11
B Li MDProfessor of Pediatrics
Northwestern UniversityChildren’s Memorial Hospital, Chicago, IL
B Li MDProfessor of Pediatrics
Northwestern UniversityChildren’s Memorial Hospital, Chicago, IL
Cyclic vomiting syndrome: Diagnosis and treatment
Cyclic vomiting syndrome: Diagnosis and treatment
22
Despite the fact that this is an episodic illness in which affected children are well most of the time, this slide highlights the substantial medical morbidity, academic disability and medical costs incurred. Over half of the children develop clinical dehydration at some point, and 1/5 of the entire group require IV hydation with each episode. School-aged children missed 3-5 weeks of school per year. The average annual cost of care amongst our cohort in Ohio – i.e. lab, x-ray, endoscopic testing, ER and Drs. visits, in-patient admissions, and parent’s missed work.
Mostly well – 90% of time – but …Mostly well – 90% of time – but …
58% rate of IV hydration - 19% every time
14, 24 schooldays miss (med, mean) / year in children > 7 years of age
$17,035 average annual cost of care and missed work
58% rate of IV hydration - 19% every time
14, 24 schooldays miss (med, mean) / year in children > 7 years of age
$17,035 average annual cost of care and missed work
Adv Pediatr 47:117, 2000Adv Pediatr 47:117, 2000
33
Recurrent ⇒ cyclic and chronicRecurrent ⇒ cyclic and chronic
0
10
20
30
40
50
0 10 20 30 40 50 60
0
10
20
30
40
50
0 10 20 30 40 50 60DaysDays
#e
me
ses
#e
me
ses
Contemp Pediatr 13:48, 1996Contemp Pediatr 13:48, 1996 Pediatrics 97:364, 1996Pediatrics 97:364, 1996
1/3rd1/3rd 2/3rds
2/3rds
GI:extraGI - 7:1GI:extraGI - 7:1extraGI:GI - 5:1extraGI:GI - 5:1
We differentiated recurrent vomiting (> 3 episodes) into two groups, based on distinct temporal patterns.The number of emeses is plotted over a 2-month time line. The most familiar is the low grade, frequent pattern that never results in dehydration that we call chronic. The other is the high intensity (20-40X over 24-48 hours), infrequent pattern that often results in dehydration that we call cyclic. The child returns to normal or baseline health in between. In our consecutive series, 2/3rd were found to have the chronic pattern and 1/3rd the cyclicpattern. The cut off was > 4 emeses/hr at the peak and < 2 episodes/week = cyclic.These 2 patterns carry diagnostic implications. Those with the chronic pattern were found to have more GI disorders (esophagitis, gastritis – Hp, duodenitis) than extra-intestinal disorders by a ratio of 7:1. Whereas, those with the cyclic pattern had more extraintestinal than GI disorders (neuro, renal, metabolic, endocrine) by a ratio of 5:1.
44
PearlsPearls
Two patterns of recurrent vomiting are qualitatively and quantitatively different
cyclic pattern ⇒ look outside the GI tract (e.g. CNS, renal, metabolic, CVS)
chronic pattern ⇒ look inside the GI tract (e.g. GERD, gastritis)
CVS – 2nd most common to GERD
CVS – academic and medical morbidity
Two patterns of recurrent vomiting are qualitatively and quantitatively different
cyclic pattern ⇒ look outside the GI tract (e.g. CNS, renal, metabolic, CVS)
chronic pattern ⇒ look inside the GI tract (e.g. GERD, gastritis)
CVS – 2nd most common to GERD
CVS – academic and medical morbidity
55
The natural history? (n=463)The natural history? (n=463)
0
5
10
15
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
0
5
10
15
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
%%
Age, yearsAge, years
Onset = 5Onset = 5
Diagnosis = 8
Diagnosis = 8
Migraines = 10
Migraines = 10Last episode = 10
Last episode = 10
27 episodes / 3.6 yrs
27 episodes / 3.6 yrs
The %’tage of our CVS patients is plotted against the age of onset.CVS can begin in infancy although is often confounded by the presence of GERD.The median age of onset is 5 years. The median age of diagnosis 8 years, some 2.6 years later. In those who have ended their episodes thus far, the last episode (this will shift to the right with longer follow-up) occurred at age 10 years with migraine headaches beginning in 1/3rd so far. Overall, they had 27 episodes over 3.6 years and experienced 15 episodes before the appropriate diagnosis was made!
