What is the culprit? Speaker: YF Shea Supervisor: Winnie Mok,

What is the
culprit?
Speaker: YF Shea
Supervisor: Winnie Mok,
LW Chu
History
• 79 years old female.
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Lived with the son.
Activities of daily living independent.
No known drug or food allergy history.
Used to be a housewife and did not receive any formal
education.
• Chief complaint at AED (9pm, 11/07/2010): slurring of
speech, generalised weakness and clumsiness since 4 pm
today.
Past medical history
• Eczema.
• A fall injury with left distal radius fracture which
was treated conservatively in 2005.
• From the electronic medical record of Hospital
Authority, she was not on any medications.
History
• Time of onset:
– Relatives noted the patient started to have bilateral upper
limbs clumsiness at around 16:00 on 11/07/2010.
– Increasing severity during the dinner.
– Later she developed generalized weakness with inability to
walk, slurring of speech and dizziness.
– She was found to have disorientation.
History
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No recent head injury.
No fever.
No photophobia.
No neck stiffness, headache or vomiting.
No insect bites.
No joint pain.
No localizing symptoms of infection.
Physical examination
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154/80 mmHg, 92 beats per minutes.
Oxygen saturation at room air was 100%.
Afebrile.
Uncooperative.
Disorientation to time, place and person.
Cardiovascular, respiratory and abdominal
examinations were unremarkable.
Physical examination
• Neurological exam:
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No cranial nerve deficit.
Power was grade 4 with normal muscle tone.
There was no sensory deficit.
Failed to follow command for testing the cerebellar sign.
Apparently there was no horizontal nystagmus.
Investigations
Investigations
Investigations
CXR
CT brain
Investigations
• Chest x-ray: no consolidation.
• Serum toxicology: unremarkable. Urine
toxicology: T/F.
• Computed tomography of the brain showed
mild generalized cerebral atrophy.
Progress of our patient
• Diagnosis: delirium.
• Geriatric team was consulted on 12/07/2010.
• So I attended this patient…
Let’s have a short review on
approach to delirium
Confusion Assessment Method
(CAM)
The diagnosis of delirium requires the presence of a
and b & either c/ d:
a. Acute onset and fluctuating course.
b. Inattention.
c. Disorganized thinking.
d. Altered consciousness.
Reference: S Saxena, D Lawley et al. Delirium in the elderly: a clinical review. Postgrad Med J (2009); 85; 405413.
Admission screening
Clinical assessment including
AMT, pre-admission history
from carer or relative reveals
cognitive impairment or
confusion
SUSPECTED DELIRIUM
Conduct delirium screening
using CAM
CONFIRMED DELIRIUM
Identify and treat underlying cause: Physical & Neuro-examination, CBP, Calcium,
RFT, LFT +/- NH3, Glucose, TFT
Chest X-ray, ECG, Blood cultures, Urinalysis
and
Withdraw incriminated drugs (where possible),
correct biochemical abnormalities and
promptly treat infections
MANAGEMENT
Avoid sedatives & restraints
Maintenance or restoration of normal sleep
pattern
Ensuring fluid balance & nutritional needs
are met
Continuity of care
Avoid intra/inter ward transfers
OT/Physiotherapy input
Good sensory environment
Reality Orientation approach
Approach to delirium
Reference: S Saxena, D Lawley et al.
Delirium in the elderly: a clinical review.
Postgrad Med J (2009); 85; 405-413.
Common causes of delirium
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•
•
•
•
Infection.
Electrolytes disturbances.
Dehydration.
Constipation or AROU.
Pain.
Stroke.
Hepatic encephalopathy.
Drugs or drug withdrawal.
Reference: S Saxena, D Lawley et al. Delirium in the elderly: a clinical review. Postgrad Med J (2009); 85; 405413.
Neurobiology and etiologies
Reference: US Pharmacists website: http://www.uspharmacist.com/continuing_education/ceviewtest/lessonid/105762/
Remember…
• In about 13% of elderly patients, delirium is
superimposed on a pre-existing dementia!
• Delirium may be the 1st indicator of
dementia in elderly and may “unmask” an
insidiously developing cognitive decline.
Reference: S Saxena, D Lawley et al. Delirium in the elderly: a clinical review. Postgrad Med J (2009); 85; 405413.
Now…
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11 am on 12/07/2010.
Oriented to time, place and person.
Cooperative and muscle power grade 5.
Able to walk with 1 mild assistant around the
bedside.
