Keywords

FormalPara Practice Points/Clinical Pearls
  1. 1.

    Fluid management in both routine neurosurgery and neurocritical care should be targeted at euvolemia using isotonic fluids.

  2. 2.

    Balanced fluid prevents hyperchloremia and better preserves acid-base milieu, electrolyte balance, and renal function as compared to saline solutions, with preservation of intracranial pressure.

  3. 3.

    Larger studies are required to investigate the effects of balanced solutions on brain swelling and neurological recovery in specific neuropathological disorders.

Introduction

Fluid management in brain-injured patients has several distinct requisites not seen with other non-neurological patients:

  1. 1.

    Tonicity of the transfused intravenous fluid has a significant impact on the cerebral dynamics.

  2. 2.

    Fluid-induced/fluid-aggravated cerebral edema produces an antagonistic volume-pressure intracranial relationship, resulting in impairment of both cerebral blood flow and oxygenation.

  3. 3.

    Cerebral perfusion pressure goal-directed fluid therapy is intrinsically challenging due to the need for sophisticated CBF and cerebral oxygenation monitoring.

However, the above goal of maintenance of cerebral oxygenation and adequate CPP is met by unique challenges for anesthesiologists and intensivists involved in fluid management of the neurosurgical patient [1]. While on one hand brain-injured patients are often on diuretics for prevention or treatment of cerebral edema and/or intracranial hypertension, they may also require infusion of large quantities of intravenous fluids to correct preoperative dehydration and/or to maintain perioperative hemodynamics as mandated for the management of vasospasm or intraoperative blood loss [1]. The above concerns make appropriate type and composition of the perioperative intravenous fluid an important determinant in the outcome.

While searching for the “ideal” intravenous solution for the brain injured, and with increasing evidence that the commonly used crystalloid solution, 0.9% NaCl, may be harmful [2], novel crystalloid solutions are finding a foothold in neurosurgical practice, namely, intravenous “balanced solutions” [2, 3]. At the present time, no conclusive human data exists, concerning the impact of different compositions of intravenous fluids and balanced solutions in particular, on the injured brain to make firm recommendations.

This chapter will address some of the physical determinants of water movement between the intravascular space and the central nervous system (CNS) and the current evidence surrounding balanced salt solutions in detail. These factors would help make some reasonable recommendations regarding balanced fluid therapy in the neurological patient.

Water Movement Across the Blood-Brain Barrier: Determinants and Physiopathology

The three properties of the blood that are amenable to manipulation with intravenous fluids include [2, 3]:

  1. 1.

    Osmotic pressure (determined by concentrations of small and large molecules)

  2. 2.

    Colloid oncotic pressure (COP; determined by large molecules alone)

  3. 3.

    Hematocrit

  1. 1.

    Osmotic pressure: This is the hydrostatic force that equalizes the concentration of water on both sides of an impermeable membrane. Osmolarity describes the molar number of osmotically active particles per liter of solution. In practice, the osmolarity of a solution can be “calculated” by adding up the mEq concentrations of the various ions in the intravenous fluid. Osmolality describes the molar number of osmotically active particles per kilogram of solvent. This value is directly “measured” by determining either the freezing point or the vapor pressure of the solution. For most dilute salt solutions, osmolality is equal to or slightly less than osmolarity.

  2. 2.

    Colloid oncotic pressure: COP is the osmotic pressure generated by large molecules (e.g., albumin, hetastarch).

  3. 3.

    Hematocrit: Fluid infusion is often accompanied by a reduction in hematocrit. In the normal brain, this hemodilution and decreased arterial oxygen content is often compensated by an increase in cerebral blood flow (CBF) [4,5,6,7]. However, it is important to realize that in the backdrop of brain injury, the normal CBF responses to hemodilution and hypoxia are attenuated, and both changes may contribute to secondary tissue damage [4,5,6,7]. A hematocrit level of 30–33% provides the ideal combination of viscosity and O2 carrying capacity, and may improve neurological outcome [1, 4]. However, marked hemodilution (HCT < 30%) exacerbates neurologic injury [6].

