Singultus

Justin Cole; Michael Plewa

Singultus

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Continuing Education Activity

Hiccups can be acute, lasting less than 48 hours, persistent, lasting over 2 days, or intractable, lasting more than one month. They can result from a variety of causes. In particular, hiccups are often caused by gastrointestinal disorders such as gastroesophageal reflux. Other causes include medication side-effects, cardiovascular disorders, central nervous system disorders, ear, nose, and throat disorders, psychogenic disorders, or metabolic disorders. Ths activity reviews the spectrum of hiccups from acute to intractable, outlines the causes, and offers recommendations for medical treatment based on clinical presentation. This activity stresses the role of the interprofessional team in the care of affected patients.

Objectives:

Outline medications and medical conditions known to cause hiccups.
Describe useful bedside maneuvers for aborting acute hiccups.
Identify medical therapies for aborting persistent or intractable hiccups.
Explain a well-coordinated interprofessional team approach to provide effective care to patients affected by persistent or intractable hiccups.

Introduction

Hiccups are a not uncommon occurrence that most people experience at some point in their lifetime. The medical term is singultus, which derives from the Latin “singult” meaning ‘to catch one’s breath while sobbing.’ Hiccups result from a sudden and involuntary contraction of the diaphragm and intercostal muscles. An abrupt closure of the glottis follows the contractions which produces the characteristic “hic” sound. Often, these episodes are transient and resolve within 48 hours. They can occur in adults, children, infants, and in utero. In adults, they serve no physiological purpose. The belief is that they may play a role in respiratory muscle training in utero.[1] Acute hiccups can be uncomfortable, and a brief annoyance, however persistent and intractable hiccups have a significant impact on quality of life by interfering with eating, sleeping, speaking, and social activities, and can be a harbinger of serious medical pathology.[2]

Etiology

The classification of hiccups is by their duration. Acute hiccups are of less than 48 hours duration, persistent last over 2 days, and intractable last over a month. As acute hiccups are self-limited and usually unreported, most of the research has focused on persistent and intractable hiccups. There are various causes of hiccups including organic causes, psychogenic, idiopathic, or medication-induced. Persistent and intractable hiccups may signify a more serious underlying etiology.

Gastrointestinal processes, particularly gastroesophageal reflux disease (GERD) and associated hiatal hernias, are implicated as the most common cause of acute hiccups.[3][4] The incidence of hiccups in GERD patients has been reported as high as 10%.[5] Distension of the stomach by large meals or carbonated beverages or irritation from spicy foods or alcohol are common associations. In patients with esophageal tumors, as many as one in four can present with persistent hiccups.[6] Similarly, overexcitement or anxiety, especially if accompanied by over breathing or air swallowing (such as with laughing fits), can trigger the hiccups reflex. [7]

Many drugs correlate with hiccups, especially alcohol. Some drugs, such as benzodiazepines, have a dose-dependent and an inverse relationship with hiccups. At low doses, benzodiazepines correlate with the development of hiccups. At higher doses, they may be useful in the treatment of hiccups. Chemotherapeutic agents and some glucocorticoids have shown a strong association with hiccups. Nearly 42% of patients taking both cisplatin and dexamethasone develop hiccups.[8][9] Other medications associated with hiccups include various chemotherapeutic agents, alpha-methyldopa and inhaled anesthetics.

Numerous reports exist of persistent and intractable hiccups due to a multitude of etiologies, including:

Cardiovascular disorders: atrial pacing, aortic aneurysm (thoracic or abdominal), catheter ablation of atrial fibrillation, myocardial infarction, pericarditis, temporal arteritis
Central nervous system (CNS) disorders: aneurysms (especially posterior inferior cerebellar artery), encephalitis, lateral medullary syndrome,[10] meningitis, multiple sclerosis, neuromyelitis optica,[11] neoplasms (astrocytoma, brain stem tumor), Parkinson disease, seizure, stroke, syringomyelia, vascular malformations (cavernoma)[12][13][14]
Drugs: alpha-methyldopa, aripiprazole, azithromycin, benzodiazepines (diazepam, midazolam), chemotherapeutics (carboplatin, cisplatin, etoposide, fluorouracil, irinotecan, levofolinate, oxaliplatin), dexamethasone, donepezil, ethanol, levodopa, methohexital, morphine, pergolide, piribedil, sulfonamides, tramadol
ENT disorders: a cough, foreign body irritation of tympanic membrane (e.g., hair), goiter, laryngitis, neck cyst, neoplasms, pharyngitis, recent intubation
Infectious disorders: Helicobacter pylori, herpes simplex, herpes zoster, influenza, malaria, neurosyphilis, tuberculosis
Intrathoracic disorders: asthma, bronchitis, diaphragmatic tumor or a hernia, empyema, lymphadenopathy, mediastinitis, neoplasms, pleuritis, pneumonia, pulmonary embolus
Gastrointestinal disorders: aerophagia, bowel obstruction, gastric distention, esophageal cancer, esophagitis (infectious or erosive),[15] gallbladder disease, gastric distention, hepatitis, neoplasms, pancreatitis, peptic ulcer disease, stomach volvulus, subphrenic abscess
Metabolic/endocrine disorders: hypocapnia, hypocalcemia, hypokalemia, hyponatremia, diabetes mellitus, uremia
Psychogenic disorders: excitation, hyperventilation, malingering, somatization, stress[16][17]
Surgery: anesthetic agents (barbiturates, bupivacaine epidural, isoflurane, methohexital, propofol), bronchoscopy, gastric insufflation during endoscopy, post-operative,[18] tracheostomy, sedation during endoscopy (20% incidence)[19]

