From Evidence-Based Medicine to Evidence-Based Care

From Evidence-Based Medicine to Evidence-Based Care

Halden F. Scott, MD

Medical Director, Sepsis Treatment and Recognition Program Children’s Hospital Colorado

Assistant Professor of Pediatrics and Emergency Medicine University of Colorado School of Medicine

Financial Disclosures

• No relevant financial relationships with any commercial interests.

Halden F. Scott, MD

A Child Arrives in Triage

• 4 year old – language barrier • Won’t drink and has a fever • Previously healthy

• Seen 14 days prior with febrile illness: treated

with oseltamivir (sibling +Flu A) • Recovered, was back at school

• Now 4 days of new fever, worsening cough • No urine output in 12 hours

Triage Exam

• T=100 HR:132 RR:30 SpO2: 86%

• Moaning and grabbing abdomen

• Refuses to walk – carried to stretcher

Triage Exam

• T=100 HR:132 RR:30 SpO2: 86%

• Moaning and grabbing abdomen

• Refuses to walk – carried to stretcher

What do you notice? What do you do?

Pop Quiz!

What would you do next? A. Give acetaminophen

B. Provide supplies for oral rehydration

C. Obtain a full set of vital signs

D. Place oxygen

Pop Quiz!

The ED is pretty full. Where would you put this patient?

T=100 HR:132 RR:30 SpO2: 86%

A. A resuscitation/trauma room

B. A regular ED room (telling attending about patient)

C. A regular ED room (no notification)

D. Back to the waiting room (frequent rechecks)

Brought Back to a Regular Room

• Placed on 2L nasal canula

• HR to 160s

• Acetaminophen

• ORT teaching

• Chest xray shows pneumonia

• Amoxicillin ordered

Two Hours Later

• Did not take ORT. Threw up amoxicillin.

• Nurse turned up to 4-5L NC

• Sleepy, HR 160s, RR 60-70

• Extremities cool, weak pulses

• Cannot obtain access

• Antibiotics ordered

Uh-Oh

• Moved to a front room, higher-level attending

• IV, fluids started

• Hypotensive, dopamine started

• Gas: 7.02/67

Uh-Oh

• Moved to a front room, higher-level attending

• IV, fluids started

• Hypotensive, dopamine started

• Gas: 7.02/67

• Ketamine, versed - Intubation

• Desaturation – bradycardia - asystole

• CPR x 8 minutes, pulmonary hemorrhage at time of intubation

Case

• ECMO team called

• Ceftriaxone 1 hour post-arrest

• Vancomycin 1 hour post-arrest

• Oseltamivir the next morning

Case

• ECMO

• Multi-system organ failure

• Severe hypoxic injury

• Death

• Group A Strep grew from pulmonary fluid

• +Influenza

What do you notice about this case?

• What were the warning signs?

• What were the reassuring signs?

• What steps could have been better?

Pop Quiz!

• Chief complaint: 4 year old – won’t drink and has a fever

• Where do you usually room a patient with this complaint on a busy night?





Pop Quiz!

• Vital signs: T=100 HR:132 RR:30 SpO2: 86%

• Where do you usually room a patient with these vital signs on a busy night?





Pop Quiz!

Could this patient have a similar first several hours of care at your institution? A. Yes

B. I would like to think no, but maybe… yes

C. No

What do you notice about this case?

• Initial vitals not that bad

• Exam findings may be subtle

• Warning signs: – Return of fever after initial febrile prodrome

– Urine output

– Can’t get a blood pressure easily

• No focus on blood pressure, early access, IV fluid, antibiotics in the treatment plan until too late

photo: T. Brayman, Children’s Colorado

Pressure to Improve Care

Level of Evidence

de Caen Circulation 2015

Objectives

1. Develop a working definition of pediatric sepsis that facilitates clinical recognition.

2. Discuss key evidence surrounding elements of pediatric sepsis care:

1. Diagnosis

2. Fluid Resuscitation

3. Protocolized Treatment

3. Develop practical approaches to improving outcomes despite incomplete “proof” of effectiveness.

Objectives



1. Diagnosis




Pop Quiz!

What is sepsis?

Pop Quiz!

What is sepsis?

