to her illness
› Unresponsive, P not palpable, BP unrecordable at
4.10pm
› No activity on cardiac monitor >15 minutes
› Pupils fixed dilated

18.  DNR as requested by family
members
 Informed family members
 Time of death: 4.25pm
 Cause of death:
Sepsis 2’ UTI complicated with:
› Acute kidney injury
› Acute coronary syndrome
› Nosocomial infection

20. • Infection: A microbial phenomenon
characterized by an inflammatory
response to the presence of
microorganisms or the invasion of
normally sterile host tissue by those
organisms.
• Bacteremia: The presence of viable
bacteria in the blood.

21. • Systemic Inflamatory Response
Syndrome (SIRS): The systemic
inflammatory response to a variety of
severe clinical insults (For example,
infection).
• Sepsis: The systemic inflammatory
response to infection.

22. • Temperature >38 degrees Celsius or <36
degrees Celsius.
• Heart rate>90 beats per minute.
• Respiratory rate>20 breaths per minute or
PaCO2<32mmHg.
• White blood cell count > 12,000/cu mm,
<4,000/ cu mm, or >10% band forms.

23. • Sepsis:
• Known or suspected infection, plus
• >2 SIRS Criteria.
• Severe Sepsis:
• Sepsis plus >1 organ dysfunction.
• MODS.
• Septic Shock.

24. • Septic Shock: Sepsis induced with
hypotension despite adequate
resuscitation along with the presence of
perfusion abnormalities which may
include, but are not limited to lactic
acidosis, oliguria, or an acute alteration
in mental status.

25. • Multiple Organ Dysfunction Syndrome
(MODS): The presence of altered organ
function in an acutely ill patient such that
homeostasis cannot be maintained
without intervention.

26.  Lungs  Adult Respiratory Distress Syndrome
 Kidneys  Acute Tubular Necrosis
 CVS  Shock
 CNS  Metabolic encephalopathy
 PNS  Critical Illness Polyneuropathy
 Coagulation  Disseminated Intravascular
 GI Coagulopathy
 Liver  Gastroparesis and ileus
 Endocrine  Cholestasis
 Skeletal Muscle  Adrenal insufficiency
 Rhabdomyolysis
Specific therapy exists

27. Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Opal SM et al. Crit Care Med. 2000;28:S81-2.

28. Infection/
Trauma SIRS Sepsis Severe Sepsis
A clinical response arising SIRS with a presumed or
from a nonspecific insult, confirmed infectious
including ≥2 of the process
following:
› Temperature ≥38oC or
≤36oC
› HR ≥90 beats/min
› Respirations ≥20/min
› WBC count
≥12,000/mm3 or
≤4,000/mm3 or >10%
immature neutrophils SIRS = systemic inflammatory response
syndrome.
Bone et al. Chest. 1992;101:1644.

29. Infection/
Trauma SIRS Sepsis Severe Sepsis
• Sepsis with ≥1 sign of organ failure
– Cardiovascular (refractory
hypotension)
– Renal
– Respiratory
Shock – Hepatic
– Hematologic
– CNS
– Unexplained metabolic acidosis
Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.

32. Infection Physiologic
Inflammation Biochemical
Severe
Sepsis
Specific Organ
Severity

33.  Pre-existing disease
› Cardiac, Pulmonary, Renal
› HIV
 Age (extremes of age)
 Gender (males)
 Genetics
› TNF polymorphisms (TNF promoter high
secretor genotype)

34.  Physiology  Markers of
› Heart rate Inflammation
› Respiration › TNF
› Fever › IL-1
› Blood pressure › IL-6
› Cardiac output › Procalcitonin
› WBC
› Hyperglycemia

35. • Fever.
• Leukocytosis.
• Tachypnea.
• Tachycardia.
• Reduced Vascular Tone.
• Organ Dysfunction.

36. • Hemodynamic Alterations
• Hyperdynamic State (“Warm Shock”)
• Tachycardia.
• Elevated or normal cardiac output.
• Decreased systemic vascular resistance.
• Hypodynamic State (“Cold Shock”)
• Low cardiac output.

