Skip to main content

Opposite changes in blood pressure and pulse rate in two patients with distigmine and rivastigmine intoxication

Abstract

Background

Cholinergic crisis caused by cholinesterase inhibitors is rare but life-threatening. Clinical manifestations are thought to be similar to those caused by organophosphates.

Case presentation

A 77-year-old woman on a standard dose of distigmine presented with impaired consciousness, blood pressure (BP) of 69/40 mmHg, a pulse rate (PR) of 60 beats/min, miosis, bronchorrhea, and serum cholinesterase (ChE) of 8 IU/L. After discontinuation of distigmine, altered mental status and pupil miosis were gradually resolved in 5 days with a concomitant increase of serum ChE. A 91-year-old woman presented with a headache, BP of 202/86 mmHg, PR of 83 beats/min, miosis, 9 rivastigmine patches on her knees, and ChE of 22 IU/L. The day after close observation without rivastigmine use, her symptoms were almost resolved with a concomitant increase of serum ChE.

Conclusion

Our cases and a literature review suggested that, in contrast to distigmine, rivastigmine-induced cholinergic crisis caused hypertension and tachycardia.

Background

Cholinergic crisis is an adverse drug effect associated with cholinesterase inhibitors. A nationwide database study showed that the iatrogenic cholinergic crisis is a rare but potentially life-threatening condition in Japan [1]. The clinical features resemble carbamate and organophosphate poisoning with symptoms that include both muscarinic (e.g., salivation, lacrimation, urination, defecation, miosis, bronchorrhea, and bradycardia) and nicotinic (e.g., muscle weakness, fasciculations, and paralysis) stimulation [2, 3]. Here, we present 2 cases of cholinergic crisis caused by the reversible cholinesterase inhibitors; distigmine and rivastigmine focused on changes in blood pressure (BP) and pulse rate (PR).

Case presentation

Case 1

A 77-year-old bedridden Japanese woman with a body mass index (BMI) of 19.8 kg/m2 receiving 5 mg of distigmine daily for a neurogenic bladder was transferred to the emergency department of our hospital because of impaired consciousness. On admission, she was disoriented with a Glasgow coma scale of 10 (E4V2M4), and her vital signs were BP 69/40 mmHg, PR 60 beats/min, and oxygen saturation 79% with oxygen therapy via a nonrebreather face mask at 10 L/min. Physical examination revealed pupil miosis, excess salivation, urinary incontinence, and watery diarrhea, but no obvious signs of dehydration. A blood gas analysis suggested acute hypercapnic respiratory failure (arterial carbon dioxide, 51.8 mmHg; arterial oxygen tension, 41.5 mmHg). Laboratory data showed mild leukocytosis and serum cholinesterase (ChE) of 8 IU/L. Other blood tests, including kidney function, liver function including serum albumin, C-reactive protein, and blood glucose, were within normal ranges. Her head computed tomography (CT) scan, electrocardiography, and chest X-ray were unremarkable. Her chest CT scan revealed slight centrilobular nodules with a large amount of intrabronchial secretion. She was diagnosed with distigmine-induced cholinergic crisis followed by acute hypercapnic respiratory failure because of alveolar hypoventilation due to bronchorrhea.

After admission, distigmine was discontinued, and she received supplemental oxygen therapy and ceftriaxone treatment for a possible concurrent pneumonia. Altered mental status, pupil miosis, respiratory failure, excess salivation, urinary incontinence, and watery diarrhea were gradually resolved in 5 days with a concomitant increase of serum ChE (Table 1 (A)).

Table 1 Changes in vital signs and serum cholinesterase before and after both patients’ admissions

Case 2

A 91-year-old Japanese woman with Alzheimer’s disease was taken to her primary care physician for a headache and lightheadedness. The patient had normal BMI, and her nutritional status seemed to correspond to the chronological age. Her vital signs were BP 202/86 mmHg, PR 83 beats/min, and oxygen saturation 98% in room air. She was referred to our department for further evaluation. On admission to our hospital, physical examination revealed pupil miosis but no findings of lacrimation, urination, or bronchorrhea. The emergency physician noticed 9 rivastigmine patches (4 patches of a 9-mg/day formula and 5 of a 13.5-mg/day formula) attached to her both knees. She said that she mistakenly used these patches instead of topical analgesia. Laboratory data showed mild leukocytosis and a serum ChE of 22 IU/L. Other blood tests, including kidney function, liver function, C-reactive protein, and blood glucose, were within normal ranges. Her head CT scan, electrocardiography, and chest X-ray were unremarkable. She was suspected to be in cholinergic crisis caused by rivastigmine overdose and was admitted for close observation without rivastigmine use. The day after her admission, her symptoms, headache, lightheadedness, and miosis were almost resolved with a concomitant increase of serum ChE (Table 1 (B)). On day 7, her serum ChE levels returned to baseline at 236 IU/L. Consequently, she was diagnosed with rivastigmine-induced cholinergic crisis.

