The toxic honey that destroyed several armies

The toxic honey that destroyed several armies

Ingestion of “mad honey” causes severe hypotension and bradycardia. Let us learn about the intoxication given by the grayanotoxin family.

In Italian, there is a literary expression known as: “losing the Trebizond,” which means losing control, feeling confused and disoriented. Trebizond was an important port on the southern coast of the Black Sea, where the maritime lighthouse was strategically located for sailors, especially the Venetians, whose colonial rule extended from the coasts of western Greece to the straits of the Dardanelles and the Bosporus. In the province of this seaside town, a type of honey produced disorientation, confusion, and fainting. We then explored why it is called “mad honey.”

Panoramic view of the city of Trabzon and its port on the Black Sea (from Wikipedia – Nezih Durmazlar – Flickr: Panoromik Trabzon – CC BY-SA 2.0)

What is meant when we talk about “mad honey?

“Mad honey” is toxic, and is from the nectar of various species of rhododendron, in particular Rhodendrum ponticum and Rhododendrum luteum. These plants are largely found in Turkey (in the Black Sea area near the city of Trebizond), but are also in Japan, Nepal (especially in the area where the Gurung people live), and Brazil. This honey, made by local bees, is called “mad,” because it contains several toxins of the grayanotoxin family (GTX). GTXs belong to liposoluble diterpenoids [1]; similar to veratridine, aconitine, and batrachotoxin, they are known for poisoning and killing livestock.

Rhododednrum luteum (from Wikipedia – Chrumps – CC BY 3.)
Rhododendron ponticum (from Wikipedia – Ragnhild&Neil Crawford – CC BY-SA 2.0)

Why did this honey undermine two armies?

In 401 BC, the Greek general Xenophon described one of the first intoxications with this honey, which affected over 10,000 men of his army:

“For the most part, there was nothing which they found strange; but there were numerous swarms of bees in the neighbourhood, and soldiers who ate it went out of their heads,suffering from vomiting and diarrhea: not one of them could stand up, but those who had eaten a little were like very drunk people, while those who had eaten a lot seemed like crazy, or in some cases, dying men.”

(Anabasis 4.8.20)

In 67 BC, another case of intoxication was described by the Roman general, Pompey the Great. His retreating troops were the protagonists of the first bioweapon case in history. Their adversary, King Mithridates, deliberately placed combs of mad honey in the path of the advancing Romans, staging a strategic withdrawal. The Roman troops were so weakened (from intoxication), that they were defeated by Mithridates’ army. In 946 AD, Queen Olga of Kiev massacred over 5,000 Drevians, who rushed to her husband’s funeral using mad honey as poison; in 1489 AC, about 10,000 Tatar soldiers were killed after drinking too many flasks of mead, who were purposely abandoned by the Russian soldiers. In the past, however, the mad honey was also used as a drug. Aristotle [2], Dioscorides [3], and Pliny the Elder [4] had described the therapeutic properties of this honey

The statue of Xenophon is located near the Greek Parliament. (from Wikipedia – Wienwiki / Walter Maderbacher – CC BY-SA 3.0)

Is mad honey still used today?

“Mad honey” is still sold today in an unprocessed form in rural markets, under the Turkish name “DELI BAL.” In fact, studies and clinical cases on GTX intoxication come from the Trabzon province (more widely, from Turkey [5] where the honey is used not only as a food, but in folk medicine as a sexual stimulant [6], antihypertensive [7], and hypoglycemic drug. Other uses of this honey in folk medicine were to treat peptic ulcer, abdominal pain, indigestion, flu, and arthritis.

How long does it take from ingestion to onset of symptoms?

On average, symptoms appear about one to two hours after ingestion. The average quantity for symptoms is varied (people report from 1 to 5 tablespoons, so it is estimated as 5 to 180 g). Given that the diffusion of grayanotoxins is not uniform in honey, we should think of this data as not highly predictive [8]: we note that the severity of symptoms also depends on other factors, such as the quantity of toxin ingested, the body’s sensitivity to it, and when the honey was produced.

What are the most common symptoms of intoxication with mad honey?

The symptoms would usually be:

  • nausea and vomiting
  • profuse sweating
  • blurred vision
  • hypersalivation
  • prostration
  • bradycardia
  • severe hypotension
  • syncope

For a more complete history for reaching the diagnosis of mad honey intoxication, it was helpful to ask a patient if he traveled to areas where it existed if he has ingested it, the reason for that (for pharmacological purposes, this question helps us understand if a patient is suffering from certain diseases, such as hypertension or diabetes), and where this mad honey was bought.

Are there any electrocardiographic changes?

