Hiccup is described as 'a spasm of the diaphragm that causes a sudden inhalation followed by rapid closure of the glottis which produces a sound' (Mesh term search). Unlike chronic hiccup in conscious subjects, acute and temporary hiccup is a minor complication that occurs, for instance, during sedation or general anaesthesia. The pathophysiology of hiccup is poorly understood. The reflex pathways involved remain speculative, as do the possible sites of actions of the suggested remedies to treat it. Serious consequences from hiccup are unlikely and in the state of sedation or anaesthesia it does not impair patients' well-being. However, the intermittent involuntary spasmodic contraction of the diaphragm can disturb the surgical field, it may interfere with lung ventilation or spontaneous breathing, and hamper diagnostic procedures such as magnetic resonance imaging or endoscopic investigations and interventions. While anaesthesia itself has been considered an appropriate treatment option for intractable chronic hiccup , drugs [2,3] and anaesthesia devices such as laryngeal mask airways , and surgical stimuli may themselves cause hiccup. Anaesthesia textbooks have suggested many ways to alleviate the symptoms of hiccup, for instance, deepening anaesthesia, inserting a nasogastric tube, local anaesthesia of the vagal nerve or neuromuscular blockade . Since the phenomenon is not rare - frequencies up to 26% during anaesthesia have been reported  - we aimed systematically to search for treatment options for hiccup occurring during general anaesthesia or sedation.
The study was performed following the QUORUM standards for conducting systematic reviews  and was adapted to the needs of this topic. We initially searched for controlled clinical trials (Phase A), and later expanded that search to include any clinical reports relating to interventions to treat hiccup during anaesthesia or sedation (Phase B).
Inclusion and exclusion criteria
In Phase A, relevant studies were full reports of randomized controlled trials of any intervention to treat hiccup (active) compared with placebo or no treatment (control) in the anaesthesia or sedation setting. Publications in any language were considered. Initially, we decided not to consider data from retrospective analyses or case reports. In Phase B, we searched for any reports irrespective of the study architecture that described the use of an antihiccup treatment in the defined setting.
Two authors independently searched MEDLINE (from 1966), Oldmedline (from 1960), EMBASE (from 1976) and the Cochrane Controlled Trials Register databases, using different search strategies. The free text words used were 'hiccup OR hiccough OR singultus'. We restricted the search to 'anaesthesia OR anesthesia OR sedation OR surgical'. In Phase B, the latter restriction was not used. Titles were first screened for relevance, and then to see if they were in accordance with the inclusion criteria. The last electronic search was conducted in December 2001. Reference lists of the retrieved literature and of relevant review articles were screened. Locally available anaesthesia journals were hand-searched.
Data extraction and scoring for validity were performed using established procedures  that have been described before . Quantitative analyses (meta-analyses) or vote counting were not feasible owing to a lack of relevant efficacy data. All retrieved reports were tabulated in a spreadsheet, and qualitatively analysed.
Phase A: Randomized trials
The initial search for randomized controlled trials revealed one report only, published in 1969 . Gregory and Way investigated the use of methylphenidate - a central nervous system stimulant - 10 mg intravenously (i.v.) compared with placebo to treat hiccup during anaesthesia. Currently, this substance is used as part of treatment programmes for attention-deficit hyperactivity disorders (ADHD) . The investigation was based on previous non-controlled observations that methylphenidate might be helpful in stopping hiccup during anaesthesia [11,12]. The Oxford score  was 1 for randomization, 2 for blinding and 0 for description of exclusions or withdrawals. Anaesthesiologists were instructed to give 1 mL (10 mg) of the unknown solution i.v. when hiccup occurred and to repeat the same volume from the same vial 2 min later if the symptoms persisted. Anaesthetic procedures were not standardized. Twenty-four patients received methylphenidate and 27 patients a placebo. Following the initial dose, hiccup stopped in 75% (n = 18) and 56% (n = 15) of patients in the methylphenidate and placebo group, respectively (p = 0.147). It is important to note that hiccup occurred in approximately 50 additional patients who were excluded from the trial because their symptoms ceased spontaneously.
