Sepsis David Hassin Tel-Aviv Medical Center “The Human Race is a Transient Episode in the History...

SepsisSepsisDavid Hassin David Hassin

Tel-Aviv Medical CenterTel-Aviv Medical Center

““The Human Race is a Transient Episode The Human Race is a Transient Episode in the History of Bacteriain the History of Bacteria””

SepsisSepsis::Clinical evidence of infection, plus evidence of a Clinical evidence of infection, plus evidence of a systemic response to infection, manifested by systemic response to infection, manifested by two or more of the following conditionstwo or more of the following conditions::

11 . .Temperature > 38°C or < 36°CTemperature > 38°C or < 36°C

22 . .Heart rate > 90/minHeart rate > 90/min

33 . .Respiratory rate > 20/minRespiratory rate > 20/min

or PaCOor PaCO22 < 32 mmHg < 32 mmHg

44 . .WBC > 12000 < 4000WBC > 12000 < 4000

or > 10% band formsor > 10% band forms

Severe SepsisSevere Sepsis::

Sepsis with evidence of organ hypo-perfusionSepsis with evidence of organ hypo-perfusion

With at least one of the followingWith at least one of the following::

11 . .HypoxemiaHypoxemia

22 . .Elevated lactate – metabolic acidosisElevated lactate – metabolic acidosis

33 . .OliguriaOliguria

44 . .Acute alteration in mental statusAcute alteration in mental status

Septic ShockSeptic Shock::

Severe sepsis with hypotension despiteSevere sepsis with hypotension despite Adequate fluid resuscitation. (20-30ml/kg/30min)Adequate fluid resuscitation. (20-30ml/kg/30min)HypotensionHypotension::Arterial blood pressure ofArterial blood pressure of

9090 mmHg systolic or 40 mmHg less thanmmHg systolic or 40 mmHg less thanpatient’s normal blood pressurepatient’s normal blood pressureRefractory Septic ShockRefractory Septic Shock::

Septic shock that lasts for > 1h and does not Septic shock that lasts for > 1h and does not respond to fluid administration or respond to fluid administration or pharmacologic interventionpharmacologic intervention

MODS:MODS:

Multiple Organ Dysfunction SyndromeMultiple Organ Dysfunction Syndrome:: Dysfunction of more than one organ,requiring Dysfunction of more than one organ,requiring intervention to maintain homeostasisintervention to maintain homeostasis..

SIRSSIRS::Systemic Inflammatory Response SyndromeSystemic Inflammatory Response Syndrome

Response to a wide variety of clinical insults, Response to a wide variety of clinical insults, which can be infectious,as in sepsis, but which can be infectious,as in sepsis, but

can be noninfectious in etiologycan be noninfectious in etiology . .

Sepsis is SIRS Caused by an InfectionSepsis is SIRS Caused by an Infection

TNF-TNF-αα IL-1IL-1ββ

IL-6 IL-6 INF gamma INF gamma IL-12 IL-12

IL-10IL-10

Activation of coagulation cascade Activation of coagulation cascade Activation of complement cascade Activation of complement cascade

Activation of adaptive immunityActivation of adaptive immunity

MacrophageMacrophage

Innate immune responseInnate immune response

Toll-like receptor signaling pathwaysToll-like receptor signaling pathways..

Endothelial cell activationEndothelial cell activation

KATP

Atrial Natriuretic Peptide

Inflamation-activated coagulationInflamation-activated coagulation..

Von willibrand factorVon willibrand factor ADAMTS13ADAMTS13

Von Willibrand Factor and its Inactivation by ADAMTS13Von Willibrand Factor and its Inactivation by ADAMTS13

The Cardiovascular Physiology of SepsisThe Cardiovascular Physiology of Sepsis..

Parker et al Ann Intern Med 1984Parker et al Ann Intern Med 1984

Sever sepsisSever sepsis

RecoveryRecovery

Mechanisms of Vasoconstriction and Vasodilatation Mechanisms of Vasoconstriction and Vasodilatation in Arteriolar Smooth Muscle Cellsin Arteriolar Smooth Muscle Cells

SepsisSepsis

VasopressinVasopressin

Landry & Oliver NEJM 2001Landry & Oliver NEJM 2001

SepsiSepsiss

INF gamma Up-regulation of iNOS and Nitric-oxideINF gamma Up-regulation of iNOS and Nitric-oxide

