Newer Trends in Sepsis and Septic Shock

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Newer Trends in Sepsis and Septic Shock

• Dr. S. K. Jindal
• www.jindalchest.com

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Changing Trends in Sepsis

1. Definitions Prevalence
2. Risk factors
3. Pathophysiology
4. Organ system dysfunction
5. Establishing diagnosis
6. Treatment strategies
7. Future directions

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Definitions

• Infection Invasion of sterile tissue by
  microorganism
• Bacteremia Viable bacteria in blood
• Sepsis Systemic inflammatory response
• Severe sepsis Sepsis and organ dysfunction
• Septic shock Sepsis with hypotension
• Multiple organ Altered organ function in severely
  sick
• dysfunction patients
• syndrome

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Systemic Inflammatory Response Syndrome

• Inflammatory response to a variety of severe
  clinical insults (vs. sepsis)
• Two or more of the following
• Temp gt38C or lt36C
• HR gt90 beats/min
• RR gt20 breath/min or PaCO2 lt32 mm Hg
• WBC gt 12000/mm3 or lt 4000/mm3 or
• 10 immature band form

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Clinical Frequency Mortality () (Mortality
included in parentheses)
Study SIRS Sepsis Severe sepsis Septic shock
Rangel Frausto (1995) 68 (7) 26 (16) 18 (20) 4 (46)
Pittet (1995) 93 (6) 49 (0) 16 (35) 7 (58)
Salvo (1995) 52 (27) 5 (36) 2 (52) 3 (82)
Saez-Llorem (1995) - 21 (16) 61 (40) 18 (62)
Proulx (1996) 82 23 4 2
Jones Lowes (1996) 55 (23) 16 5 (38) 3 (56)
Muckart (1997) 88 (8) 14 (10) 14 (18) 20 (53)
Bossink (1998) 95 (6) 44 (13) - -
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Risk of Death in First 30 Days

• Overall ICU 20
• Severe sepsis 30-50
• Stroke 12-19
• Ac. Myocardial infarction 8

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ARDS in Tropics
Infective cause No. of patients (Mortality) No. of patients (Mortality)
1. Severe Pneumonia 27 (51.8)
2. Sepsis 25 (52.0)
Immunosuppresive drugs 9
Post operative 6
Chronic respiatory disease 3
Neurological 3
Enteric fever 2
Diabetes 2
3. Malaria 7 (42.9)
4. Enteric fever 1 (0)
5. Viral synd. 4 (25.0)
Jindal et al CCM 2002
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Risk Factors

• Diabetes mellitus
• Burns, wounds, multiple trauma
• Immunosuppressives
• Hepatic failure
• Invasive catheters, devices
• Hyposplenism

• Extremes of age
• Malignancy
• Organ transplant
• Radiation therapy
• Renal failure
• Indwelling urine catheter
• A.I.D.S.

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Pathophysiology
Infecting organism
Exotoxins
Endotoxins
Stimulation activation of macrophages, vascular
endothelial and humoral protein cascade system
(both pro anti inflammatory)
Mediators (AAM, Complement, cytokines, ACTH,
histamine, NO, OFR, PAF, Kinins, etc.)
Activation of neutrophils endothelial cells
OFRs, NO, Proteases, VAS (etc.)
Cellular adhesion molecules (Selectins,
integrins, ICAM, etc.)
Tissue and organ injury
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Organ Dysfunction

1. Cardiovascular
2. Pulmonary ARDS
3. Neurological
4. Hepatic failure
5. Renal failure
6. Haematological Coagulopathy
7. Others Gastrointestinal, Metabolic

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ARDS
ALI
Septicemia
SIRS
MODS
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Pathophysiology of Pulmonary Damage
Acute microvascular damage
Hypoxic pulmonary vasoconstriction
Increased permeability

• In situ thrombosis
• Platelet neutrophil aggregation

Fluid exudation
Increased Ppa
Alveolar flooding
Increased RV load
Hypoxaemia
Decreased RV function
Hypoxic organ damage
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Cardiovascular Dysfunction
Sepsis
Mediators (NO)
Arteriolar and venous dilatation damaged
endothelium
Extravascular exudation

• Cardiac output
• Depressed myocardium
• Cardiac failure

Normal to low filling pressures
Decreased SVR
Hypotension
Septic shock
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Diagnosis Issues in Sepsis

