2. Patient profile
Name 林X榆 HT 163 cm
Age 23 y/o BW 39.2 kg
Gender female BMI 14.7
Drug Allergy NKDA Family History Not contribution
Social History • Smoking (-)
• Drinking (-)
• Betel nut (-)
• Drug abuse (-)
2
2011/
10/06 • R’t flank pain and bilateral shoulder, L’t subcostal, bilateral hip,
bilateral knee soreness
• Diagnosis: muscle sprain
Diclofenac 25mg TID x 3 days
ER
3. History of present illness-12/4 ER
3
2011/
12/04
• R’t nasal bleeding this morning
• Bil hydronephrosis (+), septal perforation(+)
• Diagnosis: epistaxis, right
Fexofenadine 60mg BID
Tranexamic acid 250 mg QID
ER
4. History of present illness-12/10 ER
4
4
2011/
12/10
• CC: 咳嗽, 上腹痛與腹脹感, 嘔吐多次
• Cough with whitish sputum, N/V(+), fever(-), sorethroat(-),
general malaise(+), rhinorrhea(+)
• PH:
bil. Hydronephrosis
• Diagnosis:
1. Common cold, r/o airway infection
2. CKD
3. Anemia
metochlopramide, strocain, desloratadine, cough mix
Hb (g/dL) 8.7 WBC (/μL) 6.8 BUN (mg/dL) 83
MCV (fl) 85 Seg(%) 71 Crea(mg/dL) 7.85
According to patient’s statement:
Past SCr baseline level: 5 mg/dL, lost of F/U 6 months
ER
7. Past history
Impression
Pyuria, suspected UTI
Acute on CKD, suspected ketamine related uropathy
Anemia, related to CKD
Admission
7
According to patient’s statement:
• Ketamine abuse history
5#/day for 1 year many years ago, but quit now
• Frequency, urgency, nocturia, and intermittent gross hematuria
since 5 years ago
• Bil hydronephrosis secondary to bil ureteral stricture was told
- s/p D-J stenting at 2009 奇美醫院, no improvement after insertion
and loss of follow up
- Remove D-J at 2011/05 台南市立醫院 due to forgotten D-J with
infection
- SCr around 5 mg/dL at 2011/05
8. Hospital course 12/16-12/21
8
Medication
• Cefuroxime 12/16-21 (UTI)
• Amlodipine 5 mg QD (HTN 130-150/90-110 mmHg)
• Ferall 1# BIDAC, epoetin 4000 IU QW (Anemia with CKD)
• Calcium acetate 1334 mg TID (Hyperphosphatemia)
• Tramadol 50 mg BID (Pain control)
• 12/19 Echo:
₋ The urinary bladder is not distended and poorly studied
₋ Bilateral hydronephrosis, with some intraluminal echogenic
material
contracted bladder (capacity <30 ml)
• 12/20 U/C: (-)
• 12/21 Stable condition discharge
8
2011/
12/16
|
12/21
12/16 12/19 12/21
BUN(mg/dL) 93 89 116
CREA(mg/dL) 7.65 6.87 6.99
eGFR 7 7 7
Lost of F/U after discharge…
9. History of present illness
9
9
• Abdominal (epigastralgia) pain and L’t flank knocking pain
• WBC: 10900/μL, seg: 84%, CRP 75.4 mg/L, Scr: 7.8 mg/dL
UA: pyuria, WBC:1973, bacteria(-)
Suspect UTI
• Urologist suggest PCN insertion for hydronephrosis with turbid content
drainage Patient refused, AAD 至奇美醫院
2012/
02/06
• CC: abdominal pain and flank soreness, N/V (+)
Impression:
• Acute on CKD impending ESRD
• UTI
2012/
03/12
|
03/29
Hb (g/dL) 5.8 Electrolye Urine Analysis
WBC (/μL) 12000 Na (mmol/L) 126 PRO(mg/dL) 100
Seg(%) 91.5 K (mmol/L) 2.2 RBC(/HPF) 11
BUN (mg/dL) 153 Mg 1.3 WBC(/HPF) 470
Crea(mg/dL) 8.72 Ca (mg/dL) 5.4 Bacteria Trace
eGFR 6 P (mg/dL) 9.5
Albumin (g/dL) 4
Admission
ER
Admission
15. 細胞學檢查報告-2012/3/15
Diagnosis:
Urine cytospin smear: Negative for malignancy.
