SEPSIS

CCM SENIOR RESIDENT HALF DAY

AUGUST 24, 2011

OUTLINE

• DEFINITIONS• PATHOPHYSIOLOGY• TREATMENT• COMPLICATION

DEFINITION

• Evolving:– Long history– Sepsis: derived from Greek word for the

decomposition of animal or vegetable matter– First used by Homer over 2700 yrs ago– Over 100 yrs ago the link between bacteria and

systemic infection was first described. (Schottmueller, AIM 1914)

DEFINITION

• Sepsis is a HOST RESPONSE to an invading organism and really reflects that response as much if not more than the organism

• Sepsis Syndrome:– R. Bone 1989– Hypo or hyperthermia– Tachycardia – Tachypnea– Presence of a site of infection– At least one site of end organ damage / hypoperfusion

• Altered LOC• Hypoxia• Elevated lactate• oliguria

DEFINITION• CONSENSUS CONFERENCE: (ACCP / SCCM / ESICM/ SIS) (‘92, 2001)

– SIRS: (at least 2 of):• Temp < 36C or > 38C• HR > 90bpm• RR >20 or PaCO2 < 32mmHg• WBC > 12 or <4

– SEPSIS: • systemic response + 2 or more SIRS criteria

– Severe Sepsis: • Sepsis + organ dysfunction, hypotension or hypoperfusion (lactate, oliguria,

altered LOC)

– Septic Shock:• Hypotension despite fluid resuscitation + perfusion abnormalities including

lactic acidosis, oliguria, altered LOC, requiring vasopressors or inotropes

DEFINITION

• PIRO Grading System: (Moreno)– P: predisposing factors: age/ sex / social / comorbidities / meds– I: Insult / infection: microbe / site– R: Host Response: WBC / coag / biomarkers / temp / HR / BP /

CO– O: Organ dysfunction: PaO2/FiO2 / Cr / Bili / Plt/ u/o / GCS

• PROBLEM:– All of the definitions include a very heterogeneous population– Moving target: evolving as the understanding of sepsis increases– Heterogeneity: may explain the negative results of may of the

large trials in sepsis. Or may explain the positive results of others (Prowess)

PATHOPHYSIOLOGY

• 1. MICROBIAL / PATHOGEN FACTORS• 2. HOST FACTORS– INNATE IMMUNE SYSTEM FUNCTION /

DYSFUNCTION– ENDOTHELIAL CELL DYSFUNCTION /

COAGULATION• 3. MICROCIRCULATORY CHANGE

PATHOPHYSIOLOGY

• MICROBIAL FACTORS:– VIRULENCE FACTORS– QUORUM SENSING SYSTEMS– VIRULENCE GENE UPREGULATION

PATHOPHYSIOLOGY

• MICROBIAL FACTORS: virulence• 5

1. mechanisms of bacterial adherence to host epithelial surfaces2. mechanisms of bacterial invasion3. bacterial host defense evasion mechanisms4. virulence factor-mediated host immune dysfunction ****5. virulence factor-induced host tissue injury****

PATHOPHYSIOLOGY

• Mechanisms of bacterial adherence to host epithelial surfaces

• Adhesins: secreted proteins enabling adhesion• Flagella, fimbrae, pili• Secretion system: attach and inject• Ligand mimicry

PATHOPHYSIOLOGY

• Mechanism of bacterial invasion following adherence:– Bacterial protein secretion systems• Transporter systems allowing delivery of bacterial

products into the extracellular matrix

– Lipidrafts• Avoid the apical area of the cell• Bind near the cell base which is rich in cholesterol and

pathogen recognition factors

PATHOPHYSIOLOGY

• Bacterial host defense evasion mechanisms:– Anti-phagocytosis:

• Inhibit opsonization• Surface antigenic variation to prevent recognition• Inhibition of uptake via the release of toxic proteins• Intracellular survival and replication in cytoplasm and

lysosomes• Induction of immune effector cell apoptosis

– Biofilm formation:• Polysaccharide matrix that encapsulate entire bacterial

colonies– Avoid phagocytosis and drugs

PATHOPHYSIOLOGY

• BACTERIAL CELL TO CELL COMMUNICATION: QUORUM-SENSING SYSTEMS (QSS)– Gram +vs and Gram –vs (different mechanisms)– Secretion of signaling molecules– Avoid detection by the host until there is enough

bacteria present (critical mass)• Once critical mass is attained virulence genes are

expressed and cellular proliferation signals are produced• Leads to swift invasion and establishment of infection• Hence concept of a INNOCULUM

