医薬品相互作用研究

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医薬品相互作用研究
ケースレポート
43（2） 43-48 （2019）

Elevated serum lithium concentration due to the voluntary refusal
to eat and drink
Takashi TOMITA*1）,2），Hidekazu GOTO2），Kenji SUMIYA3），Tadashi YOSHIDA4）
Katsuya TANAKA5），Kenzo KUDO1）and Yukinao KOHDA2）,6）
1）

Department of Clinical Pharmaceutics and Pharmacy Practice, School of Pharmacy
Department of Pharmacy, Hospital Bando，3）Faculty of Pharmacy, Iwaki Meisei University
4）
Department of Internal Medicine, Hospital Bando，5）Department of Psychiatry, Hospital Bando
6）
Faculty of Health Sciences, Tsukuba International University2）（Received November 27, 2018; Revised January 17, 2019; Accepted February 14, 2019）
We report a case of increased serum lithium concentration due to the decreased sodium chloride intake, which
was caused by the patientʼs refusal to eat and drink. A 76-year-old male inpatient received lithium carbonate orally
at 200-600 mg/day for the treatment of the manic phase of bipolar disorder. His serum lithium concentration
reached 0.61-0.85 mEq/L. Because the patient had difficulty eating due to pneumonia, he received parenteralnutrition. Because of the patientʼs voluntary refusal of parenteral nutrition, enteral nutrition by oral route wasstarted. Upon receiving enteral nutrition, the patient voluntarily refused to eat, significantly decreasing his nutrition
intake and lowering his sodium chloride intake by 6.6-11.5 g/day than that by parenteral nutrition. As a result, thepatientʼs dietary salt intake was decreased, which led to an increase in serum lithium concentration. In addition, thepatientʼs voluntary refusal to drink water markedly reduced his water intake, leading to dehydration and increased
serum lithium concentration. At 17 days after the start of enteral nutrition by oral route, the patientʼs serum lithium
concentration increased to 2.59 mEq/L and his serum sodium concentration was 147 mEq/L, but no adverse event
occurred. Enteral nutrition was immediately discontinued and parenteral nutrition was started. Because the patient
received a sufficient amount of water and sodium chloride intake, his serum lithium concentration rapidly decreased
to 1.56 mEq/L. Enteral nutrition by oral route was subsequently started; however, because of the decrease in sodium
chloride intake due to the refusal of food, the decrease in the serum lithium concentration was gradual, with theconcentration decreased to 0.20 mEq/L.
Key Words: Lithium; drug-level monitoring; sodium chloride intake; parenteral nutrition; enteral nutrition

Introduction

Therefore, to prevent atrophy of the intest inal

Lithium carbonate is a widely used drug for themucosa, enteral nutrition supply is preferred fortreatment of the manic phase of bipolar disorderpatients with a functioning intestine 2) . It has been(manic-depressive illness). Patients receiving thisreported that lithium carbonate administration todrug are required to be monitored for serum

patients receiving enteral nutrition is associatedlithium concentration to prevent lithium overdose

with an increase in serum lithium concentrationand subsequent toxicity. The use of this drug isand a decrease in total sodium chloride intake 3). In

also contraindicated for patients prone to lithium

addition, it is possible to prevent increased serum

accumulation in the body 1).

lithium concentration in these patients byEnteral nutrition is a feeding method that ismore physiological than parenteral nutrition.

increasing the sodium chloride intake with oral
administration of sodium chloride 4).

Department of Clinical Pharmaceutics and Pharmacy Practice, School of Pharmacy, Iwate Medical University; 2-1-1, Nishitokuta,Yahabacho, Shiwagun, Iwate 028-3694, Japan.
2）
Department of Pharmacy, Hospital Bando; 411 Kutsukake, Bando, Ibaraki 306-0515, Japan.
3）
Faculty of Pharmacy, Iwaki Meisei University; 5-5-1 Chuodai Iino, Iwaki, Fukushima, 970-8551, Japan.
4）
Department of Internal Medicine, Hospital Bando; 411 Kutsukake, Bando, Ibaraki 306-0515, Japan.
5）
Department of Psychiatry, Hospital Bando; 411 Kutsukake, Bando, Ibaraki 306-0515, Japan.
6）
Faculty of Health Sciences, Tsukuba International University; 6-20-1 Manabe, Tsuchiura, Ibaraki 300-0051, Japan.
*E-mail：tatomita@iwate-med.ac.jp
Tel: +81-19-951-5111 Fax: +81-19-698-18531）

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医薬品相互作用研究

Here, we report a case of increased serum
lithium concentration due to the decreased sodium
chloride intake, which was caused by the patientʼsrefusal to eat and drink.