GROSS FINDING:
The specimen measures 40 ml with a yellow-turbid
appearance. There is one slide totally, which is a
Papanicolaou stain.
15
16. Outline
Introduction of Ketamine
Ketamine induced cystopathy/cystitis
Presentation
Investigation
Management
Other chronic complications related to ketamine use
Summary
16
18. History of Ketamine
1962
First synthesized as a replacement for phencyclidine by Stevens in at
Parke-Davies laboratories (now part of Pfizer)
1970
FDA approved ketamine for human use
Introduced into the Vietnam war as battlefield anesthetic
Late 1970s and early 1980s
“Emergence phenomena” led to increasing illicit use and
withdrawn from mainstream anaesthetic use with humans
18
Common street names
Special K, Kit-Kat, Cat Valium, K
褲子(取字母開頭諧音,與Ecstacy的衣服相似)
下面(相較於衣服(上面),取其相對)
19. Pharmacology of Ketamine
Multiple binding Sites
NMDA-receptor
Non competitive NMDA receptor antagonist that blocks glutamate
Bind to PCP binding site and prevents neuronal Ca2+ influx
S(+)-isomer showing 4 times greater affinity than R(-)-isomer
Norketamine is also an NMDA-R antagonist
Opioid Receptors: Weak agonist (µ > κ > δ)
GABA Receptors: Weak agonist, reduce GABA reuptake
Sympathomimetic
agonist activity at ɑ1- and β2-adrenoceptors
Muscarinic Ach receptors: inhibitor, anticholinergic effect
19
J Pain Symptom Manage. 2011 Mar;41(3):640-9.
20. Physiological effect
Cardiovascular: tachycardia, hypertension
Respiratory: bronchodilation
Neurological:
hallucinations, amnesia, mental clouding, loss of memory,
impaired attention, out of body experiences (K-hole effect)
Gastrointestinal: nausea
Physical features: paralyzed feeling, numbness
Muscles: dystonia, convulsions
20
J Pain Symptom Manage. 2011 Mar;41(3):640-9.
Emerg Health Threats J. 2011; 4: 10.3402
21. Pharmacokinetics
21
Emerg Health Threats J. 2011; 4: 10.3402
Micromedex
Ketamine and its metabolites are renally excreted
Can be detected in urine
Half-life elimination: Alpha: 10-15 minutes; Beta: 2.5 hours
Hepatic metabolism
Major: CYP3A4
Minor: CYP2B6 &2C9
N-demethylation
33% activity
Dehydrogenated
Activity unspecified
Hydroxylation
22. Drug interactions
Long-term use of ketamine leads to hepatic enzyme induction,
including enzymes responsible for its own metabolism
The development of tolerance in recreational users abusing it in high doses
CYP3A4 Inhibitors (eg. Clarithromycin, ketoconazole)
Increase plasma concentrations of ketamine
CNS depressants (eg. Tramadol, opiods, alcohol)
Increased risk of respiratory depression, profound sedation, and
coma
Tubocurarine, atracurium (Nimbex)
Increased neuromuscular blockade
Theophylline
May result in a lower seizure threshold
22
BJU Int. 2011;107:1881-4.
J Pain Symptom Manage. 2011 Mar;41(3):640-9.
Micromedex
23. Medical use of ketamine
Originally – Dissociative anaesthetic
Now- 3rd line Rx option for chronic and acute pain
General anaesthesia
Particularly paediatrics, veterinary anaesthesia and field medicine
Relative preservation of airway reflexes and haemodynamic
stability
Analgesia/sedation (unlabeled use)
Particularly in neuropathic pain & complex regional pain
syndrome
Treatment-resistant depression (unlabeled use)
23
Addiction. 2012 Jan;107(1):27-38.