• Diagnosis of Infection Bacteraemia
• Central venous catheter infection
• Ventilator associated pneumonia
• Surgical site and intra abd. sepsis
• Acute cholecystitis sinusitis
• Invasive candidiasis
• 2. Organ system dysfunction

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Suspecting Sepsis

• Clinical signs
• Fever / hypothermia
• Unexplained tachycardia, tachypnoea
• Signs of peripheral vasodilation
• Unexplained shock, Obtunded mentality
• Haemodynamic or Laboratory parameters
• Low SVR / increased C.O.
• Increased O2 consumption
• Leukocytosis / neutropaenia
• Thrombocytopaenia / DIC
• Unexplained lactic acidosis or alterations in
  liver or renal function
• Increased procalcitonin, cytokines, CRP

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Bacteraemia

• Symptoms Signs
• Fever, chills, hypothermia
• Leucocytosis, left shift of neutrophils,
  neutropaenia
• Hypoalbuminaemia Renal failure
• What to do?
• Immediate blood cultures (2 to 3)
• Skin decontamination
• Adequate blood (10-30 ml per bottle)

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• CV Catheter Infection
• Blood and cath removal culture
• Insertion site swab culture
• Reinsertion same or different site
• Sinusitis
• Suspected with NT and NG tubes
• Maxillary sinus X-rays/CT
• Antral puncture

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Ventilator Associated Pneumonia

• Risk Factors
• Intubation, aspiration
• NG / enteral feeding tube
• Use of antacids, PPIs
• What to do?
• Blood cultures
• Pl. aspiration (gt10 mm)
• Endotracheal secretions
• Bronchoscopic specimens

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Management Issues

1. Use of antibiotics
2. Haemodynamic support
3. Source control
4. Airways and lung
5. Immunological therapy
6. Supportive ancillary therapies
7. Future interventions

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Antibiotic use Principles

1. Early use appropriate drug
2. Avoid indiscriminate choices
3. Carefully analyse the costs
4. Avoid glycopeptides (vancomycin or teicoplanin)
   for presumed Gram ve infections (unless MRSA
   suspected)
5. No routine use of antifungals
6. Empiric therapy chosen on basis of clinical and
   prevalence data

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Antibiotic Use Empiric choices

• Severe sepsis no neutropaenia
• Carbapenam monotherapy
• 3rd or 4th generation cephalosporin
• Beta lactam and aminoglycoside
• Febrile, neutropaenia
• Extended spectrum carboxy- or ureido- penicillin
  with beta lactamase inhibitor
• Documented Gram ve sepsis
• Aztreonam monotherapy or beta lactam and
  aminoglycoside

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Haemodynamics in Shock
Type PA occlusion pressure Cardiac output SVR
Cardiogenic ? ? ?
Hypovolaemic ? ? ?
Distributive (sepsis) ?or N ?or N or? ?
Obstructive ?or N or? ? ?
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Haemodynamic Support Goals

• MAP gt60-65 mmHg
• PCWP 15-18 mmHg
• C.I. gt4.0 L/min/m2 BSA for septic or Hmgic shock

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Haemodynamic Support

• Volume repletion CVP monitoring
• Optimal Hb (9-10 gm/dl)
• Vasopressors
• Dopamine Increases CI and BP
• Norepinephrine Improves BP, GFR
• Dobutamine Increases CI (SV, HR)

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Fluid Management in Shock
Fluid challenge (5-20 ml/kg over 10 min)
Assess haemodynamic response (BP, HR, urine
output, mental state)
CVP monitoring
Increase by gt7 mm Hg over initial value
Increase by lt3 mm Hg over initial value
Repeat fluid challenge
Discontinue
(Crystalloids are the mainstay of therapy)
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Airway and Lungs - ARDS

• Adequate supplemental O2
• Endotracheal intubation mech vent
• Avoid NIPPV
• Use permissive hypercapnia low tidal volume
  (Pplat lt30 cmH2O)
• Prone positioning ventilation if FiO2 requirement
  gt0.60
• Restrict NO as salvage therapy

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Immunological Therapy Do Not Use

• Corticosteroids in high doses (30 mg/kg) and for
  just 1-2 days
• Ibuprofen
• Prostaglandins (esp. PGE1)
• Pentoxifylline
• N-acetyl cysteine
• Selenium
• Antithrombin III
• Immunoglobulins
• Granulocyte Colony Stimulating Factor
• Growth hormones
• Haemofiltration (with renal indication)

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Ancillary Issues

1. DVT prophylaxis
2. Gastric mucosal cytoprotection
3. Nutritional support
4. Blood products
5. Intubation and mech. ventilation
6. Renal support - dialysis