Epidemiology

Hiccups occur in all ages, from in utero to the elderly. The incidence and prevalence of hiccups in the community are unknown, and there does not appear to be differences based on racial or geographic variation. Reports suggest there are as many as 4,000 admissions yearly in the U.S. for hiccups.[20] Intractable hiccups have a predominance for older males, with an odds ratio of 2.4, and those with greater height and weight.[5][21][22][23] The incidence of persistent hiccups is higher in patients with certain disorders, especially those with central nervous system disorders such as Parkinson’s Disease, advanced cancer where the incidence may be as high as 4-9%, and 8-10% in those with gastroesophageal reflux disease (GERD).[7][5][24][25]

Pathophysiology

Hiccups are thought to be due to a complex reflex arc composed of three main units. Any condition that acts on one of these pathways has the potential to induce hiccupping.

First, the afferent limb is composed of the vagus nerve, the phrenic nerve, and the peripheral sympathetic nerves supplying the viscera. Second, the central processing unit likely involves the interaction between various midbrain and brainstem structures, such as the medulla oblongata and reticular formation, chemoreceptors in the periaqueductal gray, glossopharyngeal and phrenic nerve nuclei, solitary and ambiguous nuclei, hypothalamus, temporal lobes and upper spinal cord at levels C3 to 5.[9][20] Central neurotransmitters involved in this reflex include dopamine, gamma-aminobutyric acid (GABA) and serotonin.[20][26] Third, the efferent portion of the reflex is composed of the phrenic nerve supplying the diaphragm and the accessory nerves supplying the intercostal muscles.[20]

Hiccups commonly repeat at cycles of 4 to 60 per minute, depending on the individual. The diaphragmatic spasm is often unilateral, and the left hemidiaphragm is involved more than the right.[2] After diaphragmatic spasm, the reflex is completed by activation of the recurrent laryngeal nerve causing closure of the glottis. Without closure of the glottis, hyperventilation would occur.[20] Hiccups are inhibited by elevations in partial pressure of carbon dioxide (PCO2), vagal maneuvers, GABA-ergic agents (such as baclofen, gabapentin) and dopamine antagonists (such as chlorpromazine, haloperidol, metoclopramide) or agonists (amantadine).[26] Hiccups become persistent as a form of diaphragmatic myoclonus due to excess activity of the solitary nucleus of the medulla.[27][28]

History and Physical

Evaluating a patient with hiccups warrants a thorough medical history review. Ask about precipitating causes, such as large meals, excitement or emotional stress. Inquire regarding associated symptoms such as gastroesophageal reflux, coughing, weight loss, and abdominal pain. Ask about neurologic symptoms that might suggest a medullary stroke, multiple sclerosis or Parkinson's disease. Hiccups during sleep are uncommon and can occur with gastroesophageal, neurologic or pulmonary disorders, but negate psychogenic cause. Ask about recent surgery, known cancer or chemotherapy. A detailed medication review may identify a likely cause, and if discontinuing this offending medication provides significant relief then causality is confirmed.

In cases of persistent and intractable hiccups, one should investigate organic causes. A full HEENT evaluation may reveal processes such as a hair or foreign body pressing against the tympanic membrane, masses, goiters, tonsillitis, and pharyngitis. Listen to the lung sounds to assess for thoracic causes such as pneumonia or empyema. Palpate the abdomen for tenderness or mass to exclude obstruction, volvulus, pancreatitis, hepatitis or mass. A full neurological exam may expose CNS pathology such as strokes and tumors, though it is rare for hiccups to be the only presenting symptom.

Evaluation

Acute hiccups are typically benign and usually do not require a workup, however persistent and intractable hiccups should trigger a thorough evaluation to identify a treatable cause. It is reasonable to obtain lab work for evaluation of electrolyte abnormalities or to rule out infectious and neoplastic processes not identified on history and physical exam. Laboratory studies such as electrolytes, calcium, blood urea nitrogen (BUN), creatinine, lipase, and liver tests can be useful. A chest radiograph may identify intrathoracic sources of hiccups such as pneumonia, empyema, diaphragmatic hernia, adenopathy or aortic disease.[29]

The guiding of further imaging or interventions is best by the duration of hiccups, history and physical exam findings. For persistent or intractable hiccups associated with neurologic symptoms or signs, brain imaging by computerized tomography (CT) or magnetic resonance imaging (MRI) may demonstrate causes such as stroke, multiple sclerosis, tumor, syringomyelia, neuromyelitis optica, aneurysm or vascular malformation.[30] In rare cases, cerebrospinal fluid is necessary to exclude meningitis or encephalitis. For some cases, thoracic or abdominal CT imaging may identify cancer, aneurysm, abscess or a hernia. Referral to gastroenterology for upper endoscopy is essential to exclude lesions (such as esophageal cancer) in those cases of persistent hiccups refractory to initial antacid and proton pump inhibitor therapy.