A) Systemic Inflammatory Response Sydrome (SIRS) + Infection

B) Life-threatening organ dysfunction caused by a dysregulated host response to infection

C) I know it when I see it

D) qSOFA >= 2

Pediatric Definitions: SIRS

Systemic Inflammatory Response Syndrome

(2/4, 1 must be temp or wbc):

Core Temp > 38.5°C or <36°C

Tachycardia / Bradycardia if <1 y/o

Tachypnea

WBC elevated or depressed

Goldstein PCCM 2005

Pediatric Definitions

• Infection – Suspected or proven infection caused by any pathogen OR

a clinical syndrome w/ probability of infection

• Sepsis – SIRS in the presence of infection

• Severe Sepsis – Sepsis + CV dysfunction OR ARDS OR ≥2 other organ

dysfunction

• Septic Shock – Sepsis and CV organ dysfunction (hypotension, pressors or

elevated lactate)

Goldstein PCCM 2005

Pediatric Definitions

• Infection – Suspected or proven infection caused by any pathogen OR

a clinical syndrome w/ probability of infection

• Sepsis – SIRS in the presence of infection

• Severe Sepsis – Sepsis + CV dysfunction OR ARDS OR ≥2 other organ

dysfunction

• Septic Shock – Sepsis and CV organ dysfunction (hypotension, pressors or

elevated lactate)

Goldstein PCCM 2005

Weiss article

Weiss BMC Critical Care 2015

Sepsis 3.0

• Life-threatening organ dysfunction caused by a dysregulated host response to infection

Seymour JAMA 2016

2005

Sepsis

(SIRS + Infection)

Severe Sepsis

(Organ Dysfunction)

Septic Shock

(Hypotension or Lactate)

Infection

(No SIRS)

Sepsis

(qSOFA)

Septic Shock


2016 (Adults Only)

2005

Sepsis

(SIRS + Infection)

Severe Sepsis

(Organ Dysfunction)

Septic Shock


Infection

(No SIRS)

Sepsis

(qSOFA)

Septic Shock


2016 (Adults Only)

2005

Sepsis

(SIRS + Infection)

Severe Sepsis

(Organ Dysfunction)

Septic Shock


Infection

(No SIRS)

Sepsis

(qSOFA)

Septic Shock


2016 (Adults Only)

2005

Sepsis

(SIRS + Infection)

Severe Sepsis

(Organ Dysfunction)

Septic Shock


Infection

(No SIRS)

Sepsis

(qSOFA)

Septic Shock


2016 (Adults Only)

What is sepsis?

What is sepsis?

• Many competing, evolving definitions

• Pick a case definition for quality work

– Goldstein 2005

– Children’s Hospital Association Improving Pediatric Sepsis Outcomes collaborative

– Centers for Medicare Services

• Develop a useful clinical definition

Audience Poll

Does your hospital have a working definition for pediatric sepsis for internal quality improvement?

A) Yes

B) I think so

C) I don’t know

D) I think no

E) No

Infection + Organ Dysfunction • Hypotensive 8 year-old, ALL, central line;

blood culture +gram negative rods

• 2 year-old intubated, ventilated with pneumonia

• Lethargic 4 year-old, spina bifida, fever, and leukocytes & nitrites in her urine

• 16 year-old, right lower quadrant pain and fever, heart rate 140 bpm, capillary refill of 5 seconds

Sepsis Stat

Fever and/or concern for infection AND: • Tachycardia despite absence or

treatment of fever & dehydration?

• Immunosuppression/immuno-deficiency or central line?

• Consider for clinically uncertain / borderline abnormalities in: o Mental status o Capillary refill o Peripheral pulse quality

Objectives



1. Diagnosis




Evaluating Diagnostic Strategies

• Agreeing on meaningful outcomes

• A good test for sepsis detects…

– patients with infection & hypotension

– patients with infection & organ dysfunction

– patients with infection & who need ICU

– patients with infection & who die

Brierley CCM 2009

Brierley Crit Care Med 2009 Brierley Crit Care Med 2009

Brierley CCM 2009

Capillary Refill Time

Mortality: Referred for Transport to Pediatric ICU

Carcillo Pediatrics 2009

Physical Exam for Detection Inclusion: ED, SIRS, receiving IV

Outcome: Organ dysfunction within 24 hours

Scott BMC Emer Med 2014







Physical Exam for Detection

• Capillary refill time, peripheral pulse quality, mottled extremities

– Useful in patients already identified as critically ill/septic

– Less useful for triage

• Altered mental status

– Better than the other findings

– Still misses half of severe sepsis patients

What about SIRS vital signs?

Pop Quiz!

