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• W2018289312 abstract "To the Editor: Hiccups are a pathologic reflex characterized by a sudden and repetitive spasm of one or both of the hemidiaphragms associated with closure of the vocal cord and/or the glottis, and an irregular involvement of the accessory muscles.1Ripamonti C. Fusco F. Respiratory problems in advanced cancer.Support Care Cancer. 2002; 10: 204-216Crossref PubMed Scopus (31) Google Scholar The pathophysiology of this reflex is complex.2Wagner M.S. Stapezynnsky J.S. Persistent hiccup.Ann Emerg Med. 1982; 11: 24-26Abstract Full Text PDF PubMed Scopus (30) Google Scholar The incidence of hiccups in cancer patients is unknown, but intractable hiccups are rare. By definition, intractable hiccups are defined as persistent symptoms for more than 24 hours.3Folstad H. Nilson S. Intractable singultus: Diagnostic and therapeutic challenge.Br J Neurosurg. 1993; 24: 306-310Google Scholar We describe a patient in the terminal stage of illness, who was distressed by persistent hiccups that did not respond to commonly recommended pharmacological treatments. We successfully controlled this symptom with a continuous infusion of midazolam and morphine. A 69-year-old man with colon cancer and massive liver metastases was admitted to our department due to a 5-day history of persistent hiccups and vomiting. Two days before, he had a gastric endoscopy, which showed a gastric ulceration. He was taking a proton pump inhibitor. Previously, metoclopramide (to a maximum dose of 60 mg/day), haloperidol (to a maximum dose of 4 mg/day), and chlorpromazine (50 mg three times daily) had been administered without effect on hiccups and vomiting. Haloperidol was not increased due to drowsiness and hallucinations. On admission, he was dehydrated and exhausted. A plain radiograph of the abdomen showed gastric distension. Gastrografin transit showed gastric hypotonia, with no mechanical interruption. A thoracic and abdominal CT scan showed pulmonary progression of disease, with no mediastinal involvement. Renal function evidenced mild dehydration (creatinine 1.7mg/dl). Liver function tests were normal. The patient was hydrated, all oral medications were stopped, and a nasogastric tube was positioned. He started parenteral nutrition. The patient stopped vomiting, but his hiccups persisted, making it impossible to speak or to sleep. Furthermore, he complained of a retrosternal burning pain. We started a continuous subcutaneous infusion with midazolam 15 mg/day and morphine 20 mg/day. Hiccups and pain rapidly resolved. The patient was awake and could talk with family and medical staff. The hiccups returned in the following days but were controlled again by increasing the dose of midazolam to 60 mg/day and morphine to 30 mg/day and introducing chlorpromazine for episodic hiccup. The patient asked for chlorpromazine usually once daily. Even if mild sedation occurred so that he was sleeping all night long and for brief periods during the day, he could be easily awakened to talk. He was not confused until the last week. Twenty days after admission, the patient died due to liver function deterioration, jaundice and hepatic coma. Hiccups may be a result of a persistent disturbance of one of the reflex arc components,3Folstad H. Nilson S. Intractable singultus: Diagnostic and therapeutic challenge.Br J Neurosurg. 1993; 24: 306-310Google Scholar, 4Oshima T. Sakamoto M. GABAergic inhibition of hiccup-like reflex induced by electrical stimulation in medulla of cats.Neurosci Res. 1998; 30: 287-293Crossref PubMed Scopus (49) Google Scholar, 5Moretti R. Torre P. Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: A three-year follow up.Neurologist. 2004; 10: 102-106Crossref PubMed Scopus (52) Google Scholar, 6Walker P. Watanabe S. Baclofen as a treatment for chronic hiccup.J Pain Symptom Manage. 1998; 16: 125-132Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar which include vagal and phrenic sensory afferents, medullary respiratory center, descending fibers to C3 and C5, and the efferent motor phrenic fibers to the diaphragms. Gastric distension and diaphragmatic irritation were probably the principle cause of hiccups in this patient. In general, benzodiazepines act as depressants of the central nervous system (CNS), producing all levels of CNS depression from mild sedation to hypnosis to coma, depending on dose. Midazolam is a water-soluble, short-acting benzodiazepine. Usual doses for induction of anesthesia are 0.15 to 0.3 mg/kg intravenously; intramuscular doses of 0.1 mg/kg have been effective for anesthetic premedication. The drug is metabolized in the liver and excreted in the urine (0.3% unchanged). The elimination half-life is 2 to 5 hours. It is highly protein-bound (95%). Midazolam, as all the other benzodiazepines, acts as an agonist at benzodiazepine receptors. This forms a component of a functional, supramolecular unit, known as the benzodiazepine-GABA receptor-chloride ionophore complex. This receptor complex, which resides on neuronal membranes, functions mainly in the gating of the chloride channel. Activation of the GABA receptor results in the opening of the chloride channel, allowing the flow of chloride ions into the neuron. This results in hyperpolarization, which inhibits firing of the neuron, and translates into decreased neuronal excitability, thus attenuating the effects of subsequent depolarizing excitatory transmitters. The nucleus raphe magnum is most likely the source of the GABAergic inhibitory inputs to hiccup reflex arc.4Oshima T. Sakamoto M. GABAergic inhibition of hiccup-like reflex induced by electrical stimulation in medulla of cats.Neurosci Res. 1998; 30: 287-293Crossref PubMed Scopus (49) Google Scholar Midazolam's central action, along with anticonvulsant and general sedation effects, probably allows a tonic depressant effect on striated muscle reflexes, reducing the number of hiccup episodes and making the remaining episodes responsive to chlorpromazine. We usually employ a nasogastric tube in these settings. In this case, we obtained resolution of the vomiting, but the hiccups responded only to subcutaneous midazolam. Baclofen could not be used because of oral administration.6Walker P. Watanabe S. Baclofen as a treatment for chronic hiccup.J Pain Symptom Manage. 1998; 16: 125-132Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 7Burke A.M. White A.B. Baclofen for intractable hiccup.N Engl J Med. 1988; 319: 1354Crossref PubMed Scopus (130) Google Scholar, 8Yaqoob M. Prabhu P. Ahmad R. Baclofen for intractable hiccup.Lancet. 1989; 2: 562-563Abstract PubMed Scopus (24) Google Scholar In previous case reports,9Wilcock A. Twycross R. Case report: Midazolam for intractable hiccup.J Pain Symptom Manage. 1996; 12: 59-61Abstract Full Text PDF PubMed Scopus (52) Google Scholar midazolam was maintained for very short periods because rapid patient deterioration and death occurred in no more than 2 days. In this case, longer symptom control has been obtained with a minimal midazolam escalation and mild sedation. Even if the hiccups returned, increasing the dose of midazolam might make the hiccup episodes more rare and easily controlled by chlorpromazine, which was ineffective before. This case report suggests that midazolam, a drug usually selected for terminal sedation or premedication, can be safely employed for gastrointestinal symptom control for a longer period than in previous reports." @default.
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• W2018289312 title "Midazolam for Long-Term Treatment of Intractable Hiccup" @default.
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