Introduction
Both colloids and crystalloids have been extensively used in the management of raised
intracranial pressure (ICP) after traumatic brain injuries (TBIs). Compared with the
colloid solutions, crystalloids better mimic the plasma characteristics and are associated
with reduced incidences of alterations in electrolyte and pH balances.[1]
[2] Crystalloid solutions have always been the preferred first-line agent in the fluid
resuscitation for shock patients.[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11] They have recently become the preferred agents for osmotherapy for neurotrauma patients[12]
[13] due to their ability to modulate the inflammatory reaction in the neural parenchyma.[14]
[15]
[16] Numerous studies to establish the superiority of one over the other have been conducted
in the past comparing mannitol and hypertonic saline.[17]
[18]
[19]
[20]
[21] Even though no consensus could be reached, individual recommendations have been
made.[17] Here we attempt to review the role of hypertonic saline in the management of TBI.
Raised Intracranial Pressure
The Monro–Kellie doctrine implies the need for management of raised ICP in patients
with TBI to avoid secondary damage. In these cases, the measurement of ICP becomes
an important outcome predictor.[20] This ICP reading, along with the blood pressure, volume, and viscosity, determines
the cerebral blood flow (CBF). This is the reason why reducing the ICP is the main
objective in the management of TBI patients,[11]
[21]
[22]
[23]
[24]
[25] and osmotherapy plays the central role in achieving this goal.[23]
[24]
[25]
After the primary insult to the neuroparenchyma, if ICP rises, it leads to a fall
in the cerebral perfusion pressure (CPP), which further leads to a reduction in CBF.
This reduction in CBF is the major cause of secondary brain injury.[26]
[27] Other than this, the next major cause of morbidity and mortality is acute blood
loss (hemorrhagic shock), which may lead to massive tissue ischemia, an exaggerated
systemic inflammatory response syndrome and multiorgan dysfunction syndrome (MODS).[28] When this cascade sets in, it can be associated with cerebral death, neurologic
deficits, permanent disability, brain herniation, and even death.[9]
[21]
[23]
[29]
The main objective of the management of TBIs is to control the ICP to maintain CPP
and CBF in physiological ranges.[26] Even before a surgical intervention is undertaken, osmotherapy is the first-line
treatment in the medical management to reduce the raised ICP.[30] The timing of initiation of hyperosmolar therapy is critical to contain the progressive
neuronal loss after the trauma.[10]
Intracranial Pressure and Physiological Effects of Hypertonic Saline Solution
Intravenous fluid therapy with hypertonic saline solution (HSS) for reducing elevated
ICP dates back to almost 100 years ago.[3]
[22]
[24]
[31] The physiological effects of the HSS are diverse, and there are multiple mechanisms
through which it exerts its therapeutic effects. The basic mechanism of action of
any hyperosmolar agent is to generate an osmotic gradient across the endothelial barrier
between the endovascular and tissue environments.[3] The HSS is a solution with a concentration of NaCl (sodium chloride) higher than
the normal or physiological value. It has been extensively subjected to basic and
clinical research in the last couple of decades. Its efficacy has been demonstrated
in reducing an elevated ICP after TBI or due to other causes including intracranial
bleeding of spontaneous or traumatic etiology.[9]
[18]
[19]
[20]
[22]
[23]
[29]
[32]
[33]
[34]
[35]
[36] One of the main advantages of the HSS usage is the rapid reduction of the ICP with
extended responsiveness greater than 2 hours without pressure rebound, which is related
to improved neurologic outcomes.[23]
Additionally, HSS has shown other rheological effects such as plasma expansion, improvement