37. • Myocardial Depression.
• Altered Vasculature.
• Altered Organ Perfusion.
• Imbalance of O2 delivery and
Consumption.
• Metabolic (Lactic) Acidosis.

38. • Stage 1. In response to injury /
infection, the local environment produces
cytokines.
• Stage 2. Small amounts of cytokines
are released into the circulation:
• Recruitment of inflammatory cells.

39. • Stage 3. Failure to control
inflammatory cascade:
• Loss of capillary integrity.
• Stimulation of Nitric Oxide Production.
• Maldistribution of microvascular blood flow.
• Organ injury and dysfunction.

41. • Bacterial Endotoxin
• TNF-α
• Interleukin-1
• Interleukin-6
• Interleukin-8
• Platelet Activating Factor (PAF)
• Interferon-Gamma
• Prostaglandins
• Leukotrienes
• Nitric Oxide

42. • Interleukin-10
• PGE2
• Protein C
• Interleukin-6
• Interleukin-4
• Interleukin-12
• Lipoxins
• GM-CSF
• TGF
• IL-1RA

44. • Answer: Organ Failure

45. •Knaus, et al. (1986):
•Direct correlation between number of organ systems failed
and mortality.
•Mortality Data:
#OF D1 D2 D3 D4 D5 D6 D7
1 22% 31% 34% 35% 40% 42% 41%
2 52% 67% 66% 62% 56% 64% 68%
3 80% 95% 93% 96% 100 100 100
% % %

46. • Multiple Organ Dysfunction (MODS) and
Multiple Organ Failure (MOF) result from
diffuse cell injury / death resulting in
compromised organ function.
• Mechanisms of cell injury / death:
• Cellular Necrosis (ischemic injury).
• Apoptosis.
• Leukocyte-mediated tissue injury.
• Cytopathic Hypoxia

47. • Cytokine production leads to massive production
of endogenous vasodilators.
• Structural changes in the endothelium result in
extravasation of intravascular fluid into
interstitium and subsequent tissue edema.
• Plugging of select microvascular beds with
neutrophils, fibrin aggregates, and microthrombi
impair microvascular perfusion.
• Organ-specific vasoconstriction.

48. Infection
Inflammatory Endothelial
Vasodilation
Mediators Dysfunction
Hypotension Microvascular Plugging Vasoconstriction Edema
Maldistribution of Microvascular Blood Flow
Ischemia
Cell Death
Organ Dysfunction

49. • Loss of Sympathetic Responsiveness:
• Down-regulation of adrenergic receptor
number and sensitivity, possible altered signal
transduction.
• Vasodilatory Inflammatory Mediators.
• Endotoxin has direct vasodilatory effects.
• Increased Nitric Oxide Production.

50. • Vasoactive Intestinal Peptide
• Bradykinin
• Platelet Activating Factor
• Prostanoids
• Cytokines
• Leukotrienes
• Histamine
• NO

51. • Decreased red cell deformability in inflammatory states.
• Microvascular sequestration of activated leukocytes and
platelets.
• Sepsis is a Procoagulant State.
• The extrinsic pathway may be activated in sepsis by
upregulation of Tissue Factor on monocytes or
endothelial cells.
• Fibrinolysis appears to be inhibited in sepsis by
upregulation of Plasminogen Activator Inhibitor.
• A variety of pathways result in reduced Protein C
activity in sepsis.

52. • Endothelial cell expression of Selectins
and ICAM / ELAM is upregulated in Sepsis
due to inflammatory activation.
• Selectins bind carbohydrate ligands on the
surfaces of PMN’s.
• ICAM bind Integrins on the surfaces of PMN’s.
• The Selectins initiate a weak bond between
the PMN and the endothelial cell causing
PMN’s to tumble along the vessel wall.

