Red lips, black teeth, and Betel nut toxicity

Red lips, black teeth, and Betel nut toxicity

Arecoline toxicity is rarely seen in the Emergency Department [1]; however, doctors and emergency workers should be aware of this plant and the intoxication it causes. The alkaloids associated with this intoxication are reported in multiple regions of the world. It is important to emphasize how arecoline is the fourth most consumed psychoactive substance after nicotine, ethanol, and caffeine.

What is the “Betel nut”?

The tropical Betel palm (Areca catechu) produces the Betel nut (it is not a fruit but the seed of this plant). The Betel nut contains piperidine alkaloids which have substantial psychostimulating effects. Among these alkaloids, arecoline isprimarily responsible for the muscarinic, nicotinic, and psychostimulating effects of Betel nut consumption. Other alkaloids are arecaine, arecolidine, isoguvacin, and guvacine.

Coloured areca nuts [Areca catechu] in the market. Bago, Burma [Myanmar] It is this red color that determines the color of the spits of the people who consume the “paan” (from: LBM1948 – Wikipedia – CC BY-SA 4.0)

What is the “Betel leaf”?

It is the leaf of a tropical liana belonging to the Piperaceae family. It contains phenolic aromatic compounds, such as cavibetol and cavitol, and in some plants, also a third compound called caditene. Also, it, like the paper of a candy, contain chopped Betel nut mixed with lime (calcium hydroxide, which has a preservative action) and other substances typical of the community that produces it (e.g., tobacco, tamarind, or cardamom)

How is Betel nut consumed?

The Betel nut is thinly cut, combined with lime (to extract the alkaloids), and wrapped in a Piper beetle leaf, giving it its aroma and increasing salivation. It is consumed through chewing, which is usually not accompanied by swallowing, instead being spat out.

Photograph of an areca nut vendor on the island of Hainan, China. (from: Rolfmueller – Wikicommons – CC BY-SA 3.0)

Where is Betel nut chewed?

About 200 million people around the world consume Betel nuts. Primarily produced in Southeast Asia (Myanmar, Thailand, Laos, Cambodia, and Taiwan), it is consumed in Southern China (Yunnan, Xingtan, Hainan Island), Ceylon, Micronesia (Saipan, Guam, Palau, Mariana Islands), Papua, New Guinea, the Indian subcontinent (India, Pakistan, Bangladesh), and the Philippines.

New consumption territories are Melanesia, New Zealand, Australia, and immigrants living in Europe and North America [2].

Why is Betel nut consumed?

The consumption of Betel nut is voluptuous, and the reasons given by consumers are many. In general, it is consumed to “stay awake” and therefore “work harder” and the sensation of heat and energy during chewing. The reasons also include supposed medical and health reasons, such as “strengthening the teeth”, “helping digestion”, and “freshening the breath”. The cultural aspect of its consumption should not be underestimated in Buddhist culture and during some marriage ceremonies in Maharashtra. Betel leaf and Areca nut consumption are common. At the same time, in many countries, it is convivial to consume Betel at the end of the meal.

What is arecoline?

It is a potent agonist of muscarinic and nicotinic receptors [3]. In addition, the calcium hydroxide in the product causes the arecoline to be hydrolyzed into arecaidine, which is a potent inhibitor of Gaba uptake. The result is a strong excitation of the nervous system due to the release of catecholamines (adrenaline and noradrenaline). Pregnant women who chewBetel nuts can transfer the active ingredients via the placenta to the fetus [4].

What are the symptoms of acute Arecoline intoxication?

It is a rare event [5].

The psychological acute arecoline intoxication symptoms are:

  • increased heart rate/palpitations
  • increased systemic pressure
  • increased temperature
  • increased sweating
  • increased salivation
  • nausea, vomiting

In some cases, it can lead to coma, respiratory failure, myocardial infarction.Therefore it is recommended that the patient be monitored closely and treated for cholinergic, neurological, cardiovascular, and gastrointestinal manifestations.

The psychological acute arecoline intoxication symptoms are [6]:

  • well-being
  • euphoria
  • increased alertness
  • increased ability to support hard work
  • feeling of heat

From the EEG point of view, we have widespread cortical desynchronization. So, in case of high consumption, psychosis can arise [7].