Discussion

Distigmine is considered as the main causative drug of cholinergic crisis in Japan [1]. Table 2 (A) summarizes case reports describing distigmine-induced crisis. Most reports showed development of hypotension and bradycardia. In some patients, vital signs showed a circulatory shock state, requiring vasopressors. Distigmine can induce bradycardia, which is consistent with the report that pyridostigmine, a combination of two molecules in distigmine, shows heart rate reduction in patients with heart failure [26]. In contrast, as in case 2, patients with rivastigmine intoxication developed elevated BP and a relatively increased PR. These findings are compatible with previous reports (Table 2 (B)). Excessive doses of donepezil, a central acetylcholinesterase inhibitor, induces bradycardia [27,28,29]; therefore, cholinesterase inhibition in the central nervous system may not participate in the mechanism by which rivastigmine cause tachycardia. A standard dose of rivastigmine was shown not to be associated with any changes in BP or PR [30, 31]. Future studies are needed to elucidate the mechanisms of hyperdynamic state induced by rivastigmine overdose.

Table 2 Previous reports showing distigmine and rivastigmine intoxication

In case 1, a clinical dosage of distigmine had been administered for 7 years until the patient developed cholinergic crisis. Because her caregivers administered the drug, we ruled out the possibility of distigmine abuse. Her routine checkup before admission showed a stable serum creatinine level of 0.3–0.4 mg/dL over several years, suggesting a ≥ 100 mL/min/1.73m2 estimated glomerular filtration rate (eGFR). However, her serum creatinine was mildly elevated to 0.76 mg/dL on admission to our hospital, meaning that the eGFR decreased to 57 mL/min/1.73m2. Because distigmine is mainly eliminated by renal excretion [32], the relative decrease in distigmine clearance might have been associated with her distigmine overdose.

Our previous study showed an age-dependent decline in serum ChE levels in physically independent adults [33]. As shown in Table 2, a marked decrease in ChE activity was observed in all cases in which the serum ChE was measured. Lower ChE activity may be associated with lower BP and PR in patients who have experienced a distigmine overdose (Table 2 (A)). In acute organophosphate pesticide poisoning, however, associating ChE activity with disease severity remains controversial [34]. Further studies are needed to clarify whether serum ChE reflects the severity of cholinesterase-inhibitor intoxication.

Conclusion

Our findings suggest that, in contrast to distigmine, rivastigmine-induced cholinergic crisis increases the BP and PR. Serum ChE should be periodically measured in patients with cholinesterase inhibitors to avoid life-threatening adverse effects.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

References

  1. 1.

    Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H. Cholinergic crisis caused by cholinesterase inhibitors: a retrospective nationwide database study. J Med Toxicol. 2018;14:237–41.

    CAS  Article  Google Scholar 

  2. 2.

    Sidell FR. Clinical effects of organophosphorus cholinesterase inhibitors. J Appl Toxicol. 1994;14:111–3.

    CAS  Article  Google Scholar 

  3. 3.

    Lee DH, Choi YH, Cho KH, Yun SY, Lee HM. A case of rivastigmine toxicity caused by transdermal patch. Am J Emerg Med. 2011;29:695.e1-2.

    Article  Google Scholar 

  4. 4.

    Sakurai T, Yamada S, Kitada M, Hashimoto S, Hashimoto S, Kimura F, et al. A case of cholinergic crisis caused by distigmine bromide administered for paralytic ileus. Jpn Soc Intensive Care Med 201;21: 635-8. (Abstract in English).

    Article  Google Scholar 

  5. 5.

    Katayama S, Kumasawa J, Oe K, Tazawa N, Lee H, Ito C, A case of cholinergic crisis induced by chronic distigmine bromide intoxication J Jpn Soc Intensive Care Med 2011;18:227-31. (Abstract in English).

  6. 6.