It is essential to review blood gases in any ventilated patient that develops hiccups. Hiccups in ventilated patients may cause ventilator desynchronization, severe respiratory derangements, and hemodynamic changes.[31]

Treatment / Management

In the acute phase, hiccups are likely to be terminated by a variety of simple physical maneuvers supported by anecdotal evidence. Most of the maneuvers aim for some portion of the hiccup reflex arc. The frequency of hiccups decrease as PCO2 rises,[32] so Valsalva, breath holding, and breathing into a paper bag may be therapeutic. Supra-supramaximal inspiration is a technique where subject exhales completely, then inhale deeply and hold for 10 seconds, then without exhaling inhale two times again, each time holding for 5 seconds.[33] Other techniques include stimulation of the vagus nerve through the nose, ear, and throat by using cold drinks, pulling on the tongue,[34] pressure on the carotid, eyeballs or in both external auditory canals, sipping vinegar, swallowing sugar, stimulating the uvula or posterior nasopharynx (with smelling salts or nasal vinegar), Valsalva maneuver, and gargling, gagging or even self-induced vomiting.[7][35] More bizarre techniques reported have included sexual stimulation and digital rectal massage.[36][37] There are reports of suboccipital release and osteopathic/chiropractic manipulation techniques.[38][39] All of these techniques appear to be much more effective in the acute phase. The persistent phase is usually multifactorial and more difficult to treat.

Important steps in the treatment of persistent and intractable hiccups are, first, to assess whether the patient is using a medication known to induce hiccups, and second, to determine whether hiccups are associated with GERD. Discontinuation of an offending medication or use of an alternative agent (such as methylprednisolone instead of dexamethasone) can resolve medication-induced hiccups.[40] With as many as 80% of persistent hiccup cases related to GERD,[41][3] an initial therapeutic trial of antacids, antihistamines (such as famotidine) or proton pump inhibitor (such as omeprazole) may be successful,[42][41] and this approach has been suggested as first-line therapy.[7]

In the persistent phase, most studies have evaluated pharmacotherapies acting on one or more components of the reflex arc. Pharmacotherapy is aimed at neurotransmitters and can be broken down into central and peripheral treatments though some act on both. The neurotransmitters involved in central processing include GABA, dopamine, and serotonin. Peripherally, they include acetylcholine, histamine, epinephrine, and norepinephrine. Classically, chlorpromazine had been the drug of choice for persistent hiccups and remains the only drug for hiccups approved by the U.S. Food and Drug Administration (FDA). Chlorpromazine acts as an antagonist on multiple central and peripheral neurotransmitter sites including dopamine, serotonin, histamine receptors, alpha-adrenergic receptors, and muscarinic receptors.[20] Due to the multiple sites of action, the drug may have significant side effects for some patients. Other typical antipsychotics, such as haloperidol or risperidone, have been tried with varying degrees of success. Often, the side effects of the typical antipsychotic drugs may be unbearable for the patient.

The most commonly studied drugs for persistent or intractable hiccups are metoclopramide and the GABA agonists baclofen and gabapentin.[26] Compared to the typical antipsychotics, these three drugs have a better side effect profile. If no etiology is found with a thorough exam, metoclopramide, gabapentin or baclofen are reasonable second-line therapies. Metoclopramide acts centrally as a dopamine antagonist and peripherally by increasing gastric motility and has been successful in relief of hiccups from cancer, stroke and brain tumors.[7][43] Baclofen acts to decrease neuroexcitation and induce muscle relaxation and has been effective for intractable hiccups in stroke patients and idiopathic causes without gastroesophageal disease.[44][45][46] Similarly, gabapentin, structurally similar to GABA, decreases neuroexcitation by binding voltage-gated calcium channels and decreasing the release of excitatory neurotransmitters. In one case series, gabapentin has been reported to be 66 to 88% effective in cancer and brainstem stroke patients.[9][24][27]

There are a variety of medications suggested for the treatment of persistent hiccups in anecdotal reports such as amantadine,[47] amitriptyline, antipsychotic agents (haloperidol, risperidone, olanzapine),[9] atropine, benzonatate, carvedilol, glucagon, ketamine, midazolam, nifedipine, nimodipine, orphenadrine, and valproic acid.[26] Treatment for intraoperative hiccups has been with various intravenous medications including atropine, ephedrine, dexmedetomidine, ketamine, and lidocaine.[48] Several other delivery methods have found use with local anesthetic including oral viscous lidocaine,[49] lidocaine gel in the external auditory canal,[50] and subcutaneous infusions.[51]

For cases refractory to medical therapy, more invasive techniques for management include acupuncture, positive pressure ventilation, vagus nerve stimulators,[52]and stellate or phrenic nerve block.[53][54] Small trials support acupuncture with promising results for intractable hiccups in the setting of cancer and stroke.[55][56][57] Given the relatively low complication rate with a potential benefit, it may be a reasonable alternative for some patients who are too sick or elderly to undergo pharmacotherapy or more invasive techniques.[58] Positive pressure ventilation with elective intubation has shown to work in some case reports.[59] If considering cutting or blocking the phrenic nerve for symptomatic relief, it is important to ensure both hemi-diaphragms are functional prior to the procedure.

Differential Diagnosis

The diagnosis of hiccups is relatively easy to make though it could be confused with coughing or gagging
Numerous medications can lead to hiccups
Hiccups may occur during anesthesia, endoscopy, sedation, and during the post-operative period
Hiccups are often a manifestation of other diseases, and the list of differentials can be extensive - these include but are not limited to ear, nose and throat, CNS, cardiovascular, gastrointestinal, infectious, intrathoracic, metabolic and psychogenic disorders

Prognosis

Hiccups are usually a self-limited process and relatively benign. Management of underlying etiologies typically improves the hiccup frequency and duration.

