Hiccups 

The term hiccup derives from the sound of the event; the alternative spelling hiccough erroneously implies an association with respiratory reflexes. Brief episodes of hiccups, which often induce annoyance in patients and merriment in observers, are a common part of life. Prolonged attacks, however, are a more serious phenomenon and often pose a diagnostic dilemma. These attacks have been associated with significant morbidity and even death.

A hiccup bout is any episode lasting more than a few minutes. Hiccups lasting longer than 48 hours are considered persistent or protracted.[2, 3] Hiccups lasting longer than 1 month are termed intractable. The longest recorded attack of hiccups lasted for 6 decades.

Hiccups appear to serve no purpose in humans or other mammals. Often, only a single hemidiaphragm is affected. The left hemidiaphragm is affected in 80% of cases, though bilateral involvement may occur.

Hiccups occur 4-60 times per minute until a certain number has been delivered. Typically, this is fewer than four or more than 30. The frequency is relatively constant for a given individual and varies inversely with arterial carbon dioxide tension (PaCO2). The loudness and rapidity of hiccups are unrelated. Hiccups are more common in the evening and may continue for a few waking hours. They occur most frequently during the first half of the menstrual cycle, especially in the few days before menstruation, and become markedly less frequent during pregnancy.

Despite centuries of contemplation, the exact pathogenesis of hiccups remains a mystery. Hippocrates and Celsus associated hiccups with liver inflammation and other conditions. Galen believed that hiccups were due to violent emotions arousing the stomach. In 1833, Shortt first recognized an association between hiccups and phrenic nerve irritation.

The hiccup reflex, originally proposed by Bailey in 1943, consists of the following:

• Afferent limb - Phrenic and vagus nerves and sympathetic chain arising from T6 to T12
• Hiccup center - Nonspecific location between C3 and C5
• Connections to the respiratory center, phrenic nerve nuclei, medullary reticular formation, and hypothalamus
• Efferents - Phrenic nerve (C3-5), anterior scalene muscles (C5-7), external intercostals (T1-11), glottis (recurrent laryngeal component of vagus), inhibitory autonomic processes, decreasing esophageal contraction tone, and lower esophageal sphincter tone

The cause of hiccups in children and infants is rarely found. Brief episodes in adults are usually benign and self-limiting. Typical causes include the following:

• Gastric distention (ie, from food, alcohol, or air)
• Sudden changes in ambient or gastric temperature
• Use of alcohol or tobacco in excess

Psychogenic causes (ie, excitement and stress) also may elicit hiccups.

Persistent or intractable episodes are more likely to result from serious pathophysiologic processes affecting a component of the hiccup reflex mechanism. More than 100 causes have been described; however, in many cases, the cause remains idiopathic.[2, 3]

Male predominance exists in patients with non–central nervous system (CNS)-related hiccups and those of unknown origin.[4] About 82% of persistent or intractable episodes also occur in men. An organic cause can be identified in 93% of men and in 8% of women, resulting in an overall organic incidence of 80%; the remaining 20% of cases are considered psychogenic in origin. Psychogenic conditions associated with hiccups include the following:

• Hysteria
• Shock
• Fear
• Personality disorders
• Conversion disorders
• Malingering

CNS-related causes of hiccups include the following:

• Structural lesions ^{[5, 6]} - Congenital malformations, malignancies, or multiple sclerosis
• Vascular lesions
• Infection
• Trauma

Conditions that can give rise to diaphragmatic irritation causing hiccups are as follows:

• Hiatal hernia
• Subphrenic abscess or collection
• Myocardial ischemia ^[7]
• Pericarditis

Conditions associated with irritation of the following branches of the vagus nerve irritation can cause hiccups:

• Meningeal branches – Meningitis or glaucoma
• Auricular branches - Foreign body or hairs
• Pharyngeal branches - Pharyngitis
• Recurrent laryngeal nerve - Mass lesions in the neck, goiter, or laryngitis ^[8]
• Thoracic branches - Infection, tumors, ^[9] esophagitis (ie, reflux), myocardial infarction (MI), asthma, trauma, thoracic aortic aneurysm, or pacemaker lead complications ^[10]
• Abdominal branches - Tumors, ^[11] gastric distention, peptic ulcer, abdominal aortic aneurysm, infection, organ enlargement, or inflammation (eg, appendicitis, cholecystitis, pancreatitis, ^[12] or inflammatory bowel disease)

