Rhabdomyolysis Complicated with Hyponatremia Due to Water Intoxication and Severe Aspiration Pneumonia: Description of a Patient with Chronic Schizophrenia and Literature Review

Abstract

Hyponatremia due to water intoxication is frequently observed in patients with chronic schizophrenia. We herein present a 49-year-old man who developed schizophrenia at the age of 23 and had been admitted to the closed ward of our hospital for 7 years. He was found by a round nurse standing at the bedside, covering both ears with his hands and making groaning noises. He was disoriented and immediately after being returned to bed, a general tonic-clonic seizure occurred. Severe hyponatremia (Na 104 mEq/L) was noted and intravenous sodium correction was started. A few hours later, due to glossoptosis and massive vomiting, ventilation got worse to the point where he had to be put on a ventilator. On the following day, he developed aspiration pneumonia and antimicrobial treatment was started. In addition, a blood sample taken 36 hours later revealed an extensive elevation of creatine kinase (41,286 U/L), pointing to a possibility of rhabdomyolysis as a complication. Subsequently, the general condition gradually improved with antimicrobial therapy and sodium correction. He eventually recovered without any complications including central pontine myelinolysis. He had no history of polydipsia before this event but it was later found that esophageal stricture triggered complusive fluid intake, resulting in acute hyponatremia, seizure, aspiration pneumonia and rhabdomyolysis. A brief discussion will be provided on the issues surrounding hyponatremia, rhabdomyolysis and schizophrenia.

Background

Patients with schizophrenia frequently exhibit hyponatremia due to polydipsia or water intoxication, and its prevalence is estimated to be 11–20%.^1,2 Hyponatremia, when acute and severe, leads to impaired consciousness and convulsions, and can be directly related to mortality. Furthermore, correction of sodium needs to be monitored strictly because a rapid increase in serum sodium concentration may induce central pontine myelinolysis, resulting in grave neurological sequelae including paresis and dysphagia.³ On the other hand, there have been some reports of rhabdomyolysis associated with hyponatremia or rapid fluctuations in blood sodium concentration during the correction process.^4–6 We herein present a case of a sudden onset of extreme hyponatremia along with severe pneumonia, complicated by rhabdomyolysis. We also provide discussion on the management issues surrounding such a problem.

Case History

Written informed consent was obtained from the patient and his family about the case presentation. A 49-year-old male patient first came to our hospital with delusional complaints of being watched and monitored by someone in 1996. He was diagnosed with schizophrenia and had a medical history of gastroesophageal reflux disease. In January 2016, he was readmitted as fourth hospitalization and had been treated with haloperidol 18mg/d, risperidone 12mg/d, olanzapine 20mg/d, chlorpromazine 400mg/d, aripiprazole long-acting injection 400mg/m. Finally with such high dose polypharmacy, his psychiatric symptoms including excitement, agitation, hallucination and delusion have witnessed some improvement. Although occasional monologue has been observed, he was spending his time calmly and had no trouble in the ward, attending to an in-hospital day care. In March 2022, esophageal stricture due to gastroesophageal reflux disease worsened, resulting in frequent episodes of vomiting. As a result, esophageal dilation with a balloon was performed in March and April of that year, and dietary format was changed to finely cut meals. Nevertheless, occasional complaints of dysphagia and vomiting while eating were still observed. He had no history of polydipsia during the hospitalization periods thus far.

