Microsoft PowerPoint - cyanogenic compounds []2
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Cyanogenesis • The production of HCN by living organisms • In plants (more than 3000 species) one orIn plants (more than 3000 species), one or
more compounds liberate HCN on hydrolysis • The source of cyanogenesis could be identified
in only 300 – Cyanogenic glycosides & lipids
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– The num. of known glycosides (23) & lipids (4) is small.
Cyanogenic compounds. Ann Rev. Plant Physiol. 1980. 31: 433-51. Cyanogenesis in plants. Plant Physiol. 1990. 94: 401-5.
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• Traditional medicine – Cough, HTN, headache, GI upset, diarrhea,
constipation, amenorrhea, cancer, musculoskeletal disorder
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Acute cycas seed poisoning in Taiwan. J Toxicol Clin Toxicol. 2004. 42(1): 49-54.
Cyanogenic foods. Medical toxicology of natural substances. 2008. p44-53.
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Varieties of Cassava
• In tropical Africa, an important food source – Root: very starchy – Leave: source of protein and vitamin
• Traditionally classified into 2 categories – Bitter (higher cyanide potential) or sweet cassava
(lower)
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(lower)
Uptake of wetting method in Africa to reduce cyanide poisoning and konzo from cassava.
Food & chemical toxicology. 2011. 49: 539-42.
Cassava
– Leaves, peel of root: 900-2000 mg HCN equivalent/kg
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equivalent/kg
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pH 5.5

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Human intestinal bacteria may possess glycosidase activity poisoned in the absence of plant enz.
11 Goldfrank’s toxicologic emergencies. 9th edition. 2011

• Lotus spp.
• Prunus spp.
• Sorghum spp.
• Phaseolus spp.
– Peaches
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Factors influence the toxicity
• Type, age, amount of tissue ingested A t t t ( ki t t ti )• Any treatment (eg. cooking, storage, extraction) – which lower the glycosides or inactivates the
catabolic enzs. • Cyanogenesis is “polymorphic” in many if not
all plant species
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– Select strain of lower potential to release HCN (eg. Sorghum (), T. repens (), sweet almond, macadamia nuts())
Cyanogenic compounds. Ann Rev. Plant Physiol. 1980. 31: 433-51.
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Strategies for elimination of cyanogens from cassava for reducing toxicity and improving food safety.
Food and chemical toxicology. 2011. 49: 690-693.
FAO/WHO safe level of cyanogens in cassava food: < 10mg/kg dry weight
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– Tropical ataxic polyneuropathy – konzo
• Cycas – Amyotrophic lateral sclerosis/parkinsonism
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y ( ) • Environmental vs. genetic ? • L-BMAA (β-N-methylamino-L-alanine) β-sitosterol- β-D-glucosideor some toxic metabolite
Cycad seeds and chronic neurologic disease. DM. 2009. 55: 353-60. The ALS/PDC syndrome of Guam and cycad hypothesis. Neurology. 2008. 70: 1984-90
Others cyanogenic plants poisoning in Taiwan (acute)
• 21 cases of cycad seeds poisoning – Ingested 1~30 seeds (washing then cooking) – S/S began 0.5~7 hours
• vomiting (90%), abd pain (43), headache/dizzy (38), weakness (24), then tachycardia, diarrhea, HTN…
– Duration all < 24 hours
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Acute cycas seed poisoning in Taiwan. J Toxicol Clin Toxicol. 2004. 42(1): 49-54.
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• Cycasin • Neocycasin (A, B, C, E) • Macrozamin
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• among 4, cyanide level were available:
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Acute cycas seed poisoning in Taiwan. J Toxicol Clin Toxicol. 2004. 42(1): 49-54.
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Summarize of cyanide contents
Generally < 0.1 mg/g Some bitter cultivar: up to 0.5 mg/g
Cycad seed ?
Flaxseed 124-196 ug HCN/g
#TDI (sod/pot. cyanide): 0.04/0.05 mg/kg (USEPA) #Fatal dose of cyanide: 200-300 mg for salt; 50-100 mg for HCN in adult
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– Amygdalin: < 3% – Prunasin: 50 %Prunasin: 50 %
• Peak blood cyanide level (p.o.) – In hamsters
• Amygdalin: 1 hour • Linamarin: 3 hours
– In human
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• single meal of well-processed cassava root, cyanide level elevated at 7±2 hours
• 2 cases of poisoning in pediatric: s/s began 9 hours after ingestion of boiled cassava root
Cyanogenic foods. Medical toxicology of natural substances. 2008. p44-53. Exposure to cyanide following a meal of cassava food. Toxicol lett. 2002 135(1-2): 19-23.
Cyanide poisoning, 2 cases report and treatment review. J Med Asso Thai. 1999. 82 suppl (1): s162-7.
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Exposure to cyanide following a meal of cassava food. Toxicol lett. 2002 135(1-2): 19-23.
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• Biotransformation/Elimination – Amygdalin
• In animals, 62-96 % absorbed dose in urine unchanged within 24 hours
• In patients (iv., treat cancer), elimination half life 2 hours, plasma clearance 100 ml/min
Linamarin in human
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– Linamarin, in human • ½ converted to cyanide, then thiocyanate • ¼ excreted in urine unchanged • The rest converted to other compounds
Cyanogenic foods. Medical toxicology of natural substances. 2008. p44-53.
Current developments in cyanide detection
• Optical methods • Electrochemical methods: potentiometry and
amperometry • Mass spectrometry • Gas chromatography
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• Quartz crystal mass monitor
Recent developments in cyanide detection: a review. Analytica Chimica Acta 2010. 673: 117-25.
