Stephen Freedman, MDCM, MSc, FRCPC, FAAP

1
Gastroenteritis Hydration Techniques Beyond Oral
Rehydration Therapy

• Stephen Freedman, MDCM, MSc, FRCPC, FAAP
• The Hospital for Sick Children
• Toronto, ON

2
Disclosure

• Current research support is provided by Institut
  Rosell Lallemand Inc., the manufacturer of a
  probiotic agent.
• Previous research support was provided by
  GlaxoSmithKline, the manufacturer of Zofran
  (ondansetron).

3
Objectives

• Review evidence regarding antiemetic use
• Provide an update on IV rehydration strategies
• Discuss the maintenance fluid controversy
• Describe evidence for/against probiotics

4
Impact of Vomiting

• Oral rehydration therapy
• Treatment of choice for mild-moderate dehydration
• Continues to be underused
• Vomiting
• Common symptom in pediatric gastroenteritis
• Unpleasant and distressing
• Increases risk of dehydration IV rehydration
• ED physicians more likely to use IV rehydration
• Patient refusing to drink 96
• Vomiting as major symptom 85

Conners et al. Ped Emerg Care 200016335-8
Ozuah et al. Pediatrics 2002109259-261.
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Antiemetic Agents

• Why attempt to alleviate vomiting?
• Prevent further distress (patient family)
• Prevent further dehydration
• Avert need for IV rehydration /- hospitalization
• Why do guidelines not recommend their use?
• Self-limited condition
• Vomiting rids the body of toxins
• Lack of evidence of benefit
• Potential adverse events
• Cost

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Self-Limited Condition?

• Canadian estimates in children lt 5 years
• 2 million cases/year
• Cost 1.3 billion/year
• 200 000 emergency visits/year
• 20 000 hospitalization/year
• 30 deaths/year

7
Ridding the body of Toxins
Damage to Gastrointestinal mucosa
Serotonin release from Enterochromaffin Cells
5-HT3 Vagal Afferent Nerve Receptors in GIT
Chemoreceptor Trigger Zone
Vomiting Center
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Evidence of Benefit Lacking

• Dopamine receptor antagonists
• Extrapyramidal reactions
• Neuroleptic malignant syndrome
• Respiratory depression
• QT prolongation
• Antihistamines
• Drowsiness
• Dizziness

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Pediatric Use of Antiemetic Medications
Pfeil et al. J Peds 2008153659-62.
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Evidence of Benefit now Exists

• Ondansetron
• Selective serotonin receptor antagonist
• Chemoreceptor trigger zone
• Peripheral vagal nerve terminals
• First study published in 1987
• Emetogenic chemotherapy radiotherapy
• Postoperative nausea vomiting
• 6 studies reporting use in pediatric
  gastroenteritis

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Relative Risk of Persistent Emesis
DeCamp et al. Arch Pediatr Adolesc Med
2008162858-65.
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Relative Risk of IV Rehydration
DeCamp et al. Arch Pediatr Adolesc Med
2008162858-65.
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Relative Risk of Admission
DeCamp et al. Arch Pediatr Adolesc Med
2008162858-65.
14
Ondansetron Summary

• Single dose preferred
• Short term increase in diarrhea

DeCamp et al. Arch Pediatr Adolesc Med
2008162858-65.
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Antiemetics are Frequently Used

• Cohort of 20,222 children with gastroenteritis
• 9 filled a prescription for an antiemetic
• No increase in adverse events
• No increase in subsequent health care use
• Ondansetron
• Over 250 million patient treatment days

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Antiemetic Use in Eligible Children2009 Survey
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Ondansetron Saves

• Annual impact of administration to eligible CDN
  children (37,411) would
• Prevent 6,309 intravenous insertions
• Prevent 1,567 hospitalizations
• Annually save society 1.8 million
• Break-even price/dose administered 59

Freedman et al. Abstract Pediatric Academic
Societys Annual Meeting May 2-5 2009.
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(No Transcript)
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Rapid IV Rehydration

• Proposed indication
• Dehydration requiring IV rehydration
• Method
• Rapid administration of large volume of IV
  fluids
• Goals
• To expedite rehydration improve patient
  well-being
• Decrease ED length of stay reduce ED
  overcrowding
• Reduce admission rate reduce resource use

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Deficit Therapy

• Traditional method (Darrow 1946)
• Slow replacement over 1-3 days
• Permits restoration of ICF ECF
• Assumes need for significant K replacement
• Resulted in most children not receiving a bolus
• Nearly all children hospitalized for several days

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Gradual Evolution

• Evidence against need for slow rehydration
• Acute dehydration is primarily ECF contraction
• Interstitial space serves as a reservoir to
  offset losses
• High concentration K administration is
  unnecessary
• Each institution has own protocol
• 20 ml/kg then 1.5 times maintenance
• Repeat 20 ml/kg boluses
• 50 ml/kg over 3 hours
• No scientific evidence of improved outcomes

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Evidence to Date

• 10 Studies 382 patients
• 20 mL/kg/1 hr 100 mL/kg/4 hrs
• Administered isotonic fluid
• Excluded significant sodium abnormality
• From developing countries
• Inadequate randomization and blinding
• Did not compare efficacy of RIVR to standard

Gorelick. Pediatric Emergency Medicine Database,
pemdatabase.org.
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Evaluation Summary

• Safe
• No complications related to treatment
• No clinically relevant electrolyte changes noted
• Effective
• Nearly all patients improved by end of therapy
• Relied on subjective clinical assessment
• Reduction in hospitalization rates
• Patients receiving 50 ml/kg discharged

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Why not use Rapid Rehydration for Everyone?