The fluid movement across the BBB is determined by the “total” osmotic gradient, generated both by large molecules and small ions (Fig. 1). Since there are very few protein (large) molecules, their effect on serum osmolality is minimal. Also this has an attenuated effect on the alterations in colloid oncotic pressure. These differences explain the peripheral edema due to dilutional reduction of COP and not cerebral edema with the administration of large volumes of isotonic crystalloids [2, 8, 9]. When plasma osmolality decreases, the osmotic gradient drives water into the brain tissue. Even small changes in plasma osmolality (<5%) increase brain water content and ICP [2, 10, 11]. The above scenario describes the situation in conditions of normal BBB (Fig. 1). After a brain lesion, according to the severity of the damage (head trauma, tumor, seizure, abscess, or other damage), there can be varying degrees of loss of BBB integrity, which can respond differently to the osmotic/oncotic changes. With complete breakdown of the BBB, no osmotic gradient can be established [1, 15, 16]. It is possible that with a less severe injury to the BBB, the barrier may function similarly to the peripheral tissue [11]. Finally, there is usually a significant portion of the brain where the BBB is normal. The presence of a functionally intact BBB is essential if osmotherapy is to be successful [10,11,12].

Fig. 1
figure 1

Schematic representation of fluid and molecular movement across (a) systemic capillary membrane and (b) blood-brain barrier [2, 3, 8,9,10,11,12]

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Implications in Designing an Intravenous Fluid for Neurosurgical Population

  • First is the requisite for osmolarity (hence, the need for electrolytes present in the solution) to be as close as possible to plasma osmolarity. There is definite evidence of increased cerebral edema and intracranial hypertension, consequent to infusion of hypoosmotic solutions in the already injured brain.

  • Second is the need, in specific clinical scenarios, for the presence of oncotic pressure in the intravenous fluid. This is imperative to contain or restrict the infused volume within the intravascular compartment.

Intravenous “Balanced” Solutions

Definition

The term “balanced fluids” encompasses intravenous solutions having an electrolyte composition equal to or closest to the plasma composition and also displaying electrical neutrality (total free cations = total free anions) [11,12,13,14,15]. These concepts have further been expanded to the manufacture of “balanced colloid solutions” in which the colloid molecules are incorporated into “balanced” solvents.

Historically, 0.9% sodium chloride has been the most frequently administered intravenous fluid in neurosurgical practice. However, the perioperative use of these saline solutions is seen to be associated with hyperchloremia with its attendant ill effects. With the aim to avoid these deleterious effects of supraphysiological concentrations of chloride as in 0.9% NaCl, more recently, researchers have broadened the term “balanced” solution to also indicate intravenous solutions with low chloride content as compared to plasma [11].

Balanced Fluids and Acid-Base Balance

Bearing the above assumptions in mind, there are two important aspects which need to be considered while designing an ideal “balanced fluid.”

Firstly, most of the available intravenous solutions (excepting 0.9% NaCl and pure dextrose-containing solutions) have organic anions added to them (e.g., acetate, lactate, malate, gluconate, etc.), as precursors of HCO3 in order to balance the total cations (Table 1) [11, 12]. This is necessary as the process of including HCO3 directly to the intravenous fluid is complex and often unrealistic.

Table 1 Composition of common balanced intravenous fluids
Full size table

Secondly, to meet the goals of maintaining electrical neutrality and to avoid both hypotonicity and a high strong ion difference (SID, hence maintaining the Na+-Cl– difference between 24 and 30 mEq L−1), balanced salt solutions have been developed with a relatively high concentration of chloride (Table 1).

Conversely, with the mounting evidence of the deleterious renal effects of supraphysiologic Cl–-containing solutions, balanced fluids have been expected to have lower chloride content as compared to plasma.

Composition of Balanced Fluids: Qualitative and Quantitative

It would be easy to understand from the previous section that two classifications of intravenous “balanced” solutions are available:

  1. (1)

    Balanced solutions with minimal effect on acid-base equilibrium, with a SID value close to 24–29 mEq L−1, e.g., lactated Ringer’s, acetated Ringer’s, Sterofundin ISO, Hartmann’s solution, Tetraspan, and Hextend

  2. (2)

    Balanced solutions with a Cl– content equal or lower than 110 mEq L−1, e.g., lactated Ringer’s, acetated Ringer’s, Hartmann’s solution, Plasma-Lyte, Elo-Mel Isoton, Isoplex, and Gelaspan (Table 1).

Thus, it is apparent that an “ideal” balanced solution meeting all these three goals of acid-base neutrality, iso-osmolarity, and physiological chloride concentrations cannot be realized in a single intravenous formulation or rather has not been designed so far. All the available balanced solutions fit into just one of the categories described above (i.e., have an effect on acid-base equilibrium with normal chloride content or vice versa) or when fitting into both present with obvious limitations of hypotonicity, as in Hartmann’s solution, acetated Ringer’s, and lactated Ringer’s [12, 15].

Electrolyte Content of Balanced Solutions and the Neurological Patient

Apart from Na + and Cl-, the other important aspect related to “balanced” solutions and bearing relevance in the neurosurgical patient concerns the content of specific electrolytes, in particular of magnesium, calcium, and potassium.

