Normal saline: Past,present,and future

Abstract

Normal saline (NS) is the most widely used agent in the medical field. However, from its origin to its widespread application, it remains a mystery. Moreover, there is an ongoing debate on whether its existence is reasonable, harmful to the human body, or will still exist in the future. The current review traces back to the origins of NS and provides a brief overview of the current situation of infusion. The purpose may shed some light on the possibility of the existence of NS in the future by elaborating on the origin of NS and the research status of the impact of NS on the human body.

Introduction

Normal saline (NS), also known as physiological saline, is a 0.9% sodium chloride solution. It is mainly used to treat dehydration caused by various reasons and as a solvent for drugs in clinics. However, the origin and widespread use of NS remain historical mysteries, ¹ despite being used for less than a century. In the long process of use, people believe that NS is almost harmless to the human body. Moreover, NS is often used as the normal control (mock) in the experiments. Additionally, NS is also a commonly used placebo. ² However, recent studies demonstrate that NS is not so “normal” and harmless, ³ and no one advocates NS as the preferred crystal solution,^4,5 even though there is more evidence that NS is harmful to the human body due to its large difference from body fluids,^6–8 and even advocates replacing NS. Currently, NS is used as a diluted antirelease drug in clinics because its osmotic pressure is almost equal to that of the human body. ⁹ Indeed, this is a key factor in the application of NS. Human cells and tissues must be at a certain osmotic pressure to maintain a stable state. However, questions arise regarding how many solutions have the same osmotic pressure as the human body, who invented NS, why it may be harmful, and whether NS will still exist or be replaced in the future. To solve this series of problems, we must first understand how NS is produced. This paper discusses the possibility of future use of NS by tracing the history of NS and the current dispute over NS.

Origin of NS

In ancient times, frequent wars resulted in a large number of wounded people in need of medical treatment. The most effective treatment for wounded people with severe blood loss was a blood transfusion. ¹⁰ It was not until the 17th century that people began to truly understand hematology and transfusion medicine. ¹¹ In 1616, William Harvey, a British scientist, put forward the theory of blood circulation for the first time, ¹² which made intravenous blood transfusion possible. In 1656, Christopher Wren and Robert, two British doctors, injected drugs into the veins of dogs using feather tubes, establishing a precedent for intravenous infusion treatment. ¹³ In 1665, Richard Lower, a British scientist, conducted the first blood transfusion experiment between dogs. ¹⁴ The experimental dogs that received blood transfusions were in good condition afterward. In 1667, Jean Baptiste Denis, a French physician, performed the first transfusion on a human patient. That same year, Richard Lower transfused blood from a lamb into the bloodstream of a clergyman named Arthur Coga, which shocked society at the time.^14,15 At the same time, Guglielmo Riva also conducted blood transfusion experiments on three patients, one of whom may have been suffering from malaria, but they only survived for a few months after the blood transfusion. ¹⁵ In ancient times, the safety of life during fluid replacement therapy could not be ensured due to the absence of evidence-based medicine. In cases of medical accidents, they were attributed to the disease since there was no concept of blood type, ¹⁶ and doctors did not have access to an adequate supply of blood. Blood from pigs, goats, and dogs was all accepted for blood transfusions, which had different outcomes. However, not everyone was lucky enough to have the chance for a blood transfusion. ¹⁷ In the absence of blood transfusions, some people attempted to infuse water into their veins as an alternative, but it proved to be ineffective and potentially harmful. People eventually discovered that blood had a salty taste, leading them to add salt to the water. However, this earliest saline was not NS. After more than 100 years of such attempts and explorations, Thomas Latta, a doctor in Edinburgh, Scotland, “filled some hot water and dissolved some salt in the water.” He injected saline into dogs and published the results in The Lancet magazine in 1831. ¹⁸ In 1832, he slowly injected 3400 mL of saline into an elderly woman who had “received various conventional treatments” with none of them working. Unfortunately, she died after receiving the saline injection. However, Lata's second patient recovered within 2 days after receiving a similar injection. At the same time, he found that water and salt were being lost in the patients with cholera, and he saved many of their lives by injecting boiled salt water into their veins to supplement the body fluids lost due to cholera-induced vomiting and diarrhea. The use of salt water by Lata to save patients with cholera was a milestone in the history of infusion. ¹⁹ Modern medical knowledge has revealed that the use of NS to treat cholera is effective in correcting peripheral circulation failure caused by dehydration. The positive results of this treatment were rapidly reported by The Lancet magazine and implemented clinically by other doctors. However, with the end of the cholera epidemic and the poor results and severe adverse reactions associated with this treatment method, Lata's method was soon buried in the river of history. Modern medical knowledge has shown that the reason for the limited effectiveness of this treatment was due to the unclear composition ratio of saline water (specifically, the ratio of water to sodium chloride) at that time. Therefore, patients injected with nonphysiological “saline” are prone to hemolysis, hypothermia, and other common infusion complications. Thus, the infusion attempt at that time had limited success in saving patients.