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27Artifacts in the definition of toxicity by cyanides and cyanogens. Fundamental and applied toxicology. 1983. 3: 400-8.
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Hypochlorite
Pyridine
Clin Chem. 1985. 31/4, 591-595. Used with Permission by
Division of Clinical Toxicology, Medicine,VGHTPE
Microdiffusion in PCC-Taipei or VGH-TC
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Used with Permission by Division of Clinical Toxicology, Medicine,VGHTPE
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• Cyanide production during analysis – Cyanide formation from thiocyanate in the
presence of free Hb, eg. • Smoker: 3-75 ng/ml • Nonsmoker: 9-180 ng/ml
– Cyanide extraction from RBCs during h d b l i h
Different methodology
hydroxocobalamin therapy • Elevate plasma cyanide level but not whole blood
False cyanide detection. Analytical chemistry. 2002. p134A-141A. Elevated plasma cyanide level after hydroxocobalamin infusion for cyanide poisoning.
AJEM. 2004. 22 (6): 492-3.
free
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• thiocyanate reacts with salivary peroxidase, horseradish peroxydase, myeloperoxidase to generate “hypothiocyanate”
Ali h ti it il ( ith h d
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– Cyanamide (by catalases ?)
Cyanide detection
envir.) • Alkyl nitrite: isobutyl nitrite (food adulterant)
isobutyl alcohol + nitrite – Bacteria production during putrefaction
i fl
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Storage conditions
36Artifacts in the definition of toxicity by cyanides and cyanogens. Fundamental and applied toxicology. 1983. 3: 400-8.
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Storage Recommendations
• When high conc. are envisaged, then storage at d f t i f bldeep-freeze temp. is preferable
• When interest is in low concentrations, then refrigerator conditions are more appropriate.
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Artifacts in the definition of toxicity by cyanides and cyanogens. Fundamental and applied toxicology. 1983. 3: 400-8.
False negative
thiocyanate – Hydrolysis to
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& polysulfides
Artifacts in the definition of toxicity by cyanides and cyanogens. Fundamental and applied toxicology. 1983. 3: 400-8.
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• Direct binding H d b l i– Cyanide antidote kit
– 4-dimethylaminophenol (4-DMAP, in Europe)
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Under investigated
Thanks for your attention.
42The role of cyanide liberation in the acute toxicity of aliphatic nitriles. Toxicology and applied pharmacology. 1981. 59(3): 589-602.
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reviewreview
Salicylate intoxicationSalicylate intoxication ---- A case report and A case report and literature literature
reviewreview
disorientation in 2 days.disorientation in 2 days.
•• Physical Examination Physical Examination Cons: disorientation, mild respiratory distressCons: disorientation, mild respiratory distress
Neck/HEENT: intactNeck/HEENT: intact
•• Vital sign:Vital sign:•• Vital sign: Vital sign: BT:37.5BT:37.5c BP:126/75mmHg HR:103/min RR:26/minc BP:126/75mmHg HR:103/min RR:26/min
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A B Deteriorated bilateral pulmonary edema and ARDS in figure A and figure B
diffuse cerebral edema with effacement of basal cisterns and generalized loss of gray-white differentiation
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IV hydration with inotropic agentIV hydration with inotropic agent
Deterioration of drowsy status and dyspneaDeterioration of drowsy status and dyspnea
CXR rapidly deterioration of pulmonary edemaCXR rapidly deterioration of pulmonary edema
ETT + sedation for ARDSETT + sedation for ARDS
What happenWhat happen
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IntroductionIntroduction Aspirin is one of the oldest medications that Aspirin is one of the oldest medications that remain a part of current practice The use of remain a part of current practice The use of remain a part of current practice. The use of remain a part of current practice. The use of aspirin has aspirin has declineddeclined due to its association with due to its association with Reye's syndrome in children, and the development Reye's syndrome in children, and the development of other nonsteroidal antiinflammatory drugs.of other nonsteroidal antiinflammatory drugs. However, aspirin is a widely prescribed However, aspirin is a widely prescribed antiplatelet therapyantiplatelet therapy for patients with for patients with cardiovascular and cerebrovascular disease, and cardiovascular and cerebrovascular disease, and
i i t i it i i t t li i l i i t i it i i t t li i l aspirin toxicity remains an important clinical aspirin toxicity remains an important clinical problem.problem.
Int J Pediatr Otorhinolaryngol 2001 May 11;58(3):229-32.
Arch Pediatr Adolesc Med 2002; 156:929.
IntroductionIntroduction In USA (per year)In USA (per year)
20,892 patients in admission 12,658 in aspirin use (61%) 45 death (0.2%) due to salicylte intoxication
Am J Emerg Med 19:337, 2001.
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IntroductionIntroduction ProductionProduction Salicylic acidSalicylic acid is an organic acid biosynthesized from the is an organic acid biosynthesized from the amino acid amino acid phenylalanine.phenylalanine.
Sodium salicylateSodium salicylate
KolbeKolbe--Schmitt reactionSchmitt reaction
high pressure (100 atm) & high temperature (390K)high pressure (100 atm) & high temperature (390K)
Sulfuric acidificationSulfuric acidification Hydrolysis
Salicylic acid - Wikipedia, the free encyclopedia.htm
IntroductionIntroduction Aspirin (acetylsalicylic acid)Aspirin (acetylsalicylic acid) is rapidly converted is rapidly converted to to salicylic acidsalicylic acid in the body Other salicylates in the body Other salicylates to to salicylic acidsalicylic acid in the body. Other salicylates, in the body. Other salicylates, such as salicylic acid (a topical keratolytic agent such as salicylic acid (a topical keratolytic agent and wart remover) and and wart remover) and methyl salicylatemethyl salicylate (Oil of (Oil of Wintergreen), can also cause intoxication when Wintergreen), can also cause intoxication when ingested. ingested.