Complications

Acute hiccups result in temporary discomfort, GERD, emotional disturbance and rarely aspiration, however persistent and intractable hiccups can have profound effects on quality of life, with decreased ability to tolerate oral intake leading to dehydration, malnutrition, fatigue, and weight loss, as well as insomnia, despair, depression, and exhaustion.[2] Intubated neuro ICU patients who develop hiccups may have complications from ventilatory desynchronization and hemodynamic changes. Hiccups can interfere with surgery or threaten the integrity of post-operative thoracic or abdominal wounds. Forceful hiccups can lead to bradycardia, carotid dissection, barotrauma such as pneumothorax or pneumomediastinum, and decreased venous return leading to hypotension.[60]

Deterrence and Patient Education

Hiccups are often benign and self-limiting. Patients with acute hiccups should be advised to try some aforementioned physical maneuvers and should receive reassurance. In healthy patients with no overt cause for intractable and persistent hiccups, treatment of reflux may provide relief. Patient education and therapies aimed at improving reflux and gastrointestinal motility are reasonable first steps. The provider should give guidance on the potential for any quality of life issues that may occur.

Pearls and Other Issues

An extensive diagnostic workup is usually not necessary in healthy patients with acute hiccup presentations
Acute hiccups can often be easily terminated by maneuvers that increase the partial pressure of carbon dioxide or stimulate the vagus nerve
Persistent hiccups can result from a variety of medications especially dexamethasone, benzodiazepines, opioids, chemotherapeutics, and anti-Parkinson medications
GERD is a common cause of persistent hiccups, and antacids, antihistamines or proton pump inhibitors are recommended as first-line therapy especially when no other cause is identifiable
GABA agonists and dopamine antagonists are standard recommendations for persistent hiccups especially in cases caused by cancer or neurologic disease
Intractable hiccups unrelieved by medications may require invasive intervention such as vagal nerve stimulator or stellate or phrenic nerve block

Enhancing Healthcare Team Outcomes

Those with persistent and intractable hiccups may present to the emergency department, urgent care clinics, health clinics, or to their primary care physicians for evaluation. Providers in these settings may initiate treatment based on history and physical examination. A full history and physical should be obtained to rule out more serious underlying etiologies. Any area of concern should prompt consultation with the appropriate specialist. It is crucial for triage nurses and other healthcare providers to recognize that hiccups may seem insignificant, but the complaint deserves a detailed history and thorough examination.

Consultation and referrals are appropriate if there is an apparent or suspected underlying condition, and the patient is either not a candidate for outpatient therapy or has failed outpatient therapy. Patients who fail initial outpatient therapy and have no apparent cause may require referral to gastroenterology for endoscopy, and/or otolaryngology, neurology or pulmonology. In rare situations, intractable cases might need a referral to anesthesia for nerve block.

Hiccups are not an infrequent complaint among those with cancer in hospice care. As recurrent hiccups can be detrimental to the quality of life, it would be prudent for palliative care physicians and nurses to develop treatment regimens to address these complaints.[24]

Details

References

[1]

Kahrilas PJ, Shi G. Why do we hiccup? Gut. 1997 Nov:41(5):712-3 [PubMed PMID: 9414986]

[2]

SAMUELS L. Hiccup; a ten year review of anatomy, etiology, and treatment. Canadian Medical Association journal. 1952 Oct:67(4):315-22 [PubMed PMID: 13009550]

[3]

de Hoyos A, Esparza EA, Cervantes-Sodi M. Non-erosive reflux disease manifested exclusively by protracted hiccups. Journal of neurogastroenterology and motility. 2010 Oct:16(4):424-7. doi: 10.5056/jnm.2010.16.4.424. Epub 2010 Oct 30 [PubMed PMID: 21103425]

[4]

García Callejo FJ, Redondo Martínez J, Pérez Carbonell T, Monzó Gandía R, Martínez Beneyto MP, Rincón Piedrahita I. Hiccups. Attitude in Otorhinolaryngology Towards Consulting Patients. A Diagnostic and Therapeutic Approach. Acta otorrinolaringologica espanola. 2017 Mar-Apr:68(2):98-105. doi: 10.1016/j.otorri.2016.05.005. Epub 2016 Aug 16 [PubMed PMID: 27542994]

[5]

Rey E, Elola-Olaso CM, Rodríguez-Artalejo F, Locke GR 3rd, Díaz-Rubio M. Prevalence of atypical symptoms and their association with typical symptoms of gastroesophageal reflux in Spain. European journal of gastroenterology & hepatology. 2006 Sep:18(9):969-75 [PubMed PMID: 16894310]

[6]

Khorakiwala T, Arain R, Mulsow J, Walsh TN. Hiccups: an unrecognized symptom of esophageal cancer? The American journal of gastroenterology. 2008 Mar:103(3):801. doi: 10.1111/j.1572-0241.2007.01612_4.x. Epub [PubMed PMID: 18341501]

[7]

Steger M, Schneemann M, Fox M. Systemic review: the pathogenesis and pharmacological treatment of hiccups. Alimentary pharmacology & therapeutics. 2015 Nov:42(9):1037-50. doi: 10.1111/apt.13374. Epub 2015 Aug 25 [PubMed PMID: 26307025]

[8]

Liaw CC, Wang CH, Chang HK, Wang HM, Huang JS, Lin YC, Chen JS. Cisplatin-related hiccups: male predominance, induction by dexamethasone, and protection against nausea and vomiting. Journal of pain and symptom management. 2005 Oct:30(4):359-66 [PubMed PMID: 16256900]

[9]

Chang FY, Lu CL. Hiccup: mystery, nature and treatment. Journal of neurogastroenterology and motility. 2012 Apr:18(2):123-30. doi: 10.5056/jnm.2012.18.2.123. Epub 2012 Apr 9 [PubMed PMID: 22523721]

[10]