Phase B: Uncontrolled observations
There were 25 reports on case series and single observations (Table 1). In those, approximately 530 patients received some kind of supposed active hiccup remedy during anaesthesia or sedation. Retrieved reports were published from 1954 to 2001 in peer-reviewed journals. Three reports were in Italian, one in Dutch and one in German; all others were in English. Two reports on seven  and three  patients, respectively, were published in 2001. Older reports were published as clinical reports, while, more recently, observations were published as case reports or in correspondence sections. The median number of patients per report was 11 (range 1-124). Most of these uncontrolled observations dealt exclusively with one specific intervention.
Two reports referred to a specific lung ventilation technique [14,15], i.e. positive end-expiratory pressure. Four applied an antihiccup remedy topically [3,16-18], i.e. intranasal ethyl chloride spray. Six authors presented seven case series in which any kind of 'stimulation' was applied [19-25], for instance pharyngeal 'stimulation' with a suction catheter. Finally, pharmacological interventions were tested in 12 reports [4,11-13,26-33].
Apart from methylphenidate that was used in three publications [11,12,27] and ketamine that was tested twice [30,32], all interventions were described in one report only (Table 1). In all reports, the tested intervention was a success; there was no report on a treatment failure. Data on the time-course from the occurrence of the symptom to the initiation of the treatment and the treatment success were usually lacking. Adverse effects were reported infrequently. This was especially true for pharmacological interventions. Topical treatments were presented with a more rigid follow-up as far as adverse effects were concerned. For instance, three of four reports made statements on the safety of the topical intervention (for instance, mucosal defects in the nose) [3,16,17].
The following treatments were reported to be ineffective before the tested intervention: nasal or pharyngeal stimulation, for instance with catheters [13,19,26,31], carbon dioxide accumulation [13,19], optic compression  and positive pressure ventilation/manual ventilation [30,31]. Sixteen reports on uncontrolled observations were published after the randomized controlled trial [3,4,13-21,25,28,30-32]; four of those cited the randomized trial [14,16,18,30]. None of the reports suggested a research agenda. An up-to-date literature review on this topic - apart from theoretical considerations why a specific intervention might work - was rare. Discussion on the validity of the observed results in the light of the limitations of uncontrolled observations was sparse, even in more recently published reports.
Apart from these reports on uncontrolled but original observations, we retrieved 40 narrative reports on hiccup, published between 1924 and 2001. Most were mainly on chronic hiccup (a Table of these reports can be obtained from P.K.).
The main result of this systematic review is that there is insufficient sound evidence that would support the use of any specific antihiccup remedy in the anaesthesia setting. From that point of view, the results are rather disappointing. However, there are other issues that seem sufficiently worthwhile to be discussed. We will not cover the historical and sometimes anecdotal aspects of hiccup treatment going back to the explanations given by our medical and philosophic ancestors Hippocrates (c.460-c.377 BC), Plato (427-347 BC) or Galen (129-199 AD) and others . Furthermore, we will not discuss aetiology, pathophysiology and underlying diseases since these have already been covered by existing reviews (a compilation is available from P. K.).
The only randomized controlled trial available on this topic did not show the efficacy of methylphenidate versus the placebo. This may be considered as 'evidence for lack of effect'. An even more important finding of this trial was that 'approximately 50 more patients (in addition to the 51 cases that received a study drug) developed the disorder, but it ended before treatment could be instituted' . On first sight, this seems self-evident since almost everyone experiences hiccups at one time or another and hopefully will have observed that the symptom was self-limiting. However, this wisdom was neglected in most reports and narrative reviews. In two recently published case reports it was stated, 'Finally, the hiccups stopped 2 min after 0.5 mg atropine i.v.'  and 'when standard therapeutic manoeuvres fail, i.v. nefopam will promptly and reliably relieve refractory postoperative hiccups without inducing severe adverse reactions' .
The methodological message resulting from this systematic review is that an uncontrolled observation is not adequate to establish treatment efficacy. This seems to be especially true for transient symptoms such as hiccup in the anaesthesia setting. Case reports or case series cannot give an estimation of the spontaneous course of an event that might play a crucial role in the estimation of an intervention's efficacy. An inactive control group is a prerequisite to gain a realistic estimation of the efficacy of an experimental intervention. The fact that in many of the reports interventions that were previously classified as being successful were described as being ineffective emphasizes the inadequacy of uncontrolled observations for the estimation of efficacy. This stands in contrast to the reporting of adverse events. Uncontrolled observations may be appropriate qualitatively and quantitatively to describe events that occur so rarely that the risk of missing them even in a very large prospective trial is high [35-37]. Data from uncontrolled observations may then influence medical decision-making.
