A reappraisal of the role of fever in the occurrence of neurological sequelae following lithium intoxication: a systematic review.

INTRODUCTION: We aimed to review cases of Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) characterized by neurological sequelae following acute lithium toxicity and to explore whether cerebellar sequelae are more frequent in cases presenting with fever and/or infection. AREAS COVERED: Case reports were identified from: (i) 6 reviews published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search. EXPERT OPINION: We identified 123 SILENT cases published from 1965 to 2019, in which cerebellar sequelae were observed in an overwhelming proportion (79%). SILENT may occur at any time during lithium treatment. This complication is most frequently observed during routine lithium treatment, with fewer than 10% of cases occurring after accidental or intentional overdoses. SILENT may occur even when lithium plasma levels are within the therapeutic range: 63% of cases had lithium plasma level <2.5 mEq/l (low/mild toxicity). Fever and/or infection were reported in nearly half of the patients (48%). The likelihood of presenting with cerebellar vs. other neurological sequelae was independently increased by elevated plasma lithium level (≥ 2.5 mEq/l) and by a history of fever and/or infection. Lithium users should be warned of the need to consult in case of fever to adjust their lithium dosage.

Case of Severe Acute-on-Chronic Lithium Intoxication with 8.6 mmol/l and Prompt Hemodialysis.

Lithium has been the gold standard in the long-term treatment of bipolar disorder for more than 40 years 1. Due to a narrow therapeutic index lithium intoxication still is a common but potentially avoidable clinical problem 2. The possibility of SILENT-syndrome (syndrome of irreversible lithium-effectuated neurotoxicity) illustrates that prevention and optimal treatment of lithium intoxication is vitally important 3.

Early hemoperfusion for emergency treatment of carbamazepine poisoning.

OBJECTIVES: To investigate the clinical value of early hemoperfusion (HP) in emergency treatment of carbamazepine (CBZ) poisoning. METHODS: 104 patients with acute CBZ poisoning treated from August 2004 to October 2015 in the Emergency Department were reviewed. Patients were categorized into three groups: group A, who received HP treatment in the Emergency Department; group B, who received HP treatment in the blood purification room; and group C, who did not received HP treatment. Pharmacokinetic parameters of CBZ and remission of complications were compared among the three groups. RESULTS: Both groups A and B had lower time to peak, area under curve and maximum concentration values than group C (P<0.05), and these kinetics indexes were significantly lower in group A than in group B (P<0.05). The mean retention times were 0.85±0.08, 1.20±0.15 and 2.52±0.29days in the three groups, respectively, and were significantly lower value in group A than in group B (P<0.05). The incidences of respiratory depression and seizure in group A were significantly lower than those of groups B and C (P<0.05). Group A had significantly higher Glasgow coma scale (GCS) scores at 4h after admission than the other two groups (P<0.05), and group B had significantly higher GCS scores than group C at 6h after admission (P<0.05). CONCLUSIONS: Initiation of HP in the early treatment stage of CBZ poisoning upon admission to an emergency department can significantly reduce the plasma concentration and retention period of CBZ, relieve the symptoms and shorten the overall treatment period.

Valproic Acid Overdose Review of a Case With Electrocardiographic Changes.

BACKGROUND: Valproic acid (VPA) is increasingly used to treat a variety of medical disorders, such as seizures, psychiatric disorders, and headaches. Therefore, accidental and intentional ingestions with valproic acid are increasing. OBJECTIVES: A case is presented in an adolescent with ischemic electrocardiographic changes after an acute overdose with VPA. DISCUSSION: Major features of a valproic acid overdose include respiratory depression, progressive coma, hepatotoxicity, thrombocytopenia, and hemodynamic instability. Electrocardiographic abnormalities usually consist of tachycardia and nonspecific changes. Supportive care is indicated in most overdoses and involves the monitoring and correction of electrolyte abnormalities, coagulopathies, and acid-base imbalances. Treatment may include activated charcoal, naloxone, l-carnitine, and extracorporeal detoxification. CONCLUSIONS: Valproic acid overdose is a relatively rare and electrocardiographic changes usually consist of tachycardia and nonspecific changes, but ischemic changes may occur and usually transient and require only recognition.