Symptomatology

At night on March 16, 2023, he was found by a round nurse in his room standing at the bedside, covering both ears with his hands and making groaning noises. Immediately after being prompted to bed rest, he showed a general tonic-clonic seizure for about 1–2 minutes intermittently. He was disoriented, and the Glasgow Coma Scale (GCS) was 7 (E1V2M4), the blood pressure was 146/93 mmHg, with oxygen saturation at 93% (room air). The body temperature was 36.5°C, and the blood glucose level was 183 mg/dl. The pupils were equal in size, measuring 5 mm bilaterally, and the pupillary light reflex was normal. There were no specific findings on the head CT and MRI. The laboratory test revealed a serum sodium level of 104 mEq/l (reference range of 138–145 mmol/l) and a creatine kinese (CK) level of 278 U/l (reference range of 59–248 Ul/l).⁷

Diagnosis and Treatment

A total intravenous dose of 10 mg of diazepam was administered for the treatment of generalized tonic-clonic seizures, resulting in abortion of convulsions. Considering acute severe hyponatremia as a cause of seizure and altered consciousness, serum sodium correction was initiated by intravenous infusion of 0.9% NaCl (1,500 ml/day). Additionally, due to glossoptosis and massive vomiting, ventilation got worse and oxygen supplementation with flow rate of 10 L/min was initiated using bag-valve mask with reservoir; tracheal suctioning was performed as appropriate. However, oxygenation showed no improvement beyond the latter half of the 80% range. We therefore initiated non-invasive positive pressure ventilation (NPPV) for respiratory support. Subsequently, an improvement was observed up to the mid-90% range under conditions of Fraction of Inspired Oxygen (FiO2) of 100%. Additionally, due to a sluggish correction of hyponatremia with a risk of precipitating cerebral edema, it was decided to switch to 3% NaCl and continue sodium correction at a rate of 40 ml/h. However, after six hours, a rapid increase in serum sodium level to 117 mEq/l was observed, prompting a return to 0.9% NaCl (1500 ml/day) and addition of maintenance fluid (500 ml/day).

The urine output was 3,950 ml over a 24-hour, indicating polyuria. Considering a plasma osmolality of 229 mOsm/l, a urine osmolality of 79 mOsm/l, and a urine sodium level of 18 mEq/l, the possibility of hyponatremia due to polydipsia was strongly supported rather than syndrome of inappropriate antidiuretic hormone secretion (SIADH). Furthermore, the body temperature rose to 39.1°C, and a chest X-ray revealed diffuse infiltrates throughout the left lung, suggesting aspiration pneumonia. Therefore, treatment with intravenous antibiotics was initiated. Although the level of consciousness improved to GCS12 (E3V4M5) at the same evening, he remained agitated, leading to sedation with a continuous midazolam infusion under the continuation of NPPV. On the following day, March 18, the laboratory test showed an elevation in CK levels to 41,286 U/L, and dark brown urine was observed. However, on account of the absence of muscle rigidity, diaphoresis, tachypnea, tachycardia and abnormal blood pressure, it was considered that he developed rhabdomyolysis due to the hyponatremia itself or sodium fluctuation during correction process, rather than neuroleptic malignant syndrome.⁸ The serum sodium level increased modestly by approximately 5 mEq/L to 122 mEq/L within 18 hours. On March 20th, although the laboratory test revealed an elevated white blood count (WBC) of 10,000/μl and C reactive protein (CRP) level of 27.70 mg/dl, the body temperature decreased to the 37°C range. Moreover, because the serum sodium level improved to 122 mEq/L, and CK levels decreased to 20,601 U/L, the infusion was switched to acetate Ringer’s solution (1,000 ml/day). Subsequently, a decrease in the inflammatory response, improvement in the infiltrates in the left lung, and better oxygenation were observed, leading to the patient being weaned off NPPV on March 22nd. Simultaneously, sedation with midazolam was discontinued, and on March 24th, antibiotics were switched to oral administration. When asked about the situations, he testified “A week ago, I started feeling a strong sensation of food getting stuck in my throat during meals. As a result, I would drink incredibly huge amount of water to try to pass the food into the stomach.” On March 29th, balloon dilation of the esophagus was performed, and on April 6th, a head MRI was reconducted, confirming that he eventually recovered without any complications including central pontine myelinolysis