Procedure- or anesthesia-related causes of hiccups include the following[13, 14] :

• Hyperextension of the neck - Stretching the phrenic nerve roots
• Manipulation of the diaphragm or stomach
• Laparotomy
• Thoracotomy
• Craniotomy

Metabolic causes of hiccups include the following:

• Hyponatremia
• Hypokalemia
• Hypocalcemia
• Hyperglycemia
• Uremia
• Hypocarbia
• Fever

Drugs associated with hiccups include the following:

• Benzodiazepines ^[15]
• Short-acting barbiturates
• Donepezil ^[16]
• Dexamethasone
• Alpha-methyldopa

Hiccups can occur at any age. They may even be observed in utero; preterm infants spend up to 2.5% of their time hiccupping. Although hiccups occur less frequently with advancing age, intractable hiccups are more common in adult life. Females develop hiccups more frequently during early adulthood than males of the same age do.

The overall incidence of hiccups appears to be the same in males as it is in females; however, protracted and intractable hiccups occur more frequently in men (82% of cases).

A review of the literature (1990-2013) comprising 318 studies found a male predominance in hiccup patients, particularly when the causes were not related to the central nervous system or were unknown.[4]

In general, hiccups are self-limited, and the prognosis is excellent. The prognosis of protracted hiccups is related to that of the underlying etiology.

Protracted hiccups often are associated with underlying organic disease and often induce social and emotional distress. Therapy must address causative and complicating factors of protracted hiccups. Complications of hiccups may include the following:

• Arrhythmias
• Gastroesophageal reflux
• In prolonged cases, weight loss and sleep disturbance

No medical training is required to diagnose hiccups. For brief episodes that self-terminate or that respond to simple maneuvers, no investigation or follow-up care is necessary. In contrast, persistent and intractable hiccups frequently are associated with an underlying pathological process and may induce significant morbidity. The focus of the history, examination, and investigation is on identifying these causes and effects. A full systemic inquiry, surgical history, and comprehensive drug history may identify one of the many possible causes.

Hiccups that abate with sleep and temporally relate to stressful circumstances commonly are psychogenic in origin. Arrhythmia-induced syncope has been reported as both the cause and the effect of hiccups.[17]  Gastroesophageal reflux also may either cause or result from hiccups. Weight loss, insomnia, and emotional distress may complicate prolonged episodes. Alcoholism and acute alcohol ingestion may contribute to the development of hiccups.

In view of the wide range of differentials, a full physical examination is necessary. A complete and focused physical examination may yield evidence of the following:

• Head (including ears, eyes, and the entire scalp) – Foreign body or aberrant hair adjacent to tympanic membrane; glaucoma
• Mouth - Pharyngitis
• Neck – Inflammation (including laryngitis); mass lesions; goiter; voice abnormalities (recurrent laryngeal nerve); stiffness (possibly indicating tumors or infection)
• Chest – Tumors; pneumonia; asthma
• Cardiovascular system – Arrhythmias; myocardial infarction (MI); pericarditis; unequal pulses ( thoracic aortic aneurysm)
• Abdomen – Gastric atony (succussion splash); organomegaly; subphrenic abscess; cholecystitis; appendicitis; abdominal aortic aneurysm (AAA); pancreatitis; peritonitis
• Rectum – Mass lesions
• Nervous system – Focal lesions; disordered higher mental function; indications of multiple sclerosis

A wide variety of conditions may contribute to hiccups. The possibilities are narrowed down by the findings from the history and physical examination. Laboratory testing is directed toward suspected abnormalities.

