Hrev_master [page 31] [Emergency Care Journal 2024; 20:12310] Emergency Care Journal 2024 volume 20:12310 Abstract In the management of severe traumatic brain injuries (TBIs), controlling intracranial pressure (ICP) is a pivotal therapeutic goal. Historically, mannitol has been the recommended first-line osmot- ic agent; however, concerns surrounding its use, including hypotension, rebound ICP elevation, and renal toxicity, have prompted a quest for alternative strategies. Hypertonic saline (HS) has emerged as a promising substitute, demonstrating efficacy in reducing ICP without compromising cerebral perfusion. This com- prehensive analysis explores the comparative effectiveness of Mannitol and Hypertonic Saline in the context of severe TBIs. While Mannitol has been a longstanding choice, recent attention has shifted towards HS due to its reported superiority in ICP reduc- tion. Concerns associated with mannitol, such as hypotension and rebound ICP, are juxtaposed against the potential advantages offered by HS. The scarcity of clinical studies focusing on TBI- related outcomes, such as patient survival and long-term benefits, is highlighted, underscoring a critical gap in the current knowledge landscape. The review aims to provide a nuanced understanding of the comparative effectiveness of Mannitol and Hypertonic Saline, considering not only ICP control but also broader patient out- comes. By addressing the suitability of these agents in diverse clin- ical settings, this analysis seeks to guide clinicians in making informed decisions tailored to individual patient needs. Introduction Traumatic Brain Injury (TBI) is on the rise as a leading cause of death and an important contributor to morbidity and mortality. As seen by declining mortality rates, medical treatment for severe TBI has advanced significantly in recent years.1 The “silent epi- demic” of increased ICP is a prevalent life-threatening illness.2 Most neurological ailments principally traumatic brain injury can cause cerebral edema which eventually leads to the condition of Increased Intracranial Pressure (ICP). The main factor that causes death in patients with acute cerebral edema is thought to be elevat- ed intracranial pressure also known as Intracranial Hypertension (IH).3 Intracranial hypertension is one of the commonly seen clin- ical conditions in the intensive care unit which requires instant treatment. The major goal of care is to maintain normal cerebral perfusion pressure and Intracranial Pressure (ICP) to avoid sec- ondary brain injury.4 IH is caused by a major Central Nervous System (CNS) injury or a side effect of a concurrent systemic ill- ness. Acute Brain Injury (ABI), which is defined as any condition affecting the central nervous system, consists of two parts: a pri- mary brain damage that cannot be restored and a Secondary Brain Injury (SBI). Any physiological occurrence that can happen min- utes, hours, or days after the initial insult and causes additional nerve damage is referred to as a SBI. Since it is primarily caused by elevated ICP, it can be identified through medical evaluation and ICP monitoring, and verified by imaging testing.5 Several sig- nificant neurologic disorders share the pathologic state of elevated intracranial pressure, which is characterized by the addition of vol- ume to the cranial vault.5 The brain, cerebrospinal fluid, and blood are the three basic elements of the stiff structure known as the cra- nium. The pressure inside the cranial vault will rise with any increase in the volume of its contents.6 The capacity of the human skull ranges from 1400 to 1700 mL, and it is a rather unchanging structure. According to biology, it is made up of 80% brain parenchyma, 10% cerebrospinal fluid, and 10% blood. Since the Correspondence: Nagaraju Kishore, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, PES University, 560050 Bangalore, India. E-mail: nkishore2468@gmail.com Key words: traumatic brain injury, mannitol, hypertonic saline, cere- bral edema, intracranial pressure, brain trauma, osmotherapy, fluid management. Contributions: NK and LL, conceived and designed this systematic review, analyzed the data, and drafted the content accordingly; NK, LL, and MS performed the literature search; MS, edited and revised the drafted content. All authors approved the final version of the paper. Conflict of interest: the authors declare no potential conflict of inter- est, and all authors confirm accuracy. Ethics approval and informed consent: not applicable. Availability of data and materials: all data generated or analyzed during this study are included in this published article. Received: 25 January 2024. Accepted: 29 April 2024. Early view: 27 May 2024. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2024 Licensee PAGEPress, Italy Emergency Care Journal 2024; 20:12310 doi:10.4081/ecj.2024.12310 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Comparative efficacy analysis of mannitol and hypertonic saline in the management of traumatic brain injury: a scientific exploration of neuroprotective strategies Nagaraju Kishore, Leema Lobo, Manjari Sharma Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, PES University, Bangalore, India Non -co mmerc ial us e o nly skull is thought to be an immutable volume, any rise in the volume of its constituent parts or the inclusion of a pathologic component will lead to an increase in pressure inside the skull.7 Increased ICP may result from cerebral edema or mass lesions in patients with Traumatic Brain Injury (TBI). Ischemia and subsequent brain dam- age may result from elevated ICP because it lowers Cerebral Perfusion Pressure (CPP) to the point where Cerebral Blood Flow (CBF) may deteriorate significantly.8 TBI, stroke, intracranial hemorrhage, intracranial infection, hydrocephalus, brain tumor, as well as other neurological diseases, can all result in raised ICP as a consequence.9 The location and degree of brain damage due to increased ICP are related to the neurological outcome, although edema or infarction of the perilesional tissue are also causally related to permanent deterioration and death.10 Management of the intracranial hypertension After supportive care, which is crucial for neuroprotection, hyperosmolar treatment is the medical standard for treating ICH. Mannitol and hypertonic saline are the two osmotic agents current- ly used for this purpose.11 The application of hyperosmolar solu- tions has been one of the main medical treatments for cerebral edema. Over the past century, there has been a significant evolu- tion in the therapeutic targets, the medicines utilized, and how they are administered. The first to describe the ability of hyperosmolar liquids to reduce nerve tissue was Weed and McKibbens in 1919. They discovered that administering free water caused brain swelling while infusing a 30% saline solution significantly reduced brain volume.12 Several substances, including 50% glucose, 50% sucrose, 25% sodium chloride, 25% urea, 50% magnesium sulfate, glycerol, concentrated albumin, and concentrated plasma, were examined for the purpose. The warning that “most of these dehy- drating substances have only a transient effect, which may be fol- lowed by a “rebound phenomenon” during which the intracranial pressure can rise above that which existed before their administra- tion” was included in the literature used to temper its use.13 However, during neurosurgery or critical care unit admissions, hyperosmolar solutions are frequently used to lower ICP and brain volume.14 Mannitol Brain edema can be caused by a variety of neurosurgical con- ditions, most notably craniocerebral trauma, which can then increase ICP. The main factor that causes mortality among individ- uals with acute cerebral edema is thought to be elevated pressure. Mannitol’s usefulness as a regularly used medication to lower ICP has long been acknowledged.15 1,2,3,4,5,6-hexanehexol, often known as mannitol (C6H8(OH)6), is a naturally occurring polyol that is largely employed for its osmotic diuretic characteristics. Mannitol decreases ICP by raising intravascular osmotic pressure, which draws extracellular fluid into the intravascular compartment since it cannot cross the endothelium membrane. By increasing plasma volume, mannitol initially reduces blood viscosity while also increasing microvascular flow and tissue oxygenation. Increased tissue perfusion causes a vasoconstriction reflex, which reduces blood flow to the brain and lowers ICP. Meanwhile, man- nitol causes a rise in intravascular osmotic pressure, widening the osmotic gradient between the intravascular and extravascular com- partments due to its size and difficulty in permeating through the endothelium barrier. The edematous fluid will eventually be pushed into blood vessels and significantly aid in decreasing ICP.16 However, major adverse effects are becoming more and more evi- dent, like rebound cerebral edema and acute renal failure. The potential negative effects of the hyperosmolar drug are to be taken into account while deciding whether to administer it. Strong diuret- ics like mannitol can increase the potential of injury to the kidneys in hypovolemic patients. mannitol causes osmotic diuresis, the ini- tial quick rise in intravascular volume paradoxically has the poten- tial to lead to acute hypervolemia and, can cause cardiac failure or pulmonary