Electrocardiographic changes such as sinus bradycardia and atrioventricular blocks [9] of varying degrees (I-III) are frequently found. It would appear that the GTXs act by dysregulating the voltage-dependent sodium channels in the nervous system, which are activated in a permanent state of depolarization [10]. Continued activation of these cells causes bradycardia, respiratory depression, hypotension, and loss of consciousness [11].

Voltage-gated sodium channel with group II receptor site domains highlighted in red. (from Wikipedia -Cthuljew – CC BY-SA 3.0)
The patient’s initial electrocardiography (ECG) findings upon arrival to the emergency department consistent with third-degree atrioventricular block. This finding prompted consultation of the cardiology service for treatment guidance and is a common manifestation of grayanotoxin ingestion. (from JACC: CASE REPORTS – https://doi.org/10.1016/j.jaccas.2019.09.015 – CC BY-NC-ND 4.0)

What therapeutic approach should be adopted?

  • Monitor vital and cardiac parameters.
  • Support therapy with intravenous crystalloid fluid (normal saline solution).
  • Use atropine sulfate at a moderate dose from 0.5 to 2 mg intravenously to resolve marked hypotension and respiratory depression.
  • Vasopressors or pacemakers if/when the rhythm is not restored.

We should consider achieving a normal heart rate and normal blood pressure values as therapeutic goals. Once these goals are achieved, the patient should be kept for a short period of observation in the emergency department – and if no other problems arise, he can be safely discharged [12, 13]. Furthermore, I would like to emphasize that grayanotoxin metabolism and excretion take place within 24 hours, and thus the symptoms last no more than a day.

What is the take-home message?

In patients with bradycardia and hypotension of unexplained origin, this type of intoxication should be considered especially in middle-aged males who have probably taken mad honey as a sexual stimulant.

 

References and Further Reading

[1] Jansen SA, Kleerekooper I, Hofman ZLM et al (2012) Grayanotoxin Poisoning: ‘Mad Honey Disease’ and Beyond. Cardiovasc Toxicol 12:208–215. https://doi.org/10.1007/s12012-012-9162-2

[2] Aristotle (1936) De mirabilius auscultationibus. Aristotle Minor Works on Marvelous Things Heard. Loeb, Cambridge, p. 245.

[3] Dioscorides (2000) De materia medica. Ibidis Press, Johannesburg, p. 226.

[4] Mayer A (1995) Mad honey. Archaeology 46(6):32–40.

[5] Sibel Silici A, Timucin A (2015) Mad honey intoxication: A systematic review on the 1199 cases. Food Chem Toxicol 86:282-290. https://doi.org/10.1016/j.fct.2015.10.018

[6] Demircan A, Keleş A, Bildik F, Aygencel G, Doğan NO, Gómez HF (2009) Mad honey sex: therapeutic misadventures from an ancient biological weapon. Ann Emerg Med 54(6):824-829. doi: 10.1016/j.annemergmed.2009.06.010

[7] Hanson JR (2016) From ‘mad honey’ to hypotensive agents, the grayanoid diterpenes. Sci Prog 99(3):327-334. doi: 10.3184/003685016X14720691270831

[8] Aygun A, Sahin A, Karaca Y, Turkmen S, Turedi S, Ahn SY, Kim S, Gunduz A (2017) Grayanotoxin levels in blood, urine and honey and their association with clinical status in patients with mad honey intoxication. Turk J Emerg Med 18(1):29-33. doi: 10.1016/j.tjem.2017.05.001

[9] Cagli KE, Tufekcioglu O, Sen N, Aras D, Topaloglu S, Basar N, Pehlivan S (2009). Atrioventricular block induced by mad-honey intoxication: confirmation of diagnosis by pollen analysis. Tex Heart Inst J 36(4):342-344.

[10] Gunduz A, Tatli O, Turedi S (2008). Mad honey poisoning from the past to the present. Turk J Emerg Med 8:46-49.

[11] Sana U, Tawfik AS, Shah F (2018) Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Adv 8:18635-18646.

[12] Gündüz A, Meriçé ES, Baydin A, Topbas M, Uzun H, Türedi S, Kalkan A (2009) Does mad honey poisoning require hospital admission? Am J Emerg Med 27:424-427.

[13] Yaylacı S, Ayyıldız O, Aydın E, Osken A, Karahalil F, Varım C, Demir MV, Genç AB, Sahinkus S, Can Y, Kocayigit İ, Bilir C (2015) Is there a difference in mad honey poisoning between geriatric and non-geriatric patient groups? Eur Rev Med Pharmacol Sci 19(23):4647-4653.

Cite this article as: Francesco Adami, Italy, "The toxic honey that destroyed several armies," in International Emergency Medicine Education Project, January 25, 2021, https://iem-student.org/2021/01/25/the-toxic-honey/, date accessed: September 25, 2021

Triads in Medicine – Rapid Review for Medical Students

triads in medicine

One of the most convenient ways of learning and remembering the main components of disease and identifying a medical condition on an exam are Triads, and medical students/interns/residents swear by them.

