Sepsis

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Sepsis
The Human Race is a Transient Episode in the
History of Bacteria

• David Hassin
• Tel-Aviv Medical Center

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Sepsis

• Clinical evidence of infection, plus evidence of
  a systemic response to infection, manifested by
  two or more of the following conditions
• 1. Temperature gt 38C or lt 36C
• 2. Heart rate gt 90/min
• 3. Respiratory rate gt 20/min
• or PaCO2 lt 32 mmHg
• 4. WBC gt 12000 lt 4000
• or gt 10 band forms

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Severe Sepsis

• Sepsis with evidence of organ hypo-perfusion
• With at least one of the following
• 1. Hypoxemia
• 2. Elevated lactate metabolic acidosis
• 3. Oliguria
• 4. Acute alteration in mental status

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Septic Shock

• Severe sepsis with hypotension despite
• Adequate fluid resuscitation. (20-30ml/kg/30min)
• Hypotension
• Arterial blood pressure of
• 90 mmHg systolic or 40 mmHg less than
• patients normal blood pressure
• Refractory Septic Shock
• Septic shock that lasts for gt 1h and does not
  respond to fluid administration or pharmacologic
  intervention

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MODS Multiple Organ Dysfunction Syndrome

• Dysfunction of more than one organ,requiring
  intervention to maintain homeostasis.
• SIRS
• Systemic Inflammatory Response Syndrome
• Response to a wide variety of clinical insults,
  which can be infectious,as in sepsis, but can be
  noninfectious in etiology.

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Sepsis is SIRS Caused by an Infection
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Activation of coagulation cascade Activation of
complement cascade Activation of adaptive
immunity
TNF-a IL-1ß IL-6
INF gamma IL-12 IL-10
Macrophage
KATP
Endothelial cell activation
Atrial Natriuretic Peptide
Innate immune response Toll-like receptor
signaling pathways.
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Inflamation-activated coagulation.
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Von willibrand factor
ADAMTS13
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Von Willibrand Factor and its Inactivation by
ADAMTS13
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The Cardiovascular Physiology of Sepsis.
Sever sepsis
Recovery
Parker et al Ann Intern Med 1984
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Mechanisms of Vasoconstriction and Vasodilatation
in Arteriolar Smooth Muscle Cells
Sepsis
Vasopressin
Sepsis
Landry Oliver NEJM 2001
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INF gamma Up-regulation of iNOS and Nitric-oxide
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The Roll of KATP Channel in Sepsis
Vasopressin kidney water reabsorption
inactivation KATP channel cGMP
norepinephrine response
Vasopressin
Landry Oliver NEJM 2001
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• B7-CD28/CTLA-4 costimulation of T-Cell
  activation
• Anti-CD28 Ab cause cytokine storm. (Sep. 2006
  NEJM)

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• Super-antigens (Staph. Aurous and Streptococcus
  group A) activates 20 of T cells compared with
  1/10000 massive cytokine release.

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Case Report - Sepsis

• 19 years old soldier
• From a day before admission fever,
  purulent rhinitis, headache and vomits.
• On admission good general condition
• B.P.-110/70 Fever-38.5C
  R.R.-20/min
• WBC-13000 Neu-92
• Chest x-ray Normal
• Sinuses (x-ray) mucosal thickening
  of the
  Maxillary sinus
• Diagnosis Sinusitis I.V. Cefuroxime

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The day after, diffuse maculopapular rash
appeared.
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Case Report - Sepsis

• The day after, the patient feels good, diffuse
  maculopapular rash appeared.
• Two blood cultures taken on admission
• grew Neisseria Meningitidis group B
• I.V. Penicillin was started the patient
  recovered
• The patients girl friend received Rifampin as a
  preventive therapy.

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Case Report - Sepsis

• Six weeks later the girlfriend (an 18 year-old
  soldier) was hospitalized
• Presented in the morning to an emergency ward
  with fever, shaking chills and a sore throat.
• The patient and her mother informed the physician
  about the boyfriends meningococcemia but he
  chose to ignore it.
• The patient was discharged, diagnosis
  pharyngitis.

