Sepsis

David Hassin
Tel-Aviv Medical Center

The Human Race is a Transient Episode
in the History of Bacteria
Sepsis:
Clinical evidence of infection, plus evidence of a
systemic response to infection, manifested by
two or more of the following conditions:
1. Temperature > 38C or < 36C
2. Heart rate > 90/min
3. Respiratory rate > 20/min
or PaCO
2
< 32 mmHg
4. WBC > 12000 < 4000
or > 10% band forms
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
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 > 1h and does not
respond to fluid administration or
pharmacologic intervention
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.






Sepsis is SIRS Caused by an Infection
TNF-
IL-1
IL-6
INF gamma
IL-12
IL-10
Activation of coagulation cascade
Activation of complement cascade
Activation of adaptive immunity
Macrophage
Innate immune response
like receptor signaling pathways. - Toll
Endothelial cell activation
ATP K
Atrial Natriuretic Peptide
activated coagulation. - Inflamation

Von willibrand factor ADAMTS13
Von Willibrand Factor and its Inactivation by ADAMTS13
The Cardiovascular Physiology of Sepsis.
Parker et al Ann Intern Med 1984
Sever sepsis
Recovery
Mechanisms of Vasoconstriction and Vasodilatation
in Arteriolar Smooth Muscle Cells
Sepsis
Vasopressin
Landry & Oliver NEJM 2001
Sepsis
oxide - regulation of iNOS and Nitric - INF gamma Up
The Roll of KATP
Channel in Sepsis
Landry & Oliver NEJM 2001
Vasopressin
Vasopressin:
kidney water reabsorption
inactivation KATP channel
cGMP
norepinephrine response
B7-CD28/CTLA-4 costimulation of T-Cell activation
Anti-CD28 Ab cause cytokine storm. (Sep. 2006 NEJM)
Super-antigens (Staph. Aurous and Streptococcus group A)
activates ~20% of T cells compared with 1/10000
massive cytokine release.
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
The day after, diffuse
maculopapular rash
appeared.


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.


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.
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, PO
2
-66,
O
2
Sat-88%
hemorrhagic rash of meningococcemia
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


Eventually the patient recovered.
MODS in Meningococcemia
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
O2 Consumption l/min
(Arterial - Venous)
Oxygen content difference
= Cardiac Output
Fick Law
Antibiotic Treatment
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.
Sites of infection in Pt.
with severe sepsis.
Surgical Treatment !!!
Mortality after surgery for abdominal sepsis
Serratia marcescens
Intensive Insulin Therapy in Critically Ill Surgical Patients
Van Den Berghe et al NEJM 2001

P=0.005
Treatment of Sepsis.
Diagnosis !!!
Oxygen. (Tidal volume 6ml/kg) (< 30 cm H2O)
Fluids; 5 liters in 6 hours CVP
Vasoactive agents: dopamine,
norepinephrine - BP
Antimicrobial drugs, (after cultures).
Central venous oxigen saturation > 70%:
Inotropic agent: dobutamine.
Blood hematocrit > 30%.
Surgical drainage.
Intensive insulin treatment blood sugar control
Activated Protein C for the Treatment of Severe sepsis
Bernard et al NEJM 2001
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%),
p=0.02
No significant difference in responders
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%
Case Report - Sepsis
Next day Rt. Thigh swollen (Rt.>Lt. 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 PO
2
-62 Sat-90% Pco2-34.
Liver function tests-abnormal
sever sepsis
Oxygen, I.V. fluids,
Orbenin 2grx6, Clindamycin 900mgx3


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
Pyomyositis
ARDS
Secondary healing
after surgical
drainage.
After 6 months
ARDS in a patient with sever Staph-aureus sepsis
Psoas abscess in a
patient with Staph-
aureus sepsis
Psoas abcess
Bone scan: septic sacroileitis.
Pyomyositis of the paraspinal mascles resulting in
staph-aureus meningitis.
Thrombotic Thrombocytopenic Purpura (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 <10% to 80-90%

Severe Urosepsis & TTP
ADAMTS13 -
Von Willibrand Factor
multimers -
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 - 37.7C, 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.



Lt. Pyonephrosis by US
3.11.05
25.10.05
Persistence of severe sepsis for
, 22.7 - fever, WBC : days 10
PLT-51000, Hg-11, LDH-1127,
ARDS, severe metabolic
acidosis, persistent renal failure
- Cr.-3.6, normal coagulation
Functions
CT and Gallium Scan
3.11.05
Severe Urosepsis & TTP
4.11.2005: Lt. Nephrectomy
On pathology: multiple abscesses of left kidney









normal postoperative period 13.11.2005: discharge
WBC-10x10
9
/l ; Hb 10.7g/dl; Plt-213000, Cr.-2.0.



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
Severe Urosepsis & TTP
4 days on mechanical ventilation in a coma
ADAMTS13: Ag 10%, activity < 2%,
Ab > 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

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
Fibrinous Thrombus of Renal Arteriole.
Thrombi in the Renal Medulla
Diffuse Glomerular Capillary Thrombosis
ADAMTS13
in sepsis + DIC
ADAMTS13<20% -
renal function
Large vWF multimers
in 51% of pt. With
ADAMTS13 < 20%
ADAMTS13 is
cleaved by protease
& liver synthesis
ADAMTS13 Activity
ADAMTS13 Antigen
Severe Urosepsis & TTP
3.2.2006-12.2.2006:
elective Suprapubic Prostatectomy
Hb-12.7g/dl; MCV-93; WBC-11.6x10
9
/l;
Plt-399x10
9
/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-201x10
9
/l;
BUN-43mg/dl; Cr-2.5mg/dl
Pieter Brueghel 1525-1569