• I attempt to explore the underlying cause of this
episode of delirium…
Further clarification of history
• Memory history (informant: daughter, visited the
patient almost daily):
– 6 months history of anterograde episodic memory
impairment including e.g. she forgot she had meal or
taken a bath, difficulty in recalling telephone numbers.
– Remote long-term memory was preserved.
Further clarification of history
• Basic activities of daily living (ADL): independent.
• Instrumental ADL:
– Executive function impairment: the patient showed
decreased in ability to perform household task.
– Failure to distinguish commonly use vegetables for
cooking.
• Mixed up between Aberdeen & Tsuen Wan.
• More cooperative.
– Abbreviated mental score (AMT) 6/10.
– MMSE 19/30 [recall 1/3].
Mini-mental state examination
Investigations
• Vitamin B12, folate, thyroid stimulating hormone
(TSH), Venereal Disease Research Laboratory
(VDRL) were normal.
• Mild Alzheimer’s disease.
Because of the history of eczema…any
anti-histamine consumption?
• She visited general practitioner around 1 week
before the current presentation and consumed 2
tablets of homochlorcyclizine (Homoclomin)
on 06/07/2010 to 07/07/2010 for pruritus.
Also…
• But she had persistent symptoms.
• She visited Traditional Chinese Medicine (TCM)
practitioner on 08/07/2010 and received 3 days
prescription.
• The last dose she took was on 11/07/2010 3pm (1 hr
before the symptoms started).
The TCM formula of our patient
• We sent the formula to
Hong Kong Poison
Center for further
opinion.
Reply from HK Poison Center
But then…
• Urine toxicology: normal (no anti-histamine metabolites).
• MRI brain (stroke series): normal.
• The patient was discharged in the afternoon ~ 5pm on
12/07/2010 (now walk unaided).
2 tablets of homochlorcyclizine
06/07
07/07
Patient’s
admission
Patient’s
discharge
11/07
12/07
TCM medications
08/07
09/07
10/07
Toxicologist contacted again
• The urine sample collected at the time of admission
was sent to Toxicology Reference Laboratory (TRL)
for further analysis.
Results of urine toxicology
Later reported in newspaper
Is this the end?
Let’s have a look on TCM usage among Hong
Kong elderly…
Use of TCM in HK elderly
Reference: The ecology of health care in Hong Kong, Gabriel M. Leung et al, Social Science & Medicine
Volume 61, Issue 3, August 2005, Pages 577-590
Use of TCM in HK elderly
Reference: Use of traditional chinese medicine in the Hong Kong special administrative region of China. Journal of
Alternative & Complementary Medicine. 13(3):361-7, 2007 Apr
What is tropane alkaloid?
Tropane alkaloids
• Alkaloids are normal plant
metabolites.
• A nitrogen-containing
chemical ring structure.
• Anti-cholingeric action.
Atropine
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Tropane alkaloids
Acetylcholine
Atropine
Tropane alkaloids
• Highest concentration in roots and seeds.
• Relieve the respiratory symptom including
asthma, chronic bronchitis and flu symptoms
or to relieve pain e.g. in childbirth, 麻沸散,
蒙汗藥
• Recreational hallucinogen or added to
alcoholic beverages to increase intoxification.
Datura spp. 曼陀羅花
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007) 375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Tropane alkaloids
• Tropane alkaloids are lipophilic and could cross the
blood brain barrier.
• Symptoms of anticholinergic poisoning usually occur
30-60 minutes after ingestion and may continue for
24 to 48 hours because tropane alkaloids can delay
gastric emptying and absorption.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007) 375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
What is the Cause of Poisoning?
• Deliberate induction of hallucination by ingesting the seeds
or brewing tea from the seeds.
• In eastern countries (e.g. China and Hong Kong), the
anticholingeric poisonings are mainly due to the intake of
TCM for treatment .
Reference:
•
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007) 375-433.
•
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
•
Luo XC et al. Phenomenon of “Intake of Cangshu containing Chinese herbal broth causing atropine-like poisoning”; China J Chinese Materia
Medica 2000:25(11); 702-703 (in Chinese).
•
Poon WT, Lai CK, Chan AY, Mak TW et al; Traditional Chinese Medicine Related Poisonings in Hong Kong; Hospital Authority Toxicology
Reference Laboratory, Princess Margaret hospital; International Congress of the European Association of Poisons Centers and Clinical
Toxicologists 2008, Bangkok.
•
SF Hu et al. Identification of toxins in Cangshu poisoning; Chinese Pharmaceutical Affairs 2000:14(3); 173-174. (In Chinese)
•
Tse ML, Chan YC, Lau FL et al; Case series of anticholinergic poisoning after Chinese Medicine use; Hong Kong Poison Information Centre; Hong
Kong Special Administrative Region, China; 6th Congress of Asia Pacific Association of Medical Toxicology.