edema in vulnerable patients.17 In the aftermath of brain damage, mannitol is frequently administered to lower elevated intracranial pressure. Initially, mannitol reduces the swelling, but there is proof that continued use over time can eventually make the pressure worse. When it comes to the pre-operative treatment of patients with acute cerebral hemorrhages, high-dose mannitol seems to be preferred to conventional-dose mannitol. The use of mannitol as a continuous infusion in patients with elevated intracranial pressure who do not have an operative cerebral hemor- rhage is, however, not well supported by the available research. The ideal administration of mannitol after an acute traumatic brain injury is still a subject of much debate. Mannitol’s present widespread use and the dearth of knowledge when compared with other medicines that lower intracranial pressure still require appro- priate investigation.18 Hypertonic saline To lower intracranial pressure after traumatic brain injury, hypertonic saline is utilized as a hyperosmolar treatment. It is still debatable whether hypertonic saline is more successful than other intracranial pressure-lowering medications in the short- and long- term therapy of acute traumatic brain injury.19 Still, there are sev- eral potential ways for how intracranial hypertension may be treat- ed with Hypertonic Saline (HS). By establishing a pressure gradi- ent within the intracellular and intravascular spaces and by exhibit- ing some rheological effects, the HS has demonstrated a biphasic reduction in ICP. Fluid moves osmotically from the intracellular into the interstitial and intravascular area as a result of this gradi- ent. The hypertonic saline administered must remain in the intravascular area and not penetrate the blood-brain barrier to sus- tain this osmotic gradient.20 HS serves as a plasma volume expander and has an osmotic impact on the cerebral interstitium. There is proof that hypertonic saline has neurohumoral and vasoregulatory effects as well. In the context of vasospasm, it may also operate as a cerebral vasodilator.21 With the administration of HTS, ICP reduction is safe to achieve. In those who have therapy- resistant rise of ICP, repeated bolus administration of HTS may result in a considerable reduction in ICP. A proper ICP reduction can prevent subsequent damage and potentially life-threatening consequences.22 When utilized for patients with head injuries com- pounded by hemorrhagic shock, the benefit of improved survival was noted, leading to the initial recognition of HTS as a potentially more successful alternative for hemorrhagic shock resuscitation. HTS is typically administered as a bolus or continuous infusion at dosages of 1.0 to 4.0 mL/kg, with a concentration range of 3.0% to 23.4%.23 The administration of HS needs to be taken into account, it may result in demyelination syndrome in patients with a chronic condition of hypernatremia and hyponatremia.24 To prevent the negative effects, a periodic electrolyte serum check may be required. Because HS has a higher coefficient to cross the brain Review [Emergency Care Journal 2024; 20:12310] [page 32] Non -co mmerc ial us e o nly barrier than mannitol, the rebound phenomenon is less frequent when administered with HS.21 Intracranial pressure monitoring For most healthcare workers, including neurological surgeons and physicians, ICP is equivalent to a numerical figure. It might be the amount of fluid in an irrigation system or the value displayed on the display of the computer in millimeters of mercury (mmHg).25 ICP is much more than just a number. To enhance clin- ical decision-making, a variety of ICP ratings and ICP-derived assessments have been investigated.26 Normal mean ICP readings have not been determined since ICP assessments in individuals in good health cannot be justified ethically. Only indirect evidence concerning ICP from people who are “as normal as possible” is available. The aim, by TBI guidelines, is to keep mean ICP under 20 mmHg.27 The mean ICP values don’t seem to alter between the hours of day and night.28 The average mean ICP values, on the other hand, are significantly dependent on body posture. The mean ICP decreases when a person stands up straight. reported that the positional variation in mean ICP might distinguish healthy persons from CSF disturbance patients. In our clinical practice, mean ICP in a standing position of less than 5 mmHg is considered abnormal.29,30 To add clinical significance to mean ICP alone, it has been coupled with additional variables to form multiple indices. CPP, which is the variation between average arterial BP and aver- age ICP (CPP = mean arterial BP-mean