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Supportive Therapies

• DVT prophylaxis
• - Low dose unfractionated heparin (5000U BD or
  TDS) or LMWH
• - If contraindicated mech. devices
• Stress-ulcer prophylaxis
• - Antacids, sucralfate
• - H2 receptor antagonists
• - Use of enteral nutrition

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Nutritional Support

• Hypercatabolic state
• Enteral nutrition preferred
• Daily Calories 25-30 Kcal/kg usual body wt.
• Proteins 1.3 2 g/kg
• Glucose 30-70 of nonprotein calories
• Maintain s. glucose lt225 mg/dl
• Lipids 15-30 of nonprotein calories

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Risk Factors for Mortality in ARDS
RR (95 CI) RR (95 CI)
Sepsis 3.50 (1.57-7.8)
gt3 organ failure prior to admn. 3.00 (1.43-6.3)
APACHE III gt57 6.13 (1.65-22.6)
SAPS II gt39 10.18 (1.49-69.7)
Gupta et al, Respirology 2001
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Reducing Sepsis MortalityNew Directions

1. Low tidal volumes in ALI / ARDS
2. Early goal-directed therapy (EGDT)
3. Use of drotrecogin alpha (activated)
4. Moderate dose corticosteroids
5. Tight control of blood sugar

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Low Tidal Volumes in ALI

• TV of 6 ml/kg ideal body wt. significantly
  reduces mortality
• Reduces volutrauma
• Questions Acidosis
• Distressing for patient (sedation staff
  education)
• Intrinsic PEEP

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Early Goal Directed Therapy

• An attempt to adjust cardiac preload, after load
  and contractility to balance systemic O2 delivery
  with O2 demand
• CVP, arterial line Foley cath.
• CVP of 8-12 mmHg MAP gt 65 mmHg Urine output
  at least 0.5 ml/kg/h
• Monitored for SVO2 gt 70
• Given More IV fluids blood transfusion
• More inotropic support (dobutamine)

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Drotrecogin Alfa (Activated)

• Severe depletion of protein C in sepsis high
  mortality
• Activated protein C Anticoagulation
• Profibrinolysis
• Anti inflammatory
• Significantly reduces mortality
• Window period 48 hrs
• Risk of bleeding
• No biochemical markers
• Very high cost

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Moderate-dose Corticosteroids

• Relative adrenal deficiency common in septic
  shock
• Moderate dose (200-300 mg HC daily) for
  refractory septic shock
• Better to do ACTH test before starting steroids

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Corticosteroids in Sepsis
Severe sepsis / septic shock
(Prigent et al 2003)
Plasma cortisol levels
Cortisol gt15 µg/dL
Cortisol ?15 µg/dL
ACTH stimulation test
Cortisol rise gt9 µg/dL
Cortisol rise lt9 µg/dL
Cortisol gt34 µg/dL
Cortisol ?34 µg/dL
Adrenal failure
No adrenal failure
Tissue resistance to glucocorticoids
Replacement therapy
No teatment
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Tight Blood-Sugar Control

• Hyperglycaemia common
• Hyperglycaemia (gt100 mg/dl, gt6.1 mmol/L)
  predisposes to specific ICU complications
• High levels of insulin like growth factor binding
  protein predicts mortality
• Strict protocol of low-dose insulin admn. and
  repeated blood sugar assessments
• Especially for surgical patients

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Summary Recommendations

1. For mech. vent., use low TV
2. EGDT Early aggressive therapy Generous use of
   fluids inotropes
3. Drotrecogin alpha for recent onset sepsis
   septic shock
4. Moderate-dose CS for refractory shock
5. Tight control of blood sugar close to
   physiological levels

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Agents in Development

• Segara (afelimomab) Anti TNF-? Fab antibody
  fragment
• Cyto TAB Anti TNF-? polyclonal antibody
• Tifacogin Anti tissue factor
• Pafase (? PAF) Degrades PAF
• Neurprex (Opebecan) Bactericidal permeability
  increasing proteins
• Lipid A analogs (antiendotoxins), Anti CD14
  monoclonal antibody, dextran-bound polymyxin,
  Phospholipase II inhibitors, NO scavengers and
  NOS inhibitors (etc.)

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SUMMARY

• Sepsis continues to threaten hospital services
  involved in care of the sick
• Major changes have taken place in most areas
• Intensive care offering an ICU package has
  improved survival

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THANK YOU