in microcirculatory blood flow, reperfusion injury protection, and recovery of CPP,
among others.[8]
[10]
[11]
[29]
[37]
Saline solution of 0.9% is used as standard replacement and maintenance fluid in neurosurgical
patients. It is the preferred agent due to its very low propensity to cause intravenous
fluid related cerebral edema.[1]
[27] When used in hyperosmolar concentrations (3% or more), it exerts its ICP lowering
effect, mostly caused by an osmotic gradient that produces a shift of free water from
the interstitial and intracellular spaces to the intravascular space.[11]
[12]
[22]
[33] This reduction in tissue fluid by the immediate hyperosmolar effect leads to a reduction
in ICP.[11]
[13]
[23] Bolus treatment with HSS is indicated in patients with refractory raised ICP, where
intravascular fluid expansion helps maintaining CPP while reducing edema.[20]
[22]
[23]
[29]
[33] The blood–brain barrier (BBB) is a water permeable structure, which means that hypotonic
solutions lead to a water shift to the brain while hypertonic solutions lead to brain
dehydration.[27] An intact BBB is needed to achieve the beneficial effects of hyperosmolar therapy.[13] Consequently, on administration of any hyperosmolar agent, ICP reduction occurs
in the uninjured brain regions where the BBB is intact.[22]
[30] As opposed to this, in regions where BBB is damaged, there is a leakage of osmotic
substances (proteins and electrolytes) to the brain parenchyma, causing an osmotic
effect that leads to brain edema and subsequent adverse effects.[12]
[13]
[22] The use of crystalloids (e.g., HSS) in these circumstances as against the use of
colloids (e.g., mannitol) is thus preferable as NaCl being a normal constituent of
the intracellular and extracellular spaces redistributes easily. This redistribution
helps in avoiding rebound edema caused by the use of colloids. In addition to this,
it is also observed that unlike colloids, prolonged use of HSS does not open up the
endothelial tight junctions. In fact, it helps in reversing the endothelial cell swelling
caused by inflammation and ion exchange disturbance due to the loss of adenosine triphosphate
(ATP).[22] This increases the capillary lumen, which in addition to reduced blood viscosity
and improved CPP promotes better tissue perfusion.[11] By this, it counteracts the cerebral vasospasm associated with subarachnoid hemorrhage
in TBI patients, thereby improving the microcirculation. All these mechanisms have
been found to reduce the overall rate of fatal outcomes.[11] In fact, in severe TBI patients, serum biomarkers elevation could be useful in the
prediction and prognosis of clinical complications and neurologic deficits and outcomes;[38]
[39] the usage of HSS has been related to a significant reduction in the measurement
of these biomarkers. Considering this, it can be concluded that HSS usage is associated
with mitigation in the brain damage and improvement in the neurologic outcomes.[11]
[39]
Immunomodulatory Effect of Hypertonic Saline Solution
The immunomodulatory effects of HSS have been correlated to a multitude of factors
in regulating the immune system. Laboratory evidence conclusively proves that HSS
treatment affects the vasomotor tone by the release of nitric oxide, endothelins,
and eicosanoids, as well as reversal in the macrophage proinflammatory effect to an
anti-inflammatory one.[11] Some studies have demonstrated that these effects of hypertonicity on the immune
system are differentially mediated through the changes in lymphocyte and neutrophil
functions.[3]
[31] HSS effect is also related to the suppression of some functions such as expression
of adhesion molecules, cytokines production, production of reactive oxygen species
(ROS), phagocytic abilities, and degranulation.[10] The understanding of these pathophysiological and immunomodulatory effects helps
the physician in deciding the type of hyperosmolar therapy according to the patient’s
status and requirement.
