Introduction
Both functional belching and hiccup are abnormal physiological behavior activated by the air movement. Functional belching results from venting of excessive gas from stomach and it is often accompanied with gastroesophageal reflux disease (GERD). In contrast, hiccup is the sudden onset of erratic diaphragmatic and intercostal muscular myoclonus which are followed immediately by laryngeal closure, hence the abrupt air rush into lungs induces the vocal cords to close leading to a “hic” sound.
Hiccup or singultus is derived from the Latin word singult, which means “the act of catching one’s breath while sobbing”.
Hiccup occurrence is not only confined to the adults but also observed among the infants and children. It is usually a self-limited disorder meaning many episodes would subside spontaneously without any clinical significance. The self-limited hiccup is believed to be induced by the rapid stomach distension and irritation in terms of overeating, eating too fast, ingesting spicy food, drinking carbonated drinks, aerophagia and sudden change in ingested food temperature. Persistent hiccup means episode lasting for 48 hours or more, whereas those longer than 2 months are considered intractable. Severe and prolonged hiccup may lead to exhaustion, fatigue, malnutrition, weight loss, dehydration and even death in the extreme situations. Patients with intractable hiccups are likely to have structural or functional irritation involving the reflex arc.
Unfortunately there is no guideline available to direct treating this serious disorders effectively. Chlorpromazine is approved by the US Food and Drug Administration as the only drug to treat hiccup until now. However, using chlorpromazine to treat hiccup without correct diagnosis of lesion responsible for hiccup may lead to missing potentially serious conditions that may cause this symptom.
Pathophysiology
The pathophysiological mechanism of hiccup is related to lesions in its reflex arc. The hiccup reflex arc, originally proposed by Bailey in 1943, mainly consists of three components: the afferent limb, the central processing unit in the midbrain and the efferent limb.
1) Afferent limb -> Phrenic and vagus nerves and sympathetic chain arising from T6-12.
2) Hiccup center -> Nonspecific location between C3 and C5, plus connections to the respiratory center, phrenic nerve nuclei, medullary reticular formation, and hypothalamus.
3) 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
- Lower esophageal sphincter tone
Central process of hiccup remains poorly understood, it may not only be confined to the medulla but may also involve other parts of central nervous system (CNS) located between brainstem and cervical spine. The hiccup central component usually refers to chemoreceptors probably located in the peri-aqueductal gray matter and sub-thalamic nuclei.
Among the neurotransmitters involved in the process of hiccup, both dopamine (D) and gamma-aminobutyric acid (GABA) have been documented. The above pathophysiological basis explains why some inhibitors of these substances may be employed in treatment of hiccup.
Accordingly, any physical and chemicals irritants and inflammatory and neoplastic conditions involving the hiccup reflex may cause hiccup. Unfortunately, owing to the long trajectory of afferent and efferent nerves and the diffuse central processes involving the hiccup reflex arc, the accurate diagnosis of lesions in the arc and trying to terminate the pathological processes in the intractable events are often very difficult.
Etiology of Persistent and Intractable Hiccups
There are more than 100 known causes of hiccups, such as infection, trauma, or metabolic disorders. Some are well known to invade the hiccup reflex arc, whereas many others remain unexplained why they would elicit persistent or intractable hiccups since no obvious invasion to the hiccup reflex pathway was confirmed. According to the sites of lesion, hiccup may originate either from central or peripheral pathways. In patients suffering from cancer e.g. hiccups may be induced by the malignant tumor itself, by irritating the phrenic nerve or in case of cerebral metastases. Antineoplastic medication may also lead to hiccups.
In the next table are shown some of the most popular causes of hiccups, according to the lesion site and the type.
Drug treatment
As discussed above, chlorpromazine is the only approved drug in hiccups treatment until now, although many other drugs have been used with the same purpose (but not always succesfully).
Among these drugs there are:
- Anticonvulsants -> e.g.: Baclofen -> it should be used very cautiously in elderly subjects and those with renal failure because of the side effects such as nephrotoxicity, over sedation, ataxia and confusion.
- Calcium channel blockers -> Although the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with hypertension, they are often used as antiepileptics as well. In fact, such substances may play a role in reversing the abnormal depolarization in the hiccup reflex arc (e.g.: Nifedepine).
- 5HT agonists
- Prokinetics -> e.g.: Lidocaine -> can stabilize cell membrane by blocking sodium channels to reduce neuronal excitability. It has been used successfully in treating or pre-treating intractable hiccups induced via many measures.
Lidocaine
Despite of all these different treatment modalities, hiccups often persist and may cause complications like insomnia, weight loss, depression, and dehydration
Thus, a sufficient and effective treatment is wanted. Here, is presented a new therapeutical approach: oral application of a viscous 2% lidocaine solution has been successfully used in four cancer patients.
(References: Case report, Successful treatment of intractable hiccups by oral application of lidocaine; by Thomas Neuhaus & Yon-Dschun Ko & Sebastian Stier)
Since three patients received baclofen (between 20 and 30 mg/day) before lidocaine was added, and since in one patient the lidocaine effect was elongated by additional baclofen, we assume that the combination of both lidocaine and baclofen is needed for a successful approach, even though baclofen alone was not sufficient in any of the patients.
Since lidocaine blocks calcium channels and stabilizes membrane potential, as well as it blocks sodium channels in sensory neurons and thereby decreases neuronal excitability and ectopic discharges, it’s likely that this may be the decisive mechanism, and this also could be true in our patients, because it is known that low but active plasma levels of lidocaine or its metabolites are found after swallowing 15 ml of a 2% lidocaine solution.
The main difference between oral and intravenous application is the high first pass effect, resulting in a rapid decrease of lidocaine plasma concentration after the first liver passage of the blood. Based on these circumstances, we can assume a local effect of orally administered lidocaine possibly by influencing afferent nerves in the upper gastrointestinal tract, which are part of the hiccup reflex, just like esophagitis or gastric distension may cause hiccups.
Intravenous lidocaine offers several potentially severe side effects like seizures, arrhythmia, and AV blocks as well as combined with other medication heart failure. Thus, intravenous application of lidocaine is relatively or absolutely contraindicated in many patients, and its application needs to be followed closely.
The oral way of administering lidocaine is more convenient and safer, since even swallowing eight portions of 15 ml of a 2% lidocaine solution every 3 hours did not result in a plasma concentration below one fifth of the toxic level.
Conclusions
Hiccup is still object of studies its mechanism is not fully understood yet. Nevertheless among various aivalable treatments, the use of lidocaine (eventually combined with baclofen) seems to be a convenient, and safer solution for persistent and intractable hiccups, in the way of a oral application of 2% lidocaine solution.
References
Hiccup: Mystery, Nature and Treatment, April 2012.
Successful treatment of intractable hiccups by oral application of lidocaine, 2012.
http://en.wikipedia.org/wiki/Main_Page
A cura di Stefano Modica e Fabio Tutino
