SEPSIS

Trevor LanghanOctober 4th, 2007Thanks to Dr. Jason Lord FRCPC CCM

M & M Case Presentation

59 year old male 5 day Hx generalized abdo pain and

diarhea with rigors PMHx

Liver abscess 1999 Shoulder abscess 1990 EtOH abuse Pancreatitis DM II HTN

Case Presentation

Meds: Insulin, Metoprolol, Lipitor Sept 25

23:13 Temp 40.2 HR 132 BP 140/90 RR 32 Sat 88% RA Confused, flushed, dry mucous

membranes

Case Presentation

P/E: Abdomen:

generalized tenderness but no peritoneal signs, no Murphy’s,

Chest:clear bilat

CVS:HS normal, No murmurs

Remainder of exam non-contributory

Case Presentation

Labs WBC 4.1 (3.2 neuts, 0.2 bands) Hgb 142 Platelets 110 Cr 116 AP 206, TBili 26, ALT 56, GGT/Lipase N

ABG 7.52/29/49/24 Lactate 1.1

Case Presentation

ECG Sinus Tach CXR #1 clear Urine small blood nil else CT abdo:

thickened dilated GB wall with pericolic fluid

No stones, no CBD thickening c/w acute cholecystitis suggest U/S for

confirmation

Resuscitation MeasuresTime Therapy

0010 Bolus 1 L NS

0054 Bolus 1 L NS

0130 NS @ 150 cc/hr

0152 Bolus 1 L NS

0235 NS @ 150 cc/hr

0500 Bolus 1 L NS

0600 Bolus 250 cc Pentaspan

0620 Bolus 250 cc Pentaspan

Resuscitation MeasuresTime Therapy

0810 Blood c/s drawn (9 hours in)

0825 ICU consult for CT

0930 Abx given (10 hours in)

1030 U/S abd

1200 CT abd

1230 Lasix 40 mg IV

1400 ICU MD

1425 Request bed ICU

1545 Transfer to ICU

1710 Perc cholecystostomy

Vital SignsTime Temp HR BP Sats

0145 41 114 94/56 94% 4L

0235 38.8 100 100/50

0410 38.2 100 70/42 92% 4L

0615 104 84/60

0715 99 82/51 95% 4L

0825 96 87/56 90% 5L

1050 91 96/60 90% 5L

1210 62%

1425 98 105/58 90% NRB

Interesting quotes on chart

04:00 “patient looks relatively well despite BP”

05:45 “patient likely septic but no obvious focus”

05:45 “if no response to fluids consider CVP and

pressors if patient symptomatic” 07:30

“consult ICU to see if patient safe for CT abd”

Sepsis

Why are we talking about this AGAIN!

Sepsis and spectrum of infectious disease presentations to ED poorly recognized

Mild under-resuscitation – perk up pt well enough for ward followed by ICU admit 1-2 days later

Case One

42 year old woman c/o epigastric pain Onset 2 hours after eating ROS

Mildly obese Nil else

Case One

PMHx Gall stones

Meds and Allergies none

Case One

Vitals HR 110 RR 16 BP 118/70 Sat 96% room air Temp 37.6 C Glucose 9.0

Physical Tender epigastrum, no peritonitis

Case One

Labs: Hgb 140 Platelets 289 WBC 14.2 Lytes, creatinine normal Lipase 2029 LFTs normal

CT abdomen Acute pancreatitis

Case One

IV fluid 500 cc NS bolus 125 cc NS per hour maintenance

Analgesia Morphine prn Gravol prn

Plan NPO, Admit to general surgery

Diagnosis?

Case Two

14 year old male c/o sore throat x 3 days Still going to school and playing golf PMHx: nil Meds/Allergies: nil

Case Two

HR 95 BP 110/70 RR 16 Temp 38.4 Sat 99% Glucose 6.0 Throat Swab done by GP yesterday

+ve for GAS

Case Two

Plan Oral antibiotics Increase oral fluids RTER prn

Diagnosis?

Case Three

32 year old woman 3 day Hx productive cough Chills, feeling unwell PMHx: nil Meds: none Allergies: none

Case Three

HR: 110 RR: 22 O2 Sat: 91% BP: 140/76 Temp: 38.6 C

ABC’s OK O2, IV, monitor applied CBC, lytes, BUN, Cr, cultures sent CXR ordered

Are there any other investigations?

