The tablets were produced by Changzhou Siyao Pharmaceuticals Co. Patients outcomes were evaluated by using the Chinese Medicine Medical Association standard criteria [ 12 ] and classified as follows: cure, cessation of persistent hiccups within the intervention period, with no relapse in one week; improvement, reduction in the frequency and severity of hiccups and other symptoms such as abdominal discomfort ; and no effect, no amelioration of hiccups. In addition to the clinical outcomes, the efficacy and side effects in the two groups were recorded and analyzed.
We collected data on the number of eligible participants with persistent hiccups, willingness of the participants to be randomized, and compliance with the intervention, and aimed to estimate the effect size for a fully powered trial. This feasibility study estimated that a sample of 30 participants would be sufficient to provide data to answer our study questions [ 31 ]. Between-group differences in categoric data were assessed by using the Fisher Exact test or Mann—Whitney U test; the t test was used for continuous data.
Descriptive statistics were used to assess the feasibility questions. Analysis was performed by a statistician who was blinded to the study group. In this study, participants were initially screened. Of these people, 34 subjects were excluded because of the following: cancer eight patients , multiple sclerosis 11 patients , spinal cord lesions four patients , traumatic brain injury eight patients , and meningitis three patients.
The remaining patients were entered into the study. Of these patients, 65 did not meet study criteria 34 patients had acute hiccups, and 31 patients had intractable hiccups , and 18 declined to participate five patients refused baclofen; 13 patients failed to complete treatment.
Therefore, 30 individuals were randomized into the study. All 30 participants completed the study and were included in the final analysis Figure 1. The characteristics of the study sample are presented in Table 1. The two groups did not differ significantly in the majority of sociodemographic and clinical variables investigated at the baseline.
At the baseline, the mean age was The duration of hiccups was All patients had a history of stroke. In the baclofen group, 10 and five patients had had ischemic and hemorrhagic strokes, respectively, whereas in the placebo group, nine and six participants had had ischemic and hemorrhagic strokes, respectively. The ischemic and hemorrhagic strokes had occurred 3. An analysis of the clinical outcomes is presented in Table 2.
Fourteen participants in the baclofen group were cured, compared with two in the placebo group RR, 7. One participant in the baclofen group showed improvement in persistent hiccups, compared with five patients in the placebo group RR, 0. None of the patients in the baclofen group had no amelioration of the hiccups, compared with eight patients in the placebo group RR, 0. No serious adverse events related to treatment were documented, which might be due to the short treatment duration.
However, two patients in the baclofen group reported mild side effects. One patient reported mild transient drowsiness, and the other reported mild dizziness. Our study provides data indicating that further evaluation of baclofen is warranted in stroke patients with persistent hiccups. Analysis of the clinical outcomes identified trends in the cessation of persistent hiccups within the intervention period; however, the numbers were too small, with wide confidence intervals.
The study demonstrated the acceptability of baclofen by the subjects, randomization, and participation in the trial. Compliance and follow-up were also acceptable. Recruitment was slower than planned, and barriers to recruitment included the low prevalence of persistent hiccups among stroke patients and recruitment at a single hospital site.
Our results suggest that 10 mg baclofen 3 times daily is an acceptable dose, and concur with the findings of Mirijello [ 13 ]. Both studies found that persistent hiccups can be successfully treated with baclofen without any significant side effects.
Our study highlighted the need for further research on the topic. Findings from the physician interviews may not represent the views of all clinicians at the host institution or be considered representative of physicians elsewhere; however, our findings indicate a supportive research culture for this topic of study.
The side effects were generally well tolerated in this study. No serious adverse events were recorded, and only two patients reported mild side effects. This low incidence of adverse effects might be attributable to the short duration of the study. The study has several strengths. First, the trial was randomized, thereby reducing selection bias.
Second, although no consensus was found on the optimal dose of baclofen for persistent hiccups, our findings suggest that the dose used in this study was in the therapeutic range. However, the main limitation of the present study is its size, and our findings should therefore be interpreted with caution. The findings of this study will influence future decisions concerning resources and planning for trials. We consider that the randomization was acceptable, and we will explore whether the window for eligibility can be extended.
Hiccups are associated with a type of stroke that occurs in the back of the brain as opposed to the top, a type that is indeed more common in women. That doesn't mean hiccups shouldn't be on your radar, though. Sure, it could be terrible indigestion, she says, but tune in to what your body is telling you. If you notice some numbness, chest pain, or blurry vision along with those hiccups, don't brush them off. Women are all too likely to ignore signs of a stroke. Weight Loss. Abstract Hiccups are usually self-limiting and benign but can be distressing when they become persistent or intractable and produce significant morbidity.
