Sepsis and septic shockSiraprapa Tubtim

Definition of sepsis-Inflammatory response to infectionSign and symptoms of sepsis-2 or more than 2 of these signs and symptoms : Temp > 38 C or < 36 C : HR > 90, RR > 20 :PaCO2 < 32 torr :WBC >12000, 10%

Septic shock

Sepsis with hypotension despite adequate fluid resuscitation

BacteremiaPresence of viable bacteria in bloodstream

Systemic inflammatory response syndrome (SIRS)Inflammatory response to infectious causesor noninfectious causes

Severe sepsis= Sepsis with organ dysfunction, hypoperfusion, hypotension- Lactic acidosis- Oliguria- Change in mental status

Multiple Organ Dysfunction Syndrome(MODS)= Presence of altered organ function requiring intervention to maintain homeostasis

ARDS = acute respiratory distress syndrome; CI = cardiac index; DIC = disseminated intravascular coagulation; MODS = multiple-organ dysfunction syndrome.

Causes of sepsis

Most common: gram negative bacteria

Gram negative bacteria

E. coli, Klebsiella spp., Serratia spp.,Enterobacter spp, Proteus spp,P. aeruginosa

Risk factor for gram negative bacteria infection leading to sepsis

Immunocompromised patientsBroad spectrum antibioticsThe integrity of gastric mucosa (trauma, ulcer, obstruction, ischemia)

Gram negative bacterial sepsis

Higher mortality

Factors affecting outcomes- Severity of underlying conditions(Fatal condition: acute leukemia, aplastic anemia, severe burn)

Gram positive bacterial sepsisAnaerobic bacterial sepsisFungal sepsis

Gram-Positive Bacterial Sepsis

Staphylococcus aureus Streptococcus epidermidisStreptococcus pneumoniaeEnterococcus faecalis

Risk factors for Fungal sepsis

-Abdominal surgery-Poorly controlled DM-Prolonged granulocytopenia-Total parenteral nutrition-Foley catheter

Pathophysiology of Sepsis-Cell components : endotoxin from gram negative bacteriaEndotoxin: o-antigen, core , lipid Alipid A= highly immunoreactive component

Activation of macrophages

Endotoxin + lipopolysaccharide binding protein = complex

Complex + CD 14 receptors on the surface of macrophages

Release of cytokines mediators

Proinflammatory mediators TNF, interleukin 1, interleukin 6

Anti-inflammatory cytokines IL-1RA, IL-4, IL-10

Cascade of sepsis-Activation of macrophage and release of inflammatorycytokines-Cytokines affect many cells: endothelial cells, lymphocyte-Granulocytes and plasma components penetrate to tissue-Organ damage-Inflammation affect microcirculation (leak of protein andpenetration of neutrophils)-Neutrophils cause pulmonary damage

-Cytokines from macrophages activate complement system-Cytokines from macrophages have procoagulant properties

Complication of sepsis

Septic shock Dissiminated intravascular coagulation (DIC) Acute respiratory distress syndrome (ARDS)

Complication of sepsis (Continued)

- Hemodynamic effects Hyperdynamic state : cardiac output, vascular resistance

TNF and endotoxin depress CVS function

Hemodynamic effects (Continued)

Distributive shock= Inappropriately increased blood flow to particular tissues at the expense of other tissues

Tissue ischemia Organ dysfunction& failure

Complication of sepsis (Continued)

Acute renal failureAbnormal Urine Output

Fluid overload in extravascular space(eg.Lung) Impair gas exchange Hypoxemia

Hypoxemia + Compromised O2 Delivery

Exacerbate Peripheral Ischemia

Organ Damage

Prognosis

Increased MortalilySIRS Sepsis Severe sepsis

Septic shock

Septic Patients with Higher Mortality

-Advanced age-Preexisting Diseases : COPD / Cancer / HIV-ICU Care-Multiorgan failure-Pseudomonas spp infection

Signs and symptoms of SepsisEarly sepsis-Fever of hypothermia-Rigor-Tachycardia, tachypnea-Nausea, vomiting-Hyperglycemia-Lethargy-Proteinuria-Hypobilirubinemia

