CVS Guidelines 407 - NASPGHAN

1

2 3 4

5

6

7

The North American Society for Pediatric Gastroenterology, Hepatology and 8

Nutrition 9

Guideline for the Diagnosis and Management of Cyclic Vomiting Syndrome 10

11 12 13 14

Task Force: 15 16

B U.K. Li, Frank Lefevre, Gisela G. Chelimsky, Richard G. Boles, Suzanne P. Nelson, Donald 17 W. Lewis, Steve L.Linder, Robert M. Issenman, Colin 18

D. Rudolph 19 20

Coordinator: 21 22

Kathleen A. Adams B.S.N., R.N., President, Cyclic Vomiting Syndrome Association 23 24

NASPGHAN CVS Guidelines - 2

INTRODUCTION AND BACKGROUND 24

25

Cyclic vomiting syndrome (CVS) is a disorder characterized by recurrent, discrete, self-26

limited episodes of vomiting (1-3). Affected children usually experience a stereotypical pattern 27

of vomiting typified by a consistent time of onset, duration, and symptoms. The vomiting is 28

intense (six times/hour at the peak) often bilious (83% in some series), and accompanied by 29

disabling nausea (4). The resulting dehydration often necessitates a high rate of IV 30

replenishment. Associated symptoms of pallor, listlessness, anorexia, nausea, retching, 31

abdominal pain, headache and photophobia may make it difficult to distinguish episodes of CVS 32

from other causes of acute abdomen and altered consciousness. Episodes are often triggered by 33

psychological (e.g. birthdays, holidays) and physical stress (infections, lack of sleep, menstrual 34

periods). CVS commonly starts in early childhood and the vomiting symptoms may abate with 35

the onset of classical migraine headaches during adolescence. Less commonly the condition 36

persists into adulthood or starts in adulthood (5-7). 37

38

The etiology and pathogenesis remain unknown but there appears to be a strong link 39

between CVS and migraine, based upon similarities in symptoms, common coexistence of both 40

conditions in the same individual, a high family prevalence of migraine in CVS patients, and the 41

effectiveness of anti-migraine therapy (8-13). Postulated mechanisms include episodic 42

dysautonomia, mitochondrial DNA mutations that cause deficits in cellular energy production 43

and/or heightened hypothalamic stress response that activates the emetic response (13-15). CVS 44

presents with vomiting and a variety of associated symptoms that could represent either differing 45

levels of severity or even distinct pathophysiologic mechanisms. These presentations include 46

subgroups such as migraine-associated, menses-associated and Sato subtype (16, 17) with 47

episode-associated hypertension and elevated adrenocorticotropin hormone. 48

49

The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition 50

(NASPGHAN) appointed a task force to develop consensus management guidelines for CVS in 51

2003 to improve the recognition and treatment of a disorder that lacks any standard medical 52

approaches. An absence of controlled trials in this disorder necessitated that these 53

recommendations be based primarily upon small clinical trials and expert opinion. Despite these 54


limitations, the committee attempted to provide useful guidelines for patient management based 55

upon the currently available literature and clinical experience. These guidelines are intended for 56

use by pediatricians, family physicians, pediatric gastroenterologists, pediatric neurologists and 57

emergency department physicians. While there appear to be an increasing number of adults 58

diagnosed with this disorder, it was beyond the purview of this task force to develop 59

management guidelines for adult patients. 60

61

62

METHODS & LITERATURE SEARCH 63

64

The NASPGHAN convened an expert panel in order to review the evidence and propose 65

guidelines for the evaluation and treatment of CVS. The panel consisted of nine experts drawn 66

from the fields of pediatric gastroenterology, pediatric neurology, genetics, and epidemiology. 67

Guidelines were developed by consensus of the CVS panel, using a modified Delphi technique 68

for algorithm development. 69

70

A systematic review of the literature was performed to identify all published articles that 71

contained primary data on the epidemiology, clinical features, natural history, and/or treatment 72

of CVS. Particular attention was directed toward articles that addressed the efficacy of treatment 73

modalities for CVS as part of the guideline development process. 74

75

Specific questions 76

77

The panel addressed four primary questions. 78

1) How is CVS defined? 79

The panel considered the most appropriate clinical and laboratory data to be used in 80

diagnosing CVS. Recognizing the lack of definitive laboratory markers, the heterogeneous 81

nature of the disorder, and the variability of diagnostic criteria currently in the literature, the 82

panel developed an operational definition of CVS by nominal group technique. 83

84


2) What is the appropriate laboratory, radiographic and endoscopic evaluation in children with 85

a pattern of cyclic vomiting? 86

After discussion that addressed the known differences amongst international pediatric 87

gastroenterologists as to the extent of laboratory evaluation that is performed in patients with 88

suspected CVS, the panel focused on: 1) the initial screening evaluation in an undifferentiated 89

patient with episodic pattern of vomiting meeting the cyclic vomiting criteria; 2) the sensitivity 90

of the various tests for serious surgical and metabolic disorders; and 3) alarm symptoms that 91

should instigate a more thorough laboratory evaluation. The panel considered but did not focus 92

on the issues of subdividing patients by age, sex, race, ethnicity and clinical subgroups (e.g. 93

neurologically impaired). 94

95

3) In patients with CVS, does prophylactic treatment improve long-term outcomes, as compared 96

to no treatment or alternative treatment options? 97

The panel evaluated the efficacy of prophylactic treatment including lifestyle changes 98

such as avoidance of triggers, reassurance, education and family support, and anti-migraine and 99

anti-convulsant medications. The outcomes of prophylactic treatment included frequency of 100

subsequent episodes, duration and severity of episodes including number of emeses, nausea and 101

other constitutional symptoms. The panel did divide treatment groups by age above and below 102

five years, but did not focus on other subgroups. 103

104

4) During an acute attack of CVS, does treatment improve outcomes, as compared to no 105

treatment or alternate treatment options ? 106

The task force evaluated the efficacy of abortive and supportive treatment including 107

intravenous fluid(s) containing dextrose, as well medication including anti-emetics, anti-108

migraine triptans (serotonin agonists), sedatives and nonsteroidal anti-inflammatory drugs 109

(NSAID). The outcomes of the acute attack included length of episode, number of emeses, 110

severity of nausea and other constitutional symptoms. The panel did consider but did not focus 111

on issues of treatment of various subgroups and criteria for successful treatment. 112

113


Literature search strategy 114

115

MEDLINE was searched via PubMed using the following terms: ("cyclic vomiting" OR 116

"cyclic vomiting syndrome" OR “cyclical vomiting” OR "CVS" OR "abdominal migraine" OR 117

“periodic syndrome” OR “biliary attacks” OR “recurrent vomiting”) AND (pediatrics OR 118

children OR infants) NOT Review [Publication Type] during the years 1980-present. The 119

electronic search was supplemented with the ‘related articles’ function in PubMed; with hand-120

search of recent bibliographies; and by consultation with experts. Using this strategy, 236 121

citations were identified. The abstracts of all citations were reviewed, and potentially relevant 122

articles were identified that: 1) included patients with CVS, and 2) reported primary data, other 123

than in case report(s) format. Using these criteria, a total of 67 full-length articles were retrieved 124

for full review. 125

126

Studies were selected for final inclusion in the evidence base, if they met the following 127

criteria: 1) full-length article published in the peer-reviewed literature between the years of 128

1980-2003; 2) included patients with CVS, using parameters of: a) periodicity of attacks, 129

including healthy intervals between attacks, b) characteristic pattern of symptoms during attack, 130

and c) lack of other explanation(s) for nausea/vomiting; and 3) evaluated one or more of the 131

specified treatments for either abortive therapy or prophylactic therapy and reports on one or 132

more relevant outcomes. Following application of these selection criteria, a total of 12 articles 133

met the criteria for inclusion in review of evidence. 134

135

The study qualities were assessed as follows. Levels of evidence (ranging from I – 136

randomized control trial to III – expert opinion) were assigned according to the system originally 137

developed by the Canadian Task Force on the Periodic Health Examination (18) and refined by 138

the United States Preventative Services Task Force (19). For single-arm studies, four quality 139

indicators (relevant, representative patient population; uniform, unbiased treatment delivery; 140

most important outcomes measures represented; appropriate statistical analysis) were used to 141

assign an overall quality of GOOD (meets all criteria), FAIR (does not meet all criteria but no 142

fatal flaws), or POOR (study has ‘fatal flaws’ for one or more indicators). From these levels, 143


grades of recommendations were derived (A – level I evidence to D – expert opinion only). In 144

all studies, the grades of recommendation were D. 145

146

THE CONSENSUS DIAGNOSTIC CRITERIA 147

148

Recognizing the lack of definitive criteria, the heterogeneous nature of the disorder, and 149

the variability of diagnostic criteria in the literature, the panel developed an operational 150

definition of CVS. Using a combination of expert opinion, definitions used in the literature, and 151

the clinical and research experience of the panel, nominal group technique was used to achieve 152

the consensus diagnostic criteria shown in Table 1. The committee considered adoption of the 153

