Normal levels of lithium - Can it still be harmful?

Sir,

Lithium (Li) is a first-line drug for bipolar disorder which has a narrow therapeutic window (0.6–1.2 mEq/L).[12] Chronic long-term use can have prolonged elimination half-life ranging from 24 h to 60 h.[3] Increased as well as normal levels of Li both can have features of toxicity.[3] Here, we report a patient with bipolar disorder on Li therapy who developed cardiac systolic dysfunction, which improved after discontinuation of Li.

A 52-year-male presented with a 25-year history of bipolar disorder. He was on regular follow-up with his psychiatric physician, and because of increase in manic episodes, he was started on Li 1200 mg/day 20 days before his admission to our intensive care unit (ICU). His past medical history and family history were unremarkable.

He was referred to our hospital with symptoms of decreased appetite, agitation, abdominal distension, right focal seizure, and altered sensorium for 3 days. On admission, examination revealed a nonpale, anicteric, and acyanotic patient with heart rate of 120/min, blood pressure of 130/80 mmHg, and hypoxia (SPO2 of 85% on room air). He was semiconscious with Glasgow Coma Scale of E1V1M4. Initial electrocardiogram showed Prolonged QTc(460 ms) as shown in Figure 1, troponin I was 0.44 ng/ml (reference range <0.02 ng/ml), and brain naturetic peptide (BNP) – 1060 pg/ml. Abdomen examination was unremarkable, and he had Grade 1 acute kidney injury (AKI). Laboratory parameters were l within normal limits with serum Li of 0.8 meq/L and creatinine of 1.5 mg/dL, respectively. Chest skiagram showed bilateral hilar opacities. Magnetic resonance imaging of brain was essentially normal. Cerebrospinal fluid analysis was normal. Electroencephalogram revealed generalized slowing.

Figure 1

Electrocardiogram with prolonged QTc

Because of altered sensorium and hypoxic respiratory failure, he was intubated. Postintubation, he developed hypotension; two-dimensional echocardiography showed reduced left ventricular contractility with ejection fraction (EF) of 15%–20%, without any regional wall motion abnormality. Li was discontinued. He was started on broad-spectrum antibiotics, noradrenaline, and dobutamine infusion. He developed nonoliguric AKI but never required dialysis as lithium level was normal. After 4 days, his hemodynamics improved; he was weaned from vasopressor and inotrope support. Repeat echocardiography at this time showed marked improvement in EF to 60%. Serum Li level decreased to 0.6 meq/L. Blood cultures were negative. On assessment of consciousness level, he had persistent poor sensorium (glassgow coma scale (GSC) <8). He was tracheostomized on day 5 of ICU admission. Gradually, his sensorium improved, weaned off from mechanical ventilation, decannulated on day 15, and discharged to home on day 18.

In our case, decreased appetite might lead to volume depletion and dehydration. As Li is excreted almost entirely by the kidneys, factors that decrease glomerular filtration rate or increase proximal tubule reabsorption, such as volume depletion, will increase serum Li levels.[13] The most common features of Li toxicity is altered sensorium, but occasionally, cardiac toxicity can also be seen in chronic Li users.[3] Cardiac adverse events associated with Li toxicity are summarized in Table 1.[456789] Most cases are associated with high serum Li levels, only 3 case report (including ours) where systolic dysfunction is diagnosed with normal serum Li level.[410] Renal replacement therapy (RRT) is the usual treatment modality when Li levels are high; but, in our case, since Li level was within normal limit, RRT was not indicated.

Table 1

Comparison of clinical features of cardiac toxicity in reported cases

Journal	Age/Sex	Diagnosis	Lithium Level/Duration	Cardiac Features	Other Clinical Features	Outcome
J Psychopharmacol 2006.5	48/M	Bipolar disorder	0.35-0.73 mmol/L 5 Yrs	T wave inversion LV dilatation EF=48%	Breathlessness Palpitation	Survivor
J Med Toxicol 2008.8	46/M	Schizo-affective Bipolar disorder	4.69mmol/L	ST elevation in anterior leads Trop I <0.2 ng/ml ECHO: Normal	Confused, Ataxia, Anorexia	Survivor with multiple RRT
J Clin Psychopharmacol 2014.12	78/F	Bipolar disorder	2.9meq/L 2 Yrs	ST Elevation in Anterior leads Trop T – High LV dysfunction	Ataxia, Tremor	Survivor
Am J Emerg Med 2015.6	35/F	Bipolar disorder	3.7 meq/L	Bradycardia Junctional rhythm QT prolongation Trop I - 3.14 ng/mL CK-MB-6ng/L EF=15% with severe global hypokinesia w/o RWMA	Unresponsive GCS 10	Survivor
Iran Red Crescent Med J 2016.9	62/F	Bipolar disorder	2.3 mmol/L 7 days	ST elevation in leads Avl, 5,6 Trop I -0.892 ng/mL ECHO-Normal	Weakness Acute chest pain Tremor Nystagmus	Survivor
J Clin Psycho Pharmacol 2018.11	59/F	Bipolar disorder	0.9meq/l 12 Yrs	LBBB Severe dilation of LV, EF=20-30%	Breathlessness, Chest pain	Survivor
Our case	52/M	Bipolar disorder	0.8meq/L 20 days	Prolonged QTc LV dysfunction	Decreased Appetite Abdominal Distension GTCS	Survivor

RRT: Renal Replacement Therapy, LV: Left Ventricle, EF: Ejection fraction, RWMA: Regional wall motion abnormality

Hence, in psychiatric patients where clinical history is not reliable, toxicity with Li can be a diagnosis of exclusion even when normal serum levels are found. Bedside clinical judgment is of utmost value. Normal serum Li levels do not exclude toxicity in the presence of clinical features.

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Conflicts of interest

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