Sampath V, Gowda MR, Vinay HR, Preethi S. Persistent hiccups (singultus) as the presenting symptom of lateral medullary syndrome. Indian journal of psychological medicine. 2014 Jul:36(3):341-3. doi: 10.4103/0253-7176.135397. Epub [PubMed PMID: 25035568]

[11]

Wang KC, Lee CL, Chen SY, Lin KH, Tsai CP. Prominent brainstem symptoms/signs in patients with neuromyelitis optica in a Taiwanese population. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2011 Sep:18(9):1197-200. doi: 10.1016/j.jocn.2010.12.052. Epub 2011 Jul 18 [PubMed PMID: 21764586]

[12]

Amirjamshidi A, Abbassioun K, Parsa K. Hiccup and neurosurgeons: a report of 4 rare dorsal medullary compressive pathologies and review of the literature. Surgical neurology. 2007 Apr:67(4):395-402; discussion 402 [PubMed PMID: 17350413]

[13]

Musumeci A, Cristofori L, Bricolo A. Persistent hiccup as presenting symptom in medulla oblongata cavernoma: a case report and review of the literature. Clinical neurology and neurosurgery. 2000 Mar:102(1):13-7 [PubMed PMID: 10717396]

Level 3 (low-level) evidence

[14]

Zingale A, Chiaramonte I, Consoli V, Albanese V. Distal posterior inferior cerebellar artery saccular and giant aneurysms: report of two new cases and a comprehensive review of the surgically-treated cases. Journal of neurosurgical sciences. 1994 Jun:38(2):93-104 [PubMed PMID: 7891199]

Level 3 (low-level) evidence

[15]

Pooran N, Lee D, Sideridis K. Protracted hiccups due to severe erosive esophagitis: a case series. Journal of clinical gastroenterology. 2006 Mar:40(3):183-5 [PubMed PMID: 16633116]

Level 2 (mid-level) evidence

[16]

Theohar C, McKegney FP. Hiccups of psychogenic origin: a case report and review of the literature. Comprehensive psychiatry. 1970 Jul:11(4):377-84 [PubMed PMID: 5433924]

Level 3 (low-level) evidence

[17]

Mehra A, Subodh BN, Sarkar S. Psychogenic hiccup in children and adolescents: a case series. Journal of family medicine and primary care. 2014 Apr:3(2):161-3. doi: 10.4103/2249-4863.137666. Epub [PubMed PMID: 25161977]

Level 2 (mid-level) evidence

[18]

Hansen BJ, Rosenberg J. Persistent postoperative hiccups: a review. Acta anaesthesiologica Scandinavica. 1993 Oct:37(7):643-6 [PubMed PMID: 8249552]

[19]

Liu CC, Lu CY, Changchien CF, Liu PH, Perng DS. Sedation-associated hiccups in adults undergoing gastrointestinal endoscopy and colonoscopy. World journal of gastroenterology. 2012 Jul 21:18(27):3595-601. doi: 10.3748/wjg.v18.i27.3595. Epub [PubMed PMID: 22826626]

[20]

Nausheen F, Mohsin H, Lakhan SE. Neurotransmitters in hiccups. SpringerPlus. 2016:5(1):1357. doi: 10.1186/s40064-016-3034-3. Epub 2016 Aug 17 [PubMed PMID: 27588250]

[21]

Lee GW, Kim RB, Go SI, Cho HS, Lee SJ, Hui D, Bruera E, Kang JH. Gender Differences in Hiccup Patients: Analysis of Published Case Reports and Case-Control Studies. Journal of pain and symptom management. 2016 Feb:51(2):278-83. doi: 10.1016/j.jpainsymman.2015.09.013. Epub 2015 Nov 17 [PubMed PMID: 26596880]

Level 2 (mid-level) evidence

[22]

Hosoya R, Uesawa Y, Ishii-Nozawa R, Kagaya H. Analysis of factors associated with hiccups based on the Japanese Adverse Drug Event Report database. PloS one. 2017:12(2):e0172057. doi: 10.1371/journal.pone.0172057. Epub 2017 Feb 14 [PubMed PMID: 28196104]

[23]

Souadjian JV, Cain JC. Intractable hiccup. Etiologic factors in 220 cases. Postgraduate medicine. 1968 Feb:43(2):72-7 [PubMed PMID: 5638775]

Level 3 (low-level) evidence

[24]

Porzio G, Aielli F, Verna L, Aloisi P, Galletti B, Ficorella C. Gabapentin in the treatment of hiccups in patients with advanced cancer: a 5-year experience. Clinical neuropharmacology. 2010 Jul:33(4):179-80. doi: 10.1097/WNF.0b013e3181de8943. Epub [PubMed PMID: 20414106]

[25]

Calsina-Berna A, García-Gómez G, González-Barboteo J, Porta-Sales J. Treatment of chronic hiccups in cancer patients: a systematic review. Journal of palliative medicine. 2012 Oct:15(10):1142-50. doi: 10.1089/jpm.2012.0087. Epub 2012 Aug 14 [PubMed PMID: 22891647]

Level 1 (high-level) evidence

[26]

Polito NB, Fellows SE. Pharmacologic Interventions for Intractable and Persistent Hiccups: A Systematic Review. The Journal of emergency medicine. 2017 Oct:53(4):540-549. doi: 10.1016/j.jemermed.2017.05.033. Epub [PubMed PMID: 29079070]

Level 1 (high-level) evidence

[27]

Moretti R, Torre P, Antonello RM, Ukmar M, Cazzato G, Bava A. Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a three-year follow up. The neurologist. 2004 Mar:10(2):102-6 [PubMed PMID: 14998440]