• Electrolytes - Hyponatremia can be either the cause (including Addison disease) or the effect (drinking water as a cure) of hiccups; other electrolyte-related causes are hypokalemia, hypocalcemia, and hyperglycemia
• Renal function tests - Uremia
• Liver function tests - Hepatitis
• Amylase and lipase levels - Pancreatitis
• White blood cell (WBC) count

Certain infectious diseases may cause a patient to hiccup. Appropriate testing for such infections may include the following:

• Urine
• Sputum
• Cerebrospinal fluid (CSF)

Imaging modalities that may be helpful in the workup include the following:

• Chest radiography to identify tumors, detect infection, or assess the thoracic aorta
• Fluoroscopy of diaphragmatic movement to confirm the diagnosis if malingering is suspected or to determine if the diaphragmatic abnormality is unilateral or bilateral before invasive therapy
• Computed tomography (CT) of the head, thorax, and abdomen to identify tumors, infection, or structural lesions
• Magnetic resonance imaging (MRI) to detect multiple sclerosis or evaluate vascular relations to the vagus and phrenic nerves

Other studies that may be helpful include the following:

• Electrocardiography (ECG) to detect myocardial infarction (MI), pericarditis, or dysrhythmias
• Before invasive therapy, nerve conduction studies to confirm the diagnosis and to confirm the presence of unilateral or bilateral involvement
• Endoscopy or bronchoscopy
• Before corrective surgery, an esophageal acid perfusion test to determine if gastroesophageal reflux is a causative factor

Generations of physicians have failed to discover a definitive cure for hiccups. The following statement from the Mayo Clinic, though made in 1932, still describes the situation perfectly: "The amount of knowledge on any subject such as this can be considered as being in inverse proportion to the number of different treatments suggested and tried for it."

Patients rarely present to the emergency department (ED) after cessation of a brief episode of hiccups. If this occurs, the possibility of another reason for the presentation (eg, depression) should be considered first.

Supportive care is administered as indicated by the causative pathology (eg, oxygen for the patient whose hiccups may be secondary to pneumonia). Therapy is directed first toward at the cause of the hiccups (if identified) and then toward the hiccups themselves (if necessary).

Gastroesophageal reflux is associated closely with hiccups but may be either a cause or an effect. Acid perfusion studies should be done to confirm the inducibility of hiccups before antireflux surgery is performed to cure hiccups.

Treatment may be pharmacologic or nonpharmacologic. Chlorpromazine remains the only agent approved by the US Food and Drug Administration (FDA) for the treatment of intractable hiccups.[2, 18] Surgical phrenic nerve ablation has been advocated for intractable cases that are unresponsive to other treatment. This drastic approach may be associated with considerable morbidity and is not universally successful. A Cochrane review concluded that the available evidence was insufficient to guide treatment of persistent or intractable hiccups by either pharmacologic or nonpharmacologic means.[19]

Consultation is rarely necessary unless the cause of the hiccups calls for the participation of a specialist.

Various agents have been reported to cure hiccups. Gabapentin, baclofen, and metoclopramide appear to show promise for persistent hiccups alone, in combination with other drugs, including proton-pump inhibitors, or as conjoined therapy.[2, 18]  In a systematic review of pharmacologic therapy for persistent/intractable hiccups in 341 patients in 15 studies, Steger et al noted that treatment of the underlying condition was the most successful, but there were no high-quality data to allow pharmacologic treatment recommendations.[20] However, on the basis of the limited data available, the investigators indicated that owing to their lower risk of adverse effects over long-term therapy as compared with traditional neuroleptic agents, baclofen and gabapentin may be considered first-line therapy for persistent/intractable hiccups, with metoclopramide and chlorpromazine in reserve.

Chlorpromazine is the most thoroughly studied medication, is FDA-approved for intractable hiccups, and appears to be the drug of choice in many reports. Regimens in the range of 25-50 mg intravenously (IV) or intramuscularly (IM) are effective in 80% of cases. To prevent or minimize hypotension caused by this agent, preloading the patient with 500-1000 mL of IV fluid is advised.

Another major tranquilizer, haloperidol, is effective in doses of 2-5 mg. Metoclopramide has been used successfully in a dosage of 10 mg every 8 hours. Indeed, a double-blind, randomized, controlled pilot study by Wang and Wang provided evidence of the usefulness of metoclopramide against intractable hiccups.[1] In this study, 34 patients received either 10 mg of metoclopramide or placebo three times per day for 15 days. The efficacy of metoclopramide with regard to cessation or improvement of hiccups was greater in the metoclopramide group than in the placebo group; no serious adverse effects were noted.