Be it a question during rounds, a multiple-choice exam question to be solved, or even in medical practice, the famous triads help physicians recall important characteristics and clinical features of a disease or treatment in an instant.

Since exam season is here, this could serve as a rapid review to recall the most common medical conditions.

While there are a vast number of triads/pentads available online, I have listed the most important (high-yy) ones that every student would be asked about at least once in the duration of their course.

1) Lethal Triad also known as The Trauma Triad of Death
Hypothermia + Coagulopathy + Metabolic Acidosis

2) Beck’s Triad of Cardiac Tamponade
Muffled heart sounds + Distended neck veins + Hypotension

3) Virchow’s Triad – Venous Thrombosis
Hypercoagulability + stasis + endothelial damage

4) Charcot’s Triad – Ascending Cholangitis
Fever with rigors + Right upper quadrant pain + Jaundice

5) Cushing’s Triad – Raised Intracranial Pressure
Bradycardia + Irregular respiration + Hypertension

6) Triad of Ruptured Abdominal Aortic Aneurysm
Severe Abdominal/Back Pain + Hypotension + Pulsatile Abdominal mass

7) Reactive Arthritis
Can’t See (Conjunctivitis) + Can’t Pee (Urethritis) + Can’t Climb a Tree (Arthritis)

8) Triad of Opioid Overdose
Pinpoint pupils + Respiratory Depression + CNS Depression

9) Hakims Triad – Normal Pressure Hydrocephalus
Gait Disturbance + Dementia + Urinary Incontinence

10) Horner’s Syndrome Triad
Ptosis + Miosis + Anydrosis

11) Mackler’s Triad – Oesophageal Perforation (Boerhaave Syndrome)
Vomiting + Lower Thoracic Pain + Subcutaneous Emphysema

12) Pheochromocytoma
Palpitations + Headache + Perspiration (Diaphoresis)

13) Leriche Syndrome
Buttock claudication + Impotence + Symmetrical Atrophy of bilateral lower extremities

14) Rigler’s Triad – Gallstone ileus
Gallstones + Pneumobilia + Small bowel obstruction

15) Whipple’s Triad – Insulinoma
Hypoglycemic attack + Low glucose + Resolving of the attack on glucose administration

16) Meniere’s Disease
Tinnitus + Vertigo + Hearing loss

17) Wernicke’s Encephalopathy- Thiamine Deficiency
Confusion + Ophthalmoplegia + Ataxia

18) Unhappy Triad – Knee Injury
Injury to Anterior Cruciate Ligament + Medial collateral ligament + Medial or Lateral Meniscus

19) Henoch Schonlein Purpura
Purpura + Abdominal pain + Joint pain

20) Meigs Syndrome
Benign ovarian tumor + pleural effusion + ascites

21) Felty’s Syndrome
Rheumatoid Arthritis + Splenomegaly + Neutropenia

22) Cauda Equina Syndrome
Low back pain + Bowel/Bladder Dysfunction + Saddle Anesthesia

23) Meningitis
Fever + Headache + Neck Stiffness

24) Wolf Parkinson White Syndrome
Delta Waves + Short PR Interval + Wide QRS Complex

25) Neurogenic Shock
Bradycardia + Hypotension + Hypothermia

Further Reading

Cite this article as: Sumaiya Hafiz, UAE, "Triads in Medicine – Rapid Review for Medical Students," in International Emergency Medicine Education Project, June 12, 2020, https://iem-student.org/2020/06/12/triads-in-medicine/, date accessed: September 25, 2021

RUSH Course for Medical Students

Dear students,

We are pleased to open our third course for you; Rapid Ultrasound in Shock and Hypotension (RUSH).

As a part of our social responsibility initiative, iem-course.org will continue to provide free open online courses related to emergency medicine. We hope our courses help you to continue your education during these difficult times.

Please send us your feedback or requests about courses.

We are here to help you.

Best regards.

Arif Alper Cevik, MD, FEMAT, FIFEM

Arif Alper Cevik, MD, FEMAT, FIFEM

iEM Course is a social responsibility initiative of iEM Education Project

Hypotension is a high-risk sign which is associated with increased morbidity and mortality rate. The differential diagnosis for hypotension is broad and the treatment depends on the underlying etiology. In most cases of hypotension, patients present with limited history and physical examination may be inaccurate making the management of the condition a great challenge for emergency physicians.

The use of POCUS in undifferentiated hypotension has been shown to help correctly and rapidly identify the etiology and therefore initiate the appropriate management. Since 2001, there are many protocols published describing a systematic approach to the use of POCUS in undifferentiated hypotension. 

In this course, we will focus on the Rapid Ultrasound in Shock and Hypotension (RUSH) protocol.

