1 急診雜誌討論會 題目 : 鋰鹽中毒 來源 : 1. Taiwan Medical Journal Vol.50 No.7 2. Up To Date 報告者 : Stanley. Wang. 地點 : 急診討論室. 署立台中醫院. 時間 :

2 Lithium---anti-manic agent Bipolar disorders: Oral: mg/day in 3-4 divided doses or mg/day in two divided doses of extended release Note: Monitor serum concentrations and clinical response (efficacy and toxicity) to determine proper dose. ( 6th day prior to medication ). Do not confuse mEq (milliequivalent) with mg (milligram). Note: 300 mg lithium carbonate or citrate contain 8 mEq lithium. Dosage should be written in mg (milligrams) to avoid confusion. Ligilin ( lethonate ) 300 mg/cap. Therapeutic: 0.6 – 1.2 mEq/L.

3 General consideration (1) Lithium poisoning may be acute, acute-on-chronic, or chronic. The symptoms and signs of toxicity differ based upon the total body burden of lithium and the rate of onset of toxicity. Elderly patients are at higher risk for lithium toxicity due to both a lower glomerular filtration rate and a reduced volume of distribution (secondary to reductions in lean body mass and total body water). Lithium toxicity can also occur with minor declines in renal function (eg, from nephrotoxic medications) or from dehydration for any reason (eg, vomiting, diarrhea, fever).

4 General consideration (2) Patients with acute lithium toxicity often present with symptoms of nausea, vomiting, and diarrhea; neurologic findings develop late in acute poisoning. Patients with chronic lithium toxicity often present with neurologic symptoms and signs. Neurologic findings can include sluggishness, ataxia, confusion or agitation, and neuromuscular excitability. Severe poisoning can lead to seizures, nonconvulsive status epilepticus, and encephalopathy.

5 Complex partial status (nonconvulsive) epilepticus Complex partial status (nonconvulsive) epilepticus is characterized by continuous or repeated episodes of focal motor, sensory, or cognitive symptoms with impaired consciousness, and should be considered in the differential diagnosis of acute confusional states. Other symptoms, such as automatisms and behavioral disturbances, may also occur.

6 General consideration (3) The differential diagnosis for lithium poisoning includes serotonin syndrome and neuroleptic malignant syndrome. Serum lithium concentrations can be useful for determining the severity of an overdose or the need for hemodialysis and should be obtained in any patient with suspected toxicity. However, lithium concentrations often do not correlate with clinical signs of toxicity.

7 General consideration (4) Restoration of sodium and water balance in hypovolemic patients with lithium toxicity is essential to maximize lithium clearance. Gastrointestinal losses are replaced with isotonic (0.9 percent) saline. Lithium is readily dialyzable due to its low molecular weight, negligible protein binding, and small volume of distribution. Therefore, hemodialysis is the treatment of choice for severe lithium toxicity.

8 Case presentation S: Vomiting & diarrhea with stool incontinence 8 hrs post ingestion of 49 tablets of lithium this morning. History of affective disorders. O: TPR: 36.8 C/80/20, BP: 130/82 mmhg. Lab: Lithium carbonate: 4.58 mEq/L, BUN/Cr: 8.0/1.1, Na/K: 142/2.4. EKG: Sinus bradycardia with QT prolong. A: Lithium intoxication. P: Emergent hemo-dialysis. Patient discharged 6 days later & regular FU at Psy. OPD.

9 Lithium -- Mechanism Treat & prevent attack of manic-depressive disorders. Peak serum level: 30’-2 hrs post oral intake. Complete absorption: 6 – 8 hrs. Stable serum concentration: 5-6 days. Serum level best be checked 12 hrs post ingestion & 3-4 days later. Be cautious in P’t with poor renal function. ( renal excretion ) Prone to lithium intoxication: DM, Hypertension, Renal failure, Old age, Low sodium diet, NSAIDs or Diuretics use. Side effect: Early: Thirsty, Increased urine output, G-I upset, Loose stool, Tired, Hand tremor, Muscle twitching. Maintenance dose: Hand tremor, BW gain, Thyroid enlargement, edema, acne. Single H.S dose to reduce side effect.

10 Pharmacology & cellular Toxicology Lithium affects two intracellular signaling pathways, inositol monophosphate and glycogen synthase kinase-3. Lithium decreases intracellular inositol, which may be a mechanism for mood stabilization. Lithium also inhibits glycogen synthase kinase-3, a component of diverse signaling pathways involved in energy metabolism, neuroprotection, and neuroplasticity. Lithium has a narrow therapeutic index; a large proportion of patients on chronic lithium therapy experience at least one episode of toxicity during treatment. ( 0.6 – 1.2 mEq/L ) The highest intracellular lithium levels are found in the brain and the kidneys.

11 Inositol monophosphate Inositol play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation. Inositol is a substance produced by the human body and is involved with fat and cell metabolism. Adequate amounts of Inositol Monophosphate are claimed to be potentially beneficial for: Diabetic nerve disorders Kidney failure. Low birth weight infants with respiratory distress syndrome Multiple sclerosis. Depression. Obsessive compulsive disorder. Panic disorders.