What would you order next?

Two of:

•HR > 90

•RR > 30

•T > 38 or < 36

•WBC > 12 or <4

Mortality: 10%

The Septic Spectrum

SIRS

SIRS + Infection

SEPSIS

• Lactic Acidosis

• Oliguria

• Altered mental status

Mortality: 16%

The Septic Spectrum

SEPSIS

SEPSIS + Organ Dysfunction

SEVERE SEPSIS

• Severe Sepsis +/- hypotension despite

adequate fluid resuscitation

Mortality: 46%

The Septic Spectrum

SEVERE SEPSIS

SEPTIC SHOCK

Mortality: 46%

The Septic Spectrum

SEVERE SEPSIS

SEPTIC SHOCK

SEPSIS

SIRS

Mortality: 10%

Mortality: 16%

Mortality: 30%

The Septic Spectrum

EARLY Goal Directed Therapy can decrease mortality

SEPTIC SHOCK

Partially RCT Early (< 6 hours) goal directed

protocol vs. standard of care Inclusion:

Systolic BP < 90 after 30cc/kg bolus 2 of 4 SIRS criteria

Outcomes: Inhospital mortality

A priori Power Calculation

500cc boluses as needed to get CVP 8-12 sBP<90 pressors Central venous O2 sats measured

<70% pRBC to achieve HCT >.30 Dobutamine if optimized HCT and MVO2 sats

<70% ETI if not already done if unable to achieve

HD goals

Results: N=263

Case Three

HR: 110 RR: 22 O2 Sat: 91% BP: 140/76 Temp: 38.6 C

Trauma: The Golden hour

What would you do next?

Septic Shock: Early Goal Directed Therapy

Myocardial Infarct: Door-to-needle times

Successful resuscitation requires quick intervention

Lactate If not available…venous or arterial

blood gas Why?

You can’t act early if you don’t know the clock is ticking!

What would you order next?

HR: 145 RR: 28 BP: 85/35

2 litres of NS

O2Sat: 92% on FiO2 100%

CXR shows RLL consolidation Lactate 6.4

Septic ShockSeptic Shock

Patient’s condition is worsening…

What kind of shock is this?

Hypovolemic

Vasodilatory Cardiogenic Obstructive

√√√

Hinsaw/Cox 1972

What kind of shock is this?

Hypovolemic Vasodilatory Cardiogenic Obstructive

CVP 8-12

MAP > 65

ScvO2 >70%

The goals of “Early Goal Directed Therapy” address the 3 types of shock present in a

septic patient

Why are septic patients hypovolemic?

Hypovolemic ShockGoal: CVP 8-12

Hypovolemic ShockGoal: CVP 8-12

Why are septic patients hypovolemic? 3rd spacing Diaphoresis Increased losses (vomiting, diarrhea, etc)

Main reason is not because of less fluid, but because of a larger container…

…Venodilation

Different fluids distribute to different places

Doesn’t matter what – just give enough!Carlson RW. Fluid Resus. in Circulatory ShockCrit. Care Clin. 1993;9:313.

Distributive Shock Goal: MAP > 65

Once ‘tank is full’ CVP 8-12 mmHg Need to increase vascular tone Vasoactive agents

Vasopressors Inotropes

Vasoactive Agents

Adrenergic Receptors

Alpha adrenergic receptors: vascular walls - peripheral vasoconstriction

Beta adrenergic receptors Beta 1: myocardium - increase inotropy (force

ofcontraction) and chronotropy (heart rate)

Beta 2: vascular walls - peripheral vasodilatation

lungs - bronchial smooth muscle relaxation

Dopamine receptors renal and splanchnic arteries - vasodilatation

and inc blood flow

Norephinephrine (Levophed)

Acts mainly on Alpha1 receptors (small clinical effect on Beta receptors)

Inc BP through peripheral perfusion slight tachycardia

Inc afterload by vasoconstriction Use cautiously in cardiogenic shock

Dec perfusion to kidneys and peripheries “Leave ‘em Dead”

Martin, et al., Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? , Chest 1993.