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Case Report - Sepsis

• In the evening she lost her consciousness and
  sphincteric control after which she was stuporous
  for half an hour
• On admission she complained of blurred vision and
  sever muscle pain.
• Typical hemorrhagic rash
• B.P.-80/60, pulse-120, fever-38C
• WBC-3800, Hg-10.4
• PH-7.27, Bic-11.6, Pco2-26, PO2-66,
  O2Sat-88

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hemorrhagic rash of meningococcemia
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Case Report - Sepsis

• Oxygen, I.V. saline and I.V. Penicillin were
  started B.P.80/40, pulse-125, R.R.-40
• Severe Sepsis with Hypotension
• Neisseria Meningitidis in blood and CSF cultures
• MODS ARDS respiratory failure respirator
• Acute renal failure dialysis
• Anoxic hepatitis
• Myelopathy paraparesis

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MODS in Meningococcemia
Eventually the patient recovered.
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Early Goal Directed Therapy in the Treatment of
Sever Sepsis and Septic Shock

• Rivers et al NEJM 2001

• Resuscitation end points
• Mixed venous oxygen saturation
• Arterial lactate concentration
• Base deficit
• pH

Fick Law
O2 Consumption l/min (Arterial - Venous) Oxygen
content difference
Cardiac Output
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Antibiotic Treatment
Sites of infection in Pt. with severe
sepsis.

• Identity Bacteriologic statistics
• Gram stain.
• Culture.
• Immunologic, molecular.
• Susceptibility Bacteriologic statistics.
• Disc diffusion, MIC.
• Host factors Adverse reaction.
• Renal and hepatic
  function.
• Pregnancy.
• Site of infection.

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Mortality after surgery for abdominal sepsis
Serratia marcescens
Surgical Treatment !!!
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Intensive Insulin Therapy in Critically Ill
Surgical Patients

• Van Den Berghe et al NEJM 2001

P0.005
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Treatment of Sepsis.

• Diagnosis !!!
• Oxygen. (Tidal volume 6ml/kg) (lt 30 cm H2O)
• Fluids 5 liters in 6 hours CVP
• Vasoactive agents dopamine,
• 
  norepinephrine - BP
• Antimicrobial drugs, (after cultures).
• Central venous oxigen saturation gt 70
• Inotropic agent dobutamine.
• Blood hematocrit gt 30.
• Surgical drainage.
• Intensive insulin treatment blood sugar
  control

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Activated Protein C for the Treatment of Severe
sepsis
Bernard et al NEJM 2001
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Low Doses of Hydrocortisone and Fludrocortisone
in Sepsis Annane et al JAMA 2002

• Hydrocortisone 50mg x4,
  Fludrocortisone 50mcg x1 for 7 days.
• Non responders to corticotropin test
• Placebo group 115 patients 73 dead (63)
• Corticosteroid group 114 patients 60 dead
  (53), p0.02
• No significant difference in responders

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Case Report - Sepsis

• 46 years old male
• 3 weeks ago wounded the Tibial Tuberosity - 0.5cm
  scar on examination
• 10 days of fever low back pain radiating to the
  right leg
• Good general condition BP-120/80
• Pulse-80 RR-18 Temp.-38C.
• Tenderness over right thigh
• WBC-20600 Neu-88

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Case Report - Sepsis

• Next day Rt. Thigh swollen (Rt.gtLt. 7cm)
  sever pain
• Fifth day sudden deterioration pulse-108
  BP-110/60 RR-28 redness of Rt. thigh
• WBC-35500 Neu-94 Hg-9.9
• Ph-7.38 Bic-19.7 PO2-62 Sat-90 Pco2-34.
  Liver function tests-abnormal
  sever sepsis
• Oxygen, I.V. fluids,
  Orbenin 2grx6, Clindamycin 900mgx3

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Case Report - Sepsis

• CT Abscess from the rt. gluteus to the knee
• Blood cultures - Staph. Aureus
• Operation Fascia intact, 40 cm cut of fascia -
  discharge of large amount of pus Pyomyositis
• After the operation Septic shock, ARDS
  mechanical respiration for 3 days
• Wound closed after 6 month

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Pyomyositis
ARDS
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Secondary healing after surgical drainage.
After 6 months
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ARDS in a patient with sever Staph-aureus sepsis
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Psoas abscess in a patient with Staph-aureus
sepsis
Psoas abcess
Bone scan septic sacroileitis.
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Pyomyositis of the paraspinal mascles resulting
in staph-aureus meningitis.
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Thrombotic Thrombocytopenic Purpura (TTP)
Severe Urosepsis TTP

