When Low Sodium Is Not True Hyponatremia: A Critical Care Perspective on Pseudohyponatremia

Dr Neeraj Manikath , claude.ai

Abstract

Background: Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients, particularly in critical care settings. However, not all measured low serum sodium concentrations represent true hyponatremia. Pseudohyponatremia represents a laboratory artifact where serum sodium appears low due to analytical interference or osmotic shifts, while plasma tonicity remains normal.

Objective: To provide critical care physicians with a comprehensive understanding of pseudohyponatremia, focusing on recognition, pathophysiology, and clinical management to prevent misdiagnosis and inappropriate treatment.

Key Points: This review discusses the two main categories of pseudohyponatremia: laboratory artifact pseudohyponatremia (caused by severe hyperlipidemia or hyperproteinemia) and redistributive pseudohyponatremia (primarily from hyperglycemia). We provide practical formulas for sodium correction, clinical pearls for rapid bedside assessment, and evidence-based management strategies.

Conclusions: Recognition of pseudohyponatremia is crucial in critical care to avoid unnecessary interventions and focus on treating underlying conditions. Modern laboratory techniques have largely eliminated artifact-based pseudohyponatremia, making hyperglycemic pseudohyponatremia the most clinically relevant form.

Keywords: Pseudohyponatremia, hyperglycemia, hyperlipidemia, critical care, electrolyte disorders, sodium correction

Introduction

Hyponatremia, defined as serum sodium concentration <135 mEq/L, affects up to 30% of hospitalized patients and carries significant morbidity and mortality risks¹. In the intensive care unit (ICU), the prevalence can exceed 40%, making it a daily concern for critical care physicians². However, not every low serum sodium measurement represents true hyponatremia requiring immediate correction.

Pseudohyponatremia represents a clinical scenario where measured serum sodium is low, but plasma tonicity remains normal or elevated. This distinction is crucial because treating pseudohyponatremia as true hyponatremia can lead to dangerous overcorrection, potentially causing osmotic demyelination syndrome³.

This review aims to equip critical care physicians with the knowledge to rapidly identify and appropriately manage pseudohyponatremia, focusing on the most common causes encountered in the ICU setting.

Pathophysiology and Classification

Normal Physiology Review

Under physiological conditions, sodium constitutes approximately 93% of plasma osmolality, with glucose and blood urea nitrogen contributing the remainder⁴. The measured serum sodium reflects the concentration in the aqueous phase of plasma, which normally comprises about 93% of plasma volume (with 7% occupied by proteins and lipids).

Types of Pseudohyponatremia

1. Laboratory Artifact Pseudohyponatremia (Factitious Hyponatremia) This occurs when the non-aqueous phase of plasma is expanded, reducing the percentage of plasma that is water and artificially lowering the measured sodium concentration.

Causes:

Severe hyperlipidemia (triglycerides >1000 mg/dL or >11.3 mmol/L)
Extreme hyperproteinemia (rare; total protein >12 g/dL)
Mannitol administration (historically relevant)

Mechanism: In flame photometry and indirect ion-selective electrodes (ISE), the sample is diluted, and sodium is measured in the total plasma volume rather than just the aqueous phase⁵.

2. Redistributive Pseudohyponatremia (Osmotic Dilution) This occurs when osmotically active substances draw water from the intracellular to extracellular space, diluting extracellular sodium concentration.

Primary Cause:

Hyperglycemia (most common in ICU)
Other osmotically active substances: mannitol, glycine, maltose, sucrose, radiocontrast agents

Clinical Recognition: Pearls and Oysters

Pearl 1: The "Quick Screen" Triad

When encountering apparent hyponatremia in the ICU, always check:

Glucose level (>200 mg/dL suggests pseudohyponatremia)
Lipid appearance of serum (milky/turbid suggests hyperlipidemia)
Calculated vs measured osmolality (osmolar gap >10 mOsm/kg suggests unmeasured osmoles)

Pearl 2: The Glucose-Sodium Rule of Thumb

Quick bedside calculation: For every 100 mg/dL (5.6 mmol/L) glucose elevation above 100 mg/dL, sodium decreases by approximately 1.6 mEq/L⁶.