Magnesium and Cerebral Vasospasm

Magnesium, one of the most ubiquitous cations in the body, has been shown to cross the blood-brain barrier in humans and animals [16,17,18,19]. In the context of cerebral vasospasm, its role as a physiologic calcium antagonist and hence a potent vasodilator has been the subject of most interest, although some neuroprotective effects have also been documented [16, 17]. One extensively studied therapy in vasospasm is magnesium (Mg) both as a competitive antagonist of calcium at the N-methyl-D-aspartate (NMDA) receptor and a noncompetitive antagonist of both IP3 and voltage-gated calcium channels, leading to smooth muscle relaxation.

Hypomagnesemia, with plasma levels less than 1.5 mg dL−1, is a relatively common finding in critically ill neurological patients admitted to ICU. Though the evidence is sparse, low magnesium levels are associated with poor neurological outcome in patients with TBI, seizures, stroke, and cerebral vasospasm [17,18,19].

Hence, when dealing with fluid replacement, it may be prudent to employ intravenous fluids containing magnesium, in order to prevent hypomagnesemia. With this rationale, the newer generation of “balanced” fluids (Plasma-Lyte, Sterofundin ISO) has been developed with the inclusion of magnesium, as compared to the older generation (lactated Ringer’s, or Hartmann’s solution) (see Table 1). Though there are no studies investigating the effects of balanced solutions on the incidence of hypomagnesemia, it would be reasonable to favor the use of these novel balanced solutions, in neurological situations warranting large volume replacements.

Calcium and Neurological Outcome

Hypocalcemia is the commonest electrolyte abnormality observed in acutely ill patients [24] with well-documented deleterious consequences like alterations in muscle contractility, peripheral and central nervous system function, and cardiac dysrhythmias. Hypocalcemia has been implicated as a prognostic factor in mortality and morbidity in patients with stroke and in moderate and severe traumatic brain injury [24].

Though it seems an attractive option to include Ca2+ in an ideal “balanced” solution, especially in the face of large volume replacements, it is offset by the risk of precipitation as Ca2+-citrate or Ca2+-carbonate when infused through a common vascular access. This limitation underlies the rationale for development of Ca2+-free intravenous balanced solutions (Table 1).

Potassium Content

Hypokalemia is a life-threatening electrolyte abnormality often observed in the critically ill and emergent neurosurgical patient [23]. All the available intravenous balanced fluids present a concentration of K+ within normal ranges. This feature however should not be erroneously considered a reason for preferring the use of 0.9% NaCl as the only intravenous solution potentially applicable in the case of the neurological patients with acute or chronic renal failure.

Balanced Solutions Versus 0.9% Normal Saline in the Neurological Patient-Clinical Evidence

Although owing to its osmotic benefits, 0.9% sodium chloride (saline) has been the most popular intravenous fluid in neurological practice [20, 21, 25, 26], there is perpetuating evidence of the supraphysiological chloride content in normal saline to cause hyperchloremia [22, 23], acidosis [26, 27], renal vasoconstriction [28], acute renal injury [29, 36], hypotension [30], inflammation, and death [29,30,31].

Chloride-mediated renal vasoconstriction [29, 30] and decreased renal perfusion have been implicated to be mechanisms behind the renal dysfunction caused by 0.9% sodium chloride with higher rates of acute kidney injury [29], renal replacement therapy [35], and death [33,34,35] with saline than with balanced crystalloids, although results have been inconsistent [35]. Recently, several human studies reported that metabolic acidosis, vasoconstriction, and AKI are less pronounced when using a balanced salt solution, which has a physiologic level of chloride and a neutral pH, compared to 0.9% saline [34, 35] in the critically ill patient. However, BC also have potential side effects such as hyperlactacidemia [14] and may exacerbate alkalosis. This is because all BC are relatively alkaline compared to NS [37]. A recent meta-analysis of fluid resuscitation with high versus low chloride content solutions in the perioperative or critical care settings observed fewer days on mechanical ventilation with the use of balanced crystalloids [32].

On the question of neurological effects of normal saline versus balanced crystalloid, such as lactated Ringer’s solution or Plasma-Lyte A, there are still no high-quality data in neurocritically ill patients. Albeit few, all the prospective randomized trials that have been conducted in the neurosurgical population have indicated that balanced intravenous fluids provide significantly better control over acid-base balance, sodium, and chloride levels, without increasing intracranial pressure when used as intraoperative fluid maintenance and replacement during elective neurosurgery and in the brain-injured patient [38,39,40,41]. In these balanced solutions, the use of malate and acetate allows for the reduction of chloride concentration while ensuring isotonicity. Though the isotonic balanced solutions have a lower osmolarity than normal saline, they have no adverse effects on intracranial pressure due to their lower chloremia-induced neuronal chloride ion efflux, thus limiting brain swelling despite decreased osmolarity compared with 0.9%.