Vol.43, No. 2（2019）leading to dehydration and increased serum
lithium concentration.
At day 38 (17 days after the start of enteralnutrition), the patientʼs serum lithium
concentration increased to 2.59 mEq/L and hisCase report

serum sodium concentration was 147 mEq/L, but

A 76-year-old male inpatient received lithium

no adverse event occurred. The administration ofcarbonate orally at 200-600 mg/day for thelithium carbonate was discontinued because of thetreatment of the manic phase of bipolar disorderincreased serum lithium concentration. At day 38,(manic-depressive illness). His serum lithium

enteral nutrition by oral route was immediatelyconcentration reached 0.61-0.85 mEq/L. Because

discontinued and parenteral nutrition was started

the patient had diﬃculty eating due to pneumonia,(water intake: 1,000-1,700 mL/day; energy intake:he received parenteral nutrit ion (water intake:

86-510 kcal/day; sodium chloride intake: 6.0-8.7

1,100-1,700 mL/day; energy intake: 86-186g/day). The patient also had pyrexia due tokcal/day; sodium chloride intake: 5.9-11.7 g/day)

infection and was thus concomitantly treated withfrom day 1 to day 20. Because of the pat ientʼspiperacillin-tazobactam (2 g/day). Three days after

voluntary refusal of parenteral nutrition, histhe start of parenteral nutrition (at day 41),energy intake was decreased. The patient's serum

because the patient received a suﬃcient amount of

sodium concentration remained within thewater and sodium chloride intake, his serum

reference range, at 141-143 mEq/L (Fig.1).

lithium concentration rapidly decreased to 1.56

In the present case, 400 mg/day oral lithium

mEq/L. Enteral nutrition by oral route wascarbonate had been administered for

subsequently started; however, because of theapproximately the past 7 years and 6 months (daydecrease in sodium chloride intake due to the-2,744) and the dose was increased to 600 mg

refusal of food, the decrease in the serum lithiumfrom day -18 to day 8 (day 9 was 200 mg/day)concentration was gradual, with the concentrationb e c a u s e o f d e l u s i o n s a n d d a m a g e t o p r o p e r t y.

decreased to 0.20 mEq/L in 17 days. Additionally,

However, lithium carbonate administration was

the serum sodium concentration during this period

discontinued from day 10 to day 16, owing to a

was 143-148 mEq/L (Fig.1).

37.9 °C fever (axillary temperature) and sweating,Moreover, during this period, the patient showedwhich were caused by a cold. On day 17, axillaryhigh serum concentrations of electrolytes

temperature had dropped to 36.3 °C, so the oral(potassium: 2.8 to 4.6 mEq/L; chloride: 103-114

administration of lithium carbonate was restartedmEq/L; sodium: 141-148 mEq/L) and the levels ofat 400 mg/day.

renal function markers also deviated from theBecause of the pat ientʼs voluntary refusal ofreference ranges (serum creat inine: 0.73-1.20

parenteral nutrition, enteral nutrition by oral routemg/dL; estimated glomerular ﬁltration rate:

was started at day 21, 17 days before the45.9-79.0 mL/min/1.73 m 2 ; blood urea nitrogen,discontinuation of oral lithium carbonate

9.2-55.5 mg/dL). During the 6-month period ofadministration. Upon receiving enteral nutrition,

this study, the pat ientʼs bo dy weight and bo dy

the patient voluntarily refused to eat, signiﬁcantly

mass index decreased from 74.4 kg to 54.7 kg anddecreasing his nutrit ion intake (energ y intake:from 26.7 to 19.6, respectively.

210-1,050 kcal/day; sodium chloride intake:
0.2-1.2 g/day) and lowering his sodium chloride

Discussion

intake by 6.6-11.5 g/day than that by parenteralIn the present case, because the elevated serum

nutrit ion. As a result, the pat ientʼs dietary salt

lithium concentration was a result of the patientʼsintake was decreased, which led to an increase inrefusal to eat and drink, enteral nutrition wasserum lithium concentration. In addition, thediscontinued and parenteral nutrition waspatientʼs voluntary refusal to drink water markedly

resumed. After resuming parenteral nutrition, thereduced his water intake (150-200 mL/day),patientʼs sodium chloride intake was recovered,医薬品相互作用研究

Vol.43, No. 2（2019）45（120）Fig. 1 Serum lithium concentration, electrolyte concentrations, renal function marker levels, and nutrition intake of the patient.