ICP), is probably the most well-known ICP-derived measure.31 Other indicators employed in certain centers include the RAP, which stands for the relationship between amplitude and pressure, and the pressure reactivity index(PRx).32 A RAP greater than 0.6 has been regarded as indicat- ing a deteriorated pressure-volume reserve.33 The PRx (moving association of average ICP and average arterial BP) is thought to be an indicator of auto-regulatory status or a measure of cere- brovascular responsiveness.34 Hyponatremia: an emergency in traumatic brain injury The primary electrolyte imbalance seen in individuals with TBI is hyponatremia and is considered as most emergency, which is defined as serum sodium <135 meq/L. Hyponatremia has been documented to occur in 9.6% to 51% of TBI patients, and it is well-known that hyponatremia independently predicts a poor neu- rologic prognosis in TBI patients. The Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), hypopituitarism, Cerebral Salt Wasting Syndrome (CSW), and insufficient salt con- sumption in the diet are the major causes of hyponatremia in TBI patients.35 Following traumatic brain injury, dysregulation of the neuroendocrine system is a common consequence (TBI). These hormone imbalances often have mild symptoms that are simple to overlook. Usually, hyponatremia is a sign of underlying illnesses that interfere with fluid homeostasis. Hyponatremia is a character- istic of the SIADH following brain injury in the majority of TBI patients, which is caused by pituitary failure. Hyponatremia linked to traumatic brain injury is often temporary and curable.36 When mannitol is administered to reduce intracranial pressure in traumat- ic brain injury intravascular free water content is first raised, which might exacerbate electrolyte imbalances, such as hyponatremia. The second phase of action involves the excretion of mannitol in the urine together with an excess of free water, which may lead to hypernatremia because of the induced diuresis.37 Mannitol also worsens the cerebral edema. It partially penetrates the vessel wall, despite its limited cross-sectional area, in individuals with cerebral hemorrhage, mannitol crosses the vascular wall more readily. Mannitol can penetrate the blood-brain barrier when taken fequently, which can exacerbate cerebral edema because the man- nitol draws water into the brain rather than out of it. Mannitol treat- ment may cause patients’ cerebral edema to deteriorate, particular- ly in children with cerebral hyperemia.38 Hypertonic Saline Solution (HSS) restores intracranial compliance, extracts fluid from the interstitial space, and lowers intracranial pressure, mostly by preventing the buildup of extracellular osmolytes in the brain that is associated with blood-brain barrier malfunction.39 For the treatment of increased ICP, mannitol remains the cornerstone of hyperosmolar therapy, however, a bolus infusion of HSS is more effective.40 Thus in TBI patients without ICH, continuous HSS infusion enhanced Cerebral Perfusion Pressure (CPP), raised natremia and osmolarity, and reduced the likelihood of ICH.41 Comparison of hypertonic saline and mannitol Intracranial pressure is a key indicator of decline in neurolog- ical function in patients with traumatic brain injury.42 It has also been demonstrated that when cerebral perfusion pressure is severe- ly low (50 mm Hg), intracranial pressure becomes an indicator of undesirable outcome, and maintaining intracranial pressure in the range of 18 to 23 mmHg verifies that cerebral perfusion pressure remains constant for a longer period.43 Mannitol has been utilized for years to treat elevated intracranial pressure. Recommendations recently suggested that mannitol is more efficient than barbiturates in lowering intracranial pressure in people with traumatic brain injury.44 Mannitol, causes a decrease in cerebral perfusion pressure due to its diuretic mechanism of action, which can cause the devel- opment of several adverse effects, including edema in the lungs, acute kidney dysfunction, and arterial hypotension, which causes a decrease in cerebral perfusion pressure due to its diuretic impact.45 In a Randomised prospective trial conducted by Vialet et al., the patients were randomly assigned to one of the two groups: one that received 7.5% hypertonic Saline (361 mOsm) and one that received 20% mannitol (175 mOsm) in the same amount (2 mL/kg). In comparison to hypertonic saline, the mannitol group had greater total and duration of daily periods of ICP > 25 mmHg and needed more CSF fluid drainage. This study also found that treatment failure was 70% higher in the mannitol group compared to 10% in the hypertonic saline