Hypertonic Saline in ICU

Introduction 🧠💦

Tonicity refers to the ability of an extracellular solution to drive water movement in or out of a cell via osmosis. A solution is hypertonic when its solute concentration is higher than that of the cell, preventing solute movement across the membrane. Hypertonic saline (HTS) consists of fluids containing sodium and chloride at concentrations exceeding physiological saline (0.9% NaCl).

🚑 The first use of HTS to reduce brain bulge dates back to 1919, when Weed and McKibben reported its efficacy. Since then, numerous studies have investigated its role across various settings—operating theaters, ICUs, and emergency departments. Despite being a strong alternative to mannitol, HTS has not achieved widespread routine clinical adoption. Let's summarize existing literature, emphasizing HTS's benefits, applications, and limitations, ultimately guiding its clinical use.

Pharmacology of Hypertonic Saline 💉💊

HTS is available in concentrations ranging from 1.8% to 30% (Table 1), but only 3% and 5% HTS are FDA-approved for treating hyponatremia and increased intracranial pressure (ICP). Some formulations incorporate dextrans for volume expansion.

📊 Sodium Concentrations and Osmolarity of Hypertonic Saline Solutions

📌 Key Consideration: Higher osmolarity solutions require central venous administration due to the risk of phlebitis and tissue necrosis.

Mechanism of Action of Hypertonic Saline 🏥⚡

HTS exerts its effects via multiple physiological mechanisms that help decrease ICP, maintain cerebral perfusion pressure (CPP), mitigate neuronal toxicity, and prevent secondary brain injury.

1. Osmotic Effect 💧⚖️

• HTS creates a marked osmotic shift, increasing plasma osmolality and oncotic pressure, pulling intracellular fluid into the intravascular space.

• The reflection coefficient of sodium across the cell membrane is 10× higher than across the endothelium (1 vs. 0.1), meaning fluid shifts primarily from the intracellular space.

• This reduces cerebrospinal fluid (CSF) production and improves intracranial compliance.

2. Microcirculatory & Vascular Effects 🔬🩸

• HTS normalizes endothelial cell volume, reversing ion-exchange dysfunction.

• It increases capillary diameter and reduces resistance to blood flow, enhancing microcirculation and cerebral blood flow (CBF).

• Renal effects include:Increased glomerular filtration rate (GFR)Decreased sodium reabsorptionModerate diuresis & natriuresis

3. Hemodynamic Effects 🫀📈

• HTS expands intravascular volume, increasing mean arterial pressure (MAP), stroke volume, and cardiac output.

• The increase in MAP lasts 15–75 min but can be prolonged with colloids.

• It decreases myocardial edema, enhances calcium uptake, and improves myocardial activity.

4. Immunologic Effects 🦠🛡️

• HTS-dextran prevents TBI-induced leukocyte adhesion, reduces tumor necrosis factor-alpha (TNF-α) & interleukin-10 (IL-10) levels, and balances coagulation & fibrinolysis.

• It reduces cerebral edema by inhibiting Na⁺-K⁺-Cl⁻ cotransporter (NKCC1) upregulation.

5. Neurochemical Effects 🧪🧬

• Restores extracellular Na⁺ levels, normalizing the Na⁺-glutamate cotransporter.

• Reduces glutamate release, limiting neuronal excitotoxicity and secondary brain injury.

• Restores intracellular ionic balance (Na⁺, Cl⁻, Ca²⁺), decreasing neuronal excitation.

🧠 Mechanisms of Action of Hypertonic Saline

Clinical Applications of Hypertonic Saline 🏥🩺

HTS is widely used in neurocritical care and neuroanesthesia, particularly for:

1️⃣ Reducing Intracranial Pressure (ICP)

2️⃣ Intraoperative Brain Relaxation

3️⃣ Resuscitation in Various Shock States

1. Intracranial Pressure (ICP) Reduction ⚖️🧠

HTS is effective for lowering ICP in traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), stroke, and mixed brain injuries.

(a) Traumatic Brain Injury (TBI)

• 3% and 7.5% HTS are commonly used.

• Key studies:

Huang et al. 🚑 Rapid 3% HTS infusion (300 mL over 20 min) significantly decreased ICP at 20 & 60 min.Qureshi et al.

📊 Prolonged HTS infusion did not reduce mortality.Berger-Pelleiter et al.

🏥 Meta-analysis showed HTS is not superior to mannitol for ICP reduction.Shi et al.

✅ HTS provides sustained ICP & CPP control over mannitol.

(b) Subarachnoid Hemorrhage (SAH)

• HTS improves CPP, CBF, and brain tissue oxygenation.

