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Singultus
Introduction
Singultus, commonly known as hiccups, affects nearly all individuals at some point in life. The term originates from the Latin word singult, meaning “to catch one’s breath while sobbing.” Episodes result from sudden, involuntary contractions of the diaphragm and intercostal muscles, followed by abrupt glottic closure that produces the characteristic “hic” sound. Most cases are transient and resolve within 48 hours.
Singultus occurs across all age groups, including fetuses, infants, children, and adults. While no physiological function is attributed to singultus in adults, prenatal episodes may contribute to respiratory muscle training.[1] Acute singultus may cause brief discomfort, but persistent and intractable forms significantly impair quality of life by disrupting sleep, nutrition, communication, and social interaction. In some cases, singultus signals underlying serious pathology.[2]
Etiology
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Etiology
Singultus classification is based on duration. Acute singultus lasts less than 48 hours. Persistent singultus lasts longer than 2 days. Intractable singultus persists for more than 1 month. Acute singultus is typically self-limited and underreported. Thus, most research focuses on persistent and intractable forms. Etiologies include organic, psychogenic, idiopathic, and medication-induced causes. Persistent and intractable singultus may indicate a serious underlying disease.
Gastrointestinal disturbances, particularly gastric overdistension, gastroesophageal reflux disease (GERD), and associated hiatal hernia, are the most frequently implicated causes of acute singultus.[3][4][5] This symptom occurs in up to 10% of individuals with GERD.[6] Large meals, carbonated beverages, spicy foods, and alcohol commonly trigger gastric distension or irritation. Among individuals with esophageal tumors, persistent singultus is a presenting symptom in approximately 25%.[7] Psychogenic triggers, such as overexcitement or anxiety, especially when accompanied by air swallowing or overbreathing (as in laughing fits), can also provoke the singultus reflex.[8]
Numerous drugs have been associated with singultus, notably alcohol and certain agents acting on the central nervous system (CNS). Benzodiazepines demonstrate a dose-dependent effect. Low doses have been linked to the induction of singultus, whereas higher doses may exert a suppressive effect. Chemotherapeutic agents and glucocorticoids show particularly strong associations.[9] Singultus develops in 42% of individuals receiving both cisplatin and dexamethasone.[10][11] In a cohort of 337 individuals treated with oxaliplatin- or cisplatin-based chemotherapy, the incidence was 28%.[12] Other medications associated with singultus include α-methyldopa, inhaled anesthetics, and various cytotoxic agents.
Persistent and intractable singultus have been documented in association with a wide range of underlying etiologies. Recognition of these diverse causes is essential to avoid missed diagnoses and guide appropriate diagnostic workup.
Cardiovascular conditions such as atrial pacing, aortic aneurysm (thoracic or abdominal), catheter ablation for atrial fibrillation, myocardial infarction, pericarditis, and temporal arteritis have all been reported in association with singultus. CNS disorders, particularly structural and inflammatory lesions, are among the most well-documented causes. Conditions include posterior circulation aneurysms (especially of the posterior inferior cerebellar artery), encephalitis, lateral medullary syndrome, meningitis, multiple sclerosis, neuromyelitis optica, brainstem neoplasms such as astrocytoma, seizures, stroke, syringomyelia, Parkinson disease, and vascular malformations such as cavernomas.[13][14][15][16][17][14]
Pharmacologic agents implicated in drug-induced singultus include α-methyldopa, aripiprazole, azithromycin, diazepam, midazolam, a wide range of chemotherapeutic agents (including carboplatin, cisplatin, oxaliplatin, etoposide, fluorouracil, irinotecan, and levofolinate), glucocorticoids such as dexamethasone and prednisone, donepezil, ethanol, levodopa, morphine, methohexital, tramadol, sulfonamides, pergolide, and piribedil.[18][19][18] Epidural steroid injections with betamethasone, dexamethasone, methylprednisolone, or triamcinolone have also been associated with singultus, particularly in individuals older than 65 years, with symptoms typically resolving spontaneously over time.[20]
Disorders involving the ear, nose, and throat may trigger singultus through local irritation or vagal stimulation. Conditions include pharyngitis, laryngitis, neck cysts, goiter, neoplasms, recent intubation, or foreign bodies contacting the tympanic membrane (eg, hair). Infectious etiologies include Helicobacter pylori, herpes simplex, herpes zoster, malaria, influenza, tuberculosis, neurosyphilis, and COVID-19.[21][22][23] Intrathoracic disorders may provoke singultus via diaphragmatic or pleural irritation and include asthma, bronchitis, diaphragmatic tumors or hernias, pneumonia, pleuritis, pulmonary embolism, mediastinitis, empyema, neoplasms, and lymphadenopathy.
