Nayri HatsakorzianPharm.D/MPH candidate 2014

Guidelines for management of severe sepsis and septic shock

Sepsis is a systemic, deleterious host response to infection leading to - Severe sepsis : acute organ dysfunction or tissue hypoperfusion secondary to documented or suspected infection

o Systemic hypoperfusion: SBP<90 or MAP<70 or a SBP decrease >40 or less than two standard deviations- And septic shock: severe sepsis plus hypotension not reversed with adequate fluid resuscitation.

Sepsis is the presence of probable or documented infection together with systemic manifestations of infection (>=2 of SIRS criteria). Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate or oliguria. When HR is above 90 and RR is above 20 then more CO2 is being accumulated in the blood due to the rapid breathing, this can lead to acidosis and passing out. Acidosis, if not resolved can lead to mental status changes leading to encephalopathy (loss of O2 in brain leads to inflammatory cytokines and CNS depression). In addition, continuous hypotension can lead to myocardial ischemia. Site of Infection: it usually results from lung infections, followed by intra-abdominal, genitourinary, soft tissue, primary bacteremia, IV catheter associated, surgical site and CNS. Risk Factors: DM, surgery, cancer, immunosuppressive therapy (Prednisone > 10mg), EtOHism, COPD, chronic renal and liver, and heart failure. Presentation: Signs and symptoms:

- CNS o Altered mental status

- Cardiovascularo SBP <90 or >40 reduction or MAP <65-70o Myocardial ischemia: troponin elevationso Tachycardia; HR >90

- Respiratoryo Hypoxemia: decrease PaO2o Hypercapnia: increase PaCO2 poor ventilation o Tachypnea; RR>20 and more CO2 accumulation acidosis

- Renalo Oligouria: decrease urine outputo Increase SCr

- Metabolico Metabolic acidosis pH<7.4 metabolic dysfunction organic acid accumulation (lactic acid)

Lactic acid elevation or persistent elevation is poor prognostic indicator. o Hyperglycemia > 120

- Hematologic o Increase WBC, increase neutrophilso Fevero Thrombocytopenia

- Liver o Increase in ALT/AST and bilirubin (bilirubin is a sign of liver insult)o Coagulopathy (Increase INR and aPTT)

- Inflammatory markerso ESR, CRP

- Localized signs of infectiono Swelling, erythema, tenderness, pain, warmth, purulent drainage, or not so apparent d/t deep seated infections

Initiation of therapy:- Start ABX within the first 30min of onset of hypotension, every 1 hr delay is reducing chance of survival by ~8% in

the first 6 hours—use broad spectrum - Draw cultures without delaying ABX- Resuscitation with crystalloid or colloid

o Crystalloids: NS, 1/2NS, D5W, D5W-1/2NS, LR; up to 6-10L in the first 24 hours LR is the most physiologically suitable for Na, Cl concentrations NS may induce hypercholoremic metabolic acidosis since Cl=154 mEq/L

A disadvantage for crystalloids is that it may reduce osmotic pressure by diluting colloids and may contribute to pulmonary edema

o Colloids: albumin 5% is used for resuscitation rather than 25%. It will decrease edema by drawing fluid from interstitial space; but usually reserved for refractory cases

or low albumin levels

- Fluid challenges of 300-500ml every 30-60 min, then assess BP, MAP, and urine output

Agent & dose 1α 2α 1β 2β Predominant clinical effects

Side effects/notes

Epinephrine (2 mg/250 ml D5W,NS)

-0.01-0.5 mcg/kg/min

- > 0.5 mcg/kg/min- 2nd best line

- ++

- Most potent

- ++

- Most potent

- Most potent

- +++

- +++

- +

- Increase HR, CO, SVR- Both inotropic and chronotropic- Relaxes smooth muscles of bronchial tree

- Arrhythmogenic potential increase cardiac oxygen demand myocardial ischemia and direct toxicity to arterial walls- Cardiac dysrhythmias (supraventricular tachycardia, A fib)- Small doses can cause vasodilation thru B2 vascular receptors- Large doses may produce skeletal and vasculature vasoconstrictions- Phentolamine is a adrenergic blocking agent

Norepinephrine (4 mg/250 D5W, NS)Levophed

- 0.01-3 mcg/kg/min

- 1st line for septic shock- Often combined with dobutamine

+++ +++ +++ +++

- Little change in HR and CO- Increase SVR vasoconstriction

- Cardiac arrhythmias are likely to occur in patients with existing MI- Norepinephrine has been shown to cause platelet hyper-reactivity and enhance platelet-mediated coagulation associated with thrombotic risk.- Phentolamine is a adrenergic blocking agent

