Fluid, electrolytes, and nutrition are vital components in the management of critically ill patients. Patients with neurotrauma present certain challenges and considerations, specifically with the need to mitigate secondary injury while addressing the systemic sequelae of trauma. With regard to crystalloid administration, isotonic normal saline remains the choice fluid, especially in patients with traumatic brain injury. The preference for saline formulations extend to hyperosmolar therapy as well, with hypertonic saline becoming, in general, preferential to mannitol. Electrolyte disturbances can emerge in critically ill patients. Optimizing nutrition requires a multidisciplinary approach as patients with especially traumatic brain injury have unique needs.
Key points
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Fluid physiology in the central nervous system is unique and understanding of brain injury plays a role in fluid selection.
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Crystaloids are the resuscitative fluid of choice in traumatic brain injury.
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Patients with neurotrauma often experience electrolyte perturbations that can be associated with worse outcomes.
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The evaluation and provision of proper nutrition is important in addressing the inherent catabolic state of neurotrauma.
| BBB | blood–brain barrier |
| Ca 2+ | calcium |
| Cl − | chloride |
| HSD | hypertonic saline with dextran |
| HTS | hypertonic saline |
| ICF | intracellular fluid |
| ICP | intracranial pressure |
| ICU | intensive unit care |
| K + | potassium |
| LR | lactated ringer’s |
| MAP | mean arterial pressure |
| Mg 2+ | magnesium |
| Na + | sodium |
| NS | normal saline |
| PBS | phosphate-buffered saline |
| RCT | randomized controlled trial |
| RR | relative risk |
| TBI | traumatic brain injury |
| TBST | Tris-buffered saline with Tween-20 |
| Tris-NaCl | Tris-sodium chloride |
Introduction
The critical care of neurotrauma is centered on limiting secondary injury. This extends from preventing hypotension, which leads to downstream ischemia and neurotoxicity, to optimizing nutritional status in patients who are inherently catabolic. A thorough understanding of the role fluids, electrolytes, and nutrition play in the daily management of patients is key to ensuring good outcomes.
Fluids
Fluid Physiology and Pathophysiology of Cerebral Edema
A basic understanding of fluid physiology is key to optimizing resuscitation efforts in patients with neurotrauma. Fluids in the body are divided into distinct intracellular and extracellular compartments that are separated by semipermeable cellular and basement membranes. The extracellular compartment can be further divided into intravascular and interstitial components ( Fig. 1 A ).
The majority of fluid and solute exchange occurs at the capillary level. The movement of fluid between compartments is largely dependent on passive and facilitated diffusion as a product of osmotic solute gradients . Another related concept in fluid management is tonicity , or how well a solution directs redistribution of water across a membrane. This depends on both the osmolarity of the fluid and the selective permeability of the membrane. Fluids with relatively higher osmolarity than the intracellular space pull water from the intracellular to the extracellular space and are considered hypertonic . Conversely, readily diffusing hypotonic fluids have lower osmolality and pull fluid into the intracellular space ( Table 1 ). Hydrostatic pressure also plays a role in fluid dynamics. Pressure caused by blood volume against vessel walls contributes to the net movement of molecules from the intravascular space to the interstitium. The balance between the outward push of hydrostatic pressure and the inward draw of osmotic/oncotic pressure creates a net effect on fluid movement across the capillary , ( Fig. 1 B).