Gastrointestinal pathology remains a dominant contributor to persistent singultus, especially when involving the diaphragm or vagus nerve. Documented causes include aerophagia, gastric distension, bowel obstruction, gastrointestinal or esophageal neoplasms, erosive or infectious esophagitis, gallbladder disease, hepatitis, pancreatitis, peptic ulcer disease, stomach volvulus, and subphrenic abscess.[24][25][24] Metabolic and endocrine disturbances such as hypocalcemia, hypokalemia, hyponatremia, hypocapnia, diabetes mellitus, and uremia have also been implicated.
Psychogenic causes, including stress, somatization, malingering, hyperventilation, and emotional excitation, can provoke or sustain singultus in the absence of identifiable organic disease.[26][27] Surgical procedures may precipitate the symptom through mechanical or pharmacologic mechanisms. Common triggers include sedation during endoscopy (20% incidence), general anesthesia, tracheostomy, bronchoscopy, gastric insufflation during endoscopy, and various anesthetic agents such as barbiturates, bupivacaine, isoflurane, methohexital, and propofol.[28][29]
Epidemiology
Singultus affects all age groups, from the prenatal period to late adulthood. The incidence and prevalence in the general population are unknown, with no consistent differences reported based on racial or geographic factors. (Source: Rajagopalan et al, 2021) Reports estimate up to 4,000 hospital admissions annually in the U.S. for singultus-related complaints.[30][31] In a retrospective analysis of hospitalized patients, the incidence of singultus was 55 per 100,000, approximately half of which were considered persistent. No cases of chronic singultus were identified.[32] Intractable singultus shows a predominance in older men, with an odds ratio of 2.4, and greater height and weight have also been associated with increased risk.[33][34]
The incidence of persistent singultus is elevated in certain populations. People with neurologic conditions such as Parkinson disease demonstrate a heightened risk for persistent singultus. The incidence may be as high as 4% to 9% in individuals with advanced cancer. Among patients with GERD, the incidence has been reported at 8% to 10%.[35][36] Ergen et al observed singultus in 23% of 160 patients receiving cancer chemotherapy.[37] Wieland et al estimate a broader range, suggesting singultus affects 15% to 40% of individuals with cancer.[38]
Pathophysiology
Singultus is attributed to a complex reflex arc involving 3 principal components. Any process affecting one or more of these components may initiate the reflex.
The afferent limb is composed of the vagus nerve, the phrenic nerve, and sympathetic fibers innervating the thoracic and abdominal viscera. Central processing likely occurs through interactions among brainstem and midbrain structures, including the medulla oblongata, reticular formation, periaqueductal gray, glossopharyngeal and phrenic nerve nuclei, solitary and ambiguous nuclei, hypothalamus, temporal lobes, and the upper cervical spinal cord (C3 to C5). Central neurotransmitters implicated in singultus include dopamine, γ-aminobutyric acid (GABA), and serotonin.[39] The efferent limb consists primarily of the phrenic nerves innervating the diaphragm and accessory nerves supplying the intercostal muscles.