Rome III criteria for CVS (two periods of intense nausea and vomiting and return to normal 154

health). However, the lack of specificity raised concerns about the utility of that definition in 155

these guidelines (20-22). 156

157

158

DIAGNOSTIC APPROACH TO RECURRENT, EPISODIC VOMITING 159

160

A pattern of recurrent, episodic vomiting in children that fulfills the revised historical 161

criteria listed in Table 1 is likely (about 90%) to be ultimately diagnosed as idiopathic cyclic 162

vomiting syndrome (23). The challenge to the practitioner is to differentiate those with specific 163

and serious underlying causes of vomiting ( about 10 %) for which prompt treatment may alter 164

outcomes (24). Testing to exclude all possible diagnoses would subject many children to 165

unnecessary and costly radiographic and endoscopic procedures (25). Therefore, the diagnostic 166

guidelines below are intended to help identify those children with a cyclic vomiting pattern 167

between the ages of 2 and 18 years at greatest risk of having an organic cause. Although 168

children less than two years may have CVS , serious underlying metabolic and surgical disorders 169

are more frequent and more difficult to diagnose in this age range. 170

171

There are no specific laboratory markers to diagnose CVS. The diagnostic criteria were 172

modified by nominal group technique from previously published consensus criteria (22) and 173

those established by the Headache Classification Subcommittee of the International Headache 174


Society (26) (Table 1). The diagnosis of CVS is thus based upon the fulfillment of these criteria 175

in the absence of another explanation for the symptoms. Clinicians experienced in evaluating 176

CVS may treat without performing an extensive evaluation, but expert opinion supported 177

performing screening tests in all children with a cyclic vomiting pattern just prior to 178

administration of intravenous fluids to include electrolytes (Na+, K+, Cl-, HCO3-), glucose, and 179

upper gastrointestinal radiographs to exclude malrotation (27-29). An abdominal ultrasound to 180

rule out transient hydronephrosis, preferentially during a crisis, could also be considered in 181

refractory cases (30, 31). If a patient has hyponatremia or hypoglycemia further evaluation 182

should be performed to exclude Addison disease (32, 33) and disorders of fatty acid oxidation 183

(34). A thorough history and physical examination at presentation helps identify those children in 184

whom further diagnostic testing is prudent. Suspicious “alarm” symptoms and physical findings 185

include: 186

1. Bilious vomiting, abdominal tenderness and/or severe abdominal pain 187

2. Attacks precipitated by intercurrent illness, fasting and/or high protein meal 188

3. Abnormalities on neurologic exam including severe alteration of mental status, abnormal 189

eye movements, papilledema, motor asymmetry and/or gait abnormality (ataxia). 190

4. Progressively worsening episodes or conversion to a continuous or chronic pattern 191

192

Depending upon the presenting symptoms and signs other than vomiting, different diagnostic 193

approaches are recommended as illustrated in Figure 1. 194

195

Evaluation of children with cyclic vomiting pattern and alarm symptoms or signs: 196

197

Bilious emeses, severe abdominal pain and/or hematemesis: Although children with CVS 198

frequently have bilious emesis (83%) and/or severe abdominal pain (80%) (4), serious surgical 199

and non-surgical disorders can present similarly. These disorders include intermittent bowel 200

obstruction from malrotation with volvulus (27, 28, 35) and post-operative adhesions/strictures, 201

gallbladder disease (36), choledochal cyst (37), hepatitis, pancreatitis, or uretero-pelvic junction 202

obstruction (31). When bile-stained vomitus or severe discomfort (e.g. writhing) are present, the 203

panel further recommends, in addition to an upper GI radiograph, obtaining amylase (38) and 204

lipase (39) to detect pancreatitis, ALT and GGT to screen for hepatitis and gallbladder disease, 205


and an abdominal ultrasound and/or abdominal CT scan to evaluate the biliary (40) and urinary 206

tracts (41). Abnormal results would warrant further testing. If test results do not suggest an 207

alternate diagnosis, empirical treatment of CVS is recommended. 208

209

Recurrent episodes vomiting accompanied frequently by small amounts of hematemesis 210

raises the question about the role of esophagogastroduodenoscopy in the evaluation of these 211

children. Because the endoscopic biopsies usually do not reveal an etiologic cause of the 212

vomiting and typically demonstrate mild esophagitis or prolapse gastropathy as a cause of the 213

acute bleeding, the panel did not recommend a routine endoscopy unless there are chronic 214

symptoms in between episodes suggestive of a specific disorder (peptic/bacterial, allergic, 215

inflammatory or celiac), or, large amounts of hematemesis warrant endoscopic intervention (24) 216

217

Acute intermittent porphyria occurs infrequently and generally does not present before 218

puberty (42). It can present with recurrent vomiting and abdominal pain, mimicking CVS, but 219

usually has one or more of anxiety, depression, hallucination, seizures, cranial nerve weakness 220

and paresis of the extremeties. The diagnosis can be confirmed by finding an increased urinary 221

δ-aminolevulinic acid and porphobilinogen in a spot urine during the episode (43). 222

223

Attacks precipitated by intercurrent illness, fasting and/or a high protein meal. 224

225

Vomiting induced by metabolic disorders, including disorders of fatty acid oxidation 226

(FAO), the urea cycle, organic and amino acid metabolism, and mitochondrial energy 227

metabolism often follow a catabolic state induced by acute illness, fasting or a high protein meal. 228

Fasting can result from the anorexia and vomiting that accompanies mild viral upper respiratory 229

or GI infections, dieting or pre-surgical preparation. Although severe enzymatic deficiencies 230

generally present immediately after birth, partial enzymatic defects tend to affect toddlers. 231

232

A symptomatic metabolic disorder constitutes a medical emergency with substantial 233

risks for morbidity and mortality if appropriate treatment is not instituted promptly. If a 234

metabolic disorder is suspected, immediately obtain blood and urine for testing (Figure 1), 235


deliver 10% dextrose-containing IV fluid at a rate of 1.5 times maintenance (simultaneously with 236

fluid boluses as necessary) and contact a metabolic specialist. 237

238

In partial urea cycle enzyme deficiencies, ammonia accumulation may present following 239

the ingestion of a high protein meal or with fasting. Although both sexes can be affected, most 240

are heterozygote girls with partial ornithine transcarbamylase (OTC) deficiency because the gene 241

is located on the X-chromosome. A urea cycle disorder is suggested by a plasma ammonia level 242

of ≥ 150 μm/L when symptomatic. Amino and organic acidemias often present in the first days 243

of life, but a subset with partial enzymatic deficiencies are silent until an illness-related fast 244

precipitates symptoms that can include episodes of vomiting. Altered mental status (see next 245

section), severe anion gap metabolic acidosis, substantial ketosis, and/or an unusual odor are 246

possible clues to the presence of the underlying condition. Developmental and growth delay are 247

present in many, but not all cases and can be subtle. Fatty acid oxidation disorders can present 248

with a cyclic vomiting pattern including medium-chain acyl-CoA dehydrogenase deficiency 249

(MCAD). 250

251

The diagnosis of these disorders is established with plasma amino acid and urine organic 252

acid analyses. The sensitivity of metabolic testing, both screening and sophisticated analyses, is 253

improved when performed early in an acute episode before dextrose containing IV fluid is given 254

(34). Analyses of plasma acylcarnitines and urine acylglycines are more sensitive than urine 255

organic acids in FAO disorders (44), and may be diagnostic even when asymptomatic (34). If 256

any of the screening tests are abnormal, the patient should be referred to a metabolic specialist 257

for further evaluation. 258

259

Biochemical, enzymatic and pedigree (maternal inheritance) data suggests that some 260

degree of mitochondrial dysfunction is present in many cases of CVS, and, although not the sole 261

cause, may contribute via insufficient cellular energy production (13, 45, 46). It is typical to find 262

mild-to-moderate degrees of an anion gap metabolic acidosis (calculated serum Na+ minus Cl- 263

minus HCO3- is often 15-20 mg/dl), lactic acidosis, urinary ketosis (early in an episode and thus 264

not a direct result of fasting) and/or hypoglycemia during vomiting episodes. These findings are 265

consistent with CVS and by themselves do not necessitate a comprehensive metabolic work-up. 266