Late sepsisLactic acidosisOliguriaLeukopeniaDisseminated intravascular coagulationPulmonary edemaHypotension, shockHypoglycemiaThrombocytopeniaAcute respiratory distress syndrome (ARDS)Gastrointestinal hemorrhage, coma

Goal of sepsis treatment

- Correct diagnosis and identification of pathogens - Get rid of source of infection - Prevention of septic shock - Prevention of organ failures

Evidence-Based Treatment for Sepsis and Septic Shock

Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system

Quality of evidenceHigh (grade A), Moderate (grade B)Low (grade C), Very low (grade D) Strength of recommendationStrong (grade 1) or Weak (grade 2)

Treatment RecommendationInitial ResuscitationAntibiotic therapyFluid TherapyVasopressorsInotropic TherapyGlucose Control

Steroid TherapyRecombinant human activated protein C (drotrecogin)Deep Vein Thrombosis- (DVT) prophylaxisStress Ulcer Prophylaxis

Tx of sepsis and septic shock

-Aggressive Tx with antimicrobial therapy-Tx hypotension-supportive Tx

Initial Resuscitation

Early goal-directed goals (1C)CVP 812 mm HgMAP 65 mm Hgcentral venous oxygen saturation 70%

Mean Arterial Pressure (MAP) = 1/3 (SBP) + 2/3 (DBP)

(Central Venous Pressure Monitoring) Central Venous Pressure (CVP) Superior Vena Cava right atrium preload right ventricle right ventricular end-diastolic pressure CVP right ventricle venous capacitance

monitor CVP

1. sepsis 2. 3.

CVP CVP Elevated vascular volume Increased cardiac output (hyperdynamic cardiac function) Depressed cardiac function (RV infarct, RV failure) Pulmonary hypertension Chronic left ventricular failure

CVP Reduced vascular volume Decreased mean systemic pressure (e.g., as in late shock state) Venodilation (drug induced)

Antibiotic Therapy

-IV broad-spectrum antibiotic within 1 hour of diagnosis of septic shock and severe sepsis against likely bacterial/fungal pathogens (1B)

-Reassess antibiotic therapy daily with microbiology and clinical data to narrow coverage (1C)

Aggressive Treatment with antimicrobial drugs

Empirical Treatment

Antimicrobial Therapy

Aggressive early antimicrobial Tx is criticalSelection of antimicrobial regimens should be based on:- : Suspected site of infection : Most likely pathogens : Community-acquired or hospital acquired infection : Patients immune status : Antibiotic susceptibility and resistance profile

When serious gram negative sepsis is suspected :-Aggressive Tx with antimicrobial activity against P. aeruginosa and Enterobacter spp.A combination regimen is recommended: To provide additive or synergistic effect: To expand spectrum of coverage: To reduce resistance

Ex. ..

Methicillin-resistant Staphylococcus aureus (MRSA)

Catheter or medical device-related infectionsVancomycin should be addedIn case of glycopeptide-resistant S.aureus or vancomycin-resistant enterococci

teicoplanin, quinupristin/dalfopristin and linezolid

Empiric antimicrobial regimen in Sepsis

Urinary tract infection : .Respiratory tract infection :..Intra-abdominal infection :Skin / soft tissue infection :.Cather-related infection :

Urinary Tract InfectionCommunity-acquired ceftriaxone or ciprofloxacin/levofloxacinHospital-acquired ciprofloxacin/levofloxacin or ceftriaxone or ceftazidime

Respiratory Tract Infection

Community-acquired.Hospital-acquired .

Respiratory Tract InfectionCommunity-acquiredLevofloxacin / moxifloxacin orCeftriaxone + clarithromycin / azithromycinHospital-acquired Piperacillin / tazobactam or ceftazidime or cefipime+ levofloxacin/ciprofloxacin or aminoglycoside(+Vancomycin or linezolid if MRSA is suspected)

Intraabdominal InfectionCommunity-acquiredPiperacillin / tazobactam orCiprofloxacin + metronidazoleHospital-acquired Piperacillin / tazobactam orCarbapenem

Skin and soft tissue Infection (SSTIs)