Several anticonvulsant agents have been used to treat intractable hiccups. Phenytoin, valproic acid, and carbamazepine have all been effective when used in typical anticonvulsant doses. Gabapentin has been shown to be effective in patients with central nervous system (CNS) lesions and in some other etiologic groups.[21, 22, 23]

Of the anesthetic agents, ketamine has been the most successful in a dose of 0.4 mg/kg (one fifth of the usual anesthetic dose). The centrally acting muscle relaxant baclofen,[24] in a dosage of 10 mg orally every 6 hours, is particularly useful in patients for whom other agents are contraindicated (eg, those with renal impairment). A case report described success with oral baclofen for persistent hiccups occurring after an epidural steroid injection.[25] Another case report has described the combination of baclofen and low-dose olanzapine.[26] IV lidocaine, in a loading dose of 1 mg/kg followed by an infusion of 2 mg/min, has cured patients after other agents were unsuccessful. Oral lidocaine was reported to be successful in four cancer patients with hiccups.[27]

Other agents reported to be beneficial are as follows:

• Muscle relaxants
• Sedatives
• Analgesics (eg, orphenadrine, amitriptyline, chloral hydrate, and morphine)
• Stimulants (eg, ephedrine, methylphenidate, amphetamine, and nikethamide)
• Miscellaneous agents (eg, edrophonium, dexamethasone, amantadine, ^[12] and nifedipine)

A randomized, single-blind, crossover phase III trial of 65 cancer patients treated with chemotherapy who had dexamethasone-induced hiccup found that rotation of the antiemetic corticosteroid from dexamethasone to methylprednisolone significantly reduced hiccup intensity, without a change in emesis intensity, compared to that when dexamethasone was maintained.[28] When dexamethasone was readministered instead of methyprednisolone at the crossover phase, the hiccup intensity increased again. Note: All 65 patients were female, although the investigators did not exclude female patients in the enrollment process.

Benzodiazepines exacerbate or precipitate hiccups and should be avoided.[15]

Many of the traditional nonpharmacologic remedies used in the emergency department have a sound physiologic basis, in that they have an effect on components of the hiccup reflex. The following are examples:

• Stimulation of the nasopharynx by applying forcible traction to the tongue, swallowing granulated sugar, gargling with water, sipping ice water, drinking from the far side of a glass, biting on a lemon, or inhaling noxious agents (eg, ammonia)
• C3-5 dermatome stimulation by tapping or rubbing the back of the neck, coolant sprays, or acupuncture
• Direct pharyngeal stimulation by a nasal or oral catheter (90% effective)
• Direct uvular stimulation by a spoon or cotton-tip applicator
• Removal of gastric contents by means of emetics or a nasogastric tube

The following remedies lead to vagal stimulation (only one should be used at any given time):

• Iced gastric lavage
• Valsalva maneuver
• Carotid sinus massage (performed only by experienced personnel after exclusion of contraindications)
• Digital ocular globe pressure (performed only by experienced personnel after exclusion of contraindications)
• Digital rectal massage

Various techniques are used that interfere with normal respiratory function, such as the following:

• Breath holding
• Hyperventilation
• Gasping (as in fright)
• Breathing into a paper bag (which increases arterial carbon dioxide tension [PaCO ₂])
• Pulling the knees up to the chest and leaning forward
• Using continuous positive airway pressure
• Rebreathing 5% carbon dioxide

Mental distraction sometimes works. For example, the patient may be asked to "think of a loved one remembering you." An inventive naval doctor achieved success by offering $10 if the patient could continue to hiccup immediately.

The following nonpharmacologic approaches have also been tried:

• Behavioral conditioning (including other members of the family unit)
• Hypnosis
• Acupuncture (including near-infrared irradiation of acupoints) ^{[29, 30, 31, 32]}
• Phrenic nerve or diaphragmatic pacing – Incidental cure of hiccups during cardioversion has been reported
• Prayer - One patient, after 8 years of hiccupping and more than 60,000 suggested treatments, finally obtained relief after praying to St Jude, the Catholic patron saint of lost causes

The final and most drastic treatment for hiccups is phrenic nerve ablation. Fluoroscopic examination may reveal unilateral involvement, which allows directed therapy. Initially, temporary blockade is advisable. Bilateral phrenic nerve interruption may lead to significant respiratory complications and may not always cure hiccups, because other respiratory muscles are involved. All other treatments must be explored before this step is embarked on.

