Transcript SEPSIS SEVERE SEPSIS SEPTIC SHOCK

SEPSIS
SEVERE
SEPSIS
SEPTIC
SHOCK
Rontgene M. Solante,M.D.,FPCP,FPSMID
Internal Medicine – Infectious Diseases
SEPSIS: WHAT DO WE KNOW?

Sepsis (Greek): “rotten flesh and putrefaction”

“complex medical condition that begins with an
infectious stimulus and results in an exaggerated
immune response”

European Study: >35% of patients develop sepsis
at some point during their ICU stay; 30% severe
sepsis; mortality- 27% sepsis and >50% if septic
shock
- Jean-Louis Vincent, et al. Sepsis in European Intensive Care Units: Results of SOAP Study. 2006
Sepsis: A Complex Disease

This Venn diagram
provides a conceptual
framework to view
the relationships
between various
components
of sepsis.

The inflammatory
changes of sepsis are
tightly linked to
disturbed hemostasis.
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Opal SM et al. Crit Care Med. 2000;28:S81-2.
Sepsis: ACCP/SCCM Definitions
Infection
– Inflammatory response to microorganisms, or
– Invasion of normally sterile tissues
Systematic Inflammatory Response Syndrome(SIRS)
–
–
–
–
> 2 of the following:
Core temperature >38o C or <36oC (>100.4o F or <96.8o F)
Elevated heart rate (>90 beats/min)
Respiratory rate >20 breaths/min or PACO2 <32 mm Hg
or mechanical ventilation for acute respiratory process
WBC count > 12,000 cells/mm3 or <4,000 cells/mm3 or
>10%
immature neutrophils
Sepsis: ACCP/SCCM Definitions
Known or suspected infection, plus
>2 SIRS criteria:
– Core temperature >38o C or <36oC (>100.4o F or
<96.8o F)
– Elevated heart rate (>90 beats/min)
– Respiratory rate >20 breaths/min or PACO2 <32
mm Hg or mechanical ventilation for acute
respiratory process
– WBC count > 12,000 cells/mm3 or <4,000
cells/mm3 or >10% immature neutrophils
Severe Sepsis: Acute Organ
Dysfunction and Disordered Hemostasis

Severe Sepsis:
Sepsis with signs of
organ dysfunction in 1
of the following systems:
–
–
–
–
–
–
–
Cardiovascular
Renal
Respiratory
Hepatic
Hemostasis
CNS
Unexplained metabolic
acidosis
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Severe Sepsis (Sepsis syndrome)
1. Cardiovascular:
Arterial systolic BP< 90 mmHg or mean arterial pressure
(MAP) <70 mmHg that responds to administration of fluid
2. Renal:
Urine output < 0.5 ml/kg per hour for 1 hr despite
adequate fluid resuscitation
3. Respiratory:
PaO2 /FiO2 <250 or, if the lung is the only dysfunctional organ,
<200
4. Hematologic:
Platelet count <80,000/uL or 50% decrease in platelet count
from highest value recorded over previous 3 days
Septic Shock
-Sepsis with hypotension despite adequate
fluid resuscitation accompanied by perfusion
abnormalities
Systemic Inflammatory Response Syndrome (SIRS)
INFECTION
Inflammatory response to
the presence of or invasion
of normally sterile host
tissue by microorganisms
SEPSIS
Systemic response to infection with
Same manifestation as SIRS
BACTEREMIA
The presence of live
bacteria in the blood
SEVERE SEPSIS
Sepsis associated with organ dysfunction, hypopefusion or hypotension.
Perfusion abnormalities may include but are not limited to:
• Lactic acidosis
• Oliguria
• Acute mental status changes
2º MODS
Altered organ function
in acutely ill patient
requiring intervention
SEPTIC SHOCK
Sepsis with hypotension despite adequate
fluid resuscitation accompanied by
perfusion abnormalities
HYPOTENSION
Systolic BP < 90 or
↓ from baseline
> 40 mmHg
Severe Sepsis: A Complex and
Unpredictable Clinical Syndrome