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. 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 ].
Gender differences in hiccups frequency have not been seen in healthy subjects. No racial, geographic, or socioeconomic variation in hiccups has been documented. Overall, the prevalence of hiccups in advanced cancer has been reported to be 3.
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 afferent impulse in this proposed arc is carried by the vagus nerve, phrenic nerves, or sympathetic nerve fibers thoracic outflow T6—T 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. 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. Cns Lesions The dorsal area of the medulla is commonly associated with hiccups as it incorporates a number of complex structures which conciliate the reflex arc, including the vagus nerve, respiratory center, solitary nucleus, nucleus ambiguus, central sympathetic tract, and spinal tract of trigeminal nucleus.
Chronic hiccups have been reported following hemorrhagic and ischemic strokes, cerebellar aneurysms, and neuromyelitis optica [ 32 - 38 ]. Peripheral nervous system lesions Involvement of the hiccup reflex arc in conditions like sarcoidosis, diaphragm tumors, or other causes of abdominal distension may lead to persistent hiccups.
Gastrointestinal and abdominal causes GERD is commonly associated with persistent hiccups and is responsive to treatment with proton pump inhibitors [ 39 , 40 ]. Helicobacter pylori infection may lead to persistent hiccups secondary to increased acid production causing irritation of esophageal vagal afferents [ 41 ]. Hiccups under anesthesia Hiccups can occur during administration of general or regional anesthesia [ 42 ], particularly under lighter plane of anesthesia especially with the usage of short acting barbiturates and during intubation, patient positioning, or visceral manipulation during surgery.
Surgeries in thorax and abdomen often lead to hiccups in the postoperative period probably due to gastroparesis [ 43 ]. Anesthetic drugs like propofol induced hiccups [ 44 ]. Hiccups following epidural anesthesia have been reported with possible mechanism of action being deafferentation of sensory nerves in the viscera coupled with increased diaphragmatic stimulation secondary to interruption of phrenic nerve motor reflex [ 45 , 46 ].
Cancer patients Hiccups are frequently seen in patients with cancer either due to involvement of any portion of the hiccup reflex arc by the tumor, or as a secondary response to chemotherapy.
Cisplatin is most commonly implicated [ 47 ]. Drug-induced hiccups Steroids have been implicated in chronic hiccups. Dopamine agonists may induce bouts of hiccups in Parkinsonism patients owing to their high affinity towards D3 receptors. Macrolides like azithromycin and psychiatric medications like aripiprazole have also been known to be associated with persistent hiccups. In essence, it is imperative to thoroughly review the medication history and identify and stop the offending drugs inducing hiccups [ 48 ].
Instrumentation-associated hiccups Atrial pacing, catheter ablation of atrial fibrillation, and central venous catheter placement have been reported to cause hiccups presumably due to mechanical irritation of right phrenic nerve which is in close proximity to the right atrium [ 49 - 51 ].
Esophageal instrumentations like stenting induces hiccup by stimulating the reflex arc afferent component [ 52 ]. Psychogenic causes Hiccups are seen in patients with acute anxiety, stress, fear, or excitement. In cases where behavioral therapy has been successful in ameliorating hiccups, a diagnosis of hysterical hiccups has been made [ 53 ].
Miscellaneous causes Dyselectrolytemias, tuberculosis, ethanol abusers, diabetes mellitus, and chronic renal failure due to uremia [ 54 ] can all cause persistent hiccups.
Electroencephalogram findings in patients with epilepsy suggest that chronic hiccup can be the result of seizure activity. Certain antiepileptic drugs have shown a beneficial role in the treatment of hiccups mainly due to their GABAergic effects. However, in many patients, chronic hiccups occur without the presence of cerebral dysfunction and diazepam, a potent anti-convulsant drug, can precipitate or exacerbate hiccups in such conditions [ 55 ]. 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 ]. 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 ]. 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. 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.
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. 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. 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 ]. Pharmacological There is inadequate data to formulate treatment guidelines for persistent hiccups [ 57 ]. A complete medical history regarding the ongoing medications and comorbid conditions should be available, and the possible drug interactions and probable side effects should be kept in mind before the choice of medication is made.
Combination therapy for IH has also been proposed in certain case reports [ 65 ]. The drug therapy could be tapered out or discontinued if hiccups cease, and alternative drug or treatment modality could be considered in case of IH.