| Fluid Composition | ICF (Neuron) | Interstitial (Brain) | Plasma | LR | Plasma-Lyte | NS | HTS (7.5%) | HTS (7.5%)/Dextran (6%) | Albumin (5%) |
|---|---|---|---|---|---|---|---|---|---|
| Osmolarity (mOsm/L) | 300 | 300 | 290 | 273 | 296 | 308 | 2567 | 2567 | 290 |
| Colloid osmotic pressure (mm Hg) | Essentially negligible | Variable, <10 | 18–28 | 0 | 0 | 0 | 0 | 75 | 20–29 |
| pH | 7.3 | 7.4 | 7.4 | 6.5 | 7.4 | 5.7 | 5.7 | 5.7 | 7.0 ± 0.3 |
| Buffer (mM) | HCO 3 (10) | HCO 3 (22) | HCO 3 (22–26) | Lactate (28) | Acetate, gluconate, or lactate | NA | NA | NA | TBST, PBS, or Tris-NaCl; albumin |
| Na + (mM) | 15 | 146 | 140 | 130 | 140 | 154 | 1283 | 1283 | 145±15 |
| Cl − (mM) | 10 | 118 | 103 | 109 | 98 | 154 | 1283 | 1283 | 150 |
| K + (mM) | 150 | 4.1 | 4 | 4 | 5 | 0 | 0 | 0 | <2 |
| Ca 2+ (mM) | 10 −5 | 2 | 4 | 3 | 0 | 0 | 0 | 0 | 0 |
| Mg 2+ (mM) | 5 | 2 | 2 | 0 | 3 | 0 | 0 | 0 | 0 |
Cerebral fluid dynamics is of particular importance given the largely rigid cranial vault and associated risk of cerebral edema. Given that cerebral perfusion pressure (CPP) is the driving pressure for cerebral blood flow, dependent upon the difference between intracranial pressure (ICP) and mean arterial pressure (MAP), it is key that intravascular volume is maintained at a level to support an adequate MAP but without worsening cerebral edema. The movement of fluid in the brain is tightly regulated, and the significant influx of vascular fluid and solute is largely prevented via the blood–brain barrier (BBB). The main structural components ( Fig. 2 A left panel) of the BBB include the capillaries, tight junctions, pericytes, and astrocyte foot processes. An intact BBB works to ensure adequate uptake of key energy substrates and nutrients, prevent influx of neurotoxins, and maintain appropriate fluid dynamics and intraparenchymal electrochemical gradients. However, when the BBB is disrupted and/or there is a loss of autoregulation in the setting of traumatic brain injury (TBI), these homeostatic mechanisms are compromised. This can lead to the unregulated influx of toxic solutes and fluid, disrupting neurotransmission and thereby leading to excitotoxicity, cytotoxic edema, and vasogenic edema (see Fig. 2 A right panel and B).
Fluid Selection in Patients with Neurotrauma
Numerous studies have examined the question of what fluid is safest and most appropriate, comparing various crystalloids and colloids and their impact on outcomes including mortality and long-term functional recovery.
Crystalloids
Crystalloids are made up of small, water-soluble molecules that diffuse easily through semipermeable membranes, the majority of which (75%–80%) redistribute from the intravascular to the interstitial fluid compartment ( Fig. 3 A ). Therefore, crystalloids with relatively lower tonicity carry a theoretic risk of worsening cerebral edema when the BBB is compromised. Hypotonic fluids such as 0.45% normal saline of 5% dextrose in water should generally be avoided for this reason. The class of isotonic crystalloids includes derivatives of saline (eg, normal/0.9% saline; NS) as well as balanced crystalloids such as lactated ringer’s (LR) and Plasma-Lyte A ( Baxter Inc, Deerfield IL ) (see Table 1 ). Studies in general intensive unit care (ICU) patients have demonstrated a benefit in mortality with balanced crystalloids over saline. However, the same has not held true for neurocritical care patients. While all of these agents are considered isotonic, NS has both a greater tonicity and osmolarity (308 mOsm/L) as compared to LR (273 mOsm/L) and Plasma-Lyte (295 mOsm/L) making it potentially more desirable in the setting of an altered BBB ( Fig. 3 B).
In the prehospital setting, a critical time for interventions aimed at minimizing secondary injury, studies have compared the effect of administering NS versus LR on outcomes. In a prospective observational study, Rowell and colleagues found that there was a higher 30 day mortality with LR usage in TBI over NS; this was not the case for patients without TBI. NS shows evidence for potential superiority in the Emergency/ICU setting as well. A subgroup analysis of TBI participants in the BaSICS randomized trial found that patients randomized to receive Plasma-Lyte experienced a higher 90 day mortality and fewer survival days free of ICU as compared with those receiving NS.
Colloids
Colloids can be natural products such as albumin, as well as synthetic agents including dextrans, gelatins, and starches. They contain larger molecules (eg, proteins and starches) that exert significant oncotic pressure, thereby increasing plasma volume. As compared to the 20% intravascular volume expansion gained by crystalloid administration, colloids can achieve greater than 100% expansion (see Fig. 3 A) as a consequence of both oncotic pressure and, in the case of some colloids such as albumin, negative charge that attracts Na+ thereby increasing its osmotic capability by 20% (the Gibbs–Donnan effect). One possible benefit of colloid administration is based on the Lund principle, which is targeted at optimizing ICP and improving tissue perfusion by many means, including via plasma oncotic pressure. Moreover, colloids have been shown to preserve the glycocalyx in animal models. However, there is a potential risk. If the BBB is already disrupted, a more osmotically active product can pull additional fluid into the intraparenchymal compartment thereby worsening cerebral edema. In addition, colloids are more expensive in most of the world, and starches come with associated coagulopathic complications due to the lowering of coagulation factors.
