Transcript LITHIUM TOXICITY - Ma Antoinette Tan 04062008

MEDICAL
GRANDROUNDS
Mary Antoniette M. Tan, M.D.
First Year Resident
Objectives

To present a case of lithium toxicity

To discuss the use of lithium in mood
disorder and its adverse effects

To discuss the management of lithium
toxicity
Identifying Data
CF
77 years old
Female
Filipino
Separated
Education Graduate
Homebound
Chief Complaint
Decreased sensorium
History of Present Illness
Patient is a known case of bipolar
mood disorder since 1981, maintained on
lithium 900 mg per day.
1 year PTA ------ apparently well
free from medications for
5 months
(+) paranoia, irritability
no consult, no meds
History of Present Illness
1 month PTA ----- persistence of paranoia
and irritability
(+) poor appetite
(+) sleeping problems
consult with a private
psychiatrist, advised
admission
History of Present Illness
1 month PTA ----- maintained on
Olanzapine 10mg OD
and lithium carbonate
1350 mg per day
along with Valsartan,
ISMN and Centrum
History of Present Illness
4 days PTA ----- (+) right hand tremors
more withdrawn
3 days PTA ----- tremors more generalized
and pronounced
(+) episodes of passing
out loose to watery stools
(+) very poor oral intake
History of Present Illness
1 day PTA ------ tremors persistent, involved the
lips
(+) decreased SBP: 70mmHg
(+) decreased sensorium,
aroused only by painful stimulus
Patient rushed to a local hospital – IV
hydration done, serum electrolytes
unremarkable. Relatives opted transfer to our
institution.
Past Medical History

(+) HPN x 15 years on Valsartan 40mg OD
and ISMN 30mg OD

(-) DM, asthma
Personal/Social History
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(-) smoking
(-) alcoholic beverage drinking
Family History
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
(-) Hypertension, DM, asthma, cancer
(-) Psychiatric illness
Review of Systems
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(-) headache, (-) dizziness, (-) BOV, (-) nausea,
(-) vomiting
(-) fever, (-) cough and colds, (-) nasal
congestion, (-) dyspnea
(-) chest pain, (-) palpitations, (-) orthopnea, (-)
PND, (-) edema
(-) abdominal pain, (-) hematemesis, (-)
hematochezia, (-) melena, (-) weight loss
(-) hematuria, (-) dysuria, (-) polyuria
(-) joint pains, (-) skin lesions
Physical Examination
General
Survey
Drowsy, lethargic, uttering incomprehensible sounds, not
in respiratory distress
Vital Signs
BP = 130/80
mmHg
HEENT
Anicteric sclerae, pink palpebral conjunctivae, no
tonsillophrayngeal
congestion,
no
cervical
lypmhadenopathies, neck veins not distended
Chest
Lungs
HR = 64 bpm
RR = 20 cpm
Temp = 36.8C
/ Symmetric chest expansion, no retractions, clear breath
sounds, no rales or wheezes
CVS
Adynamic precordium, normal rate, regular rhythm,
distinct S1 and S2, no murmurs
Abdomen
Flabby, soft, normoactive bowel sounds, no masses or
tenderness
Extremities Full and equal pulses, no cyanosis, no edema, no
clubbing
Neurologic Examination
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Fairly kempt and groomed
Lethargic, responded to vigorous sternal rubbing, uttering
incomprehensible sounds
Cranial Nerves
Pupils 2-3mm equally briskly reactive to light
EOMS full and equal
Able to localize sound
Tongue at midline on protrusion
Motor : able to move all extremities spontaneously and to
withdraw to pain
Sensory : responds to vigorous sternal rubbing, withdraws to
pain
Meningeal : (-) nuchal rigidity
Pathologic : (-) Babinski sign, (-) ankle clonus
Diagnostics done at the ER

CBC, Na, K, Ca, Mg : Normal

BUN = 27, creatinine = 2.0
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Chest xray : clear lung fields, left ventricular
enlargement, atherosclerotic aorta

12-L ECG : Bifascicular block (first degree AV
block and left anterior hemiblock)
Diagnostics done at the ER
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Arterial blood gas : slight metabolic acidosis pO2 98.0, pH 7.33, PCO2 39.8, HCO3 20.6,
O2sat 97.1%, BE -4.9, total CO2 21.8
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Urinalysis : leukocyte esterase +2, blood +3,
RBC 32.1, WBC 6.3