Norepinephrine or Dopamine in septic shock? DBRCT dopamine 10-25mcg/k/m levo 0.5-5.0 mcg/k/min N=32 Outcomes: HD endpoints after fluid

resuscitation

Martin, et al., Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? , Chest 1993.

Successful achievement of endpoints more common with levo than dop

91% vs 31%, p=<0.0001. 10/11 unable to achieve HD endpoints

with dopamine achieved EP with levo

Marik, et al., JAMA. (272), 1994.

RCT N=20 with MAP<60 but still with CI>3.2 to levo or dope

Intervention: titrating pressor to MAP>75 Outcomes:

HD Endpoints. Survival not reported. Results

Norepi increases MAP by increasing SVRI not CI Dop by increasing CI. Also sig increased

splanchnic O2 requirements (?increased risk of ischemic gut)

Cochrane Review:(updated) Feb. 11, 2005. RCTs1. Levo vs Dop (3 studies, N=62)

RR death 0.88 (0.57,1.36)

2. Levo + dob vs epi (N=52) RR death 0.98 (0.57,1.67)

3. Vasopressin vs placebo (N=58) RR death 1.04 (0.06,19.33)

Vasopressin??

RCT levo-resistant septic shock N=48. All pts NE>0.5 mcg/k/m Vaso 4U/hr Cross-over permitted at 24hrs Endpoints: primarily HD

Take Home: Vasopressin when added to levo:

improves myocardial performance No demonstrable benefit on:

kidneys or mortality Less pro-arrhythmic than levo

stat significant decrease in arrhythmias

Case Four

You have just intubated a 71 yr male with a COPD exacerbation.

Post intubation, the nurses report his BP as 60 systolic.

Resuscitating with fluids What are likely etiologies

of the new shock state?

Ventilator malfunction

Natural Hx of disease

Side effect of medication

Loss of vascular tone

Tension Pneumo

Decrease Preload & CO

Case Four

Loss of vascular tone with sedation for intubation

Worsening vasodilation Resuscitating with fluids What agent might you use

peripherally to increase the BP?

Ephedrine

Direct Beta1 and Beta2 receptor Indirect Alpha1

through noradrenaline release Inc BP and HR, some

bronchodilation

Ephedrine

Preparation: 5% solution (50mg in 1cc ampule) Dilute 1/10 with NS 1cc (5 mg) IV increments

Duration of action – 5-15 min Ideal for pregnancy as does not

reduce placental blood flow

Phenylephrine

Pure direct-acting Alpha1 agonist Inc BP via peripheral

vasoconstriction Associated with reflex dec HR Dosing – 10 mg/cc vial

Mix 10 mg (1cc) in 100cc NS – provides concentration of 100 mcg/cc

Administer as 1-2cc increments IV Infusion 20-50 mcg/min

Epinephrine

Direct Alpha1, Beta1 and Beta2 receptors

Inc HR, force of contraction, CO Increase SBP

may dec DBP via vasodilation in skeletal muscle beds

Bronchodilation through Beta2 response

What kind of shock is this?

Hypovolemic Vasodilatory Cardiogenic Obstructive

CVP 8-12

MAP > 65

ScvO2 >70%

The goals of “Early Goal Directed Therapy” address the 3 types of shock present in a

septic patient

Cardiogenic – ScvO2 > 70%

ScvO2 – Used as a marker of success of O2

delivery need a central line preferred superior vena cava

True or False ScvO2 is measured in the coronary

sinus

Cardiogenic – ScvO2 > 70% 51 year male New diagnosis pneumonia HR 120, RR 24, Sat 91%, BP 100/60 Lactate is normal What do you expect his ScvO2 to

be?

Cardiogenic – ScvO2 > 70% Early in sepsis spectrum heart is

hyperdynamic ScvO2 may even be high/normal

Severe sepsis and septic shock Toxins and hostile environment

lead to cardiac dysfunction Pump begins to fail Poor delivery of O2 to periphery

Dobutamine

Targets: Beta1 and Beta2 receptors

minimal action on Alpha1

Increases CO: Inotropy Chronotropy decreased afterload

Dosing 2-20 mcg/kg/min

Cardiogenic – ScvO2 > 70% Oxygen delivery Carrying capacity of O2 formula:

CaO2 = (SaO2 x Hb x 1.34) + .003(PaO2)

Can impact the formula by providing more carrying substrate

Dissolved gas is negligible in this setting

Packed RBCs

Increase the O2 carrying capacity Intravascular volume expansion 1U PRBC

increase Hgb by 10 x 10E9/L Availability:

O neg. – Immediate Type specific blood – 15 min Type & Cross Matched – 45 min.