66
On-off, intense, stereotypicalOn-off, intense, stereotypical
24-46 hrs24-46 hrs
Prodrome (1.5 hrs):lethargy, pallor, anorexia, nausea
Prodrome (1.5 hrs):lethargy, pallor, anorexia, nausea
Episode: vomiting 15-30X, pallor, lethargy, anorexia, nausea, pain, retching (79-93%)
Episode: vomiting 15-30X, pallor, lethargy, anorexia, nausea, pain, retching (79-93%)
Vomiting: 6X/hrVomiting: 6X/hr
Recovery-sleep (6 hrs)Recovery-sleep (6 hrs)
Well Well
WellWell
Adv Pediatr 47:117, 2000Adv Pediatr 47:117, 2000
nauseanausea
4 week interval 4 week interval
Typical episodes are depicted with the blue line representing the peak vomiting intensity from 0-6 times an hour. After being well for weeks, the child has a brief 1.5 hour non-visual (no teichopsia) prodrome of symptoms premonitory to vomiting – lethargy, pallor, anorexia, nausea prior to reaching a peak emetic rate of 1 every 10 minutes.The episode lasts 24-46 hours and is associated with vomiting 15-30X, pallor, lethargy, anorexia, nausea, midline abdominal pain and retching in 4/5ths.The recovery from the point of last emesis to the point of turning the corner (to oral intake and playfulness) is a short 6 hours, often with sleep leading to awakening well.The yellow dotted line represents nausea that unlike GI-based nausea continues unabated and unrelieved by emesis throughout the episode except when the child is asleep. Hence the therapeutic strategy of sedation during acute episodes.
77
Systemic symptoms (n=463)Systemic symptoms (n=463)
0 20 40 60 80 100
Drooling
Fever
Flushing
Withdrawal
Pallor
Lethargy
0 20 40 60 80 100
Drooling
Fever
Flushing
Withdrawal
Pallor
Lethargy
%%%Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999
The %’tage of patients who consistently have specific symptoms is shown in next 3 slides. This shows the rate of systemic symptoms associated with acute attacks of CVS.Lethargy (to the point of not talking and walking) and pallor affect over 90% of individuals.Social withdrawal (unable to interact) affects 40%.Note that fever, usually low-grade, affects 30% and promotes clinical confusion with viral gastroenteritis.
88
GI symptoms (n=463)GI symptoms (n=463)
0 20 40 60 80 100
Constipation
Diarrhea
Retching
Anorexia
Abd Pain
Nausea
Vomiting
0 20 40 60 80 100
Constipation
Diarrhea
Retching
Anorexia
Abd Pain
Nausea
Vomiting
%%%Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999
The rate of GI symptoms associated with acute attacks of CVS.Vomiting, nausea, abdominal pain, anorexia and retching affect 80% of the children.Interestingly, diarrhea affects 30%. The 30% that has fever andthe 30% that has diarrhea can lead the mistaken diagnosis of viral gastroenteritis in the ER.
99
Neurological symptoms (n=463)Neurological symptoms (n=463)
0 20 40 60 80 100
Seizures
Vertigo
Phonophobia
Photophobia
Headaches
Sleep-to-well
0 20 40 60 80 100
Seizures
Vertigo
Phonophobia
Photophobia
Headaches
Sleep-to-well
%%%Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999
The rate of migraine-type symptoms associated with acute attacks of CVS.Except for ‘sleeping it off’, none of the migraine features reaches the 50% threshold and therefore are of little help in diagnosing a migraine variant.However, the significantly higher prevalence of these features in the cyclic than chronic vomiting (5%-10%, mostly esophagitis and gastritis) underscores the association between CVS and migraine headaches.
1010
Pearls – worse than viral GEPearls – worse than viral GE
IV hydration - 75X more likely than rotavirus
pale - to point of appearing in shock
lethargic or semi-comatose - unable to walk, talk, play or respond
fetal position - sensitive to light, sound, touch …
severe abdominal pain - can mimic an acute abdomen
IV hydration - 75X more likely than rotavirus
pale - to point of appearing in shock
lethargic or semi-comatose - unable to walk, talk, play or respond
fetal position - sensitive to light, sound, touch …
severe abdominal pain - can mimic an acute abdomen
Kids with CVS are sicker than those with gastroenteritis.IV hydration required – 58% (CVS) vs. 0.75% (rotavirus).The child is often listless in the absence of dehydration to thepoint of being semi-comatose. In comparison, the child with viral gastroenteritis remains playful in between bouts of vomiting anddiarrhea until the point of dehydration.Severe abdominal pain has resulted in laparotomy with normal findings. Despite the severe doubling-over midline pain, the exam reveals a soft abdominal wall.