However, when encountered, quantitative urine organic acids and plasma amino acid analyses 267

obtained early in an episode can confirm mild mitochondrial dysfunction (elevated urine ketones, 268

Krebs cycle intermediates and/or dicarboxylic acids), and exclude other metabolic disorders. If 269

obtained either while asymptomatic or after several hours of IV dextrose, urine organic acids are 270

typically normal. 271

272

In some cases, episodic vomiting may be one manifestation of frank mitochondrial 273

disease; vomiting episodes can then be associated with a severe anion gap metabolic acidosis (> 274

20 mg/dl), insulin-resistance, and/or multi-system failure (e.g. cardiomyopathy, seizures etc.). 275

276

Abnormalities on neurological exam 277

278

Progressive or focal neurological findings, as well as new-onset ataxia, abnormal eye 279

movements, papilledema, motor asymmetry, gait abnormality, developmental regression or 280

stagnation, or recent personality changes, are not typical of CVS and should alert the clinician to 281

evaluate for increased intracranial pressure or a metabolic disorder. Intracranial pressure can be 282

due to underlying posterior fossa or hypothalamic tumor, Chiari malformation, hydrocephalus, or 283

subdural hematoma. Although one-quarter of children with brain tumors initially present with 284

vomiting, the majority will have other symptoms such as headache (often occipital), seizures or 285

behavioral changes, and demonstrable neurological signs of papilledema, abnormal eye 286

movements, motor asymmetry, gait ataxia or abnormal deep tendon reflexes (47). In 287

medulloblastoma, the most common brain tumor in childhood, about three-quarters present with 288

chronic vomiting, rarely cyclical, usually along with other signs such as papilledema, abnormal 289

eye movements, or ataxia (48). 290

291

If the vomiting is associated with progressive focal or diffuse neurological symptoms or 292

signs, neuroimaging with MRI is warranted. MRI is superior to CT scanning for visualization of 293

the posterior fossa. Skull X-rays have no value in this clinical setting. 294

295

Rarely, certain forms of complex partial seizures (e.g. temporal lobe or benign occipital 296

epilepsy) may be associated with episodic vomiting. Some degree of transient alteration of 297


mental status, post-ictal confusion, and abnormal involuntary movements will likely be present. 298

If seizures are suspected, electroencephalography during awake, drowsy and sleep states is 299

indicated (49,50). 300

301

The most difficult sign to clarify is alteration of mental status. Children with CVS often 302

have altered consciousness during episodes that parents describe as a “conscious coma” in which 303

the child is lethargic, listless, withdrawn, disoriented and/or difficult to arouse. Since acute or 304

episodic neurological or metabolic diseases commonly produce distortions of mental status, it is 305

important to distinguish true encephalopathy from the listlessness typical of CVS. In CVS, the 306

child is usually oriented and able to respond appropriately to commands, but prefers not to 307

because of incapacitating nausea. In metabolic encephalopathy, the patient is frequently 308

disoriented, confused, excessively irritable, and/or difficult to arouse. With hyperammonemic 309

states, a rapidly shifting mental status and/or psychosis can also be observed. 310

311

Static non-focal neurological findings, including global developmental delay, generalized 312

seizures and/or hypotonia are found in some series upwards of 25% of CVS cases. When these 313

findings are present, the term “CVS+” has been applied (13, 45, 51), which predicts an earlier 314

age of onset for vomiting episodes, and a 3 to 8-fold increased prevalence for certain 315

dysautonomic-related (migraine, chronic fatigue, regional pain syndromes) and constitutional 316

(growth retardation and birth defects) disorders. Because these static non-focal neurological 317

findings are also present in many metabolic disorders associated with episodic vomiting, the 318

expert panel recommended that a screening metabolic evaluation be performed to include 319

quantitative plasma amino acids and quantitative urine organic acids obtained early in an episode 320

(Figure 1). 321

322

Suggested work-up in cases at higher risk for neurometabolic disease: The panel recommends 323

that children with cyclic vomiting be evaluated for a possible metabolic or neurologic disorder if 324

any of the following conditions are met (Figure 1): 325

Presentation under age 2 years (with cyclic vomiting or co-morbidities below) 326

Vomiting episodes associated with: intercurrent illnesses, prior fasting, increased protein intake 327

Any neurological finding: ataxia, dystonia, or another gait disturbance, mental retardation, 328


seizure disorder or acute encephalopathy (including true lethargy, severe irritability, confusion, 329

psychosis or rapidly changing/unstable mental status) 330

Laboratory metabolic findings: hypoglycemia, substantial anion gap metabolic acidosis, 331

respiratory alkalosis or hyperammonemia 332

A referral to a specialist in metabolic disorders and/or a neurologist is suggested in patients with 333

any of the above findings. 334

335

No finding suggestive of another disorder 336

In children with a cyclic pattern of vomiting and no alarm findings in the history and 337

physical examination, an initial trial of empiric therapy can be considered (Figure 1). If the 338

patient responds to therapy with at least a 50% reduction in episode frequency and/or severity of 339

vomiting during attacks, then further evaluation is not required. If the patient does not improve 340

with initial therapy over a two month period, further evaluation is recommended. 341

342

Although uncommon as a cause of episodic vomiting, Munchausen-by-proxy may mimic 343

CVS. The perpetrator may describe vomiting episodes in a dehydrated child that has had 344

feedings withheld or may give the victim ipecac to induce vomiting (52). However, patients 345

have been inappropriately diagnosed with Munchausen-by-proxy when in fact CVS was causing 346

recurrent vomiting. 347

348

349

TREATMENT OF CYCLIC VOMITING SYNDROME 350

351

OVERALL APPROACH 352

353

The clinical course of CVS can be divided simply into the episode phase and the well 354

phase, during which the child returns to their normal or baseline state of health (4). The episode 355

phase is further divided into the prodrome as the child becomes ill up to the point when vomiting 356

begins, the vomiting phase and the recovery phase during which the vomiting ceases and the 357

child returns to baseline health. Each phase has therapeutic implications (53). During the well 358

phase, the avoidance of identified triggers can lead to fewer episodes. Treatment with abortive 359


therapy as early as possible in the prodrome or vomiting phase may terminate the attack. If the 360

vomiting phase becomes full blown, supportive therapy at home or in hospital is focused on 361

providing relief from nausea, vomiting and abdominal pain. If abortive therapy fails consistently 362

or if episodes are frequent and/or severe, daily prophylactic therapy to prevent subsequent 363

episodes is recommended. 364

365

The management of CVS requires an individually tailored regimen that takes into 366

consideration the clinical course, the frequency and severity of attacks, and resultant disability 367

balanced with the potential side effects of treatment. The two key treatment arms are 368

prophylactic (or preventive) measures and medications administered between attacks, and acute 369

and supportive interventions given during attacks. Despite the absence of FDA approved 370

medications for use in children with CVS, the panel recommendations below include off-label 371

uses. In the larger context of pediatric medication use, over 70% of prescribed medications lack 372

pediatric approval (54). 373

374

Families should be strongly encouraged to contact the Cyclic Vomiting Syndrome 375

Association [cvsaonline.org] for information and ongoing support. 376

377

PROPHYLACTIC MEASURES 378

There is a paucity of controlled data on the prophylactic treatment of CVS – mostly case 379

series (level II evidence) (Table 2). The existing evidence consists of small, retrospective 380

clinical series that evaluate symptomatic responses to medications. The treatment 381

recommendations are based upon limited evidence (level II) and consensus opinion (level III, 382

Grade D) of an expert panel of clinicians with broad experience with CVS. 383

During the well phase, lifestyle changes such as avoidance of excessive excitement, 384

energy-depleted states (e.g. fasting, illness), sleep deprivation, triggering foods (e.g. chocolate, 385

cheese), menses, and motion sickness may reduce episode frequency. If episodes occur 386

frequently (e.g. more than every 1-2 months), are severe enough to cause repeated hospitalization 387

and school absences, and/or fail to respond to abortive therapy, preventative prophylactic 388

pharmacotherapy is recommended. 389

390


Because fear and anticipation of future episodes can trigger episodes of CVS , the use of 391

reassurance and anticipatory guidance may help reduce the frequency of attacks. This includes 392

confirming that the attacks are not self-induced and that the child will typically improve with 393

age, as well as providing an individualized management protocol. 394

395

Lifestyle changes 396

Although there are no published trials that evaluate the impact of life style alterations on 397