Singultus typically occurs in cycles of 4 to 60 per minute. The diaphragmatic contraction is often unilateral, with the left hemidiaphragm more commonly affected. The reflex is completed by recurrent laryngeal nerve (RLN) activation, leading to abrupt glottic closure. Absence of glottic closure would otherwise result in hyperventilation. Suppression of singultus may occur through elevations in the partial pressure of carbon dioxide (PCO2), vagal maneuvers, GABA-ergic agents such as baclofen, gabapentin, and pregabalin, and dopaminergic agents, either antagonists such as chlorpromazine, haloperidol, metoclopramide, and levosulpiride, or agonists such as amantadine. Persistent singultus may represent a form of diaphragmatic myoclonus associated with hyperactivity of the solitary nucleus in the medulla.[40][41][42][43]
Recent findings suggest that transforming growth factor β (TGF-β) may influence the singultus reflex through modulation of GABA neurotransmission. Transforming growth factor β enhances dopaminergic growth and regulates the GABAergic system, potentially through interaction with the scaffolding protein gephyrin. This interaction may inhibit gephyrin phosphorylation and thereby increase GABAergic activity.
Additionally, the nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2–ARE) signaling pathway, which governs antioxidant enzyme expression in response to oxidative stress, may play a role in singultus inhibition. Although reports linking oxidative stress and singultus are limited, drugs associated with singultus, including dexamethasone and nicotine, are known to induce oxidative stress, raising the possibility that oxidative mechanisms contribute to the pathogenesis or modulation of singultus.[44]
History and Physical
Evaluation of singultus requires a detailed medical history. Potential triggers, such as large meals, emotional stress, or excitement, should be elicited. Associated symptoms should be assessed, including gastroesophageal reflux, coughing, abdominal pain, or unintentional weight loss. Neurologic complaints should raise suspicion for central processes such as medullary stroke, multiple sclerosis, or Parkinson disease. Singultus occurring during sleep, while uncommon, may indicate underlying gastroesophageal, neurologic, or pulmonary pathology and generally excludes a psychogenic origin. Recent surgical procedures, a history of malignancy, or exposure to chemotherapy should prompt further inquiry. A comprehensive medication review is essential. Resolution of symptoms after withdrawal of a suspected agent supports causality.
Investigation for organic causes is warranted in patients with persistent or intractable singultus. Head and neck examination may identify sources such as foreign bodies contacting the tympanic membrane, masses, goiters, tonsillitis, or pharyngitis. Pulmonary evaluation should include auscultation for findings consistent with pneumonia or empyema. Abdominal palpation may reveal tenderness or mass suggestive of obstruction, volvulus, pancreatitis, hepatitis, or intraabdominal neoplasm. A complete neurologic examination is necessary to evaluate for CNS pathology. However, singultus is rarely the sole presenting symptom of CNS disease.
Evaluation
Acute singultus is typically benign and self-limiting, requiring no further workup. In contrast, persistent and intractable singultus warrant thorough evaluation to identify a reversible cause. Laboratory testing may uncover electrolyte abnormalities or reveal infectious or neoplastic conditions not evident on history and physical examination. Useful studies include serum electrolytes, calcium, blood urea nitrogen, creatinine, lipase, and liver function tests. Chest radiography may reveal intrathoracic sources such as pneumonia, empyema, diaphragmatic hernia, lymphadenopathy, or aortic pathology.[45]
The duration of singultus, along with historical and physical findings, should guide additional imaging and diagnostic interventions. In patients with persistent or intractable singultus accompanied by neurologic symptoms or signs, brain imaging with computed tomography or magnetic resonance imaging may identify stroke, multiple sclerosis, tumor, syringomyelia, neuromyelitis optica, aneurysm, or vascular malformation.[46] In select cases, cerebrospinal fluid analysis may be required to evaluate for meningitis or encephalitis. Thoracic or abdominal computed tomography may reveal malignancy, aneurysm, abscess, or hernia. Referral for upper endoscopy is appropriate when singultus persists despite initial treatment with antacids or proton pump inhibitors (PPIs), particularly to assess for esophageal lesions such as malignancy.