Discussion

Psychiatric Disorders and Hyponatremia

Hyponatremia is a relatively common condition that is reported to occur in approximately 5% of psychiatric patients who are chronically hospitalized.⁹ Psychiatric disorders in which hyponatremia has been often observed include schizophrenia, mood disorders, and substance related disorders.^10,11 One of the prevailing theories of the mechanism by which psychiatric patients develop hyponatremia is due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by side effects of psychotropic medications, or dilutive polydipsia.¹¹ Although the mechanism of SIADH with psychotropic medication is not clearly understood, the possible theory is that noradrenaline induces release of antidiuretic hormone (ADH) via α-1 adrenergic receptors, which seems to be one of the most important regulatory pathways of ADH secretion.¹² Additionally, serotonin and dopamine may relate to regulation of ADH release.¹³ In our instance, there was no history of polydipsia and the most recent laboratory test on March 10 showed a serum sodium level of 133 mEq/dl. It was presumed that the complication of esophageal stricture had worsened approximately a week prior to the event, leading to stagnation of food in the esophagus and the forced passage through excessive water intake, which was considered the cause of polydipsia. Additionally, the increased frequency of vomiting due to worsened esophageal stenosis was considered to have further exacerbated the hyponatremia by prompting sodium loss. While the reasons of polydipsia in psychiatric patients are somewhat elusive, one hypothesis is that it is the result of a combination of factors such as worsening psychiatric symptoms, adverse effects of antipsychotics, and genetic predispositions.¹⁴ However, it is generally expected that with the progression of hyponatremia, clinical symptoms such as nausea and headache would appear,¹⁵ and it is likely that drinking behavior would be inhibited before it further worsens. Possible factors contributing to the decrease in serum sodium concentration to 104 mEq/L include a large amount of drinking occurring within a very short period of time and the influence of insensitivity to painful stimulus in patients with schizophrenia.¹⁶ Furthermore, detecting polydipsic behavior early on was challenging because there was no monitoring of body weight fluctuations or assessment of water intake, given the absence of a clear history of polydipsia or hyponatremia in the past. Moreover, the fact that excessive water intake occurred in his room made it difficult to identify polydipsic behavior promptly.

Treatment of Hyponatremia with Polydipsia

In cases of severe hyponatremia, rapid correction is necessary to prevent precipitating cerebral edema. However, swift correction of serum sodium levels can induce central pontine myelinolysis, resulting in irreversible neurologic sequelae such as quadriplegia and parkinsonism, as well as an increased risk of mortality. Additionally, in the case of hyponatremia caused by polydipsia, there can be excessive diuresis,¹⁷ leading to an unexpectedly rapid correction of serum sodium levels; the rate of correction requires careful and strict monitoring. According to the guideline in the United States, it is recommended to initially increase serum sodium levels by 4–6 mEq/L within the first 1–2 hours, followed by a correction of up to 10 mEq/L within 24 hours and up to 18 mEq/L within 48 hours.^18,19 In terms of the concentration of NaCl used for correction, it recommends the use of 3% NaCl to facilitate early improvement of cerebral edema. In our patient, there were no apparent signs of cerebral edema on the head MRI, and initially, 0.9% NaCl was used for correction due to concerns for central pontine myelinolysis. However, since the increase in serum sodium was only 2 mEq/L after 8 hours, the intravenous infusion was changed to 3% NaCl in order to protect against cerebral edema, with a rate of 1 ml/kg per hour.²⁰ However, after 6 hours, the correction rate exceeded an expectation that reached 11 mEq/L, necessitating a change back to 0.9% NaCl. In cases of hyponatremia caused by polydipsia, a careful attention should be exercised since there is a risk of diuresis due to the suppression of antidiuretic hormone (ADH), potentially leading to a rapid increase in serum sodium levels.¹⁷ In the correction of severe hyponatremia, it is necessary to measure serum sodium levels at least every 8 hours¹⁸ and adjust the fluid replacement content and rate according to the rise in sodium concentration.