CVS attacks, the panel’s consensus experience is that life style changes reduce episode 398

frequency in children with CVS (Table 3). Fleisher reported that 70% of patients initially 399

respond to consultation alone without drug therapy by reduced episode frequency (55). This 400

response may result from alleviation of known precipitating factors and/or from reductions in 401

stress (commonly a trigger of episodes) due to a positive diagnosis, knowledge that effective 402

therapies are available, and interaction with a caring physician. Because of common parental 403

concerns about potential side effects of preventative medications, lifestyle changes may be 404

recommended first, and, may delay or occasionally circumvent the use of daily medications. A 405

time-limited trial to assess the impact of lifestyle changes for one or two months or through one 406

or two typical cycles may be instituted concurrent with the testing to exclude organic causes of 407

vomiting (see Diagnostic Approach). 408

409

- Avoidance of triggers 410

A careful history and/or detailed “vomiting diary” that records intervals between episodes, 411

time of onset and ending, contents of preceding meals, and aggravating life events can help identify 412

potentially avoidable triggers in three-quarters of children (4). It is important that families 413

recognize that episodes can be precipitated by common infections, exciting occasions such as 414

birthdays and holidays, and lack of sleep and/or overexertion. 415

Avoidance of migraine triggering foods (e.g. chocolate and cheese) or food allergens can 416

reduce episode frequency in CVS. In one small study, seven of eight children with documented 417

food sensitivities to cow, soy or egg white protein, improved following specific dietary elimination 418

(56). Although total elimination of potential allergenic foods is not recommended by the panel, 419

it may be prudent to introduce a trial elimination of particular foods or chemical substances that 420

are consistently aggravating factors. Marijuana has been used for treatment of chronic nausea 421


and vomiting of chemotherapy and also by adolescents to self-treat CVS. However in one series 422

of adult patients with CVS, marijuana use was found to worsen the cyclic hyperemesis and 423

cessation decreased episodes of vomiting (57). 424

425

- Supplemental carbohydrate 426

The use of supplemental carbohydrate can provide additional energy during times of high 427

energy demands. Published observations have noted that fasting induces some episodes and, 428

conversely, frequent feedings prevent others, even in the absence of documented hypoglycemia 429

(13). Furthermore, a rapid response to IV dextrose infusion can be seen during acute attacks (4). 430

When the history suggests fasting-induced attacks, high-carbohydrate snacks may be given 431

between meals, before physical exertion, and at bedtime. 432

433

- Migraine lifestyle interventions 434

Given that CVS is considered to be within the migraine spectrum as a “childhood 435

precursor to migraine”, it is appropriate to mention lifestyle changes commonly incorporated into 436

pediatric migraine management strategies. These include good sleep hygiene (e.g. regular sleep 437

schedules, avoiding sleepovers), regular aerobic exercise, regular meal schedules (i.e. avoid 438

skipping meals), maintenance of good hydration, and moderation (30 mg/day) or avoidance of 439

caffeine (58-60). 440

441

Prophylactic or preventive medications – general approach 442

Published clinical trials consist of uncontrolled or retrospective reports (i.e. level II 443

evidence) (Table 2). The literature does not permit the panel to provide evidence-based guidelines. 444

The recommendations which follow are based upon expert opinion (i.e. level II and III evidence, 445

grade D recommendations) (Table 4). 446

447


Before initiating daily prophylactic pharmacotherapy, clinicians must consider the age of 448

the child, medical and psychological co-morbidities, dosage format, and side effect profiles of 449

the medications. We recommend beginning a low initial dose, and then increasing it 450

incrementally, “titrating to effect”. The rationale is that the lower doses may be therapeutic in 451

some cases and may limit side effects that emerge at higher doses. 452

453

Medications 454

Cyproheptadine, propranolol (61, 62), amitriptyline (5, 11, 13, 63), phenobarbital (64) and 455

pizotifen (65, 66) were five medications in which high response rates were observed in at least 10 456

patients (Class II evidence). However, these studies were prone to bias because they did not 457

account for the non-specific treatment effects, e.g. placebo response and recall (i.e. retrospective 458

reporting) effects. The differing inclusion criteria and qualitative outcomes used in these studies 459

does not allow comparison of relative efficacies. 460

461

The antihistamine and serotonin receptor antagonist cyproheptadine has a moderate 462

response rate in young children and is the first choice of the expert panel in children less than five 463

years of age (Table 4) (11, 13, 63). Increased weight due to enhanced appetite may be an 464

unacceptable side effect in school-aged girls, although cyproheptadine may be the appropriate first 465

choice in an underweight patient. Because the pharmacokinetics do not allow once-a-day dosing, 466

tiredness after the morning dose can interfere with school performance. Pizotifen was shown to be 467

highly efficacious in a case series of six CVS subjects (67) and one randomized placebo-controlled 468

trial in 16 abdominal migraine patients (66). However, pizotifen is only available in Canada and 469

the U.K. but not in the U.S. 470

471

The tricyclic antidepressant amitriptyline has a moderate-to-high response rate and is the 472

preferred first choice in the older child more than five years of age (Table 4) (5, 11, 13, 63). 473

Clinical experience indicates a higher response rate if given at an adequate dosage (1.0 mg/kg/day, 474

occasionally 1.5-2.0 mg)) for at least four weeks. To minimize side effects, dosing is commonly 475

initiated at a single night-time dose of 0.25-0.5 mg/kg/day (likely subtherapeutic) and increased 476

incrementally by 5-10 mg. The risk of ventricular arrhythmia is reduced by monitoring the QTc 477

interval (to maintain ≤ 460 msec) before and after establishing targeted dose (68). If a tricyclic 478


medication is effective, but the child cannot tolerate tablets, amitriptyline can be solubilized by a 479

compounding pharmacist or at home. Although anecdotal experience has shown potential 480

efficacy in younger ages the panel has not recommended use in younger children because of 481

frequent side effects and a risk of overdose. 482

483

The β-blocker propranolol has moderate efficacy and is recommended as the second 484

choice in children of all ages (Table 4) (11, 13, 61, 62). The resting heart rate should be 485

monitored for potential bradycardia (< 60 beats/min) and, if propranolol is discontinued, it 486

should be tapered over 1-2 weeks. Alternatives, atenolol and nadalol, have fewer side effects, 487

but may be less effective because of inability to cross the blood-brain barrier. 488

489

The anti-convulsant, phenobarbital demonstrated efficacy in one study at a low single 490

nighttime dose of 2 mg/kg/day (64). Potential cognitive impairment limits the panel’s 491

enthusiasm for recommending this drug as first line therapy. In migraine there is an evolving 492

literature supporting the efficacy of other anticonvulsants (e.g. topiramate) but the side effects 493

and necessary titration of each of these medications require that an individual experienced in the 494

use of these agents in children (e.g. pediatric neurologist) should guide use of these agents in 495

patients with CVS (60, 69). 496

497

RECOMMENDATIONS ON PROPHYLAXIS 498

The panel recommends cyproheptadine or propranolol prophylaxis for children ≤ 5 years 499

of age. In the older child (> 5 years of age), amitriptyline or propranolol are recommended as 500

shown in Table 4. The dose can be titrated to effect by increasing it every 1-4 weeks to achieve 501

at least an average therapeutic dose for two CVS cycles (e.g. if monthly, then for two months). 502

If the medication causes intolerable side effects and/or proves to be ineffective, it is appropriate 503

to switch to another medication. The common side effects tend to be dose-related and may be 504

addressed by reducing the dosage. 505

506

In the panel’s experience, most CVS patients will respond to amitriptyline, cyproheptadine and/or 507

propranolol . If a patient does not respond, consider: 508

1) alternative diagnoses other than CVS and need of additional diagnostic testing; 509


2) whether an adequate trial was administered, e.g. a high-end dose given for at least a two-510

cycle trial period, or lack of adherence; 511

3) combination therapy of two medications (e.g especially amitriptyline with one of the 512

other main drugs); 513

4) adding an alternative therapy from the list below 514

515

Alternate approaches for prophylaxis 516

Carnitine (commonly prescribed dose of 50-100 mg/kg/d, adults = 1.0 g TID), a nutrient 517

that serves as a transport cofactor for long-chain fatty acids into mitochondria, may help cases with 518

suspected mitochondrial or metabolic dysfunction, and has a benign side effect profile (70). 519

Another mitochondrial co-factor, coenzyme Q (commonly prescribed dose of 5-10 mg/kg/d, adults 520

= 100 mg TID) is receiving interest, but there is no data regarding efficacy. Although there are no 521

published data, low estrogen oral contraceptives have been used to treat girls with catemenial 522

(menstrual-related) CVS (71). Anecdotal experience suggests that acupuncture at the P6 523

(pericardial) point may attenuate the severity of CVS attacks (72). Psychotherapy, especially 524

stress reduction, may help as adjunctive therapy (73). 525 526 527 ACUTE INTERVENTION – SUPPORTIVE CARE AND ABORTIVE THERAPY 528