Woman with red gingivas chewing paan in Don Det in Laos. Paan is a preparation combining betel leaf with areca nut and tobacco. It is chewed for its stimulant and psychoactive effects. (from: Basile Morin, Wikipedia, CC BY-SA 4.0)

What symptoms does chronic arecoline intoxication give?

Chewing Betel nut leads to discoloration of normal dental enamel, similar to that observed in those who chew tobacco (often Tabac and Betel nut are chewed together). The saliva in the chewing of this nut becomes red and with a markedly alkaline pH. The mucous membranes, gums, and teeth take on this color. Consumption is associated with the development of necrotizing ulcerative gingivitis (ANUG), which is a bacterial infection of the periodontal tissue that can also cause systemic symptoms, such as lymphadenopathy and malaise.

What are the risks of chronic exposure to arecoline?

Betel consumers have an increased risk of cancer of the oropharynx, liver, and uterus [8] . Chronic consumption leads to evident stains on the dental enamel (black tartar) and marked red salivation for the release of tannins. Also, its consumption is predisposing for the development of oropharyngeal carcinoma as nitrogenous compounds deriving from the alkaloids are released. About 60% of oro-pharyngeal cancers occur in areas where people chewed Betel nut.

References

[1] Deng JF, Ger J, Tsai WJ, Kao WF, Yang CC. Acute toxicities of betel nut: rare but probably overlooked events. J Toxicol Clin Toxicol. 2001;39(4):355-60. doi: 10.1081/clt-100105155. PMID: 11527229.

[2] Nelson BS, Heischober B. Betel nut: a common drug used by naturalized citizens from India, Far East Asia, and the South Pacific Islands. Ann Emerg Med. 1999 Aug;34(2):238-43. doi: 10.1016/s0196-0644(99)70239-8. PMID: 10424931.

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: November 28, 2022

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: November 28, 2022

Giant Hogweed Burns

Giant Hogweed…and the Lesions it Causes.

Summer is the time when outdoor work and leisure activities increase. It is also the season when plants like giant hogweed grow and bloom most. Direct contact with this beautiful umbrella plant, however, leads to serious skin lesions and skin burns[1] that often necessitates a visit to the emergency room.

Have you ever heard of the giant hogweed?

The giant hogweed is an extremely toxic exotic plant particularly present in the British popular culture. It is also mentioned in the 1971 studio album entitled “Nursery Cryme” by the English rock band Genesis where the eternal struggle between this exotic plant and the English authorities trying to eradicate it is (humorously) narrated. Historically this plant was rediscovered in 1895 by two Italian doctors: Emile Levier and Carlo Pietro Stefano Sommier, to which they gave the botanical name of Heracleum mantegazzanium, in honour of their friend and physician Paolo Mantegazza, the first popularizer of Darwin’s scientific theories in Italy.

How can you recognize giant hogweed?

Giant hogweed, also known as Heracleum mantegazzianum, is considered to be the largest and most beautiful umbrella plant in the world[2]; it can reach a height of over 3 meters[3]. It is recognizable due to the colour of its leaves, which are a bright light green colour tending towards yellow with deep lobes and segmentations. The trunk is very thick and robust, similar to that of artichoke, with dark red streaks and surrounded by spiky hairs. The diameter of the umbrella makes it the largest among the umbrella plants. 

The fruits have an ovoid appearance, and at the moment of flowering, their envelopes remain attached to the base of the umbrella and subsequently tend to wither. Giant hogweed blooms from early spring until late summer, especially in the vicinity of wetlands (streams or canal banks). These characteristics differentiate it from the garden angelica (Angelica archangelica) and the common hogweed (Heracleum sphondylium).

Who is most at risk of coming across giant hogweed?

Gardeners, trekkers, forest workers, and people who work outdoors in wooded or undergrowth areas where giant hogweed is present are most at risk of injury caused by giant hogweed.

How is giant hogweed sap toxic?