TCM causing tropane alkaloid
poisoning in HK
Datura metel L. (洋金花; 茄科植物白曼陀羅)
Reference:
Website – HK commonly confused Chinese medicines
Chan TY et al; Anticholinergic Poisoning due to Chinese herbal medicines; Vet Hum Toxico 1995 37(2): 156-7.
Contaminated TCM
Reference: Luo XC et al. Phenomenon of “Intake of Cangshu containing Chinese herbal broth causing atropinelike poisoning” [in Chinese]; China J Chinese Materia Medica 2000: 25(11); 702-703.
Contaminated TCM
Hu SF et al reported that prevalence of contamination may be up to 8%. The
contaminant was tentatively identified as Scopolia japonica Maxim.
Reference: Hu SF, et al. Identification of toxins in Cangshu poisoning [In Chinese]; Chinese Pharmaceutical
Affairs 2000:14(3); 173-174.
In 2004…
• 衞 生 署 發 言 人 今 日 (二 〇 〇 四 年 六 月 三 十 日 ) 表 示 ， 已 收
到醫院管理局通報三宗因服用摻有雜質的中藥蒼朮而中
毒的懷疑個案。
• 三 名 病 人 包 括 一 男 二 女 ， 年 32 至 52 歲 ， 在 聯 合 醫 院 接 受
治療後，已康復出院。
• 衞生署調查顯示，三名病人服用的中藥藥方包含一種摻
有雜質的中藥蒼朮，相信這些雜質是引起中毒的成因。
• 衞生署已指令有關的零售商及批發商暫停售賣中藥蒼朮
，直至另行通知為止，調查仍在進行中。
• 已購買或正服用這種藥材的市民，如感到不適應立即停
止使用，並諮詢中醫師或醫生的意見。
Reference: http://www.dh.gov.hk/tc_chi/press/2004/040630_1.html
In 2006…
摻不純正成分蒼朮須回收
衞生署今天指令協成行藥業有限公司回收批號為「060608」的中藥材蒼朮，
該批蒼朮摻雜的有害不純正成分，導致1名9歲男童中毒。蒼朮是常用中藥材
，本身並沒有毒性。
該男童6月10日在柴灣由1名中醫師診治後為其開出處方，處方的中藥材由該
中醫師註診的中藥零售商舖配發。
男童服用1劑中藥後，短時間內出現面紅
短時間內出現面紅、
短時間內出現面紅、語無倫次、
語無倫次、精神混亂、
精神混亂、口乾等不良
口乾
反應。6月13日入伊利沙伯醫院接受治療，現已康復出院。
他服用的中藥處方中含有中藥材蒼朮，經測試顯示，蒼朮中摻雜有害的不純
正成分，相信這些不純正成分是引起中毒的原因。
Reference: http://www.news.gov.hk/tc/category/healthandcommunity/060620/html/060620tc05012.htm
Clinical Features
• Anti-cholinergic effects.
– Central Nervous System (CNS).
– Peripheral Nervous System (PNS).
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
CNS manifestations
• Agitation and confusion.
– Undressing behavior.
• Hallucination.
• Seizures or coma.
• Mumbling or incomprehensible speech.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
PNS manifestations
• Blurred vision & photophobia.
• Dysphagia.
• Muscle incoordination and paralysis.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Physical Examination
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•
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Hyperthermia (flushing).
Dry skin & dry mucous membrane.
Mydriasis.
Tachycardia, inconsistent hypertension or hypotension.
Tachypnea or rarely respiratory depression.
Diminished bowel sounds.
Distended urinary bladder.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
In a case series by TRL
• Involved HK patients suffering from anticholinergic poisoning
due to TCM between 2004 and 2008.
• 17 cases (4 males and 13 females).
– 9 to 83 years old.
– Delirium (82%), tachycardia (82%), dilated pupils (65%), dry skin
(53%), flushing (29%), urinary retention (18%) and fever (6%).
• 53% were associated with contaminated Rhizoma Atractylodis
(蒼朮) by other anticholinergic plants.
Reference: Poon WT, Lai CK, Chan AY, Mak TW et al. Traditional Chinese Medicine-Related Poisonings in
Hong Kong [abstract]; Clinical Toxicology 2008; 46: 381.
How should we manage these
patients?
Management
• Airway and Breathing.
– Oxygen therapy or even intubation for CNS or
respiratory depression.