• Unknown high risk
• Myocarditis
• Renal failure

• Known high risk patients
• Hypoalbuminemic states
• Renal insufficiency
• Congenital heart disease
• Hypertension
• Chronic lung disease
• Diabetes mellitus
• Chronic inflammatory disease

Fluid overload Electrolyte abnormality
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IV Rehydration Practices2009 Survey

• PERC-bolus therapy
• 86 administer 16-25 ml/kg initial bolus
• 2 administer 26-35 ml/kg initial bolus
• 57 perform over 60 minutes
• 16 repeat the bolus gt 50 of the time
• PEM-CRC bolus therapy
• 88 administer 16-25 ml/kg initial bolus
• 10 administer 26-35 ml/kg initial bolus
• 70 perform over 30 minutes
• 60 repeat the bolus gt 50 of the time

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Recommendations

• No formal guidelines exist
• Personal preference
• 20 cc/kg over 30-60 min
• Reassess repeat
• Ongoing double blind RCT
• 20 cc/kg vs 60 cc/kg over 1 hour
• 190/226 subjects enrolled
• No significant adverse events to date

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What Maintenance Fluids should we Choose?

• Holliday and Segar prescription (1957)
• Based on cow human milk content urinary
  excretion
• Healthy infants
• Recommended hypotonic IV maintenance solutions
• Emerged prior to SIADH reports
• Associated with severe hyponatremia
• Not related to total volume of fluids received
• Related to volume of electrolyte free water
• Combined with non-osmotic ADH secretion

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Meta-AnalysisDevelopment of HyponatremiaHypotoni
c vs. Isotonic Fluids
Choong et al. Arch Dis Child. 200691828-35.
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Isotonic vs. Hypotonic Saline

• Randomized, prospective study
• D2.5-0.9NS vs. D2.5-0.45NS
• Eligibility
• 102 children aged 6 months - 14 years
• Gastroenteritis requiring IV fluids
• Electrolytes at time 0 and 4 hours

Neville et al. Arch Dis Child. 200691226-232.
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Decrease of Na 2 mmol/L
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Mean Change in Na
Indicates result was statistically significant.
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Recommendations

• Hospital for Sick Children maintenance fluid
  guidelines
• If serum Na lt 138 ? 0.9 NaCl
• If serum Na 138-144 ? 0.45 - 0.9 NaCl
• If serum Na 145-154 ? 0.45 NaCl
• If serum Na gt 154 ? 0.9 NaCl
• High risk of cerebral edema with hypotonic
  solutions
• Daily electrolytes

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Can We Modify the Disease?
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Probiotics Infectious Diarrhea

• Definition
• Live organism of benefit to the host
• Modify the composition of enteric flora
• Mechanism of action
• Synthesis of antimicrobial substance
• Competition for nutrients
• Competitive inhibition of adhesion
• Modification of toxins or toxin receptors
• Stimulate/modify the immune response

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Therapeutic use of Probiotics

• Not controlled by legislation similarly to
  pharmaceuticals
• Use has become widespread based on limited
  evidence
• Often considered as alternative therapy
• Research has provided proof of concept

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Potential Roles in Pediatrics

• Acute infectious diarrhea
• Antibiotic associated diarrhea
• Necrotizing enterocolitis
• Atopic disease
• Inflammatory bowel disease
• Viral upper respiratory tract infections
• Dental caries

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Duration of Diarrhea in Hospitalized Children
Huang et al. Dig Dis Sci 2002 472625-2634
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Meta-Analysis - Limitations

• Several probiotics tested
• Closely related strains have different clinical
  effects
• Wide variation in treatment regimens
• of organisms
• Timing of intervention
• Duration of therapy
• How do we apply the results to our patients?
• Concrete guidelines lacking

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Safety

• 118 infants received 18 months of probiotics
• Reduction in colic, health care visits
  antibiotic use
• Over 200 billion doses consumed worldwide
• No serious adverse effects in well people
• Risk of bacteremia
• Estimated to be lt 1/million
• Congenital heart disease, central venous line

Saavedra et al. Am J Clin Nutr. 200479261-27.
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Expert Consensus

• Effect is strain and dose dependent
• Lactobacillus rhamnosus GG - most effective
• Benefit greatest in viral gastroenteritis
• Especially when administered early
• More data required
• Outpatient/ED
• North American products and subjects
• Optimal dose unknown
• Accurate labelling is essential

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Conclusions

• Therapeutic options beyond ORT exist
• Ondansetron should be used to reduce vomiting,
  use of IV fluids
• Rapid IV rehydration may expedite discharge
• Hypotonic maintenance fluids should be used with
  caution
• Probiotics may be considered for use to reduce
  diarrhea duration