1111
ChronobiologyChronobiology
January
1 2 3 4 5 6 7
8 9 10 11 12 13 14
15 16 17 18 19 20 21
22 23 24 25 26 27 28
29 30 31
January
1 2 3 4 5 6 7
8 9 10 11 12 13 14
15 16 17 18 19 20 21
22 23 24 25 26 27 28
29 30 31
2-7 am2-7 am
Onset: 42% amOnset: 42% am ‘Cyclic’: 49%‘Cyclic’: 49% Seasonal: 30%Seasonal: 30%
q. 1-4 wkq. 1-4 wk
better in summerbetter in summerDig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999
CRFCRF
estrogen ↓estrogen ↓
↓ stress,
↓ infection,↑ sleep↓ stress,
↓ infection,↑ sleep
2 of the interesting clinical features – the chronobiology of and triggers of episodes – provide clues to possible pathogenesis and are shown in the next two slides.The most common time of onset is between 2-4 am or upon awakening at 6-8 am. That coincides with the period that corticotropin-releasing factor peaks.‘Cyclic’ is a slight misnomer since 51% have episodic bouts that have irregular intervals. The most common regular interval is q. 4 weeks but most of the girls are prepubertal. Catemenial CVS does occur in post-menarchal girls.The most common seasonal pattern is one of frequent episodes during the winter months and few or none during the summer. We speculate that less stress, fewer infections and lengthened sleep help reduce the number.
1212
CVSCVSCVS
Psychological 47%Psychological 47%
Infectious 31%Infectious 31% Exhaustion 24%Exhaustion 24%
Dietary 23%Dietary 23% Menses 22%Menses 22%
Motion 12%Motion 12% AtopicAtopic 6%6%
Dig Dis Sci 44(Suppl):13S, 1999Dig Dis Sci 44(Suppl):13S, 1999
↑CRF↑CRF
↑CRF↑CRF
Triggers - 76% (n=463)Triggers - 76% (n=463)
76% of the parents can identify a recurring trigger or proximateevent.The most common is psychological stressors, and interestingly 2/3rds are positive stressors including birthdays, holidays, and vacations.Infections are 2nd and can include any infection the most common being chronic sinusitis.Both psychological stressors and cytokines raise corticotropin-releasing factor levels in animal studies.Dietary triggers, similar to those in migraines, include chocolate, aged cheese and MSG.Menses are triggers in 22% of post-menarchal girls. We have treated this subtype with low estrogen birth control pills or depo-Provera.
1313
These are the rates of positive fulfillment of each of the International Consensus Criteria in our cohort of patients. Positive answers to these essential diagnostic questions help make the diagnosis of CVS. The fact that 6% are not normal interictally and 3% have an ‘etiologic’ finding reflects that a few have other concomitant vomiting disorders (e.g. GERD) and a few have malrotation or hydronephrosis that, based on a poor outcome to surgical correction, are not the cause of the vomiting.
How to identify CVS? How to identify CVS?
Recurrent episodes (≥ 3)? 100%
Normal in between? 94%
Episodes similar to others? 99%
Absence of etiologic findings? 97%
Ill appearing (pallor & lethargy)? ≥91%
FH of migraine headache? 82%
Intense vomiting (≥ 4 emeses/hr)? 77%
Recurrent episodes (≥ 3)? 100%
Normal in between? 94%
Episodes similar to others? 99%
Absence of etiologic findings? 97%
Ill appearing (pallor & lethargy)? ≥91%
FH of migraine headache? 82%
Intense vomiting (≥ 4 emeses/hr)? 77%Adv Pediatr 47:117, 2000Adv Pediatr 47:117, 2000
1414
Dx profile in cyclic pattern (n=225)Dx profile in cyclic pattern (n=225)
non-GI (5%)non-GI (5%)
GI (7%)GI (7%)
CVS (88%)CVS (88%)
Pediatrics 102:583, 1998Pediatrics 102:583, 1998
Non-CVS (12%)Non-CVS (12%)
Of those children who present with a cyclic pattern of vomiting, 7/8 will turn out to have a final diagnosis of cyclic vomiting syndrome based on the absence of etiologic findings on diagnostic testing.However 7% will have a GI disorder and 5% will have a non-GI disorder, many of which will be surgical – malrotation, duplication cyst, hydronephrosis, brainstem glioma, cerebellarmedulloblastoma and Chiari malformation.
