HICCUPS

HICCUPS

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    Mechanistic Description

    Hiccup (Latin, singultus) is caused by an involuntary, usually repetitive and rhythmic, spasmodic contraction of the diaphragm (or hemidiaphragm) and accessory inspiratory muscles followed shortly (within 35 msec) by the sudden closure of the glottis. The forcefully inspired air meeting a closed glottis causes the typical hiccup sound. Occasional hiccups are generally perceived as being “funny”; however, hiccupping of extended duration can be incapacitating. Its most common direct consequence is esophagitis, due to concomitant relaxation of the lower esophageal sphincter favoring reflux, but extended hiccupping can also lead to wound dehiscence, depression, weight loss, malnutrition, insomnia, and exhaustion.

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    Classifications

    Most classifications use arbitrary time limits to categorize hiccupping. Generally hiccups lasting less than 1 day are considered transient (acute), those lasting less than 1 week are labeled persistent, and hiccupping for more than 1 week is described as chronic. A simplified categorization draws the line at 48 hours: any hiccupping episode lasting longer is described as chronic. The practical value of these classifications is questionable; by the time the practitioner sees the patient, almost invariably the case involves persistent or chronic hiccup forms requiring drug therapy. The exceptions (in terms of time between appearance and presentation) are hiccup forms presenting immediately postoperatively or in critical care units. Brief episodes of hiccupping, as experienced by the vast majority of people at some point in time, are certainly physiologic. The point of transition to a pathologic form is not well defined. The rule of thumb of hiccup therapy, however, is that the longer the duration of the hiccupping, the less amenable it will be to nonpharmacologic interventions.

    Etiologic classifications are also fraught with problems. Hiccup is not a disease, but a symptom. Literally, there is no known disease that has not been associated with hiccups. Although the categories psychogenic, organic, and idiopathic are most commonly used in practice, the situation most commonly encountered is that of hiccup of unknown (idiopathic) origin. In this context, “idiopathic” describes one’s inability to demonstrate, rather than the absence of, an organic origin.

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    Epidemiology

    During intrauterine life, hiccups are universally present, their incidence peaking in the third trimester. They can also be seen regularly in the newborn, the frequency of occurrence decreasing slowly over the first year of life. In adults, occasional transient hiccup is also so frequent that it can be viewed as physiologic. Persistent and chronic idiopathic singultus, the pathologic forms, are rare, their prevalence being estimated at 1 in 100,000. Males are almost exclusively affected (the male-to-female patient ratio is approximately 80:1), suggesting a hormone (estrogen) protective effect. The incidence increases with age. The psychogenic form, though less frequent overall by one order of magnitude, is believed to be more prevalent in females, with an even distribution among all age groups; however, data to support this view are almost nonexistent.

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    Pathophysiology

    The universality of hiccups during fetal life begs the question of purposefulness. As early as 1887, it was suggested that hiccups might represent a necessary and vital primitive reflex that would permit intrauterine training of the diaphragm without aspiration of amniotic fluid. During intrapartum and postpartum maturation, higher centers would then suppress this primitive reflex. Immaturity or damage to the central nervous system would favor the persistence or reappearance of the reflex. The putative reflex arch includes autonomic afferent fibers (the majority vagal fibers) from the digestive tract to a putative medullary hiccup center and motor efferent fibers via the phrenic nerve (diaphragm) and other branches of the vagus nerve to the intrinsic muscles of the larynx adducting the vocal cords. In an analogy with the vomiting center, the assumed role of the medullary hiccup center is to coordinate and fine-tune the sequence of events required for hiccupping; it is therefore a “pattern generator.” The concept described, though useful for the purpose of designing a quasi-rational treatment protocol for hiccup, is neither proven nor generally accepted.