12 Lithium intoxication – S/S Mild: Sleepy, Proximal muscle weakness, Impaired memory, G-I: nausea, vomiting, diarrhea. Moderate: Neurotoxic: Delirium, Convulsion, Coma, Incontinence, hyper- reflexia, Fasciculation, Parkinson-like s/s : Ataxia. Un-coordination. Severe: Nephrotoxic: Nocturia, Distal tubular acidosis, Impaired RFT. Cardiotoxic: ST-T change, QT prolong, Flat T Conduction delay, Hypotension. Acute intoxication– Less CNS depression.

13 Long-term neurologic sequelae (1) In some cases, neurologic complications persist despite lithium removal by hemodialysis. The syndrome of irreversible lithium effectuated neurotoxicity (SILENT) consists of prolonged neurologic and neuropsychiatric symptoms following lithium toxicity. In typical cases of SILENT, neurologic toxicity develops along with an elevated lithium concentration, but symptoms persist despite successful removal of the drug.

14 Long-term neurologic sequelae (2) Cerebellar dysfunction, extrapyramidal symptoms, brainstem dysfunction, and dementia can develop as part of SILENT (syndrome of irreversible lithium effectuated neurotoxicity ). Other neurologic sequelae may include nystagmus, choreoathetoid movements, myopathy, and blindness. A review of 90 published cases identified cerebellar dysfunction as the most common sequelae, and proposed that demyelination at multiple sites in the CNS may be the cause. SILENT can continue for months and in rare cases effects persist for years.

15 Lithium intoxication - Diagnosis History: Psychiatry ( Mania ) P’t with conscious change + S/S of lithium intoxication. Serum level: Therapeutic: 0.6 – 1.2 mEq/L. Intoxication: Mild- Moderate: 1.5 – 2.5 mEq/L. Severe: 2.5 – 3.0 mEq/L. Lethal dose: 3.0 – 4.0 mEq/L. EKG, ABG, Biochemistry, BR.

16 Lithium intoxication - Tx Hydration and electrolyte balance, beware of hypernatremia. Gastric lavage if ingested within 1 hour. Charcot is useless ( poor absroption ). Block proximal tubule re-absorption: Sod. Bicarbonate, Diuretics, Amino-phylline. Moderate to severe intoxication with conscious change – Hemo-dialysis: hrs ( indication: Li level >4mEq/L ) Goal: Li level < 1 mEq/L 8 hrs later.

17 Nephrogenic diabetes insipidus NDI is a known complication of chronic lithium poisoning. In patients on chronic lithium therapy who are suspected of concomitant NDI, the serum sodium concentration should be followed closely, particularly in patients receiving IV hydration and those with altered mentation who may not drink in response to thirst. In patients admitted with chronic lithium toxicity, measure the serum sodium concentration every 6 to 12 hours for the first 24 to 48 hours. Care must be taken to avoid hypernatremia from IV hydration in patients with inadequate free water intake.

18 H.D for lithium intoxication (1) Lithium is readily dialyzable due to its low molecular weight, negligible protein binding, and small volume of distribution. Therefore, hemodialysis is the treatment of choice for severe lithium toxicity. The appropriate indications for the treatment of lithium poisoning with hemodialysis remain controversial. We recommend treatment with hemodialysis for lithium poisoning in the following settings regardless of the nature of the ingestion (ie, acute, acute-on-chronic, or chronic) :

19 H. D for lithium intoxication (2) The serum lithium concentration is > 4 mEq/L (4 mmol/L), regardless of the clinical status of the patient. Lithium concentrations above 4 mEq/L represent a large total body lithium burden and suggest a window in which hemodialysis can remove substantial amounts of toxin. The serum lithium concentration is > 2.5 mEq/L (2.5 mmol/L) and the patient manifests signs of significant lithium toxicity (eg, seizures, depressed mental status), has renal insufficiency or other conditions that limit lithium excretion, or suffers from an illness that would be exacerbated by aggressive IV fluid hydration (eg, decompensated heart failure).

20 H.D for lithium intoxication (3) Lithium clearance with hemodialysis ranges from 70 to 170 mL/min, compared to normal renal clearance of 10 to 40 mL/min (due to extensive reabsorption of lithium in the proximal tubules), and only 15 mL/min with peritoneal dialysis. Lithium equilibrates slowly between the extracellular and intracellular fluids. As a result, a rebound increase in serum lithium levels occurs after the cessation of hemodialysis, as intracellular lithium diffuses into the extracellular space. Continued gastrointestinal drug absorption may contribute to the rebound effect. Therefore, it is generally recommended that a serum lithium concentration be measured six hours after hemodialysis to confirm that levels are decreasing.

21 H.D for lithium intoxication (4) Some experts recommend extending the duration of hemodialysis to minimize the rebound phenomenon and repeating dialysis as necessary until the serum lithim level remains < 1 mEq/L (1 mmol/L) for six to eight hours after treatment. Nine hours of hemodialysis removes approximately 60 percent of the total lithium stores. Some authors suggest that at least two sessions of hemodialysis are required for adequate treatment. However, in most cases, unless serum lithium concentrations are extremely high, one session of hemodialysis is usually sufficient. We suggest obtaining consultation with a medical toxicologist or poison control center if additional hemodialysis treatment may be needed.

22 Lemat for H.D., Chebic no charcot No Charcot: Corrosive agent, Hydrocarbon, Ethanol ( Methanol ), Boric acid, Metal ion, Cyanide. H.D: Lithium, Ethylene glycol, Methanol, Aspirin, Theophylline.

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