The Roll of KThe Roll of KATPATP Channel in SepsisChannel in Sepsis

Landry & Oliver NEJM 2001Landry & Oliver NEJM 2001

VasopressinVasopressin

Vasopressin: Vasopressin: kidney water reabsorptionkidney water reabsorption inactivation Kinactivation KATPATP channel channel cGMP cGMP norepinephrine responsenorepinephrine response

B7-CD28/CTLA-4 costimulation of T-Cell activationB7-CD28/CTLA-4 costimulation of T-Cell activation► Anti-CD28 Ab cause cytokine storm. Anti-CD28 Ab cause cytokine storm. (Sep. 2006 NEJM)(Sep. 2006 NEJM)

Super-antigens (Staph. Aurous and Streptococcus group A) Super-antigens (Staph. Aurous and Streptococcus group A) activates ~20% of T cells compared with 1/10000 activates ~20% of T cells compared with 1/10000

massive cytokine release. massive cytokine release.

Case Report - SepsisCase Report - Sepsis

19 years old soldier19 years old soldier► From a day before admission: fever, From a day before admission: fever,

purulent rhinitis, headache and vomits. purulent rhinitis, headache and vomits. ► On admission: good general condition On admission: good general condition B.P.-110/70 B.P.-110/70 Fever-38.5°CFever-38.5°C R.R.-20/minR.R.-20/min WBC-13000WBC-13000 Neu-92% Neu-92% Chest x-ray: NormalChest x-ray: Normal Sinuses (x-ray): mucosal thickening of the Sinuses (x-ray): mucosal thickening of the

Maxillary Maxillary sinussinus

► Diagnosis: Sinusitis – I.V. Cefuroxime Diagnosis: Sinusitis – I.V. Cefuroxime

The day after, diffuse The day after, diffuse maculopapular rash maculopapular rash

appearedappeared..


► The day after, the patient feels good, diffuse The day after, the patient feels good, diffuse maculopapular rash appeared.maculopapular rash appeared.

► Two blood cultures taken on admissionTwo blood cultures taken on admission grew: grew: Neisseria Meningitidis group BNeisseria Meningitidis group B

► I.V. Penicillin was started – the patient recovered I.V. Penicillin was started – the patient recovered

► The patient’s girl friend received Rifampin as a The patient’s girl friend received Rifampin as a preventive therapy.preventive therapy.


► Six weeks later the girlfriend (an 18 year-old soldier) Six weeks later the girlfriend (an 18 year-old soldier) was hospitalized was hospitalized

► Presented Presented in the morningin the morning to an emergency ward with to an emergency ward with fever, shaking chills and a sore throat.fever, shaking chills and a sore throat.

► The patient and her mother informed the physician The patient and her mother informed the physician about the boyfriend’s meningococcemia but he chose about the boyfriend’s meningococcemia but he chose to ignore it.to ignore it.

► The patient was discharged, diagnosis: “pharyngitis”. The patient was discharged, diagnosis: “pharyngitis”.


► In the eveningIn the evening she lost her consciousness and she lost her consciousness and sphincteric control after which she was stuporous sphincteric control after which she was stuporous for half an hourfor half an hour

► On admission she complained of blurred vision On admission she complained of blurred vision and sever muscle pain.and sever muscle pain.

► Typical hemorrhagic rash Typical hemorrhagic rash ► B.P.-80/60, pulse-120, fever-38°CB.P.-80/60, pulse-120, fever-38°C

WBC-3800, Hg-10.4WBC-3800, Hg-10.4

PH-7.27, Bic-11.6, Pco2-26, POPH-7.27, Bic-11.6, Pco2-26, PO22-66, -66,

OO22Sat-88%Sat-88%

hemorrhagic rash of meningococcemiahemorrhagic rash of meningococcemia


► Oxygen, I.V. saline and I.V. Penicillin were started: Oxygen, I.V. saline and I.V. Penicillin were started: B.P.–80/40, pulse-125, R.R.-40 B.P.–80/40, pulse-125, R.R.-40

Severe Sepsis with HypotensionSevere Sepsis with Hypotension ► Neisseria Meningitidis in blood and CSF culturesNeisseria Meningitidis in blood and CSF cultures

► MODS:MODS: ARDS – respiratory failure – respiratorARDS – respiratory failure – respirator

Acute renal failure – dialysisAcute renal failure – dialysis

Anoxic hepatitisAnoxic hepatitis

Myelopathy – paraparesisMyelopathy – paraparesis

Eventually the patient recoveredEventually the patient recovered..