PATHOPHYSIOLOGY

2 MAIN QUORUM MECHANISMS:• 1. GRAM POSITIVES– Synthesize cytosolic autoinducers– Actively transported to the extracellular

environment where they bind to neighbouring bacteria

– Induce a signaling cascade resulting in QSS control of relevant aspects of cellular function

PATHOPHYSIOLOGY

• 2. GRAM NEGATIVES:– Acyl-homoserine lactones (AHL)– Diffuse between the intra and extracellular

environments until a critical population density of bacteria attained.

– High signal molecule concentration which binds to the intracellular promotor regions of the QSS genes leading to relevant gene expression

PATHOPHYSIOLOGY

• VIRULENCE GENE UPREGULATION & INCREASED EXPRESSION:– Ability is dependent on quality and quantity of virulence

factors– Must be able to adapt to host systems which are many and

varied– PATHOGENECITY UNITS:

• Genes encoding virulence factors are in close proximity to specific sequences of chromosomal DNA

• Unstable DNA regions – allowing for “fortuitous” mutations– C. difficiele outbreak in Quebec– Able to exchange DNA with these unstable areas by lateral transfer

PATHOPHYSIOLOGY

• HOST DEFENSE MECHANISMS:– 2• Innate• Fluid phase

– Endothelial cell dysfunction

PATHOPHYSIOLOGY

• NORMAL IMMUNE RESPONSE:– Structural barriers

• Mucosa• Endogenous flora

– Innate followed by adaptive• Innate: early, containment• Adaptive: fine tunning

– 7-10 days– Ab response

– Initially pro-inflammatory then immunosuppressive– Cross-talk between different systems: ANS, coagulation– Heterogeneity (genetic and non-genetic)

• Success of invasion is dependent on the host response

PATHOPHYSIOLOGY

• HOST RESPONSE: PATHOGEN RECOGNITION– PRRs: pattern recognition receptors– PAMPs: pathogen associated molecular patterns– DAMPs: danger-associated molecular patters

• Concept:– Bacteria and viruses: molecular structures that are conserved /

shared / consistent (PAMPs)• = molecular signatures

– DAMPs:• PAMPs + Alarmins (intracellular proteins expressed or released with

host cell injury)

PATHOPHYSIOLOGY

• PRRs:– 4 families– 1. TOLL-like receptors– 2. NOD-LRR proteins– 3. cytoplasmic caspase activating and recruiting

domain helicases– 4. C-type lectin receptors

PATHOPHYSIOLOGY

• TOLL-LIKE RECEPTORS:– Cool or weird– Drosophila mutated and looked weird– 10-13 toll-like receptors described– Initiate the immune response and regulate the

adaptive response– Transmembrane proteins

• Extracellular: Leu rich repeats – bind ligand• Intracellular: toll-like interleukin-1R resistance domain

– 4 adapter molecules which activate protein kinases amplifying the signal

PATHOPHYSIOLOGY

• TOLL-LIKE RECEPTORS:– TLR 1: lyme disease and N. meningitides– TLR 2: Grams +s / most bacteria / Candida albicans

/ DAMPs– TLR 4: Gram –vs / LPS / Candida / DAMPs– TLR 5: salmonella / flagellated bacteria

PATHOPHYSIOLOGY

• TRANSMEMBRANE PROTEINS:– Phosphorylation by a KINASE– CASCADE: • Often more than one kinase

– SIGNAL AMPLIFICATION • as phosphorylation of several kinases can in turn

activate several cascade: NON-SPECIFIC

– Control: • Dephosphorylation

PATHOPHYSIOLOGY

• TRANSMEMBRANE PROTEINS:– CASPASES:• Activated and produce many of the changes leading to

apoptosis

– RESULT:• Synthesis and release of increased amounts of

mediators into the systemic circulation in an attempt to activate and recruit more effector cells.