Microvascular decompression of the vagus nerve has been reported to be successful in case reports.[33, 34]

Various agents have been reported to cure hiccups. Chlorpromazine appears to be the drug of choice. Haloperidol and metoclopramide have been used successfully. Several anticonvulsant agents (eg, phenytoin, valproic acid, and carbamazepine) have effectively treated intractable hiccups in typical anticonvulsant doses. Gabapentin has been effective in patients with central nervous system (CNS) lesions and in some other groups.

Of the anesthetic agents, ketamine has been the most successful. Baclofen is particularly useful in patients for whom other agents are contraindicated. Lidocaine has cured patients after other agents were unsuccessful. Other reportedly beneficial agents include muscle relaxants, sedatives, analgesics, stimulants, and various miscellaneous agents (eg, edrophonium, dexamethasone, amantadine, and nifedipine). Benzodiazepines should be avoided.

Class Summary

Antiemetic agents are effective in treating hiccups.

Chlorpromazine

Chlorpromazine

Chlorpromazine is the drug of choice in this setting. It is an antidopaminergic agent that blocks postsynaptic mesolimbic dopamine receptors. Chlorpromazine has an anticholinergic effect, can depress the reticular activating system, blocks alpha-adrenergic receptors, and depresses the release of hypophyseal and hypothalamic hormones.

Metoclopramide (Reglan, Metozolv ODT)

Metoclopramide blocks dopamine receptors in the chemoreceptor trigger zone of the CNS.

Class Summary

Anticonvulsants are used for severe muscle spasms.

Phenytoin (Dilantin, Phenytek)

Phenytoin inhibits the spread of motor activity by acting in the motor cortex.

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

Although the mechanism by which valproic acid acts is not established, it may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. This agent may also potentiate postsynaptic GABA responses, affect potassium channels, or exert a direct membrane-stabilizing effect.

Carbamazepine (Tegretol, Carbatrol, Equetro, Epitol)

Carbamazepine may block post-tetanic potentiation by reducing summation of temporal stimulation.

Class Summary

Anesthetics that affect muscle contractions appear to be effective.

Ketamine (Ketalar)

Ketamine acts on the cortex and limbic system, decreasing muscle spasms.

Lidocaine (Xylocaine)

Lidocaine inhibits depolarization of type C sensory neurons by blocking sodium channels.

Class Summary

Muscle relaxants may reduce muscle contractions.

Orphenadrine (Norflex)

Although the exact mode of action is not well understood, orphenadrine has shown clinical effectiveness in treating hiccups.

Baclofen (Lioresal, Gablofen)

Baclofen may induce the hyperpolarization of afferent terminals and inhibit both monosynaptic and polysynaptic reflexes at the spinal level. It is useful in patients for whom other agents are contraindicated (eg, those with renal impairment).

Class Summary

Sedative agents with effects in spastic muscles have shown effectiveness.

Morphine (Duramorph, Astramorph, Avinza, Kadian, MS Contin)

Morphine is the drug of choice for analgesia because of its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Various IV doses are used; the dose is commonly titrated until the desired effect is obtained.

Class Summary

These agents affect dopamine receptors but also affect serotonin receptors involved with frontal lobe functions.

Haloperidol (Haldol)

Haloperidol is useful in treatment of irregular spasmodic movements of muscles. It blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. It also decreases hypothalamic and hypophyseal hormones.

Class Summary

Chloral hydrate from this drug category has been reported to be beneficial.

Chloral hydrate

Has central nervous system depressant effects. Mechanism unknown.

Class Summary

Tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. They block the active reuptake of norepinephrine and serotonin.

Amitriptyline

Amitriptyline inhibits reuptake of serotonin and norepinephrine at the presynaptic neuronal membrane, which increases concentrations in the CNS. It may also have analgesic effects.

Class Summary

The mechanisms by which stimulants act in the treatment of hiccups are not well understood.

Ephedrine

Ephedrine stimulates release of epinephrine stores, producing alpha-adrenergic and beta-adrenergic effects.

Methylphenidate (Ritalin, Concerta, Metadate, Methylin, Daytrana)

Methylphenidate stimulates the cerebral cortex and subcortical structures.