1515
GI and renal surgical lesions GI and renal surgical lesions
Hydronephrosis X10Hydronephrosis X10
Malrotation X7Malrotation X7
1616
Neurosurgical lesions Neurosurgical lesions
Chiari type I X5Chiari type I X5
Brainstem glioma X2Medulloblastoma X1Brainstem glioma X2Medulloblastoma X1
1717
This is a list of diagnostic testing that we undertake divided into 1st line (yellow) and 2nd line (white) tests. The UGI to r/o small bowel malrotation/intermittent volvulus and ultrasound to exclude hydronephrosis are performed in most. An EGD and head MRI are reserved for those with a peptic history, failure to respond to therapy and/or persistent headaches. Because these disorders are episodic, testing for metabolic and endocrine disorders must be obtained during the episode before IV glucose has been administered: blood glucose for hypoglycemia, NH3 for urea cycle defects, lactate for mitochondriopathies, carnitine for disorders of FAOx, amino acids for aminoacidurias, and urine organic acids for organic acidurias, carnitine for elevated E:F ratio for disorders of FAOx, and d-ALA/porphobilinogen for acute intermittent porphyria.If Munchausen-by-proxy is suspected, toxicology studies (for Ipecac) can be useful for up to 2 months post administration.
Dx evaluation - 1st line, 2nd lineDx evaluation - 1st line, 2nd line
X-ray: UGI/SBFT, abdominal U/S, sinus films, head MRI
Endoscopic: EGD + biopsies
Metabolic: During the episode!• Blood: electrolytes, glucose, NH3, lactate,
amino acids + SGPT, GGTP, amylase, lipase
• Urine: UA, organic acids, δ-ALA & porphobilinogen
Miscellaneous: EEG, HCG, toxicology
X-ray: UGI/SBFT, abdominal U/S, sinus films, head MRI
Endoscopic: EGD + biopsies
Metabolic: During the episode!• Blood: electrolytes, glucose, NH3, lactate,
amino acids + SGPT, GGTP, amylase, lipase
• Urine: UA, organic acids, δ-ALA & porphobilinogen
Miscellaneous: EEG, HCG, toxicology
1818
PearlsPearls
Can have a surgical lesion as the cause of the cyclic vomiting pattern, or unrelated to the vomiting, i.e. T ⇒ T, unrelated
Can have CVS with GI symptoms in between, i.e. caused by a 2nd disorder
Hydronephrosis best mimics CVS
Biliary tree dysmotility & SOOD – new
Can have a surgical lesion as the cause of the cyclic vomiting pattern, or unrelated to the vomiting, i.e. T ⇒ T, unrelated
Can have CVS with GI symptoms in between, i.e. caused by a 2nd disorder
Hydronephrosis best mimics CVS
Biliary tree dysmotility & SOOD – new
We have found 5 children who have had sphincter of Oddidysfunction with severe episodic RUQ pain that persisted after laparoscopic cholecystectomy for either documented stones or dyskinesia. Elevated SOO pressures on ERCP were demonstrated and a sphincterotomy led a positive clinical response.
1919
Cost-decision analysisCost-decision analysis
Olson & Li, J Peds 141:724, 2002Olson & Li, J Peds 141:724, 2002
Initial evaluation & treatmentInitial evaluation & treatment
Extensive testing before treatment
Extensive testing before treatment
Empiric anti-migraine Rx before extensive testing
Empiric anti-migraine Rx before extensive testing
UGI/SBFT + empiric anti-migraine Rx before extensive testing
UGI/SBFT + empiric anti-migraine Rx before extensive testing
$3,017$3,017 $1,825$1,825 $1,602$1,60265% fewer EGDs65% fewer EGDs
Alan Olson and I compared the costs of 3 initial diagnostic and treatment approaches to a child who presents with a cyclic vomiting pattern. First was the typical approach used in the US in which extensive diagnostic testing was performed to r/o specific organic disorders before therapy initiated.Second was the typical approach used in the UK in which empiric therapy was initiated before extensive testing. The cost of a missed malrotation with small bowel necrosis (know of two such cases) with lifelong TPN was factored in. Third was an UGI to exclude malrotation followed by empiric anti-migraine therapy. Based on the high rate of positive response to therapy, this approach eliminated 2/3rds of the EGDs. The 3rd was the most cost-effective initial approach based on the high cost of a missed malrotation with volvulus, and, on the other hand, the low yield of testing.