529

There are no controlled or open trials of supportive measures (e.g. nonstimulating 530

environment), pharmacologic (e.g. anti-migraine, anti-emetic) agents, or complementary 531

approaches (e.g. acupuncture) in managing acute CVS (Table 5). Based on small case series 532

(level II evidence), anecdotal experience and expert opinion (level III), the panel recommends 533

supportive and symptomatic care during acute episodes (grade D recommendation) (Table 6). 534

535

Expert opinion supports the efficacy of early intervention within the first several hours of 536

the onset. Some experts advocate an approach similar to that employed for migraine headache in 537

which nonsteroidal analgesics (e.g. ibuprofen) are administered orally during the early prodrome 538

before the vomiting begins. Once the vomiting starts, evaluation in an emergency department or 539

direct admission to the hospital ward before dehydration ensues is appropriate in some patients 540

for protocolized treatment specifying intravenous fluids, medications and admission criteria. 541


Providing the patient with a letter that explains CVS and specifies an individualized management 542

protocol can facilitate prompt institution of therapy. A template of such a letter is provided at 543

(CVSA Website) and a sample protocol is shown in Table 7. 544

545

Some behaviors during episodes may appear to be odd but are in fact quite common in 546

CVS episodes. Many children become noncommunicative and curl into a fetal position because, 547

in their hypersensitive state, any further stimulation heightens their nausea and can trigger more 548

vomiting (74). At best, the child should not be unnecessarily disturbed. There are other children 549

who drink obsessively to induce vomiting. Reductions in these behavioral responses generally 550

are observed when patients receive adequate symptom relief with anti-emetics and sedation. 551

552

Most CVS patients will respond partially to one of the regimens discussed below. If a child 553

does not respond, or the episode differs substantially from previous ones by greater severity, longer 554

duration, or, new or different symptoms, reconsider the possibility of an underlying surgical lesion 555

and the need of new or repeated diagnostic testing, e.g. abdominal ultrasound or brain MRI. 556

557

Supportive care 558

Supportive care during acute episodes includes providing a less stimulating (dark, quiet) 559

environment, replacement of fluid, electrolyte and energy, use of anti-emetics with or without 560

sedation to lessen the nausea and vomiting, and provision of analgesia for pain (53). 561

562

Some experts recommend higher amounts of IV dextrose-containing fluids (D10 0.45 563

normal saline) (Table 6). If the child is evaluated in the later phases and substantial fluid and/or 564

electrolyte deficits are found, the panel recommends infusing 0.9% NaCl replacement fluid 565

through a “Y” connecter parallel to the D10. An increased anion gap (> 18-20 meq/L), may reflect 566

either severe dehydration or signal metabolic decompensation, and the need for hospital admission. 567

The ensuing catabolism following two to three days of minimal energy and/or protein intake can 568

prolong the illness, and can be reversed with parental nutrition to provide an adequate caloric 569

intake and 1.5 grams of protein/kg/day. 570

571


Episodic vomiting can occasionally result from metabolic decompensation in frank 572

mitochondrial disease and be associated with metabolic acidosis with an anion gap (i.e. lactic 573

acidosis), hyperglycemia (insulin resistance) and/or multi-system failure. In such seriously ill 574

patients, administering higher amounts of glucose (e.g. 8-12 mg glucose/kg/min) with or without 575

concomitant insulin, closely monitoring the acidosis, and obtaining a metabolic consultation are 576

critical to management. 577

578

Abortive (triptans) and supportive (5HT3 receptor antagonist anti-emetic, sedative & 579

analgesic) medications 580

There are no controlled and no open trials of pharmacologic (e.g. anti-migraine, anti-581

emetic) agents in greater than 10 patients. Panel recommendations are made below for their off-582

label use (Table 6). 583

584

Triptans, 5HT1B/1D agonists, are not approved for use in children under age 18 years. 585

However, the panel recommend a trial as abortive agents in children aged ≥ 12 years who have 586

infrequent and/or mild episodes (e.g. < 1/month). One open label report and expert experience 587

indicate that triptans can terminate an episode (75) if administered early. The transient burning 588

sensation in the neck and upper chest appears to be uncommon with nasal form. Zolmitriptan 589

also comes in a nasal form. 590

591

5HT3 receptor antagonists are supportive rather than abortive anti-emetic agents 592

available in oral (liquid, tablet or dissolving tablet), rectal (reconstituted by pharmacy) and 593

intravenous forms (13, 23, 61). Because they are well tolerated and more effective at higher 594

doses, expert experience recommends ondansetron doses of 0.3-0.4 mg/kg with a usual upper 595

limit of 20 mg/dose. Safe use of doses up to 32 mg have been reported in children (76). 596

Granisetron is also available in IV form but there is little experience in CVS. Widely used 597

phenothiazine (D2 antagonists) anti-emetics, promethazine and prochlorperazine, are ineffective 598

when compared to ondansetron (22% vs. 58%, p < .05) (4). 599

600

When anti-emetics fail to control unrelenting nausea and vomiting, expert opinion 601

recommends adding sedatives. Parallel to the experience in severe migraines, sleep may be the 602


only mode that provides symptomatic relief, and may occasionally shorten the episode. The 603

most effective combination therapy is ondansetron and lorazepam. Alternatively, 604

chlorpromazine and diphenhydramine can be used together but provides less anti-emetic and 605

more sedative effect (4, 53). 606

607

- Treatment of pain, hypertension and complications 608

Midline abdominal pain can be severe and treated empirically with analgesics. On 609

physical exam, even when the child is writhing in pain, the abdominal wall is typically soft to 610

palpation. To manage pain, the expert panel recommends the use of IV H2RAs e.g. ranitidine, 611

and the use of ketorolac, then morphine or fentanyl (77,78). If the pain has an epigastric location 612

and dyspeptic quality, IV administration of a H2 receptor antagonist or proton pump inhibitor 613

may be necessary to lessen the distress (53). The transient hypertension found in the Sato subset 614

of CVS should be treated, if needed, with short-acting ACE inhibitors during the episode only, 615

because it resolves promptly when the episode ends. 616

617

The main complications of an acute episode include dehydration (covered above), 618

electrolyte derangement including inappropriate secretion of anti-diuretic hormone (SIADH), 619

metabolic acidosis, hematemesis from prolapse gastropathy or Mallory-Weiss tear, chronic 620

esophagitis and weight loss (53). If SIADH with hyponatremia, low serum osmolality and high 621

urine specific gravity (despite adequate hydration) occurs, one restricts water intake until values 622

normalize. Because metabolic acidosis can have several potential causes including hypovolemia, 623

sepsis, lactic acidosis and ketosis from mitochondrial dysfunction, and hyperventilation 624

(respiratory alkalosis with renal compensation), obtaining serum electrolytes, urine pH and 625

ketones, and an arterial blood gas may clarify the situation. Hematemesis most commonly 626

results from prolapse gastropathy in which the vomiting bruises the stomach fundus by forcing it 627

retrograde through the GE junction and usually resolves without therapy (79). If the bleeding 628

persists and/or vital signs are affected, fluid replacement and endoscopic management may be 629

necessary. Moderate esophagitis may require ongoing acid suppression. Growth failure can 630

result from prolonged episodes without oral intake or other causes and may require dietary 631

counseling as well as nasogastric or parenteral nutrition between episodes to provide restorative 632

calories. 633


634

Alternative abortive approaches 635

For those who have panic anxiety-triggered episodes or anticipatory attacks (i.e. akin to 636

anticipatory vomiting pre-chemotherapy), the use of either anxiolytic medications or stress 637

relaxation techniques (e.g. deep breathing and relaxation imagery) has been reported anecdotally 638

to abort episodes (53, 80). 639

640

Recovery and refeeding 641

The recovery phase from the last emesis to the point of being able to retain foods 642

typically lasts a few hours. Once children state that they are hungry and want to eat food, they 643

can generally resume a normal diet without gradual progression. However, this should be 644

individualized because some children require stepwise reintroduction of foods to prevent the 645

recurrence of nausea. 646

647

RECOMMENDATIONS – SUPPORTIVE AND ABORTIVE INTERVENTION 648

During the acute episode of vomiting, the panel recommends supportive measures 649

including placing children in less stimulating environs, replenishing fluids, electrolytes and 650

energy , treating symptomatic nausea, vomiting and severe abdominal pain. Early intervention 651

within the first two to four hours of onset either at home or at a hospital may be more effective 652

than that later on. At all ages, use of IV D10 and high dose 5HT3 antagonist anti-emetics (e.g. 653