PATHOPHYSIOLOGY

• INFLAMMATORY MEDIATORS RELEASED:– HIGH MOBILITY GROUP BOX 1 PROTEIN (HMGB1)• Nuclear and cytoplasmic protein• Active in DNA transcription / repair / replication

– MACROPHAGE MIGRATION INHIBITORY FACTOR:• Cytokine / activates T-cells• Can induce pro-inflammatory cytokines in macrophages• Elevated levels early = poor outcome

PATHOPHYSIOLOGY

• IMMUNE AND NON-IMMUNE EFFECTOR CELL DYSFUNCTION:– Normal effector response in response to Cyk release

is lost in severe sepsis– NEUTROPHILS:

• NORMAL:– Phagocytosis and release of cytotoxic molecules– Apoptosis in 7 hrs

• SEPSIS:– Loss of regulation with excessive activation and prolonged survival– Leads to ENDOTHELIAL DAMAGE

PATHOPHYSIOLOGY

• IMMUNE AND NON-IMMUNE EFFECTOR CELL DYSFUNCTION:– LYMPHOCYTES:• NORMAL:

– Pro-inflammatory response followed by regulatory response

• SEPSIS:– Accelerated apoptosis– Loss of regulatory function

PATHOPHYSIOLOGY

• COAGULATION CASCADE IN SEVERE SEPSIS:– Range of pathology: clinically silent to DIC– Coagulation: 3 phases• 1. initiation• 2. amplification• 3. thrombin action • There is considerable overlap and counterbalancing

mechanisms between these phases

PATHOPHYSIOLOGY

• COAGULATION CASCADE:– INITIATION:

• TF (injury) + VII VIIa-TF complex Thrombin

– AMPLIFICATION:• Thrombin / Plt / cofactors• Release of prothrombin (X)+plt+factors prothrombin complex thrombin burst clot

– THROMBIN:• Thrombin recruitment of additional factors

– Maintains platelet activation– Facilitates fibrinogen fibrin

PATHOPHYSIOLOGY

• COAGULATION CASCADE DYSFUNCTION:– 2 PHASES:

• 1. initial activation– TF– Immune effector cells (neutrophils)– cytokines

• 2. largely deregulated response with suppression of the autofibrinolytic pathway– TF, thrombin, APC bind to receptors on endothelial cells leading to cyk

production and alters apoptosis– Endothelial cells

» TF mediated initiation of thrombin» Dysfunction of anticoagulant pathways» Inhibition of fibrinogen

PATHOPHYSIOLOGY

• COAGULATION CASCADE DYSFUNCTION:– Activated Protein C: APC• Activated by thrombomodulin• Acts with protein S to deactivate clotting factors Va and

VIIIa – shuts down thrombin production• ± inhibit Cyk production• ± Prevent neutrophil activation• ± Inhibit leukocyte adhesion• ± Inhibit leukocyte rolling

PATHOPHYSIOLOGY

• MICROCIRCULATION:– Despite aggressive resuscitation, normal blood

pressure and adequate global 02 delivery, septic patients often persist in exhibiting signs of tissue hypoperfusion which may lead to acidosis and multiorgan failure D. Angus, CCM, 2003

– Macrocirculatory measurements fail to adequately assess the function of microvessles (<100υM)

PATHOPHYSIOLOGY

• MICROCIRCULATION AND ENDOTHELIAL DERANGEMENTS IN SEPSIS:– ANIMAL MODELS:• decreased microcirculatory flow velocity• Increased heterogeneity of flow• Increased stopped flow vessels• Decreased density of perfused capillaries

• Ellis, AJRCCM 2003

• Blood is effectively shunted from tissues

PATHOPHYSIOLOGY

• MICROCIRCULATION AND ENDOTHELIAL DERANGEMENTS IN SEPSIS:– ARTERIOLES / CAPILLARIES / VENULES• Deregulation of vasomotor control• Endothelial injury• Coagulation• Disordered leukocyte trafficking

PATHOPHYSIOLOGY

• MICROCIRCULATION AND ENDOTHELIAL DERANGEMENTS IN SEPSIS:– ENDOTHELIUM: CENTRAL ROLE• Regulation of microvessel thrombosis• Profibrinolysis• Leukocyte adherence NITRIC OXIDE• Microvascular tone• Permeability• Blood flow