group. There was no significant difference in mortality or neurological improvement after 90 days. It was noted that the study used both fluids with different osmolar- ities.46 The optimum therapeutic agent for controlling intracranial pressure should reduce intracranial pressure while maintaining cerebral perfusion. Hypertonic saline boosts serum sodium and osmolality considerably. Excessive salt levels and osmolarity pro- duce an overload of volume, edema of the lungs, and heart failure, or they might begin coagulopathy and hyperchloremic metabolic acidosis. Thus, hypertonic solutions should be administered with caution and under constant cardiac surveillance in individuals with impaired cardiac function.47-48 In patients with head trauma (whether single or numerous injuries), it is important to avoid hypotension, since it boosts the incidence of mortality in this con- text.49 In contrast to mannitol, an osmotic diuretic, HTS preserves and even improves the mean arterial blood pressure in various Review [page 33] [Emergency Care Journal 2024; 20:12310] Non -co mmerc ial us e o nly kinds of shock.50 Isotonic resuscitation using fluids in the trauma circumstance, necessitates a large amount of fluid, which can raise ICP. The significant benefit of HTS in this context is that blood pressure is maintained with minimal volume resuscitation, pre- venting possible iatrogenic ICP elevations.51 Intravenous adminis- tration of hypertonic saline increased cerebral perfusion and shift- ed the oxygen dissociation curve, thus boosting the availability of oxygen and brain responsiveness while decreasing intracranial pressure and cerebral edema.52 HTS may have a role in brain cell immune system regulation, perhaps leading to beneficial effects on inflammation and a better prognosis for TBI patients. The inflam- matory cascade is activated by severe trauma, resulting in systemic allergic reaction syndrome. Furthermore, cerebral leukocytes move to wounded regions in response to TBI, resulting in peroxi- dase- and protease-mediated cell death.53 The study conducted by Battison et al. in 2005 discovered that both mannitol and hyperton- ic saline considerably lowered ICP, however hypertonic saline dra- matically reduced ICP more strongly and for an extended period than mannitol. The usage of the identical osmolarity between the two fluids is the study’s key strength.54 In the final analysis, man- nitol is regarded as the “standard of care” treatment for TBI- induced intracranial hypertension because of its historical use rather than its efficacy against HTS. HTS offers numerous theoret- ical benefits over mannitol in terms of physiology. In clinical terms, HTS appears to be more effective than mannitol in lowering ICP, both in terms of degree and duration of decrease. Ultimately, HTS appears to promote brain tissue oxygenation more than man- nitol. All of these benefits imply that HTS should be thoroughly researched so that it might potentially be utilized as an alternative to mannitol as a first-line treatment for the management of elevat- ed ICP in TBI patients. It is uncertain if a bolus dosage or an infu- sion is required. The bolus dosage was administered at various pro- portions with no indication of superiority of any concentration in particular, although total osmolar load must be considered. Infusions with 3% HTS at a rate of 0.1-2mL/kg/h have been proven to be successful, with step-wise titration of the dosage to a goal of 145-155mEq/L NA+ (maximum 160mEq/L) and an osmo- lality of 320-330mOsm/L (maximum 360mEq/L). According to the literature, HTS infusion decreases ICP over 72 hours, however, this effect cannot be sustained with continued treatment. The bolus dosage can be administered alone or in conjunction with continu- ous infusion treatment. It is also used to reduce ICP in people who have not had surgery.55 In the study conducted by De Vivo et al. the first group received mannitol, the following one received Mannitol+HTS, and the third group received solely HTS and the treatment continued for 72 hours, utilizing boluses three times each day. They concluded that HTS is a viable option for decreasing ICP in humans without affecting CVP or serum osmolality. It is unlike- ly to cause allergic responses or to transfer infectious agents, and it is readily managed by serum Na levels. In intracranial surgery, it is an acceptable substitution for mannitol.56 Following elective craniotomy, mannitol, and HTS enhance CSF osmolality and are associated with comparable levels of cerebral relaxation, arteriove- nous O2 differential, and lactate. They propose that HTS should be employed instead of mannitol to reduce brain size in patients with and