GHB/GBL overdose in Recreational Settings

GHB/GBL overdose in Recreational Settings

GHB and GBL are two drugs of abuse frequently used as stimulants at parties for various reasons. Acute intoxication quickly leads to coma, respiratory depression, cardiac arrest and death.

One of the usage of these agents is for psychoactive substances in sexual contexts. With respect to jargon, we speak of Party and Play (PNP). Psychoactive substances are taken both recreational purposes and because they reduce self-control and inhibitions, they act as a sexual enhancer. In some cases, gamma hydroxybutyrate/gamma butyrolactone (GHB/GBL) mixed with alcoholic drinks facilitate criminal actions, such as robbery or non-consensual sexual acts (date rape drugs).Use of these drug is not very common in the general population and can be ascribed to distinct user groups[1].

What are the psychoactive substances most used in these parties?

The most frequent psychoactive substances used these parties are usually five:

  • GHB (gamma hydroxybutyrate)
  • GBL (gamma-butyrolactone)
  • Cathinones (Mephedrone, methylenedioxypyrovalerone [MDPV], methylone)
  • Methamphetamine
  • Ketamine

However, concomitant use of other abuse drugs [2], such as cocaine, ethanol, benzodiazepines, cannabinoids, and methamphetamines, can lead to the more significant severity of poisoning caused by GHB/GLB.

What are the effects of GHB?

GHB is a drug used in liquid or powder form. In liquid form, it is a clear, salty, and odorless. GHB is gamma aminobutyric acid (GABA) sodium salt, a molecule present in many body tissues; it is linked to GABA neurotransmitters, which are inhibitory to the neurons to which it binds. It activates its receptors (GHB receptors) and also activates GABA-B receptors [3]. Binding of GHB o to the latter group of receptors leads to a release of dopamine in the brain and causes the depression of the central nervous system (CNS), which can lead to decreased consciousness or unconsciousness, especially when ingested together with other depressants, such as alcohol.

From a pharmacological point of view, GHB has a narrow therapeutic range. At low doses (20–30 mg/kg), it produces a euphoric effect. Higher doses (> 50 mg/kg) provoke a sedative–hypnotic effect, which can further induce coma, bradycardia, and hypoventilation. Absorption into the body is relatively fast (5–15 min.) With a relatively short half-life, the peak of plasma concentrations occurs after 20 to 45 min. The clinical symptoms and the duration of the symptoms are dose-dependent so that it is almost not present in the body after 4 to 6 hours.

Structural formula of GBL
Structural formula of the chemical compound gamma-hydroxybutyrate (from Wikipedia – Neurotiker – Public Domain)
Metabolic pathway of GBL and GHB.
Metabolic pathway of 1,4-butanediol, GBL and GHB. (from Wikipedia-Anypodetos – Public Domain)

What are the effects of GBL?

GBL is a liquid product of the chemical industry. GBL differs from GHB because it has a chemical smell and acid taste, but after ingestion, our body converts GBL to GHB. Compared to GHB, we have seen how GBL has faster absorption, a longer-lasting effect, and higher plasma concentrations. These characteristics indicate quicker absorption and explain how GBL intake rapidly evolves toward an overdose characterized by coma, respiratory depression, cardiac arrest, and death. The pharmacodynamics of GBL are even faster than those of GBH.

2D structure of GBL (from Wikipedia-Harbin – Public Domain)

What are the symptoms of GHB / GBL overdose?

Symptoms of GHB / GBL overdose include several features:

  • Unconsciousness (GCS 3–7)
  • Reduced consciousness (narcolepsy, cataplexy)
  • Psycho-motor agitation
  • Cardio-circulatory problems (bradycardia, hypotension)
  • Respiratory depression
  • Seizures

How to diagnose GHB/GBL overdose?

The diagnosis of acute GBL and GHB intoxication is clinical. The symptoms include two main forms of depression:

  • CNS depression
  • Respiratory depression

GHB/GBL blood or urine tests are not always available in all hospital settings, while diagnostic confirmation through chromatography or mass spectrometry takes several days. Obtaining a patient’s medical history is difficult, if not impossible, due to his/her altered mental state or coma onset. However, the discovery of bottles and participation in a rave/nightclub event can help recreate the events and form the clinical picture.

What to do in front of a patient with a GBL/GHB overdose?

Treatment of the patient suffering from a GBL/GBH overdose is primarily supportive. The patient should be monitored via pulse oximetry, cardiorespiratory monitoring, capnography, and temperature monitoring.

The patient’s airway should be protected and the patient should be managed conservatively (if possible). Ways to treat the airways are highly debated and are currently left to the treating physician’s discretion.  Intubation [4] should be avoided in the patient which he used only GHB as the half-life of this drug is extremely short, and the patient could awaken in 2 to 3 hours. On the other hand, if poly-intoxication is present, the patient is in critical condition, or there is a real risk of aspiration pneumonia, intubation should be performed. It should also be remembered that GBL is a highly inflammatory molecule for the upper respiratory tract tissues.