Formula for Glucose Correction:

Corrected Na = Measured Na + [(Glucose - 100) ÷ 100] × 1.6

Alternative Formula (more accurate for severe hyperglycemia >400 mg/dL):

Corrected Na = Measured Na + [(Glucose - 100) ÷ 100] × 2.4

Pearl 3: Modern Laboratory Considerations

Most modern laboratories use direct ISE methods, which have largely eliminated lipid and protein interference. If your lab reports pseudohyponatremia from hyperlipidemia, confirm they're using direct ISE methodology⁷.

Oyster 1: The Normal Osmolality Clue

In true hyponatremia, measured osmolality should be low (<280 mOsm/kg). If osmolality is normal or high with low sodium, suspect pseudohyponatremia.

Calculated Osmolality Formula:

Calculated Osmolality = 2 × [Na] + [Glucose]/18 + [BUN]/2.8
(All concentrations in mg/dL)

Oyster 2: The Asymptomatic Patient Paradox

Patients with severe hyperglycemic pseudohyponatremia (corrected sodium normal) typically don't exhibit neurological symptoms of hyponatremia, despite very low measured sodium levels⁸.

Specific Clinical Scenarios

Hyperglycemic Pseudohyponatremia

Clinical Context: Most commonly seen in:

Diabetic ketoacidosis (DKA)
Hyperosmolar hyperglycemic state (HHS)
Stress hyperglycemia in critically ill patients
Post-cardiac surgery patients receiving dextrose-containing solutions

Management Approach:

Do NOT treat the low sodium directly
Focus on glucose management with insulin and fluid resuscitation
Monitor corrected sodium as glucose normalizes
Watch for true hyponatremia development as glucose corrects (due to water shifts)

Clinical Hack: Create a "sodium tracking sheet" showing measured sodium, glucose, and corrected sodium over time to visualize the relationship.

Hyperlipidemic Pseudohyponatremia

Clinical Context: Increasingly rare with modern lab techniques but consider in:

Severe hypertriglyceridemia (familial or secondary)
Acute pancreatitis with extreme lipid elevation
Patients receiving high-dose propofol (propofol infusion syndrome)

Recognition: Serum appears milky or creamy; triglycerides >1000 mg/dL

Management:

Confirm lab methodology (direct vs indirect ISE)
Treat underlying lipid disorder (plasmapheresis for severe cases)
Avoid hypertonic saline unless true concurrent hyponatremia confirmed

Diagnostic Algorithm: A Practical Approach

Low Serum Sodium (<135 mEq/L)
↓
Check: Glucose, Lipids, Osmolality
↓
Glucose >200 mg/dL? → YES → Calculate Corrected Sodium
                    ↓
                   Is Corrected Na >135? → YES → Pseudohyponatremia
                                         → NO → Mixed disorder
↓
Serum turbid/milky? → YES → Check triglycerides
                           → >1000 mg/dL → Confirm lab method
↓
Osmolar gap >10? → YES → Consider unmeasured osmoles
↓
Normal/high osmolality with low Na? → Pseudohyponatremia likely

Treatment Considerations and Pitfalls

Critical Management Pearl: The "Correction Conundrum"

As glucose normalizes in hyperglycemic pseudohyponatremia, be prepared for:

Apparent worsening hyponatremia (actually revealing true sodium concentration)
Development of true hyponatremia (from water shifts and ongoing losses)
Need for sodium monitoring every 4-6 hours during active glucose correction

Dangerous Pitfall: Overcorrection Risk

Treating pseudohyponatremia with hypertonic saline can cause:

Rapid sodium overcorrection as glucose simultaneously normalizes
Risk of osmotic demyelination syndrome
Hypernatremia and volume overload

ICU-Specific Considerations

Post-operative patients: Watch for iatrogenic causes (dextrose-containing fluids, mannitol)
Cardiac surgery patients: High glucose loads from cardioplegia solutions
Burn patients: Propylene glycol from topical agents can cause pseudohyponatremia⁹
Renal replacement therapy: Consider dialysate composition effects

Evidence-Based Guidelines and Recommendations

When to Suspect Pseudohyponatremia

Strong Indicators:

Measured sodium <120 mEq/L with no neurological symptoms
Normal or elevated plasma osmolality
Significant hyperglycemia (>300 mg/dL)
Osmolar gap >15 mOsm/kg