Sepsis-induced organ
failure:
-? Cause (autopsies):
discordant findings
- tissue hypoxia
(microvascular blood flow
studies in mucosal
membranes)

Alterations in cell
metabolisms- oxidative
modifications of proteins,
lipids, DNAs
SEPSIS
ACUTE ORGAN
DYSFUNCTION
(Severe Sepsis)
DEATH
- Vincent JL and Abraham E. The Last 100 Years of Sepsis. AJRCCM 2006; 173:256-63.
PATHOPHYSIOLOGY:
Microcirculatory dysfunction
Cytopathic hypoxia –diminished production of ATP
despite normal PO2 values in the vicinity of
mitochondria within cells
↓
Activation or Injury of the vascular endothelium
Secondary to alteration of vascular tone, vascular
permeability and coagulation
↓
↓
Activation of cytokines and other mediators
↓
Complement Activation
↓
Coagulopathy
↓
Immunosuppression
Microorganisms Involved in Episodes of
Severe Sepsis
Episodes with
bloodstream
infection, %
(n=436)
Gram negative bacteria
Gram positive bacteria
Fungi
Polymicrobial
Classic Pathogens
35
40
7
11
<5
Episodes with
Documented
Infection But No
Bloodstream
infection, %
(n= 430)
44
24
5
21
<5
Total Episodes,
%
(n= 866)
40
31
6
16
<5
Balance between proinflammatory and counter-regulatory
events in response to infection determines clinical outcome
Outcome
Proinflammatory
cytokine, coagulation system,
neutrophil activation
Excessive Response
Fulminant SIRS
Early Mortality
Antiinflammatory
Cytokine, natural inhibitor release,
Stress hormones,
immune cell activation
Excessive Response
Immunoparalysis
Late Mortality
Normal Host Responses to Infection



Local Defenses: Walling Off and Killing Invading Microbes
Systemic Responses: Keeping Infection and Inflammation localized
a.) CNS Regulation of Systemic Response
b.) Essential Roles of Liver and Spleen
Acute Phase Responses
a.) Anti-infective Responses
b.) Anti-inflamatory responses
c.) Metabolic responses
d.) Procoagulant responses
e.) Thermoregulatory Responses
Walling off and Killing Invading
Microbes

Innate Immunity
 Senses microbes through proteins that bring highly
conserved microbial molecules (lipopolysaccharides,
peptiglycan)
 “Hard-wired” –inferited in the genome; shaped by
evolution
 Responds rapidly to microbial invasion
 Elements: mannose-binding-lectin, alternative
complement pathway, “natural” antibodies, pattern –
recognition proteins, the “professional” phagocytes,
mast cells, (NK) natural killer cells
Systemic Responses: Keeping Infection and
Inflammation localized
a.) CNS Regulation of Systemic Response
The CNS senses microbial invasion via:
1.
afferent impulses along nociceptive and vagal nerves
rapidly transmit signals from infected local tissues to
the hypothalamus and brainstem where they can
activate the hypothalamic-pituitary-adrenal (HPA) axis,
the autonomic nervous system and the hypothalamic
thermoregulatory center
2.
Blood-borne mediators (IL-Iβ, TNF, IL-6, interferons
and prostaglandins) can cross the blood-brain barrier
or be transported passively through capillaries in the
circumventricular organs to reach the hypothalamus
Systemic Responses: Keeping Infection
and Inflammation localized