J Pediatr Otorhinolaryngol 2001 May 11;58(3):229-32.
Salicylic acid - Wikipedia, the free encyclopedia.htm
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IntroductionIntroduction Methyl salicylate is a common ingredient in Methyl salicylate is a common ingredient in li i ts d i t ts s d i t f li i ts d i t ts s d i t f liniments and ointments used in management of liniments and ointments used in management of musculoskeletal pain. musculoskeletal pain. One teaspoon (5 mL) of Oil of Wintergreen One teaspoon (5 mL) of Oil of Wintergreen contains approximately contains approximately 7 g7 g of salicylate, the of salicylate, the equivalent of equivalent of 21.7# adult aspirin tablets21.7# adult aspirin tablets, and , and ingestion of just ingestion of just 4 mL can be fatal in a child4 mL can be fatal in a child..g jg j
J Toxicol Clin Toxicol 2003; 41:355.
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therapeutic rangetherapeutic range1010--30mg/dL(0.730mg/dL(0.7--2.2 mmol/L)2.2 mmol/L)
symptomaticsymptomatic4040--5050 mg/dL(2.9 to 3.6 mmol/L) mg/dL(2.9 to 3.6 mmol/L)
N b l t l tiN b l t l ti b t th l b t th l No absolute correlationNo absolute correlation between the plasma between the plasma salicylate concentration and symptomssalicylate concentration and symptoms
N Engl J Med 1973; 288:1110.
Mechanism of actionMechanism of action Inhibition of cyclooxygenaseInhibition of cyclooxygenase decreased synthesis of prostaglandins decreased synthesis of prostaglandins decreased synthesis of prostaglandins, decreased synthesis of prostaglandins, prostacyclin, and thromboxanesprostacyclin, and thromboxanes Chemoreceptor trigger zone in the medullaChemoreceptor trigger zone in the medulla nausea and vomitingnausea and vomiting Respiratory center of the medullaRespiratory center of the medulla respiratory alkalosis (rarely, early stage, adult)respiratory alkalosis (rarely, early stage, adult)p y y y gp y y y g Interference with cellular metabolismInterference with cellular metabolism metabolic acidosis (anion gap, late stage, infant)metabolic acidosis (anion gap, late stage, infant)
N Engl J Med 1973; 288:1110.
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Absorption and MetabolismAbsorption and Metabolism At therapeutic levels, 90 percent of salicylate is At therapeutic levels, 90 percent of salicylate is
t i b dt i b d li it d t th l li it d t th l protein boundprotein bound limited to the vascular space.limited to the vascular space. The higher doses, the higher protein bound The higher doses, the higher protein bound Aspirin is metabolized via several different routes Aspirin is metabolized via several different routes in thein the liverliver with a with a halfhalf--life of two to four hourslife of two to four hours. . The drug is partially The drug is partially glycinated glycinated in the liver to in the liver to salicyluric acid, which is both less toxic and more salicyluric acid, which is both less toxic and more rapidly excreted by the kidney than salicylate rapidly excreted by the kidney than salicylate rapidly excreted by the kidney than salicylate. rapidly excreted by the kidney than salicylate. Aspirin Aspirin decreased gastric emptyingdecreased gastric emptying
Ann Pharmacother 2004 Jul-Aug;38(7-8):1186-8.
Absorption and MetabolismAbsorption and Metabolism As aspirin levels rise, As aspirin levels rise, normal protective normal protective mechanismsmechanisms become overwhelmed. The degree of become overwhelmed. The degree of protein binding falls to 50 percentprotein binding falls to 50 percent, and , and hepatic hepatic detoxificationdetoxification becomes saturated.becomes saturated. As the normal hepatic detoxification is saturated, As the normal hepatic detoxification is saturated, elimination is dependent on (slow) renal excretion elimination is dependent on (slow) renal excretion and and drug halfdrug half--life increases from two to four life increases from two to four hourshours to as long as 30 hours.to as long as 30 hours. Ever reported as long as 60hoursEver reported as long as 60hours
Ann Pharmacother 2004 Jul-Aug;38(7-8):1186-8.
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Absorption and MetabolismAbsorption and Metabolism Following overdose, absorption and elimination are Following overdose, absorption and elimination are drastically altered. drastically altered. Peak levels are frequently Peak levels are frequently drastically altered. drastically altered. Peak levels are frequently Peak levels are frequently delayed, and may occur six hours or moredelayed, and may occur six hours or more after after absorption as a result of absorption as a result of pylorospasmpylorospasm, , bezoarbezoar formation, or the use of extendedformation, or the use of extended--release, release, entericenteric--coated formulations.coated formulations. In one extreme case, peak levels did not occur In one extreme case, peak levels did not occur until until 35 hours35 hours after ingestionafter ingestionunt l unt l 35 hours35 hours after ngest onafter ngest on
Ann Pharmacother 2004 Jul-Aug;38(7-8):1186-8.
Ann Pharmacother 2004 Jul-Aug;38(7-8):1186-8.
Clinical featuresClinical features Dose and level ofDose and level of intoxicationintoxication 150mg/kg (Mild)150mg/kg (Mild)
GI irritationGI irritation
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
Clinical featuresClinical features Early symptomsEarly symptoms ti it f ti iti ti it f ti iti tinnitus, fever, vertigo, nausea, vomiting, tinnitus, fever, vertigo, nausea, vomiting, diarrhea (maybe delayed till 30diarrhea (maybe delayed till 30--60hours)60hours) More severeMore severe altered mental status, nonaltered mental status, non--cardiac pulmonary cardiac pulmonary edema, coma, death. edema, coma, death. uncommon, but greater mortality & morbilityuncommon, but greater mortality & morbility Aspirin toxicity is associated with several Aspirin toxicity is associated with several clinical and laboratory findingsclinical and laboratory findings
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
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uncouple oxidative phosphorylationuncouple oxidative phosphorylation in the mitochondriain the mitochondria Lack of hyperthermia, never be used to exclude.Lack of hyperthermia, never be used to exclude.