ondansetron 0.3-0.4 mg/kg/dose) off label rather than D2 anti-emetics (e.g. phenothiazine-type) 654

is recommended to treat the energy deficits and vomiting respectively. If ineffective, 655

concomitant sedation is recommended. Severe abdominal pains are treated with parenteral acid 656

suppression and/or NSAID or narcotics. As an abortive approach, intranasal triptans may be 657

used off label in children age 12 and over with infrequent (< 1/month) or milder episodes (≤ 24 658

hours). 659

660

Alternative abortive approaches 661

For those who have panic anxiety-triggered episodes or anticipatory attacks (i.e. akin to 662

anticipatory vomiting pre-chemotherapy), the use of either anxiolytic medications or stress 663


relaxation techniques (e.g. deep breathing and relaxation imagery) has been reported anecdotally 664

to abort episodes (53, 80).665

TABLE 1: Criteria for cyclic vomiting syndrome* • At least 5 attacks or a minimum of 3 attacks occurring over a 6-month period • Episodic attacks of intense nausea and vomiting lasting from 1 hour to 10 days and occurring

at least 1 week apart • Stereotypical pattern and symptoms in the individual patient • Vomiting during attacks occurs at least 4 times/hour for at least 1 hour° • A return to baseline health between episodes • Not attributed to another disorder * All criteria must be met to meet this consensus definition of CVS º This quantitative threshold was observed in a series of 35 CVS patients when compared to chronic vomiting patients (23). Some panel members recognized that atypical CVS may exist with less frequent vomiting. However, the panel opted for this definition to assure appropriate specificity.

Table 2 – Summary of evidence for efficacy of prophylactic treatment of CVS Treatment N

(studies) N (pts)

Level of evidence

Study Quality

Response rates 100%* 50-100% <50%

Comments

Propranolol (11, 13, 61, 62)

4 101 II-3 Fair (2/4) Poor (2/4)

75% (18/24)

65% (66/101)

35% (35/101)

Cyproheptadine (11, 13, 62, 63)

4 69 II-3 Fair (3/4) Poor (1/4)

40% (8/20)

61% (42/69)

39% (27/69)

Amitriptyline (5, 11, 13, 63)

4 64 II-3 Fair (3/4) Poor (1/4)

73% (16/22)

81% (52/64)

19% (12/64)

Pizotifen (66) 1 16 II-1 Poor ↓ 66% in number of days of abdominal pain RCT of poor quality P<0.01 for all comparisons

“ (81) 1 20 II-3 Poor 70% (14/20)

100% (20/20)

0% (0/20)

20% response rate in no-treatment comparison group

Erythromycin (82) 1 20 II-3 Poor 65% (13/20)

75% (15/20)

25% (5/20)

Other tricyclic

Antidepressants (5) 1 15 II-3 Fair NR 67%

(10/15) 33%

(5/15)

L-carnitine (70) 1 6 II-3 ↑ 87% in average time between episodes Pre- post- comparison, statistical testing not reported

*The % reduction in numbers of episodes following treatment.

TABLE 3. Therapeutic approaches to CVS PROPHYLACTIC MEASURES Lifestyle changes (for 1-2 months or 1-2 cycles)

Reassurance (e.g. episodes are not self-induced) and anticipatory guidance (e.g. natural history)

- Avoidance of triggers Keep a ‘vomiting diary’ of potential precipitating factors Avoid fasting Recognize the potential role of excitement as a trigger (e.g. downplay big events) Maintain good sleep hygiene (e.g. avoid sleep deprivation) Avoid triggering foods – chocolate, cheese, MSG, antigenic foods Avoid excessive energy output

- Supplemental carbohydrate – for fasting-induced episodes

Provide fruit juices, other sugar-containing drinks Provide extra snacks between meals, before exertion, or bedtime

- Migraine headache lifestyle interventions Regular aerobic exercise (avoid over-exercise)

Regular meal schedules (i.e. avoid skipping meals) Moderation or avoidance of caffeine


Table 4. Prophylactic or preventive medications* in CVS Children < 5 years of age

- Antihistamines: cyproheptadine (1st choice) and pizotifen (U.K., Canada) Cyproheptadine 0.25-0.5 mg/kg/day divided b.i.d. or t.i.d. Side effects: increased appetite, weight gain, sedation Alternatives: pizotifen (available in U.K. and Canada)

- β-blockers: propranolol (2nd choice)

Propranolol 0.25-1.0 mg/kg/day, most often 10 mg b.i.d. or t.i.d. Monitor: resting heart rate keep ≥ 60 beats/minute Side effects: lethargy, reduced exercise intolerance Contraindications: asthma, diabetes, heart disease, depression Discontinuation: tapered over 1-2 weeks

Children ≥ 5 years of age

- Tricyclic antidepressants: amitriptyline – 1st choice in children > 5 years of age Amitriptyline begin at 0.25-0.5 mg/kg q.hs, increase weekly by 5-10 mg, until 1.0-1.5 mg/kg Monitor: √ EKG QTc interval before starting and 10 days after the peak dose Side effects: constipation, sedation, arrhythmia, behavioral changes (especially in young children) Alternatives: nortriptyline (available in liquid)

- β-blockers: propranolol (2nd choice) – see above

Other agents

- Anti-convulsants: phenobarbital Phenobarbital 2 mg/kg q.hs Side effects: sedation, cognitive impairment Alternatives: topiramate, valproic acid, gabapentin, levetiracetam – consult neurology

- Supplements

L-carnitine 50-100 mg/kg/day divided b.i.d. or t.i.d. (maximum 1 gm t.i.d.) Co-enzyme Q10 10 mg/kg/day divided b.i.d. or t.i.d. (maximum 100 mg t.i.d.) Side effects: diarrhea, fishy body odor (for L-carnitine)

*All medications recommendations are made for off-label use.

Table 5. Summary of evidence for treatment of acute attacks of CVS Treatment N

(studies) N (pts)

Level of evidence

Study Quality

Response rates 100% 50-100% <50%

Comments

Sumatriptan (11) 1 38 II-3 NR 66% (25/38)

34% (13/38)

Ondansetron (11, 13, 61)

3 83 II-3 Fair (1/3) Poor (2/3)

NR 64% (53/83)

36% (30/83)

Phenothiazines (11) 1 63 II-3 Fair NR 21% (13/63)

79% (50/63)

Carbohydrate (13) 1 60 II-3 Poor NR 58% (35/60)

42% (25/60)

Prokinetic agents* (11) 2 41 II-3 Fair (1/2) Poor (1/2)

NR 20% (8/41)

80% (33/41)

* Includes erythromycin (1 pt)

Isometheptene (11) 1 13 II-3 Fair NR 31% (4/13)

69% (9/13)

Table 6. Supportive and abortive treatment approaches in CVS Supportive care

- Fluid, electrolyte and nutritional management

D10 0.45 Normal Saline + KCl as appropriate @ 1.5 times maintenance fluid rates OR through a Y-connector D10W at 1.0 times maintenance and Normal Saline at 0.5 times maintenance If no enteral intake for 3-5 days, initiate peripheral parental nutrition with 1.5 grams of amino acids/kg/day and calories above the catabolic threshold of 55-70 kcal/kg/day

- Anti-emetic (5HT3 antagonist) agents:

Ondansetron 0.3-0.4 mg/kg/dose IV q. 4-6 hours (up to 20 mg) Side effects: constipation Alternatives: granisetron

- Sedatives

Diphenhydramine 1.0-1.25 mg/kg/dose IV q. 6 hours Lorazepam 0.05-0.1 mg/kg/dose IV q. 6 hours Side effects: respiratory depression, hallucinations Chlorpromazine 0.5-1.0 mg/kg/dose q. 6 hours + diphenhydramine IV Side effects: dystonic reactions with chlorpromazine alone

- Analgesics (nonsteroidal and narcotic) agents:

Ketorolac 0.4-1.0 mg/kg IV q. 6 hours (maximum dose 30 mg, maximum daily 120 mg) Side effects: GI hemorrhage Alternatives: narcotics IV morphine or fentanyl by bolus or by patient-control infusion

- Treatment of specific signs and symptoms: epigastric pain, diarrhea and hypertension

Epigastric pain – acid suppression by H2RAs or PPIs e.g. IV ranitidine or pantoprazole Diarrhea – antidiarrheals e.g. immodium Hypertension – short-acting ACE inhibitors e.g. captopril

- Treatment of specific complications

Dehydration and electrolyte deficit – replace calculated deficits Metabolic acidosis – determine cause (refer to Diagnostic Approach) and treat accordingly SIADH – restrict free water intake Hematemesis – IV H2RAs or PPIs (see text) Weight loss – nasogastric or parenteral nutrition