• Key studies:

Bentsen et al. 🧪 7.2% HTS infusion reduced ICP by 58% and increased CPP by 26%.Tseng et al.

📈 23.5% HTS bolus improved CBF & reduced cerebrovascular resistance.

(c) Stroke

• HTS reduces ICP but does not improve mortality.

• Chugh et al. 📑 Meta-analysis found no neurological outcome benefit.

(d) Mixed Brain Injuries

• HTS outperforms mannitol in sustained ICP reduction.

• Koenig et al. 💉 23.4% NaCl reversed transtentorial herniation in 75% of cases.

2. Hypertonic Saline in Neuroanesthesia 🏥🔬

HTS plays a crucial role in routine brain surgeries to achieve intraoperative brain relaxation, ensuring optimal surgical exposure. It serves as an alternative hyperosmolar agent to mannitol, particularly in patients with hemodynamic instability.

🔹 Intraoperative Brain Relaxation 🧠⚖️

📌 HTS vs. Mannitol for Brain Relaxation:

• Toung et al. (Experimental model) 🧪 🔹 Continuous 7.5% HTS infusion for 48 hours improved cerebral edema compared to mannitol or furosemide.

• Hernández-Palazón et al. 🎯 (Dose-response study) 🔹 3% HTS (3 vs. 5 mL/kg) had a similar effect on brain relaxation score (BRS), with no differences in postoperative outcomes.

• Rozet et al. ⚖️ (Comparative study) 🔹 7.5% HTS vs. 20% Mannitol: Both had comparable intraoperative BRS, but HTS led to better hemodynamic stability.

📊 Comparison of HTS vs. Mannitol for Brain Relaxation in Surgery

✅ Key Takeaway: HTS is as effective as mannitol in achieving brain relaxation but offers better hemodynamic stability, making it preferable in patients with cardiovascular instability.

3. Hypertonic Saline in Shock Resuscitation 🚑💓

HTS has vasoactive and volume-expanding properties, making it a promising fluid in various shock states:

🔹 I. Hypovolemic Shock 🩸⚠️

• HTS restores blood volume and tissue perfusion in trauma patients.

• 7.5% HTS + Dextran rapidly increases blood pressure but only one study showed sustained effects >1 hour.

📝 Key Trials:

• Younes et al. 📊 HTS/Dextran significantly increased BP in emergency trauma cases.

• Vassar et al. 🚑 Helicopter-transport trauma patients had better volume resuscitation with HTS/Dextran.

🔹 II. Cardiogenic Shock ❤️⚡

• HTS improves myocardial contractility by: 1️⃣ Increasing left ventricular preload 2️⃣ Decreasing afterload 3️⃣ Enhancing calcium uptake for better cardiac function

📝 Key Studies:

• Goertz et al. 🏥 HTS/HES infusion improved left ventricular systolic function in anesthetized patients.

• Licata et al. 💓 HTS proposed as an adjunctive therapy for refractory heart failure.

• Zampieri et al. 🚨 10% HTS successfully stabilized acute decompensated heart failure within 3 minutes.

🔹 III. Neurogenic Shock 🧠💥

• HTS counters hypotension caused by spinal anesthesia and spinal cord injury.

• Nout et al. 🏥 Repeated 5% HTS injections reduced spinal cord edema in experimental spinal cord injury.

🔹 IV. Septic Shock 🦠🔥

• HTS improves hemodynamics, reduces inflammation, and enhances tissue oxygenation in septic shock.

• Effat et al. 📊 HTS significantly decreased CRP levels, improved cardiac function, reduced vasopressor use, and shortened ICU stays.

✅ Key Takeaway: HTS offers a valuable resuscitative fluid in shock states, particularly in hypovolemia, cardiogenic shock, and sepsis.

4. Complications of Hypertonic Saline ⚠️🚨

Despite its benefits, HTS carries risks, especially with prolonged or rapid infusion.

🔹 1. Renal Complications 🩺💀

• Upper safe osmolarity limit: 365 mOsm/L in TBI patients.

• Hypernatremia (>160 mEq/L) increases risk of acute renal failure (ARF).

• Kumar et al. ⚠️ Hypernatremia in SAH patients correlates with higher creatinine levels.

🔹 2. Rebound Intracranial Hypertension (RIH) 🧠📈

• Prolonged HTS use may cause osmotic equilibration across the blood-brain barrier (BBB).

• Stopping HTS abruptly → Water shifts back into the brain → Rebound ICP elevation.

• Idiogenic osmoles may form, worsening cerebral edema.

🔹 3. Osmotic Demyelination Syndrome (ODS) 🧠⚠️

• Rapid sodium correction can cause central pontine myelinolysis (CPM).

• However, no reported ODS cases in TBI patients treated with HTS.