Tachycardia Tachycardia hypovolemia, agitation, or general distress.hypovolemia, agitation, or general distress.
Hypotension Hypotension vasodilatationvasodilatation
Clinical featuresClinical features Vital signsVital signs (SIRS and pseudo(SIRS and pseudo--sepsis sepsis syndrome)syndrome)y m )y m )
Tachypnea and hyperventilation Tachypnea and hyperventilation medullary respiratory center, sti. Muscle medullary respiratory center, sti. Muscle
metabolismmetabolism HypoventilationHypoventilation ((↑↑ CO2 production)CO2 production)
high doses later coursehigh doses later coursehigh doses, later coursehigh doses, later course
Young children are prone to develop Young children are prone to develop hyperpyrexia, which indicates a worse prognosishyperpyrexia, which indicates a worse prognosis
Chest 1991 Nov;100(5):1391-6.
Clin Toxicol 18:247, 1981 5 patient case series Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
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Clinical featuresClinical features Airway and BreathAirway and Breath
d l d d l d l d d l Noncardiac pulmonary edema and Acute lung injuryNoncardiac pulmonary edema and Acute lung injury OOlder patients with chronic salicylate intoxicationlder patients with chronic salicylate intoxication Altered vascular permeability in the lungsAltered vascular permeability in the lungs TTwo mainstays of treatment in this settingwo mainstays of treatment in this setting VVolume resuscitationolume resuscitation
S di bi b tS di bi b tSodium bicarbonateSodium bicarbonate Pulmonary edema is unusual in the pediatric populationPulmonary edema is unusual in the pediatric population
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
Clinical featuresClinical features CirculationCirculation IInappropriate systemic vasodilationnappropriate systemic vasodilation
hypotensionhypotension
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Alterations in mental statusAlterations in mental status Three mechanismsThree mechanisms
Direct toxicity in the CNSDirect toxicity in the CNS Cerebral edemaCerebral edema N l iN l iNeuroglycopeniaNeuroglycopenia
Concentration in the brainConcentration in the brain mortalitymortality
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
Clinical featuresClinical features Disability Disability ddirect toxicity in the CNSirect toxicity in the CNS
Salicylic acidSalicylic acid is a weak acid that exists in is a weak acid that exists in Charged (deprotonated) form (SalCharged (deprotonated) form (Sal--) ) (ionized)(ionized)
Uncharged (protonated) formUncharged (protonated) form (HS) (non(non--ionized)ionized)
HS easily across cellular barriers blood-brain barrier & epithelium of renal tubule
SalSal-- + + H+H+ HSHS Metabolic acidosis
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
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Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
Clinical featuresClinical features Disability Disability nneuroglycopeniaeuroglycopenia
NormalNormal CSF Glu/serum Glu > 50%CSF Glu/serum Glu > 50%
Salicylates lower CNS glucose levelsSalicylates lower CNS glucose levels Neuroglycopenia Neuroglycopenia despite normal serum glucose levelsdespite normal serum glucose levels
Mortality strongly correlated with CNS salicylate levelsMortality strongly correlated with CNS salicylate levelsMortality strongly correlated with CNS salicylate levels.Mortality strongly correlated with CNS salicylate levels.
J Clin Invest 1970; 49:2139.
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Clinical featuresClinical features ElseElse
Ti itTi itTinnitusTinnitus commoncommon may do so at levels within the therapeutic rangemay do so at levels within the therapeutic range (>19.6mg/dl)
Nausea and vomitingNausea and vomiting direct irritation of the gastric mucosadirect irritation of the gastric mucosa
JAMA 226:142, 1973.
direct irritation of the gastric mucosadirect irritation of the gastric mucosa decreased production of prostaglandinsdecreased production of prostaglandins
leading to deterioration of the protective mucosal barrierleading to deterioration of the protective mucosal barrier
direct stimulation of chemoreceptor trigger zone in medulladirect stimulation of chemoreceptor trigger zone in medulla
N Engl J Med 1973; 288:1110.
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OtOt t i itt i itOtoOto--toxicitytoxicity RReversible sensorieversible sensori--neuronal hearing lossneuronal hearing loss When serum salicylate concentrations exceed 40 mg/dL, When serum salicylate concentrations exceed 40 mg/dL,
hearing loss reaches its maximum of 40 dB.hearing loss reaches its maximum of 40 dB.
Rare complicationRare complication N Engl J Med 1973; 288:1110
Rare complicationRare complication RhabdomyolysisRhabdomyolysis Gastric perforationGastric perforation HypocalemiaHypocalemia
SIADHSIADH N Engl J Med 1973; 288:1110.
Clinical featuresClinical features Risk factor to deathRisk factor to death feverfever unconsciousnessunconsciousness severe acidosissevere acidosis seizureseizure cardiac dysrhythmiascardiac dysrhythmiascardiac dysrhythmiascardiac dysrhythmias advanced ageadvanced age
N Engl J Med 1973; 288:1110.
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Laboratory abnormalitiesLaboratory abnormalities Plasma salicylate
h i l iTherapeutic plasma concentration 10 to 30 mg/dL (0.7 to 2.2 mmol/L)
Toxicity values above 40 mg/dL (2.9 mmol/L).