Lithium Toxicity in a Pregnant Woman.

Lithium is recommended in bipolar disorder and can be accompanied by significant toxicity in pregnant women. A 25-year-old single-gestation pregnant woman (28 weeks) was referred with suspicion of lithium toxicity. Serum lithium was 2.1 meq/L. Despite conservative therapy with intravenous fluids, lithium concentration increased to 5.0 meq/L 6 hr after admission mandating an emergent haemodialysis during which foetal heart rate decreased to 90 bpm. The gynaecologist ordered termination of pregnancy while the mother was still on haemodialysis. Caesarean section was carried out, but the born baby had an apgar of 2 and died. Autopsy findings of the foetus revealed a cord blood lithium concentration of 4.8 mEq/L with no physical abnormalities. Although the foetus had the signs/symptoms of distress, continuation of haemodialysis could probably have saved it as it saved its mother's life. In lithium toxicity in a pregnant woman, it is reasonable to continue haemodialysis even with the signs and symptoms of foetal distress. In similar situations, emergency haemodialysis instead of immediate caesarean section should be considered.

Lithium Poisoning.

Lithium is a commonly prescribed treatment for bipolar affective disorder. However, treatment is complicated by lithium's narrow therapeutic index and the influence of kidney function, both of which increase the risk of toxicity. Therefore, careful attention to dosing, monitoring, and titration is required. The cause of lithium poisoning influences treatment and 3 patterns are described: acute, acute-on-chronic, and chronic. Chronic poisoning is the most common etiology, is usually unintentional, and results from lithium intake exceeding elimination. This is most commonly due to impaired kidney function caused by volume depletion from lithium-induced nephrogenic diabetes insipidus or intercurrent illnesses and is also drug-induced. Lithium poisoning can affect multiple organs; however, the primary site of toxicity is the central nervous system and clinical manifestations vary from asymptomatic supratherapeutic drug concentrations to clinical toxicity such as confusion, ataxia, or seizures. Lithium poisoning has a low mortality rate; however, chronic lithium poisoning can require a prolonged hospital length of stay from impaired mobility and cognition and associated nosocomial complications. Persistent neurological deficits, in particular cerebellar, are described and the incidence and risk factors for its development are poorly understood, but it appears to be uncommon in uncomplicated acute poisoning. Lithium is readily dialyzable, and rationale support extracorporeal treatments to reduce the risk or the duration of toxicity in high-risk exposures. There is disagreement in the literature regarding factors that define patients most likely to benefit from treatments that enhance lithium elimination, including specific plasma lithium concentration thresholds. In the case of extracorporeal treatments, there are observational data in its favor, without evidence from randomized controlled trials (none have been performed), which may lead to conservative practices and potentially unnecessary interventions in some circumstances. More data are required to define the risk-benefit of extracorporeal treatments and their use (modality, duration) in the management of lithium poisoning.

[Role of hemodialysis in the management of acute lithium intoxication]. / Place de l'hémodialyse dans la prise en charge de l'intoxication aiguë au lithium.

We report the case of a 47-years old patient, traited with lithium for manic-depressive psychosis over a period of twenty and admitted to hospital with a disorder of consciousness after suicide attempt with lithium overdose (ingestion of 30 tablets of Téralithe(®) LP 400, delayed action galenic forms corresponding to 12 g of lithium carbonate), clinically improved after three hemodialysis sessions. This study illustrates the therapeutic role of hemodialysis in voluntary intoxications with extended release lithium even a week after the ingestion and the therapeutic insufficiency of a single hemodialysis session.

Antihypertensive therapy in patients on chronic lithium treatment for bipolar disorders.