Origin of 0.9% sodium chloride solution

At the end of the 19th century, although salt water had certain clinical applications, people had not yet used 0.9% sodium chloride solution and the concentration of NS became the key problem. The discovery of some basic research has helped to solve this difficult problem. For example, Jacobs Henricus Van Tehoff discovered osmotic pressure and won the first Nobel Prize in Chemistry in 1901. ²⁰ The electrolyte theory proposed by Svante Arrhenius pointed out that if a large amount of liquid with insufficient electrolyte content is transfused, hypotonic hemolysis may occur, while a hypertonic solution can further aggravate dehydration. ²¹ Svante Arrhenius won the Nobel Prize in Chemistry in 1903 for this discovery. In 1923, Florence Seibert discovered pyrogen and also invented the method of preparing distilled water, which greatly increased the safety of intravenous injection. ²² The discovery of these basic research theories facilitated the development of NS. Finally, in 1936, James Gamble successfully improved the patient's prognosis by administering NS for the first time, breaking the inherent view that saline solution should not be used indiscriminately. ²³ During that time, saline infusion required strict operation, and intravenous infusion was only an additional treatment for critical diseases, which was solely performed by doctors. The use of NS also gradually expanded with the development of infusion technology and saved countless lives. However, the excessive infusion has also caused problems in some countries. ²⁴ It is still a mystery how NS became widely used. With the maturity of infusion technology, NS has continued to be used up to the present day.