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Obtained via foley catheterization; initial output =
130cc in 8 hrs
Serum lithium : 2.57 mmol/L (NV 0.5-1.5)
Salient Features
77 years old
Female
Known to have bipolar mood disorder
Maintained on lithium carbonate 1350 mg/day
tremors, altered sensorium, anorexia, diarrhea
Elevated serum BUN and creatinine
Elevated serum lithium
Known hypertensive x 15 years
ADMITTING IMPRESSION
1.
2.
3.
4.
Lithium Toxicity
ARF prerenal, sec to volume depletion,
on top of CRI sec to Hypertensive
Nephrosclerosis
Bipolar Mood Disorder
Hypertensive Atherosclerotic
Cardiovascular Disease
Problem #1: Tremors, altered sensorium,
anorexia, diarrhea
(elevated serum lithium level + CRI)

lithium level: 2.57 mmol/L (NV 0.5-1.5)
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referral to Nephrology
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hydration with PNSS at 150cc/hour
Problem #1: Tremors, altered sensorium,
anorexia, diarrhea
(elevated serum lithium level + CRI)

stat hemodialysis : extended hemodialysis (8 hours)
done (indication: increased lithium level > 2.5 + CRI,
presence of neurologic symptoms) and tolerated

serum lithium level post dialysis : 0.35 mmol/L

marked clinical improvement post dialysis : more
awake, (-) tremors and fasciculations, adequate
verbal output
4/9/07
4/10/07
post-HD
4/10/07
(4pm)
4/11/07
0.64
0.59
(10am)
Serum lithium
(NV 0.5-1.5 mmol/L)
2.57
0.35
4/9/07
4/10/07
(postHD)
4/11/07
4/12/07
4/14/07
4/16/07
Na
140
138
138
141
138
141
K
4.1
4.1
4.0
4.4
3.9
4.0
BUN
27
7.0
Crea
2.0
1.1
Ca
8.9
Mg
1.8
18
1.4
1.2
1.7
1.8
1.3
1.4
Problem #2: Restlessness and
agitation
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attributed to patient’s bipolar mood disorder
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Haloperidol 1.25mg slow IV push PRN for
anxiety and aggression

cranial CT scan with contrast planned to rule
out any neurologic problem; plain CT scan
suggested due to moderate risk for contrast
nephropathy (CRI and age)
Problem #2: Restlessness and
agitation
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Urine osmolality requested for plans of
resuming lithium and other psych meds
= normal at 399mOsm/kg H20
Divalproex sodium (Depakote)
500mg/tab 1tab BID started on the 3rd HD
Problem #2: Restlessness and
agitation
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MRI with gadolinium suggested instead; no
further behavioral changes noted on the 4th
HD
cranial CT scan eventually deferred
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Serum valproic acid level = 79.23ug/ml
(optimum therapeutic level: 50-100 ug/ml) on
the 9th HD
Depakote 500mg/tab 1tab PO
BID continued
Problem #3: Catheter-related urinary tract
infection
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(+) dysuria on the 10th hospital day
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urinalysis : protein +1, leukocyte esterase
+1, blood +1, RBC 8.6, WBC 58.1,
epithelial cells 3.2, bacteria 457.0
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Cefuroxime (Zinnat) 250mg/tab BID to
complete 10days
Hospital Course
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11th hospital day
discharged improved and clinically
stable
Final Diagnosis
1.
2.
3.
4.
5.
Lithium Toxicity, S/P Hemodialysis
(4/10/07)
ARF prerenal, sec to volume depletion,
resolved, on top of CRI sec to
Hypertensive Nephrosclerosis
Bipolar Mood Disorder
Urinary Tract Infection, catheter-related
Hypertensive Atherosclerotic
Cardiovascular Disease
DISCUSSION
Lithium carbonate

“anti-manic” drug
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“mood-stabilizing” agent - mainstay of
treatment in patients with bipolar
affective (manic-depressive) disorder
Pharmacokinetics of lithium
Absorption
Virtually complete within 6-8 hours; peak
plasma levels in 30 minutes to 2 hours.
Distribution
In total body water; slow entry into
intracellular compartment. Initial volume
of distribution 0.5L/kg, rising to 0.70.9L/kg; some sequestration in bone. No
protein binding.
None
Metabolism
Excretion
Virtually entirely in urine. Lithium
clearance  20% of creatinine. Most of
the filtered lithium is reabsorbed in the
proximal tubule.
Pharmacokinetics of lithium