• Circulation
– Isotonic fluids and inotrope for hypotension.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Management
• Hyperthermia.
– Sedation/ paralysis or active.
• Early consultation of local poison center.
• Gut decontamination using charcoal.
• Benzodiazepine for agitation.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Antidote - Physostigmine
• Reversible acetylcholinesterase inhibitor
capable of directly antagonizing CNS
manifestations of anticholinergic toxicity.
• Consult with a poison center or medical
toxicologist before the usage
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Indications for Physostigmine
• Respiratory depression.
• Hemodynamically significant
tachydysrhythmias.
• Coma or intractable seizures.
• Severe agitation or psychosis.
• Severe dyskinesias.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Contraindications for
Physostigmine
• Patients receiving tricyclic antidepressants,
disopyramide, quinidine, procainamide,
cocaine, or other agents producing cardiac
conduction abnormalities.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Relative Contraindications for
Physostigmine
• Relative contraindications include reactive
airway disease, intestinal obstruction, and
recent administration of depolarizing paralytic
agents.
Reference:
1.
Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emergency Medicine Clinic of North America; 25(2007)
375-433.
2.
Richard A Wagner, Samuel M Keim et al; Plant Poisoning, Alkaloids – Tropane; eMedicine Emergency Medicine
(http://emedicine.medscape.com/article/816657).
Local Usage of Physostigmine
• Tse ML et al reported on the use of
physostigmine in 4 patients with
anticholinergic delirium which resulted in
dramatic and complete recovery
Reference: Tse ML, Chan YC, Lau FL et al; Case series of anticholinergic poisoning after Chinese Medicine use
[oral presentation]; 6th Asia Pacific Association of Medical Toxicology Congress, Bangkok, Thailand.
Avoid
• Phenothiazines and diphenhydramine should
be avoided.
• Haloperidol does not seem to be effective for
resolution of central anticholinergic effects.
Reference: Blake Froberg, Danyal Ibrahim, R Brent Furbee et al; Plant poisoning; Emerg Med Clin N Am 2007; 25:
375–433.
Useful resources for TCM
poisoning
E-Knowledge Gateway
Toxicology Reference Laboratory
• http://trl.home.
• Downloadable in pdf
format.
How did the investigation
proceed?
First, the Department of
Health analyzed the
herbs from the Tung
Wah Hospital (Chinese
Medicine out patient)…
Further Investigations
It was also noted that Cangshu (蒼朮
蒼朮)
蒼朮 from TWH contain
Aconite.
Then, the Department of
Health analyzed the herbs
from herbal shop (永和興
永和興)…
永和興
Contaminated Strobilanthes forrestii
Diels (味牛膝
味牛膝)
味牛膝
• During the analysis of herbs
sample from 永和興,味牛膝
was found to contain
atropine.
• There was a mixed-up of 川
牛膝 (Cyathula officinalis
Kuan) and 味牛膝.
• 調查顯示該批「味牛膝」
是由「黃澤記有限公司」
從佛山進口，並供應給包
括「永和興」的本地零售
商。(衞生署 28/07/2010)
One of the most commonly confused
pair of herbs
川牛膝 Cyathula officinalis Kuan
味牛膝 Strobilanthes forrestii Diels
Confused nomenclature
Reference: A Systematic Study on Confused Species of Chinese Materia Medica in the Hong Kong Market; Zhongzhen
Zhao et al; Ann Acad Med Singapore 2006; 35: 764-9
Final diagnosis
• Delirium due to tropane alkaloids poisoning due to
contaminated Strobilanthes forrestii Diels (味牛膝)
(1st reported case).
• With a background of mild Alzheimer’s disease.
• The patient was referred to Memory Clinic for further
follow-up.
Our Patient
• Now being followed up in Memory clinic.
– Diagnosed to have mild Alzheimer’s disease.
– She has been started on Rivastigmine.
• Eczema being followed up in skin clinic of
QMH.
Take Home Message
• Find the culprit for delirium (which can be
very interesting).
• Explore the usage of TCM especially when
common causes have been ruled out.
• Tropane alkaloid is the most common anticholinergic plant poisoning in HK.
Acknowledgement
• Hong Kong Poison Information Centre, United
Christian Hospital
• Dr. Anthony Chow (周天溢).
• Dr. CK Chan (陳志強).
• Dr. ML Tse (謝萬里).
• Toxicology Reference Laboratory, Princess
Margaret Hospital, Hospital Authority
• Dr. Tony WL Mak (麥永禮).
Thank You
Any question?