CChecked every two hours until two consecutive levels show decreaseuntil two consecutive levels show decrease.
N Engl J Med 1973; 288:1110.
Laboratory abnormalitiesLaboratory abnormalities Levels rise until five or six hours after ingestion
l b f tipylorospasm, bezoar formation, or use of enteric-coated tablets. may peak as late as 35 hours after ingestion.
Monitoring plasma salicylate may help assess the response to therapy and determine the need for more aggressive measures.
LLevels above 100 mg/dL (7.2 mmol/L) associated with profound morbidity and mortality.
N Engl J Med 1973; 288:1110.
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Laboratory abnormalitiesLaboratory abnormalities Done nomogram
correlate plasma salicylate levels with toxicity NNo longer in clinical use
fails to accurately predict toxicity based upon the plasma concentration alone, although it is generally true that patients with higher levels are sicker thantrue that patients with higher levels are sicker than those with lower values.
Ann Emerg Med 1989 Nov;18(11):1186-90.
Ann Emerg Med 1989 Nov;18(11):1186-90.
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Laboratory abnormalitiesLaboratory abnormalities Done nomogram potential usefulnessDone nomogram potential usefulness The of the nomogram is to assist in predicting the degree of toxicity after an acute single ingestion of ASA in patients who have not been taking salicylate recently.
N Engl J Med 1973; 288:1110.
Laboratory abnormalitiesLaboratory abnormalities Done nomogram not usefulo e o og a ot use u
salicylate ingested over several hours or days an enteric-coated or a sustained-release tablet oil of wintergreen, absorbed rapidly renal insufficiency or failure the time of ingestion is unknown or uncertain salicylate level drawn before 6 h after ingestion
returns nontoxic.
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acute renal failureacute renal failure eliminated almost exclusively via the kidneys renal vascular inguryproteinuria (>30mg/dl)--early
Plasma potassiump Hypokalemia
promotes absorption of potassium in the distal tubule; this absorption occurs via a K+-H+ exchange pump.
N Engl J Med 1973; 288:1110.
Laboratory abnormalitiesLaboratory abnormalities Blood glucose
li l ff b h l i h l lli l ff b h l i h l lSalicylate affects both central & peripheral glucose Salicylate affects both central & peripheral glucose homeostasis. homeostasis. Mobilization of glycogen storesMobilization of glycogen storeshyperglycemia. hyperglycemia. Potent inhibitor of gluconeogenesisPotent inhibitor of gluconeogenesishypoglycemia. hypoglycemia. Normoglycemia, hyperglycemia, or hypoglycemia.Normoglycemia, hyperglycemia, or hypoglycemia.
Animal studies demonstrate that toxic doses ofAnimal studies demonstrate that toxic doses ofAnimal studies demonstrate that toxic doses of Animal studies demonstrate that toxic doses of salicylate produce a profound decrease in brain glucose salicylate produce a profound decrease in brain glucose concentration despite normal serum glucose levels. concentration despite normal serum glucose levels.
N Engl J Med 1973; 288:1110.
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RarelyRarely Large salicylate overdosesLarge salicylate overdoses
hepatotoxicity & vitamin Khepatotoxicity & vitamin Kfactor VIIfactor VIImetabolismmetabolism PT & INR prolong.PT & INR prolong.
Chronic administration of large doses of salicylate may cause significant hypoprothrombinemia when the serum salicylate concentration exceeds 60 mg/dL.
N Engl J Med 1973; 288:1110.
Laboratory abnormalitiesLaboratory abnormalities Acid-base abnormalities
Variety of acid-base disturbances SStimulate the respiratory center directly
early fall in PCO2 & respiratory alkalosis.
N Engl J Med 1973; 288:1110.
bicarbonate and potassium excretion ↑↑ impair compensation for the metabolic acidosis
Arch Intern Med 1978 Oct;138(10):1481-4.
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Laboratory abnormalitiesLaboratory abnormalities Acid-base abnormalities
i b li id iAn anion-gap metabolic acidosis ↑↑lipolysis, uncouples oxidative phosphorylation, and inhibits various Krebs cycle enzymes involved in energy production and amino acid metabolism
(1) ↑↑ catabolism ↑↑ carbon dioxide production (2) ↑↑ heat production (3) ↑↑ glycolysis and peripheral demand for glucose (4) ↑↑ lactate, pyruvate, and keto acids
Arch Intern Med 1978 Oct;138(10):1481-4.
Laboratory abnormalitiesLaboratory abnormalities Net effectNet effect
IIn most adultn most adult either a respiratory alkalosis or aeither a respiratory alkalosis or a mixedmixedIIn most adult,n most adult, either a respiratory alkalosis or a either a respiratory alkalosis or a mixedmixed respiratory alkalosisrespiratory alkalosis--metabolic acidosis.metabolic acidosis. UUnusualnusual ppure metabolic acidosis. (wide anion gap)ure metabolic acidosis. (wide anion gap) IIntoxication between 12 to 24 h, metabolic acidosis and ntoxication between 12 to 24 h, metabolic acidosis and acidemia (pH < 7.35) occur primarily in children acidemia (pH < 7.35) occur primarily in children younger than age 4younger than age 4 and nearly all children younger than and nearly all children younger than age 1 have acidosis.age 1 have acidosis.gg
Arch Intern Med 1978 Oct;138(10):1481-4.
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Laboratory abnormalitiesLaboratory abnormalities Acute respiratory acidosisAcute respiratory acidosis
rarely, may seen in rarely, may seen in later stageslater stages of profound poisoning. of profound poisoning. occurs early in the course should suggest occurs early in the course should suggest coco--ingestion ingestion
with a respiratory depressantwith a respiratory depressant.. Approximately Approximately oneone--thirdthird of adults.of adults.