Role of Liver and Spleen
The liver acts as a blood filter that collects and kills
blood-borne microbes, as a “listening station” that
senses low concentration of circulating cytokines and
transmits this information to the CNS, as a factory for the
production of many elements of the systemic response,
and as a major site of infection-associated metabolic
adaptations.
The spleen functions as the major filter for
opsonized microorganisms.
Acute Phase Responses
A.
Anti-infective responses
- increases synthesis of complement factors,
microbe pattern-recognition molecules (mannosebinding lectin, LBP, CRP, CD14 and others)
- sequesters iron (lactoferrin) and zinc
(metallothionein)
B.
Anti-inflammatory Responses
- releases anti-inflammatory neuroendocrine
hormones (cortisol, ACTH, epinephrine,
MSH)
- increases synthesis of proteins that help
prevent inflammation within the systemic
compartment
. Cytokinase antagonists (IL-1Ra)
. Anti-inflammatory mediators
. Protease inhibitors
. Antioxidants
- reprograms circulating leukocytes
(epinephrine, cortisol, PGE)
C.
Metabolic Responses
- preserves euglycemia, mobilizes fatty acids,
epinephrine, cortisol, glucagon, cytokines
D.
Procoagulant Responses
- walls off infection, prevents systemic spread by:
. increasing synthesis or release of
fibrinogen, PAI-I, C4b
. decreasing synthesis of protein C, antithrombin III
E.
Thermoregulatory Responses
Inhibits microbial growth (fever)
CLINICAL MANIFESTATIONS
Identifying Acute Organ Dysfunction as
a Marker of Severe Sepsis
Altered
Consciousness
Confusion
Psychosis
Tachycardia
Hypotension
 CVP
 PAOP
Tachypnea
PaO2 <70 mm Hg
SaO2 <90%
PaO2/FiO2 300
Oliguria
Anuria
 Creatinine
Jaundice
 Enzymes
 Albumin
 PT
 Platelets
 PT/APTT
 Protein C
 D-dimer
Nervous and Neuroendocrine
Systems
a. Cerebral function
- confusion and other subtle
abnormalities in cognitive
function
- focal signs, seizures and
cranial nerve palsies
- encephalopathy is
associated with poor
prognosis
b.
Hypothalamic-Pituitary-Adrenal axis
high plasma concentration of vasopressin are
followed by relatively low levels, probably
reflecting both loss of baroreflex feedback
regulation and vasopressin depletion from the
posterior pituitary
c.
Adrenal Insufficiency
- due to anatomic damage to the adrenals or
pituitary, hypoperfusion, cytokine-induced
dysfunction of adrenals, drug induced steroid
hypermetabolism, inhibitionof steroidogenesis
and desensitization to glucocorticoid
responsiveness at the cellular level
- manifested as hypotension and
hypoglycemia
d.
Autonomic dysfunction
manifested as oscillations in heart rate, blood
pressure, respiration
e.
Peripheral Nerves, Muscles
polyneuropathy and myopathy manifested as
difficulty in weaning from ventilator,
generalized wasting of limbs and diffuse
weakness
THE BLOOD STREAM
A.
The Heart
- reduced left and
right ventricular
ejection fractions
- increased left and
right ventricular
end-diastolic volume
- elevated heart rate and
cardiac output
SEPTIC SHOCK
Phases of septic shock:
1.
Vasoconstrictive (cold) shock
low cardiac output and high peripheral
resistance in hypovolemic pts. secondary to
redistribution of blood flow, venous pooling,
increased capillary permeability, increased
insensible losses and poor fluid intake
2.
Vasodilation
Clinical hallmarks:
 decreased systemic vascular
resistance
 high cardiac output.
Lipids
- decrease in levels of HDL and LDL
- increase in levels of triglycerides, free
acids and VLDL
fatty
Glucose
- hypoglycemia is uncommon since the body
can maintain glucose levels through
gluconeogenesis, glycogenolysis and insulin
resistance
Lactate
- increased blood lactate concentrations and
increased lactate to pyruvate ratio due
impaired hepatic lactate clearance and
mitochondrial dysfunction
Coagulopathy / DIC
diagnostic criteria for DIC:
1. platelet count <100,000/mm3 or rapid decrease in
platelet count;
Acute Lung Injury

Hyperventilation with
respiratory alkalosis
 Diagnostic criteria:
- arterial hypoxemia
(PAO2/FIO2 <300)
- bilateral infiltrates on chest
radiograph in the absence
of pneumonia and heart
failure
Renal Dysfunction

