European Journal of Cardiovascular Medicine

Stroke is defined by the World Health Organization (WHO) as the clinical syndrome of rapid onset (usually seconds or minutes) of focal (or global, as in subarachnoid haemorrhage) cerebral deficit, lasting more than 24 hours or leading to death, with no apparent cause other than a vascular one.1 Stroke is a leading cause of lifelong disability and mortality, with a higher incidence in India compared to Western countries. Prevalence varies from 84-262/100,000 in rural areas to 334-424/100,000 in urban areas.2

Timely correction of electrolyte imbalances is vital for enhancing acute stroke outcomes, with hyponatremia, hypernatremia, and hypokalemia being common disturbances.3 Hyponatremia is often categorized into three volumes: hypovolemic hyponatremia, euvolemic hyponatremia, or hypervolemic hyponatremia, depending on the person's bodily fluid state. Vomiting, perspiration, diuretics, and diarrhoea can all cause low-volume hyponatremia; dilute and concentrated urine instances can cause normal-volume hyponatremia.4 Large amounts of hyponatremia are typically caused by liver, heart, and renal failure. Hyperglycemia, hyperproteinaemia in multiple myeloma, and hyperlipidemia might cause low-volume hyponatremia to be evaluated incorrectly.5 Although stroke and hyponatremia correlate with poor prognosis, the mortality rates in acute stroke patients with hyponatremia remain variably documented, ranging from 14% to 44%, indicating an area warranting further investigation.6

Hyponatremia is usually either due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or cerebral salt wasting syndrome (CSWS).7 Antidiuretic hormone (ADH), stored in the posterior pituitary gland, regulates water permeability in the kidneys, facilitating water reabsorption or serum osmolality increase.8

In SIADH, constant ADH production despite hypotonic body fluid disrupts negative feedback, leading to unsuppressed ADH release and hyponatremia due to plasma solute dilution. CSWS is characterized by the occurrence of excessive sodium excretion in urine, dehydration and resultant hyponatremia, in patients with intracranial disease, trauma and cerebral lesions.9 Depletion of blood volume occurs in CSWS instead of volume expansion. The most common cause of CSWS is Subarachnoid Haemorrhage (SAH). The hyponatremia and decrease in plasma osmolality causes movement of water into the brain causing cerebral oedema which is said to be the adaptive mechanism of osmotic gradient.10

Decreased serum sodium levels in stroke patients necessitate thorough investigations before treatment initiation. Some patients may manifest hyponatremia symptoms early due to rapid hypoosmolality exceeding the brain's adaptive capacity. Differentiating between hypervolemic conditions like SIADH and hypovolemia with disproportionately low total body sodium, such as CSWS, is crucial, as their treatment approaches differ significantly.11 This study aimed to assess serum sodium levels and investigate the prevalence and causes of hyponatremia in patients with newly diagnosed cerebrovascular accidents.

Type of study: Cross sectional study

Study population and study period: A total of 210 stroke patients attending or admitted in the tertiary care teaching hospital, Gujarat over period of January 2023 to June 2023 (6 months)

Sampling technique:  Consecutive sampling

Inclusion criteria: Patients >18 years of age and admitted within 48 hours of the onset of stroke which includes Haemorrhagic stroke, Ischemic stroke and Transient Ischemic Attack (TIA) diagnosed by appropriate imaging, either Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) were included in the study.

Exclusion criteria

• Patients with residual paralysis, head injury, renal failure and liver failure, congested cardiac failure, meningitis, encephalitis, malignancy, gastroenteritis
• Patients who had had a previous stroke
• Patients on drugs which affect the electrolyte levels (diuretic or steroid therapy).

Diabetic patients presenting with severe hyperglycemia (>300 mg/dl) and hypertriglyceridemia (> 400 mg/dl). 

After taking informed consent from the patient/ attenders, data was collected using a pre designed questionnaire.  Detailed history was taken regarding age, gender, time of the stroke, clinical manifestations, co-morbid diseases, concomitant drug intake and treatment before hospitalization.

Under strict aseptic precautions, 3 mL of venous blood was collected from the stroke patients. Measurements of urinary sodium, serum osmolality, serum uric acid, serum sodium, urine specific gravity blood glucose, blood urea, blood urea nitrogen, were made. Serum sodium level less than 135 mEq/L was considered as hyponatremia.