Arch Intern Med 1978 Oct;138(10):1481-4.
Arch Intern Med 1978 Oct;138(10):1481-4.
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ManagementManagement Airway Breath Circulation Decontamination Elimination FFP transplantationFFP transplantation Glucose
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ManagementManagement Airway
Intubation dangerous and should be avoidedIntubation dangerous and should be avoided.. Aspirin acts on respiratory center of medullaAspirin acts on respiratory center of medulla ↑RR and a dramatic ↑ in minute ventilation.↑RR and a dramatic ↑ in minute ventilation. respiratory alkalosis "traps" salicylate anions in the respiratory alkalosis "traps" salicylate anions in the blood preventing them from crossing into CNSblood preventing them from crossing into CNSblood, preventing them from crossing into CNS. blood, preventing them from crossing into CNS.
Acad Emerg Med. 2008 Sep;15(9):866-9.
ManagementManagement Breath
l l h ld b d i i dl l h ld b d i i dSupplemental oxygen should be administeredSupplemental oxygen should be administered.. Acute lung injury lead to very high oxygen requirements.Acute lung injury lead to very high oxygen requirements. After intubationAfter intubation
High MV & maintain alkalemiaHigh MV & maintain alkalemia with with serum pH 7.50 to 7.59.serum pH 7.50 to 7.59. But delivering such high minute ventilation, But delivering such high minute ventilation, can we do it?can we do it? Ventilator asynchrony ↓patient's ability to maintain appropriate Ventilator asynchrony ↓patient's ability to maintain appropriate acidacid--base homeostasis.base homeostasis.
J Toxicol Clin Toxicol 2004;42(1):1-26.
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ManagementManagement Paralyzed and sedated prior to intubationParalyzed and sedated prior to intubation
respiratory acidosis during the brief period of apnearespiratory acidosis during the brief period of apnea SalSal-- + + H+H+ HSHS HS diffuse across the BBB and increase toxicity.HS diffuse across the BBB and increase toxicity.
Intubation should be reserved for those patients Intubation should be reserved for those patients with hypoventilationwith hypoventilation as determined by clinicalas determined by clinicalwith hypoventilationwith hypoventilation, as determined by clinical , as determined by clinical evaluation or blood gas analysis. evaluation or blood gas analysis.
Ann Emerg Med 2003; 41:583.
ManagementManagement Circulation
Hypotension due to systemic vasodilation.Hypotension due to systemic vasodilation. Aggressive volume resuscitation unless cerebral Aggressive volume resuscitation unless cerebral
edema or pulmonary edema present. edema or pulmonary edema present. Vasopressor for hypotensive patients who do not Vasopressor for hypotensive patients who do not
respond to fluid resuscitation.respond to fluid resuscitation.respond to fluid resuscitation.respond to fluid resuscitation.
J Toxicol Clin Toxicol 2004;42(1):1-26.
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ManagementManagement Decontamination
Activated charcoalActivated charcoal at least one initial dose (1 g/kg up to 50 g PO)at least one initial dose (1 g/kg up to 50 g PO) MultipleMultiple--dose ACdose AC should be given if tolerated. should be given if tolerated. DosesDoses25 g PO q2h for 3 doses 25 g PO q2h for 3 doses
or 50 g PO q4h for 2 doses after initial doseor 50 g PO q4h for 2 doses after initial doseor 50 g PO q4h for 2 doses after initial dose.or 50 g PO q4h for 2 doses after initial dose.
J Toxicol Clin Toxicol 2004;42(1):1-26.
ManagementManagement Decontamination
J Toxicol Clin Toxicol 2004;42(1):1-26.
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J Toxicol Clin Toxicol 2004;42(1):1-26.
ManagementManagement Elimination Alkalinizationlkalinization
SalSal-- + + H+H+ HSHSHSHSweak acid with a pKa of 3.0weak acid with a pKa of 3.0 PH PH = = 3.03.0 ++ log [sallog [sal--] / [HS]] / [HS]
Charged (deprotonated) form (SalCharged (deprotonated) form (Sal--)) polarpolarionizedionizedcrosses membranes poorlycrosses membranes poorly
Uncharged (protonated) formUncharged (protonated) form (HS) li id l bl l i i di i d bblipid-solublenon-polarnonnon--ionizedionizedcrosses membranescrosses membranes
NNormal extracellular pH of 7.40ormal extracellular pH of 7.40 [HS][HS] / [sal/ [sal--] ] 1:25,0001:25,000 only 0.004only 0.004%% of the total extracellular salicylate exists as HSof the total extracellular salicylate exists as HS
J Toxicol Clin Toxicol 2004;42(1):1-26.
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ManagementManagement ↑↑systemic pH
PHPH 3 03 0 l [ ll [ l ] / [HS]] / [HS]PH PH = = 3.03.0 ++ log [sallog [sal--] / [HS]] / [HS] ↑ ← ↑ ←
SalSal-- + H+ + H+ ←← HS HS ↓↓plasma HS HSCNS & other tissuetrapped to sal- & diffuse into ECF ↓↓ CNS HS concentration causes SalSal-- + H+ + H+ HS HS (brain cell)(brain cell) This increase in the cellular HS concentration promotes furtherThis increase in the cellular HS concentration promotes further drug movement out of the CNS.
AArterial pHrterial pH7.20 7.20 7.507.50 fractional concentration of HSfractional concentration of HS0.006 to 0.0030.006 to 0.003..
Although this change appears trivial, it will promote a Although this change appears trivial, it will promote a significant reduction in the tissue salicylate concentration.significant reduction in the tissue salicylate concentration.