One study has shown that combination of a balanced crystalloid with colloid results in lower serum chloride concentrations and maintenance of acid-base balance compared to unbalanced crystalloid in combination with an unbalanced colloid [38].

At the present time, balanced fluids can at best be said to have the potential to be a better alternative to 0.9% normal saline in the neurosurgical patient, but barring high-quality evidence, firm recommendations cannot be made.

Balanced Fluids in Specific Neurological Scenarios

Traumatic Brain Injury

In TBI, a blunt or penetrating injury incites mechanical and autodigestive destruction of the normally tightly intact endothelium of the blood-brain barrier. This allows uncontrolled movement of fluid and serum proteins into the brain parenchyma, eventually leading to vasogenic cerebral edema and increased ICP. Intracranial hypertension (ICH) is the primary cause of secondary brain insult and death after brain injury [39]. These patients are prone to ion homeostasis disruption, plausibly due to hormonal dysfunction such as diabetes insipidus and cerebral salt wasting syndrome or through alterations of chloride-dependent channels such as the NKCC1 transporter [39, 41, 42].

Thus, administration of hypo-osmolar solutions should be avoided in brain-injured patients [39, 43]. Hyposmolarity and hyperchloremia with its attendant acidosis are touted to be the two major modifiable implicates of cerebral edema after brain injury.

Chloride channels regulate cell edema [39, 42], and dyschloremia contributes to brain swelling. With the recognition that chloride-rich fluids are the primary cause of hyperchloremic acidosis in critically ill neurological patients [2], a general chloride-restrictive strategy can be recommended for decreased incidence of renal failure and improved neuronal homeostasis.

Balanced solutions have been inconclusively proven to decrease the incidence of hyperchloremic acidosis, in patients with severe brain injury as compared with saline solutions. This feature along with the isotonicity of the balanced solutions may authorize their utilization in the neuro-ICU, but few data are available to make firm recommendations. The Neuro-Intensive Care and Emergency Medicine (NICEM) Section of the European Society of Intensive Care Medicine consensus document stated that HES is not recommended in the context of brain injury [44]. The effect of albumin or artificial colloids in isotonic fluids on outcome in traumatic brain injury has not been investigated.

Subarachnoid Hemorrhage (SAH)

Secondary brain injuries related to cerebral vasospasm and consecutive ischemic brain injury and intracerebral edema are the main contributors to mortality and morbidity in these patients. Hyponatremia and hypovolemia secondary to cerebral salt wasting have been identified as the two most important culprits for these cerebral events.

Traditionally, patients with SAH have been managed with normal saline for baseline and substitution requirements. If hyponatremia is more severe or significant cerebral edema exists, the use of mild hypertonic fluids (1.25 or 1.5% saline) and strict avoidance of free water administration are usually successful in reversing the hyponatremia.

The guidelines of the American Heart Association [45] recommend that volume contraction be treated with isotonic fluids (Class IIa, Level of Evidence B) and that “administration of large volumes of hypotonic fluids should generally be avoided after SAH (Class I, Level of Evidence B).” Similarly, guidelines of the Neurocritical Care Society for the management of patients with SAH recommend maintaining euvolemia and avoiding both prophylactic hypervolemia therapy and fluid restriction to treat hyponatremia [46] (high-quality evidence; strong recommendation). Neither set of guidelines addresses the composition of baseline fluid administration in patients without oral intake.

In SAH, standard fluid management with saline may have alternatives with more balanced solutions resulting in more stable electrolytes, less fluid intake, and less activation of the pituitary axis stress hormones (cortisol, TSH) [40].

A randomized, double-blind trial demonstrates a greater incidence of hyperchloremia, hyperosmolality, and positive fluid balance with 0.9% saline in early SAH, with balanced solutions not causing frequent hyponatremia or hypoosmolality [40]. Awaiting the results of few ongoing studies [47] and need for larger studies, no appropriate conclusions can be drawn on the beneficial effects of balanced crystalloids in SAH.

Ischemic Injury

The 2018 AHA/ASA guidelines for the early management of patients with acute ischemic stroke [48] stress upon the use of isotonic fluids rather than hypotonic fluids (might exacerbate ischemic brain edema). AHA/ASA recommendations for the management of cerebral and cerebellar infarction with swelling make similar recommendations advocating the use of isotonic fluids [49]. Balanced intravenous fluids being isotonic seem to be an attractive option in such scenarios.

