1. Lab Rounds Juliette Sacks CCFP-EM August 10, 2006

2. Case  L.W. 49 y.o. Female  3-4 day hx of: disorientation disorientation dysarthria dysarthria progressing ataxia progressing ataxia dysphagia dysphagia no vomiting no vomiting acute on chronic diarrhea acute on chronic diarrhea no hx of trauma, seizures or LOC no hx of trauma, seizures or LOC no drug or EtOH abuse no drug or EtOH abuse

3. Case cont’d  FHx: adopted  Collateral Hx: from pt’s daughter who is primary caregiver  NKDA  Meds: Lithium 120mg qhs Lithium 120mg qhs Zyprexa 10mg at noon and 20mg qhs Zyprexa 10mg at noon and 20mg qhs Zopiclone 22.5mg qhs Zopiclone 22.5mg qhs Propanolol 40mg at noon and 40mg qhs Propanolol 40mg at noon and 40mg qhs

4. Case cont’d:  PMHx/Sx: Bipolar disorder Bipolar disorder Chronic diarrhea Chronic diarrhea Multiple laparotomies with ileostomy Multiple laparotomies with ileostomy  Px: Tremulous, dysarthric Tremulous, dysarthric 118/56 61 18 36.7C 02 sats 97% on 3L by NP 118/56 61 18 36.7C 02 sats 97% on 3L by NP Chest clear Chest clear CVS N CVS N Abdo distended but nontender Abdo distended but nontender CN intact, clonus, incr. DTRs, generalized muscle weakness CN intact, clonus, incr. DTRs, generalized muscle weakness

5. Results  Na 133, K 3.9  Troponin, CK, LFTs N, Cr 100  EtOH, APAP, ASA negative  Hgb 136, WBC 5.2, Plt 272  Li 3.96  EKG: Anterior T wave depression  AXR: ++ dilated loops of large bowel with air fluid levels; no free air  CT head: N

6. Lithium  Commonly used to treat depressive and bipolar affective disorder  Low therapeutic index  Intoxication seen with acute and chronic use  Multisystem dysfunction with intoxication  T1/2: 29h

7. Lithium Dosing  Therapeutic indices: 0.6 - 1.2 mEq/L (prophylactic control) 0.6 - 1.2 mEq/L (prophylactic control) 1.0 - 1.5 mEq/L (acute mania) 1.0 - 1.5 mEq/L (acute mania)  Oral administration only  Absorbed from GIT 2-4h postingestion  Minimally protein bound  Steady state plasma levels achieved in 5d

8. Lithium Excretion  Excreted through the kidneys therefore dosing is dependent on: renal function, volume status, age  Reabsorbed in the proximal tubule  20% is excreted in urine  Li reabsorption follows Na reabsorption but may be reabsorped preferentially to counter Na losses in volume depleted pts

9. More about Li…  Lithium alters the cation transport across cell membranes in nerve and muscle cells  Influences reuptake of serotonin and epinephrine  Inhibits second messenger systems involving phosphatidylinositol cycle  Inhibits postsynaptic D2 receptor sensitivity

10. Factors predisposing to Li Toxicity (courtesy of Tintinalli)  Renal failure  Volume depletion  Hyperthermia/NMS  Infection  CHF  Diabetes mellitus  Gastroenteritis  Surgery  Cirrhosis  Decreased Na intake

11. Drug interactions with Li (courtesy of Tintinalli)  Major: Haloperidol  Moderate: ACEI- Methyldopa ACEI- Methyldopa Anorexiants- Metronidazole Anorexiants- Metronidazole Benzodiazepines- NSAIDs Benzodiazepines- NSAIDs Caffeine- Phenytoin Caffeine- Phenytoin CCB- Tetracyclines CCB- Tetracyclines Carbamazepine- Theophyllines Carbamazepine- Theophyllines Clozapine- Thiazide diuretics Clozapine- Thiazide diuretics Fluoxetine- Urea Fluoxetine- Urea Iodide salts- Succinylcholine Iodide salts- Succinylcholine Loop diuretics- Nondepolarizing muscle paralytics Loop diuretics- Nondepolarizing muscle paralytics - Phenothiazines- TCAs Minor: Carbonic anhydrase inhibitors, sympathomimetics