Arterial blood gas analysis is critical in ventilated patients who develop singultus. Ventilator-associated singultus can lead to desynchronization, respiratory compromise, and significant hemodynamic instability.[47]
Treatment / Management
Acute singultus often resolves with simple physical maneuvers supported by anecdotal evidence. Most techniques target components of the hiccup reflex arc. The frequency of singultus decreases with rising PCO2, making breath-holding, Valsalva maneuvers, and rebreathing into a paper bag potentially therapeutic.[48]
Supra-supramaximal inspiration involves complete exhalation, followed by deep inhalation held for 10 seconds, then 2 additional inhalations, each held for 5 seconds without exhaling in between.[49] Additional approaches stimulate the vagus nerve through the ear, nose, or throat. Examples include cold drinks, tongue traction, carotid sinus pressure, eyeball pressure, bilateral stimulation of the external auditory canals, sipping vinegar, swallowing sugar, stimulating the uvula or posterior nasopharynx with smelling salts or vinegar, Valsalva maneuver, gargling, gagging, or self-induced emesis.[50][51](B3)
Anecdotal reports describe nasal spraying of 0.1 mL of grain vinegar via a 2.5 mL injector to terminate singultus.[52] Commercial products include HiccAway™ (Aim Dynamics), a device designed to generate high-negative intrathoracic pressure via breath-holding and swallowing, and Hiccupops® (Meter Health), a textured sugar-vinegar lollipop.[53][54] Unconventional techniques such as sexual stimulation and digital rectal massage have also been reported.[55][56] Suboccipital release and osteopathic or chiropractic manipulation may offer benefit in select cases.[57][58](B3)
These interventions tend to be most effective in the acute phase. Persistent singultus is often multifactorial and more resistant to physical maneuvers.
Important steps in treating persistent and intractable singultus include identifying any medications known to induce singultus and evaluating for GERD. Discontinuation of an offending agent or substitution with an alternative, such as methylprednisolone instead of dexamethasone, can resolve medication-induced cases.[59] Withdrawal of benzodiazepines may also improve symptoms, particularly when the onset of singultus coincides with their use. As many as 80% of persistent cases are associated with GERD, and a therapeutic trial of antacids, H2-receptor antagonists such as famotidine, or PPIs like omeprazole, may be effective. This strategy has been proposed as first-line therapy.[60][61](B2)
For persistent singultus, most studies focus on pharmacologic agents targeting one or more portions of the reflex arc. These therapies act on neurotransmitter pathways, classified as central or peripheral, although some affect both. Central neurotransmitters include GABA, dopamine, and serotonin, while peripheral targets include acetylcholine, histamine, epinephrine, and norepinephrine.
Baclofen and gabapentin are increasingly regarded as 1st-line therapies for persistent and intractable singultus due to their demonstrated efficacy and favorable side effect profiles. In contrast, dopamine antagonists such as chlorpromazine, haloperidol, and metoclopramide may be considered 2nd-line options, primarily for short-term use, given the risk of adverse effects and regulatory concerns regarding long-term safety. (Source: Diaz-Mayoral et al, 2024)
Baclofen reduces neuroexcitation and promotes muscle relaxation, with demonstrated benefit in cases related to stroke or idiopathic causes not associated with GERD.[62][63][64] Gabapentin, structurally related to GABA, decreases neuroexcitation by binding voltage-gated calcium channels and inhibiting excitatory neurotransmitter release. In a case series, gabapentin achieved 66% to 88% efficacy in patients with cancer or brainstem stroke.(A1)
Chlorpromazine has historically been the preferred agent and remains the only drug approved by the U.S. Food and Drug Administration for treating singultus. The efficacy of this drug stems from antagonism at multiple central and peripheral sites, including dopamine, serotonin, histamine, α-adrenergic, and muscarinic receptors. However, this broad activity increases the likelihood of adverse effects. Other typical antipsychotics, such as haloperidol and risperidone, have been used with varying success, though side effects may limit tolerability.
Metoclopramide acts centrally as a dopamine antagonist and peripherally by enhancing gastric motility. This drug has shown effectiveness in relieving singultus in patients with cancer, stroke, and brain tumors.[65] However, as mentioned, use should be restricted to short-term applications.(B3)
A wide range of additional agents has been proposed based on anecdotal evidence, including amantadine, amitriptyline, anticonvulsants (phenytoin, valproic acid, carbamazepine), antipsychotics (haloperidol, risperidone, olanzapine), atropine, benzonatate, carvedilol, glucagon, ketamine, midazolam, nifedipine, nimodipine, orphenadrine, and the centrally acting sympathomimetic, nonopioid analgesic nefopam.[66][67][68] Pregabalin has also been reported to reduce persistent singultus, particularly when introduced following benzodiazepine withdrawal.