Bipolar disorders are chronic conditions treated with lithium, which exerts deleterious effects on the kidney, among which nephrogenic diabetes insipidus, tubular acidosis and ultimately chronic kidney disease. Conversely, drugs that alter renal function can modify its serum levels and lead to the potentially fatal lithium intoxication. A search in the main library databases from 1975 to 2015 to identify interactions between antihypertensive drugs and lithium using the Population Intervention Comparison Outcome strategy provided only 30 reports of lithium intoxication. A regression analysis showed that the severity of lithium intoxication was significantly predicted by female, age, and use of certain classes of antihypertensive agents. A model including certain albeit not all diuretics and/or inhibitors of the renin-angiotensin system, but not age, serum lithium or creatinine levels at baseline and/or on admission to the hospital, predicted lithium toxicity. The true incidence of lithium intoxication is unknown but probably low, albeit underestimated. Nonetheless, in patients treated with lithium, monitoring of the serum lithium levels and clinical conditions is mandatory after the introduction of antihypertensive drugs, as diuretics and renin-aldosterone system inhibitors.

Lithium overdose: early hemodialysis is the key!

A 65-year-old gentleman was referred to our hospital with encephalopathy and renal failure. His medications included lithium for the treatment of bipolar disorder. The clinical examination and the laboratory investigations that followed revealed findings classical of lithium overdose. The patient was successfully managed and discharged from the hospital on Day 9 of admission. Clinicians should be aware of this rather unusual and relatively rare differential cause of acute on chronic renal failure with encephalopathy.

Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.

The Extracorporeal Treatments in Poisoning Workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments in poisoning. Here, the EXTRIP workgroup presents its recommendations for lithium poisoning. After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations. In total, 166 articles met inclusion criteria, which were mostly case reports, yielding a very low quality of evidence for all recommendations. A total of 418 patients were reviewed, 228 of which allowed extraction of patient-level data. The workgroup concluded that lithium is dialyzable (Level of evidence=A) and made the following recommendations: Extracorporeal treatment is recommended in severe lithium poisoning (1D). Extracorporeal treatment is recommended if kidney function is impaired and the [Li(+)] is >4.0 mEq/L, or in the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of the [Li(+)] (1D). Extracorporeal treatment is suggested if the [Li(+)] is >5.0 mEq/L, significant confusion is present, or the expected time to reduce the [Li(+)] to <1.0 mEq/L is >36 hours (2D). Extracorporeal treatment should be continued until clinical improvement is apparent or [Li(+)] is <1.0 mEq/L (1D). Extracorporeal treatments should be continued for a minimum of 6 hours if the [Li(+)] is not readily measurable (1D). Hemodialysis is the preferred extracorporeal treatment (1D), but continuous RRT is an acceptable alternative (1D). The workgroup supported the use of extracorporeal treatment in severe lithium poisoning. Clinical decisions on when to use extracorporeal treatment should take into account the [Li(+)], kidney function, pattern of lithium toxicity, patient's clinical status, and availability of extracorporeal treatments.

Evolving Electrocardiographic Changes in Lamotrigine Overdose: A Case Report and Literature Review.

Lamotrigine overdose usually follows a benign pattern, and the majority of cases reported involve a co-ingestant. Prior reports have suggested the possible use of intravenous lipid emulsion in cases of severe sodium channel blockade. We describe the electrocardiographic changes in a massive lamotrigine overdose treated with intravenous lipid emulsion. A 36-year-old male with bipolar disorder ingested 13.5 g of lamotrigine in a suicidal attempt. The lamotrigine level was 78.0 µg/mL. Comprehensive drug screen was negative for all screened compounds. The electrocardiogram demonstrated a prolonged QRS complex and signs suggestive of sodium channel blockade. Refractory to treatment with sodium bicarbonate was treated with intravenous lipid emulsion, with immediate resolution of the electrocardiographic changes. Lamotrigine inhibits the voltage-gated sodium channel opening, attenuating the release of excitatory neurotransmitters. Cardiac intraventricular conduction could be delayed in cases of lamotrigine overdose resulting in QRS and QTc prolongation and R waves >3 mm in leads I and aVR. A potential role for intravenous lipid emulsion therapy has been described in patients with toxic levels of lamotrigine and electrocardiographic changes refractory to the treatment with sodium bicarbonate. Intravenous lipid emulsion has been successfully used in the treatment of lamotrigine cardiac toxicity.

Peripheral mononeuropathy associated with valproic acid poisoning in an adult patient.