Statistical analysis: The collected data was entered in Microsoft Excel 2016 and analyzed using Epi info version 7.1.4.0 Continuous data was presented with mean and standard deviation (SD) while categorical data was presented with frequency and percentage. The differences between categorical variables among study group were analysed by chi-square. Comparison of continuous data between two groups was analysed with student t- test. p value less than 0.05 was considered as significant.

Table 1 depicts characteristics of patients with stroke. Majority of stroke patients were in the 56-75 age group (128, 61.0%) followed by 41-55 age group (65, 31.0%). The mean age was 58.5 ± 11.0 years. Total 155 (73.8%) were males. Out of 210, 95 (45.2%) patients were smokers, and 101 (48.1%) were alcoholics. Hypertension and Diabetes mellitus were recorded in 80 (38.1%) and 67 (31.9%) patients respectively. Ischemic strokes accounted for the majority patients (148, 70.5%), whereas hemorrhagic strokes was in 62 (29.5%).  About 58.6% of strokes occurred on the left side, with the remaining 41.4% occurring on the right. Smaller stroke volumes including lacunar strokes measuring less than or equal to  6.28 cm3, which corresponds to a cylinder with a maximum diameter and height of 2 cm were more common ( 175 , 83.3 %) compared to  Large size strokes measuring more than 6.28 cm3( 35, 16.7 %). Hyponatremia was detected in 84 (40.0%). Mild, moderate and Profound hyponatremia were observed in 53 (25.2%), 21 (10.0%) and 10 (4.8%) patients.  SIADH was more prevalent, affecting 54 (64.3%) patients, compared to CSWS in 30 (35.7%) patients.

Table 1: Characteristics of patients with stroke

The mean age of patients with hyponatremia was slightly higher (64.2 ± 10.2 years) compared to 57 years in patients without hyponatremia (57.2 ± 9.8 years) but this difference was not statistically significant (p-023). There was higher prevalence of hyponatremia among males (43.2%) compared to females (30.9%), although this difference did not reach statistical significance (p=0.10).  There was significantly higher proportion of smokers among patients with hyponatremia (52.6%) compared to patients without hyponatremia (29.6%, p – 0.001). Comorbidities such as hypertension and diabetes were not significantly different among patients with hyponatremia compared to patients without hyponatremia (p value - 0.24 for hypertension and p - 0.56 for diabetes mellitus).

Table 2: Comparison of characteristics between patients with Hyponatremia and patients without Hyponatremia

Regarding stroke characteristics, significant associations were found between hyponatremia and the size and type of stroke, as well as the site of stroke. Patients with large-sized stroke were significantly more likely to have hyponatremia compared to small size stroke (p=0.001). Prevalence of hyponatremia was higher in patients with ischemic stroke (44.6%) compared to patients with haemorrhagic stroke (29.0%, p -0.04) Additionally, certain sites of stroke, such as Capsuloganglionic Hemorrhage, Pareito Occipital Hemorrhage, and Pareito Occipital Infarct, exhibited significant associations with hyponatremia (p-value < 0.001).

Table 3: Association between type of Hyponatremia and type of stroke

Out of 148 patients with ischemic strokes, 44 (29.7%) patients had SIADH and 22 (14.1%) had CSWS. Similarly, out of 62 patients with haemorrhagic stroke, 10 (16.1%) patients had SIADH and 8 (12.9%) had CSWS. Proportion of SIADH was higher in patients with ischemic strokes compared to patients with haemorrhagic stroke but statistically not significant (p-0.55). Mean sodium level was also not significantly different in patients with ischemic strokes compared to patients with haemorrhagic stroke (p-0.09).

Table 4: Comparison of lab investigation between SIADH and CSWS

Patients with SIADH showed lower serum sodium and uric acid levels, but higher urine osmolality compared to CSWS patients. Conversely, CSWS patients exhibited higher urine sodium levels and lower urine volume. These differences underscored distinct biochemical profiles between the two conditions.

Table 5: Mortality rate according to type of hyponatremia

Patients with hyponatremia had significantly higher mortality rates (42.9%) compared to those without hyponatremia (18.3%), with a p-value of 0.0001. Further analysis by hyponatremia types, there was no significant difference in mortality rate between SIADH (42.6%) and CSWS patients (43.3%, p=0.94).