Proteinuria- renal failure
secondary to hypovolemia,
hypotension, renal
vasoconstriction and toxic
drugs
 oliguria
Gastrointestinal Tract injury

Hypoperfusion of visceral
organs leads to impairment of
the gut barrier function allowing
the translocation of bacteria
into the lymph and blood
stream

Aspiration of the microbial and
chemical contents of the upper
GI tract
GI bleeding
Ileus


Hepatic Dysfunction
Cholestatic jaundice – elevation in conjugated
and unconjugated bilirubin(<10mg/dl)
 Elevated alkaline phosphatase, bilirubin and
aminotransferases are common
 Frank hepatic failure (“shock liver”) is
uncommon

Cutaneous Manifestations

Cellulitis and thrombophlebitis
 Ecthyma gangrenosum or bullous lesions
 Symmetrical peripheral gangrene associated
with DIC, fibrin thrombi are seen in small
vessels, but neither inflammatory cells nor
bacteria are found
Diagnosis

Timely diagnosis and early intervention are key factors
in preventing morbidity and mortality
1. History
a. Clinical History (Underlying diseases)









immunosuppression – cell mediated vs. humoral
diabetes mellitus – poor glycemic control ↑risk
hormonal abnormalities
chronic obstructive pulmonary disease- ↑risk pneumonia and
bronchitis
valvular and congenital heart disease - ↑risk of IE
hyposplenism or asplenia
Malignancy
cirrhosis
malnutrition
Diagnosis
b. Medication History (provides clues to infection
type and severity)
Prior antimicrobial therapy –alters disease epidemiology
and warrants broadening microbiologic differential
diagnosis (resistant and unusual pathogens)
 NSAIDS and corticosteroid therapy
 allergic reactions
 drug-related adrenal insufficiency

Diagnosis
1. History
c. Invasive procedure or surgery
d. Obstetric and gynecologic history
e. Social History
- travel history, residence, occupation,
recreational activities, alcoholism, smoking,
sexual history
Diagnosis
2. Physical examination
a. Vital
signs - temperature, Pulse, Blood pressure,
respiratory rate
b. General findings- apprehensive, tachypneic, toxic or illlooking
c. Skin- petechiae, ecthyma gangrenosum, purpuric
macules, rashes, cellulitis, furuncles, abscess, pustules
d. heart murmurs
e. lungs
f. abdominal, rectal and pelvic examination
g. extremities
h. wound and soft tissues
i. central nervous system
Diagnosis
3. Diagnostic microbiology
a. Blood cultures
- blood volumes (10-20 ml adults)
- blood culture set number – 2 to 3 sets
- site selection- antecubital veins or upper extremities
not from catheters
b. Gram stains and other stains
c. Cultures
d. Hematology
e. Coagulation studies
f. Chemistries – electrolytes, hepatic and renal panels, CRP,
cytokine levels
g. Arterial blood gases
h. Urinalysis
Diagnosis
3. Diagnostic microbiology
i. Serologic tests
- acute and convalescent antibody titers
j. Radiology
k. CT and MRI
l. ultrasonography
m. Nuclear medicine imaging
Severe Sepsis Therapy:
Standard Care

Source control

Sedation/analgesia

Antibiotics

Ensure adequate

Hemodynamic support

Mechanical ventilation


Renal replacement
therapy
Provide hematological
support

Other supportive
measures
nutrition
Wheeler AP, Bernard GR. N Engl J Med. 1999;340:207-14.
THANK YOU FOR YOUR
ATTENTION!
Other Sources:
1. Principles and Practice of Infectious Diseases
6th edition, 2005 (Mandel et al)
2. Approach to Infectious Diseases
5th edition, 2003 ( Reese and Betts)
3. Washington Manual on Infectious Diseases
2005 edition
4. Harrison’s Principle of Internal Medicine
17th edition 2008
5. Surviving Sepsis Campaign: International
Guidelines for Management of Severe Sepsis and
Septic Shock: 2008 (Crit CareMed. 2008;36(1):296-327)