Community-acquiredvancomycin or linezolid or daptomycin

Hospital-acquired Vancomycin + ampicillin/sulbactamor piperacillin/tazobactam

Cather-Related Infection

Hospital-acquired Vancomycin

Unknown Infection

Hospital-acquired Piperacillin/tazobactam orCeftazidime/cefipime orImipenem/meropenem

Reassessment of Antibiotic Therapy

Reassessed after 48 to 72 hours based on the microbiological and clinical data

Reassessment of Antibiotic Therapy

After C/S is known , therapy should bedirected toward the isolated pathogen to 1. Prevent drug toxicities 2. Prevent development of nosocomial superinfections with Candida species, Clostridium difficile, or vancomycin-resistant enterococcus

Reassessment of Antibiotic Therapy

Reassessed after 48 to 72 hours based on the microbiological and clinical data

Pathophysiologic changes in sepsis can affect drug distribution

Adjusted dosing regimens are required in critically ill patients with sepsis

Fungal Infection

Candidemia-Those receiving TPN, with bowel perforation- Persistent or new signs and symptoms of infections despite receiving broad-spectrum antibacterial therapy

Fungal Infection

Amphotericin BAzole antifungal agentsEchinocandin

Shock

- A syndrome of impaired tissue perfusion- Usually accompanied by hypotension

Impairment of tissue perfusion

Cellular dysfunction

Organ damage

Death

Most common causes of shock -Reduction of intravascular volume (hypovolemic shock) -Myocardial pump failure (cardiogenic shock) -Increased vascular capacitance (distributive shock, sepsis)

Classification of shock and precipitating factorsHypovolemic shock Hemorrhagic : Gastrointestinal bleeding, trauma, internal bleeding (ruptured aortic aneurysm,etc) Nonhemorrhagic : Dehydration (vomiting, diarrhea, diabetes insipidus, overuse of diuretics) Sequestration ( ascites, etc) Cutaneous ( burns, etc)

II. Cardiogenic shock Nonmechanical causes : -Acute MI, low cardiac output syndrome, Right ventricular infarction, end-stage cardiomyopathy Mechanical causes : -Rupture of septum -Mitral of aortic insufficiency, etc.

III. Distributive shock -Septic shock -Anaphylaxis -Neurogenic (spinal injury, cerebral damage, etc.) -Drug-Induced (anesthesia, ganglionic and adrenergic blockers, overdose of barbiturates, narcotics) -Acute adrenal insufficiency

Pathophysiology of shock Tissue perfusion : Complex process of oxygen and nutrient delivery, waste removal

Impaired tissue perfusion

Can end in death

Causes of progression of impairment of tissue perfusion to cell death and organ dysfunction

-Ischemia-Endogenous cytokine release-Generation of oxygen free radicals

Prolong ischemia

Anaerobic metabolism begins

Decrease of ATP and build up of lactic acid and other toxic substances

Alter cellular function

Cell death

Ischemia, injury or infection

Inflammatory cytokines produced

Clinical presentation of shock - Systolic BP (SBP) < 90 mmHg (or > 60 mmHg decrease from baseline in a hypertensive patient) - Tachycardia ( HR > 90 beats/min) - Tachypnea ( RR > 20 breaths/min) - Cutaneous vasoconstriction : cold, clammy skin - Mental confusion ( agitation, stupor, coma) - Oliguria (urine output < 20 mL/ hr) - Metabolic acidosis ( lactic acid secondary to anaerobic glycolysis)

Compensatory changes in response to a sudden decrease in volume (preload)

Increase in heart rate and contractility maintain COPeripheral vasoconstriction Maintain BPFluid shift from the interstitial spaces into blood vessels

Increase preload

In severe condition

Intravascular losses are not rapidly replaced

Myocardial dysfunction

Irreversible shock

Hemodynamic SupportFluid Therapy-Correct hypotension-Improve tissue perfusion

Decrease anaerobic metabolism

Decrease lactic acidosis

Crystalloids

Isotonic solutions that contains - saline (0.9% Sodium chloride) or - saline equivalent ( Lactated Ringers solution, LR)

Colloidal solutions

Contains large oncotically active molecules that are derived from natural products- Proteins (albumin)- Carbohydrates (dextrans, starches)- Animal collagen (gelatin)

Crystalloids Freely distribute within the extracellular fluid compartment (interstitial and intravascular spaces)