MODS in MeningococcemiaMODS in Meningococcemia

Early Goal – Directed Therapy in the Treatment of Early Goal – Directed Therapy in the Treatment of Sever Sepsis and Septic ShockSever Sepsis and Septic Shock

Rivers et al NEJM 2001Rivers 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 LawFick Law

Antibiotic TreatmentAntibiotic Treatment

► Identity:Identity: Bacteriologic statistics:Bacteriologic statistics:

Gram stain.Gram stain.

Culture.Culture.

Immunologic, molecular. Immunologic, molecular. ► Susceptibility:Susceptibility: Bacteriologic statistics.Bacteriologic statistics.

Disc diffusion, MIC.Disc diffusion, MIC.► Host factors:Host factors: Adverse reaction.Adverse reaction.

Renal and hepatic function.Renal and hepatic function.

Pregnancy.Pregnancy.

Site of infection.Site of infection.

Sites of infection in Pt. Sites of infection in Pt. with severe sepsis with severe sepsis..

Surgical TreatmentSurgical Treatment!!! !!!

Mortality after surgery for abdominal sepsisMortality after surgery for abdominal sepsis

Serratia marcescensSerratia marcescens

Intensive Insulin Therapy in Critically Ill Surgical PatientsIntensive Insulin Therapy in Critically Ill Surgical PatientsVan Den Berghe et al NEJM Van Den Berghe et al NEJM

20012001

P=0.005P=0.005

Treatment of SepsisTreatment of Sepsis..

► DiagnosisDiagnosis !!! !!!► Oxygen. (Tidal volume 6ml/kg) (< 30 cm H2O)Oxygen. (Tidal volume 6ml/kg) (< 30 cm H2O)► Fluids; 5 liters in 6 hours – CVPFluids; 5 liters in 6 hours – CVP► Vasoactive agents: dopamine,Vasoactive agents: dopamine,

norepinephrine - BPnorepinephrine - BP► Antimicrobial drugs, (after cultures).Antimicrobial drugs, (after cultures).► Central venous oxigen saturation > 70%:Central venous oxigen saturation > 70%:

Inotropic agent: dobutamine.Inotropic agent: dobutamine. Blood – hematocrit > 30%.Blood – hematocrit > 30%.

► Surgical drainage.Surgical drainage.► Intensive insulin treatment blood sugar controlIntensive insulin treatment blood sugar control

Activated Protein C for the Treatment of Severe sepsisActivated Protein C for the Treatment of Severe sepsis

Bernard et al NEJM 2001Bernard et al NEJM 2001

Low Doses of Hydrocortisone and Fludrocortisone Low Doses of Hydrocortisone and Fludrocortisone in Sepsisin Sepsis

Annane et al JAMA 2002Annane et al JAMA 2002

► Hydrocortisone 50mg x4, Hydrocortisone 50mg x4, Fludrocortisone 50mcg x1 for 7 days.Fludrocortisone 50mcg x1 for 7 days.

► Non responders to corticotropin test:Non responders to corticotropin test:► Placebo group 115 patients – 73 dead (63%)Placebo group 115 patients – 73 dead (63%)► Corticosteroid group 114 patients – 60 dead (53%), Corticosteroid group 114 patients – 60 dead (53%),

p=0.02p=0.02► No significant difference in responders No significant difference in responders


46 years old male46 years old male► 3 weeks ago wounded the Tibial Tuberosity 3 weeks ago wounded the Tibial Tuberosity

- 0.5cm scar on examination- 0.5cm scar on examination► 10 days of fever low back pain radiating to 10 days of fever low back pain radiating to

the right legthe right leg► Good general condition BP-120/80Good general condition BP-120/80

Pulse-80 RR-18 Pulse-80 RR-18 Temp.-38°C.Temp.-38°C.► Tenderness over right thighTenderness over right thigh► WBC-20600 Neu-88% WBC-20600 Neu-88%


► Next day Rt. Thigh swollen (Rt.>Lt. – 7cm) Next day Rt. Thigh swollen (Rt.>Lt. – 7cm) sever painsever pain

► Fifth day sudden deterioration:Fifth day sudden deterioration: pulse-108 pulse-108 BP-110/60 BP-110/60 RR-28RR-28 redness of Rt. thigh redness of Rt. thigh

► WBC-35500 WBC-35500 Neu-94% Hg-9.9Neu-94% Hg-9.9

► Ph-7.38 Ph-7.38 Bic-19.7 POBic-19.7 PO22-62-62 Sat-90% Pco2-34. Sat-90% Pco2-34.