Of all children who come to the ED and end up intubated or on vasopressors within 24 hours, how many have SIRS? (excluding trauma)

A) 20%

B) 40%

C) 60%

D) 80%

SIRS for Sepsis Triage

All Medical ED Visits in 2011-12 40,356

Scott Acad Emer Med 2015



SIRS 6,122

No SIRS 34,234




SIRS 6,122

Vasopressor or Intubation

23 (0.38%) Vasopressor or Intubation

76 (0.22%)

No SIRS 34,234




SIRS 6,122



76 (0.22%)

No SIRS 34,234




SIRS 6,122



76 (0.22%)

No SIRS 34,234


22% Sensitive

So physical exam and vitals don’t help?


• Of course they help!

• Consider others besides

– Capillary Refill

– Peripheral Pulses

– Cold Extremities

– SIRS


• Of course they help!

• Consider others besides

– Capillary Refill

– Peripheral Pulses

– Cold Extremities

– SIRS

• Likely Better

• Hypotension

• Altered mental status

• Urine output decreased

• Respiratory distress/fast breathing

• Overall ‘looks sick’

• Can’t sit up or walk

“I passed out at home”

• Healthy 16 yo female

• Fever, muscle pain x 1 day. Tried to stand and passed up.

• 39, HR 122, RR 28, BP 92/47, Pox 95%


• Healthy 16 yo female

• Fever, muscle pain x 1 day. Tried to stand and passed up.

• 39, HR 122, RR 28, BP 92/47, Pox 95%

What do you notice? What do you do?


• IV placed, 1L bolus started

• Patient tries to sit up and passes out

• HR=125, BP = 85/35

• Receives more boluses

• Antibiotics given

• Develops rash, lips peeling, red all over

Pop Quiz!

What is the most likely source of infection?

A) Pneumonia

B) Urinary Tract Infection

C) Toxic Shock Syndrome

D) Bacteremia

You ask another question…

• Currently on day 7 of menstrual period, tampon use • Antibiotics given, tampon removed, good recovery

• Toxic Shock Syndrome: Usually Strep or Staph

– 20% source not identified – 50% related to tampon use

• CDC Criteria: – >38.9°C – Hypotension – Erythroderma, desquamation – >= 3 organ systems

Diagnosis of Pediatric Sepsis: ED Experiences

Algorithmic Alert vs. Physician Judgment Algorithmic (EHR) Alert:

• Fever (complaint or ≥38.5 or <36)

• Any 3:

– Temperature

– Heart rate

– Respiratory rate

– Blood pressure

– High risk condition

– Capillary refill

– Pulse quality

– Abnormal mental status

Physician Judgment

• Treatment pathway used

Outcome: Severe sepsis or septic shock within 24 hours

Balamuth Acad EM 2015

Severe Sepsis +

Severe Sepsis -

Alert + 81 3220

Alert - 7 16,216

Algorithmic Alert

92% sensitive

83% specific

Physician Judgment 73% sensitive 99% specific

Severe Sepsis +

Severe Sepsis -

PJ + 64 95

PJ - 24 19,341

Algorithmic Alert vs. Physician Judgment

Severe Sepsis +

Severe Sepsis -

Alert + 81 3220

Alert - 7 16,216

Algorithmic Alert

92% sensitive

83% specific


Severe Sepsis +

Severe Sepsis -

PJ + 64 95

PJ - 24 19,341


Severe Sepsis +

Severe Sepsis -

Alert + 81 3220

Alert - 7 16,216

Algorithmic Alert

92% sensitive

83% specific


Severe Sepsis +

Severe Sepsis -

PJ + 64 95

PJ - 24 19,341


Audience Poll

Does your hospital use a sepsis screening tool for children?

A) Yes – in the ED

B) Yes – in inpatient

C) Yes – in both ED and inpatient

D) I don’t know

E) No

Diagnosis: Screening/Triage Tests

• Some system probably better than none

• Several examples available

– AAP Septic Shock Collaborative

– Balamuth Acad Emerg Med 2015

– Cruz Pediatrics 2011, Ped Emerg Care 2012

– Goldstein Ped Crit Care Med 2005

• Nothing proven

Sepsis Stat

Fever and/or concern for infection AND: • Tachycardia despite absence or

treatment of fever & dehydration?

• Immunosuppression/immuno-deficiency or central line?

• Consider for clinically uncertain / borderline abnormalities in: o Mental status o Capillary refill o Peripheral pulse quality

Two Critical Diagnostic Elements

• Hypotension

• Lactate

Lactate in sepsis

• Produced by anaerobic metabolism

– Global hypoperfusion

– Regional hypoperfusion

– Adrenergic state

– Metabolic and mitochondrial dysfunction?