Although various studies in rodent models of neurotrauma have demonstrated a putative benefit of colloid infusions, this has not been borne out by clinical trials. One of the most influential studies in patients with neurotrauma was the 2007 SAFE study. This randomized controlled trial (RCT) compared 4% albumin and normal saline in terms of outcomes defined as 24 month mortality. The study found a significant increase in risk of mortality for all-comers in the albumin group (relative risk [RR] = 1.63). When divided by Glasgow Coma Scale (GCS) score (GCS) into “severe” vs “mild-moderate” TBI groups, this was true for the severe (RR = 1.88) but not mild-moderate (RR = 0.74). A post hoc analysis suggested an association between albumin administration and increased ICP as a possible mechanism for higher mortality. , As a result, albumin is considered contraindicated, especially in severe TBI.
Synthetic colloids such as dextrans, gelatins, and starches have been found to have dose-related side effects that include coagulopathy and nephrotoxicity with potential renal failure. Hydroxyethyl starch was found to carry an increased risk of death or end-stage renal failure when compared to LR when used in sepsis patients, but the data in trauma are quite variable. The body of work by Vassar and colleagues compared various crystalloids with dextrans. While in 1 RCT, hypertonic saline with dextran (HSD) showed a trend toward improved mortality when compared against LR, subsequent studies comparing NS, hypertonic saline (HTS), and HSD did not find a survival benefit for any group. , Therefore, in the general patients with trauma, crystalloid is generally preferred.
In neurotrauma specifically, prior study has suggested that HSD compared to NS was associated with lower levels of biomarkers of acute brain injury including S100 B, neuron-specific enolase, and myelin-basic protein as well as vascular and inflammatory biomarkers, but have not been shown to have an impact on mortality or functional outcomes. , A prior meta-analysis on hospital and 30 day survival did not favor HSD versus NS.
Osmotherapy
Hypertonic saline
HTS, available in a variety of formulations ranging from 3% to 23%, is a staple fluid for ICP management. Its proposed mechanism is to create an osmotic gradient across the BBB that pulls fluid out of the intracellular and interstitial spaces into the intravascular space, thus reducing cerebral edema. In addition, animal models of acute brain injury have demonstrated a potential anti-inflammatory effect that may thereby reduce ICP and mitigate secondary injury. However, there are limitations. One is its high tonicity and the resulting rapid expansion of intravascular volume. This can increase hydrostatic pressure, resulting in pulmonary edema; caution should be used in congestive heart failure. The high chloride content can also cause a hyperchloremic acidosis that limits its use. In these cases, amps of sodium bicarbonate or, where available, sodium acetate, are alternatives to consider as they will still reduce ICP by the same mechanism but avoid significant renal injury and acid–base derangements.
HTS also has been studied as fluid replacement rather than specifically for ICP management. Cooper and colleagues compared 7.5% HTS to LR and found a small trend toward improved survival with HTS, but almost identical outcomes at 6 months by glasgow outcome scale extended (GOSE). Interestingly, the HTS group did maintain consistently higher Na but had no significant difference in mean ICP. A meta-analysis comparing HTS to normotonic crystalloids regarding hospital and 30 day survival did not favor HTS.
Mannitol
Mannitol, a commonly used osmolar agent, is a sugar alcohol (C 6 H 14 O 6 ) available in concentrations ranging from 5% to 25%, which acts through various mechanisms. Through its rheological effect, mannitol reduces blood viscosity and consequently improves cerebral blood flow and oxygen delivery. Plasma expansion from mannitol also leads to reflexive cerebral vasoconstriction and a decrease in cerebral blood volume. This effect is near-immediate. Similar to HTS, mannitol’s osmotic effect also pulls fluid out of the parenchyma into the intravascular space. Peak osmotic effect occurs between 20 and 60 minutes postadministration, lasting from 4 to 6 hours. The ICP reduction is dose-dependent, and depending on an institution’s protocol, may be given as 0.25 to 2.5 g/kg/dose every 4 to 6 hours; some evidence suggests that its effect may be more sustained when dosed at 0.5 to 1.5 g/kg/dose. Clinical endpoints include a serum osmolality of 320 mosm/L and an osmolar gap of 20, due to concern that the osmotic diuretic effect may increase the risk of renal tubule injury. Ideally, it is administered over 15 to 30 minutes as rapid infusion (within 5 minutes) increases the risk of acute hypotension.
Many studies have examined which osmotherapy is more effective. Some have found that although both agents are effective at reducing ICP and improving CPP, the use of HTS did so to a greater extent and in a more sustained manner with fewer breakthrough ICP crises. Some evidence suggests that the greatest benefit in these parameters was seen in patients with diffuse injuries. However, studies are mixed as to whether either affects tissue oxygenation, glucose metabolic rates, or functional outcomes. , Surgical considerations are critical as well. One systematic review and meta-analysis suggests that HTS is more effective at brain relaxation, though no clear benefit in ICU length of stay or neurologic status was demonstrated.