[28]

al Deeb SM, Sharif H, al Moutaery K, Biary N. Intractable hiccup induced by brainstem lesion. Journal of the neurological sciences. 1991 Jun:103(2):144-50 [PubMed PMID: 1880531]

[29]

Kolodzik PW, Eilers MA. Hiccups (singultus): review and approach to management. Annals of emergency medicine. 1991 May:20(5):565-73 [PubMed PMID: 2024799]

[30]

Kulkarni GB, Kallollimath P, Subasree R, Veerendrakumar M. Intractable vomiting and hiccups as the presenting symptom of neuromyelitis optica. Annals of Indian Academy of Neurology. 2014 Jan:17(1):117-9. doi: 10.4103/0972-2327.128575. Epub [PubMed PMID: 24753677]

[31]

Howard RS, Radcliffe J, Hirsch NP. General medical care on the neuromedical intensive care unit. Journal of neurology, neurosurgery, and psychiatry. 2003 Sep:74 Suppl 3(Suppl 3):iii10-5 [PubMed PMID: 12933909]

[32]

Davis JN. An experimental study of hiccup. Brain : a journal of neurology. 1970:93(4):851-72 [PubMed PMID: 5490279]

[33]

Morris LG, Marti JL, Ziff DJ. Termination of idiopathic persistent singultus (hiccup) with supra-supramaximal inspiration. The Journal of emergency medicine. 2004 Nov:27(4):416-7 [PubMed PMID: 15498627]

[34]

Petroianu GA. Treatment of singultus by traction on the tongue: an eponym revised. Journal of the history of the neurosciences. 2013:22(2):183-90. doi: 10.1080/0964704X.2012.728389. Epub [PubMed PMID: 23586546]

[35]

Petroianu GA. Treatment of hiccup by vagal maneuvers. Journal of the history of the neurosciences. 2015:24(2):123-36. doi: 10.1080/0964704X.2014.897133. Epub 2014 Jul 23 [PubMed PMID: 25055206]

[36]

Petroianu GA. Treatment of singultus by sexual stimulation: Who was George T Dexter, MD (c1812-?)? Journal of medical biography. 2016 May:24(2):252-61. doi: 10.1177/0967772014525742. Epub 2014 Mar 27 [PubMed PMID: 24677563]

[37]

Fesmire FM. Termination of intractable hiccups with digital rectal massage. Annals of emergency medicine. 1988 Aug:17(8):872 [PubMed PMID: 3395000]

[38]

Seidel B, Desipio GB. Use of osteopathic manipulative treatment to manage recurrent bouts of singultus. The Journal of the American Osteopathic Association. 2014 Aug:114(8):660-4. doi: 10.7556/jaoa.2014.131. Epub [PubMed PMID: 25082974]

[39]

Kwan CS, Worrilow CC, Kovelman I, Kuklinski JM. Using suboccipital release to control singultus: a unique, safe, and effective treatment. The American journal of emergency medicine. 2012 Mar:30(3):514.e5-7. doi: 10.1016/j.ajem.2011.01.012. Epub 2011 Mar 29 [PubMed PMID: 21447433]

[40]

Lee GW, Oh SY, Kang MH, Kang JH, Park SH, Hwang IG, Yi SY, Choi YJ, Ji JH, Lee HY, Bruera E. Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone rotation. The oncologist. 2013:18(11):1229-34. doi: 10.1634/theoncologist.2013-0224. Epub 2013 Oct 9 [PubMed PMID: 24107973]

[41]

Cabane J, Bizec JL, Derenne JP. [A diseased esophagus is frequently the cause of chronic hiccup. A prospective study of 184 cases]. Presse medicale (Paris, France : 1983). 2010 Jun:39(6):e141-6. doi: 10.1016/j.lpm.2010.01.006. Epub 2010 Apr 28 [PubMed PMID: 20427147]

Level 3 (low-level) evidence

[42]

Petroianu G, Hein G, Petroianu A, Bergler W, Rüfer R. Idiopathic chronic hiccup: combination therapy with cisapride, omeprazole, and baclofen. Clinical therapeutics. 1997 Sep-Oct:19(5):1031-8 [PubMed PMID: 9385490]

[43]

Wang T, Wang D. Metoclopramide for patients with intractable hiccups: a multicentre, randomised, controlled pilot study. Internal medicine journal. 2014 Dec:44(12a):1205-9. doi: 10.1111/imj.12542. Epub [PubMed PMID: 25069531]

Level 3 (low-level) evidence

[44]

Zhang C, Zhang R, Zhang S, Xu M, Zhang S. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial. Trials. 2014 Jul 22:15():295. doi: 10.1186/1745-6215-15-295. Epub 2014 Jul 22 [PubMed PMID: 25052238]

Level 1 (high-level) evidence

[45]

Boz C, Velioglu S, Bulbul I, Ozmenoglu M. Baclofen is effective in intractable hiccups induced by brainstem lesions. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2001 Oct:22(5):409 [PubMed PMID: 11917982]

[46]

Guelaud C, Similowski T, Bizec JL, Cabane J, Whitelaw WA, Derenne JP. Baclofen therapy for chronic hiccup. The European respiratory journal. 1995 Feb:8(2):235-7 [PubMed PMID: 7758557]

[47]

Hernandez SL, Fasnacht KS, Sheyner I, King JM, Stewart JT. Treatment of Refractory Hiccups with Amantadine. Journal of pain & palliative care pharmacotherapy. 2015:29(4):374-7. doi: 10.3109/15360288.2015.1101640. Epub [PubMed PMID: 26654411]

[48]