– Lung?

• Hepatic clearance

• Renal clearance

Lactate in Adult Sepsis

Reprinted from Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign:

International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care

Med 2013; 41:580-637.

Lactate in Pediatric Sepsis

Brierley Crit Care Med 2009

• Setting: ED tertiary pediatric hospital

• Population: <18 years, ED, SIRS, IV placed

• Intervention:

– Measurement of lactate (blinded to clinicians)

• Outcome: Organ dysfunction within 24 hours (Goldstein)

• 239 enrolled

• Routine clinical care

Lactate & Organ Dysfunction in Pediatric Sepsis

Scott Acad EM 2012

239 Children in the ED with Systemic Inflammatory Response Syndrome

Fever

+

Fast Heart Rate

Scott Acad EM 2012

3%

17%

4%

22%

0

5

10

15

20

25

Lactate<4 mmol/L Lactate≥4mmol/L

Per

cent

age

with

Org

an D

ysfu

nctio

n

Organ Dysfunction In ED

Organ Dysfunction Within24 Hours

Risk of Organ Failure 5 Times Higher RR= 5.5 [1.9-16.0]


Risk of Death 2 Times Higher RR= 2.90 [1.11-7.57]

Scott PAS 2016

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

≤36 mg/dL (4 mmol/L) >36 mg/dL (4 mmol/L)

Mo

rta

lity

Initial Lactate Level

30-Day Mortality

3-Day Mortality


Scott PAS 2016

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%


Mo

rta

lity


30-Day Mortality

3-Day Mortality


Scott PAS 2016

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%


Mo

rta

lity


30-Day Mortality

3-Day Mortality

Scott PAS 2016

Scott PAS 2016

Among children in the ED with clinical sepsis, across all outcomes, more severe outcomes occur more frequently in patients with higher lactate

Definitions

• Lactate Clearance

Decrease by ≥10%, or <2 mmol/L if initial level <2 mmol/L

• Lactate Normalization:

Lactate < 2 mmol/L

Scott JPeds 2015

Scott JPeds 2015

Diagnosis

• Diagnosis prior to late-stage illness is ideal

• Many institutions fail even AFTER hypotension or high lactate… and these are patients most likely to die

• QI Teams: Check your institution’s performance in hypotensive patients

• Consider use of lactate testing in your sepsis program

Objectives



1. Diagnosis




Pop Quiz!

What is the right amount of IV fluid to give a 15-kg child with septic shock?

A) 60 mL/kg in the first 15 minutes

B) 60 mL/kg in the first 60 minutes

C) 40 mL/kg in the first 60 minutes

D) It depends

Fluid in Pediatric Sepsis

Brierley Crit Care Med 2009

• All children with septic shock with PA catheter by 6 hours • 34 patients, mean age 13.5 months

• ARDS (n=11), cardiogenic pulmonary edema (n=5) not associated with volume received

• At time of PA placement: Hypovolemia more frequent in Groups 1&2, all hypovolemic patients died (n=8)

1st Hour Fluid n Mortality

Group 1 <20 ml/kg 14 57%

Group 2 20-40 ml/kg 11 64%

Group 3 >40 ml/kg 9 11%

Carcillo JAMA 1991

Paul Pediatrics 2012

Populations: Landmark Pediatric Sepsis Studies

• Severe febrile illness (Africa)

• Maitland NEJM 2011

Population: “Severe febrile illness”

• 60 days - 12 years

• Febrile

• Impaired consciousness (prostration or coma)

• Respiratory distress

• Impaired perfusion: capillary refill ≥3 seconds, lower-limb temperature gradient, weak radial-pulse volume, or severe tachycardia

Maitland NEJM 2011

Maitland NEJM 2011

• Patients admitted to the ICU with sepsis

• Community ED patients transported to a pediatric hospital with septic shock

• Consecutive PICU patients with fluid-refractory septic shock with a PA catheter within 6 hours

• ED patients with severe sepsis or septic shock

• Severe febrile illness (Africa)

PALS Fluid Recommendations

• Administration of an initial fluid bolus… in shock is reasonable (Class IIa, LOE C-LD)

• When caring for children with severe febrile illness in settings with limited access to critical care resources… administration of bolus intravenous fluids should be undertaken with extreme caution (Class IIb, LOE B-R)

de Caen Circulation 2015

PALS Fluid Recommendations

• Continued emphasis on fluid resuscitation for shock

• Fluid not safe for all patients in all settings

– e.g. shouldn’t have ‘standing orders’ for 60 mL/kg for all patients

• Increased emphasis on

– Individual patient assessment and reassessment

– Consideration of vulnerabilities to fluid • Nutrition status

• Diseases (i.e. anemia, malaria)