The sap of giant hogweed contains different photoactive agents called furocoumarins, of which the most predominant is 5-MOP (5-methoxypsoralen). Injuries are caused when these photoactive agents are exposed to and activated by UV-A rays present in sunlight. This gives rise to a toxic process in which the furan ring of the photoactive agent is cross-linked with the pyrimidine bases of DNA in the patient’s skin, thus causing an increase in oxidative stress leading to cell membrane damage and subsequent inflammation and oedema. The culmination of these processes leads to the development of phytophotodermatitis (PPD)[4].

Similar to other plants capable of phototoxicity, skin damage is dependent on certain factors[5] such as:

  • The concentration of the phototoxic agent
    • During summer months, levels of phototoxic agents are higher. Moreover, they are more concentrated in fruit, present in intermediate levels in the leaves, and are minimally present in the stem.
  • The thickness of the skin
    • Damage is more extensive and deeper in the skin that is thinner.
  • Sun exposure
    • When sun exposure is prolonged, there is greater photoactivation and therefore greater damage.
  • Skin moisture
    • Sweat or dew that may be present on the skin can accelerate the toxicity process.

What are its symptoms?

Symptoms of giant hogweed exposure usually involve an erythematous lesion[6] accompanied by extremely intense pain. If not treated early, erythematous lesions evolve into burns[7] with the appearance of one or more liquid-filled vesicles. Generally, patients may have fatigue and slight tachycardia, but vital signs and laboratory test may be normal.

During the history and physical examination, staphylococcal infection, allergic dermatitis, purpura, impetigo, and fungal infection must be considered in the differential diagnosis.

Therapy

Upon contact, the subject should immediately wash the red area abundantly, dry it, and cover it to avoid sun exposure. Other recommendations would include avoiding to take baths and showers and apply high protection sunscreen to the lesion.

If erythema appears, the use of sulfadiazine cream and analgesic anti-inflammatory drugs should be considered. Moreover, the use of ice to reduce inflammation can also be useful. In the event of an injury characterized by one or more blisters or loss of tissue, a conservative treatment[8] consisting of cleansing with antiseptic solution (i.e. Clorexidine) and bandaging with synthetic microporous membranes[9] have proven effective. In cases where the phototoxicity process has been prolonged enough to cause extensive and deep burns, skin grafting and surgical debridement are necessary.

Take-home message

In conclusion, the message for our patients who operate or live in areas where giant hogweed is present is to “look but absolutely don’t touch” this beautiful plant. Secondarily, it is also important to subsequently report its presence to public authorities; in fact, many countries or regions follow a specific eradication program for this plant which can prove dangerous for humans and animals.

Look but absolutely don't touch this beautiful plant.

References and Further Reading

[1] https://www.plymouthherald.co.uk/news/plymouth-news/man-suffers-horror-burns-hogweed-4216136

[2] Heracleum mantegazzianum (giant hogweed) – Invasive Species Compendium – https://www.cabi.org/isc/datasheet/26911

[3] Derraik JG. Heracleum mantegazzianum and Toxicodendron succedaneum: plants of human health significance in New Zea-land and the National Pest Plant Accord. N Z Med J 2007;120: U2657.

[4] Marcos LA, Kahler R. Phytophotodermatitis. Int J Infect Dis 2015;9(July (38)):7–8.

[5] Pira E, Romano C, Sulotto F, et al. Heracleum mantegazzianum growth phases and furocoumarin content. Contact Derm 1989; 21:300e3.

[6] J Emerg Nurs. 2006 Jun;32(3):246-8. A 43-year-old woman with painful, vesicular lesions from giant hogweed photodermatitis. Langley DM(1), Criddle LM.

[7] Baker BG, Bedford J, Kanitkar S. Keeping pace with the media; Giant Hogweed burns – A case series and comprehensive review. Burns. 2017 Aug;43(5):933-938. DOI: 10.1016/j.burns.2016.10.018.

[8] Chan JC, Sullivan PJ, O’Sullivan MJ, Eadie PA. Full thickness burn caused by exposure to giant hogweed: delayed presentation, histological features and surgical management. J Plast Reconstr Aesthet Surg. 2011;64(1):128-130. doi:10.1016/j.bjps.2010.03.030

[9] Pfurtscheller K, Trop M. Phototoxic plant burns: report of a case and review of topical wound treatment in children. Pediatr Dermatol 2014;31:e156–9.

