
==== Front
JA Clin Rep
JA Clin Rep
JA Clinical Reports
2363-9024
Springer Berlin Heidelberg Berlin/Heidelberg

39230624
738
10.1186/s40981-024-00738-9
Letter to the Editor
Comment on: “Treatment-resistant hiccups during general anesthesia possibly caused by remimazolam: a case report”—a reply
Matsui Yusuke 1
http://orcid.org/0000-0002-0119-3532
Takazawa Tomonori takazawt@med.u-toyama.ac.jp

2
1 https://ror.org/03ntccx93 grid.416698.4 Department of Anesthesiology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-Cho, Takasaki, 370-0829 Japan
2 https://ror.org/0445phv87 grid.267346.2 0000 0001 2171 836X Department of Anesthesiology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194 Japan
4 9 2024
4 9 2024
12 2024
10 5616 8 2024
16 8 2024
26 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
issue-copyright-statement© The Japanese Society of Anesthesiologists 2024
==== Body
pmcTo the Editor,

We thank Mizutani and Tsuchiya for their thoughtful commentary on our article [1]. They argued that hiccups in our case were induced because of the weak hypnotic effect and weak brainstem reflex inhibition under remimazolam, compared to propofol or inhaled anesthetics. We disagree with their argument for the following reasons.

Assuming that remimazolam induced the hiccups because it has a weak inhibitory effect on brainstem reflexes, in that case, additional doses of remimazolam should have reduced or eliminated the hiccups, but this did not happen. Furthermore, the hiccups persisted even after surgery but disappeared as the predicted blood level of remimazolam decreased [2]. These facts do not support their idea that hiccups were induced because remimazolam was less effective in suppressing brainstem reflexes, including hiccups.

They cited a paper stating that propofol is less effective at suppressing blink reflex activity, which is also a brainstem reflex, than sevoflurane, even at the same bispectral index (BIS) value [3]. Based on this paper, they suggested that remimazolam might also have a weaker inhibitory effect on the brainstem reflex of hiccups. However, the paper they cited was about sevoflurane and propofol and states nothing about remimazolam [3]. To justify their argument, they must show that remimazolam is a weak inhibitor of brainstem reflexes.

Indeed, the BIS value is a good reference for the depth of anesthesia but does not always help predict adverse reflexes during general anesthesia, including hiccups. In addition to BIS value, other vital signs, such as blood pressure and heart rate, should also be consulted to determine whether adequate sedation and analgesia are achieved during general anesthesia. In this case, since the patient’s vital signs did not suggest a lack of sedation and analgesia during anesthesia [2], we believe that the hiccups were not induced by inadequate sedation or analgesia.

In a study on sedation with remimazolam for endoscopic examination in elderly patients, hiccups occurred in eight of 64 patients (12.5%). This rate is much higher than the incidence of one out of 65 cases (1.5%) reported for propofol [4]. A recent randomized crossover trial showed a higher incidence of hiccups in patients with general anesthesia with remimazolam than with propofol (29% vs. 0%) [5]. Furthermore, hiccups caused by benzodiazepines, especially midazolam, which is very similar in action to remimazolam, have been reported several times in the past [6–8]. Hiccups after midazolam administration have been reported to disappear after flumazenil administration [9]. This evidence supports our hypothesis that like midazolam, remimazolam also has the potential to induce hiccups.

Our report is a single case report and does not demonstrate the mechanism by which remimazolam induces hiccups. Further research is needed to clarify the relationship between remimazolam and hiccups. In this case report, we emphasize that when hiccups occur during general anesthesia with remimazolam, anesthesiologists should consider using muscle relaxants or changing the anesthetic used.

Abbreviation

BIS Bispectral index

Acknowledgements

Not applicable.

Authors’ contributions

YM wrote the original version of the manuscript. TT helped revise the manuscript. All authors read and approved the final manuscript.

Funding

The authors have no sources of funding to declare.