• Critical care resources

Summary: Fluid One Size Does Not Fit All

• In US/UK studies – 40-60 ml/kg associated with improved outcome in

septic shock/severe sepsis – Some populations harmed by fluid – Clinical assessment of fluid status during

resuscitation challenging

• Rapid fluid, rapid reassessment – Physical exam – Augment assessment when possible

• ScVO2, CVP • Lactate • Ultrasound/echo

Objectives



1. Diagnosis




Time to Antibiotics Saves Lives

Weiss, Fitzgerald CCM 2014

Time to Antibiotics Saves Lives

Weiss, Fitzgerald CCM 2014

2011

Bolus in First Hour Antibiotic in 3 Hours Lactate Measured

Pre Post p-value

Length of Stay 181 hours 140 hours <0.05

Mortality 7 (13%) 7 (7%) 0.19

Pre Post p-value

Time to First Bolus 65 min 34 min 0.01

Time to Antibiotics 141 min 54 min 0.001

Fluid Volume 48.7 ml/kg 55.9 ml/kh 0.01

Acute Kidney Injury 53 (54%) 30 (29%) <0.001

Mortality 10 (10%) 3 (3%) 0.037

Cruz Pediatrics 2011 Ayse JPeds 2015

Time to Bolus Time to Antibiotic

Pre Post p-value

Time to First Bolus 65 min 34 min 0.01

Time to Antibiotics 141 min 54 min 0.001

Fluid Volume 48.7 ml/kg 55.9 ml/kh 0.01

Acute Kidney Injury 53 (54%) 30 (29%) <0.001

Mortality 10 (10%) 3 (3%) 0.037

Cruz Pediatrics 2011 Ayse JPeds 2015

Time to Bolus Time to Antibiotic

Paul



Sepsis STAT Sepsis Yellow

Concept Septic Shock Full resuscitation now

High-risk for bacterial infection; not critical Prevent deterioration Ongoing clinical-decision making

Location Move to a resuscitation bay Stay in regular ED room

Staffing Additional nurse to bedside Bedside nurse (charge nurse watches the bedside nurse’s other patients)

Pharmacy Hand-delivers antibiotic Expedited tubed antibiotic with nurse page

Fluid Rapid bolus start, reassess Consider, reassess *If faster than on a pump needed, upgrade to STAT

Antibiotics Rapid antibiotics Consider, reassess (stewardship)

PROS Phenomenal coordinated resuscitation response

Lowers psychological barrier to clinicians activating & may prevent full shock state Allows expedited evaluation without committing to antibiotics Unifying protocol for all high-risk conditions

CONS Resource-intensive Underuse of Sepsis STAT

Summary: Protocolized Care

• Institutional sepsis processes facilitate timely delivery fluids, antibiotics

• Improves mortality, length of stay, AKI

• Not the same as “Protocolized Care” or “Early Goal-Directed Therapy”

– SVcO2 monitoring

– Transfusion

Sepsis STAT Sepsis Yellow

Concept Septic Shock Full resuscitation now

High-risk for bacterial infection; not critical Prevent deterioration Ongoing clinical-decision making

Location Move to a resuscitation bay Stay in regular ED room

Staffing Additional nurse to bedside Bedside nurse (charge nurse watches the bedside nurse’s other patients)

Pharmacy Hand-delivers antibiotic Expedited tubed antibiotic with nurse page

Fluid Rapid bolus start, reassess Consider, reassess *If faster than on a pump needed, upgrade to STAT

Antibiotics Rapid antibiotics Consider, reassess (stewardship)

PROS Phenomenal coordinated resuscitation response

Lowers psychological barrier to clinicians activating & may prevent full shock state Allows expedited evaluation without committing to antibiotics Unifying protocol for all high-risk conditions

CONS Resource-intensive Underuse of Sepsis STAT

Yellow

Stat

Missed

Sepsis Yellow Patients: 30% No Antibiotics

Controversies in Diagnosis, Fluid, Protocolized Care:

So What Should We Do?

• Not controversial: – Early antibiotics

– Do not tolerate hypotension

• Patient-Specific, Systems-Standardized

• Process Improvement & Standardization – Recognition/Screening

– Antibiotic, Fluid Delivery Systems

– Measure what you are doing

Future directions

From Evidence-Based Medicine to Evidence-Based Care

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