Cite this article as: Francesco Adami, Italy, "Giant Hogweed Burns," in International Emergency Medicine Education Project, August 31, 2020, https://iem-student.org/2020/08/31/giant-hogweed-burns/, date accessed: November 28, 2022

The Little-Known Dark Side of the Cannabis

the little known dark side of the cannabis

Bradycardia and Cannabinoid Hyperemesis Syndrome (CHS): two clinical pictures that are increasingly seen in the Emergency Department.

What are cannabinoids?

Cannabinoids are a series of extremely liposoluble chemical substances present in the Cannabis sativa plant. The most pharmacologically active among them is the delta-9-tetrahydrocannabinol (Δ9-THC). The prolonged or intense use of high doses of cannabis[1] could lead to acute cannabinoid intoxication causing bradycardia and cannabinoid hyperemesis syndrome (CHS).

Illustration of the Cannabis Sativa plant contained in the botanical atlas entitled "Köhler's medicinal plants" by the German botanist Hermann Adolph Köhler.
By Franz Eugen Köhler, Köhler's Medizinal-Pflanzen - List of Koehler Images

What do cannabinoids do in our body?

Cannabinoids are chemical substances that interact with two types of receptors present in the human body:

CB1 is a class of receptors distributed mainly in the central nervous system, but it is also found in the peripheral nervous system, the lungs, heart, and liver. The activation of this class of receptor at the central level causes a release of dopamine from the brain producing euphoria, analgesia, perceptual alteration, reduction of memory, and motor control. At the peripheral level, it inhibits the response of the sympathetic system, causing vasodilation and tachycardia.

CB2 is a class of receptors present at the peripheral level, in particular in the cells of the lymphoid system. They are implicated in the reduction of the inflammatory response and the reduction of hyperalgesia.

Who uses cannabinoids?

In Europe and the United States, cannabinoids are recreational drugs. Young people between 18 and 25 are main users[2]. In addition, cannabioids are used for medical-therapeutic purposes. For instance, in treating vomiting and nausea caused by chemotherapy, to stimulate appetite in AIDS patients, to treat chronic pain and muscle stiffness caused by multiple sclerosis, and in the treatment of depression.

What are the symptoms?

The common belief is that the intake of even large quantities of cannabinoids is harmless. However, subjects with acute cannabinoid intoxication are present more and more frequently in emergency departments (EDs) or clinics. They present a vast array of symptoms, including nausea, cyclical vomiting, agitation, short-term memory loss, cognitive deficits, psychosis, seizures, and arrhythmias. In addition, symptoms associated with the sympathetic system activation, such as mydriasis, hypertension, and tachycardia, are often described.

In the ED, what should we pay attention to?

There are two particularly relevant clinical pictures related to acute cannabinoid poisoning: CHS and bradycardia.

What is cannabinoid bradycardia?

The effects of cannabinoids on the heart depend on their dosage. At a low to moderate dose, there is tachycardia and arterial hypertension (through an increase in the activity of the sympathetic nervous system); at a high dose, there is sinus bradycardia, hypotension, and decreased myocardial contractility[3],[4]. The beginning of the arrhythmic effect peaks at 30 minutes from the intake and can last several hours. In the literature, the arrhythmic effects are described together with cases of sinus tachycardia, sinus bradycardia, atrioventricular blockages, and cardiac arrest.

What is CHS?

CHS is characterized by episodes of prolonged cyclic vomiting, with an average duration of 24–48 h, accompanied by abdominal pain separated by extended periods (even months) of an absence of symptoms. These episodes of vomiting are incredibly resistant to conventional therapy using drugs, such as metoclopramide, ondansetron, or promethazine. In addition, the acute phases can be so severe as to be responsible for dehydration, water, and electrolyte disturbances and disorientation.

How do we diagnose CHS?

The diagnosis of CHS is clinical and can potentially be represented by the triad:

  • Marijuana use over a prolonged period;
  • Intractable vomiting that can last for hours or days and does not respond to the common anti-emetic therapy; and
  • Improvement of symptoms after a hot shower or hot bath or use of topical capsaicin.

However, this syndrome enters into differential diagnosis with psychogenic vomiting, cyclic vomiting syndrome [5], and hyperemesis gravidarum [6],[7].