PATHOPHYSIOLOGY

• MICROCIRCULATION AND ENDOTHELIAL DERANGEMENTS IN SEPSIS:– ENDOTHELIUM:

• Normally homeostatic• Sepsis:

– Endothelial damage from Il-1, Il-6, TNF-α, oxidative stress– Increased Cyk release from endothelial cells– Loss of tight junctions– Edema– Tissue hypoxia– Leukocyte adhesion and rolling– RBCs: impaired deformability aggregates decreased O2 delivery

DIAGNOSIS

• BASICS:– History– Physical exam– Labs: CBC– Cultures

DIAGNOSIS

• BIOMARKERS– LACTATE– VENOUS OXYGEN SATURATION– PRO-CALCITONIN– CRP– TNF, IL-6, IL-1

DIAGNOSIS

• LACTATE:– From anaerobic respiration– Absolute vs clearance:– Absolute lactates:• > 4 mmol/L predicted short term and in-hospital risk of

death (Trzeciak ICM, 2007)

• However other studies have shown lactates >8 in normotensive patients and > 18 in septic shock to be predictive

DIAGNOSIS

• LACTATE:– Absolute:• Mickkelsen et al CCM 2009

– Septic shock– Initial lactate was associated with mortality independent of

clinically apparent organ dysfunction and shock in patients with severe sepsis

– 3 levels: low <2, intermediate 2-3.9, high >3.9– OR: intermediate 2.05, high 4.87 in non-shock groups– OR: intermediate 3.27, high 4.87

DIAGNOSIS

• LACTATE:– Clearance:• Nguyen et al CCM 2004

– Lactate clearance early in hospital course is associated with decreased mortality

– Mortality reduction correlates with degree of lactate clearance

– ~ 11% decrease in likelihood of mortality with every 10% decrease in the lactate (in 6 hrs)

DIAGNOSIS

• ScvO2

– “gold standard”– But not validated– ScvO2 vs MvO2:

• Higher in shock due to decreased oxygen extraction• Higher due to line position:

– Coronary sinus flow– Redistribution of flow from splanchnic, renal & mesenteric beds– Some studies: 5-18% higher– Trends are the same– Needs to be studied

DIAGNOSIS

• Procalcitonin:– Levels are elevated in sepsis– Source: little known– Serum calcitonin levels are normal– More accurate at diagnosing sepsis than CRP or Il-

6– Some studies have shown prognositic value for

mortality

DIAGNOSIS

• CRP:– Acute phase reactant from the liver– Increase with exposure to Il-1, Il-6 or TNF– Marker of systemic inflammation– Nutritional assessment

DIAGNOSIS

• BIOMARKERS:– IL-1, IL-6, TNF– Not used in clinical practice• Cost• Value

DIAGNOSIS

• ORTHOGONAL POLARIZING SPECTRAL IMAGING (OPS)– Polarized green light– 3mm depth– Visualization of the microcirculation (RBC transit)– Non-invasive: sublingual mucosa– Finicky: motion artifact, positioning– DeBacker et al 2002: decreased microvessel density

and proportion of perfused vessels were common is sepsis and more severe in non-survivors

DIAGNOSIS

• FLOWMETRY:– LASER DOPPLER FLOWMETRY:

• Doppler flow to detect frequency shifts in laser light illuminating RBCs

• Non-invasive• Finicky

– ANIMAL MODELS: (Septic, hemorrhagic, cardiogenic shock)• Increased flow with resuscitation• Persistent low flow to liver, pancreas, kidneys• Regional flow disturbances persisted in the jejunum and colon

END ORGAN CHANGE

• Myocardium:– Relative hypovolemia• Vasodilation• Insensible losses• Third spacing

– Cardiovascular depression• RVEF LVEF• RVEDP LVEDP• CO 20 HR with normal SV• SVR

END ORGAN CHANGE

• Myocardium:– Reversible depression: 40% pts– Resolves over ~ 10 days– Etiology:

• Cyk• NO• Myocardial ischaemia with reperfusion injury • Increased coronary flow and net lactate consumption

– Ventricular dilation:• Resolves over 10 days• Failure to dilate is a predictor of mortality

END ORGAN CHANGE

• Acute Lung Injury (ALI):– Either pulmonary or extra-pulmonary etiology– Extrapulmonary:

• Circulating Cyk and bacterial products activated endothelial cells which then become prothrombotic.