Liver function tests-abnormal Liver function tests-abnormal sever sepsissever sepsis

► Oxygen, I.V. fluids, Oxygen, I.V. fluids, Orbenin 2grx6, Clindamycin 900mgx3Orbenin 2grx6, Clindamycin 900mgx3


► CT: Abscess from the rt. gluteus to the kneeCT: Abscess from the rt. gluteus to the knee► Blood cultures - Blood cultures - Staph. AureusStaph. Aureus► Operation:Operation: Fascia intact, 40 cm cut of fascia Fascia intact, 40 cm cut of fascia

- discharge of large amount of pus – - discharge of large amount of pus – Pyomyositis Pyomyositis

► After the operation: After the operation: Septic shock, ARDS – Septic shock, ARDS – mechanical respiration for 3 daysmechanical respiration for 3 days

► Wound closed after 6 month Wound closed after 6 month

PyomyositisPyomyositis

ARDSARDS

Secondary healing Secondary healing after surgical after surgical

drainagedrainage..

After 6 monthsAfter 6 months

ARDS in a patient with sever Staph-aureus sepsisARDS in a patient with sever Staph-aureus sepsis

Psoas abscess in a Psoas abscess in a patient with Staph-patient with Staph-

aureus sepsisaureus sepsis

Psoas abcessPsoas abcess

Bone scan: septic sacroileitisBone scan: septic sacroileitis..

Pyomyositis of the paraspinal mascles resulting in Pyomyositis of the paraspinal mascles resulting in staph-aureus meningitis staph-aureus meningitis..

Thrombotic Thrombocytopenic Purpura (TTP)Thrombotic Thrombocytopenic Purpura (TTP)► Moschowitz,1925Moschowitz,1925: new disease characterized by : new disease characterized by

unique pathological findings of thrombi in many unique pathological findings of thrombi in many organs.organs.

► Amrosi and Ultmann,1964Amrosi and Ultmann,1964: : review of all 217 published cases and review of all 217 published cases and definition of classic pentad:definition of classic pentad: 1) Thrombocytopenia1) Thrombocytopenia 2) Microangiopathic hemolytic anemia2) Microangiopathic hemolytic anemia 3) Neurologic symptoms and signs3) Neurologic symptoms and signs 4) Renal function abnormalities4) Renal function abnormalities 5) Fever5) Fever► Plasma exchange therapyPlasma exchange therapy:: improved survival from <10% to 80-90% improved survival from <10% to 80-90%

Severe Urosepsis & TTPSevere Urosepsis & TTP

ADAMTS13 - Von Willibrand Factor Von Willibrand Factor

multimersmultimers- -

► 67 y old man67 y old man► BPH with permanent urinary catheter for 2 monthsBPH with permanent urinary catheter for 2 months► 24.10.2005:24.10.2005: urinary retention - replacement of urinary retention - replacement of

urinary catheter in Afula hospitalurinary catheter in Afula hospital► 25.10.2005: 25.10.2005: severe sepsis with hypotension: severely ill, severe sepsis with hypotension: severely ill,

T - 37.7ºC, T - 37.7ºC, blood pressure - 80/49blood pressure - 80/49; ; pulse – 100/minpulse – 100/min, , creatinine -3.4, creatinine -3.4, WBC – 12.8WBC – 12.8 Hg -12.9 PLT -199000 Hg -12.9 PLT -199000 ABG: PH –7.4; PO2-87.5; PCO2-19. ABG: PH –7.4; PO2-87.5; PCO2-19. HCO3-12HCO3-12; ; ABE-(-)10; Sat.-96% ABE-(-)10; Sat.-96%

Coagulation tests – Fibrinogen-308, INR-1.3, PTT-31 Coagulation tests – Fibrinogen-308, INR-1.3, PTT-31 ► I.V. Ceftriaxone and Ciprofloxacin were startedI.V. Ceftriaxone and Ciprofloxacin were started► Blood and urine cultures: Klebsiella Pneumoniae. Blood and urine cultures: Klebsiella Pneumoniae.

Lt. Pyonephrosis by USLt. Pyonephrosis by US

3.11.053.11.05

25.10.0525.10.05 Persistence of severe Persistence of severe sepsis for 10 dayssepsis for 10 days: fever, fever, WBC-22.7, WBC-22.7, PLT-51000PLT-51000, Hg-, Hg-11, 11, LDH-1127LDH-1127, ARDS, , ARDS, severe metabolic acidosis, severe metabolic acidosis, persistent renal failure - persistent renal failure - Cr.-3.6, normal coagulation Cr.-3.6, normal coagulation FunctionsFunctions

CT and Gallium ScanCT and Gallium Scan3.11.053.11.05

Severe Urosepsis & TTPSevere Urosepsis & TTP► 4.11.2005:4.11.2005: Lt. Nephrectomy Lt. Nephrectomy

On pathology: multiple abscesses of left kidneyOn pathology: multiple abscesses of left kidney

► normal postoperative period normal postoperative period 13.11.2005:13.11.2005: discharge discharge► WBC-10x10WBC-10x1099/l ; Hb –10.7g/dl; Plt-213000, Cr.-2.0. /l ; Hb –10.7g/dl; Plt-213000, Cr.-2.0.