Various intravenous agents have been used for intraoperative singultus, including atropine, ephedrine, dexmedetomidine, ketamine, and lidocaine.[69][70][71] Local anesthetics have also been administered using other methods, such as subcutaneous infusion. Other examples include the transmucosal route for oral viscous lidocaine and the transcutaneous mode for lidocaine gel applied to the external auditory canal.[72][73][74](B3)
In rare cases, intractable singultus unresponsive to pharmacologic therapy may require invasive interventions such as vagus nerve stimulation or block, phrenic nerve block, stellate ganglion block, or cervical epidural block. For example, vagus nerve stimulation has been used for intractable singultus with variable outcomes.[75][76] Notably, hiccups have been reported as a side effect following vagal nerve stimulator insertion for seizure management.[77](B3)
Ultrasound-guided phrenic nerve block has achieved resolution of intractable singultus in several reports.[78][79][80][81] Repeat procedures or continuous infusions through a cannula are seldom necessary. Although transient diaphragmatic paralysis results, the intervention is usually well tolerated in patients with preserved pulmonary function. Caution is advised in individuals with contralateral diaphragm paralysis, diaphragmatic hernia, asthma, or other respiratory compromise.(B3)
Using a small volume of anesthetic may reduce the risk of respiratory dysfunction due to diaphragmatic paralysis.[82] Even with ultrasound guidance, identifying the phrenic nerve may be difficult given its small diameter. Nerve stimulation may assist localization. Complications include brachial plexus blockade, pneumothorax, vascular injury, and, rarely, local anesthetic systemic toxicity.[83] Pulsed radiofrequency lesioning of the phrenic nerve has also been reported as a less destructive alternative to phrenectomy or crush techniques.[84](B3)
Although the exact mechanism is unclear, ultrasound-guided stellate ganglion block has been effective in resolving intractable singultus.[85][86][87] A right-sided approach may be preferred to avoid the thoracic duct and the RLN, as well as the increased risk of pneumothorax on the left. Complications include persistent Horner syndrome (transient Horner syndrome is expected), phrenic nerve block, hoarseness from RLN injury, vascular injury, pneumothorax, hypertension, airway compromise from swelling or hematoma, epidural or intrathecal injection with high spinal anesthesia, and damage to the stellate ganglion, thyroid, esophagus, or trachea, as well as local anesthetic systemic toxicity.(B3)
Intractable singultus has also responded to continuous cervical epidural infusion of ropivacaine and intrathecal baclofen pump placement.[88][89][90] Cervical epidural administration is invasive and may lead to epidural abscess, vascular injury, postdural puncture syndrome, total spinal block with bradycardia, hypotension, and respiratory compromise, myoclonus, numbness, or weakness.
Small trials support the use of acupuncture for intractable singultus, particularly in cancer and stroke.[91][92][93] Wang et al reviewed 16 studies involving 1,206 patients with stroke and found a significantly higher cessation rate and reduction in Hiccup Symptom Score with acupuncture compared to control in most studies.[94] Given the low complication rate and potential benefit, acupuncture may be a reasonable option for patients who are of advanced age or too ill for pharmacotherapy or invasive procedures.[95] Positive pressure ventilation with elective intubation has also been effective in isolated reports.[96] External cervical repetitive peripheral magnetic stimulation has shown success in a small case series.[97](A1)
Note that, although several invasive and nonconventional interventions have been described, the supporting evidence remains limited to case reports, small series, or low-quality trials. High-quality comparative studies are lacking, and these modalities should be considered only after failure of conservative and pharmacologic therapies.
Differential Diagnosis
The diagnosis of singultus is typically straightforward, although it may occasionally be mistaken for coughing or gagging. Numerous medications have been implicated as triggers. Singultus may arise during anesthesia, endoscopy, sedation, or the postoperative period. This symptom is frequently a manifestation of underlying disease, with a broad differential that includes disorders of the ear, nose, throat, CNS, and cardiovascular and gastrointestinal systems, as well as infectious, intrathoracic, metabolic, and psychogenic sources.