ManagementManagement Alkalemia
Respiratory alkalosis not a contraindication to sodium bicarbonate therapy. common an arterial pH between 7.50 and 7.55 Blood gas analysis q2h indicated for monitoring to prevent severe alkalemia (arterial pH >7.60).prevent severe alkalemia (arterial pH 7.60). Correction of acidemia might exacerbate hyopkalemia due to a shift of potassium into cells.
J Toxicol Clin Toxicol 2004;42(1):1-26.
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beneficial by increasing salicylate excretionbeneficial by increasing salicylate excretion. highly protein bound urine secretion in the proximal tubule, not glomerular filtration.
SalSal-- + H+ + H+ ←← HS HS alkalinizationalkalinization
Am J Physiol 1990 Oct;259(4 Pt 2):F613-8.
Raising the urine pH from 6.5 to 8.1 by the administration of sodium bicarbonate can increase total salicylate excretion more than fivefold. Maintaining high urine flow rate with hydration will enhance this process.
J Toxicol Clin Toxicol 2004;42(1):1-26.
ManagementManagement Elimination HemodialysisHemodialysis
IndicationIndication Altered mental status or cerebral edema NonNon--cardiogenic pcardiogenic pulmonary edema ulmonary edema early HDearly HD Renal insufficiency Renal insufficiency PPlasma concentration >100 mg/dL (7.2 mmol/L)lasma concentration >100 mg/dL (7.2 mmol/L) ?? s co ce o g/d (7. o / )s co ce o g/d (7. o / ) ?? Clinical deterioration despite aggressive and Clinical deterioration despite aggressive and
appropriate supportive careappropriate supportive care
N Engl J Med 1973; 288:1110.
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Hemorrhagic complications rare in single massive overdoses Chronic administration of large doses hypoprothrombinemia when salicylate > 60 mg/dL
SSignificant bleeding ignificant bleeding g gg g treated with freshtreated with fresh--frozen plasma. frozen plasma. Large doses of vitamin K after hypoprothrombinemia Large doses of vitamin K after hypoprothrombinemia little or no effectlittle or no effect when high serum salicylate.when high serum salicylate.
N Engl J Med 1973; 288:1110.
ManagementManagement Glucose
↓↓CNS glucose levels despite a normal peripheral CNS glucose levels despite a normal peripheral glucose level. glucose level.
Supplemental glucose should be given to patients Supplemental glucose should be given to patients with altered mental status regardless of serum with altered mental status regardless of serum glucose concentrationglucose concentrationglucose concentration.glucose concentration.
N Engl J Med 1973; 288:1110.
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ManagementManagement Glucose
IV of 50 g/L of IV of 50 g/L of D5WD5W because hypoglycemia has because hypoglycemia has been implicated in the pathophysiology of been implicated in the pathophysiology of salicylate CNS injury. (even if serum ok)salicylate CNS injury. (even if serum ok)
HHypoglycemia or neurologic symptomsypoglycemia or neurologic symptoms minimum of 100 g/Lminimum of 100 g/L D10WD10Wminimum of 100 g/L minimum of 100 g/L D10WD10W..
N Engl J Med 1973; 288:1110.
Salicylate serum level:
ICU courseICU courseICU courseICU course Airway and breathAirway and breath
low TV high PEEP rapid rate for ARDSlow TV high PEEP rapid rate for ARDSlow TV, high PEEP, rapid rate for ARDSlow TV, high PEEP, rapid rate for ARDS
Emergency HD for acute pulmonary edemaEmergency HD for acute pulmonary edema
CirculationCirculation
Dopamin for inotropic effect and tapping Dopamin for inotropic effect and tapping
DisabilityDisability
ICU courseICU courseICU courseICU course Elimination
urine alkalizationurine alkalizationurine alkalization urine alkalization
Emergency HD x2Emergency HD x2
FFPFFP
for prolong PT, add vit k. for prolong PT, add vit k.
GlGlGlucoseGlucose
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DC Improvement of oxygenation and ventilation after emergency HD and mechanical ventilation support in C. Successful weaning in D.
ICU courseICU courseICU courseICU course (3(3--44(( )) 6060

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Take Home MessageTake Home Message Despite extensive clinical experience with aspirin and
other salicylates, and the evolution of therapeutic alternatives, salicylate intoxication remains a significant clinical problem.
Early recognition is the key to successful management, and this diagnosis must be considered in any patient following therapeutic drug overdose and in those with an unexplained increase in the anion gap.
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
Take Home MessageTake Home Message General measures to decrease systemic absorption and
alkalinization of the serum with intravenous sodium bicarbonate are the mainstays of therapy.
The early initiation of hemodialysis should be considered in all patients with clinical evidence of severe intoxication.
Goldfrank's Toxicologic Emergencies, 9th, 2011. p.508.
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Ketamine abuse associated cystitis, acute renal failure and dilatation of
biliary tract: a case report

Management4
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Gender: male
A i l d t t ED 100/03/21Arrival date to ED: 100/03/21
Chief complaint
Abdominal cramping pain, dysuria, hematuria, nocturia off and on about 3 weeks.
Febrile sensation few days ago
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Frequent abdominal pain, constipation and dysuria.
Physical examination
Mentality: oriented
Neck: supple
Chest and lungs: clear breathing sound, tatoo over trunk. No respiratory distress
Heart: RHB
Extremities: freely movable
Patient ask for discharge, thus GU OPD arranged
100/03/21
The patient did not go to GU OPD, visit MER again on 4/8
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No fever
Lab Data
ED course
MBD with GU OPD F/U
Final diagnosis
Ketamine related lower urinary tract symptoms complicated with acute renal failure, bilateral hydronephrosis and abnormal liver functions s/p bilateral PCN.