This course aims to provide the necessary information on ultrasonography, its use in a hypotensive patient, and to prepare you for a RUSH practice session.

The course content is prepared and curated from iEM Education chapters, iEM image and video archives, and various FOAMed resources.

At the end of this course, you will be able to;

  • Describe the basics of ultrasound (terminology, knobology, image acquisition, artifacts, etc.)
  • Describe indications of RUSH protocol
  • Describe patient and machine preparations
  • Describe ultrasound examination views
  • Recognize normal anatomical structures
  • Recognize abnormal findings
  • Feel confident to take a practical session for RUSH protocol

Who can get benefit from this course?

  • Junior and senior medical students (course specifically designed for these groups)
  • Interns/Junior emergency medicine residents/registrars

Other Free Online Courses

Cite this article as: Arif Alper Cevik, "RUSH Course for Medical Students," in International Emergency Medicine Education Project, May 27, 2020, https://iem-student.org/2020/05/27/rush-course-for-medical-students/, date accessed: September 25, 2021

Airway Tips by Manrique Umana

Dr. Manrique Umana from Costa Rica presented a fantastic lecture during the 30th Emergency Medicine Conference of Mexican Society in Cancun/Mexico. Every emergency physician should know the airway tips he gave in the talk. Moreover, medical students and interns should also be aware of these clues. Therefore, we asked him to summarize his speech for iEM. You will find English and Spanish version of the summary on the below videos. Enjoy!

Airway Tips

This video includes a summary of “physiologically difficult airway” presentation given by Dr. Manrique Umana from Costa Rica.

Consejos de la vía aérea

Este video incluye un resumen de la presentación de la “vía aérea fisiológicamente difícil” realizada por el Dr. Manrique Umana de Costa Rica.

Cite this article as: iEM Education Project Team, "Airway Tips by Manrique Umana," in International Emergency Medicine Education Project, March 22, 2019, https://iem-student.org/2019/03/22/airway-tips-by-manrique-umana/, date accessed: September 25, 2021

Shock Index

A 57-year-old male presented to the ED with severe abdominal pain for 1 day. No allergies or significant past medical history. His vitals are: Temp 37.6 Celsius, BP 100/55, HR 110/min, RR 20/min and O2 Saturation is 99% on room air. 

What level of care does this patient require?

To learn more about it, read chapters below.

Read "Shock" Chapter

Read "Scores" Chapter

Quick Read

Shock Index

SHOCK INDEX (SI) = Heart Rate / Systolic Blood Pressure

Application

SI can be used to identify patients needing a higher level of care despite vital signs that may not appear strikingly abnormal. This index is a sensitive indicator of left ventricular dysfunction and can become elevated following a reduction in left ventricular stroke work.

Interpretation

The answer to the above clinical scenario: By applying the above equation, (110/100 = 1.1), this patient has a high shock index and requires a high level of care.

To learn more about it, read chapters below.

Read "Shock" Chapter

Read "Scores" Chapter

Sharp Chest Pain

Aortic Dissection chapter written by Shanaz Sajeed from Singapore is just uploaded to the Website!

469 - wide mediastinum - chest X-ray

A 56-year-old male presented to the emergency department with sudden onset of severe tearing chest pain radiating to the back. He had a history of hypertension and hyperlipidemia. He was a smoker. Upon arrival, he appeared to be diaphoretic and in severe pain. He denied any prior history of chest pain. He had been without any infective symptoms lately. He was compliant with his medications, namely, amlodipine and simvastatin. At triage, his blood pressure was noted to be 80/60 mmHg with a pulse rate of 130 bpm. His oxygen saturation was 95% on room air, and his respiratory rate was 22 breaths per minute. On examination, he had muffled heart sounds, jugular venous distention, and radio-radial pulse delay.

Shanaz Matthew Sajeed
by Shanaz Matthew Sajeed from Singapore.

Is this AAA going to be ruptured?

AAA rupture

Abdominal Aortic Aneurysm (AAA)

Lit Sin Quek

A 75-year-old obese man comes to the emergency department. He has history COPD, hypertension. He is a smoker and on regular follow-up with primary care. He describes sudden onset severe flank and back pain for past 2 hours. He denies any chest pain or dyspnea. He informs the physician about his chronic abdominal pain. His initial vital signs are HR 98 bpm, RR 24/min, BP 190/105 mmHg, T 36.9C. His examination revealed mild abdominal pain without rigidity or rebound tenderness. Bedside ultrasonography performed and the result is shown on the side.

What is the risk of rupture?

Touch Me

Risk of Rupture

increases with emphysema, smoking, hypertension. Regarding Powell’s (2003, 2007) study aneurisms above 5.5 cm have 9.4% to 32.4% rupture risk in one year.
Answer