Sepsis in Children

Past, Present, FutureArjun Rao

A short story to start …A 6yr old girl presented to the ED at about 2am. At handover the morning before the team were commenting that every child on the ward was on IV cefotaxime and that maybe we should be rationalising our use of antibiotics. The girl had been found unresponsive at home and was gradually becoming more alert and awake. She had a fever. By the time she was seen she was sitting up in bed eating an ice block and “looked well”.The only concerning feature was a persistent tachycardia. She was admitted for observation but no bloods were done and she was not started on antibiotics.On clinical review at about 5am she was noted to still be well, but was still tachycardic. Bloods were taken and an IV line placed. She was handed over to the day team with a plan to check her bloods.It took the day team a while to get around to review her and by that stage her WCC had come back as 30 and she was developing a purpuric rash.She was fluid resuscitated and given IV anitbiotics and ultimately did well.

http://www.smh.com.au/national/health/emergency-doctor--what-did-i-miss-20151006-gk2ir5.html

The ideal with regards to sepsis

• Don’t miss any children with sepsis• Don’t over investigate febrile children• Only admit children who have sepsis

1977

• Let take a trip back in time …• Why have I chosen to start in 1977?

1977

This was the year of the Tenerife Airport disaster when KLM and Pan Am 747s collided on a runway killing 583 people – to this date the deadliest accident in aviation history

The accident led to lasting changes to systems in the airline industry which we are starting to adopt in medicine

Safety and systems

1993

Fast forward to 1993How were we managing children with fever and suspected sepsis then?What was the evidence base?It was largely based on the flowsheet published by Larry Baraff ->

Baraff, Larry J., et al. "Practice guideline for the management of infants and children 0 to 36 months of age with fever without source." Pediatrics 92.1 (1993): 1-12.

1998

By 1998 we had some more evidence from Nathan Kupermann and his paper which published relative risks for occult pneumococcal bacteremia based on temperature and WCC …

Kuppermann, Nathan, Gary R. Fleisher, and David M. Jaffe. "Predictors of occult pneumococcal bacteremia in young febrile children." Annals of emergency medicine 31.6 (1998): 679-687.

So What’s changed since then?

• Vaccination (Pneumococcus / Meningococcus)• New investigations (CRP / PCT)• Continuously monitored BC systems• New bacteria patterns (19A)• Goal-directed therapy• Patient safety / Systems / “Care bundles”• “FEAST” Trial

Some definitions

FeverSIRSSBI

SEPSISSEVERE SEPSISSEPTIC SHOCK

WHAT DOES IT ALL MEAN?

Fever

• > 38• But > 38.5 improves specificity• Core Temperature:– “rectal, bladder, oral, or central catheter probe”– “Temperatures taken via the tympanic, toe, or

axillary route are not sufficiently accurate”

Goldstein, Brahm, Brett Giroir, and Adrienne Randolph. "International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*." Pediatric critical care medicine 6.1 (2005): 2-8.

SIRS The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count:

● Core temperature of >38.5°C or <36°C. ● Tachycardia, defined as a mean heart rate 2 SD above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli; or otherwise unexplained persistent elevation over a 0.5- to 4-hr time period OR for children <1 yr old: bradycardia, defined as a mean heart rate <10th percentile for age in the absence of external vagal stimulus, beta-blocker drugs, or congenital heart disease; or otherwise unexplained persistent depression over a 0.5-hr time period. ● Mean respiratory rate 2 SD above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia. ● Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or >10% immature neutrophils.

Goldstein, Brahm, Brett Giroir, and Adrienne Randolph. "International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*." Pediatric critical care medicine 6.1 (2005): 2-8.

Serious bacterial infection (SBI)

• Bacteraemia, UTI, pneumonia, bacterial meningitis, osteomyelitis or septic arthritis

• [Bacteraemia: Positive blood culture with bacteria not considered a skin contaminant]

Manzano, Sergio, et al. "Markers for bacterial infection in children with fever without source." Archives of disease in childhood 96.5 (2011): 440-446.

Craig, Jonathan C., et al. "The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses." Bmj 340 (2010).

Sepsis

• SIRS in the presence of or as a result of suspected or proven infection

Goldstein, Brahm, Brett Giroir, and Adrienne Randolph. "International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*." Pediatric critical care medicine 6.1 (2005): 2-8.

Severe Sepsis

Sepsis plus one of the following: cardiovascular organ dysfunction OR acute respiratory distress syndrome OR two or more other organ dysfunctions

Goldstein, Brahm, Brett Giroir, and Adrienne Randolph. "International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*." Pediatric critical care medicine 6.1 (2005): 2-8.

Septic shock

Sepsis and cardiovascular organ dysfunction

Goldstein, Brahm, Brett Giroir, and Adrienne Randolph. "International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*." Pediatric critical care medicine 6.1 (2005): 2-8.

SO HOW COMMON IS THIS NOW?

The investigation and management of sepsis will depend on the population prevalence …

Incidence / Prevalance of sepsis

• Ix and Mx of sepsis depends on population prevalence

• Before HIB vaccination: 3-11%– S.Pneumoniae (65-85%); HIB (5-20%)

• After HIB Vaccination– 96% decrease in HIB vaccination– 1.9% sepsis– 83-92% S.Pneumoniae

Alpern, Elizabeth R., et al. "Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome." Pediatrics 106.3 (2000): 505-511

Incidence / Prevalance of sepsis

• After pneumococcal vaccination– 0.4% - 1%– SBI ~ 7%– UTI (3.4%) / Pneumonia (3.4%)– Meningitis (0.04%)

Craig, Jonathan C., et al. "The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses." Bmj 340 (2010).