2020
In the final 9 slides, we will cover therapeutic approaches acknowledging that all of those listed have not been validated in controlled trials. The treatment approach is divided into five categories.Supportive care includes fluids, analgesia, and sedation, but the most important may be IV glucose. Anecdotal experience suggests that a D10 bolus w/o fluids has the same attenuating effect as a fluid infusion. This suggests that terminating ketosis can be helpful. Prophylactic therapy is indicated for more frequent episodes > 1/mo or severe multi-day ones. Abortive therapy, i.e. therapy given only at the onset of the episode, is targeted for less frequent and severe episodes such at < 1/month and < 24 hours long.In some cases, identification and avoidance of triggers, e.g. dietary cheese, can present episodes.Parent support is critical when the child and parents have gone 2.5 yrs with unexplained, disruptive vomiting episodes in the face of repeated misdiagnosis and disbelieving doctors.
‘Kitchen sink’ approach‘Kitchen sink’ approach
Supportive measures• dark quiet room, IV fluids – D10 0.2NS,
sedation, analgesia
Prophylaxis - ≥ 1 episode/mo or severe
Abortive therapy - < 1 episode/mo or mild
Identify and avoid triggers
Parent support - CVS Association
Supportive measures• dark quiet room, IV fluids – D10 0.2NS,
sedation, analgesia
Prophylaxis - ≥ 1 episode/mo or severe
Abortive therapy - < 1 episode/mo or mild
Identify and avoid triggers
Parent support - CVS AssociationCurr Treat Opt GI 3:395, 2000Curr Treat Opt GI 3:395, 2000
2121
Current preventative RxCurrent preventative Rx
Anti-migraine agents• β-blockers, cyproheptadine (liq DC), tricyclics,
Ca++-channel blockers, pizotyline (in U.K.)
Antiepileptic agents• phenobarbital, valproate (Depakote ER®),
gabapentin (Neurontin®), topiramirate(Topamax®)
Prokinetic agents• erythromycin (motilin analog)
Anti-migraine agents• β-blockers, cyproheptadine (liq DC), tricyclics,
Ca++-channel blockers, pizotyline (in U.K.)
Antiepileptic agents• phenobarbital, valproate (Depakote ER®),
gabapentin (Neurontin®), topiramirate(Topamax®)
Prokinetic agents• erythromycin (motilin analog)
Pizotyline available only in the UK and Australia, is similar to cyproheptadine, but has fewer side effects.
2222
Responses to prophylactic Rx (n)Responses to prophylactic Rx (n)
(100)
(228)
(67)
(95)
(110)
(210)
0 20 40 60 80 100
prokinetic
H2/PPI
amitriptyline
cyproheptadine
propranolol
anti-migraine
(100)
(228)
(67)
(95)
(110)
(210)
0 20 40 60 80 100
prokinetic
H2/PPI
amitriptyline
cyproheptadine
propranolol
anti-migraine
% > 50% response % % > 50% response > 50% response
This represents our prophylactic therapeutic experience with the %’tage of positive responders for each medication. A positive response is defined as having a > 50% reduction in episode frequency or severity.No therapy works in more than a slight majority and amitriptylineis the most efficacious. As expected, H2RAs have a placebo-type effect. Cyproheptadine frequently induced unacceptable weight gain and had to be stopped.
2323
Current preventative Rx – doses Current preventative Rx – doses
Anti-migraine agents• propranolol √ pulse, titrate 1 mg/kg/d div. t.i.d.• cyproheptadine 0.25-.5 mg/kg/d div. b.i.d-t.i.d.• amitriptyline √ QTc, titrate 0.5-1 mg/kg q.hs
Antiepileptic agents• phenobarbital 2-3 mg/kg q.hs• valproate 500-1000 mg ER q.hs (10-50 mg/kg/d)• gabapentin titrate 15-30 mg/kg/d divided t.i.d.
Prokinetic agents• erythromycin 5 mg/kd/dose t.i.d.-q.i.d.