Large volume of crystalloid fluid are required to expand intravascular space

ColloidsIntact capillary membranes are impermeable to colloids

Colloids effectively expand the intravascular space with little loss into the interstitium

Because of the lack of evidence for a significant clinical difference between crystalloids and colloids and greater expense of colloids

Crystalloids should be the initial fluid resuscitation

Hypertonic saline

Advantage of hypertonic saline Smaller of fluid volume required to expand the intravascular compartment as compared with isotonic solutions

High concentration of sodium in hypertonic saline

Osmotic effect

Translocate fluid from the interstitial and cellular compartments to intravascular space

Plasma volume is greatly expanded

BP, CO and oxygen transport are increased

Hypertonic saline may be safe and effective for initial resuscitation of hemorrhagic shock

But further study is needed before widespread clinical use

Fluid Status Monitoring

- Monitor Central Venous Pressure (CVP), volume status- Closely monitor volume status to avoid pulmonary and systemic edema / hypoxemia

Blood replacement

Primary determinants of blood transfusion -Patient response to initial fluid resuscitation -Clinical signs of inadequate tissue perfusion

Inotropic Tx

Vasopressors or inotropic agentsDopamine, dobutamine, norepinephrine, phenylephrine,Epinephrine(When Fluid Tx alone cannot restore adequate arterial pressure and organ perfusion)

Norepinephrine

-First-choice vasopressor in septic shock--adrenergic > -adrenergic activity-Increases MAP and vascular resistance by vasoconstrictive effects on peripheral vascular beds

Dopamine-Dose-dependent pharmacologic effects- and -adrenergic agent with dopaminergic activity-Doses of >5 mcg/kg/min stimulate -receptor, Higher doses stimulate - receptor Dopamine is more useful in patients with hypotension and compromised systolic functionMore Arrhythmogenic agent

Phenylephrine

-Selective 1-agonist-Rapid onset / short duration-Primary vascular effects-Least likely to produce tachycardiaPhenylephrine is useful when tachycardia limits the usage of other vasopressors

Epinephrine

-Nonspecific - and -adrenergic agonist-Lower dose increase cardiac output-Higher doses vasoconstriction-Impairs blood flow to the splanchnic system, increases the lactate level, causes more dysrhythmia Reserved for use in patients who fail to respond traditional Tx

Dobutamine- adrenergic inotropic agent-Improvement of cardiac output and oxygen delivery, particularly in early sepsis before significant peripheral vasodilation has occurred- should be used in severe sepsis with low CI but adequate filling pressures and blood pressure

A vasopressor (such as norepinephrine) + an inotrope (such as dobutamine)

Maintain both MAP and cardiac output.

Agent1212dopaminergicDopamine++ / +++?++++++++++Dobutamine++++++++0Norepinephrine++++++++++ /++0Phenylephrine++ / ++++?00Epinephrine+++++++++++++++0

Early-Goal Directed Therapy

Goals during the first 6 hours :CVP of 8 to 12 mm Hg, MAP 65 mmHg, :Urine output 0.5 mL/kg/h, :Central venous or mixed venous oxygen- saturation 70%Initial resuscitation should begin as soon as the syndrome is recognized

Early goal-directed therapy

1. Central venous catheter placed 2. More fluid than with traditional therapy (5 L vs 3.5 L)3. Dobutamine therapy to a maximum of 20 mcg/kg/min4. Red blood cell transfusions

Traditional Therapy

Fluid resuscitation, followed by vasopressor therapy if required

Adjunctive Tx

Oxygen or mechanical ventilation support Tx of hyperglycemia Corticosteroids Others (Antibodies for inflammatory cytokines, Inhibitors of cytokine receptors)

Adjunctive Tx

- Deep Vein Thrombosis prophylaxis(Unfractionated heparin or Low-molecular weight heparin)- Stress Ulcer prophylaxis(Proton-pump inhibtors or H2-blockers)- Enteral nutrition

Immunotherapy

-Drotrecogin alfa (recombinant human activated protein C, rhAPC)-Antiinflammatory agent to be approved for sepsis, promotes fibrinolysis and theinhibition of coagulation and inflammation-Bleeding is major risk

The EndThank you for your attention