• Moschowitz,1925 new disease characterized by
  unique pathological findings of thrombi in many
  organs.
• Amrosi and Ultmann,1964
• review of all 217 published cases and
• definition of classic pentad
• 1) Thrombocytopenia
• 2) Microangiopathic hemolytic anemia
• 3) Neurologic symptoms and signs
• 4) Renal function abnormalities
• 5) Fever
• Plasma exchange therapy
• improved survival from lt10 to 80-90

ADAMTS13 - Von Willibrand Factor
multimers -
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• 67 y old man
• BPH with permanent urinary catheter for 2 months
• 24.10.2005 urinary retention - replacement of
  urinary catheter in Afula hospital
• 25.10.2005 severe sepsis with hypotension
  severely ill, T - 37.7ºC, blood pressure -
  80/49 pulse 100/min, creatinine -3.4, WBC
  12.8 Hg -12.9 PLT -199000 ABG PH 7.4
  PO2-87.5 PCO2-19. HCO3-12
  ABE-(-)10 Sat.-96
• Coagulation tests Fibrinogen-308,
  INR-1.3, PTT-31
• I.V. Ceftriaxone and Ciprofloxacin were started
• Blood and urine cultures Klebsiella Pneumoniae.
  

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Lt. Pyonephrosis by US
25.10.05
Persistence of severe sepsis for 10 days fever,
WBC-22.7, PLT-51000, Hg-11, LDH-1127, ARDS,
severe metabolic acidosis, persistent renal
failure - Cr.-3.6, normal coagulation Functions
3.11.05
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CT and Gallium Scan
3.11.05
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Severe Urosepsis TTP

• 4.11.2005 Lt. Nephrectomy
• On pathology multiple abscesses of left
  kidney
• normal postoperative period 13.11.2005 discharge
• WBC-10x109/l Hb 10.7g/dl Plt-213000, Cr.-2.0.
  

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Severe Urosepsis TTP

• 15.11.2005 recurrent hospitalization because of
  generalized weakness.
• Hb -7 MCV-90, WBC-14.5, Plt -2000
• Creatinine 2.9, T. Bil.-2.6, direct
  B.-0.7, LDH-2211, fibrinogen-308,
  coagulation tests - normal
• 17.11.2005 confusion and stupor
• RBC fragmentation on peripheral blood smear
• brain CT normal

TTP
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Severe Urosepsis TTP

• 4 days on mechanical ventilation in a coma
• ADAMTS13 Ag 10, activity lt 2,
  Ab gt 100 u/ml (n 0-15u/ml)
• Plasma exchange therapy and corticosteroids were
  started
• Seven plasma exchanges
• Dramatic clinical and laboratory improvement,
  neurological outcome
• lt. homonymous hemianopsia and lt. hemiparesis
• recurrent brain CT ischemic changes in the
  Rt. Occipitotemporal area

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CT of the Brain with ischemic changes in the Rt.
Occipitotemporal area at the time of lt.
homonymous hemianopsia and lt. hemiparesis
23.11.05
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Fibrinous Thrombus of Renal Arteriole.
Thrombi in the Renal Medulla
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Diffuse Glomerular Capillary Thrombosis
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ADAMTS13 is cleaved by protease liver
synthesis
ADAMTS13lt20 - renal function
Large vWF multimers in 51 of pt. With ADAMTS13
lt 20
ADAMTS13 in sepsis DIC
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ADAMTS13 Antigen
ADAMTS13 Activity
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Severe Urosepsis TTP

• 3.2.2006-12.2.2006
• elective Suprapubic Prostatectomy
• Hb-12.7g/dl MCV-93 WBC-11.6x109/l
  Plt-399x109/l
• Cr-3.3 BUN-50mg/dl
• normal postoperative period
• 10.6.2006
• Follow up examination normal, no neurological
  signs
• Hb-13 g/dl MCV-95 WBC-7.5X10 9/l
  Plt-201x109/l
• BUN-43mg/dl Cr-2.5mg/dl

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Pieter Brueghel 1525-1569