Dopamine (800 mg/250 D5W, NS)- 1-5 mcg/kg/min- 5-15 mcg/kg/min->10-20 mcg/kg/min

- 1st line for septic shock- A precursor to NorEpinephrine

- 0- 0/+- +++

- 0- 0- 0

- +- Most potent- Most potent

- 0- ++- +

- Low doses (1-5 mcg/kg/min): increase renal blood flow and urine output- Intermediate doses: increase renal blood flow, HR, contractility and CO- High doses: alpha adrenergic effects predominates, vasoconstriction increase BP

- Commonly induces tachycardia and arrhythmias when dose exceed 20 mcg/kg/min- Profound effect on HR and CO- Minimum effect on SVR

Phenylephrine (50 mg/250 D5W, NS)- 0.5-9 mcg/kg/min- Synthetic a-adrenergic with no B effects used for sudden severe hypotension

+++ + 0 0 - No effects on HR, CO.- Increases SVR

- Reserved for patients that develop tachycardia or arrhythmia to other agents- NorEpi is associated with serious arrhythmias- Cardiac output is known to be high and BP persistently low- As salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve the MAP target.

Dobutamine (500 mg/250 D5W, NS)- 2-10 mcg/kg/min- > 10-20 mcg/kg/min

- +- ++

- 0- 0

- Most potent- Most potent

- ++- +++

- Profound effect on HR and CO- Profound decrease in SVR using alone exacerbates hypotension bc it lowers central venous pressure never use alone in pt with MAP= 60

- Vasodilator especially at low doses at hypovolemic patients- Used in burned patients to increase circulation to extremities- Do not use Dobutamine in heart failure patients due to increase mortality- Dobutamine significantly increases myocardial oxygen consumption induction of ischemia

Vasopressin- 0.01-0.03 U/min- Increases cAMP which increase water permeability to renal tubules resulting in decrease urine volume

- Direct vasoconstrictor without inotropic or chronotropic effects

- Doses over 0.03U/min should be reserved for salvage therapy (failure to achieve MAP)- May be useful in Hemophiliacs bc it increases Factor VIII levels

and increased osmolality - Increase BP, SVR, and urine output- DO NOT administer vasopressin as initial vasopressor in septic shock pt

- Mainly used for diabetes insipidus- May be added to norepinephrine to increase MAP or to decrease norepinephrine dose.

CO= HR x Stroke Volume; Stroke Volume= End diastolic volume – End systolic volume

SIRS - Fever >38.3 or hypothermia < 36

- HR > 90 - RR > 20

- Leukocytosis > 12 or leukopenia <4

Severe sepsis

- Systemic hypotension: SBP<90 or MAP<70 or a SBP

decrease >40 or less than two standard dev - Lactate above NL

- Uop < 0.5ml/kg/hr >2 hr despite fluid resuscitation

- Pa O2/FiO2 <250 in absence of PNA

- SCr > 2- Bilirubin > 2

-Thrombocyotpenia < 100,000

- INR > 1.5

Septic shock- Severe sepsis plus

hypotension not reversed with adequate fluid resuscitation.

First 3 hrs- lactate, blood Cx- broad spectrum

ABX- 30ml/kg

crystalloid for hypotN & lactate>

4 Unseccessful resuscitation --> Vasopressors -->

- MAP>65- Normalized lactate- Uop > 0.5ml/kg/hr

- O2 saturation of 70%

Mechanical ventilation of sepsis

induced ARDS - elevated head of

bed to prevent VAP

Glucose controle with insulin if

BG> 180; goal < 180

VTE PPX- Daily LMWH

- SCD Stress Ulcer PPX

- H2RA- PPI

Nutrition- Enteral vs. TPN

Reference: Dellinger RP, et al. Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. DOI: 10.1097/CCM.0b013e31827e83af

Vasopressors:- Vasopressor therapy initially target a MAP of 65- Norepinephrine as the 1st choice vasopressor- Epinephrine (added or substituded to NorEpi) when an additional agent is needed to maintain adequate blood

pressure- Vasopressin (up to 0.03U/min) can be added to NorEpi with the intent of raising MAP to target or decreasing

NorEpi dosage- Low dose Vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced

hypotension, and vasopressin doses higher than 0.03-0.04 U/min should be reserved for salvage therapy (failure to achieve an adequate MAP with other vasopressor agents)

- Dopamine as an alternative vasopressor agent to NorEpi only in highly selected patients (patients with low risk of tachyarrhythmias and absolute or relative bradycardia)

- Phenylephrine is not recommended in the treatment of septic shock except in the following circumstances: o NorEpi is associated with serious arrhythmiaso Cardiac output is known to be high and BP persistently lowo As salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to

achieve the MAP target.

Crystalloids: NS, 1/2NS, D5W, D5W-1/2NS, LRColloids: albumin Intropic: influencing contractility of muscle, especially myocardial tissue Chronotropic: affecting the rate of rhythmic movement of myocardial tissue