The clinical message is that despite the volume of published reports, there is still no valid recommendation for the treatment of anaesthesia-related hiccup. This stands in contrast to the statements made in a large number of narrative reviews. In those, uncontrolled studies were frequently cited to support the efficacy of an intervention. However, the only randomized trial  has not been frequently cited, neither in the case reports nor in the narrative reviews. Only four of 16 case reports and six of 25 retrieved narrative reviews that were published after 1969 (i.e. after the publication of the randomized trial) cited that trial.
As early as 1932, Mayo found a felicitous description and stated, "The amount of knowledge on any subject such as this can be considered as being in inverse proportion to the number of different treatments suggested and tried for it' . We are inclined to add: in inverse proportion to the number of published reviews and uncontrolled observations as well! This means that treatment of perioperative hiccup remains completely empirical.
Hiccup may be considered as a symptom that is not relevant for the anaesthesia setting any more. It may be argued that this symptom has been suppressed by the development of medical knowledge and practice, for instance by modern hypnotic and muscle-relaxant agents, rather than by a specific treatment. However, the latter arguments cannot fully explain why reports on hiccup persist in the anaesthesia literature. Therefore, if hiccup is considered an issue - and the continuous debate suggests this  - future research has to incorporate the same rigorous prerequisites in terms of randomization and an inactive control group that has been applied a long time ago . Otherwise, the debate and uncertainty will never end.
To summarize, considering the topic from a purely humorous angle and broadening the issue to chronic hiccup, we may conclude that anything from the soft palate  to the rectum [41,42] can be stimulated to stop hiccup. (This intervention has potential serious side-effects as reported by Lieberman .) Sugar , vinegar [38,45] and mustard  may be eaten. An alternative is to pray intensely to St Jude, the patron saint of lost causes, to deal with this annoying symptom; this was the hiccup cure for the 1974 Guinness world record holder Jack O'Leary of Los Angeles, CA, after 60 000 other suggested cures had failed . To be judged a success and earn the gratitude of patients and colleagues, physicians must do anything to stop hiccup. Whatever they do, the intervention cannot possibly be too exotic. We would guess that exactly the same intervention has already been published in the world's medical literature, and has been claimed to be 100% successful. Our favourite intervention, which is only feasible whilst awake, is to think of some dear one remembering us .
The results of this systematic review were presented in part at the 10th Meeting of the European Society of Anaesthesiology, 6-9 April 2002, Nice, France. The authors are grateful to Hanniik Milliken, Per E. Jørgensen and Heiko Vogel for their help with translating the Dutch, Danish and Italian papers. Our warm thanks are due to David Gavaghan for help with editing the manuscript.
1. Mühlenberg K, Weinerth J, Wiedmann KH. Short-acting anesthesia interrupts persistent hiccups. Dtsch Med Wochenschr
2. Weksler N, Stav A, Ovadia L, et al.
Lidocaine pretreatment effectively decreases the incidence of hiccups during methohexitone administration for dilatation and curettage. Acta Anaesthesiol Scand
3. Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M. Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. Paediatr Anaesth
4. Kanaya N, Nakayama M, Kanaya J, Namiki A. Atropine for the treatment of hiccup after laryngeal mask insertion. Anesth Analg
5. Roewer N, Thiel H. Anästhesie Compact.
Stuttgart, Germany: Thieme, 1999.
6. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUORUM statement. Lancet
7. Jadad AR, Moore RA, Carroll D, et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials
8. Kranke P, Morin AM, Roewer N, Eberhart LHJ. Dimenhydrinate for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomised controlled trials. Acta Anaesthesiol Scand
9. Gregory GA, Way WL. Methylphenidate for the treatment of hiccups during anesthesia. Anesthesiology
10. Greenhill LL, Findling RL, Swanson JM. A double-blind, placebo-controlled study of modified-release methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics
11. Macris SG, Macris GJ, Cacouri AN, Karapiperis SN. Intravenous methylphenidate for the treatment of singultus. Anesth Analg
12. Vasiloff N, Cohen DD, Dillon JB. Effective treatment of hiccup with intravenous methylphenidate. Can J Anaesth
13. Bilotta F, Pietropaoli P, Rosa G. Nefopam for refractory postoperative hiccups. Anesth Analg
14. Baraka A. Inhibition of hiccup by pulmonary inflation. Anesthesiology
15. Saitto C, Gristina G, Cosmi EV. Treatment of hiccups by continuous positive airway pressure (CPAP) in anesthetized subjects. Anesthesiology
16. Bannon MG. Termination of hiccups occurring under anesthesia. Anesthesiology
17. Moses JA, Ramachandran KP, Surendran D. Treatment of hiccups with instillation of ether into nasal cavity. Anesth Analg
18. Ravindran RS. A simple technique to stop hiccups during endotracheal anesthesia. Anesth Analg
19. Electrical stimulation of phrenic nerve in treatment of hiccups. N Y State J Med
20. Bondi N, Bettelli A. Treatment of hiccups with acupuncture in anesthetized and conscious subjects. Minerva Med
21. Mangar D, Patil VU. Elimination of hiccups with a nasopharyngeal airway. J Clin Anesth
22. Maritano M, Trompeo MA. La compressione dei bulbi oculari nella terapia intraoperatoria del singhiozzo. Minerva Anestesiol
23. Salem MR. An effective method for the treatment of hiccups during anesthesia. Anesthesiology
24. Salem MR, Baraka A, Rattenborg CC, Holaday DA. Treatment of hiccups by pharyngeal stimulation in anesthetized and conscious subjects. JAMA
25. Visetti E, Costa P. Auriculotherapy for intra-operative hiccup in anesthetized patients. Am J Acupunct
26. Butt HR, Hamelberg W, Jacoby J. Hiccup: its possible cause and treatment in anesthesia. Anesth Analg
27. Calligari G, Marchetti M. Sulla utilità di un nuovo preparato nella terapia del singhiozzo. Gazz Internaz Med
28. Gilston A. Nikethamide for hiccough. Anaesthesia
29. Ruggerini R, Zecca C. Der intraoperative Singultus - Behandlung mit Dextromoramid. Anaesthesist
30. Shantha TR. Ketamine for the treatment of hiccups during and following anesthesia: a preliminary report. Anesth Analg
31. Sohn YZ, Conrad LJ, Katz RL. Hiccup and ephedrine. Can J Anaesth
32. Tavakoli M, Corssen G. Control of hiccups by ketamine: a preliminary report. Alabama J Med Sci
33. Voorhoeve HC. Singultus in patients during and after anaesthesia. Nederlands tijdschrift voor geneeskunde
34. Lewis JH. Hiccups: causes and cures. J Clin Gastroenterol
35. Wulf H. Epidural anaesthesia and spinal haematoma. Can J Anaesth
36. Tramèr MR, Moore RA, Reynolds DJM, McQuay HJ. Quantitative estimation of rare events which follow a biological progression: a new model applied to chronic NSAID use. Pain
37. Krombach J, Hunzelmann N, Koster F, Bischoff A, Hoffman-Menzel H, Buzello W. Anaphylactoid reactions after cisatracurium administration in six patients. Anesth Analg
38. Mayo C. Hiccup. Surg Gynecol Obstet
39. Borromeo CJ, Canes D, Stix MS, Glick ME. Hiccupping and regurgitation via the drain tube of the ProSeal laryngeal mask. Anesth Analg
40. Goldsmith S. A treatment for hiccups. JAMA
41. Fesmire FM. Termination of intractable hiccups with digital rectal massage. Ann Emerg Med
42. Odeh M, Bassan H, Oliven A. Termination of intractable hiccups with digital rectal massage. J Intern Med
43. Lieberman ME. Ventricular tachycardia as a complication of digital rectal massage. Ann Emerg Med
44. Engleman EG, Lankton J, Lankton B. Granulated sugar as treatment for hiccups in conscious patients. New Engl J Med
45. Margolis G. Hiccup remedies. BMJ
46. Guinness Book of World Records,
13th. edn. New York, USA: Sterling, 1974.
47. Bhargava RP, Datta S, Badgaiya R. A simple technique to stop hiccups. Ind J Physiol Pharmac