Controversy and discussion on NS

Looking back at history, we can see that the emergence of NS was not verified by many rigorous scientific standards. In that era, salt and water were relatively easy to obtain, and people did not consider the potential consequences of injecting them into the human body. Upon careful consideration, this was a significant problem. Our blood or other body fluids are not solely composed of sodium chloride and water. They also contain potassium ions, calcium ions, lactic acid, and other components. However, NS has excessively high concentrations of sodium and chloride ions ³ and lacks other essential ions. The concentration of chloride ions in 0.9% sodium chloride solution is 154 mmol/L, which is higher than the 103 mmol/L concentration found in human extracellular fluid, resulting in a difference of 51 mmol/L.^25,26 Additionally, the pH value of normal human arterial blood ranges from 7.35 to 7.45, whereas the pH value of NS for infusion is around 5.5. ²⁷ Therefore, 0.9% sodium chloride solution does not conform to human physiological conditions. The intravenous infusion of NS has little impact on the human body under normal circumstances, as the normal kidney has a strong function of retaining bicarbonate and eliminating chloride ions. ²⁷ However, in cases of poisoning, dehydration, shock, heart failure, and impaired renal function, the renal blood flow decreased significantly, and the function of eliminating chloride ions was reduced. ²⁸ If large amounts of NS are intravenously injected at this time, it can lead to perchloric acid poisoning. This was noticed in the 19th century when Sydney Ringer, a British physiologist, prepared a Ringer's solution that was highly similar to the ionic composition of body fluid in strict accordance with the ionic composition of body fluid in 1882.^29,30 However, NS is too familiar to doctors and scientists, and they did not realize that it was not scientific enough. Before the 1980s, people were not aware of the harm of NS. It was not until 2010 that research on the harm of NS began to increase. In a clinical trial conducted in 2012, it was found that the use of NS could increase the incidence rate of patients with acute renal injury. ³¹ A study in 2018 seems to confirm this conclusion even more. It was found that in critically ill patients, the incidence of a compound outcome of death from any cause, whether new renal replacement therapy or persistent renal insufficiency, caused by intravenous infusion of balanced crystalloid solutions (e.g. lactated Ringer's solution), was lower than that of NS. ⁸ In a study of critically ill adults with sepsis or septic shock enrolled in a trial comparing balanced crystalloid solutions to NS, 30-day in-hospital mortality was lower with balanced crystalloid solutions compared with saline. These findings suggest that balanced crystalloid solutions may be more effective resuscitation fluids for sepsis than saline. ¹² It has been reported that early resuscitation with sodium bicarbonate Ringer's solution can better maintain acid-base balance and hemodynamic stability in patients with hemorrhagic shock and reduce the risk of related complications compared to NS. ³² While blood transfusion is now an important treatment for massive hemorrhage or traumatic shock, isotonic crystalloid is still recommended for volume expansion treatment in patients who cannot obtain constituent blood. However, there is still controversy about the choice of crystalloid. From this point of view, it seems that NS may be replaced. Nevertheless, a clinical study in 2022 found that balanced crystalloid solutions could not reduce the incidence of acute renal failure in critically ill patients. ²⁸ Other studies have also found that lactated Ringer's solution has no advantages in acute diarrhea and dehydration compared to NS.^33,34 On the contrary, NS is often used as the first choice from an economic perspective. ³⁵ This makes it controversial whether NS is harmful.

At the same time, the controversy surrounding NS has aroused people's concern and discussion. While some advocate for discontinuing the use of NS, others argue that its status should be protected. ³⁶ Those who defend NS believe that it is a better choice than lactated Ringer's solution in three clinical situations: hyperkalemia with renal impairment, brain edema, and advanced liver disease. It is believed that NS will not have much impact on clinical treatment. The controversy over NS continues, and the research on NS continues. Nowadays, the limitations of NS are discussed by more and more people.^3,20 Ultimately, it remains to be seen where NS will fit in the future of medical treatment.

A prospect or vision for the future

Due to the controversy surrounding NS, the clinical decision on which kind of crystal liquid to use has become delicate. ³⁷ It is necessary to consider the personalized treatment of patients to meet their pathophysiological needs of patients. At the same time, we cannot stay on course with using NS. One potential solution is to develop new infusions that meet the physiological characteristics of the human body. Alternatively, 0.9% sodium chloride solution may be mixed with an appropriate amount of 5% to 10% glucose solution and 5% sodium bicarbonate solution, which can not only prevent perchloric acidosis but also provide a certain amount of heat supplementation. For the controversy surrounding NS, clinical trials with larger sample sizes should be designed in the future to verify, and more comparative studies of balanced crystalloid solutions and NS are needed to prove the advantages of balanced crystalloid solutions. At present, some clinical problems are not caused by rehydration therapy with NS but by using NS as a drug solvent. It is also worth thinking about how to reduce NS for use as a drug solvent.

Conclusion

Historically, the origin of NS was accidental, and its widespread use in clinical practice remains a mystery. Due to the great difference between NS and normal body fluid composition, more and more studies have shown that balanced crystalloid solutions have advantages in some clinical applications, but whether they can replace NS is controversial, and more scientific large-scale clinical trials are needed to verify. Whether NS will be replaced or disappear in the future is still a topic that we need to be concerned about.