How do we treat CHS?

First of all, resuscitation through the administration of fluids and electrolytic rebalancing are priorities. After that, CHS seems to resolve a few minutes after a hot shower or bath [8] or the use of topical Capsaicin cream applied in a thin layer at the abdominal, thoracic, or lumbar level[9]. However, the reasons for such therapy are not yet clear. In addition, Haloperidol[10] and the use of Beta-blockers[11] were also found to be effective in the treatment of CHS. After medical treatment, it is important to educate the patient about cannabinoid hyperemesis and to inform how the cessation of cannabinoid use can resolve this clinical picture.

What is the take-home message?

The liberalization of the laws on the use of cannabinoids and a growing favorable public opinion about them will likely increase acute cannabinoid intoxication cases in the EDs. In conclusion, a better knowledge of these two clinical pictures among emergency clinicians could avoid costly and time-consuming tests, scans, and procedures in these patients.

Cite this article as: Francesco Adami, Italy, "The Little-Known Dark Side of the Cannabis," in International Emergency Medicine Education Project, April 17, 2020, https://iem-student.org/2020/04/17/dark-side-of-the-cannabis/, date accessed: November 28, 2022

References

  1. Smart R, Caulkins JP, Kilmer B, Davenport S, Midgette G. Variation in cannabis potency and prices in a newly legal market: evidence from 30 million cannabis sales in Washington state. Addiction. 2017 Dec;112(12):2167–77.
  2. National Institute on Drug Abuse. Nationwide Trends. 2015; https://www.drugabuse. gov/publications/drugfacts/nationwide- trends. Accessed May 26, 2018.
  3. Pacher, P., Steffens, S., Haskó, G. et al. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 15151–166 (2018) doi:10.1038/nrcardio.2017.130
  4. David O. Andonian, Shauna R. Seaman, Elaine B. Josephson, Profound hypotension and bradycardia in the setting of synthetic cannabinoid intoxication – A case series The American Journal of Emergency Medicine, Volume 35, Issue 6, June 2017, Pages 940.e5-940.e6
  5. Bhandari S, Jha P, Thakur A, Kar A, Gerdes H, Venkatesan T. Cyclic vomiting syndrome: epidemiology, diagnosis, and treatment. Clin Auton Res. 2018 Apr;28(2):203–9.
  6. Alaniz VI, Liss J, Metz TD, Stickrath E. Cannabinoid hyperemesis syndrome: a cause of refractory nausea and vomiting in pregnancy. Obstet Gynecol. 2015 Jun;125(6):1484–6
  7. Volkow ND, Compton WM, Wargo EM. The Risks of Marijuana Use During Pregnancy. JAMA. 2017 Jan;317(2):129–30
  8. Lapoint J, Meyer S, Yu CK, Koenig KL, Lev R, Thihalolipavan S, et al. Cannabinoid Hyperemesis Syndrome: Public Health Impli- cations and a Novel Model Treatment Guideline. West J Emerg Med. 2018 Mar; 19(2):380–6.
  9. Graham J, Barberio M, Wang GS. Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome in Adolescents: A Case Series. Pediatrics. 2017 Dec;140(6):e20163795.
  10. Hickey JL, Witsil JC, Mycyk MB. Haloperidol for treatment of cannabinoid hyperemesis syndrome. Am J Emerg Med. 2013 Jun; 31(6): 1003.e5–6.
  11. Richards JR, Dutczak O. Propranolol Treatment of Cannabinoid Hyperemesis Syn- drome: A Case Report. J Clin Psychopharmacol. 2017 Aug;37(4):482–4.

19 Questions and Answers on the COVID-19 Pandemic from a Emergency Medicine-based Perspective

covid 19 - from a Emergency Medicine-based Perspective

1) What is COVID-19?

Corona Virus Disease 2019 (COVID-19) is the disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

2) What is SARS-CoV-2?

SARS-CoV-2 is a virus belonging to the Coronaviridae family. Spike proteins (S proteins) on the outer surface of SARS-CoV-2 are arranged in a way that resembles the appearance of a crown when viewed under an electron microscope (see Figure 1). S proteins facilitate viral entry into host cells by binding to the angiotensin-converting enzyme 2 (ACE2) host receptor. Several cell types express the ACE2 receptor, including lung alveoli cells. [1].