12. Clinical Manifestations  GI: Nausea and vomiting Nausea and vomiting Diarrhea Diarrhea  CNS: Weakness and fatigue Weakness and fatigue Lethargy and confusion Lethargy and confusion Tremor (coarse, irregular) Tremor (coarse, irregular) Ataxia Ataxia Seizures Seizures Neuromuscular excitability/fascicular twitching Neuromuscular excitability/fascicular twitching Stupor Stupor Coma Coma

13. Clinical Manifestations 2  Renal: May cause acute renal failure May cause acute renal failure Decreased CrCl Decreased CrCl Nephrogenic diabetes insipidus Nephrogenic diabetes insipidus With polyuria and polydipsiaWith polyuria and polydipsia  CV: Hypotension Hypotension Sinus bradycardia Sinus bradycardia Ventricular dysrhythmias (including complete heart block) Ventricular dysrhythmias (including complete heart block) EKG findings in chronic Li use: depressed ST segments and T wave flattening/inversion; QTc prolongation EKG findings in chronic Li use: depressed ST segments and T wave flattening/inversion; QTc prolongation CV collapse and respiratory failure CV collapse and respiratory failure

14. Clinical Manifestations 3  Neurological sequelae: 10% risk of permanent damage 10% risk of permanent damage Truncal and gait ataxia Truncal and gait ataxia Nystagmus Nystagmus Short term memory deficits Short term memory deficits Dementia Dementia

15. Lithium Toxicity (chronic ingestion) Level s[Li] mEq/L Clinical Features Treatment Grade 1 1.5-2.5NauseaVomitingTremorHyperreflexiaAtaxiaAgitation Muscular Weakness Hydration (x 4-6h) Kayexalate

16. Level s[Li] mEq/L Clinical Manifestations Treatment Grade 2 2.5-3.5StuporRigidityHypertoniaHypotensionHydration,Kayexalate, +/- dialysis Grade 3 >3.5ComaSeizures Myoclonus Collapse Hemodialysis

17. Treatment  ABCs  iv fluids, cardiac monitoring  EKG  Identification of agents and amount ingested (get the pill bottles if possible)  Beware sustained release preparations!  Rule out co-ingestions  Serum Li with 2 nd sLi 2h later  Lytes, Cr, BUN, tox screen  Hx and Px  +/- CT head depending on neurological presentation

18. Treatment cont’d  Restore fluid volume and correct electrolyte abnormalities  Oral charcoal does not bind Li but may bind other drugs taken  Whole bowel irrigation may be considered especially with SR preparations If given within 1h of ingestion may remove 60% of drug If given within 1h of ingestion may remove 60% of drug

19. Hemodialysis  For severe lithium toxicity  When? s[Li] >4.0 mEq/L regardless of clinical status s[Li] >4.0 mEq/L regardless of clinical status s[Li] >2.5 mEq/L with symptoms; with renal insufficiency or other factor(s) that limit Li excretion s[Li] >2.5 mEq/L with symptoms; with renal insufficiency or other factor(s) that limit Li excretion s[Li] 2.5-4.0 mEq/L asymptomatic patient but who is not expected to have s[Li] <1.0mEq/L w/i 36h s[Li] 2.5-4.0 mEq/L asymptomatic patient but who is not expected to have s[Li] <1.0mEq/L w/i 36h

20.  Goal: decrease sLi levels to <1 mEq/L within 6-8h post dialysis  Li clearance of 70-170 ml/min  Use of continuous venovenous hemofiltration reduces the post dialysis rebound in sLi level  Addition of bicarbonate to dialysate may improve Li extraction

21. Adjuncts  Consult renal service  Consult psychiatric service  Consult poison control/toxicology service

22. What about L.W.?  After 4h of fluid replacement, Li level was 3.53 but she remained symptomatic  Sent for hemodialysis  No role for gastric lavage, whole bowel irrigation  Serial Li levels and >1 course of dialysis  Persistent neurological deficits despite s[Li] of 1.0-1.1 mEq/L  Lithium discontinued; replaced by olanzepine