Atropine or catecholamines if the perfusion is not adequate should be used, but this event is rare in these patients.Moreover, the onset of the withdrawal symptoms [5] such as anxiety, insomnia, tremors, tachycardia, agitation, delirium, and hallucinations should be monitored and treated with benzodiazepines and muscle relaxants [6].

What are the other risks?

Patients who inject drugs via the intravenous route should be informed of the risk of contracting infectious diseases [7], such as human immunodeficiency virus, hepatitis C and B viruses (HIV, HCV, and HBV, respectively). Those on retroviral therapy should be notified that these agents decrease the effectiveness of antiretroviral drugs [8].

The patient should be informed that taking GBL/GHB with other drugs can lead to severe and potentially fatal conditions. It should be remembered that GHB and cocaine mixed with alcohol react by forming toxic metabolites, such as cocaethylene, or that GHB and opioids can lead to coma and death.

The patient who is dependent on GHB should be informed about the onset of withdrawal symptoms, which is of rapid onset and progression and can often be fatal as hallucinatory, delusional, upon sudden drug cessation. Epileptic seizures can occur and can endanger a patient’s life. Planning for reductions in GHB/GBL use before stopping altogether can reduce withdrawal symptoms and make them less severe. If a person is  a regular user of one or more of these drugs, a doctor should be consulted before discontinuing use as sudden withdrawal can be life-threatening. Also, withdrawal symptoms can last up to 15 days.

Useful links

References and Further Reading

  1. Tomkins A, Ahmad S, Cannon L, Higgins SP, Kliner M, Kolyva A, Ward C, Vivancos R. Prevalence of recreational drug use reported by men who have sex with men attending sexual health clinics in Manchester, UK. Int J STD AIDS. 2018 Mar;29(4):350-356. doi: 10.1177/0956462417725638. Epub 2017 Aug 23. PMID: 28835196.
  2. Madah-Amiri, D., Myrmel, L. & Brattebø, G. Intoxication with GHB/GBL: characteristics and trends from ambulance-attended overdoses. Scand J Trauma Resusc Emerg Med 25, 98 (2017). https://doi.org/10.1186/s13049-017-0441-6
  3. Le JK, Richards JR. Gamma-Hydroxybutyrate Toxicity. [Updated 2020 Oct 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430781/
  4. P Dietze, D Horyniak, P Agius, V Munir, de Villiers Smit, J Johnston, C L Fry, L Degenhardt. Effect of intubation for gamma-hydroxybutyric acid overdose on emergency department length of stay and hospital admission Acad Emerg Med2014 Nov;21(11):1226-31
  5. Wojtowicz JM, Yarema MC, Wax PM. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review. CJEM 2008; 10:69–74
  6. Cappetta M, Murnion BP. Inpatient management of gamma-hydroxybutyrate withdrawal. Australas Psychiatry. 2019 Jun;27(3):284-287. doi: 10.1177/1039856218822748. Epub 2019 Jan 17. PMID: 30652947.
  7. Sewell, Janey et al. Poly drug use, chemsex drug use, and associations with sexual risk behaviour in HIV-negative men who have sex with men attending sexual health clinics. International Journal of Drug Policy 43, 33–43, 2017
  8. Pufall, EL et al. Sexualized drug use (‘chemsex’) and high-risk sexual behaviours in HIV-positive men who have sex with men, HIV medicine 19.4, pp. 261–270, 2018
Cite this article as: Francesco Adami, Italy, "GHB/GBL overdose in Recreational Settings," in International Emergency Medicine Education Project, April 12, 2021, https://iem-student.org/2021/04/12/ghb-gbl-overdose/, date accessed: October 18, 2021

Question Of The Day #25

question of the day
qod25
835 - 3rd degree heart block

Which of the following is the most likely diagnosis of this patient’s condition?

This patient has marked bradycardia on exam with a borderline low blood pressure. These vital sign abnormalities are likely the cause of the patient’s dizziness. Bradycardia is defined as any heart rate under 60 beats/min. The most common cause of bradycardia is sinus bradycardia (Choice A). Other types of bradycardia include conduction blocks (i.e. type 2 or type 3 AV blocks), junctional rhythms (lack of P waves with slow SA nodal conduction), idioventricular rhythms (wide QRS complex rhythms that originate from the ventricles, not atria), or low atrial fibrillation or atrial flutter. About 80% of all bradycardias are caused by factors external to the cardiac conduction system, such as hypoxia, drug effects (i.e., beta block or calcium channel blocker use or overdose), or acute coronary syndromes.

ecg qod25Sinus bradycardia (Choice A) occurs when the electrical impulse originates from the SA node in the atria. Signs of sinus bradycardia on EKG are the presence of a P wave prior to every QRS complex. This EKG shows P waves prior to each QRS complex, but there are extra P waves that are not followed by QRS complexes. Some P waves are “buried” within QRS complexes or within T waves. The EKG below marks each P wave with a red line and each QRS complex with a blue line.

