Abstract
Hiccups, also called hiccoughs, are sudden, involuntary and rapid expulsion of air from the lungs with synchronous closure of the glottis causing blockade of the air flow. Hiccups may be induced by a multitude of etiologies such as central nervous disorders, gastrointestinal disorders, cardiovascular disorders, psychogenic factors, and metabolic disorders. Hiccups induced by medications are rare. The diagnosis of drug-induced hiccup is difficult. The exact mechanism responsible for this adverse drug reaction is still unknown. Herein, we report the first case of cefotaxime-induced hiccups and briefly review the literature on antibiotic-induced hiccups.
Keywords: hiccups, antibiotics, adverse drug reaction
Introduction
Hiccups, also called hiccoughs, are sudden, involuntary and rapid expulsion of air from the lungs with synchronous closure of the glottis causing blockade of the air flow. They are spasmodic contractions of the diaphragm and inspiratory intercostal muscles. Acute hiccups last less than 48 hours. Hiccups can be persistent lasting more than 48 h, or intractable, lasting more than 1 month. Persistent hiccups can disturb sleep patterns and daily activities of patients and may cause hypotension, bradycardia, pneumomediastinum, subcutaneous emphysema, and bradyarrhythmias.1,2 Antibiotic-induced hiccups are rare. The exact mechanism responsible for this adverse drug reaction is still unknown. Herein, we report the first case of cefotaxime-induced hiccups and briefly review the literature on antibiotic-induced hiccups.
Case Report
A 38-year old man presented to the emergency department with a 3-day history of continuous pain in the lower right abdominal quadrant associated with a fever. Gastroesophageal reflux disease, hiatal hernias, diabetes, hypertension and metabolic disorder were not noted in his past medical history. He denied alcohol consumption. On physical examination, all his vital signs were normal except for pyrexia up to 39°C. Abdominal palpation revealed a tenderness in the lower right quadrant. Laboratory findings showed leukocytosis at 17 000 cells/ml and a high level of the C-reactive protein at 250 mg/ml. Abdominal CT-scan revealed an intra-abdominal abscess originating from an acutely inflamed and ruptured appendix.
Based on the clinical findings, the imaging and laboratory investigations the main suspected diagnosis was appendiceal abscess. Intravenous medical treatment was initiated. Antibiotic therapy included cefotaxime (3 g/day by intravenous infusion; 1 g every 8 hours), a third generation cephalosporin, and metronidazole. For analgesia, paracetamol was used. In the same-day, laparoscopic findings were consistent with the suspected diagnosis. Therefore, the patient underwent appendectomy. 48-hours after the surgery, he developed recurring bouts of hiccups. Even with the use of metoclopramide, the symptoms did not subside for 3 days. The patient denied having gastroesophageal reflux or epigastric or chest pain. Abdominal and Neurologic examination were normal.
Five days after the surgery, drug-induced hiccups was suspected, paracetamol and metronidazole were initially withdrawn without amelioration. The hiccups became more persistent and produced considerable distress. A repetitive aggravation of hiccups after each injection of cefotaxime was also noted. At day seven, the hiccups started again a few minutes after taking the morning dose of cefotaxime. Therefore, cefotaxime was withdrawn. Few hours later, the hiccups were attenuated and completely ceased 1 day later. At a 1-week follow up after being discharged, the patient had no complaints.
Temporal association of hiccups with the drug was prominent as hiccups started after 48 hours of initiation of cefotaxime treatment and prompt relief occurred with cessation of the drug. Based on Naranjo’s algorithm, the reaction was categorized as possible adverse drug reaction. Cefotaxime rechallenge to verify the association of the adverse effect was refused by the patient. Metronidazole and paracetamol rechallenges were negative.