OBJECTIVE: To present the case of axillary nerve neuropathy associated with valproic acid (VPA) poisoning. CASE REPORT: A 26-year-old man was hospitalized because of a suicide attempt with VPA overdose. Toxicology analysis revealed high serum VPA level (2,896 µmol/L; therapeutic range: 350 - 690 µmol/L). Three days after admission, the patient complained of weakness in his right arm. Neurological examination revealed weakness of flexion and abduction of the right arm and loss of sensation in the skin over the lateral upper right arm. A nerve conduction velocity test was normal in the ulnar, radial, median, musculocutaneous, and suprascapular nerves. Compound muscle action potential showed reduced amplitude and prolonged latencies in the right axillary nerve taken from Erb's point and absent taken from distal stimulation point. Right axillary nerve paresis was diagnosed and the patient underwent a physical therapy program, which resulted in gradual recovery. DISCUSSION: In the presented case, other possible causes of neuropathy were excluded by medical history, laboratory and radiological tests, and clinical course of the disease.The temporal relationship between the VPA poisoning and the occurrence of neuropathy supports the hypothesis of a VPA-caused axillary neuropathy. According to the Naranjo's Adverse Drug Reaction (ADR) Probability Scale, VPA-induced neuropathy was rated "probable". CONCLUSION: VPA-induced neuropathy may be a serious ADR, but it is potentially preventable and reversible. Thus, clinicians should be aware of this rare ADR.

Successful treatment of severe carbamazepine toxicity with 5% albumin-enhanced continuous venovenous hemodialysis.

Carbamazepine overdose is a common, toxic ingestion, manifesting as central nervous system (CNS) and respiratory depression. Carbamazepine is highly protein bound with a large volume of distribution and, therefore, inefficiently removed by conventional hemodialysis. We describe the successful use of continuous venovenous hemodialysis (CVVHD) with 5% albumin enhanced dialysate in a 31-year-old female who developed CNS depression, hypotension and respiratory failure, requiring mechanical ventilation, after an intentional ingestion of approximately 10 g of extended release carbamazepine, Tegretol CR(®). The peak drug level was 26 mcg/ml, therapeutic range 8-12 mcg/ml, with toxicity often developing a level above 15 mcg/ml. Normal half-life of drug elimination is 35-60 h in carbamazepine naïve patients. In contrast, with albumin-enhanced dialysis, we observed a drug half-life of 18 h. She was extubated on day two and was transferred to inpatient psychiatry by day 3 without significant neurologic sequelae. In vitro studies have been done with bovine blood demonstrating significant carbamazepine removal using CVVHD with albumin-enhanced dialysate. There has been very limited experience using albumin-enhanced CVVHD in an adult patient with carbamazepine toxicity.

The toxic trio: valproic acid, lithium, and carbamazepine.

Patients with altered mental status and seizure or psychiatric disease often present with an unclear medication history. Commonly prescribed medications include valproic acid (VPA), lithium (Li), or carbamazepine (CZN) of which the regional poison center (RPC) often recommends obtaining these serum concentrations. Regularly ruling out supratherapeutic concentrations without a known history of ingestion may help direct care. Cases from the RPC coded as VPA, Li, and CZN, from January 1, 2006 to December 31, 2008, were searched. All patients with supratherapeutic concentrations (VPA >100 µg/mL, Li >1.2 mEq/L, and CZN >12 µg/mL) were evaluated for the following criteria: (1) those with altered mental status and an unclear history of seizure or psychiatric disorder and (2) a mediation profile not including VPA, Li, or CZN. Twenty-six patients met the inclusion criteria: 8 patients in the VPA group (113-247 µg/mL; mean, 158), 9 patients in the Li group (1.9-5.2 mEq/L; mean, 2.9), and 9 patients in the CZN group (13.4-38.8 µg/mL; mean, 23.2). All patients survived and were treated with supportive care; however, 1 patient had a Li level of 5.2 mEq/L and received hemodialysis. In altered patients potentially being treated for seizure or psychiatric disorders and unknown ingestions or medication lists, obtaining concentrations of VPA, Li, and CZN may help direct care and provide clinically relevant information. The RPC detected 26 patients with supratherapeutic VPA, Li, or CZN concentrations in patients with potential indications for the agent but no available history of drug ingested or medication list. A prospective study is warranted to evaluate the usefulness of obtaining these concentrations in this patient population.