Anti-migraine agents• propranolol √ pulse, titrate 1 mg/kg/d div. t.i.d.• cyproheptadine 0.25-.5 mg/kg/d div. b.i.d-t.i.d.• amitriptyline √ QTc, titrate 0.5-1 mg/kg q.hs
Antiepileptic agents• phenobarbital 2-3 mg/kg q.hs• valproate 500-1000 mg ER q.hs (10-50 mg/kg/d)• gabapentin titrate 15-30 mg/kg/d divided t.i.d.
Prokinetic agents• erythromycin 5 mg/kd/dose t.i.d.-q.i.d.
Often the choice of initial prophylactic medication is intended to avoid specific side effects: propranolol contraindicated in asthma, cyprohepatidine (weight gain) avoided in girls, and amitriptylinecontraindicated in QT prolongation.We check the QTc interval before we start amitriptyline at 0.5 mg/kg q.hs and then again after we reach the target dose of 1.0-1.5 mg/kg q.hs.
2424
Current abortive therapy – doses Current abortive therapy – doses
Anti-migraine – triptans (5HT1B/1D agonist)• sumatriptan (Imitrex®) 5-20 NS, if < 24 h attacks• Zomatriptan (Zomig®) 2.5 mg PO, if > 24 h
Antiemetics ± sedatives• ondansetron 0.3-0.4 mg/kg/dose IV q. 4-6 ±
lorazepam 0.05-0.1 mg/kg/dose IV q. 6
• chlorpromazine 0.5-1.0/kg/dose IV q. 6 +diphenhydramine 1 mg/kg/dose IV q. 6
• ondansetron ± diazepam 0.2-0.5 mg/dose PR
Anti-migraine – triptans (5HT1B/1D agonist)• sumatriptan (Imitrex®) 5-20 NS, if < 24 h attacks• Zomatriptan (Zomig®) 2.5 mg PO, if > 24 h
Antiemetics ± sedatives• ondansetron 0.3-0.4 mg/kg/dose IV q. 4-6 ±
lorazepam 0.05-0.1 mg/kg/dose IV q. 6
• chlorpromazine 0.5-1.0/kg/dose IV q. 6 +diphenhydramine 1 mg/kg/dose IV q. 6
• ondansetron ± diazepam 0.2-0.5 mg/dose PR
Triptans can stop an episode within 2 hours in some cases if administered early on in the attack. In data not shown, triptansappear to work better on episodes that are < 24 hours in duration. Sumatriptan is the only one that can be administered non-orally –by nasal or subcutaneous route.If triptans fail, we use a combination of antiemetic and sedative therapy to simultaneously attenuate the nausea and vomiting and put them to sleep. Ondansetron and lorazepam generally ameliorate but do not abort the episode.
2525
Responses to abortive Rx (n)Responses to abortive Rx (n)
(167)
(20)
(202)
(97)
(158)
0 20 40 60 80 100
phenothiazine
Midrin
IV D5
sumatriptan
ondansetron
(167)
(20)
(202)
(97)
(158)
0 20 40 60 80 100
phenothiazine
Midrin
IV D5
sumatriptan
ondansetron
% > 50% response % % > 50% response > 50% response
XX
This represents our abortive therapeutic experience with the %’tage of positive responders indicated for each medication. Again, no therapy works in more than a slight majority with ondansetron being the most efficacious. Interestingly D5 has a 40% effect. The fact that phenothiazine antiemetics (Compazine and Phenergan) have less than a placebo response argues that CVS pathways involve 5HT3 more than D2 receptors.
2626
% Response to anti-migraine Rx % Response to anti-migraine Rx
0
20
40
60
80
100
0
20
40
60
80
100
%%
CVS+FHMig iCVS GI non-GICVS+FHMig iCVS GI non-GI
J Pediatr 134:567, 1999J Pediatr 134:567, 1999
This %’tage of positive responders to some form of anti-migraine therapy is compared between four groups:
1) migraine-associated CVS i.e. patients with a FH of migraines [red]
2) idiopathic CVS i.e. without a FH of migraines [blue]3) patients who ultimately had a GI diagnosis (e.g. GERD not
CVS) [dark grey]4) patients who had a non-GI diagnosis (e.g. hydronephrosis not
CVS) [light grey]The FH of migraine predicted a significantly (2 ½ times) higher
response rate to anti-migraine therapy. The low response rate in those without a FH migraine was similar to the placebo-like response rate in those that had either GI and extraintestinaldisorders. These strikingly different response rates suggest that there may be two subtypes – migraine-associated and non-migraine CVS.