Severe Urosepsis & TTPSevere Urosepsis & TTP► 15.11.2005:15.11.2005: recurrent hospitalization because of recurrent hospitalization because of

generalized weakness. generalized weakness. Hb -7Hb -7; MCV-90, WBC-14.5, ; MCV-90, WBC-14.5, Plt -2000Plt -2000 Creatinine –2.9, T. Bil.-2.6, direct B.-0.7,Creatinine –2.9, T. Bil.-2.6, direct B.-0.7,

LDH-2211, LDH-2211, fibrinogen-308, coagulation tests - normalfibrinogen-308, coagulation tests - normal► 17.11.2005:17.11.2005: confusion and stuporconfusion and stupor ► RBC fragmentationRBC fragmentation on peripheral blood smear on peripheral blood smear ► brain CT – normalbrain CT – normal

TTPTTP


► 4 days on mechanical ventilation in a coma4 days on mechanical ventilation in a coma► ADAMTS13: Ag – 10%, activity < 2%, ADAMTS13: Ag – 10%, activity < 2%,

Ab > 100 u/ml (n 0-15u/ml)Ab > 100 u/ml (n 0-15u/ml) ► Plasma exchange therapy and corticosteroids Plasma exchange therapy and corticosteroids

were startedwere started► Seven plasma exchanges Seven plasma exchanges ► Dramatic clinical and laboratory improvement, Dramatic clinical and laboratory improvement,

neurological outcome: neurological outcome: lt. homonymous hemianopsia and lt. hemiparesislt. homonymous hemianopsia and lt. hemiparesis recurrent brain CT: ischemic changes in the Rt. recurrent brain CT: ischemic changes in the Rt.

Occipitotemporal area Occipitotemporal area

CT of the Brain withCT of the Brain with ischemic changes ischemic changes in the Rt. in the Rt. Occipitotemporal area at the time of Occipitotemporal area at the time of

lt. homonymous hemianopsia and lt. hemiparesislt. homonymous hemianopsia and lt. hemiparesis

23.11.023.11.055

Fibrinous Thrombus of Renal ArterioleFibrinous Thrombus of Renal Arteriole..

Thrombi in the Thrombi in the Renal Renal MedullaMedulla

Diffuse Glomerular Capillary ThrombosisDiffuse Glomerular Capillary Thrombosis

ADAMTS13 ADAMTS13 in sepsis + DICin sepsis + DIC

ADAMTS13<20% - ADAMTS13<20% - renal functionrenal function

Large vWF multimers Large vWF multimers in 51% of pt. With in 51% of pt. With ADAMTS13 < 20%ADAMTS13 < 20%

ADAMTS13 is ADAMTS13 is cleaved by protease cleaved by protease & liver synthesis& liver synthesis

ADAMTS13 ActivityADAMTS13 Activity

ADAMTS13 AntigenADAMTS13 Antigen


3.2.2006-12.2.20063.2.2006-12.2.2006: : ► elective Suprapubic Prostatectomy elective Suprapubic Prostatectomy ► Hb-12.7g/dl; MCV-93; WBC-11.6x10Hb-12.7g/dl; MCV-93; WBC-11.6x1099/l; /l;

Plt-399x10Plt-399x1099/l /l ► Cr-3.3; BUN-50mg/dl Cr-3.3; BUN-50mg/dl ► normal postoperative period normal postoperative period

10.6.200610.6.2006::► Follow up examination normal, no neurological signsFollow up examination normal, no neurological signs► Hb-13 g/dl; MCV-95 ; WBC-7.5X10 Hb-13 g/dl; MCV-95 ; WBC-7.5X10 99/l; /l;

Plt-201x10 Plt-201x1099/l; /l; ► BUN-43mg/dl; Cr-2.5mg/dlBUN-43mg/dl; Cr-2.5mg/dl

Pieter Brueghel Pieter Brueghel 1525-15691525-1569

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Sepsis David Hassin Tel-Aviv Medical Center “The Human Race is a Transient Episode in the History...

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