Gomez, B., et al. "Bacteremia in previously healthy children in Emergency Departments: clinical and microbiological characteristics and outcome."European Journal of Clinical Microbiology & Infectious Diseases 34.3 (2015): 453-460.

Presentations

• Fever without source accounts for about 15-20% of presentations to ED

• 3-6 febrile illnesses /yr• 20-40% of parents seek advice

Simon, Alan E., Susan L. Lukacs, and Pauline Mendola. "National trends in emergency department use of urinalysis, complete blood count, and blood culture for fever without a source among children ages 2–24 months in the PCV-7 era." Pediatric emergency care 29.5 (2013): 560.

Craig, Jonathan C., et al. "The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses." Bmj 340 (2010).

We work in a low prevalence settingSo we are trying to find a needle of

sepsis in the haystack of presentations

What tools can help us do this?

CLINICAL ACUMEN?

Clinical acumen

Van den Bruel, Ann, et al. "Diagnostic value of clinical features at presentation to identify serious infection in children in developed countries: a systematic review." The Lancet 375.9717 (2010): 834-845.

Temperature

Clinical features of use

• Parental concern that illness is different• Clinician “instinct”• “Unwell appearance”• Cyanosis, Tachypnoea, SOB, Poor perfusion• Changed crying pattern• Petechial rash• Loss of consciousness

Clinical Accumen

• With clinical suspicion alone we sometimes end up in the following situation:

– Risk of SBI being too high to ignore, yet too low to justify hospital admission

Investigations

Manzano, Sergio, et al. "Markers for bacterial infection in children with fever without source." Archives of disease in childhood 96.5 (2011): 440-446.

Investigations

Van den Bruel, Ann, et al. "Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review." Bmj 342 (2011).

Investigations• A cut off of 80mg/L (CRP) 2ng/mL (PCT)– Specificity >90%– Sensitivity 40-50%

• A cut off level of 20mg/L (CRP) 0.5ng/mL (PCT)– Sensitivity >80%– Specificity 70%

• Pre test probability 23% – CRP >80 or PCT >2 increases probability to 72% BUT <80 or <2

risk still 15% – To reduce risk to 5% CRP needs to be <20, PCT <0.5

Can we put these concepts into an update guideline or flowsheet now?

NSW Health has tried:

NSW Clinical Practice Guidelines - 2010

NSW Clinical Practice Guidelines - 2010

Ok, we’ve got a child who we want to treat for suspected sepsis – what now?

Goal-directed therapy

But what about for children?

Goal directed therapy in children

• Retrospective data shows benefit• Decreased mortality and increased survival

with early shock reversal• End points: CR, urine output, mental status,

pulses• ScvO2• Limitation – CV access in children in ED

de Oliveira, Cláudio Flauzino. "Early goal-directed therapy in treatment of pediatric septic shock." Shock 34.7 (2010): 44-47.

Global Sepsis Initiative

Kissoon, Niranjan, et al. "World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative*." Pediatric Critical Care Medicine 12.5 (2011): 494-503.

Putting it all together

• Febrile children are common• Identifiable SBI is relatively common (UTI,

Pneumonia)• Sepsis is rare• Recognition is difficult• Clinical accumen is variable• Investigations not a “golden bullet”• Early recognition and Rx can reduce mortality

Thinking back to systems …

The NSW Clinical Excellence Commission has developed a paediatric sepsis pathway

http://www.cec.health.nsw.gov.au/programs/sepsis

CEC Paediatric Sepsis Pathway

http://www.cec.health.nsw.gov.au/programs/sepsis

CEC Paediatric Sepsis Pathway

CEC Paediatric Sepsis Pathway

Sepsis pathway “performance”

Paediatric Emergency Department – January 1 2014 to October 31 2015 (N = 555 patients)

Sepsis pathway “performance”

0-60 61-120 121-180 181-240 >2400

10

20

30

40

50

60

70

54

27.4

9.5

4.2 4.8

32.4

25.4

17.1

9.7

15.3

64.2

17.2

6.13.3

11

47.6

0

23.8

4.8

23.8

NSW Time to 1st antibiotics (Mins)

January 1 2014 - October 31 2015

Adult EDPaed EDAdult InptPaed Inpt

Minutes

% o

f Pati

ents

Past and present

• Past– High prevalance– High mortality– Poor systems

• Present– Low prevalence and mortality– Systems starting

Future

• Implications of “FEAST”• Broader vaccination (7-13-?)• Antibiotic resistance• Point of care testing and risk stratification?

FEAST

• Being in FEAST improved mortality from shock• Mortality for no bolus 7.3%• Mortality for bolus 10.5%

1. Maitland, Kathryn, et al. "Mortality after fluid bolus in African children with severe infection." New England Journal of Medicine 364.26 (2011): 2483-2495.

2. Maitland, Kathryn, et al. "Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial." BMC medicine 11.1 (2013): 68.

Mechanisms of FEAST

1. Maitland, Kathryn, et al. "Mortality after fluid bolus in African children with severe infection." New England Journal of Medicine 364.26 (2011): 2483-2495.

2. Maitland, Kathryn, et al. "Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial." BMC medicine 11.1 (2013): 68.

Point of care testing?

Galetto-Lacour, Annick, Samuel A. Zamora, and Alain Gervaix. "Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center." Pediatrics 112.5 (2003): 1054-1060.

Not yet useful, but wouldn’t it be nice!

Summary

• Individualised approach based on subjective and objective thorough clinical assessment and appropriate use of Ix

• But also a standardised approach• Care pathways for septic children• More evidence needed• Awareness of how things may change in the

future