Electrolytes
Electrolyte abnormalities are commonly observed in patients with neurotrauma, but there is no universally accepted approach to management. Studies have consistently highlighted the prevalence of electrolyte imbalances in TBI, with hypernatremia and hypokalemia occurring in up to half of affected patients. These disturbances can result from the injury itself or from secondary systemic responses such as neuroendocrine dysregulation, fluid shifts, and therapeutic interventions. This section explores the common electrolyte disturbances seen in patients with TBI, emphasizing underlying pathophysiology and clinical significance.
Sodium
Induced hypernatremia—with a goal of transient hyperosmolarity—is commonly used to lower acute elevations in ICP after TBI. , However, numerous studies have consistently shown that hypernatremia following TBI is independently associated with poor prognosis and higher mortality rates. , , One retrospective study of 1749 patients with TBI revealed an L-shaped correlation between sodium levels and in-hospital mortality, with significantly increased mortality rates when sodium levels exceeded 144.1 mmol/L. It has been suggested that overall serum sodium variability also matters: in a study of 240 patients with severe TBI, the serum sodium variability was significantly, independently associated with 28 day mortality.
It is not clear whether hypernatremia independently worsens outcomes or rather is a surrogate of illness severity. For example, severe TBI can be associated with central diabetes insipidus, a potentially confounding variable that causes hypernatremia and has been shown to independently increase mortality in TBI. , Other noniatrogenic factors include insensible free water losses and hypovolemia. Interestingly, a retrospective study of 458 patients with moderate-to-severe TBI showed that hyperchloremia, rather than hypernatremia, was independently associated with in-hospital mortality when concomitantly adjusting for the burden of both. Given these complexities, the utility of therapeutic hypernatremia after TBI and its effect on prognosis continues to be unclear, with current guidelines for severe TBI offering no specific recommendations on the use of hypertonic saline or target sodium levels.
Potassium
Hypokalemia is seen in up to 65% of patients with TBI, with peak incidence between 24 and 96 hours postinjury. It is hypothesized to be related to the catecholamine discharge that occurs in severe TBI, which activates beta-adrenergic receptors, promoting intracellular potassium shifts and enhancing the activity of the renin-angiotensin-aldosterone system, leading to increased aldosterone secretion and renal excretion of potassium. Hypokalemia can be exacerbated by therapeutic interventions such as the use of osmotic agents like mannitol, diuretics, or aggressive fluid resuscitation. In a study of 375 patients, severe hypokalemia (<2.5 mmol/L) was associated with hypernatremia and hypophosphatemia. Patients with severe hypokalemia had worse outcomes than those with normal potassium levels, and all patients diagnosed with concurrent hypokalemia, hypernatremia, and hypophosphatemia died. Given these data, maintaining potassium levels within a normal range is a reasonable management strategy in TBI.
Calcium
Hypocalcemia is a common electrolyte abnormality in trauma, with ionized calcium less than 1.0 mmol/L associated with hypotension, increased transfusion requirements and increased mortality. , Hypocalcemia in TBI is less studied, though Vinas-Rios and colleagues found that hypocalcemia (<8.5 mg/dL) on postinjury day 3 was associated with increased mortality. Mechanisms of hypocalcemia following TBI include hyperphosphatemia and resultant calcium phosphate precipitation, and citrate-binding from large volume transfusions. Prolonged hospitalizations can result in vitamin D deficiency, impairing enteral calcium absorption. The European guideline on management of major bleeding and coagulopathy following trauma recommends that ionized calcium levels be monitored and maintained in normal range during massive transfusion. Current military guidelines recommend administering 1 g of calcium after the first unit of blood product, followed by an additional gram after every 4 units of blood products. Further studies are needed to determine if this strategy is beneficial to patients with TBI.
Magnesium
In a retrospective analysis of 216 patients with severe TBI, 57% presented with hypomagnesemia, and those with serum magnesium levels less than 1.3mEq/L were 2.37 times more likely to have a poor outcome, as measured by 6 month Glasgow Outcome Scale scores. The prognostic significance of hypomagnesemia persisted even in patients whose serum magnesium levels were corrected within 24 hours; in fact, this group did worse than those who had their magnesium levels corrected more slowly. There have been multiple studies demonstrating a neuroprotective effect of magnesium in animal models of TBI. However, a large, double-blinded RCT found that continuous infusions of magnesium for 5 days given to patients with moderate or severe TBI were not neuroprotective and in fact produced poorer outcomes, with double the mortality rate in the higher magnesium target group (average 2.15 mmol/L) versus placebo. Additionally, the lower magnesium target group (average 1.45 mmol/L) fared significantly worse than placebo. It is worth noting that both magnesium treatment groups had average serum magnesium levels far above those considered normal (5.22 mg/dL, 3.52 mg/dL). Based on these studies, it is conceivable that aggressive correction of hypomagnesemia should be avoided, while routine supplementation as part of standard care is reasonable.