    Ueki M. Shirakawa Y, Aibiki M, Tukamoto I, Taie S, Umegaki O, et al. A case of distigmine bromide poisoning. Chudoku Kenkyu. 1991;4:383-5. (Abstract in English).

  7. 7.

    Niinou N, Matsubara Y, Yamamori Y, Sasaki A, Ohshima Y, Kajitani H, et al. A case of cholinergic crisis associated with distigmine bromide administration. Shimane Kenritsu Chuo Byoin Igaku Zasshi. 2005;28:43–5 (in Japanese).

    Google Scholar 

  8. 8.

    Yamanaka S, Fujita I, Murota T, Kawakita M, Matsuda T. Cholinergic crisis following administration of distigmine bromide: a case report. Hinyokika Kiyo. 2002;48:21-3. (Abstract in English).

  9. 9.

    Tokimasa Y, Fujiwara K, Higo H, Kameyama N, Kayatani H, Matsuo K, et al. A case of cholinergic crisis induced by distigmine bromide successfully treated with noninvasive positive pressure ventilation. Nihon Kyobu Rinsho. 2013;72:894-9. (Abstract in English).

  10. 10.

    Shinya H, Hakoda S, Kiuchi S. An aged patient with dementia of cholinergic crisis by distigmine bromide. Nihon Rinsho Kyukyu Igakkai Zasshi (Journal of Japanese Society for Emergency Medicine). 2009;19:453-7. (in Japanese).

  11. 11.

    Kaneko S, Kobayashi K, Morita K, Teruya M, Kaminishi M. A case of cholinergic crisis caused by distigmine bromide associated with toxic megacolon after rectal cancer resection. Geka. 2016;78:190–3 (in Japanese).

    Google Scholar 

  12. 12.

    Kobayashi K, Sekiguchi H, Sato N, Hirose Y. Bowel obstruction-induced cholinergic crisis with progressive respiratory failure following distigmine bromide treatment. Chudoku Kenkyu. 2016;29:26-9. (Abstract in English).

  13. 13.

    Nishizawa T, Matsumoto T, Nakamura T, Sasano M, Mayama Y. Cholinergic crisis with cardiac arrest following distigmine bromide overdose. J Jpn Soc Intensive Care Med. 2019;26:123–4 (in Japanese).

    Article  Google Scholar 

  14. 14.

    Hasegawa S, Takagi T, Hirai N, Takita T. A case of cerebral infarction with cholinergic crisis for term administration of distigmine bromide. Journal of Clinical Rehabilitation. 2009;18:283–6 (in Japanese).

    Google Scholar 

  15. 15.

    Nitta K, Tsushima H, Kajihara K, Kajiwara S, Jyo H, Hara M, et al. A case of cholinergic crisis presenting with difficulties in diagnosing the cause of impaired consciousness. Hiroshima Igaku. 2016;69:442–5 (in Japanese).

    Google Scholar 

  16. 16.

    Tada M, Fujita N. Umeda M. Koike H, Nagai H. A case of acute distigmine bromide intoxication in the therapeutic dosage for treatment of underactive neurogenic bladder. No To Shinkei. 2004;56:415-9. (Abstract in English).

  17. 17.

    Iwata M, Matsui S, Maruyama M, Taniguchi H, Oda H. Miwa T, et al. A case of acute respiratory failure associated with cholinergic crisis induced by distigmine bromide. Nihon Kyobu Rinsho. 2002;61:84-91. (Abstract in English).

  18. 18.

    Matsuki Y, Matsuki Y, Yasuda Y, Murakami T, Takakura K, Shigemi K, Severe bradycardia associated with cholinergic crisis induced by a small dose of distigmine bromide. Junkan Seigyo. 2013;34:78-81. (Abstract in English).

  19. 19.

    Kaneko N, Kaneshige H, Suzuki H. A case of acute respiratory failure with a decrease of serum cholinesterase caused by distigmine bromide. J Jan Soc Intensive Care Med. 1996;4:277-81. (Abstract in English).

    Article  Google Scholar 

  20. 20.

    Morita S, Miwa H, Kondo T. A case of cholinergic crisis induced by distigmine bromide during a course of Bickerstaff encephalitis. Wakayama Igaku. 2003;54:222-4. (Abstract in English).

  21. 21.

    Lövborg H, Jönsson AK, Hägg S. A fatal outcome after unintentional overdosing of rivastigmine patches. Curr Drug Saf. 2012;7:30–2.