The most common electrolyte abnormality in neurological clinical practice is hyponatremia, predominantly affecting patients with acute central nervous system (CNS) diseases.3 Symptoms of hyponatremia are mainly associated with acute and significant decreases in plasma sodium levels, indicating neurological dysfunction due to cerebral edema and potential adaptive responses of brain cells to osmotic swelling. Cerebral edema induced by hyponatremia typically occurs with rapid reductions in plasma sodium concentration over 1 to 3 days, and the severity of symptoms correlates with the extent of cerebral over-hydration.

Characteristics of Stroke

In the present study, total 210 patients diagnosed with stroke were enrolled. The mean age was 58.5 ± 11.0 years with a predominant male distribution (73.8%). This finding consistent with prior research by Ezhumalai et al.12 (Mean age: 56 years, and Male: 81%) and Karunanandham et al.13 (Mean age: 64.8 years, and Male: 86.6%). Ischemic stroke was the most common subtype in the present study (70.5%) followed by haemorrhagic stroke (29.5%). It consistent with the findings of Karunanandham et al.13 (80.7% Ischemic stroke, 19.3% haemorrhagic stroke) and Ezhumalai et al.12 (68% Ischemic stroke, 32% haemorrhagic stroke).

Hyponatremia

In the present study, the incidence of hyponatremia among stroke patients was 40.0%, with 25.2%, 10.0%, and 4.8% experiencing mild, moderate, and profound hyponatremia, respectively. This aligns with findings from Karunanandham et al.13 and Saleem et al.7 who reported a similar incidence of hyponatremia in stroke patients (38.6% and 35% respectively), Mahesar et al.3 found that 38.6% of stroke patients had hyponatremia, with the majority had mild (25%), and followed by moderate (9.8%) and profound (3.8%) cases. Ezhumalai et al.12, noted that 19% of stroke patients had hyponatremia, predominantly mild (15.5%) followed by moderate (1.2%) and profound cases (2.5%).

In the present study, no notable gender or age-specific disparities in incidence of hyponatremia were observed, similar to the study of Karunanandham et al.13 However, several studies indicated higher incidence of hyponatremia in males compared to females.12,14

SIADH and CSWS

Hyponatremia is prevalent in stroke patients and crucial to distinguish its causes (SIADH, CSWS) due to differing pathophysiology and management. SIADH typically involves fluid restriction and medications like furosemide, demeclocycline, or lithium, while CSWS necessitates addressing underlying causes, volume replacement with normal or hypertonic saline, and medications such as fludrocortisone.7

The present study reveals a higher prevalence of SIADH (64.3%) compared to CSWS (35.7%) among stroke patients. Ischemic stroke was more commonly associated with both SIADH (81.4%) and CSWS (73.3%) compared to haemorrhagic stroke (28.6% in SIADH and 26.7% in CSWS). Karunanandham et al.13 reported 21.28% and 7.42% of cases diagnosed with SIADH and CSWS respectively. Saleem et al.7 reported 23.8% patients with SIADH and 11.5% patients with CSWS and 65.0% ischemic stroke and 35.0% hemorrhagic stroke among the 238 patients with SIADH and 67.0% ischemic stroke and 33.0% hemorrhagic stroke among the 115 patients with CSWS. Singh S et al.15 also reported that CSWS is less common than SIADH.

Laboratory investigation

In the present study, patients with SIADH had lower serum sodium and uric acid levels but higher urine osmolality compared to CSWS patients, whereas CSWS patients showed higher urine sodium levels and lower urine volume. These distinctions highlight unique biochemical profiles between the two conditions. Similarly, Karunanandham et al.13 found high urine osmolality and specific gravity in both disorders, with increased urine sodium excretion noted in both but higher in CSWS compared to SIADH.

Hyponatremia in SIADH is attributed to volume overload, resulting in dilutional hyponatremia. Conversely, in CSWS, natriuresis occurs due to disrupted sympathetic neural input signal to the kidneys, exacerbated by natriuretic peptides such as ANP, BNP, CNP, and DNP. This disruption leads to decreased sodium resorption in the proximal tubule, subsequently decreasing effective arterial blood volume and triggering ADH release to maintain intravascular volume. Furthermore, depressed sympathetic drive correlates with decreased renin and aldosterone levels, inhibiting sodium retention. Distinguishing between SIADH and CSWS necessitates a battery of laboratory tests.13

Mortality rate

In the present study, patients with hyponatremia exhibited significantly higher mortality rates (42.9%) compared to those without hyponatremia (18.3%). However, further analysis by hyponatremia types, SIADH and CSWS, revealed no significant difference in mortality rates between them (42.6% and 43.3% respectively, p=0.94). These findings are consistent with Saleem et al.7, where a higher mortality rate was observed in hyponatremic patients (44.2%) compared to those without hyponatremia (14.5%), with comparable mortality rates between SIADH (45.7%) and CSWS (40.8%) patients. Conversely, Ezhumalai et al.12 found similar mortality rates in hyponatremic patients (6.7%) compared to those without hyponatremia (6.5%, p=0.976).