Nutrition
TBI provokes a series of neuroendocrine and adrenergic events that result in significant metabolic changes. Hypermetabolism and the subsequent catabolism of protein, carbohydrates, and triglycerides, as well as the negative nitrogen balance manifest in weight loss, loss of lean body mass, and significant changes in electrolytes. These conditions are associated with higher rates of infection, overall prevalence of sepsis, other types of morbidity, and increased mortality. Nutritional optimization, ideally started within the first 1 to 2 days following injury, has been demonstrated in some studies to lower rates of morbidity and mortality, shorten length of ICU and hospital stay and even enhance neuronal recovery.
In general, enteral nutrition is preferred over parental nutrition as there is evidence to suggest there is a reduction in infection, particularly pneumonia, and abdominal abscess in patients with trauma, and overall ICU length-of-stay is decreased when nutrition is administered enterally. The reduction in infection from enteral feeds is thought to be secondary to the protection of bowel mucosa from tube feeds and protection against translocation. Contraindications to enteral nutrition are bowel obstruction, concern for acute ischemia, hemodynamic instability, significant pressor requirement, or metabolic acidosis.
Gastroparesis is a common finding in patients with neurotrauma. Approximately 45% to 50% of patients with neurotrauma may have difficulty tolerating enteral feedings due to gastroparesis. Autonomic nervous system damage, ICP, and sedatives may delay gastric emptying. Although a point of controversy, no evidence demonstrates a significant correlation between gastric residual volume and risk of aspiration. Recommendations support continuation of enteral feedings to avoid worsening malnutrition in this critical population. Raising the head of the bed to 45° and administration of higher concentrations of supplementation in less volume may provide some relief. Prokinetic medications, such as metoclopramide (dopamine antagonist), erythromycin (motilin receptor stimulator), and naloxone (opiate receptor antagonist in gut) have little evidence to suggest they are effective in increasing motility, and they have an array of adverse side effects.
When considering parental nutritional supplementation, glucose concentrated parental solutions can be administered through a peripheral vein for roughly 24 hours. After that, central lines are more suitable for total parental administration as central lines better tolerate the hyperosmolarity of dextrose. While enteral is preferred, if malnutrition persists beyond 7 to 10 days, despite enteral administration of nutrition, parental supplementation may be necessary to resolve a negative energy balance.
Calculation of energy needs in the ICU patient is essential to optimizing nutritional support. There is a fair amount of variability when evaluating the impact of head trauma on resting energy expenditure, which is the energy used in a 24 hour nonactive period to drive functions such as body temperature regulation, respiration, and cardiac function, among others. Evidence suggests a greater than 100% increase in resting energy expenditure in patients with neurotrauma. Patient weight, diet prior to hospitalization, and comorbidities are all also relevant considerations when calculating resting energy expenditure. When quantifying nutritional needs in the patient with neurotrauma, many conditions related to injury, including brain function, endocrine status and stress, play a role in calculating energy output. Medications can also impact energy expenditure; in particular, head injury patients in a barbiturate-induced coma or on a neuromuscular blockade may have reduced energy expenditure.
Indirect calorimetry is one of the most frequently utilized methods for optimizing nutritional supplementation in the ICU. When indirect calorimetry is not available, the American Society for Parenteral and Enteral Nutrition-Society of Critical Care Medicine recommends that a simple approximation of caloric needs can be calculated by multiplying the patient’s weight in kilograms × 25 to 30 kcal to give a daily estimate.
Protein plays a critical role in recovery of the ICU patient. Body mass, immune function, and brain recovery are dependent on protein supplementation in amounts that maintain a high ratio of protein to total energy needs. Nitrogen loss during the early weeks following brain injury make it challenging to maintain nitrogen balance and meet the patient’s proteins requirements. The overall recommended amount of protein intake is approximately 0.8 to 1.0 g/kg for the average patient, but in critically ill patients, it is estimated to be higher, about 1.2 to 1.6 g/kg. Determining whether the correct protein amount is being administered can be calculated by looking at the nitrogen balance with a goal positive balance between 4 and 6 g. Nitrogen balance is the difference between intake and excretion, and is reflected by the following formula:
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