24. Study design:
A randomized, placebo-controlled, double-blind crossover trial
Patient:
18 adults with treatment-resistant major depressive disorder
- failure of at least 2 adequate antidepressant trials and
- 21-item HAM-D score ≥ 18 after 2-week drug-free period
Intervention:
IV infusion ketamine HCl 0.5 mg/kg vs. saline 50 mL over 40 minutes
Outcome:
Changes in HAM-D score
24
Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
25. Results
Ketamine significant improved depression scores compared to
placebo from 110 minutes after injection through 7 days
In patient treated with ketamine
71% response at day 1
35% response at 1 week
29% remission at day 1
29% remission at 1 week
25
Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
* indicates P<.05; †, P<.01; ‡, P<.001
Response ( ≥ 50% decrease in HAM-D score)
Remission ( HAM-D score ≤ 7)
26. Medical use of ketamine
Treatment-resistant depression
Antidepressants typically take weeks to produce a response
Intravenous infusion of ketamine 0.5 mg/kg has rapid and
profound short-term effect on reducing depression symptom in
patients with treatment-resistant major depressive disorder
However, its long-term safety and effectiveness need to be
evaluated
26
Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
Ann Pharmacother. 2012 Jan;46(1):117-23.
27. Recreational use of ketamine
Ketamine is fast becoming a popular recreational drug
Relatively cheap to other substance (NTD 1000-1200/g)
Easy accessibility
Absence of any physical withdrawal syndrome
Policy: 第三級管制藥品 (98.5 持有/施用: 1-5萬罰鍰, 4-8 h講習)
User’s acute experiences (Emergence phenomena)
Sense of melting into surroundings
Visual hallucinations
Spiritual and out of body experiences
K-hole (dissociative sensation): a near death experience, with the
sensation of rising above one’s body, inner peace, and radiant light
27
Dose
31. Route of abuse
Ketamine is water soluble, has a pKa of 7.5 and a high lipid solubility 10
times that of thiopental
Allows administration by many routes and rapidly crosses BBB
Injected: IV, IM
Orally
Bitter taste, slower onset of action
Extensive first-pass hepatic metabolism reduces its bioavailability
Snorting or inhaling
31
Emerg Health Threats J. 2011; 4: 10.3402
32. Nasal septum perforation and ketamine snorting
Clinical signs of drug use through nasal consumption:
Nasal discharge, epistaxis, nasal septal perforation (occurs
with cocaine, inhalants)
As with other substances, long-term nasal consumption cause
chronic inflammation and necrosis of the nasal mucosa
In extreme cases, intense necrosis can result in an opening in
the nasal septum
The sense of smell can also be damaged by chronic nasal
consumption
32
Donald G. Barceloux. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants.
33. Chronic complications related to ketamine use
Ketamine-induced cystitis
Kidney dysfunction
‘K-cramps’
Neuropsychological effects and neurotoxicity
33
Addiction. 2012 Jan;107(1):27-38.
34. Chronic complications pattern in ketamine abusers
From June 2008 to July 2011, 96 cases of chronic ketamine
poisoning in Hong Kong
Duration of ketamine abuse: mean 8.6 years (SD 4.1 years); median:4 years
92 % presented with features of ketamine cystitis
66 % presented with chronic epigastric pain
42 % nasal problems (3 cases of septal perforation)
16 % psychiatric features
34
J Med Toxicol. 2012 Sep;8(3):267-70.
37. Ketamine-induced ulcerative cystitis
First documented in 2007
37
Urology 2007: 69:810-812
Hong Kong Med J 2007; 13:S1-3
Urology 2007: 69:810-812
Described nine patients who were daily ketamine users
• Severe dysuria, frequency, urgency and gross hematuria
• Urine culture: sterile in all cases
• CT scan: marked thickening of the bladder wall, a small capacity and
perivesicular stranding consistent with severe inflammation
• Cystoscopy: all patients had severe ulcerative cystitis
• All these patients benefited from cessation of ketamine use and the
addition of pentosan polysulfate (Elmiron)
38. Epidemiology
Prevalence data are difficult to obtain
Recent reports suggest that approximately 20–30% of ketamine
abusers suffer from lower urinary tract symptoms (cystitis or
bladder problems)
The presence of urinary symptoms were related to the dose
and frequency of ketamine used:
38% of those reporting less than daily use
50% of those using <2g/day
75% using 2-5g/day
100% of those using >5g/day
38
Drug Alcohol Depend 2008;95: 219–29.
Eur Urol Suppl 2009; 8: 170.