Elective Supratentorial Craniotomy for Brain Tumors

The existing evidence, albeit sparse, indicates more stable electrolytes, particularly chloride, magnesium, calcium, and phosphate levels as well as a preserved acid-base balance with balanced fluids especially during prolonged elective supratentorial craniotomy, all distinct advantages over 0.9% NS. Day et al. published a study comparing normal saline with Plasmalyte as intraoperative maintenance fluid during craniotomy for excision of brain tumors [53]. Like the findings of the earlier studies, they find that the acid-base status and renal profile were better with Plasmalyte. Two novel findings of this study were the preservation of brain relaxation and a significantly lower level of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of kidney injury with the use of Plasmalyte for resuscitation.

Perceived advantages of balanced crystalloid solutions over non-buffered solutions are reflected in the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP) [55] that recommend the use of balanced solutions for crystalloid fluid resuscitation or replacement.Evidence level 1b1–6.

Major Spine Surgery

The combined physiologic effects of prone positioning and the risk of substantial blood loss pose patients undergoing multilevel spine surgery at high risk for intraoperative hemodynamic instability. Emerging evidence suggest that balanced crystalloids and third-generation colloids in balanced salt solution are potentially safer with no significant effect on coagulation when compared to crystalloids [56, 57].

Dose of Balanced Intravenous Fluids for Perioperative Replacement/Resuscitation: How Much Is “Balanced?”

As a general ordinance, intraoperative balanced fluids when used should be administered at a rate sufficient to replace the urinary and insensible losses. As a rough guide, 1 L of isotonic crystalloid and 1 L of hetastarch result in 250 ml and 750 ml of the intravascular volume expansion, respectively. Current data indicates that as long as normal serum osmolality and oncotic pressure are maintained and cerebral hydrostatic pressures are not markedly increased (e.g., due to true volume overload and elevated right heart pressures), volume replacement will not have any effect on cerebral edema and ICP.

In the critically ill neurological patient, the goal of fluid administration is to maintain near normal serum osmolality by repeated monitoring of this parameter. Any reduction in osmolality should be strictly avoided. When feasible, fluid management based on volumetric hemodynamic monitoring like CVP or pulmonary artery occlusion pressure (PAOP)-directed management and transpulmonary thermodilution (TPT) techniques [54] could provide real-time and more accurate guides to fluid management in the critically ill neurological patient.

Lactated Ringer’s when administered in small volumes (not strictly isoosmotic, measured osmolality 252–255 mOsm/kg) are not likely to be detrimental, and can be used safely. However, when the clinical situation mandates large volume replacements (blood loss or other source of volume loss), a change to a more isotonic balanced fluid is advisable. With large volume loss, a combination of isotonic crystalloids and colloids may be the most prudent choice. The combined use of these fluids can avoid reductions both in serum osmolality and COP. Even when administered in a balanced substrate, hetastarch should be used with caution due to coagulation factor VIII depletion when administered at volumes >1000 mL [52]. The newer formulation, pentastarch with minimal effects on coagulation, presents as a better alternative [51]. Future investigations to determine the end point of fluid resuscitation should focus on the parameters of cerebral perfusion and oxygenation where direct effects of systemic fluid management on the brain are examined, such as PBrO2 [50].

The Clinical Equipoise

The SPLIT trial, the first large randomized controlled trial prospectively comparing the effects of a balanced solution (Plasma-Lyte 148) with those of 0.9% NaCl in critically ill patients, showed, unexpectedly, precise equipoise between the two treatments, although presenting important limitations [14]. However, the small number of neurological patients included in this study makes it difficult to draw appropriate conclusions in the neurocritically ill.

Conclusion

Indubitably, intravenous balanced fluids are gaining a foothold in clinical neurosurgery owing to their multitude of physiologically relevant advantages. However, the actual translation of such physiological effects into clinically relevant outcomes is still unclear, especially in the high-risk neurosurgical population (sepsis, trauma, AKI) exposed to larger amounts of such fluids.

Moreover, the “ideal” intravenous balanced solution incorporating all the defined characteristics (electrolyte content equal to plasma with maintenance of acid-base equilibrium) is yet to be made available.

Awaiting multicentric high-quality research on the potential mechanisms underlying their clinical effects and patient-centered clinical outcome in neurosurgery, such fluids continue to be considered as “drugs” and must be used with consideration to physiological rationale, clinical supporting evidence, and awareness of the adverse effects.