    Another school of thought that questions the assumption that hiccupping is a reflex phenomenon suggests instead a similarity with cardiac arrhythmias: hiccups would therefore be due to arrhythmias of the breathing center. Still other researchers work on the assumption that hiccup is a myoclonic event, or that it represents brainstem seizures. These views are not necessarily mutually exclusive, because hiccup is not primarily a disease but a symptom, possibly representing different pathophysiologies.

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    Evaluation of the Hiccup Patient

    Hiccup is a symptom associated with a multitude of pathologies. The practioner must take the hiccupping patient seriously, and for the purpose of finding and treating hidden pathology, persistent and chronic hiccups should be investigated. No consensus exists, however, concerning the extent of such investigations. Even the most enthusiastic users of modern imaging technologies will in most cases end up with a working diagnosis of chronic idiopathic singultus.

    Nonetheless, a detailed history, a thorough physical examination, and basic laboratory and diagnostic procedures are essential.

    History

    Ask about previous episodes, as well as precipitating and alleviating factors. The patient who describes vomiting as a “cure” for previous hiccup episodes gives a telltale sign that acidity is an etiologic factor, and omeprazole is a drug to consider. If the patient indicates that hyperventilation is a “sure bet” to worsen his or her hiccups, you can assume that drugs lowering the excitability of the nervous system are likely to help. Elucidating present drug consumption (medical and recreational) is essential: benzodiazepines, barbiturates, alcohol, and steroids are well-known hiccup inducers.

    Physical Examination

    Foreign bodies in the external auditory canal can induce hiccups, so look in the ears. Examine neck, chest, and abdomen, looking for possible sources of irritation (infection, neoplastic processes, or both) to the vagus and phrenic nerves and the diaphragm. Perform a neurologic examination, keeping in mind the association of hiccup with multiple sclerosis and intracranial processes.

    Laboratory and Diagnostic Procedures

    An upright chest x-ray, together with complete blood count (CBC) with differential, will help exclude neoplastic or infectious disease. An electrocardiogram (ECG) will help exclude pericarditis and malfunctioning pacemakers, and electrolyte and urea determinations will exclude known metabolic causes (hyponatremia and uremia).

    To what extent magnetic resonance imaging (MRI), ultrasound scanning, or endoscopic examinations are necessary is a judgment call, and no generalizations are possible; they might occasionally be indicated.

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    Nonpharmacologic Interventions

    A multitude of nonpharmacologic interventions to terminate hiccup belong to the public-domain hiccup “mythology” or have been described in the medical literature as case reports. Though usually effective in terminating bouts of acute hiccup, they are mostly ineffective in cases of hiccupping that has been present for an extended period. The common denominator of these maneuvers (also used to terminate paroxysmal supraventricular tachycardia) is their ability to directly or indirectly increase efferent vagal activity; the increased parasympathetic tone has a limiting effect on hiccupping.

    Interestingly, estrogens are also considered to be parasympathomimetic, which offers a plausible explanation of why the singultus prevalence in females is much lower than in males.

     

  7. 7
    Pharmacologic Interventions

    Probably only a few drugs in the Physician’s Desk Reference have not been tried in the therapy of singultus, and anyone who looks hard enough at the literature will be able to find anecdotal support for the use of almost any drug. However, prospective controlled studies to support the use of a particular therapy are very few and rare.

    Conceptually, all drugs potentially successful in the therapy of chronic hiccups work either by decreasing the input from the gastrointestinal tract to a (putative) hiccup center or by decreasing the excitability of the nervous system and therefore the output from the (putative) hiccup center.

    Sedative-Hypnotics

    Both benzodiazepine and barbiturate γ-aminobutyric acid receptor type A (GABAA) agonists have been tried for treatment of hiccups.

    The consensus is that these substances not only are ineffective, but can actually worsen the clinical picture, producing a situation similar to the paradoxical excitation seen with the use of sedatives and explained by inhibitory effects on inhibitory centers.