39. Presentation
Time of onset of lower urinary tract symptoms varies from a
few days to a few years following the onset of abusive use
Symptoms are consistent with interstitial cystitis, ulcerative
cystitis and lower urinary tract symptoms
Dysuria, haematuria, urgency and frequency, nocturia, urge
incontinence, pelvic, bladder and urethral pain
Severe complications include intractable symptoms, renal impairment
and hydronephrosis
39
BJU Int. 2012 Sep;110(6):E164-5.
40. A study in Taiwan
11 patients with urinary tract symptoms and a history of
ketamine abuse in recent years
mean age: 24 y/o, duration of drug abuse: 1-4 years
40
Int J Urol. 2009 Oct;16(10):826-9.
41. Ketamine and bladder damage
Causal relationship
The possibility that other co-use substance (adulterant) is responsible for
the major bladder damage?
1. As the use of adulterants would be expected to vary, ketamine appears to
be the common factor
2. The low cost of ketamine mitigates against the need for, or regular use of
adulterants
3. An animal model suggests a causal link
4. There are case reports in adult and paediatric patients using therapeutic
ketamine
5. There is both a dose and time relationship
41
BJU Int. 2011 Jun;107(12):1881-4
Toxicol Lett. 2009 Dec 15;191(2-3):275-8.
Toxicol Lett. 2009 Dec 15;191(2-3):275-8.
42. Bladder symptoms in pain care patients
A pain clinic reports the case of a pediatric pain patient developing bladder
symptoms as a result of ketamine prescribed for pain
42
Urology. 2008 Jun;71(6):1232-3.
• This 16 y/o female patient was being treated for complex regional pain
syndrome (CRPS-Type1). After unsuccessful trials of multiple medications, oral
ketamine was added to a regimen and she reported a significant decrease in
her neuropathic pain.
• After 9 days on ketamine 8mg/kg/day, she started to develop dysuria,
frequency, urgency and incontinence. The urinalysis was normal and the
urine culture was negative. Her symptoms decreased as the dosage was
decreased and eventually resolved at 2mg/kg/day.
• A few months later, the patient was again started on ketamine and the urinary
symptoms reappeared at a dose of 5mg/kg/day. The symptoms again
resolved when the dosage was reduced to 3mg/kg/day.
A potential dose-related effect of the ketamine on the bladder mucosa
43. Possible mechanism of bladder damage (1)
The aetiopathological mechanism of disease development
remains unknown
Ketamine and its metabolites are renally excreted and can be
measured in high quantities in the urine of patients using
ketamine
Conjugates (80%), dehydronorketamine (16.2%), ketamine (2.3%),
norketamine (1.6%)
It is plausible that ketamine and its active metaboiltes can
accumulate in the urine and induce significant bladder irritation
43
Urology 2007: 69:810-812
44. Possible mechanism of bladder damage (2)
A number of different theories have been proposed
Direct toxic effect of ketamine or its metabolites on bladder
interstitial cells
Microvascular damage to the urinary tract leading to chronic
ischaemia and fibrosis
Indirect effect of ketamine by causing an autoimmune
reaction against the bladder urothelium and submucosa due
to circulating ketamine or urinary ketamine and its
metabolites
Unrecognized bacteriuria (less likely)
44
BJU Int. 2011 Jun;107(12):1881-4
45. Clinical investigation (1)
Urinalyses showed nonbacterial pyuria and sterile on culture
Renal impairment with raised serum creatinine was observed in
many cases
Imaging studies
Bladder wall thickness
Small capacity bladder
Perivesical inflammation
Papillary necrosis
Hydronephrosis
(bilateral hydronephrosis in 50% of patients)
45
46. 46
Tzu Chi Med J 2008;20(2):144-146.
A reduced cavity and irregular wall thickening in
the urinary bladder
IVP showed a contracted urinary bladder,
narrowing of bilateral cystoureteral junctions,
bilateral hydroureters and bilateral hydronephrosis
47. Ureteric wall thickening and enhancement were also
observed in advanced cases
47
Clin Radiol. 2010 Oct;65(10):795-80
A 32 y/o man presented with dysuria, haematuria, and suprapubic pain with
a 4 year history of ketamine use (4 g/day)
Bilateral upper ureteric narrowing
with associated mild bilateral
hydronephrosis
Marked
thickening on
the bladder wall
Ureteric wall
thickening and
enhancement
48. Clinical investigation (2)
Urodynamics
Detrusor over-activity and decreased bladder compliance
Small capacity bladder
48
BJU Int. 2008 Dec;102(11):1616-22.