 

First-degree AV Block (Choice B) is a benign arrhythmia characterized by a prolonged PR interval. This patient’s EKG has variable PR intervals (some prolonged, some normal). This is a result of a more severe AV conduction block. Second-Degree AV Blocks are divided into Mobitz type I and Mobitz Type II. Mobitz type I, also known as Wenckebach, is characterized by a progressive lengthening PR interval followed by a dropped QRS complex. This can be remembered by the phrase, “longer, longer, longer, drop.” Wenckebach is a benign arrhythmia that does not typically require any treatment. Mobitz type II (Choice C) is characterized by a normal PR interval with random intermittent dropping of QRS complexes. This patient’s EKG has consistent spacing between each QRS complex (blue lines) and consistent spacing between each P wave (red lines). However, the P waves and QRS complexes are not associated with each other. This phenomenon is known as AV dissociation. These EKG changes are signs of a complete heart block, also known as Third-Degree AV Block (Choice D). Both Second-Degree AV block- Mobitz type II (Choice C) and Third-Degree AV Block (Choice D) are more serious conduction blocks that require cardiac pacemakers. Correct Answer: D

References

  • Brady W.J., & Glass III G.F. (2020). Cardiac rhythm disturbances. Tintinalli J.E., Ma O, Yealy D.M., Meckler G.D., Stapczynski J, Cline D.M., & Thomas S.H.(Eds.), Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2353&sectionid=218687685
  • Nickson, C. (2020). Heart Block and Conduction Abnormalities. Life in the Fast Lane. Retrieved from https://litfl.com/heart-block-and-conduction-abnormalities/

 

Cite this article as: Joseph Ciano, USA, "Question Of The Day #25," in International Emergency Medicine Education Project, February 5, 2021, https://iem-student.org/2021/02/05/question-of-the-day-25/, date accessed: October 18, 2021

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: October 18, 2021

Question Of The Day #24

question of the day
qod24
738.1 - Prior ECG before 738.2 - STEMI

Which of the following is the most appropriate next step in management for this patient’s condition?

This patient is suffering from severe bradycardia with signs of poor cardiac output, shock, and diminished perfusion to the brain. Bradycardia is defined as any heart rate under 60 beats/min. Many individuals may be bradycardic at rest with no danger to the patient (i.e. young patients or athletes). Bradycardia in these scenarios is physiologic and is not associated with difficulty in perfusing the brain and other organs. This patient’s 12-lead EKG shows sinus bradycardia since there is a P wave prior to every QRS complex. Sinus bradycardia is the most common type of bradycardia. Other types of bradycardia include conduction blocks (i.e. type 2 or type 3 AV blocks), junctional rhythms (lack of P waves with slow SA nodal conduction), idioventricular rhythms (wide QRS complex rhythms that originate from the ventricles, not atria), or slow atrial fibrillation or atrial flutter. About 80% of all bradycardias are caused by factors external to the cardiac conduction system, such as hypoxia, drug effects (i.e. beta block or calcium channel blocker use or overdose), or acute coronary syndromes.  

For any patient with a bradyarrhythmia or tachyarrhythmia, it is crucial to determine if the arrythmia is “stable” or “unstable”. Signs that an arrhythmia is unstable include altered mental status, hypotension with systolic blood pressure under 90mmHg, chest pain, or shortness of breath. Patients with a stable arrhythmia can be managed supportively with observation and less invasive medical management. Patients with unstable arrhythmia are managed more aggressively with the use of electricity, often in combination with other medical treatments. This patient has an unstable bradyarrhythmia, given her altered mental status and hypotension. Intravenous metoprolol (Choice D) would make the patient more bradycardic since this medication blocks beta-adrenergic receptors of the heart that control heart rate and contractility. Intravenous Amiodarone (Choice C) is an antiarrhythmic agent used often in wide complex tachyarrhythmias (i.e. Ventricular Tachycardia). Intravenous atropine or epinephrine are agents that can be used in this patient prior to preparing for electric pacing. Transcutaneous pacing (Choice A) should always be attempted prior to Transvenous pacing (Choice B), as Transcutaneous pacing is less invasive and quicker to set up. If Transcutaneous pacing does not result in electrical “capture” or change the heart rate, the next step is Transvenous pacing. Correct Answer: A 

References

  • Brady W.J., & Glass III G.F. (2020). Cardiac rhythm disturbances. Tintinalli J.E., Ma O, Yealy D.M., Meckler G.D., Stapczynski J, Cline D.M., & Thomas S.H.(Eds.), Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2353&sectionid=218687685
  • Burns, E. (2020). Sinus Bradycardia. Life in the Fast Lane. Retrieved from https://litfl.com/sinus-bradycardia-ecg-library/
Cite this article as: Joseph Ciano, USA, "Question Of The Day #24," in International Emergency Medicine Education Project, December 11, 2020, https://iem-student.org/2020/12/11/question-of-the-day-24/, date accessed: October 18, 2021