Saline and Diuretic for High Blood Pressure

Overseen By Virginia Nuckols, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Delaware

Must not be taking: Psychiatric medications, Hypertension medications

Disqualifiers: Cardiovascular, Cancer, Metabolic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 hour

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you will need to stop taking any hypertension (high blood pressure) medications and psychiatric or neurological medications to participate in this trial.

What data supports the effectiveness of the treatment for high blood pressure?

Research suggests that combining hypertonic saline with furosemide (a diuretic that helps the body get rid of excess salt and water) may reduce mortality, hospital stay, and readmissions in patients with acute heart failure, which could indicate potential benefits for high blood pressure treatment. ^{1 2 3 4 5}

Is 3% sodium chloride solution safe for use in humans?

Research shows that 3% sodium chloride solution can be safely administered through a peripheral IV or central venous catheter, with no reported local infusion reactions over a 10-year period in a large healthcare system. ^{6 7 8 9 10}

How is hypertonic saline infusion different from other treatments for high blood pressure?

Hypertonic saline infusion is unique because it involves administering a concentrated salt solution (3% sodium chloride) directly into the bloodstream, which can influence fluid balance and sodium levels in the body. This approach is different from typical blood pressure medications that often work by relaxing blood vessels or reducing fluid volume through diuretics. ^{3 10 11 12 13}

What is the purpose of this trial?

The overall objective of this project is to identify the key salt-sensing regions of the brain and determine the underlying mechanism of sodium sensing. The investigators will assess how the brain responds to an acute increase of salt in the blood using MRI. This will be done during a 30-minute infusion of a saline solution containing 3% salt. One trial will be conducted with a salt sensing channel blocker and one trial without the salt sensing channel blocker. This will help to assess the role of a specific salt sensing channel in the brain. Salt sensitivity of BP will be assessed using 7-day dietary feeding where participants will be given food to consume for 7-days. Comparisons will be made between salt resistant (no change in blood pressure going from low to high salt diets) and salt sensitive adults (a change in blood pressure going from low to high salt diets). The investigators think the changes in MRI will be greater in salt sensitive compared to salt resistant subjects.

Eligibility Criteria

This trial is for adults aged between 40 and 60 with normal potassium levels, no history of heart, kidney, metabolic or brain diseases. Participants should have slightly elevated blood pressure but not full hypertension, and a BMI indicating they are neither underweight nor obese.

Inclusion Criteria

I have no history of heart, kidney, metabolic, or brain diseases.

I am between 41 and 59 years old.

Blood pressure: > 100/60 mmHg or < 140/90 mmHg

Exclusion Criteria

Blood pressure: < 100/60 mmHg or > 140/90 mmHg

Serum potassium: < 3.5 mmol/L or > 5.5 mmol/L

Abnormal ECG

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dietary Feeding

Participants undergo a 7-day dietary feeding to assess salt sensitivity of blood pressure

1 week

Daily monitoring

Treatment

Participants receive a 30-minute infusion of 3% saline solution with or without a salt sensing channel blocker

1 hour

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 hour

Treatment Details

Interventions

• Furosemide
• Hypertonic Saline Infusion

Trial Overview The study tests how the brain reacts to high salt levels in the blood using MRI scans during saline solution infusions. It compares responses in people who are salt-sensitive (blood pressure changes with salt intake) versus those who aren't by monitoring their diet for seven days.

Participant Groups

Group I: Salt Sensitive Experimental Treatment 2 Interventions

Adults who experience increased BP (mean arterial pressures \>5mmHg) during dietary sodium challenge

Group II: Salt Resistant Adults Experimental Treatment 2 Interventions

Adults who experience minimal BP change during dietary sodium challenge

Hypertonic Saline Infusion is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Hypertonic Saline Solution for:

• Severe hyponatremia
• Cerebral edema
• Increased intracranial pressure

Approved in European Union as Hypertonic Saline Solution for:

• Severe hyponatremia
• Cerebral edema
• Increased intracranial pressure
• Traumatic brain injury

Approved in Canada as Hypertonic Saline Solution for:

• Severe hyponatremia
• Cerebral edema
• Increased intracranial pressure

Who Is Running the Clinical Trial?

University of Delaware

Lead Sponsor

Trials

167

Recruited

25,700+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 70 hospitalized patients with acute heart failure, the addition of oral sodium chloride (NaCl) during intravenous diuretic therapy did not significantly affect renal function or weight change compared to a placebo, indicating that salt intake may not be crucial in this context.