Effects of Hypertonic Saline on Neutrophil Functions
The polymorphonuclear cells (PMN) are the first line of defense due to their ready
stock of multiple enzymes within intracellular granules and are thus the first responders
in any inflammatory condition. They are recruited at the site of inflammation within
minutes of insult. Their rapid degranulation is considered as a trigger for the organ
damage that occurs in shock patients.[8]
[15] The rapidly progressive inflammatory cascade by neutrophil migration and degranulation
is also responsible for organ failure in infectious states such as sepsis.[22]
PMN activation in trauma cases can lead to unnecessary tissue damage and severe posttraumatic
complications in various organs including the brain.[15]
[40] In these cases, it is the immunomodulatory effect of HSS that causes a reduction
in neutrophil recruitment and activation, which might improve patient outcomes and
prognosis.[41] HSS resuscitation therapy has been found to reduce the priming and activation of
the PMN by activating intracellular signaling cascades related to the cAMP (cyclic
adenosine monophosphate) mediated pathways that suppress the cell activation processes.[28] Neutrophils suppression by the HSS also happens by means of reduction in the expression
of adhesion molecule and production of ROS, as well as attenuation of the oxidative
stress.[11]
[28]
[42]
[43]
[44]
Another purported mechanism of action of HSS for reducing trauma-related inflammation
is through the toll-like receptors (TLRs). PMNs along with the TLRs are essential
compounds of the innate immunity. TLRs 1, 2, 4, 5, and 6 are expressed on the cell
surface and recognize the bacterial products. TLRs 3, 7, 8, and 9 are expressed in
the intracellular compartment and have an important role in the recognition of nucleic
acids in the viral process.[8]
[45] The activation of the TLRs regulates the chemokine receptors as well as stimulates
A2a receptors that are linked to cAMP signaling cascade. And by this, both pathways
regulate neutrophil functions,[8]
[41] and HSS modifies the TLR-4 pathway, leading to the immunomodulation of the effects
mediated by PMN cells.[8]
In vitro studies indicate that shock-mediated MODS is caused by the liberation of
ROS, proteases, hydrolytic enzymes, and inflammatory cytokines, as well as by the
neutrophil sequestration in vital organs. The usage of HSS is said to mitigate this
pathway of damage as well.[28]
Similar to HSS, a combination of HSS with dextran (HSD) is also seen to attenuate
the inflammatory response.[3]
[4]
[6] A small volume of HSD for resuscitation has been found to abolish the CD11b upregulation,
which happens in shock. This further leads to the reduction in the CD14 population
and the subsequent proinflammatory subsets and tumor necrosis factor-α activity along
with a concomitant increase in anti-inflammatory substances (interleukin [IL] 1ra
and IL-10).[3]
[7] The usage of HSD is thus associated with less inflammatory and coagulation cascade
activation that mitigates the secondary injury in TBI patients.[23] But some researchers have concluded that HSD might exacerbate subclinical inflammatory
response and, by this, be less effective than HSS in the mitigation of inflammatory
status.[28]
In conclusion, HSS weakens the neutrophil activation and cytokines production,[7]
[22] thus moderating the PMN cytotoxicity and dampening the inflammatory response.[40] The hypertonic environment reduces cellular edema that mitigates the cellular migration,[11] decreases the rolling and adherence of PMNs to endothelial cells, and improves the
microcirculation by negating the endothelial upregulation of adhesion molecules (1
and b2 integrins).[10] However, there is a theoretical possibility that mitigation of the PMN might lead
to unfavorable outcomes due to the increased risk of nosocomial infections by the
inhibition of the “first line of defense” of the patient.[11]
[41] Whether it is clinically relevant is still unknown.
Hypertonic Saline Solutions and Lymphocyte Cells Functions
Lymphocyte cells (B or T cells) are also a part of the immune system that takes over
as the acute phase changes to subacute and chronic phases. Studies show that T cells
are suppressed after an impairment of the cellular immune defense in cases of severe
trauma.[16] Administration of HSS is said to restore lymphocyte dysfunction.[14]
[42] Though the mechanisms may not be very clear, but experimental data in intestinal
mucosa have shown that HSS reduces the rate of apoptosis of lymphocytes after issue
insult, thereby downregulating inflammation and improving the immune responses.[3]
[5] The proposed mechanism may increase the IL-2 expression by releasing cellular ATP
that activates and enhances the T-cell function.[8] There are certain molecules that are related to ATP release, for example, pannexin-1
(PANX1). It is one of the three isoforms of the pannexin and is related to gap junctions
proteins that mediate the ATP release from the T cells.[16]
[41]
[46] Along with CBX-sensitive gap junctions, these channels commit to the ATP.[41] In TBI patients, HSS may exert its immunomodulatory effect by controlling ATP release
through the PANX1 hemichannels and stimulating the P2X1, P2X4, and P2X7 receptors
that will promote a p38 MAPK activation with a gene transcription of IL-2.[16]
Conclusions
In the brain-injured patients, fluid therapy is used with the aim to maintain an optimal
CBF and oxygenation.[27] It is also known that patients who required neurosurgical procedure are susceptible
to a sodium hemostasis disbalance.[47] For the purpose of resuscitation, hypotonic solutions should not be used due to
the risk of further hyponatremia and subsequent cerebral edema.[1]
Considering the previously mentioned, the use of HSS in the TBI context would help
in the modulation of the inflammatory response and reduce the risk of brain swelling
or edema that could lead to high ICP, and even lead to fatal outcomes.