The majority of stroke patients fell within the 56-75 age group, with ischemic strokes being predominant (70.5%). Notably, a considerable proportion of patients exhibited hyponatremia (40.0%), SIADH being the more prevalent type (64.3%) than CSWS (35.7%). There was association between hyponatremia and various stroke characteristics, including size, type, and site. Hyponatremic patients were shown to be exhibiting lower survival rates compared to those without hyponatremia, while no significant difference in survival rates was observed between SIADH and CSWS patients.

Maintaining electrolyte balance, particularly sodium levels, is crucial upon patient arrival, as imbalances can have widespread adverse effects. Hyponatremia, a significant concern in stroke patients, can lead to persistent altered sensorium and neurological symptoms such as seizures, altering patient consciousness levels. Assessment of hyponatremia severity is essential for understanding the associated risks and managing the condition effectively.

1. Bath PMW, Lees KR. Acute stroke. West J Med. 2000;173(3):209-12.
2. Pandian JD, Sudhan P. Stroke epidemiology and stroke care services in India. J Stroke 2013;15(3)128-34.
3. Mahesar SA, Memon SF, Mustafa S, Javed A, Butt SM. Evaluation of hyponatremia in ischemic stroke patients in a tertiary care hospital of Karachi, Pakistan. Cureus 2019; 11:e3926.
4. Huang WY. Association of Hyponatremia in acute stroke stage with three-year mortality in the patients with first-ever ischemic stroke. Cerebrovasc Dis 2012; 34 55-62.
5. Marroncini G, Fibbi B, Errico A, Maggi M, Grappone C, Peri A. The effects of low extracellular sodium on proliferation and invasive activity of cancer cells in vitro. Endocrine 2020; 67 479-484.
6. Fofi L, Dall’Armi V, Durastanti L, Valenza A, Lorenzano S, Prencipe M, et al. An observational study on electrolyte disorders in the acute phase of ischemic stroke and their predictive value. J Clin Neurosci 2012, 19513-516.
7. Saleem S, Yousuf I, Gul A, Gupta S, Verma S. Hyponatremia in stroke. Ann Indian Acad Neurol 2014 Jan 1;17(1)55-7.
8. Oh JY, Shin JI. Syndrome of inappropriate antidiuretic hormone secretion and cerebral/renal salt wasting syndrome: similarities and differences. Front Pediatr 2014;2146.
9. Saleem S, Yousuf I, Gul A, Gupta S, Verma S. Hyponatremia in stroke. Ann Indian Acad Neurol 2014;1755–57.
10. Kim DK, Joo KW. Hyponatremia in Patients with Neurologic Disorders. Electrolytes Blood Press E BP 2009;7(2)51-57.
11. Tisdall M, Crocker M, Watkiss J, Smith M. Disturbances of sodium in critically ill adult neurological patients: a clinical review. J Neurosurg Anaesthesiol 2006;1857–63.
12. Ezhumalai A, Sridevi SN, Kannan N, Kishore R. A prospective study of evaluation and assessing the correlation between hyponatremia or eunatremia in patients with acute stroke for severity and outcome. Int J Acad Med Pharm 2023;5(2)218-21.
13. Karunanandham S, Rajappa T, Selvaraju K. Hyponatremia in Patients Admitted with Stroke. J Clin Diagnostic Res 2018 Aug 1;12(8)34-6.
14. Al-Khazraji AK. Hyponatremia in a group of Iraqi patients with stroke. Iraqi J Med Sci 2016; 14191-96.
15. Singh S, Bohn D, Carlotti AP, Cusimano M, Rutka JT, Halperin ML. Cerebral salt wasting: truths, fallacies, theories, and challenges. Crit Care Med 2002;302575–9.