Abortive care

- Anti-migraine (triptan) agents: Sumatriptan: 20 mg intranasally at onset of episode Side effects: neck pain/burning, coronary vasospasm Contraindications: basilar artery migraine


- Recovery and refeeding

Feed ad lib when child declares episode over


Table 7. Sample treatment protocol order sheet for a child in an acute attack of CVS In Emergency Department and in-hospital settings, an example of a regimen would include:

1) Darkened, quiet room, vital signs q. 4-6 hours 2) If dehydrated, rehydrate with initial fluid bolus of 10 ml/kg normal saline and repeat as

clinically necessary 3) D10 0.45 NS + KCl as appropriate @ 1.5 X maintenance rates 4) IV ondansetron 0.3 mg/kg/dose q. 6 hours X 24 hours 5) IV lorazepam 0.05 mg/kg/dose q. 6 hours X 24 hours 6) If moderate to severe abdominal pain, IV ketorolac 1.0 mg/kg/dose ( ≤ 30 mg total dose) q. 6

hours 7) Admit if > 5% dehydrated, no urine output > 12 hours, Na+ < 130 mEq/L, anion gap > 18

mEq/L or inability to stop emesis 8) Allow oral fluid intake


Figure 1: Evaluation of Cyclic Vomiting Pattern in Children > 2 years old

Criteria for children in whom CVS is being considered: • At least 5 attacks or a minimum of 3 attacks occurring over a 6-month period • Episodic attacks of intense nausea and vomiting lasting from 1hour to 10 days

and occurring at least 1 week apart • Stereotypical in the individual patient • Vomiting during attacks occurs at least 4 times/hour for at least 1 hour • A return to baseline health between episodes

Attack with presence of: - Abdominal distention - Abdominal tenderness - Severe abdominal pain

All attacks precipitated by:

- intercurrent illness - high protein meal

Abnormal neurologic exam: - Severe alterated mental status - Abnormal eye movements - Papilledema* - Motor asymmetry - Gait abnormality (*may not need metabolic evaluation)

Consider at any time: -Ultrasound of the abdomen & pelvis

Obtained at the beginning of attack before IV fluid:

- glucose - electrolytes for anion gap - urine ketones - lactate - ammonia - serum aminoacids - urine organic acids - consider plasma carnitine &

acylcarnitine

Brain MRI

No findings

suggestive of

th

Electrolytes (Na+, K+, Cl-, HCO3-), glucose, BUN and creatinine

UGI series to evaluate for malrotation

Consider during an attack: - ALT/GGT - lipase ± amylase

Result of testing explains vomiting

Probable CVS Treat or refer accordingly

Yes No


Bibliography

1. Gee S. On fitful or recurrent vomiting; 1882 1882. Report No.: 18. 2. Fleisher D, Matar M. The cyclic vomiting syndrome: a report of 71 cases and literature

review. JPGN 1993;17(4):361-9. 3. Hoyt CS, Stickler GB. A study of 44 children with the syndrome of recurrent vomiting.

Pediatrics 1960;25:775-80. 4. Li BU, Balint J. Cyclic vomiting syndrome: evolution in our understanding of a brain-gut

disorder. Adv Pediatr 2000;47:117-60. 5. Prakash C, Clouse R. Cyclic vomiting syndrome in adults: clinical features and response

to tricyclic antidepressents. Am J Gastroenterol 1999;94(10):2856-60. 6. Prakash C, Staiano A, Rothbaum RJ, Clouse RE. Similarities in cyclic vomiting

syndrome across age groups. Gastroenterology 2001;96(3):684-8. 7. Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome

in 41 adults: the illness, the patients, and problems of management. BMC Med 2005;3:20.

8. Whitney HB. Cyclic vomiting. A brief review of this affection as illustrated by a typical case. Arch Pediatr 1898;15:839-45.

9. Stickler GB. Relationship between cyclic vomiting syndrome and migraine. Clin Pediatr (Phila) 2005;44(6):505-8.

10. Withers GD, Silburn SR, Forbes DA. Precipitants and aetiology of cyclic vomiting syndrome. Acta Paediatr 1998;87(3):272-7.

11. Li BU, Murray RD, Heitlinger LA, Robbins J, Hayes J. Is cyclic vomiting syndrome related to migraine? J Pediatr 1999;134(5):567-72.

12. Wang Q, Ito M, Adams K, Li BU, Klopstock T, Maslim A, et al. Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome. Am J Med Genet A 2004;131(1):50-8.

13. Boles RG, Adams K, Ito M, Li BU. Maternal inheritance in cyclic vomiting syndrome with neuromuscular disease. Am J Med Genet A 2003;120(4):474-82.

14. Boles RG, Le S, Maslim A, Adams K, Li BU, Higashimoto T, et al. Mitochondrial DNA control region sequence variations in cyclic vomiting syndrome with neuromuscular disease. unknown 2002.

15. Tache Y. Cyclic vomiting syndrome: the corticotropin-releasing-factor hypothesis. Dig Dis Sci 1999;44(8 Suppl.):79S-86S.

16. Sato T, Igarashi M, Minami S, Okabe T, Hashimoto H, Hasui M, et al. Recurrent attacks of vomiting, hypertension, and psychotic depression: a syndrome of periodic catecholamine and prostaglandin discharge. Acta Endocrinol (Copenh) 1988;117(2):189-97.

17. Sato T, Uchigata Y, Uwadana N, Kita K. A syndrome of periodic adrenocorticotropin and vasopressin discharge. J Clin Endocrinol Metab 1982;54(3):517-22.

18. Hayward RS, Steinberg EP, Ford DE, Roizen MF, Roach KW. Preventive care guidelines: 1991. American College of Physicians. Canadian Task Force on the Periodic Health Examination. United States Preventive Services Task Force. Ann Intern Med 1991;114(9):758-83.

19. Harris RP, Helfand M., Woolf, S.H. et al. Current methods of the U.S. Preventative Services Task Force: a review of the process. Am J Prev Med 2001;20(3 Suppl.):21-35.


20. Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006;130(5):1519-26.

21. Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006;130(5):1527-37.

22. Diagnostic criteria for cyclic vomiting syndrome. In: Li BU, editor. Cyclic vomiting syndrome: Proceedings of the International Scientific Symposium. J Pediatr Gastroenterol Nutr 1995;21(Suppl.).p. vi.

23. Pfau BT, Li BU, Murray RD, Heitlinger LA, McClung HJ, Hayes JR. Differentiating cyclic from chronic vomiting patterns in children: quantitative criteria and diagnostic implications. Pediatrics 1996;97(3):364-8.

24. Li BU, Murray RD, Heitlinger LA, Robbins J, Hayes JR. Heterogeneity of diagnosis presenting as cyclic vomiting. Pediatrics 1998;102((3 Pt. 1)):583-7.

25. Olson AD, Li BU. The diagnostic evaluation of children with cyclic vomiting: a cost-effectiveness assessment. J Pediatr 2002;141(5):724-8.

26. Heikkinen J, Vaheri R, Timonen U. Long-term safety and tolerability of continuous-combined hormone therapy in postmenopausal women: results from a seven-year randomised comparison of low and standard doses. J Br Menopause Soc 2004;10(3):95-102.

27. Torres AM, Ziegler MM. Malrotation of the intestine. World J Surg 1993;17(3):326-31. 28. Powell DM, Othersen HB, Smith CD. Malrotation of the intestines in children: the effect

of age on presentation and therapy. J Pediatr Surg 1989;24(8):777-80. 29. Long FR, Kramer SS, Markowitz RI, Taylor GE. Radiographic patterns of intestinal

malrotation in children. Radiographics 1996;16(3):547-56. 30. Schulte-Bockholt A, Kugathasan S, Mesrobian HG, Werlin SL. Ureteropelvic junction

obstruction: an overlooked cause of cyclic vomiting. Am J Gastroenterol 2002;97(4):1043-5.

31. Tsai JD, Huang FY, Lin CC, Tsai TC, Lee HC, Sheu JC, et al. Intermittent hydronephrosis secondary to ureteropelvic junction obstruction: clinical and imaging features. Pediatrics 2006;117(1):139-46.

32. Tobin MV, Aldridge SA, Morris AI, Belchetz PE, Gilmore IT. Gastrointestinal manifestations of Addison's disease. Am J Gastroenterol 1989;84(10):1302-5.

33. Woods M, Greenes D. An 11-year-old boy with vomiting, dehydration, and a tan complexion. Curr Opin Pediatr 1995;7(4):472-6.

34. Rinaldo P. Mitochondrial fatty acid oxidation disorders and cyclic vomiting syndrome. Dig Dis Sci 1999;44(8 Suppl.):97S-102S.