Prognosis
Singultus is usually self-limited and relatively benign. Addressing the underlying cause typically reduces both frequency and duration.
Complications
Acute singultus may cause transient discomfort, GERD, emotional disturbance, and, rarely, aspiration. However, persistent and intractable singultus can significantly impair quality of life, reducing oral intake and leading to dehydration, malnutrition, fatigue, and weight loss, along with insomnia, despair, depression, and exhaustion. In intubated patients in intensive care, singultus may cause ventilator desynchronization and hemodynamic instability. Singultus can complicate surgical outcomes and compromise the integrity of postoperative thoracic or abdominal wounds. Forceful episodes have been associated with bradycardia, carotid dissection, barotrauma presenting with pneumothorax or pneumomediastinum, and reduced venous return resulting in hypotension.[98]
Deterrence and Patient Education
Singultus is often benign and self-limiting. Patients with acute episodes may be advised to attempt the aforementioned physical maneuvers and should receive reassurance. In healthy individuals without an apparent etiology for persistent or intractable singultus, empirical treatment for reflux may provide relief. Patient education and interventions aimed at improving reflux and gastrointestinal motility are reasonable initial steps. Clinicians should also counsel patients on the symptom's potential impact on quality of life.
Pearls and Other Issues
Most cases of singultus are self-limited, but persistent or intractable episodes demand further attention. The following points provide a concise guide for clinicians:
- Extensive diagnostic workup is typically unnecessary in healthy individuals presenting with acute singultus.
- Acute episodes often resolve with maneuvers that increase PCO2 or stimulate the vagus nerve.
- Persistent singultus may be induced by medications, particularly dexamethasone, benzodiazepines, opioids, chemotherapeutic agents, and anti-Parkinson drugs.
- GERD is a frequent cause of persistent singultus. Empirical treatment with antacids, histamine-2 receptor antagonists, or PPIs is a reasonable 1st-line approach in the absence of other findings.
- GABA agonists and dopamine antagonists are commonly used in cases of persistent singultus, particularly when associated with malignancy or neurologic disease. Baclofen and gabapentin are often preferred for long-term treatment due to their favorable side effect profiles and demonstrated efficacy in these settings.
- Intractable singultus cases that do not respond to medical therapy may require invasive interventions such as vagus nerve stimulation or phrenic or stellate ganglion nerve blockade.
- No universally accepted guidelines currently exist. Most management strategies for singultus are based on case reports, small series, and clinical judgment.
Awareness of common causes and initial treatments can significantly improve patient outcomes. When medical therapy fails, timely referral for interventional procedures may be warranted.
Enhancing Healthcare Team Outcomes
Patients with persistent or intractable singultus may present to emergency departments, urgent care centers, community health clinics, or primary care settings. Providers in these contexts may initiate treatment based on the clinical history and physical examination. A complete evaluation is necessary to exclude serious underlying conditions, and any concerning findings should prompt specialist consultation. Triage nurses and other frontline providers must recognize that, while singultus may appear trivial, the symptom warrants a detailed history and focused examination.
Referral to a specialist is appropriate when an underlying condition is evident or suspected, the patient is not a candidate for outpatient therapy, or initial outpatient treatment fails. Further evaluation may require consultation with gastroenterology for endoscopy, or with otolaryngology, neurology, or pulmonology. In rare, refractory cases, referral to anesthesiology, pain medicine, or interventional radiology for nerve blockade may be indicated.
Singultus is not uncommon in patients with advanced cancer receiving hospice care. Given the potential impact on quality of life, palliative care clinicians should consider developing treatment protocols specifically for recurrent singultus in this population. Recent investigations highlight that singultus can provoke shame, social withdrawal, and even suicidality, particularly when the symptom is misunderstood or inadequately treated. Early referral to specialists or interprofessional symptom management teams may help address complex cases and provide a more holistic approach to care.
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