Cystometric bladder capacities in 47
patients who had a video-urodynamic
study, showing that most of them had
capacities of <150 mL
49. Clinical investigation (3)
Cystoscopy
One or more of epithelial inflammation, neovascularisation, petechial
(pinpoint) haemorrhages and erythematous bladder mucosa
49
BJU Int. 2008 Dec;102(11):1616-22.
Two daily ketamine abusers
who had been inhaling
ketamine nasally for 4 years
(A) and 7 years (B)
There were varying degrees of inflammation and neovascularization, with petechial
haemorrhages in more severely affected patients.
4 years 7 years
50. Clinical investigation (4)
Histology
Denuded epithelium
Infiltration of tissues with eosinophils, lymphocytes, mast cells
Immunohistochemistry
High expression of p53 (cell death)
High expression of Ki67 (cell growth)
Absence of CK20 expression (ca in situ)
50
52. Management
There is no clearly defined treatment other than symptomatic
treatment
Early diagnosis is essential to effectively manage ketamine-
induced bladder pathology and prevent irreversible renal tract
damage
Treatments reported in the literature are often those used for
interstitial cystitis, but experience is lacking
Cessation of ketamine use
The only effective treatment modality to prevent deterioration of the
renal function and indeed offer the possibility of symptom resolution
Full symptomatic resolution will not be achieved in more advanced
cases (severely reduced bladder capacity and compliance and resultant
hydronephrosis)
52
Int J Clin Pract. 2011 Jan;65(1):27-30.
53. Management-medications
Various treatment regimens include antibiotics, oral NSIADS, steroids,
anticholinergic therapy have failed to provide significant and lasting
improvement
Pentosan polysulfate (PPS, Elmiron®)
Use: Relief of bladder pain or discomfort due to interstitial cystitis
Dosage: oral 100 mg TID
Mechanism of Action
A low-molecular weight heparin-like compound
Supplement the glycos-amino-glycan (GAG) layer of the damaged
urothelium
Adhere to the bladder wall mucosa where it may act as a buffer to
protect the tissues from irritating substances in the urine
A case reported nine patients benefited from cessation of ketamine use and
the addition of pentosan polysulfate (Elmiron®)
53
Int J Clin Pract. 2011 Jan;65(1):27-30.
54. Management
Intravesical instillations
Hyaluranic acid, pentosan polysulfate (Elmiron®)
Urethral indwelling catheters
Provide relief from the suprapubic pain, urgency and dysuria
Surgical interventions
Bladder augmentation
Neo-bladder construction (created from bowel)
Potential risk: lead to re-absorption of ketamine or its metabolites
There are two reported cases of augmentation cystoplasty in the
literature, but in both cases, ketamine abuse continued leading to
continued symptoms, and disease progression to ureteric stricturing and
renal failure
54
BJU Int 2008; 102: 1616–22
NDT Plus 2008; 1: 310–2.
Int J Clin Pract. 2011 Jan;65(1):27-30.
56. Kidney dysfunction
Frequent, high-dose ketamine use appears to be
hydronephrosis secondary to urinary tract problems
Of 59 ‘ketamine bladder’ patients, 30 (51%) patients presented
with hydronephrosis
Unilateral: 4 (7%), Bilateral: 26 (44%)
Cases of disease progression renal failure
56
BJU Int. 2008 Dec;102(11):1616-22
Addiction. 2012 Jan;107(1):27-38.
57. ‘K-cramps’
‘K-cramps’—Severe gastric pain
Spontaneously reported in 33% of 90 ketamine users interviewed
Frequent ketamine users often report taking more ketamine to alleviate this
pain and this can make attempts to quit using fail
The etiology of K-cramps remains unclear
Three small case reported the existence of
‘Colicky’ upper gastric pain
Presented with abnormal liver function
Dilation of the common bile duct with a smooth tapered end, mimicking
choledochal cysts
57
Addiction. 2012 Jan;107(1):27-38.