2727
Pushing the envelope (future)Pushing the envelope (future)
Anti-migraine agents• new triptans (5HT1B/1D agonists)• 5HT1F-agonists• adenosine-A1-receptor agonist• calcitonin-gene related peptide-blocker• nitrous oxide synthase inhibitor
Antiemetics• NK1 receptor antagonists (Emend® =
aprepitant – tachykinin rec. ant.)• CRF-R1&2 antagonists (corticotropin rel. fact.)
Anti-migraine agents• new triptans (5HT1B/1D agonists)• 5HT1F-agonists• adenosine-A1-receptor agonist• calcitonin-gene related peptide-blocker• nitrous oxide synthase inhibitor
Antiemetics• NK1 receptor antagonists (Emend® =
aprepitant – tachykinin rec. ant.)• CRF-R1&2 antagonists (corticotropin rel. fact.)
There are a number of new anti-migraine medications that are in the pipeline. Whether they will have efficacy in the treatment of CVS is unknown.
Two new agents with antiemetic potential include: 1) tachykinin receptor (NK1) antagonists which have more
efficacy of the late phase of chemotherapy-induced emesis2) corticotropin-releasing factor (CRF) antagonists in phase I and
II trials that could attenuate CRF effects on gastric motility (and emesis)
2828
PearlsPearls
Supportive:dark, quiet room, regular vital signs cellular energy – 10% dextrose importantantiemetics – ondansetron 0.3-0.4 mg/kgsedatives – lorazepam (GABA inhibitor)pain – toradol 0.5-1 mg/kg ≤ 30 mg q. 6 h
Prophylaxis: 1) FH migraine, 2) > 1 epis/mo ⇒propranolol (infant) & cyproheptadine (infant, toddler)amitriptyline (school-aged)
Abortive: triptans abort short episodes
Supportive:dark, quiet room, regular vital signs cellular energy – 10% dextrose importantantiemetics – ondansetron 0.3-0.4 mg/kgsedatives – lorazepam (GABA inhibitor)pain – toradol 0.5-1 mg/kg ≤ 30 mg q. 6 h
Prophylaxis: 1) FH migraine, 2) > 1 epis/mo ⇒propranolol (infant) & cyproheptadine (infant, toddler)amitriptyline (school-aged)
Abortive: triptans abort short episodes
Our metabolic experts recommend 10% rather than 5% dextrose during episodes.We recommend high dose ondansetron 0.3-0.4 mg/kg q. 4-6 hours that appears to be more effective than the standard doses of 0.15 mg/kg.We use toradol rather than morphine or fentanyl for pain.
2929
NASPGHAN – CVS Rx guidelinesNASPGHAN – CVS Rx guidelines
B Li, Chair Northwestern
Colin Rudolph, Medical College of Wisconsin
Bob IssenmanMcMaster
Suzanne Nelson Northwestern
Gisela ChelminskyCase Western Reserve
B Li, Chair Northwestern
Colin Rudolph, Medical College of Wisconsin
Bob IssenmanMcMaster
Suzanne Nelson Northwestern
Gisela ChelminskyCase Western Reserve
Rick Boles, Biochemical Genetics, S. California
Don Lewis, Neurology Norfolk, VA
Steve Linder, Neuro, Texas Southwestern
Frank Lefevre, Internist Evidence-based program Northwestern
Rick Boles, Biochemical Genetics, S. California
Don Lewis, Neurology Norfolk, VA
Steve Linder, Neuro, Texas Southwestern
Frank Lefevre, Internist Evidence-based program Northwestern
3030
SummarySummary
CVS has a distinctive (stereotypical) temporal pattern often unrecognized or misdiagnosed - worse than rotavirus
After organic disease excluded, initiate empiric antimigraine and antiemetic therapy - new agents coming
CVS is a brain-gut disorder involving: migraine, mitochondrial DNA and CRF
CVS has a distinctive (stereotypical) temporal pattern often unrecognized or misdiagnosed - worse than rotavirus
After organic disease excluded, initiate empiric antimigraine and antiemetic therapy - new agents coming
CVS is a brain-gut disorder involving: migraine, mitochondrial DNA and CRF