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Treatment of hiccup during general anaesthesia or sedation: a qualitative systematic review

Kranke, P.*; Eberhart, L. H.; Morin, A. M.; Cracknell, J.; Greim, C.-A.*; Roewer, N.*

European Journal of Anaesthesiology (EJA): March 2003 - Volume 20 - Issue 3 - p 239-244
Original Article
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Background and objective: Acute hiccup is a minor complication that can occur during sedation or general anaesthesia. The disorder can disturb the surgical field, might interfere with lung ventilation or could hamper diagnostic procedures. The objective was to perform a systematic search for interventions aimed at treating hiccup occurring during anaesthesia or sedation.

Methods: A systematic search for reports describing interventions to treat hiccup in conjunction with anaesthesia was carried out (MEDLINE, EMBASE, Cochrane-Library, manual screening of reference lists and review articles, up to December 2001). Search terms were 'hiccup', 'singultus' or 'hiccough'.

Results: Twenty-six reports involving approximately 581 patients focused on hiccup remedies in the anaesthesia setting. Only one report was substantiated by a randomized controlled trial. This investigated methylphenidate 10 mg intravenously in 51 patients, which did not show a beneficial effect compared with placebo. Hiccup was a self-limiting phenomenon. Case series and case reports focused on various systemically applied drugs in 12 reports, stimulating techniques (e.g. pharyngeal stimulation) in seven, topical applied remedies (e.g. intranasal ice-cold water) in four, and ventilation techniques (e.g. continuous positive pressure ventilation) in two.

Conclusions: A large variety of interventions have been proposed for the treatment of hiccup during anaesthesia and sedation. However, perioperative treatment is still based on empirical findings and no treatment is 'evidence-based'. Thus, no valid recommendations for the treatment of hiccup can be derived. Uncontrolled observations are inadequate to establish treatment efficacy.

University of Würzburg, *Department of Anaesthesiology and University of Marburg,Department of Anaesthesiology, Germany;Bispebjerg University Hospital, Bispebjerg, Denmark

Correspondence to: Peter Kranke, Department of Anaesthesiology, University of Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. E-mail: peter.kranke@mail.uni-wuerzburg.de; Tel: +49 931 201 0; Fax: +49 931 201 30129

Accepted for publication April 2002 EJA 1076

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 [1], drugs [2,3] and anaesthesia devices such as laryngeal mask airways [4], 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 [5]. Since the phenomenon is not rare - frequencies up to 26% during anaesthesia have been reported [3] - we aimed systematically to search for treatment options for hiccup occurring during general anaesthesia or sedation.

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Methods

The study was performed following the QUORUM standards for conducting systematic reviews [6] 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).

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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.

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Systematic search

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.

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Data extraction

Data extraction and scoring for validity were performed using established procedures [7] that have been described before [8]. 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.

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Results

Phase A: Randomized trials

The initial search for randomized controlled trials revealed one report only, published in 1969 [9]. 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) [10]. The investigation was based on previous non-controlled observations that methylphenidate might be helpful in stopping hiccup during anaesthesia [11,12]. The Oxford score [7] 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.

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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 [13] and three [4] 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.

Table 1

Table 1

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 [13] 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.).

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Discussion

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 [34]. 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' [9]. 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.' [4] and 'when standard therapeutic manoeuvres fail, i.v. nefopam will promptly and reliably relieve refractory postoperative hiccups without inducing severe adverse reactions' [13].

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 [9] 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' [38]. 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 [39] - 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 [9]. 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 [40] to the rectum [41,42] can be stimulated to stop hiccup. (This intervention has potential serious side-effects as reported by Lieberman [43].) Sugar [44], vinegar [38,45] and mustard [38] 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 [46]. 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 [47].

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Acknowledgements

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.

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Keywords:

RESEARCH DESIGN, meta-analysis; SIGNS AND SYMPTOMS, DIGESTIVE, hiccup

© 2003 European Society of Anaesthesiology