• Leukocytes adhere and migrate into the alveolar space leading to further inflammation and release of inflammatory mediators

• Pulmonary macrophages are activated and secrete Cyk• Type 1 pneumocyte damage leads to flooding of the alveolar

airspace• Type 2 pneumocyte damage leads to loss of surfactant

END ORGAN CHANGE

• Acute Lung Injury:– Activation of the TF pathway leads to

accumulation of fibrin in the alveoli.– Followed by proliferative and fibrotic stages

END ORGAN CHANGE

• Renal:– Multifactorial:• Hypotension• Redistribution of blood flow• Renal vasoconstriction• The effects of endotoxin and Cyk on the renal vascular

endothelium• Activation of inflammatory cells• Nephrotoxic agents used to treat sepsis

END ORGAN DAMAGE

• INTESTINAL:– ~ 60% of ICU admissions have a component of

intestinal dysfunction during their course (Piton et al, 2011)

• Range from intolerance of feeds to ischaemia• Abnormal bowels sounds or GI bleeding associated

with increased mortality.

END ORGAN CHANGE

• Gastrointestinal system:– Gut hypoperfusion: important pathophysiologic

consequence of severe sepsis– Early:

• Autoregulation diverts flow from the muscularis to the more metabolically active mucosa

– Later:• Redistribution not sufficient to meet mucosal metabolic demand• Decreased pH and increased lactate• Increased inflammatory mediators appear in the lymph • ? Gut drives sepsis / inflammation via the lymph and not the

portal system

TREATMENT

• FLUID RESUSCITATION:– CHOICE:• Crystalloids: standard, no saline• Colloids: SAFE study• Synthetics: no, all evidence now in question Visep,

Boldt

– Fluids at all?

TREATMENT

FEAST STUDY:• NEJM• Sub-Saharan African children with febrile illness and

clinical evidence of impared perfusion• 3100+• 3 groups:

– 20-40mL/kg boluses of 5% albumin– 20-40mL/kg boluses of n/s– No boluses– All had maintenance fluids (2.5-4mL/kg/hr)– Transfusion for Hgb of 50

TREATMENT

• Feast Study:– 48 hr MR:• N/S: 10.5%• Albumin: 10.6%• No bolus: 7.3%

– Interesting but:• Pediatric• 59% had malaria – we don’t see that here (fortunately)• ? Causes of death• No ICU: no pressors tropes CRRT vents etc

TREATMENT

• SURVIVING SEPSIS GUIDELINES:– VENTILATION– MAP– EGDT– APC– CRRT– SEDATION HOLIDAYS– STEROIDS– TIGHT GLUCOSE CONTROL

TREATMENT

• ANTIBIOTICS:– Koleff:• 48hrs in pneumonia

– Early and broad • De-escalation with cultures

TREATMENT

• VASOPRESSORS:– Dopamine– Norepi– vasopressin

TREATMENT

• Resuscitating the Microcirculation:– VASOPRESSORS AND INOTROPES:• Animals:

– Adrenergic agents (epi, levo, phenylephrine) increase MAP but fail to improve regional or microvascular blood flow

• Krejci CCM 2006– Levo worsened regional flow– Vasopressin increased MAP and did not improve regional flow

• Lange et al Front Biosci 2009

TREATMENT

• Resuscitating the Microcirculation:– VASOPRESSORS AND INOTROPES:

• HUMANS:– “dirty studies” due to multiple drugs and adjuvant therapies– Duranteau et al CCM 1999

» 12 pts» Epi increased gastric mucosal flow over norepi» Dobutamine to norepi increased mucosal flow over that of epi

– Dopamine / vasopressin / norepi: conflicting results» Generally, MAP increased and either no change or inconsistent

change on mucosal blood flow– Dobutamine:

» Small series» Most consistently seems to show increases in microvascular flow

TREATMENT

• Resustitating the Microcirculation:– NO• Excess production leads to many of the features of

septic shock– 61

» NOS Inhibitor» Trial stopped early due to increased mortality with the

treatment arm (59% to 49%)

• USE NO AS TREATMENT:– Using NO donors (NTG, SNP)– Mixed results