While there were no significant differences in the primary endpoints, the NaCl group did show a notable reduction in serum sodium and blood urea nitrogen levels, suggesting some biochemical changes, but overall, the study concluded that liberal versus restrictive NaCl intake strategies did not impact the safety and efficacy of diuretic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Sodium to Preserve Renal Efficiency in Acute Heart Failure: A Randomized, Placebo-Controlled, Double-Blind Study. Montgomery, RA., Mauch, J., Sankar, P., et al.[2023]

In a study of 1771 patients with NYHA class III heart failure, the combination of hypertonic saline solution (HSS) and moderate sodium restriction significantly reduced hospitalization time (3.5 days vs. 5.5 days) and improved long-term outcomes, including lower readmission rates (18.5% vs. 34.2%) and mortality (12.9% vs. 23.8%).

Patients receiving HSS also experienced increased diuresis and serum sodium levels, while the control group showed elevated blood urea nitrogen and serum creatinine, indicating that HSS may provide a safer and more effective treatment option for managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (Class C) (SMAC-HF Study). Paterna, S., Fasullo, S., Parrinello, G., et al.[2013]

In a porcine model of intracranial hypertension, the infusion of a 20 mL/kg bolus of 3% hypertonic saline did not significantly reduce intracranial pressure, indicating limited efficacy in this experimental setup.

The study found no significant changes in serum sodium levels during the infusion, suggesting that the treatment was safe in terms of sodium concentration, but it did not achieve the desired therapeutic effect on intracranial pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Maintained Effect of 3% Hypertonic Saline Solution in an Animal Model of Intracranial Hypertension. Sousa, LM., de Andrade, AF., Belon, AR., et al.[2019]

Hypertonic saline solution (HTS) treatment in rats with uncontrolled hemorrhagic shock initially improved blood pressure and cardiac index but ultimately led to increased bleeding and decreased survival, highlighting potential risks associated with its use.

The increased blood loss was linked to elevated vascular pressure and impaired platelet aggregation, suggesting that while HTS can temporarily stabilize hemodynamics, it may have harmful effects on bleeding control and overall survival in traumatic injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic, hematologic and eicosanoid mediated mechanisms in 7.5 percent sodium chloride treatment of uncontrolled hemorrhagic shock. Rabinovici, R., Yue, TL., Krausz, MM., et al.[2013]

The addition of hypertonic saline to furosemide treatment in patients with acute heart failure may significantly reduce mortality, length of hospital stay, and hospital readmission rates, based on a systematic review of nine randomized controlled trials.

This conclusion is supported by a comprehensive search of the Epistemonikos database, indicating a promising new therapy for addressing diuretic resistance in acute heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What are the effects of hypertonic saline plus furosemide in acute heart failure? Zepeda, P., Rain, C., Sepúlveda, P.[2018]

The study evaluated the safety and efficacy of a hypotonic 0.225% sodium chloride infusion in 20 critically ill patients with hypernatremia, showing a significant decrease in serum sodium levels from 156 to 143 mEq/L over 3-7 days (P < .001).

While the infusion effectively lowered sodium levels, it also indicated potential minor hemolysis, as evidenced by an increase in plasma free hemoglobin, suggesting that further research is needed to confirm the safety of this treatment before it can be routinely recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of intravenous hypotonic 0.225% sodium chloride infusion for the treatment of hypernatremia in critically ill patients. Dickerson, RN., Maish, GO., Weinberg, JA., et al.[2015]

Over a 10-year study involving 2,306 patients across a large healthcare system, there were no reported local infusion reactions associated with the administration of 3% sodium chloride (NaCl), indicating its safety for use through peripheral IVs.

The findings suggest that 3% NaCl can be safely administered for treating conditions like hyponatremic encephalopathy without the risk of local infusion complications, which may encourage its use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of 3% Sodium Chloride and Local Infusion Reactions. Moritz, ML., Ayus, JC., Nelson, JB.[2022]

In a study involving Wistar Kyoto and spontaneously hypertensive rats (SHR-S), it was found that a high-sodium diet did not significantly enhance sodium and fluid excretion in SHR-S compared to other rat strains, indicating a specific renal response issue in SHR-S.