Discussion
Hiccups may be induced by a multitude of etiologies such as central nervous disorders, gastrointestinal disorders, cardiovascular disorders, psychogenic factors, and metabolic disorders. Drug-induced hiccups are rare. The diagnosis of drug-induced hiccup is difficult. It is only achieved by a process of elimination. The onset of hiccups may range from minutes to several hours after parenteral drug administration, while with the oral medications, the onset may be within hours to a few days. Many drugs are implicated in the pathogenesis of hiccups such as corticosteroids, cancer chemotherapy, psychotropic drugs, neurologic drugs, benzodiazepines, and antibiotics. 1 Antibiotics are rarely reported as a possible cause of hiccups. Few well reported cases of antibiotic-induced hiccups were published (Table 1).2 -9 All of the reported cases were of male patients. The male gender seems to be an independent risk factor for drug-induced hiccups as mentioned by Hosoya et al 10 The age varies from 10 to 76 years. Cephalosporin antibiotics were implicated in 2 cases. The other antibiotics incriminated in the pathogesesis of hiccups are azithromycin (2 cases), clarithromycin/metronidazole (1 case), cotrimoxazole (1 case), doxycycline (1 case) and imipenem/cilastatin (1 case). Esophageal ulcerations have been reported with the use of doxycycline and cotrimoxazole. In the latter cases, hiccups seem to be secondary to ulceration induced by these drugs. Between 1985 and 1997, 53 cases were reported to the French pharmacovigilance network. Of the total number, 12% were related to antibiotics. 11 Cefixime, a third-generation cephalosporin, is implicated in one case of hiccups in this study. This case was poorly documented and prednisolone was also prescribed for the patient.
Table 1.
Case Reports of Antibiotics-Induced Hiccups.
| Antibiotic | Age | Gender | Dose | Naranjo causality | Treatment | Recovery time |
|---|---|---|---|---|---|---|
| Azithromycin 3 | 55 | M | 500 mg/d | Possible | Metoclopramide | 3 d |
| Azithromycin 4 | 76 | M | 500 mg/d | Possible | Chlorpromazine Metoclopramide Baclofen |
2 wk |
| Cefotetan 5 | 62 | M | 2 g/d | Probable | Antacids H2 blockers |
4-5 h |
| Ceftriaxone 6 | 10 | M | 50 mg/kg/d | Possible | baclofen | NA |
| Cotrimoxazole 7 | 14 | M | NA | Possible | Ranitidine | NA |
| Clarithromycin Metronidazole 2 |
23 | M | 1 g/1 g/40 mg | Possible | NA | NA |
| Doxycycline 8 | 51 | M | 200 mg/d | Possible | Prochlorperazine Chlorpromazine |
Few days |
| Imipenem/cilastatin 9 | 46 | M | 4 g/d | Possible | Metoclopramide Ranitidine | NA |
Note. NA = non available.
The hiccup reflex arc is a complex interaction with the afferents, phrenic nerve, vagus and sympathetic chain, a central mediator not fully determined, and the efferents, the phrenic nerve and accessory nerves connected to the intercostal muscles and the glottis. The central neurotransmitters implicated in hiccups include gamma-amino-butyric-Acid (GABA) and dopamine. 1 Baclofen, a GABA agonist, has been shown to suppress hiccups, suggesting that the hiccup center is inhibited by GABA.1,10 Several pharmacological agents (gabapentin, pregabalin metoclopramide and baclofen) are reported to have efficacy for empirical treatment of persistent and intractable hiccups. The majority of these drugs are directed at the dopaminergic and GABA-ergic receptors. Cephalosporins are believed to exert an inhibitory effect on gamma-aminobutyric acid transmission of cortical pyramidal cells due to their beta-lactam ring structure, which shares similar molecular architecture to that of GABA neurotransmitters. 9 Neurotoxicity is attributed to their ability to cross the blood-brain barrier and produce gamma-aminobutyric acid antagonism. The possible mechanism of hiccups in our case appears to involve gamma-aminobutyric acid receptor inhibition rather than a dopamine interaction, although other mechanisms may be possible. Indeed, hiccups in our case were not improved by metoclopramide, a dopaminergic antagonist. Further studies are needed to clarify the mechanism of cefotaxime-induced hiccups. Physicians and pharmacists should report such adverse drug reactions in order to better understand their association evidence and their true incidence.
In evaluating hiccups, many etiologies such as gastrointestinal problems should be a primary consideration. However, cefotaxime and many other antibiotics should be considered as infrequent but easily reversible causes. The identification of the culprit drug and its withdrawal is usually sufficient to the cessation of hiccups without exposing the patients to needless invasive investigations.
Footnotes
Author Contributions: All authors have contributions in patient’s management and revising this manuscript content. All authors approved the final manuscript.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Chaker Ben Salem 
https://orcid.org/0000-0001-5187-5809
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