35. Lin JN. Intestinal malrotation and midgut volvulus: a 15-year review. J Formos Med Assoc 1995;94(4):178-81.

36. Friesen CA, Roberts CC. Cholelithiasis. Clinical characteristics in children. Case analysis and literature review. Clin Pediatr (Phila) 1989;28(7):294-8.

37. Buyukyavuz I, Ekinci S, Ciftci AO, Karnak I, Senocak ME, Tanyel FC, et al. A retrospective study of choledochal cyst: clinical presentation, diagnosis and treatment. Turk J Pediatr 2003;45(4):321-5.

38. Pieper-Bigelow C, Strocchi A, Levitt MD. Where does serum amylase come from and where does it go? Gastroenterol Clin North Am 1990;19(4):793-810.


39. Agarwal N, Pitchumoni CS, Sivaprasad AV. Evaluating tests for acute pancreatitis. Am J Gastroenterol 1990;85(4):356-66.

40. Wesdorp I, Bosman D, de Graaff A, Aronson D, van der Blij F, Taminiau J. Clinical presentations and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr 2000;31(4):411-7.

41. Reinberg Y, Gonzalez R. Upper urinary tract obstruction in children: current controversies in diagnosis. Pediatr Clin North Am 1987;34(5):1291-304.

42. Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medecine (Baltimore) 1970;49(1):1-16.

43. Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005;142(6):439-50.

44. Costa CG, Guerand WS, Struys EA, Holwerda U, ten Brink HJ, Tavares de Almeida I, et al. Quantitative analysis of urinary acylglycines for the diagnosis of beta-oxidation defects using GC-NCI-MS. J Pharm Biomed Anal 2000;21(6):1215-24.

45. Boles RG, Adams K, Li BU. Maternal inheritance in cyclic vomiting syndrome. Am J Med Genet A 2005;133(1):71-7.

46. Boles RG, Williams JC. Mitochondrial disease and cyclic vomiting syndrome. Dig Dis Sci 1999;44(8 Suppl.):103S-7S.

47. Dobrovoljac M, Hengartner H, Boltshauser E, Grotzer MA. Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr 2002;161(12):663-7.

48. Alston RD, Newton R, Kelsey A, Newbould MJ, Birch JM, Lawson B, et al. Childhood medulloblastoma in northwest England 1954 to 1997: incidence and survival. Dev Med Child Neurol 2003;45(5):308-14.

49. Kotagal P. The relationship between sleep and epilepsy. Semin Pediatr Neurol 2001;8(4):241-50.

50. Schauble B, Britton JW, Mullan BP, Watson J, Sharbrough FW, Marsh WR. Ictal vomiting in association with left temporal lobe seizures in a left hemisphere language-dominant patient. Epilepsia 2002;43(11):1432-5.

51. Boles RG, Burnett BB, Gleditsch K, Wong S, Guedalia A, Kaariainen A, et al. A high predisposition to depression and anxiety in mothers and other matrilineal relatives of children with presumed maternally inherited mitochondrial disorders. Am J Med Genet B Neuropsychiatr Genet 2005;137(1):20-4.

52. McClung HJ, Murray RD, Braden NJ, Fyda J, Myers RP, Gutches L. Intentional Ipecac poisoning of children. Am J Dis Child 1988;142(6):637-9.

53. Fleisher D. Management of cyclic vomiting syndrome. JPGN 1995;21(Suppl. 1):S52-S6. 54. Blumer JL. Off-label uses of drugs in children. Pediatrics 1999;104(3 Pt 2):598-602. 55. Fleisher D. Cyclic vomiting syndrome. In: Hyman P DC, editor. Pediatric

Gastroenterology Motility Disorders. New York, NY: Academy Professional Information Services; 1994. p. 89-104.

56. Lucarelli S, Corrado G, Pelliccia A, D'Ambrini G, Cavaliere M, Barbato M, et al. Cyclic vomiting syndrome and food allergy/intolerance in seven children: a possible association. Eur J Pediatr 2000;159(5):360-3.

57. Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut 2004;53(11):1566-70.


58. Hoodin F, Brines BJ, Lake AE, 3rd, Wilson J, Saper JR. Behavioral self-management in an inpatient headache treatment unit: increasing adherence and relationship to changes in affective distress. Headache 2000;40(5):377-83.

59. Rasmussen BK. Migraine and tension-type headache in a general population: precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain 1993;53(1):65-72.

60. Lewis DW, Yonker M, Winner P, Sowell M. The treatment of pediatric migraine. Pediatr Ann 2005;34(6):448-60.

61. Lee WS, Kaur P, Boey CC, Chan KC. Cyclic vomiting syndrome in South-East Asian children. J Paediatr Child Health 1998;34(6):568-70.

62. Worawattanakul M, Rhoads J, Lichtman S, Ulshen M. Abdominal migraine: prophylactic treatment and follow-up. JPGN 1999;28(1):37-40.

63. Anderson JM, Sugerman KS, Lockhart JR, Weinberg WA. Effective prophylactic therapy for cyclic vomiting syndrome in children using amitriptyline or cyproheptadine. Pediatrics 1997;100(6):977-81.

64. Gokhale R, Huttenlocher P, Brady L, Kirschner BS. Use of barbituates in the treatment of cyclic vomiting during childhood. JPGN 1997;25(1):64-7.

65. Symon D. Pizotifen. In: Gallai V GV, editor. Juvenile Headache. Amsterday: Elsevier Science Publishers; 1991. p. 405-8.

66. Symon D, Russell G. Double blind placebo controlled trial of pizotifen syrup in the treatment of abdominal migraine. Arch Dis Child 1995;72(1):48-50.

67. Salmon MA, Walters DD. Pizotifen in the prophylaxis of cyclical vomiting. Lancet 1985;1(8436):1036-7.

68. Gutgesell H, Atkins D, Barst R, Buck M, Franklin W, Humes R, et al. Cardiovascular monitoring of children and adolescents receiving psychotropic drugs: A statement for healthcare professionals from the Committee on Congenital Cardiac Defects, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 1999;99(7):979-82.

69. Clouse RE, Sayuk GS, Lustman PJ, Prakash C. Zonisamide or levetiracetam for adults with cyclic vomiting syndrome: a case series. Clin Gastroenterol Hepatol 2007;5(1):44-8.

70. Van Calcar S, Harding C, Wolff J. L-carnitine administration reduces number of episodes in cyclic vomiting syndrome. Clinical Pediatrics 2002;41(3):171-4.

71. Welch KM, Darnley D, Simkins RT. The role of estrogen in migraine: a review and hypothesis. Cephalalgia 1984;4(4):227-36.

72. Johnston W. Acupuncture may treat cyclic vomiting syndrome. Anesth News 2000 5/2000.

73. Magagna J. Psychophysiologic treatment of cyclic vomiting. JPGN 1995;21(Suppl. 1):S31-S6.

74. Fleisher D. The cyclic vomiting syndrome described. JPGN 1995;21(Suppl. 1):S1-S5. 75. Benson J, Zorn S, Book L. Sumitriptan [Imitrex] in the treatment of cyclic vomiting. Ann

Pharm 1995;29(10):997-8. 76. Sandoval C, Corbi D, Strobino B, Fevzi Ozkaynak M, Tugal O, Jayabose S. Randomized

double-blind comparison of single high-dose ondansetron and multiple standard-dose ondansetron in chemotherapy-naive pediatric oncology patients. Cancer Invest 1999;17(5):309-13.


77. Pasricha P, Schuster M, Saudek C, Wand G, Ravich W. Cyclic vomiting: association with multiple homeostatic abnormalities and response to ketorlac. Am J Gastroenterol 1996;91(10):2228-32.

78. Li BU, Misiewicz L. Cyclic vomiting syndrome: a brain-gut disorder. Gastroenterol Clin North Am 2003;32(3):997-1019.

79. Pohl JF, Melin-Aldana H, Rudolph C. Prolapse gastropathy in the pediatric patient. J Pediatr Gastroenterol Nutr 2000;30(4):458-60.

80. McRonald FE, Fleisher DR. Anticipatory nausea in cyclical vomiting. BMC Pediatr 2005;5(1):3.

81. Symon D, Russell G. Abdominal migraine: a childhood syndrome defined. Cephalalgia 1986;6(4):223-8.

82. Vanderhoof JA, Young R, Kaufmann SS, Ernst L. Treatment of cyclic vomiting syndrome in childhood with erythromycin. JPGN 1993;17(4):387-91.

CVS Guidelines 407 - NASPGHAN

Documents

Transcript of CVS Guidelines 407 - NASPGHAN