without subarachnoid hemorrhage, especially if they are hemodynamically unstable.57 Resuscitation with fluids is crucial in TBI patients because it prevents hypotension and subsequent brain damage, both of which increase mortality. The Brain Trauma Foundation’s care recommendations for TBI state unequivocally that hypotension must be avoided since it is an independent char- acteristic of poor prognosis. The administration of fluids in this patient, particularly with HTS alone or in combination with dex- tran, restores intravascular volume with less volume,58 raises CPP, decreases ICP,59 and regulates the inflammatory response.60-67 The beneficial effect of HTS over mannitol in terms of potential long- term neurological consequences is still unknown. To solve this topic, a substantial prospective randomized investigation is required. Many of the issues have yet to be resolved, necessitating more studies to reach a firm judgment on the supremacy of these hyperosmolar drugs. Evidence linking management of cerebral edema in traumatic brain injury There have been few research that compare mannitol with HTS in the context of pure cerebral relaxation in tumors. De Vivo et al. undertook a prospective, randomized comparative analysis of supratentorial tumors. The study concluded that HTS is an efficient way to reduce ICP in people without affecting CVP or serum osmolality. It is unlikely to cause anaphylaxis or spread infectious agents, and serum Na levels can readily regulate it. It is a viable alternative to mannitol in intracranial surgery.68 Several investiga- tions have examined the cerebral effects of mannitol and HTS in patients with normal ICP. Gemma et al. found that HTS and man- nitol produce acceptable cerebral relaxation in individuals under- going elective craniotomy. This investigation was carried out using several neurosurgical techniques and non-equimolar dosages of HTS and mannitol.69 The clinical evidence comparing hypertonic saline and manni- tol is discussed in the Supplementary Materials, Table 1.70-77 A summary of the comparison of safety efficacy profile of mannitol and hypertonic saline is available in the Supplementary materials, Table 2. Conclusions The significance of Intracranial Pressure (ICP) in managing conditions like traumatic head injuries and various neurologic dis- eases cannot be overstated. It is crucial to recognize that the prima- ry objective of ICP management is to optimize cerebral perfusion pressure (CPP) for the preservation of cerebral metabolism and neurologic function. Solely concentrating on ICP, without consid- ering other relevant physiologic variables such as CPP, oxygen uti- lization, and clinical outcomes, is a notable flaw in numerous pub- lished randomized controlled trials (RCTs) focusing on hyperos- molar therapy. Regardless of the specific hyperosmolar agent employed, the efficacy of hyperosmolar therapy for acute ICP management has been substantiated by both clinical experience and RCTs. Mannitol and HS are the most commonly used hyper- osmolar agents, each with distinct physiologic properties affecting blood rheology, inflammation, neurochemistry, and hemodynamic regulation. While the idea of a universally applicable, single opti- mal agent is appealing, it is more plausible that different hyperos- molar agents may exert optimal therapeutic effects in diverse clin- ical contexts. For example, the relative merit of using HS, which expands systemic volume status, versus mannitol, which depletes it, needs exploration in patients with congestive heart failure expe- riencing elevated intracranial hypertension. Trials should consider testing equimolar agents infused over the same period to mitigate the effects of molarity and infusion time, a consideration often absent in existing literature. In conclusion, a thoughtful analysis of individual clinical scenarios, coupled with a rigorous interpretation Review [Emergency Care Journal 2024; 20:12310] [page 34] Non -co mmerc ial us e o nly of existing literature, is essential for providing optimal patient care. References 1. Mangat HS, Wu X, Gerber LM, et al. Hypertonic saline is superior to mannitol for the combined effect on intracranial pressure and cerebral perfusion pressure burdens in patients with severe traumatic brain injury. Neurosurgery 2020;86:221- 30. 2. Dewan MC, Rattani A, Gupta S, et al. 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Review [page 37] [Emergency Care Journal 2024; 20:12310] Online supplementary material: Table 1. Clinical evidence comparing hypertonic saline and mannitol. Table 2. Summarising the comparison of safety efficacy profile of mannitol and hypertonic saline. Non -co mmerc ial us e o nly