Steady-state plasma levels : 5 days at the
oral dose of 1200 to 1800 mg/day

Plasma half-life for lithium :
young adults - 18 hours
elderly - 36 hours
Pharmacodynamics of lithium
Mode of action (major possibilities)
(1) Effects on electrolytes and ion transport

closely related to Na in its properties, can
substitute for it in generating action potentials
(in Na-Na exchange across membranes)

it inhibits the latter process, i.e., Li-Na
exchange is gradually slowed after lithium is
introduced into the body.
Pharmacodynamics of lithium

at therapeutic concentration (around 1
mmol/L), it does not significantly affect the
Na/Ca exchange process or the Na/K
ATPase pump.
Pharmacodynamics of lithium
(2) Effects on neurotransmitters
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enhance some of the actions of serotonin
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decreases norepinephrine and dopamine
turnover: antimanic action
Pharmacodynamics of lithium

block the development of dopamine
receptor supersensitivity
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augment the synthesis of acetylcholine
by increasing choline uptake into nerve
terminals: mitigate mania
Pharmacodynamics of lithium
(3) Effects on second messengers

lithium inhibits several enzymes in the
recycling of membrane phosphoinositides
depletion of PIP2, the membrane
precursor of IP3 and DAG (important
second messengers for -adrenergic and
muscarinic neurons)
Pharmacodynamics of lithium

also inhibits norepinephrine-sensitive
adenylyl cyclase: antimanic and
antidepressant effects

affects G proteins such as their uncoupling
with vasopressin and TSH receptors:
polyuria and subclinical hypothyroidism
Lithium Intoxication


Lithium has a low therapeutic index
Mortality rate  25% with acute overdose
 9% in patients intoxicated
during maintenance therapy
(10% in this group suffer
permanent neurologic
damage) 1
1 Hansen, HE, Amdisen, A. Lithium intoxication. Report of 23 cases and review of 100 cases from the literature. Q J
Med 1978; 47:123.
Lithium Intoxication
The recommended therapeutic serum lithium
concentration:
(1) 0.6 to 1.2 meq/L - prophylactic control of
mania
(2) 1.0 to 1.5 meq/L - treatment of acute mania
*Blood drawn to monitor the serum lithium
concentration should be obtained 12 hours after
the last dose.
Lithium Intoxication
Serum lithium levels in lithium toxicity:
(1) Mild - 1.5 to 2.5 mEq/L
(2) Moderate - 2.5 to 3.5 mEq/L
(3) Severe - above 3.5 mEq/L
Lithium Intoxication
Adverse Effects and Complications
A. Neurologic and Psychiatric:
tremor (most common)
dysarthria
choreoathetosis
aphasia
ataxia
hyperactivity
marked mental confusion
Lithium Intoxication
Adverse Effects and Complications
B. Thyroid Function:
hypothyroidism
frank thyroid enlargement (reversible,
non-progressive)
Lithium Intoxication
Adverse Effects and Complications
C. Renal:
polydipsia
polyuria
nephrogenic diabetes insipidus (resistant to
vasopressin but responsive to amiloride)
chronic interstitial nephritis
minimal change nephropathy with nephrotic
syndrome (chronic lithium therapy)
Lithium Intoxication
Adverse Effects and Complications
D. Edema:
due to sodium retention (a frequent adverse
effect)
E. Cardiac:
bradyarrhythmias (depresses the sinus node)
T wave flattening often observed on ECG
hypotension
Lithium Intoxication
Adverse Effects and Complications
F. Gastrointestinal:
nausea
vomiting
diarrhea
G. Miscellaneous:
acne erruptions
folliculitis
leukocytosis
Lithium Intoxication
Prevention
 Monitor serum levels periodically