What might supercede EGDT? Give the bug juice! Order it STAT Get the team calling pharmacy early Close the loop Double check that the patient

received it Can be on going while placing

central line and getting fluids

Early Antibiotics

JAMA, 1999

The Importance of Antibiotics

Delay in antibiotics increases mortality: 9.9% in the first hour Mean of 7.6%/hour for the first 6 hours

Kumar et al. Critical Care Medicine 2006. 34(6): 1589-1596.

• Delay in antibiotics increases mortality:– 9.9% in the first hour– Mean of 7.6%/hour for the first 6 hours

Risk of in-hospital mortality increases 9% for every hour of delay in administration of the correct antibiotic

The Importance of Antibiotics

Garnacho-Montero et al. Critical Care 2006. 10:R111

• Delay in antibiotics increases mortality:– 9.9% in the first hour– Mean of 7.6%/hour for the first 6 hours

• Risk of in-hospital mortality increases 9% for every hour of delay in administration of the correct antibiotic

Garnacho-Montero et al. Critical Care 2006. 10:R111

The Importance of Antibiotics

Rapid, broad spectrum ABx given IV as soon as possible

Antibiotic Selection Chest

Levo & ceftriaxone Azithro & Ceftriaxone

Belly Pip Tazo or AGF

Urine Cefriaxone or Gent

Skin Ancef Think about Vanco

Head Ceftriazone, Vaco &

Dex

Anti-Microbials:Critical Care Medicine, 2004.

Where did the patient come from? Home, nursing home or in-hospital (?MRSA risk) Good evidence that poor choice Abx has a bad

outcome

Source control if possible Ie. can a surgeon help? Do they have a central line or cath?

Make sure you investigate all possible sources prior to Abx if at all possible

Case Six (a)

78 year lady Urosepsis PMHx: DM, atrial fibrillation Meds: coumadin, metformin,

glyburide HR 110, BP 90/50, RR 28, Sat 91%

Case Six(a) Has received

EGDT ETT Pressors Antibiotics

Despite your care HR 110, BP 85/50, RR 26, Sat 90%

Anything else before she goes to ICU?

Case Six (b)

66 year old lady PMHx rheumatoid arthritis, OA, DM Meds: Tylenol prn, insulin,

prednisone Productive cough and progressive

respiratory distress New infiltrate on CXR Dx: pneumonia with sepsis

Case Six (b) HR 100, RR 30, Sat 90%, BP 90/60 Lactate: 5.0 Treated with

EGDTFluids (CVP approx 12 cmH2O)ETTVasopressorsTransfused blood to get Hgb > 100

Antibiotics

Case Six (b) Despite all that care HR 110, RR 24, BP 80/40, Sat 90%

She will be going to ICU Anything else to do before she

goes?

Should she get the cream or the clear?

Steroids in Septic Shock: 2 Groups of Patients

1. Relative adrenal insufficiency2. Previous steroid therapy

Supraphysiologic doses clearly shown to increase mortality

DBPRCT, n = 300 Inclusion:

septic shock on pressors SBP <90 signs end-organ hypoperfusion

Excluded: pregnant, MI, PE, CA, AIDS NB no etomidate within prev 6hrs.

Outcomes: mortality (ICU, Hosp, 28 day)

Annane, D. et al., Effect of Treatment With Low Doses of Hydrocortisine and Fludrocortisone on Mortality in Patients With Septic Shock. JAMA, 2002. vol 288 (7).

Stratified by response to corticotropin stimulation test

Short Corticotropin Test250mcg IV ACTHcortisol immediately before then at 30 and

60mins Individual pt response based on highest

post-ACTH compared with pre-ACTH Intervention

50mg solu-cortef IV Q6h and 50mcg Florinef OD

Annane, D. et al., Effect of Treatment With Low Doses of Hydrocortisine and Fludrocortisone on Mortality in Patients With Septic Shock. JAMA, 2002. vol 288 (7).

