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MEDICAL GRANDROUNDS

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

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MEDICAL GRANDROUNDS

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  1. MEDICAL GRANDROUNDS Mary Antoniette M. Tan, M.D. First Year Resident

  2. 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

  3. Identifying Data CF 77 years old Female Filipino Separated Education Graduate Homebound

  4. Chief Complaint Decreased sensorium

  5. 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

  6. History of Present Illness 1 month PTA ----- persistence of paranoia and irritability (+) poor appetite (+) sleeping problems consult with a private psychiatrist, advised admission

  7. 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

  8. History of Present Illness 4 days PTA ----- (+) right hand tremors more withdrawn 3 days PTA ----- tremors more generalized and pronounced (+) episodes of passing out loose to watery stools (+) very poor oral intake

  9. 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.

  10. Past Medical History • (+) HPN x 15 years on Valsartan 40mg OD and ISMN 30mg OD • (-) DM, asthma

  11. Personal/Social History • (-) smoking • (-) alcoholic beverage drinking

  12. Family History • (-) Hypertension, DM, asthma, cancer • (-) Psychiatric illness

  13. Review of Systems • (-) 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

  14. Physical Examination

  15. Neurologic Examination • 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

  16. Diagnostics done at the ER • CBC, Na, K, Ca, Mg : Normal • BUN = 27, creatinine = 2.0 • Chest xray : clear lung fields, left ventricular enlargement, atherosclerotic aorta • 12-L ECG : Bifascicular block (first degree AV block and left anterior hemiblock)

  17. Diagnostics done at the ER • 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 • Urinalysis : leukocyte esterase +2, blood +3, RBC 32.1, WBC 6.3 • Obtained via foley catheterization; initial output = 130cc in 8 hrs • Serum lithium : 2.57 mmol/L (NV 0.5-1.5)

  18. 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

  19. ADMITTING IMPRESSION • Lithium Toxicity • ARF prerenal, sec to volume depletion, on top of CRI sec to Hypertensive Nephrosclerosis • Bipolar Mood Disorder • Hypertensive Atherosclerotic Cardiovascular Disease

  20. Problem #1: Tremors, altered sensorium, anorexia, diarrhea (elevated serum lithium level + CRI) • lithium level: 2.57 mmol/L (NV 0.5-1.5) • referral to Nephrology • hydration with PNSS at 150cc/hour

  21. 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

  22. Problem #2: Restlessness and agitation • attributed to patient’s bipolar mood disorder • 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)

  23. Problem #2: Restlessness and agitation • 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

  24. Problem #2: Restlessness and agitation • MRI with gadolinium suggested instead; no further behavioral changes noted on the 4th HD cranial CT scan eventually deferred • 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

  25. Problem #3: Catheter-related urinary tract infection • (+) dysuria on the 10th hospital day • urinalysis : protein +1, leukocyte esterase +1, blood +1, RBC 8.6, WBC 58.1, epithelial cells 3.2, bacteria 457.0 • Cefuroxime (Zinnat) 250mg/tab BID to complete 10days

  26. Hospital Course • 11th hospital day discharged improved and clinically stable

  27. Final Diagnosis • 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

  28. DISCUSSION

  29. Lithium carbonate • “anti-manic” drug • “mood-stabilizing” agent - mainstay of treatment in patients with bipolar affective (manic-depressive) disorder

  30. Pharmacokinetics of lithium

  31. 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

  32. 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.

  33. 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.

  34. Pharmacodynamics of lithium (2) Effects on neurotransmitters • enhance some of the actions of serotonin • decreases norepinephrine and dopamine turnover: antimanic action

  35. Pharmacodynamics of lithium • block the development of dopamine receptor supersensitivity • augment the synthesis of acetylcholine by increasing choline uptake into nerve terminals: mitigate mania

  36. 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)

  37. 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

  38. 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 1Hansen, HE, Amdisen, A. Lithium intoxication. Report of 23 cases and review of 100 cases from the literature. Q J Med 1978; 47:123.

  39. 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.

  40. Lithium Intoxication Serum lithium levels in lithium toxicity: • Mild - 1.5 to 2.5 mEq/L • Moderate - 2.5 to 3.5 mEq/L • Severe - above 3.5 mEq/L

  41. Lithium Intoxication Adverse Effects and Complications A. Neurologic and Psychiatric: tremor (most common) dysarthria choreoathetosis aphasia ataxia hyperactivity marked mental confusion

  42. Lithium Intoxication Adverse Effects and Complications B. Thyroid Function: hypothyroidism frank thyroid enlargement (reversible, non-progressive)

  43. 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)

  44. 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

  45. Lithium Intoxication Adverse Effects and Complications F. Gastrointestinal: nausea vomiting diarrhea G. Miscellaneous: acne erruptions folliculitis leukocytosis

  46. Lithium Intoxication Prevention • Monitor serum levels periodically • 6 days are required for stabilization of the plasma concentration after a change in dosage

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