6 days are required for stabilization of the
plasma concentration after a change in
dosage
Lithium Intoxication
Prevention
 Reduce lithium dose in settings in which
its excretion is decreased
renal insufficiency induced by chronic
lithium therapy, older age, or acutely by
volume depletion, administration of
NSAIDS or ACE inhibitors
Lithium Intoxication
Treatment
 Adequacy of renal function and the degree of
intoxication
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Cessation of other drugs that may have additive
side effects (phenothiazine, haloperidol)2
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Patients with severe intoxication or significant
cardiac disease – ICU admission
2 Okusa, MD, Crystal, LJ. Clinical manifestations and management of acute lithium intoxication. Am J Med 1994; 97:383.
Lithium Intoxication
Treatment

Fluid repletion — restoration of sodium
and water balance in hypovolemic patients
lithium clearance

Serum Na must be monitored in patients
with nephrogenic diabetes insipidus
Lithium Intoxication
Treatment
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Combination of isotonic saline and urine
hypotonic losses
--- leads to hypernatremia, exacerbating
neurologic symptoms; a hypotonic solution
(half-isotonic saline) should be given2
2 Okusa, MD, Crystal, LJ. Clinical manifestations and management of acute lithium intoxication. Am J Med 1994;
97:383.
Lithium Intoxication
Treatment

Oral activated charcoal does not limit the
absorption of charged particles such as
lithium3-5

Whole bowel irrigation with polyethylene
glycol solution may be effective after acute
ingestion of sustained release lithium6
3 Favin, FD, Klein-Schwartz, W, Oderda, GM, et al. In vitro study of lithium carbonate absorption by activated charcoal. J Toxicol Clin Toxicol 1988; 26:443.
4 Linakis, JG, Lacouture, PG, Eisenberg MS, et al. Administration of activated charcoal or sodium polystyrene sulfonate (Kayexalate™) as gastric decontamination
for lithium intoxication: An animal model. Pharmacol Toxicol 1989; 65:387.
5 Linakis, JG, Eisenberg, MS, Lacouture, PG, et al. Multiple-dose polystyrene sulfonate in lithium intoxication: An animal model. Pharmacol Toxicol 1992; 70:38.
6 Smith, SW, Ling, LJ, Halstenson, CE. Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991; 20:536.
Lithium Intoxication
Treatment

Hemodialysis — treatment of choice for
severe lithium toxicity

lithium - the most dialyzable toxin known
low molecular weight, negligible
protein binding, volume of distribution
similar to that of water
Lithium Intoxication
lithium
clearance
Hemodialysis
Urine
Peritoneal
Dialysis
70 - 170
mL/min
10 - 40 mL/min
(due to
extensive
proximal
reabsorption)
15 mL/min
(due to low
blood flow)2
Lithium Intoxication
Treatment

Relatively slow lithium equilibration :
lithium diffusion (intracellular
extracellular)7 ----- rebound increase in
serum lithium levels after dialysis
7 Clendeninn, NJ, Pond, SM, Kaysen, G, et al. Potential pitfalls in the evaluation of the usefulness of hemodialysis for the removal of
lithium. J Toxicol Clin Toxicol 1982; 19:341.
Lithium Intoxication
Treatment

Minimizing rebound serum lithium
increase: extended dialysis of 8-12
hours1,2

Repeat dialysis : until serum lithium
remains less than 1 mEq/L for 6 to 8
hours after dialysis1,2
Lithium Intoxication
Treatment

9 hours of hemodialysis - removes 60% of
the total body lithium burden8

Hemodialysis of 6 hours – sufficient with
modern high surface area hemodialyzers9
8 Garella, S. Extracorporeal techniques in the treatment of exogenous intoxications. Kidney Int 1988; 33:735.
9 Winchester, JF. Lithium. In: Clinical Management of Poisoning and Drug Removal, 2d ed, Haddad LM, Winchester, JF (Eds), Saunders,
Philadelphia, 1990, pp 656-665.
Lithium Intoxication
Treatment

Hemodialysis is indicated if one or more of the
following is present1,2,8,9:
(1) A serum lithium level above 4 mEq/L, regardless
of the clinical status of the patient
(2) A serum lithium concentration above 2.5 mEq/L in
a patient who is markedly symptomatic or who has
renal insufficiency or other conditions that can limit
urinary lithium excretion (such as congestive heart
failure or cirrhosis)
(3) If serum lithium level is between 2.5 and 4 mEq/L
in an asymptomatic patient and is not anticipated
to be less than 0.6 mEq/L within 36 hours.
Good Day!