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医薬品相互作用研究

Vol.43, No. 2（2019）

resulting in a prompt decrease in the serummL/min, and by 50-75 % when the CCr is below 10lithium concentration. However, the patient

mL/min 5）. In the current study, as calculated using

voluntarily refused parenteral nutrition and

the Cockcroft-Gault (CG) formula, the patientʼs CCr

subsequently resumed enteral nutrition. Again, thewas 53.2-72.8 mL/min, showing a mild topatientʼs refusal to eat caused a decrease inmoderate renal function deterioration. Thus, thesodium chloride intake, leading to the persistencedose of lithium carbonate need not be reduced.

of high serum lithium concentration.

However, when the patientʼs serum lithium

The Japanese dietary reference 6) speciﬁes that inconcentration was elevated, his CCr was 40.5

men aged 70 years or older, the average required

mL/min, showing the lowest level of renal

sodium intake is 1.5 g/day from sodium chloride

function.

and less than 7.0 g/day from sodium chloride

The patient was a thin, aged man with a serum

equivalents. On the other hand, the sodium intake

creatinine level less than 0.6 mg/dL and declinedof this patient was 0.4-1.2 g/day, which is below

muscle mass. This serum creatinine value was used

the average requirement. Although the so diumto calculate the CCr using the CG formula, whichintake was decreased due to the refusal to eat andresulted in a CCr value of 88.6 mL/min. In

drink, the serum so dium concentrat ion did notconsideration of the patientʼs highly impaired renalmarkedly change and remained within thefunct ion, the serum lithium concentrat ion wasreference range. However, a study was conductedmeasured and the dose of lithium carbonate wasto investigate the association between the amountcarefully selected. Furthermore, the est imatedof urinary sodium excretion and lithium clearance

glomerular ﬁltration rate without correction forfollowing the gradual reduction of the normal

body surface area was 51.1-76.3 mL/min, showing7)

dietary intake of sodium chloride . The resultsa mild to moderate decline in renal function.

showed that along with a decrease in urinary

During the period of increased serum lithium

sodium excretion, lithium clearance decreased.

concentration, the estimated glomerular ﬁltration

Similarly, in this patient, the decrease in sodium

rate was 42.6 mL/min, representing the lowest

intake, which was caused by his refusal to eat andlevel of renal function. On the basis of the CCr anddrink, led to the increased reabsorption of sodium

glomerular ﬁltration rate, the decreased lithium

ion in the renal tubule, relatively increased

clearance due to the impaired renal function wasreabsorption of lithium ion, and decreased lithium

considered as one of the causes of the increasedclearance, which resulted in the increased serum

serum lithium concentration.

lithium concentration.

Addit ionally, we assessed the asso ciat ion

Another cause of the increased serum lithium

between a concomitant drug and the increased

concentration was renal impairment due toconcentrat ion of serum lithium in this pat ient.

dehydration, which resulted from the voluntary

Valsartan, an angiotensin II-receptor antagonist,

refusal to drink water. Although the urine volume

was administered at 40 mg/day and did not aﬀect

was not measured, the voiding frequency was low

serum lithium concentration. Oral administration

at 1-4 times/day (2.2 times on average) and theof valsartan (40 mg/day) was started on day -268

excretion of concentrated urine was noted. Because

and continuously administered since then, with nothe patientʼs body weight remained at

discontinuations. Previous reports have shown thatapproximately 55 kg, the increased serum lithium

the co-administration of angiotensin II receptor

concentration was considered to be caused by theantagonists and lithium carbonate increased serum

deterioration of renal function due to dehydration.

lithium concentration from 36% to 75% 8), 9).

Lithium carbonate requires the most careful

Therefore, it is believed that serum lithium

dosing for pat ients w ith deteriorat ion of renal

concentration should be measured approximately

function. Dose reduction is unnecessary when theonce per week until 1 month after thepatient shows creatinine clearance (CCr) of over 50

co-administration was started. Seven days before

mL/min. However, it is necessary to reduce thevalsartan was administered in the present case, thedose by 30-50 % when the patientʼs CCr is 10-50

serum lithium concentration was 0.61 mEq/L and医薬品相互作用研究

the serum sodium concentration was 135 mEq/L.

Vol.43, No. 2（2019）47（122）

Ethical considerations

The serum lithium concentration 7 days after

We obtained approval for the planning of thisvalsartan administrat ion was started was 0.65

case study from the clinical research ethics

mEq/L; 1 month later, it was 0.63 mEq/L. It

committee of Hospital Bando.

increased from 3% to 7%, but large variations were
not observed. The serum sodium concentration was137 mEq/L 1 month after valsartan administration.

Conﬂict of interest
The authors declare no conﬂict interest.

Thus, in this patient, the increased serum lithium
concentration was not attributed to theReferencesconcomitant drug. Symptoms of lithium toxicity

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