🔹 4. Systemic Side Effects 🏥📉

• Volume overload → Exacerbates heart failure in at-risk patients.

• Electrolyte Imbalances → Hypokalemia & hyperchloremic metabolic acidosis.

• Coagulation Dysfunction → Large-volume HTS infusions impair platelet aggregation.

• Local Tissue Damage → Peripheral administration may cause phlebitis & necrosis.

✅ Key Takeaway: HTS should be carefully titrated to avoid complications, particularly in patients with renal disease, cardiovascular compromise, or electrolyte imbalances.

5. Guidelines & Recommendations for Hypertonic Saline Use 📖🧠

Several international neurocritical care guidelines provide recommendations for HTS use in intracranial hypertension and neurocritical care. The most notable include:

🔹 Brain Trauma Foundation (BTF) Guidelines 🏥🔬

• HTS is recommended for pediatric traumatic brain injury (TBI) for ICP control.

• No preference between HTS & Mannitol in adults, but both agents can be used.

• Routine prehospital HTS use is not supported due to lack of survival benefits.

🔹 Neurocritical Care Society (NCS) Guidelines 🩺📑

• HTS is favored over Mannitol for acute ICP reduction in TBI patients.

• Both HTS and Mannitol can be used for acute ischemic stroke with cerebral edema, but neither improves long-term outcomes.

• In subarachnoid hemorrhage (SAH), symptom-based HTS boluses are preferred over sodium-level-targeted dosing.

• HTS should not be used in prehospital settings for neurological improvement.

🔹 American Heart Association (AHA) Stroke Guidelines 🧠🩸

• HTS or Mannitol may be used for ICP control in large hemispheric infarcts.

• No evidence supports one over the other for improving functional outcomes.

✅ Key Takeaway: HTS is an effective first-line agent for ICP control, but long-term neurological outcome benefits remain unproven.

6. Hypertonic Saline vs. Mannitol: A Comparative Analysis ⚖️🔍

Although Mannitol has been a traditional first-line osmotherapy agent, increasing evidence suggests HTS may be superior in several aspects.

🔹 Key Advantages of HTS Over Mannitol ✅📊

✅ Key Takeaway: HTS provides longer ICP control, better hemodynamic stability, and lower risk of rebound ICPthan Mannitol. However, both agents lack definitive survival benefits.

7. Future Perspectives & Unanswered Questions 🔬🚀

Despite its established role in ICP reduction and brain relaxation, several critical questions remain regarding HTS’s broader clinical impact.

🔹 Future Research Areas 🧠💡

• Long-term neurological benefits of HTS vs. Mannitol

• Optimal HTS concentration for different brain pathologies

• Combination therapy: HTS + Mannitol vs. HTS alone

• Role of HTS in neuroprotective strategies

• Impact of prolonged HTS infusion on renal function & inflammation

💡 Potential Innovations:

• Personalized HTS dosing algorithms using AI-based fluid management.

• Development of next-generation hyperosmolar agents with better safety profiles.

8. Conclusion: Where Does HTS Stand in Neurocritical Care? 🏥⚡

HTS is an important osmotherapy agent in neurocritical care and neuroanesthesia, providing:

✅ Sustained ICP control

✅ Better cerebral perfusion preservation

✅ Improved hemodynamic stability

✅ Reduced rebound ICP risk

However, major guidelines still consider HTS and Mannitol equivalent in many scenarios, given the lack of definitive survival benefits.

📌 Final Verdict: HTS is an excellent alternative or adjunct to Mannitol, particularly in hemodynamically unstable patients and those at risk of AKI.

🔗 References 📚

📖 Barik AK, Thappa P, Jangra K, Bhagat H, Kaur K. Use of Hypertonic Saline in Neuroanesthesia and Neurocritical Care Practice: A Narrative Review. J Neuroanaesthesiol Crit Care. 2023;10:12–20. DOI: 10.1055/s-0043-1763264.

🔍 Suggested Further Reading 📖🧠

Freeman N, Welbourne J. Osmotherapy: Science and Evidence-Based Practice. BJA Educ. 2018;18(09):284–90.

Joseph B, Aziz H, Snell M, et al. The Physiological Effects of Hyperosmolar Resuscitation: 5% vs. 3% Hypertonic Saline. Am J Surg. 2014;208(05):697–702.

Han C, Yang F, Guo S, Zhang J. Hypertonic Saline Compared to Mannitol for the Management of Elevated ICP in TBI: A Meta-Analysis. Front Surg. 2022;8:765784.

Cook AM, Morgan Jones G, Hawryluk GWJ, et al. Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients. Neurocrit Care. 2020;32(03):647–66.