Hiccup or hiccough is known by the medical term “singultus,” which is a derivative of the Latin word “singult,” meaning “a gasp” or “a sob” [1]. Hiccups are characterized by involuntary, intermittent, repetitive, myoclonic, and spasmodic contractions of the diaphragm and the inspiratory intercostal muscles, leading to an abrupt and early closure of the glottis, terminating inspiration and generating the characteristic “hic” sound [2,3]. Both healthy adults and children commonly experience hiccup spells. In the fetus, hiccups play a physiological role by training the respiratory muscles for their breathing function, and as a reflex preventing amniotic fluid aspiration [4,5]. Transient episodes usually do not require medical attention unlike chronic hiccups (persistent and intractable), which can be associated with long term deleterious effects.

An accurate estimate of the burden of hiccups in the neuro-intensive care unit (ICU) leading to unfavorable outcomes and morbidity is unknown. Though persistent hiccups which are intractable and of neurogenic origin can result in hyperventilation and respiratory alkalosis, and are a risk factor for ventilator associated pneumonia in intubated and mechanically ventilated patients. Hence, meticulous evaluation and treatment of persistent or intractable hiccups (IH) in neuro-ICU patients is important, in a stepwise and protocolized manner which comprise of physical maneuvers first followed by pharmacological measures in failed or resistant cases. Unfortunately, there are no clear guidelines applicable to the management of persistent or IH. Recently U.S. Food and Drug Administration (FDA) revoked the approval of chlorpromazine, citing its serious side effects in treating hiccups. In this article we strive to review the available literature on hiccups and provide a stepwise management protocol.

A single episode of hiccups can last from a few seconds to as long as several days. Based on the duration, hiccups can be divided into three categories: acute hiccups that last for up to 48 hours, persistent or protracted hiccups that last for more than 48 hours, and IH that last for over a month [6,7]. Most classifications use arbitrary time limits to categorize the phenomenon. Brief episodes of hiccupping are physiological. The point of transition to a pathological form is not well defined. The longer the duration of the hiccupping, the less amenable it will be to interventions. An episode lasting longer than a week is considered chronic while resistance to sequential therapy using three different drugs warrants the use of the label obstinate [8].

Hiccups are more common in diseases affecting the gastrointestinal or central nervous system (CNS). Gender differences in hiccups frequency have not been seen in healthy subjects. Prevalence of non-CNS origin hiccups is higher in men than CNS origin hiccups [9,10]. No racial, geographic, or socioeconomic variation in hiccups has been documented. Recurrent hiccups occur in about 3% of the healthy population, compared to approximately 20% with Parkinson disease and 10% of patients with gastroesophageal reflux disease (GERD) [11]. Overall, the prevalence of hiccups in advanced cancer has been reported to be 3.9%–4.8% [12,13]. A variety of CNS pathologies cause IH. Lateral medullary infarcts (LMIs) cause 12%–36% of central hiccups cases. Keane (1961) found 56% of patients with central hiccups to primarily have LMIs, [14] and this proportion was 14% as per the report by Park et al. [15]. There is high preponderance of developing IH following an ischemic insult to the brainstem including pons or involvement of posterior inferior cerebellar artery [16,17]. Vascular lesions of CNS are the most common cause of IH followed by infective (meningitis, encephalitis), structural lesions, such as a multitude of space occupying lesions like cavernous angiomas or tuberculomas, and inflammatory and demyelinating conditions such as multiple sclerosis and neuromyelitis optica [18].

The mechanism of hiccups is not very clear and the neuroanatomical center for hiccups has not been identified, though few hiccups provoking hypothesis have been proposed [19,20]. Bailey [21] first proposed the “reflex arc” in 1943 responsible for generating hiccups. The afferent impulse in this proposed arc is carried by the vagus nerve, phrenic nerves, or sympathetic nerve fibers (thoracic outflow T6–T12). Upper spinal cord (C3–C5), medulla oblongata near the respiratory centers, the reticular formation, and the hypothalamus appear to be the CNS centers involved in the hiccup response. Dopaminergic and gamma-aminobutyric acid (GABA)ergic neurotransmitters are involved in the modulation of this central mechanism [22]. The efferent response of the reflex is carried by the phrenic nerve to the diaphragm. Accessory nerves activation lead to the contraction of the intercostal muscles as well. Recurrent laryngeal nerve causes the reflex closure of the glottis, completing the sequence of events during a hiccup [22,23]. Davis concluded that hiccup generation was a supraspinal mechanism involving interplay between behavioral and chemical respiratory influences at the spinal level, independent of inspiratory centers [24]. Suppression of inhibitory influences on a supraspinal hiccup center could lower the threshold and cause hiccups to start. This mechanism may explain the persistent hiccups seen in multiple sclerosis or metabolic disorders. Hassler [25] propounded that hiccups may be generated at the pontomedullary level of the triangle of Guillain-Mollaret (inferior olivary nucleus, dentate nucleus, and red nucleus). Denervation super sensitivity of the inferior olivary complex, nucleus ambiguus, and adjacent reticular formation of medullary oblongata have also been hypothesized to give rise to hiccups [26-28]. Nucleus raphe magnus with its GABA-containing inhibitory cells has been shown to be the likely source of inhibitory inputs to the hiccup reflex arc [29]. Various neurotransmitter pathways of the brainstem and medulla, including those involving dopamine, serotonin, opioids, calcium channels, and GABA are possibly involved in mediating hiccups [30] (Fig. 1).