The pharmacological treatment is summarized in Table 3. Chlorpromazine Chlorpromazine, a dimethylamine derivative of phenothiazine, is a centrally acting dopamine antagonist which acts at the hypothalamus. The concerns pertaining to long-term neurological side effects along with hypotension, urinary retention, glaucoma, or delirium associated with the use of chlorpromazine has led to its U. FDA approval recently being withdrawn. The suggested dose has been 10—25 mg orally or intravenously; if no response then up to 25—50 mg three times a day can be used [ 66 ].
Other neuroleptics, like haloperidol or olanzapine, though effective are limited by their untoward effects such as such as dizziness, mood disturbance, and sedation. Haloperidol It alleviates hiccups by its dopamine antagonism in the hypothalamus. The major side effect is extrapyramidal symptoms. Olanzapine Postsynaptic serotonergic receptors augment phrenic motoneuronal activity and play a role in the generation of hiccups.
Olanzapine is proposed to act as an antagonist at these postsynaptic receptors, thereby, attenuates phrenic excitability and relieves hiccups. Alderfer and Arciniegas [ 68 ] reported that a maintenance dose of 2. Hiccup is an intermittent, involuntary and erratic contraction of the diaphragm, immediately followed by a laryngeal closure. Persistent and intractable hiccups are rare but severe, keeping a person from doing daily activities; these can result in depression, fatigue, impaired sleep, dehydration, weight loss, malnutrition, and aspiration.
Therefore, proper treatments are necessary. We present a case with intractable hiccup treated with an unusual treatment. A year-old man presented with intractable hiccups, which started 6 years ago after subarachnoid and intraventricular hemorrhage.
Conventional pharmacologic treatments including metoclopramide, gabapentin, and baclofen were unsuccessful. Cooperating with cardiothoracic surgeons, phrenic nerve clipping operation was done under intraoperative electrophysiologic monitoring. This method was successful that the symptoms were relieved.
Reversible clipping done under intraoperative electrophysiologic monitoring can be a promising therapeutic method for persistent and intractable hiccups in patients with stroke. Phrenic nerve clipping can be effective in treating intractable hiccups.
Simple hiccup is usually self-limiting. It consists of a sudden powerful activation of the inspiratory muscles of the thorax, diaphragm, neck accessory, and external intercostal muscles, followed by active movement of the tongue toward the roof of the mouth [ 1 ]. Active adduction of the vocal cords follows the initiation of the inspiratory flow.
In general, hiccups stop within 48 hours. If these continue for more than 48 hours and end within a month, these are known as persistent hiccups.
If these last longer than 2 months, these conditions are considered as intractable hiccups [ 2 ]. Persistent and intractable hiccups, which are uncommon, may prevent people from usual daily activities like sleeping and eating. This decline of quality of life can result in depression, fatigue, impaired sleep, dehydration, weight loss, malnutrition, and aspiration [ 3 ].
To figure out the mechanism of the hiccup, a hiccup reflex arc should be understood. It is thought to be composed of three parts: an afferent limb including vagus, phrenic nerves, and sympathetic chain, a central midbrain modulation, and an efferent limb including phrenic and accessory nerves [ 2 ].
Any disruption of the reflex arc can cause a hiccup, and numerous pathologic conditions can be causes. There are some serious conditions that can cause intractable hiccup including brain malignancies, cerebral vascular lesions, myocardial ischemia, herpes infection, and gastroesophageal reflux disease.
Unfortunately, there is no guideline available to treat these chronic hiccups effectively. Literature suggest that medications and methods such as nasopharyngeal catheter insertion, pharmacologic treatment, phrenic nerve blockade, and phrenic nerve stimulation may treat hiccup [ 1 , 2 ].
Here is a case that was successfully improved with phrenic nerve clipping with intraoperative electrophysiologic monitoring in a patient with stroke. A year old man was admitted to the department of rehabilitation medicine at our hospital with quadriplegia. Six years ago, he suffered from subarachnoid hemorrhage and intraventricular hemorrhage with extra-ventricular drainage operation.
He also underwent tracheostomy. Since that day, he had become quadriplegic and bedridden state. His past medical history had been unremarkable until the stroke occurred. Immediately after extra-ventricular drainage operation, he began to experience bouts of hiccups which lasted up to 13 hours.
These occurred recurrently for 6 years while sleeping or staying awake. Once hiccups occurred, they lasted for more than 10 hours. Self-induced nausea and vomiting also coincided with hiccups for a while.
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