Bahadoori A, Shafa A, Ayoub T. Comparison the Effects of Ephedrine and Lidocaine in Treatment of Intraoperative Hiccups in Gynecologic Surgery under Sedation. Advanced biomedical research. 2018:7():146. doi: 10.4103/abr.abr_82_18. Epub 2018 Nov 27 [PubMed PMID: 30596056]

[49]

Neuhaus T, Ko YD, Stier S. Successful treatment of intractable hiccups by oral application of lidocaine. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2012 Nov:20(11):3009-11. doi: 10.1007/s00520-012-1533-5. Epub 2012 Jul 22 [PubMed PMID: 22820843]

[50]

Thomas RH, Thomas NJ. Miracle hiccough cure gets the attention it deserves. BMJ (Clinical research ed.). 2006 Dec 9:333(7580):1222 [PubMed PMID: 17158401]

[51]

Kaneishi K, Kawabata M. Continuous subcutaneous infusion of lidocaine for persistent hiccup in advanced cancer. Palliative medicine. 2013 Mar:27(3):284-5. doi: 10.1177/0269216312448508. Epub 2012 Jun 1 [PubMed PMID: 22661318]

[52]

Grewal SS, Adams AC, Van Gompel JJ. Vagal nerve stimulation for intractable hiccups is not a panacea: a case report and review of the literature. The International journal of neuroscience. 2018 Dec:128(12):1114-1117. doi: 10.1080/00207454.2018.1486307. Epub 2018 Jul 3 [PubMed PMID: 29882681]

Level 3 (low-level) evidence

[53]

Lee AR, Cho YW, Lee JM, Shin YJ, Han IS, Lee HK. Treatment of persistent postoperative hiccups with stellate ganglion block: Three case reports. Medicine. 2018 Nov:97(48):e13370. doi: 10.1097/MD.0000000000013370. Epub [PubMed PMID: 30508930]

Level 3 (low-level) evidence

[54]

Jeon YS, Kearney AM, Baker PG. Management of hiccups in palliative care patients. BMJ supportive & palliative care. 2018 Mar:8(1):1-6. doi: 10.1136/bmjspcare-2016-001264. Epub 2017 Jul 13 [PubMed PMID: 28705925]

[55]

Moretto EN, Wee B, Wiffen PJ, Murchison AG. Interventions for treating persistent and intractable hiccups in adults. The Cochrane database of systematic reviews. 2013 Jan 31:2013(1):CD008768. doi: 10.1002/14651858.CD008768.pub2. Epub 2013 Jan 31 [PubMed PMID: 23440833]

Level 1 (high-level) evidence

[56]

Choi TY, Lee MS, Ernst E. Acupuncture for cancer patients suffering from hiccups: a systematic review and meta-analysis. Complementary therapies in medicine. 2012 Dec:20(6):447-55. doi: 10.1016/j.ctim.2012.07.007. Epub 2012 Aug 15 [PubMed PMID: 23131378]

Level 1 (high-level) evidence

[57]

Yue J, Liu M, Li J, Wang Y, Hung ES, Tong X, Sun Z, Zhang Q, Golianu B. Acupuncture for the treatment of hiccups following stroke: a systematic review and meta-analysis. Acupuncture in medicine : journal of the British Medical Acupuncture Society. 2017 Mar:35(1):2-8. doi: 10.1136/acupmed-2015-011024. Epub 2016 Jun 10 [PubMed PMID: 27286862]

Level 1 (high-level) evidence

[58]

Ge AX, Ryan ME, Giaccone G, Hughes MS, Pavletic SZ. Acupuncture treatment for persistent hiccups in patients with cancer. Journal of alternative and complementary medicine (New York, N.Y.). 2010 Jul:16(7):811-6. doi: 10.1089/acm.2009.0456. Epub [PubMed PMID: 20575702]

[59]

Byun SH, Jeon YH. Treatment of idiopathic persistent hiccups with positive pressure ventilation -a case report-. The Korean journal of pain. 2012 Apr:25(2):105-7. doi: 10.3344/kjp.2012.25.2.105. Epub 2012 Apr 4 [PubMed PMID: 22514778]

Level 3 (low-level) evidence

[60]

Rousseau P. Hiccups. Southern medical journal. 1995 Feb:88(2):175-81 [PubMed PMID: 7839159]

[61]

Leung AKC, Leung AAM, Wong AHC, Hon KL. Hiccups: A Non-Systematic Review. Current pediatric reviews. 2020:16(4):277-284. doi: 10.2174/1573396316666200508112951. Epub [PubMed PMID: 32384036]

Level 1 (high-level) evidence

[62]

Hosoya R, Ishii-Nozawa R, Kurosaki K, Uesawa Y. Analysis of Factors Associated with Hiccups Using the FAERS Database. Pharmaceuticals (Basel, Switzerland). 2021 Dec 24:15(1):. doi: 10.3390/ph15010027. Epub 2021 Dec 24 [PubMed PMID: 35056084]

[63]

Ehret C, Martin NA, Jatoi A. What percentage of patients with cancer develop hiccups with oxaliplatin- or cisplatin-based chemotherapy? a compilation of patient-reported outcomes. PloS one. 2023:18(1):e0280947. doi: 10.1371/journal.pone.0280947. Epub 2023 Jan 27 [PubMed PMID: 36706101]

[64]

Rao PN, Wu CL, YaDeau JT. Midazolam-Induced Hiccups Reversed by Flumazenil: A Case Report. A&A practice. 2021 Nov 17:15(11):e01547. doi: 10.1213/XAA.0000000000001547. Epub 2021 Nov 17 [PubMed PMID: 34807869]