Drug Alcohol Depend 2008; 95: 219–29.
58. Dilated common bile ducts mimicking
choledochal cysts in ketamine abusers
58
Hong Kong Med J. 2009; 15:53-6.
Case 1 Case 2 Case 3
Patient 21 y/o woman 27 y/o man 23 y/o man
Ketamine
history
Once per 1-2 month for
18 months
BIW for 2 years Once per week for 7 years
Recent 3 months: everyday
S/S
Recurrent epigastric pain,
especially after taking
ketamine
Recurrent epigastric
pain
Admission due to injuries
Occasional colicky epigastric
pain in the past few years
Liver
function test
ALP: 122 IU/L
ALT: 333 IU/L
bilirubin: 14 µmol/L
ALP: 137 IU/L
ALT: 75 IU/L
bilirubin: 7 µmol/L
Normal
Radiology Dilated common bile duct without obstruction
Resolusion
Yes
(3 moths after cessation )
Yes
(4 moths after cessation )
Unknown
Hong Kong Med J. 2009; 15:53-6.
59. Clinical picture
Recurrent epigastric pain
Increase in that pain after taking ketamine; the pain would decrease
when he temporarily ceased abusing the drug
Abnormal liver function
Mainly involved elevation in ALP and ALT levels, and a normal bilirubin
level
Dilated common bile duct on imaging
Fusiform dilatation of the entire common hepatic and bile duct
No obstructive lesion was found
It resembles Todani’s type Ic choledochal cyst
(diffuse fusiform dilatation of the common hepatic and bile duct)
Symptoms seem to be reversible on cessation of abuse
59
Hong Kong Med J. 2009; 15:53-6
60. Radiological features
60
Hong Kong Med J. 2009; 15:53-6.
Case 1
MRCP taken after cessation of ketamine abuse
for 3 months, showing resolution of biliary tree
dilatation (Diameter: 4 mm)
Case 1
ERCP showed a dilated common bile
duct with a smooth tapered end
(Diameter: 9 mm)
Endoscopic Retrograde Cholangiopancreatogram (ERCP)
Magnetic Resonance Cholangiopancreatogram (MRCP)
61. Etiology of dilated common bile ducts
Ketamine is metabolised in the liver and excreted in bile, we
postulate that this may be the reason for the dilation of the
common bile duct that we observed
The reason for the biliary tree dilatation is unknown
It is not clear whether it is caused by dysfunction in the
sphincter of oddi or the formation of a benign biliary stricture
An animal study has shown that ketamine increases the flow
resistance across the sphincter of oddi, via the activation of
opiate receptors on the sphincter
61
Hong Kong Med J. 2009; 15:53-6
62. Other chronic complications related to ketamine use
Cognitive impairment
Frequent ketamine users exhibit profound impairments in both
short- and long-term memory
Few cognitive deficits seen in infrequent users
Neurological Changes
White matter density reduction noted in frontal and parietal
regions in ketamine addicts compared to controls
62
Am J Psychiatry 2005; 162: 2352–9.
Psychopharmacology (Berl) 2006; 188: 408–24.
Addiction. 2012 Jan;107(1):27-38.
63. Summary
In young adults presenting with severe irritative lower urinary
tract symptoms, a positive history of ketamine abuse should be
considered to have ketamine associated cystopathy
Secondary renal damage can occur in severe cases which might
be irreversible
Currently, ketamine cessation is the only effective treatment
modality
The outcome of treatment depends on the severity of the
disease process
63
66. Radiological features (2)
66
Hong Kong Med J. 2009; 15:53-6
Case 3
A dilated common bile duct, measuring 11.2
mm in diameter
Case 2
MRCP scan showed fusiform dilation
of the common hepatic and bile duct
68. 68
J Formos Med Assoc. 2011 Dec;110(12):787-91.
Bladder mucosa pathology showed neutrophilic and lymphoplasma cell
infiltration in bladder mucosa, which was consistent with chronic inflammation.
69. 69
Int J Urol. 2009 Oct;16(10):826-9.
Urodynamic study of one patient showed detrusor overactivity with
phasic contraction when filling the urinary bladder with about 90
mL of normal saline