Despite lower baseline sodium excretion in SHR-S, all groups showed increased sodium and fluid excretion after hypertonic saline infusion, suggesting that the renal function deficits in SHR-S are not due to a generalized inability to respond to sodium challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renal responses to hypertonic saline infusion in salt-sensitive spontaneously hypertensive rats. Mozaffari, MS., Roysommuti, S., Shao, ZH., et al.[2019]

In a study of 122 patients with severe hyponatremia (sodium levels ⩽120 mEq/L), those treated with 3% hypertonic saline experienced a greater increase in serum sodium levels within 24 hours compared to those treated with normal saline (9.24 mEq/L vs. 6.60 mEq/L).

Patients receiving normal saline had a longer hospital stay (10.35 days) compared to those treated with hypertonic saline (4.35 days), indicating that hypertonic saline may lead to quicker recovery and fewer complications in severe cases of hyponatremia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyponatremia management among patients admitted to tertiary hospital: A retrospective evaluation. Zurnuq, S., Aljurfi, M., Albekery, M., et al.[2022]

A standardized sliding-scale protocol for administering hypertonic saline (3% NaCl) in 49 critically ill patients effectively maintained serum sodium levels within the target range (136-145 mEq/l) for 84.3% of the time, demonstrating its efficacy in treating acute neurologic hyponatremia (ANH).

The protocol resulted in minimal risk of overshooting sodium levels, with only 0.7% of the time spent above the target range, and no adverse events related to the hypertonic saline infusion were reported, highlighting its safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance characteristics of a sliding-scale hypertonic saline infusion protocol for the treatment of acute neurologic hyponatremia. Woo, CH., Rao, VA., Sheridan, W., et al.[2021]

In a study involving 12 patients with terminal hypovolemic shock who did not respond to standard treatments, injections of hyperosmotic sodium chloride (7.5%) successfully reversed shock in 11 patients, demonstrating its efficacy in critical situations.

The treatment led to immediate improvements such as increased arterial pressure, restored urine flow, and regained consciousness, while also significantly reducing the need for additional fluid replacement by 90%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of refractory hypovolaemic shock by 7.5% sodium chloride injections. de Felippe, J., Timoner, J., Velasco, IT., et al.[2022]

In a study involving 8 subjects, hypertonic saline infusion did not lead to greater sodium excretion (natriuresis) compared to isotonic saline, despite both infusions resulting in similar sodium excretion levels.

The findings suggest that while hypertonic saline increases plasma sodium levels, the natriuretic response is similar to that of isotonic saline, indicating that osmoreceptor stimulation may play a role in sodium excretion rather than volume changes alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isotonic and hypertonic sodium loading in supine humans. Andersen, LJ., Jensen, TU., Bestle, MH., et al.[2013]

The study found that HSwSA, a hypertonic saline solution buffered with sodium acetate, maintains similar hyperosmolarity to standard 3% hypertonic saline while significantly reducing serum chloride levels, which is important for preventing hyperchloremia-related complications.

Patients switched from 3% HS to HSwSA experienced a decrease in serum chloride levels, while those who continued on 3% HS saw an increase, highlighting HSwSA's potential to mitigate risks of acute kidney injury and metabolic acidosis associated with high chloride exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypertonic saline buffered with sodium acetate for intracranial pressure management. Holden, DN., Yung, FH., Entezami, P.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Oral Sodium to Preserve Renal Efficiency in Acute Heart Failure: A Randomized, Placebo-Controlled, Double-Blind Study. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (Class C) (SMAC-HF Study). [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Evaluation of the Maintained Effect of 3% Hypertonic Saline Solution in an Animal Model of Intracranial Hypertension. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Hemodynamic, hematologic and eicosanoid mediated mechanisms in 7.5 percent sodium chloride treatment of uncontrolled hemorrhagic shock. [2013]

5. Chile pubmed.ncbi.nlm.nih.gov

What are the effects of hypertonic saline plus furosemide in acute heart failure? [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of intravenous hypotonic 0.225% sodium chloride infusion for the treatment of hypernatremia in critically ill patients. [2015]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Administration of 3% Sodium Chloride and Local Infusion Reactions. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Renal responses to hypertonic saline infusion in salt-sensitive spontaneously hypertensive rats. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Hyponatremia management among patients admitted to tertiary hospital: A retrospective evaluation. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Performance characteristics of a sliding-scale hypertonic saline infusion protocol for the treatment of acute neurologic hyponatremia. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Treatment of refractory hypovolaemic shock by 7.5% sodium chloride injections. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Isotonic and hypertonic sodium loading in supine humans. [2013]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Hypertonic saline buffered with sodium acetate for intracranial pressure management. [2021]