    Antiemetics

    Following up on the analogy between the vomiting center and hiccup center as pattern generators, “setron” class antiemetics (5-HT3 receptor antagonists) have been tried, with no success. Anecdotal evidence hints at possible worsening of the hiccup under the influence of ondansetron (Zofran).1

    Analeptics

    The use of analeptics derives from the concept that hiccup is a suppressed primitive reflex. Analeptics potentiate the central suppression. Although some success has been reported with methylphenidate (Ritalin),1 caffeine produced failure.

    Anticonvulsants

    Anticonvulsants (phenytoin [Dilantin],1 carbamazepine [Tegretol],1 valproate [Depacon]1) have been used to try to suppress hiccups.

    Considering the multitude of pharmacodynamic effects of anticonvulsants, it is not surprising that some success was achieved.

    Antipsychotics

    Historically, chlorpromazine (Thorazine) has been the most widely used drug for treatment of hiccup, and it is the only drug approved by the FDA for the disorder. Aliphatic phenothiazines such as chlorpromazine have strong sedative, hypotensive, and anticholinergic properties and mild to moderate extrapyramidal effects. For hiccup control, results are mixed at best, and in view of the side effects, routine use is not warranted. Haloperidol (Haldol),1 a butyropherone derivative, has also been used for hiccup control; again, results are mixed at best, and the possibility of developing tardive dyskinesia weighs heavily against the routine use of this drug.

    Antidepressants

    The tertiary amine tricyclic antidepressant amitriptyline (Elavil)1 is one of the oldest players in the therapy of hiccup; its use was being suggested in the mid-1960s. As with anticonvulsants, considering the multitude of pharmacodynamic effects of tricyclic antidepressants, it is not surprising that some success was achieved with these drugs.

    Their effectiveness is not related to their ability to inhibit monoamine uptake, but probably to their sodium channel blocking properties.

    Calcium Channel Blockers

    Nifedipine (Adalat)1 is the dihydropyridine derivative most commonly used for hiccup control. Nimodipine (Nimotop)1 has also been tried for the same purpose. Interestingly, anecdotal reports about the use of calcium for the same purpose also exist.

    Sodium Channel Blockers

    The local anesthetic class Ib antidysrhythmic lidocaine (Xylocaine)1 and its oral analogue mexiletine (Mexitil)1 have been used for hiccup control, with mixed results.

    GABAB Agonists

    Among the substances acting on the nervous system, baclofen (Lioresal)1 has by far the best credentials in the treatment of chronic hiccup. It is one of the very few substances proven in clinical studies (albeit with small patient numbers) to be efficacious. This γ- aminobutyric acid receptor type B (GABAB) agonist, normally used to lower an increased muscle tone (spasticity), has also been shown to suppress hiccups in an animal (cat) hiccup model. GABAB agonists, by reducing transmitter release, are generally able to depress complex reflexes.

    Antacids

    Lowering the acidity of the stomach using H2-receptor blockers or proton pump inhibitors conceptually decreases the input from the gastrointestinal tract to the hiccup center. Omeprazole (Prilosec)1 has been shown in a limited number of trials to be effective in hiccup treatment.

    Gastrokinetic Drugs

    One of the few reliable methods to induce a physiologic hiccup in humans is rapidly drinking an ice-cold can of beer on a hot summer day. Although it is highly debatable whether it has to be beer, stomach distention by carbon dioxide induces hiccups. Conversely, reducing stomach distention by using a gastrokinetic drug is helpful in alleviating hiccups. The strongest evidence available for the usefulness of a gastrokinetic drug was for cisapride (Propulsid); however, this selective serotonine 5-HT4-receptor agonist was withdrawn from the market because of its propensity to prolong the QT interval and induce torsades de pointes. The available alternative is the related benzamide metoclopramide (Reglan),1 a mixed dopamine receptor antagonist, 5-HT4-receptor agonist, and cholinesterase inhibitor, with a long tradition in the treatment of hiccups, going back to the late 1960s.