Morphology of the SARS-CoV-2
Figure 1 - Morphology of the SARS-CoV-2 viewed under an electron microscope.Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion. (https://phil.cdc.gov/Details.aspx?pid=23312)

3) How is SARS-CoV-2 transmitted?

Viral particles can spread from person-to-person through airborne transmission (e.g., large droplets) or direct contact(e.g., touching, shaking hands). We have to remember that large droplets are particles with a diameter > 5 microns and that they can be spread by coughing, sneezing, talking, etc., so do not forget to wear full PPE in the Emergency Department (ED). Other potential routes of transmission are still being investigated.

4) What is the incubation time?

In humans, the incubation period of the SARS-CoV-2 varies from 4 days to 14 days, with a median of about 4 days [2].

5) Can we say the COVID-19 is like the seasonal flu?

No, we can’t say that. COVID-19 differs from the flu in several ways:

  • First of all, SARS-CoV-2 replicates in the lower respiratory tract at the level of the pulmonary alveoli (terminal alveoli). In contrast, Influenza viruses, the causative agents of the flu, replicate in the mucosa of the upper respiratory tract.
  • Secondly, SARS-CoV-2 is a new virus that has never met our adaptive immune system.
  • Thirdly, we do not currently have an approved vaccine to prevent infection by SARS-CoV-2.
  • Lastly, we do not currently have drugs of proven efficacy for the treatment of disease caused by SARS-CoV-2.

6) Who is at risk of contracting the COVID-19?

We are all susceptible to contracting the COVID-19, so it is essential that everyone respects the biohazard prevention rules developed by national and international health committees. Elderly persons, patients with comorbidities (e.g., diabetics, cancer, COPD, and CVD), and smokers appear to exhibit poor clinical outcome and greater mortality from COVID-19 [3]

7) What are the symptoms of the COVID-19?

There are four primary symptoms of COVID-19: feverdry coughfatigue; and shortness of breath (SOB).

Other symptoms are loss of appetite, muscle and joint pain, sore throat, nasal congestion and runny nose, headache, nausea and vomiting, diarrhea, anosmia, and dysgeusia.

8) What is the severity of symptoms from COVID-19?

In most cases, COVID-19 mild or moderate symptoms, so much so it can resolve after two weeks of rest at home. However, onset of severe viral pneumonia requires hospital admission.

9) Which COVID-19 patients we should admit to the hospital?

The onset of severe viral pneumonia requires hospital admission. COVID-19-associated pneumonia can quickly evolve into respiratory failure, resulting in decreased gas exchange and the onset of hypoxia (we can already detect this deterioration in gas exchange with a pulse oximeter at the patient’s home). This clinical picture can rapidly further evolve into ARDS and severe multi-organ failure.

The use of the PSI/PORT score (or even the MuLBSTA score, although this score needs to be validated) can help us in the hospital admission decision-making process.

10) Do patients with COVID-19 exhibit laboratory abnormalities?

Most patients exhibit lymphocytopenia [11], an increase in prothrombin time, procalcitonin (> 0.5 ng/mL), and/or LDH (> 250 U/L).

11) Are there specific tests that allow us to diagnose COVID-19?

RT-PCR is a specific test that currently appears to have high specificity but not very high sensitivity [12]. We can obtain material for this test from nasopharyngeal swabs, tracheal aspirates of intubated patients, sputum, and bronchoalveolar lavages (BAL). However, the latter two procedures increase the risk of contagion.

However, since rapid tests are not yet available, RT-PCR results may take days to obtain, since laboratory activity can quickly saturate during epidemics. Furthermore, poor pharyngeal swabbing technique or sampling that occurs during the early stage of COVID-19 can lead to further decreased testing sensitivity.

Consequently, for the best patient care, we must rely on clinical symptoms, labs, and diagnostic imaging (US, CXR, CT). The use of a diagnostic flowchart can be useful (see Figure 2).

diagnostic flow chart
Figure 2 - A possible diagnostic flow chart for an ill patient admitted to hospital with suspected COVID-19 (from EMCrit Blog)

12) Can lung ultrasound help diagnose COVID-19?