Rhabdomyolysis and Hyponatremia in Psychiatric Patients

Rhabdomyolysis is defined as a clinical and biochemical syndrome resulting from skeletal muscle injury that alters the integrity of the muscle cell membrane sufficiently to allow the release of the muscle cell contents into the plasma.²¹ There are various factors that can contribute to the development of rhabdomyolysis, including drug-induced (e.g., antipsychotics and lipid-lowering agents) and metabolic abnormalities, or excessive physical exertion (e.g., marathon running).²² The coexistence of rhabdomyolysis and hyponatremia has been reported in multiple cases.^4,5 Additionally, it is estimated that approximately 7% of rhabdomyolysis occurs during the treatment process for hyponatremia.^6,23 Although many aspects of the mechanism by which hyponatremia triggers rhabdomyolysis remain unclear, several hypotheses have been proposed. These include the swelling of muscle cell membranes due to the decreased osmotic pressure of extracellular fluid, subsequent membrane depolarization caused by the leakage of intracellular potassium, leading to the release of intracellular enzymes such as CK, and the reduction of extracellular sodium inhibiting the Na-Ca exchange system in the cell membrane, resulting in the accumulation of intracellular calcium and subsequent damage to muscle cells.^4,5,24–26 Alternatively though, hypernatremia is also a risk factor for rhabdomyolysis; the process is also thought to be related to inhibition of electrogenic sodium pump that impairs Na-Ca exchange system, which results in an increased cytoplasmic calcium level. Persistently high intracellular calcium may result in activation of neutral proteases and lead to the destruction of muscle.²⁷ During the treatment process, rapid changes in extracellular sodium concentration are thought to induce vulnerability in the cell membrane through mechanisms involving intracellular enzyme activity and second messenger systems.⁴ On the other hand, it is well known that antipsychotic medications can also cause rhabdomyolysis as well as neuroleptic malignant syndrome (NMS). NMS occurs primarily as a adverse effect of antipsychotic medications and is diagnosed by the presence of all three major (fever, rigidity and elevated CK), or two of three major and four of six minor (tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis and leukocytosis) manifestations.⁸ Rhabdomyolysis resulting from skeletal muscle injury, on the other hand, is caused by a variety of factors, including medication side effects and excessive physical exertion;²² NMS is often associated with rhabdomyolysis, in which case there is an elevation of CK in the blood. Rhabdomyolysis is thought to occur through the inhibition of skeletal muscle serotonin receptors by antipsychotic drugs, which suppress glucose uptake into muscle cells and increase permeability of intracellular enzymes such as CK through the cell membrane.²⁸ Kathleen et al. reported that among patients hospitalized with rhabdomyolysis, 10.5% were taking antipsychotic medications, which was significantly higher compared to the general population. They further reported a higher incidence of rhabdomyolysis in patients taking multiple antipsychotic medications;²⁸ our patients had been treated with antipsychotic high dose polypharmacy. A peak CK level of 41,286 U/L occurred 33 hours after the onset of loss of consciousness and seizure. In addition to the use of multiple antipsychotic medications, the rapid fluctuation of serum sodium levels resulting from acute hyponatremia and its correction was considered to be a predisposing factor. In cases where psychiatric patients develop hyponatremia, it is important to consider the risk of developing rhabdomyolysis and to periodically monitor serum CK levels.

Conclusion

Hyponatremia is not infrequently encountered in psychiatric patients. We described a case of severe acute hyponatremia due to polydipsia that stemmed from forced drinking owing to worsening esophageal stricture, which resulted in the development of severe pneumonia and rhabdomyolysis. The patient eventually exhibited full recovery. Management of acute severe hyponatremia poses difficulties as of two conflicting conditions, cerebral edema and central pontine myelinolysis. Additionally, the risk of rhabdomyolysis should be also in mind. A frequent evaluation of serum sodium and CK levels is critical to closely minotor patient’s general condition in the treatment of severe hyponatremia.