Level 3 (low-level) evidence

[65]

Bwalya IC. Persistent hiccups after acute COVID-19 successfully treated with chlorpromazine: a case report. Journal of medical case reports. 2024 Jun 19:18(1):294. doi: 10.1186/s13256-024-04500-8. Epub 2024 Jun 19 [PubMed PMID: 38890624]

Level 3 (low-level) evidence

[66]

Prince G, Sergel M. Persistent hiccups as an atypical presenting complaint of COVID-19. The American journal of emergency medicine. 2020 Jul:38(7):1546.e5-1546.e6. doi: 10.1016/j.ajem.2020.04.045. Epub 2020 Apr 18 [PubMed PMID: 32345563]

[67]

Ikitimur H, Borku Uysal B, Ikitimur B, Umihanic S, Smajic J, Jahic R, Olcay A. Case Report: Two Cases of Persistent Hiccups Complicating COVID-19. The American journal of tropical medicine and hygiene. 2021 Apr 1:104(5):1713-1715. doi: 10.4269/ajtmh.21-0190. Epub 2021 Apr 1 [PubMed PMID: 33793414]

Level 3 (low-level) evidence

[68]

Ehret CJ, Almodallal Y, Le-Rademacher JG, Martin NA, Moynagh MR, Rajotia A, Jatoi A. Hiccups in patients with cancer: a multi-site, single-institution study of etiology, severity, complications, interventions, and outcomes. BMC cancer. 2022 Jun 15:22(1):659. doi: 10.1186/s12885-022-09760-5. Epub 2022 Jun 15 [PubMed PMID: 35705907]

[69]

Ergen M, Arikan F, Fırat Çetin R. Hiccups in Cancer Patients Receiving Chemotherapy: A Cross-Sectional Study. Journal of pain and symptom management. 2021 Sep:62(3):e85-e90. doi: 10.1016/j.jpainsymman.2021.02.012. Epub 2021 Feb 13 [PubMed PMID: 33587996]

Level 2 (mid-level) evidence

[70]

Wieland J, Martin N, Jatoi A. Healthcare Providers' Experiences with Hiccups in Patients with Cancer: Report of a United States National Survey. The American journal of hospice & palliative care. 2023 Aug:40(8):872-880. doi: 10.1177/10499091221130042. Epub 2022 Sep 29 [PubMed PMID: 36172916]

[71]

Fong YO, Teng YS, Chen YC, Huang P. Pregabalin is effective in treating prolonged hiccups both with and without brainstem lesion: A report of 2 cases. Journal of the neurological sciences. 2020 Jan 15:408():116517. doi: 10.1016/j.jns.2019.116517. Epub 2019 Oct 31 [PubMed PMID: 31726382]

Level 3 (low-level) evidence

[72]

Chiquete E, Toapanta-Yanchapaxi L, Aceves-Buendía JJ, Ruiz-Ruiz E, Rodríguez-Perea E, Durán-Coyote S, Cantú-Brito C. Levosulpiride Relieved Persistent Hiccups in a Patient With COVID-19 and Vascular Cognitive Impairment. Clinical neuropharmacology. 2021 Sep-Oct 01:44(5):186-188. doi: 10.1097/WNF.0000000000000459. Epub [PubMed PMID: 34238784]

[73]

Ehret CJ, Jatoi A. Establishing the Groundwork for Clinical Trials With Hiccupops(®) for Hiccup Palliation. The American journal of hospice & palliative care. 2022 Oct:39(10):1210-1214. doi: 10.1177/10499091211063821. Epub 2022 Jan 5 [PubMed PMID: 34985350]

[74]

Alvarez J, Anderson JM, Snyder PL, Mirahmadizadeh A, Godoy DA, Fox M, Seifi A. Evaluation of the Forced Inspiratory Suction and Swallow Tool to Stop Hiccups. JAMA network open. 2021 Jun 1:4(6):e2113933. doi: 10.1001/jamanetworkopen.2021.13933. Epub 2021 Jun 1 [PubMed PMID: 34143196]

[75]

Marshall JM, Ladd MD, Weldon BC. Prevention of persistent postoperative hiccups with dexmedetomidine. Journal of clinical anesthesia. 2019 Feb:52():50. doi: 10.1016/j.jclinane.2018.08.033. Epub 2018 Aug 31 [PubMed PMID: 30176504]

[76]

El-Tahan MR, Doyle DJ, Telmesani L, Al'Ghamdi A, Khidr AM, Abdeen MM. Dexmedetomidine suppresses intractable hiccup during anesthesia for cochlear implantation. Journal of clinical anesthesia. 2016 Jun:31():208-11. doi: 10.1016/j.jclinane.2016.02.013. Epub 2016 Apr 16 [PubMed PMID: 27185713]

[77]

Ke X, Wu Y, Zheng H. Successful termination of persistent hiccups via combined ultrasound and nerve stimulator-guided singular phrenic nerve block: a case report and literature review. The Journal of international medical research. 2023 Dec:51(12):3000605231216616. doi: 10.1177/03000605231216616. Epub [PubMed PMID: 38041831]

Level 3 (low-level) evidence

[78]

Cai W, Xu G, Tian Z, Xiong F, Yang J, Wang T. Cervical repetitive peripheral magnetic stimulation relieves idiopathic persistent hiccups: A preliminary study of case report. Medicine. 2022 Oct 28:101(43):e31324. doi: 10.1097/MD.0000000000031324. Epub [PubMed PMID: 36316915]

Level 3 (low-level) evidence