Yes, it can help! The use of POCUS lung ultrasound is a useful method both in diagnosis and in real-time monitoring of the COVID-19 patient.

In addition, we could monitor the patient not only in the emergency department (ED) or intensive care unit (ICU), but also in a pre-hospital setting, such as in the home of a patient who is in quarantine.

In fact, POCUS lung ultrasounds not only allows one to anticipate further complications such as lung consolidation from bacterial superinfection or pneumothorax, but it also allows detection of viral pneumonia at the early stages. Furthermore, the use of a high-frequency ultrasound probe, which is an adoption of the 12-lung areas method [4] and the portable ultrasound (they are easily decontaminated), allow this method to be repeatable, inexpensive, easy to transport, and radiation-free.

There are no known pathognomonic patterns of COVID-19.

The early stages COVID-19 pneumonia results in peripheral alveolar damage including alveolar edema and a proteinaceous exudate [5]. This interstitial syndrome can be observed via ultrasound by the presence of scattered B lines in a single intercostal space (see videos below).

Subsequently, COVID-19 pneumonia progression leads to what’s called “white lung”, which ultrasound represents as converging B lines that cover the entire area of the intercostal space; they start from the pleura to end at the bottom of the screen.

Finally, the later stages of this viral pneumonia lead to “dry lung”, which consists of a pattern of small consolidations (< 1 cm) and subpleural nodules. Unlike bacterial foci of infection, these consolidations do not create a Doppler signal within the lesions. We should consider the development from “white lung” to “dry lung” as an unfavorable evolution of the disease.[6]

(the 5 videos above come from the COVID-19 gallery on the Butterflynetwork website)

13) Can CXR/CT help us in the diagnosis of COVID-19?

Yes, it can help! There are essentially three patterns we observed in COVID-19.

In the early stages, the main pattern is ground-glass opacity (GGO)[7]. Ground glass opacity is represented at the lung bases with a peripheral distribution (see videos below) .

The second pattern is constituted by consolidations, which unlike ground-glass opacity, determine a complete “opacification” of the lung parenchyma. The greater the extent of consolidations, the greater the severity and the possibility of admission in ICU.

The third pattern is called crazy paving[8]. It is caused by the thickening of the pulmonary lobular interstitium.

However, we should consider four things when we do a CXR/CT exam. First, many patients, especially in the elderly, exhibit multiple, simultaneously occurring pathologies, so it is possible to clinically observe nodular effusions, lymph node enlargements, and pleural effusions that are not typical of COVID-19 pneumonia. Secondly, we have to be aware that other types of viral pneumonia can also cause GGO, so they cannot be excluded during the diagnostic process. Thirdly, imaging can help evaluate the extent of the disease and alternative diagnoses, but we cannot use it exclusively for diagnosis. Lastly, we should carefully assess the risk of contagion from transporting these patients to the CT room.

14) What is the treatment for this type of patient?

COVID-19 patients quickly become hypoxic without many symptoms (apparently due to “silent” atelectasis). Therapy for these clinical manifestations is resuscitation and support therapy. In patients with mild respiratory insufficiency, oxygen therapy is adopted. In severe patients in which respiratory mechanics are compromised, non-invasive ventilation (NIV) or invasive ventilation should be adopted.

15) How can we non-invasively manage the airways of patients with COVID-19?

In the presence of a virus epidemic, we should remember that all the procedures that generate aerosolization (e.g., NIV, HFNC, BMV, intubation, nebulizers) are high-risk procedures.

Among the non-invasive oxygenation methods, the best-recommended solution is to have patients wear both a high-flow nasal cannula (HFNC) and a surgical mask[9]. Still, we should also consider using CPAP with a helmet interface. Furthermore, we should avoid the administration of medications through nebulization or utilize metered-dose inhalers with spacer (Figure 3).

Figure 3 – General schema for Respiratory Support in Patients with COVID-19 (from PulmCrit Blog)

16) How can we invasively manage the airways of patients with COVID-19?