Mortality decreased by 10% in ACTH ‘non-responders’

Annane, D. et al., Effect of Treatment With Low Doses of Hydrocortisine and Fludrocortisone on Mortality in Patients With Septic Shock. JAMA, 2002. vol 288 (7).

Steroids in Septic Shock

For pts naïve to steroids: Once therapy optimized And the patient is failing pressors

And circulating the drain: Draw random serum cortisol

At least > 6hrs post-etomidate Can give dex since wont interfere

with cortisol response

Case Seven

40 year old female prostitute Florid PID with pelvic abscesses and

extension into peritoneal cavity You have secured the airway The vasoactive agents are working

their magic Fluid and bug juice have been given Gyne will take to the OR

What Vent Setting Doctor?

ARDS

Non cardiogenic pulmonary edema Nonspecific response of the lung to

insult Defined as respiratory failure:

Requirement for mechanical ventilation PaO2/FiO2 ratio < 200

ARDS

Causes: Sepsis and/or

shock Toxic gas/smoke

inhalation Aspiration Pneumonia Drug reaction Trauma

Causes: Transfusion

reaction Burns Pancreatitis Fat/air/amniotic

fluid emboli DIC High altitude

exposure

ARDS

On CXR will see: New, bilateral, diffuse, patchy

pulmonary infiltrates

No clinical evidence of CHF, fluid overload or chronic lung disease Pulm wedge pressure < 18 mmHg

RCT Patients with strictly defined

ARDS** Traditional ventilatory parameters

12cc/kg (predicted ideal wt) Intervention (=low Tv)

6cc/kg , RR variable to achieve near normal pH

Trial stopped at interim analysis

Vent Protocols:

ARR Death 8.8% (2.4,15.3)

NNT = 11 Higher peak plateau

pressures in traditional arm

25 vs 33higher risk of

barotrauma

Ventilation Parameters

Ventilate patient with small tidal volume 6-8 cc/kg

Rate *** bpm required to maintain adequate minute ventilation Often requires sedation and paralysis

Peak pressure goal below 35 cm H20 Mean pressures must account for PEEP

Titrate FiO2 – start 100% but titrate down to prevent alveolar collapse

Case Eight

81 year old male Lobar pneumonia Intubated, fluid replete, pressors

and abx on board Vent set to ARDS protocol ABG – improving lactate, venting

appropriately On gas glucose 18.1 mmol/L

Bacteremic patients Lower rate of mortality

29.5% vs 12.5% ??ARR for all-comers with critical illness

3.4%, NNT = 29 Lower rate of developing sepsis

4.2% vs 7.8%, p=0.003 Reduced frequency of sepsis in all-

comers

Take home points: After everything else has been done

can aim for euglycemia Use cautiously in your optimized

patients NB

Hyperglycemia MIGHT be bad Hypoglycemia IS bad

Case Nine

91 year old lady Multiple co-morbidities Uroseptic in ED Received

EGDT Abx Tight glucose control ARDSNET parameters

Case Nine

91 year old lady Still needing increasing vasoactive

agents to maintain MAP > 55 MSOF – LFTs up, Cr up, no u/o Family asks:

“isn’t there something more you can do?”

“can’t you save my gramma?”

Activated Protein C (aka Xigris) Rationale:

The acute inflammatory response in sepsis is integrally related to endothelial activation and procoagulant state

rhAPC is an endogenous anti-coagulant and potent anti-inflammatory agent

DBPRCT Inclusion:

Severe sepsis or septic shockSick patients (APACHE >25)

all had 1 (most had 2) organs down Exclusion:

Many criteria Outcomes:

Mortality at 28d

Take-Home ICU decision

based on risk of death

Should be aware of the bleeding complications

6 Interventions that Make a Difference1. EGDT

• ARR Mortality 16% NNT 62. Early Abx3. ARDS Net Vent Strategy

• ARR 8.8% NNT 104. Steroids (for Non-Responders)

• ARR 10%, NNT 105. Insulin (tight glucose control)

• ARR 10%, NNT 106. APC (Xigris)

• ARR 6-7%, NNT 16

ED care EGDT

Fluids Pressors Blood

Early Abx Source control

Ventilate with low tidal volumes Euglycemia Consider steroid replacement Think about Xigris

Questions?