    Article  Google Scholar 

  22. 22.

    Sener S, Ozsarac M. Case of the month: rivastigmine (Exelon) toxicity with evidence of respiratory depression. Emerg Med J. 2006;23:82–3.

    CAS  Article  Google Scholar 

  23. 23.

    Brvar M, Mozina M, Bunc M. Poisoning with rivastigmine. Clin Toxicol (Phila). 2005;43:891–2.

    Article  Google Scholar 

  24. 24.

    Suzuki Y, Kamijo Y, Yoshizawa T, Fujita Y, Usui K, Kishino T. Acute cholinergic syndrome in a patient with mild Alzheimer’s type dementia who had applied a large number of rivastigmine transdermal patches on her body. Clin Toxicol(Phila). 2017;55:1008–10.

    Article  Google Scholar 

  25. 25.

    Hoffman RS, Manini AF, Russell-Haders AL, Felberbaum M, Mercurio-Zappala M. Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity. Hum Exp Toxicol. 2009;28:599–602.

    CAS  Article  Google Scholar 

  26. 26.

    Villacorta AS, Villacorta H, Caldas JA, Precht BC, Porto PB, Rodrigues LU, et al. Effects of heart rate reduction with either pyridostigmine or ivabradine in patients with heart failure: a randomized, double-blind study. J Cardiovasc Pharmacol Ther. 2018. doi: 10.1177/1074248418799364.

    Article  Google Scholar 

  27. 27.

    Pourmand A, Shay C, Redha W, Aalam A, Mazer-Amirshahi M. Cholinergic symptoms and QTc prolongation following donepezil overdose. Am J Emerg Med. 2017;35:1386.e1–3.

    CAS  Article  Google Scholar 

  28. 28.

    Shepherd G, Klein-Schwartz W, Edwards R. Donepezil overdose: a tenfold dosing error. Ann Pharmacother. 1999;33:812-815.

    CAS  Article  Google Scholar 

  29. 29.

    Yano H, Fukuhara Y, Wada K, Kowa H, Nakashima K. A case of acute cholinergic adverse effects induced by donepezil overdose: a follow-up of clinical course and plasma concentration of donepezil. Rinsho Shinkeigaku. 2003;43:482-486 (in Japanese).

  30. 30.

    Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318:633-638.

    CAS  Article  Google Scholar 

  31. 31.

    Isik AT, Soysal P, Yay A. Which rivastigmine formula is better for heart in elderly patients with Alzheimer’s disease: oral or patch? Am J Alzheimers Dis Other Demen. 2014;29:735–8.

    Article  Google Scholar 

  32. 32.

    Vree TB, Waitzinger J, Hammermaier A, Radhofer-Welte S. Absolute bioavailability, pharmacokinetics, renal and biliary clearance of distigmine after a single oral dose in comparison to i.v. administration of 14C-distigmine-bromide in healthy volunteers. Int J Clin Pharmacol Ther. 1999;37:393–403.

    CAS  PubMed  Google Scholar 

  33. 33.

    Matsuo M, Tazawa K. Reference range of clinical blood tests in physically independent patients of advanced age with groin hernia in a Japanese hospital. Geriatr Gerontol Int. 2019;19:780–5.

    Article  Google Scholar 

  34. 34.

    Yuan S, Gao Y, Ji W, Song J, Mei X. The evaluation of acute physiology and chronic health evaluation II score, poisoning severity score, sequential organ failure assessment score combine with lactate to assess the prognosis of the patients with acute organophosphate pesticide poisoning. Medicine (Baltimore). 2018;97:e10862.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

None.

Authors’contributions

SH contributed to the clinical care of patients and to the manuscript preparation. MM contributed to the manuscript preparation. All authors read and approved the final manuscript.

Funding

The authors declare that they received no funding for this work.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mitsuhiro Matsuo.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was received from the patients’ legal guardians for the publication of this case report.

Competing interests

None declared.

Additional information

Publisher’s Note

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

Rights and permissions

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/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sedogawa, H., Matsuo, M. Opposite changes in blood pressure and pulse rate in two patients with distigmine and rivastigmine intoxication. JA Clin Rep 6, 17 (2020). https://doi.org/10.1186/s40981-020-00323-w

Download citation

Keywords

  • Adverse effects
  • Cholinesterase inhibitors
  • Emergencies
  • Vital signs