We should intubate as soon as possible, even in non-critical conditions (Figure 3). Intubation is a high contagion risk procedure. As a result, we should adopt the highest levels of precaution[10]. To be more precise:

  • As healthcare operator, we should wear full PPE. Only the most skilled person at intubation in the staff should intubate. Furthermore we should consider using a video laryngoscope. Last but not least, we should ensure the correct positioning of the endotracheal tube without a stethoscope (link HERE).
  • The room where intubation occurs should be a negative pressure room. When that is not feasible, the room should have doors closed during the intubation procedure.
  • The suction device  should have a closed-circuit so as not to generate aerosolization outside.
  • Preoxygenation should be done using means that do not generate aerosols. Let us remember that HFNC and BVM both can generate aerosolization. So, it is important to remember to turn off the flow of the HFNC before removing it from the patient face to minimize the risk and to use a two-handed grip when using BVM, interposing an antiviral filter between the BVM and resuscitation bag and ventilating gently.
  • Intubation drugs that do not cause coughing should be used. In addition, we should evaluate the use of Rocuronium in the Rapid Sequence Intubation (RSI) since it has a longer half-life compared to succinylcholine and thus prevents the onset of coughing or vomiting.

In conclusion, let us remember that intubation, extubation, bronchoscopy, NIV, CPR prior to intubation, manual ventilation etc. produce aerosolization of the virus, therefore, it is necessary that we wear full PPE.

17) What is the drug therapy for COVID-19?

Currently, there is no validated drug therapy for COVID-19. Some drugs are currently under study. They include Remdesivir (blocks RNA-dependent RNA polymerase), Chloroquine and Hydroxychloroquine (both block the entry of the virus into the endosome), Tocilizumab and Siltuximab (both block IL-6).

18) Is there a vaccine available for COVID-19?

No, there is still no vaccine currently available to the public.

19) What precautions should we take with COVID-19 infected patients?

As healthcare professionals, we should wear full personal protective equipment (PPE) and know how to wear them (“DONning”) and how to remove them properly (“DOFFing”) (see video below). Furthermore, we should wear full PPE for the entire shift and when in contact with patients with respiratory problems.

Resources on COVID-19

Cite this article as: Francesco Adami, Italy, "19 Questions and Answers on the COVID-19 Pandemic from a Emergency Medicine-based Perspective," in International Emergency Medicine Education Project, March 27, 2020, https://iem-student.org/2020/03/27/19-questions-and-answers-on-the-covid-19/, date accessed: November 28, 2022

References

[1] Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. NatRev Cardiol. 2020 Mar 5.

[2] del Rio C, Malani PN. COVID-19—New Insights on a Rapidly Changing Epidemic. JAMA. Published online February 28, 2020. doi:10.1001/jama.2020.3072

[3] Yee J et al. Novel coronavirus 2019 (COVID-19): Emergence and Implications for Emergency Care. Infectious Disease 2020. https://doi.org/10.1002/emp2.12034

[4] Belaïd Bouhemad, Silvia Mongodi, Gabriele Via, Isabelle Rouquette; Ultrasound for “Lung Monitoring” of Ventilated Patients. Anesthesiology 2015;122(2):437-447. doi: https://doi.org/10.1097/ALN.0000000000000558.

[5] Qian-Yi Peng, Xiao-Ting Wang, Li-Na Zhang & Chinese Critical Care Ultrasound Study Group (CCUSG). Findings of lung ultrasonography of novel corona virus pneumonia during the 2019–2020 epidemic. 12 March 2020 Intensive Care Medicine.

[6]  Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020.

[7] Chest CT Findings in Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19)

[8] Radiographic and CT Features of Viral Pneumonia Hyun Jung Koo, Soyeoun Lim, Jooae Choe, Sang-Ho Choi, Heungsup Sung, and Kyung-Hyun Do RadioGraphics 2018 38:3, 719-739 doi: https://doi.org/10.1148/rg.2018170048

[9]  WHO – Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected.

[10] Safe Airway Society. Consensus Statement: Safe Airway Society Principles of Airway management and Tracheal Intubation Specific to the COVID-19 Adult Patient Group. MJA 2020.

[11] GUAN WJ, Ni ZY, Hu Y, Liang WH, et al  Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. doi: 10.1056/NEJMoa2002032

[12] Tao Ai et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology, published online February 26, 2020; doi: 10.1148/radiol.2020200642