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Introduction
Introduction
Ketamine first synthesized in 1962 and used in humans in 1965.
Structurally related to Phencyclidine (PCP or angel dust)
Also known as K, super K, vitamin K, special K
May be consumed via inhalation, smoking or intravenous injection
.
A dissociative anesthetic and hallucinogen that acts on NDMA receptors.
Dose dependent reuptake blockade of Norepinephrine, Dopamine and Serotonin receptors, responsible for psychomotor and sympathomimetic effectseffects
Metabolized by hepatic enzymes and excreted in urine.
Duration of action usual lasts for 1 hour after insufflation, oral ingestion may lasts 4-8 Hours. .
Introduction
Psychological dissociation: hallucination, out of body sensation, near death
Pronounced analgesia
C f i t d iConfusion, anterograde amnesia
Long term effects: impairment in episodic memory and retrieval from semantic memory
Malaysian Family Physician 2009; 4(1):15-18
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Tsai et al 2008 3 Letters to the
Tsai et al 2008 3 editor
Chen et at 2008 4 Letters to the
editor
editor
challenge
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Clinical Clinical Presentation
The symptoms of Ketamine induced cystitis include aThe symptoms of Ketamine induced cystitis include a range of LUTS that are mainly irritative in nature
Intense urgency
Urodynamic studies: decreased bladder compliance, detrusor overactivity
The VUR seen in patients with Ketamine related cystitis occurs as result of a small bladder capacity combined with high bladder pressures
Cystoscopic finding: ulcerative cystitis with severe inflammation and epithelial denudation.
Pathology presents a eosinophilic infiltrates
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Pathophysiology
High concentrations of ketamine and its metabolites in the urine may cause direct toxic effects on the bladderthe urine may cause direct toxic effects on the bladder interstitial cells
Microvascular changes in the bladder and kidney causing endothelial cell injury of microvessels, leading to compromised intrinsic microcirculations or decreased microvascular density in the subendothelium
Autoimmune reaction of the bladder urothelium and submucosa triggered by urinary ketamine or ketamine metabolites
BJUI, 102, 1616- 1622
Ketamine-associated ulcerative cystitis
Shahani was the first to describe a series of 9 patients with daily ketamine use and presented with severewith daily ketamine use and presented with severe dysuria, frequency, urgency and gross hematuria in 2007
A serial of investigations showed that all urine cultures were sterile, CT revealed marked thickening of the bladder wall, a small capacity and perivesicular stranding. Cystoscopy disclosed severe ulcerative cystitis and biospy in 4 patients revealed epithilial denudation andbiospy in 4 patients revealed epithilial denudation and eosinophilic infiltrates
This new clinical entity was named: Ketamine – associated ulcerative cystitis
Urology 2007 69: 810-812
Street Ketamine-associated bladder dysfunction
First case report of Ketamine related cystitis in Asia was published in 2007
This study included 10 ketamine abusers who visited two hospital in Hong Kong during 2000 to 2007. All of them presented with severe LUTS.
None of them had positive urine ordinary culture and TB cultureculture
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Urodynamic studies showed” detrusor overactivity withUrodynamic studies showed” detrusor overactivity with urinary leakage when the bladder was filed to a capacity of 30 to 50 ml
All of them had abnormal liver functions, ultrasonography showed no obstructive cause, and none had hepatitis B associated chronic liver disease
Ketamine associated bladder dysfunction
From 2006 to 2008, 11 patients were admitted with severe urinary tract symptoms following recreational ketamine b b i h l iabuse by inhalation
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Most patients received oral antibiotics, anticholinergics p g agents and NSAID during OPD follow up, the response was poor
6 patients received intravesical instillation of hyaluronan solution (Cystistat, 40 mg in 50 ml phosphate-buffered saline) once weekly for 4 weeks
Th i t t t d t i d ftThe urinary tract symptoms seemed to improved after therapy
All these patients have ceased ketamine use
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Management
Ketamine cessation is the only effective treatment, but the effect depends on the severity and duration of the abuse
Antibiotics, oral NSAIDs, steroids and anticholinergic therapy have been employed, but failed to prove significant improvement
Intravesical instillation of Hyaluranic acid ( Cystitstat) andIntravesical instillation of Hyaluranic acid ( Cystitstat) and oral Pentosan polysulphate (Elmiron) had varying degree of symptomatic relief, but long term follow up is needed.
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The penetration of toxic urinary compounds into the bladder wall induces urgency, frequency and pain.
Methods to repair the rebuild the glycosaminoglycan layer of the damages urothelium such as Elmiron, Hyaluronic acid have provided some degree of symptomsHyaluronic acid have provided some degree of symptoms relief to patients with ketamine related cystitis.
Augmentation enterocystoplasty was done in a patient with ketamine associated cystitis with aim to keep renalwith ketamine associated cystitis with aim to keep renal functions and improve quality of life.
However, the patient keep abusing ketamine after operation and was admitted again 3 months later due to acute renal failure.
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Augmentation enterocystoplasty or cystectomy with ileal conduits should be considered when conservative treatment fails
Whole urinary system should be evaluated, since the small bladder capacity is not the only complicationsmall bladder capacity is not the only complication, retroperitoneal fibrosis as well as uteropelvic junctions obstruction are also common.
Take Home messages
The growing popularity of Ketamine among teenagers and the effects of its abuse is an important issue needed to be discussed.
In young adults with unexplained disabling frequent urination, sterile pyuria and hematuria, the possibility of ketamine abuse should be suspected.
cyanogenic compounds [].pdf
Salicylate intoxication 2011.11.pdf