Availability of data and materials

Data relevant to this case report are not available for public access because of patient privacy concerns but are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Mizutani K. Hiccups during general anesthesia with remimazolam. JA Clin Rep. 2024. 10.1186/s40981-024-00727-y.
2. Sakurai M Matsui Y Takazawa T Kabasawa Y Nagumo W Takada R Saito S Treatment-resistant hiccups during general anesthesia possibly caused by remimazolam: a case report JA Clin Rep 2024 10 1 32 10.1186/s40981-024-00714-3 38787462
Sakurai M, Matsui Y, Takazawa T, Kabasawa Y, Nagumo W, Takada R, Saito S. Treatment-resistant hiccups during general anesthesia possibly caused by remimazolam: a case report. JA Clin Rep. 2024;10(1):32.38787462 10.1186/s40981-024-00714-3
3. Mourisse J Lerou J Struys M Zwarts M Booij L Multi-level approach to anaesthetic effects produced by sevoflurane or propofol in humans: 2. BIS and tetanic stimulus-induced withdrawal reflex Br J Anaesth 2007 98 6 746 55 10.1093/bja/aem105 17519262
Mourisse J, Lerou J, Struys M, Zwarts M, Booij L. Multi-level approach to anaesthetic effects produced by sevoflurane or propofol in humans: 2. BIS and tetanic stimulus-induced withdrawal reflex. Br J Anaesth. 2007;98(6):746–55.17519262 10.1093/bja/aem105
4. Ye E Wu K Ye H Zhang W Chu L Zhang K Xie G Jin Y Fang X Comparison of 95% effective dose of remimazolam besylate and propofol for gastroscopy sedation on older patients: a single-centre randomized controlled trial Br J Clin Pharmacol 2023 89 11 3401 10 10.1111/bcp.15839 37387195
Ye E, Wu K, Ye H, Zhang W, Chu L, Zhang K, Xie G, Jin Y, Fang X. Comparison of 95% effective dose of remimazolam besylate and propofol for gastroscopy sedation on older patients: a single-centre randomized controlled trial. Br J Clin Pharmacol. 2023;89(11):3401–10.37387195 10.1111/bcp.15839
5. Yang C Jiao J Nie Y Shao W Zhang H Huang S Comparison of the bispectral indices of patients receiving remimazolam and propofol for general anesthesia: a randomized crossover trial Anaesth Crit Care Pain Med 2024 43 3 101377 10.1016/j.accpm.2024.101377 38494158
Yang C, Jiao J, Nie Y, Shao W, Zhang H, Huang S. Comparison of the bispectral indices of patients receiving remimazolam and propofol for general anesthesia: a randomized crossover trial. Anaesth Crit Care Pain Med. 2024;43(3):101377.38494158 10.1016/j.accpm.2024.101377
6. Thompson DF Landry JP Drug-induced hiccups Ann Pharmacother 1997 31 3 367 9 10.1177/106002809703100318 9066948
Thompson DF, Landry JP. Drug-induced hiccups. Ann Pharmacother. 1997;31(3):367–9.9066948 10.1177/106002809703100318
7. Rodriguez-Nunez A Redondo L Martinon JM Hiccups due to midazolam in children Eur J Pediatr 1993 152 3 271 10.1007/BF01956165 8444261
Rodriguez-Nunez A, Redondo L, Martinon JM. Hiccups due to midazolam in children. Eur J Pediatr. 1993;152(3):271.8444261 10.1007/BF01956165
8. Marhofer P Glaser C Krenn CG Grabner CM Semsroth M Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia Paediatr Anaesth 1999 9 4 295 8 10.1046/j.1460-9592.1999.00378.x 10411763
Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M. Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. Paediatr Anaesth. 1999;9(4):295–8.10411763 10.1046/j.1460-9592.1999.00378.x
9. Rao PN Wu CL YaDeau JT Midazolam-induced hiccups reversed by flumazenil: a case report A A Pract 2021 15 11 e01547 10.1213/XAA.0000000000001547 34807869
Rao PN, Wu CL, YaDeau JT. Midazolam-induced hiccups reversed by flumazenil: a case report. A A Pract. 2021;15(11):e01547.34807869 10.1213/XAA.0000000000001547
