Definition and PathogenesisTop
Hiccups (singultus) are involuntary synchronous contractions of the intercostal muscles and the diaphragm that cause sudden inspiration. This leads to closure of the glottis and is accompanied by a characteristic sound.
Hiccups are triggered by stimulation of the vagus nerve, phrenic nerve, and sympathetic nerves innervating the chest, abdomen, ear, nose, and pharynx, or by stimulation of the hiccup center in the central nervous system (CNS). The hiccup rate may be from 2 to 60 per minute. Episodes of hiccups are usually brief (lasting several minutes) and are most frequently associated with rapid or excessive gastric distension. The vast majority of episodes of hiccups are short, self-terminating, and inconsequential, requiring no investigation.
Persistent hiccups (>48 hours) may result in exhaustion, discomfort, weight loss (due to interference with food intake), insomnia, and depression.
Causes of persistent hiccups:
1) CNS disorders: Vascular, inflammatory, neoplastic, multiple sclerosis, hydrocephalus.
2) Metabolic disorders: Diabetes mellitus, uremia, hyponatremia, hypocalcemia, hypocapnia.
3) Toxins and drugs: Alcohol, nicotine, barbiturates, benzodiazepines, etoposide, dexamethasone.
4) Neck and chest disorders: Tumor, lymphadenopathy, lung cancer, pneumonia with pleural inflammation, myocardial infarction, esophageal cancer, mediastinal tumors, diaphragmatic hernia, gastroesophageal reflux disease (GERD).
5) Abdominal disorders: Gastric cancer, peptic ulcer disease, gastric distension (a very common cause), gastrointestinal (GI) bleeding, pancreatic cancer, pancreatitis, hepatomegaly, splenomegaly, ascites, cholelithiasis, intestinal obstruction, peritonitis.
6) Psychogenic causes.
A thorough history and physical examination often elucidate the etiology of persistent hiccups. Routine supplemental investigations may include laboratory investigations (eg, complete blood count [CBC] and levels of creatinine and electrolytes including calcium), electrocardiography (ECG), and chest radiography.
Depending on clinical presentation, additional tests may be performed: Abnormal chest radiographs should be followed by computed tomography (CT) of the chest. Neurologic findings on physical examination or in history may warrant CT or magnetic resonance imaging (MRI) of the head, and possibly lumbar puncture or electroencephalography. Referral to an ear, nose, and throat (ENT) specialist should be considered to evaluate identified abnormalities of the head and neck. GI findings may be further investigated with liver function tests, endoscopy, or abdominal ultrasonography and CT. For patients with respiratory abnormalities, spirometry and bronchoscopy may be appropriate.
The initial approach to management should aim to treat the underlying condition. Pharmacologic therapy can be used for symptomatic treatment; however, no high-quality evidence exists to guide this therapy. Antipsychotic agents are considered first-line treatment. Chlorpromazine is the only US Food and Drug Administration (FDA)-approved therapy for hiccups. The initial oral dose is 25 mg tid for up to 7 days titrated up to 50 mg qid as needed. Slow IV administration of the same dose is appropriate for more severe cases. Other options include metoclopramide 5 to 10 mg IV or 10 mg orally every 6 hours for up to 5 days. Baclofen, a skeletal muscle relaxant, may be used as a second-line agent, 5 to 10 mg tid orally (up to 40 mg/d). IV infusion of midazolam may be effective in controlling refractory hiccups; however, some data suggest benzodiazepines may precipitate or worsen hiccups.
Numerous other agents have been reported in small case reports or case series to be effective treatments for intractable hiccups, sometimes in the palliative setting. These include anticonvulsant agents (eg, gabapentin up to 300-900 mg/d, pregabalin 100-300 mg/d, valproic acid, carbamazepine), neuroleptic agents (eg, haloperidol IM or orally, olanzapine), stimulants (eg, methylphenidate), and other miscellaneous drugs including nifedipine, quinidine, lidocaine (as IV infusion [2 mg/min, up to 1.5 mg/kg], subcutaneous infusion [up to 480 mg per day] or oral viscous solution), and nefopam.
Surgical treatments have been described in extreme cases of intractable hiccups. These include implantation of a diaphragmatic pacemaker and phrenic nerve ablation.