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    Physical Interventions

    Phrenic Nerve Destruction

    Irreversible surgical destruction of the phrenic nerve cannot be recommended. Even if hiccup relief is achieved after unilateral local anesthetic blockade of the phrenic nerve without serious compromise in respiratory function, the long-term effects of phrenic nerve destruction are unpredictable. Possible effects include both hiccup reappearance—even after bilateral phrenic nerve transection—and deterioration in respiratory function. More recently, diaphragmatic (phrenic) pacing has been described; however, experience is very limited.

    Hypercapnia

    Rebreathing in a paper bag is a well-known and reliable remedy for hyperventilation tetany. The increase in blood CO2 levels (hypercapnia) thus induced leads to mild acidosis and thus to a liberation of calcium ions from the protein binding. The increase in plasma-free calcium decreases neuronal excitability, thus terminating not only the tetany, but possibly also hiccupping. A more high-tech version of this is the induction of normoxic hypercapnia in ventilated patients.

    Positive End-Expiratory Pressure

    Also practicable only in intubated patients is the application of high positive end-expiratory pressure (PEEP), a high-tech version of the Valsalva maneuver.

    Nasogastric Tube

    Gastric decompression via a nasogastric tube can terminate hiccups.

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    Treatment

    The treatment algorithm described is based on the assumption that correctable organic causes have been excluded or treated.

    We start therapy with omeprazole (Prilosec)1 20 to 40 mg orally (PO) daily. If after 7 days no satisfactory change has occurred, baclofen (Lioresal)1 is introduced. With baclofen, a “start low, go very slow” approach is indicated in order to avoid excessive drowsiness, weakness, and fatigue. The maximum daily dose is 45 mg. Quite often, patients are already on a proton pump inhibitor (PPI) when presenting. In these cases, immediate introduction of baclofen and continuation of the PPI are recommended. In our experience, the time of response to the combination therapy omeprazole plus baclofen is unpredictable; however, all changes that we observed happened within the first 6 months, and the vast majority within the first 6 weeks. If the desired result is achieved, we continue therapy for another 6 months, after which a very cautious weaning from baclofen is attempted. In cases where the combination therapy omeprazole plus baclofen is not (or not entirely) satisfactory, the addition of gabapentin (Neurontin)1 “on the top” can be attempted. As with baclofen, with gabapentin a “start low, go slow” approach is indicated, the maximum dose of 400 mg three times daily used in such cases being reached after 3 weeks. An inverse approach with PPI plus gabapentin as initial combination is also possible.

    In addition to any pharmacologic therapy, the practitioner must convey to the patient the feeling that he or she understands and appreciates the seriousness of the condition. Compliance with the treatment is required from the patient, who must understand that success can take time. Lifestyle and habit changes are also required. The hiccup patient must limit the size of meals and avoid carbonated beverages and “gas-forming” foods.

    The approach presented here represents our experience in the treatment of chronic singultus. The views expressed are neither guidelines nor regulations.

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    References

    Jatzko A., Stegmeier-Petroianu A., Petroianu G.A. Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports. J Pain Symptom Manage. 2007;33:756–760.

    Petroianu G. Idiopathic chronic hiccup (ICH): phrenic nerve block is not the way to go. Anesthesiology. 1998;89:1284–1285.

    Petroianu G., Hein G., Petroianu A., et al. Idiopathic chronic hiccup: combination therapy with cisapride, omeprazole, and Baclofen. Clin Ther. 1997;19:1031–1038.

    Petroianu G., Hein G., Petroianu A., et al. ETICS study: empirical therapy of idiopathic chronic singultus. Z Gastroenterol. 1998;36:559–566.

    Petroianu G., Hein G., Stegmeier-Petroianu A., et al. Gabapentin “add-on therapy” for idiopathic chronic hiccup (ICH). J Clin Gastroenterol. 2000;30:321–324.

    1  Not FDA approved for this  indication.

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