53. • Binding of leukocytes to ICAM leads to
transmigration of PMN’s into interstitium.
• Transmigration disrupts normal cell-cell
adhesions resulting in increased vascular
permeability and tissue edema.
• Vascular permeability is also increased
by several types of inflammatory
cytokines.

55. • A physiologic process of homeostatically-
regulated programmed cell death to
eliminate dysfunctional or excessive cells.
• A number of inflammatory cytokines, NO,
low tissue perfusion, oxidative injury, LPS, and
glucocorticoids all are known to increase
apoptosis in endothelial and parenchymal
cells.
• Levels of circulating sfas (circulating
apoptotic receptor) and nuclear matrix
protein (general cell death marker) are both
elevated in MODS.

56. • Transmigration and release of elastase
and other degradative enzymes can
disrupt normal cell-cell connections
and normal tissue architecture
required for organ function.
• Reactive oxygen species cause direct
cellular DNA and membrane damage
and induce apoptosis.

57. • A defect of cellular oxygen utilization.
• May be due to activation of PARP (poly-ADP-
ribosylpolymerase-1).
• Oxidative DNA damage activates PARP which
consumes intracellular and mitochondrial
NAD+.
• NAD+ depletion leads to impaired respiration
and a shift to anaerobic metabolism.
• Affected cells may suspend normal cell-
specific activities in favor of preservation of
cell viability.

58. • Optimize Organ Perfusion
• Expand effective blood volume.
• Hemodynamic monitoring.

59. • Optimize Organ Perfusion
• Pressors may be necessary.
•Compensated Septic Shock:
 Phenylephrine
 Norepinephrine
 Dopamine
 Vasopressin
•Uncompensated Septic Shock:
 Epinephrine
 Dobutamine + Phenylephrine /
Norepinephrine

60. • Control Infection Source
• Drainage
• Surgical
• Radiologically-guided
• Culture-directed antimicrobial therapy
• Support of reticuloendothelial system
• Enteral / parenteral nutritional support
• Minimize immunosuppressive therapies

61. • Support Dysfunctional Organ Systems
• Renal replacement therapies (CVVHD, HD).
• Cardiovascular support (pressors, inotropes).
• Mechanical ventilation.
• Transfusion for hematologic dysfunction.
• Minimize exposure to hepatotoxic and
nephrotoxic therapies.

62. • Modulation of Host Response
 Targeting Endotoxin
•Anti-endotoxin monoclonal antibody
failed to reduce mortality in gram
negative sepsis.
 Neutralizing TNF
•Excellent animal data.
•Large clinical trials of anti-TNF
monoclonal antibodies showed a very
small reduction in mortality (3.5%).

63. • Modulation of Host Response
• IL-1 Antagonism
 Three randomized trials: Only 5% mortality
improvement.
• PAF-degrading enzyme
 Great phase II trial.
 Phase III trial stopped due to no demonstrable
efficacy.
• NO Antagonist (LNMA)
 Increased mortality (? Pulmonary Hypertension).

64. • Modulation of Host Response
• Antithrombin III
 No therapeutic effect.
 Subset of patients with effect when concomitant
heparin not given.
• Activated Protein C (Drotrecogin alpha /
Xigris)
 Statistically significant 6% reduction in mortality.
 Well-conducted multicenter trial (PROWESS).
 FDA-approved for use in reduction of mortality in
severe sepsis (sepsis with organ failure).

65. • Modulation of Host Response
•Corticosteroids
 Multiple studies from 1960’s – 1980’s: Not
helpful, possibly harmful.
 Annane, et al. (2002): 10% mortality
reduction in vasopressor-dependent
septic shock (relative adrenal
insufficiency, ACTH nonresponders).

66. • Components:
• Early Recognition
• Early Goal-Directed Therapy
 Monitoring
 Resuscitation
 Pressor / Inotropic Support
• Steroid Replacement
• Recombinant Activated Protein C
• Source Control
• Glycemic Control
• Nutritional Support
• Adjuncts: Stress Ulcer Prophylaxis, DVT Prophylaxis,
Transfusion, Sedation, Analgesia, Organ
Replacement