Any process that affects the peripheral afferent, central, or efferent components of the proposed reflex arc can trigger hiccups [22]. The most common benign reason being large meals or carbonated drinks causing stomach distension. Hot and spicy foods, alcohol, smoking, and other substances irritating the gastrointestinal or pulmonary tracts can also trigger the reflex. Over-excitement or anxiety, when accompanied by hyperventilation or air swallowing (aerophagia) can trigger hiccups as well.

The causes of persistent hiccups can be classified into central and peripheral (Table 1). Central hiccups could occur with any lesions along the pathway from the CNS to the phrenic nerve, especially with lesions of the brain stem, such as tumors and ischemic stroke [15,17,18,31]. Peripheral hiccups can be caused by diseases at the phrenic nerve level involving diaphragmatic irritation, such as gastric distention, subdiaphragmatic abscess, or hepatosplenomegaly.

Persistent hiccups have the capacity to induce major disabling impact on general health and cause exhaustion, sleep deprivation, malnutrition, dehydration, depression, wound dehiscence, and even death in extreme cases [2,56]. It has a detrimental effect on rehabilitation as shown by prolonged hospital stay in a study done by Kumar and Dromerick [16]. Sleep cycle is affected by hiccups with literature showing that it persists during sleep disrupting both non-rapid eye movement (NREM) and REM sleep. Chronic hiccups lead to sleep deprivation [57].

The occurrence of hiccups in a patient receiving mechanical ventilation causes desynchronization and possible respiratory alkalosis leading to lung damage and hemodynamic alterations [58]. It can be prevented by close monitoring of respiratory parameters and prompt correction, especially in patients with brain stem damage. The strong inspiratory effort does not result in a large change in lung volume due to reflex glottic closure, and, therefore, in normal subjects the ventilatory effects of hiccups are minimal. In intubated or tracheostomized patients, hyperventilation and respiratory alkalosis may happen resulting in hiccups [59].

Marinella [2] were able to demonstrate that the left hemi-diaphragm was the side of hiccup origin in 80% of their cohort of patients with advanced malignancy. Persistent and IH are a risk factor for ventilator-associated pneumonia in intubated patients. Employing continuous positive airway pressure and pressure support ventilation can stop hiccups in such patients. Salem et al. [60] demonstrated that increasing PIP to 30–40 cmH₂O immediately stopped the development of hiccup during a surgical procedure.

A thorough and detailed history is warranted focusing on trigger factors for chronic hiccups along with frequency, duration, progression, and aggravating and relieving factors. Relevant history should be elicited regarding the chronology of hiccup episodes, relationship with sleep, and any physical maneuver or pharmacological treatment the patient is undergoing with their effectiveness on the condition and any side effects experienced. A comprehensive enquiry should be made regarding the prescribed medications the patient has been administered along with over-the-counter medications and various addictive habits, such as smoking and alcohol consumption. An underlying organic pathology should be ruled out in patients with chronic hiccups.

A detailed physical examination should be done along with a systemic one focusing on the respiratory, nervous, and gastrointestinal systems. An electrocardiogram may help rule out atypical myocardial infarction especially in the beginning of a hiccup attack. Routine blood workup should be done including complete blood count, electrolytes, blood urea nitrogen, creatinine, calcium, liver function tests, and amylase/lipase. Investigation to rule out GERD is important and includes an upper gastrointestinal endoscopy, esophageal manometry, and a 24 hour–pH-impedance reflux study [61]. In patients where no organic cause can be found or those not responding to routine treatment, imaging studies like computed tomography scan and magnetic resonance imaging of head and neck are warranted [62]. Stepwise management protocol is given in flow diagram (Fig. 2).

The treatment approach of persistent hiccups is mostly based on observational reports and case series, and clear-cut guidelines are lacking. The treatment is mainly directed at treating the underlying cause when the illness causing hiccups has been identified [2,22,23]. In majority of the cases, no cause is found and the treatment is mainly empirical to ameliorate the symptoms. Table 2 shows the anecdotal and nonpharmacological treatment methods. Physical maneuvers such as interrupting normal respiratory function (e.g., breath holding, Valsalva maneuver), stimulating nasopharynx or uvula (e.g., sipping cold water, gargling with water, swallowing a teaspoon of dry sugar), increasing vagal stimulation (e.g., pressing on the eyeballs), and countering irritation of the diaphragm (e.g., pulling knees to chest, leaning forward to compress the chest) are first-line treatments for hiccups. The basic principle of the various physical maneuvers employed is to interrupt or suppress the reflex arc [7]. These, at best, provide a transient relief in cases of persistent or IH. Drug therapy should be reserved for treatment of hiccups when physical maneuvers have failed [63,64].

Hiccups are usually innocuous and frequently ignored. Patients presenting with chronic hiccups require a meticulous evaluation focusing on history and physical examination. Persistent hiccups are more often than not associated with an underlying organic pathology which requires a comprehensive workup. Pharmacological therapy should take into account the risk of long-term side effects and FDA recommendations. Considering the present literature on hiccup pharmacotherapy, baclofen may be considered as a first line therapy followed by gabapentin. Large multicenter trials are the need of the hour along with the development of robust guidelines.