Laboratory Confirmation Strategy

Immediate: Calculate corrected sodium using glucose
Confirmatory: Measure plasma osmolality
Definitive: Direct ISE sodium measurement (if available)
Additional: Consider arterial blood gas sodium (direct measurement)

Special Populations and Considerations

Pediatric Considerations

Children may develop pseudohyponatremia from:

Hyperglycemia (less common than adults)
Hyperlipidemia from genetic disorders
Mannitol use for cerebral edema
Consider lower correction factors due to different body water distribution¹⁰

Pregnancy and Pseudohyponatremia

Hyperglycemic pseudohyponatremia in diabetic pregnancy
Consider gestational factors affecting sodium regulation
Monitor for concurrent true hyponatremia from pregnancy-related causes

Future Directions and Emerging Concepts

Point-of-Care Testing

Development of bedside direct ISE measurements may eliminate pseudohyponatremia artifacts entirely¹¹.

Artificial Intelligence Integration

Machine learning algorithms incorporating multiple laboratory values to automatically flag likely pseudohyponatremia cases.

Precision Medicine Approaches

Individual correction factors based on patient-specific characteristics and underlying conditions.

Clinical Pearls Summary

Always correct sodium for glucose when glucose >200 mg/dL
Check osmolality - normal/high osmolality with low sodium suggests pseudohyponatremia
Don't treat the number - treat the patient and underlying condition
Monitor during correction - watch for true hyponatremia as glucose normalizes
Consider laboratory method - confirm direct ISE availability for lipemic samples
Think beyond glucose - consider other osmotically active substances in ICU patients

Conclusion

Pseudohyponatremia represents a diagnostic challenge that requires clinical acumen and understanding of underlying pathophysiology. In the modern ICU, hyperglycemic pseudohyponatremia is by far the most common variant, particularly in patients with diabetes, critical illness, or stress hyperglycemia. Recognition of this condition prevents unnecessary and potentially harmful interventions while directing attention to appropriate management of underlying disorders.

Critical care physicians must maintain a high index of suspicion for pseudohyponatremia, utilize appropriate correction formulas, and understand the dynamic nature of sodium and glucose relationships during treatment. As laboratory technology continues to evolve, the incidence of artifact-based pseudohyponatremia will likely decrease, but osmotic pseudohyponatremia will remain a relevant clinical entity requiring skillful management.

The key to successful management lies not in treating the laboratory number but in understanding the underlying pathophysiology and addressing the root cause while monitoring for the development of true electrolyte disorders during the treatment process.

References

Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 Suppl 1):S30-5.
Padhi R, Panda BN, Jagati S, Patra SC. Hyponatremia in critically ill patients. Indian J Crit Care Med. 2014;18(2):83-7.
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction. N Engl J Med. 2015;372(1):55-65.
Heavens KR, Kenefick RW, Caruso EM, Spitz MG, Cheuvront SN. Validation of equations used to predict plasma osmolality in a healthy adult cohort. Am J Clin Nutr. 2014;100(5):1252-6.
Dimeski G, Morgan TJ, Presneill JJ, Venkatesh B. Disagreement between ion selective electrode direct and indirect sodium measurements: estimation of the problem in a tertiary referral hospital. J Crit Care. 2012;27(3):326.e9-16.
Katz MA. Hyperglycemia-induced hyponatremia--calculation of expected serum sodium depression. N Engl J Med. 1973;289(16):843-4.
Weisberg LS. Pseudohyponatremia: a reappraisal. Am J Med. 1989;86(3):315-8.
Liamis G, Liberopoulos E, Barkas F, Elisaf M. Spuriously low sodium levels in patients with hyperglycemia. Diabetes Res Clin Pract. 2013;99(3):349-54.
Yaucher NE, Fish JT, Smith HW, Wells JA. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy. 2003;23(9):1094-9.
Moritz ML, Ayus JC. Disorders of water metabolism in children: hyponatremia and hypernatremia. Pediatr Rev. 2002;23(11):371-80.
Burnett RW, Covington AK, Fogh-Andersen N, et al. IFCC recommendation on reporting results for blood glucose (abbreviated). Clin Chem. 2000;46(12):2119-20.

Conflict of Interest: The authors declare no conflicts of interest.
Funding: No funding was received for this work.
Acknowledgments: The authors thank the critical care nursing staff for their clinical insights.

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Thursday, August 7, 2025