Key points

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability, occurring at an estimated rate of 64 to 74 million cases per year. In 2016, the cost of TBIs on the United States healthcare system was estimated to be approximately US$40.6 billion. TBI is defined as the disruption to normal brain function resulting from injury from an external source. Injury can be blunt, penetrating, focal, or diffuse and can result in brain compression, parenchymal damage, and axonal injury. ^, Such injuries can result in significant disability or mortality impacting patients and caregivers alike. The extent of TBI can be classified using the Glasgow Coma Scale (GCS), which has been the standard for categorizing impaired consciousness for 50 years. Using the GCS, mild TBI is signified by a GCS score between 13 and 15, moderate TBI as 9 to 12, and severe TBI (sTBI) with a score of less than 9. Outcome is not solely dependent on the extent of the primary injury. It is imperative that close monitoring and corrective actions are taken to prevent further ischemic damage to the brain. Adverse consequences of TBI include hypotension and hypertension; decreased cerebral perfusion pressure (CPP), increased intracranial pressure (ICP), hypothermia, decreased systemic blood pressure (BP), disturbances to serum sodium, and alterations in metabolism. Such disturbances can precipitate various secondary pathologies including seizures, stroke, herniation, and cerebral vasospasm. Therefore, it is critical that life-saving measures are not delayed while attempting to restore the brain to a version of its normal physiologic function.

Various monitoring modalities, such as ICP and CPP, are recommended to address potentially catastrophic disruptions to brain physiology in the immediate hours after injury. CPP has been shown to decrease following TBI and, as a result, so does brain oxygenation. Decreases in CPP and brain oxygenation are typically associated with unfavorable outcomes. There has been clinical debate regarding the numerical ranges at which these parameters should be maintained to attempt to achieve better outcomes. We aim to describe how the initial sTBI management is really an attempt to normalize parameters that can get violently out of control after injury, and how prompt correction of these physiologic disturbances can contribute to recovery.

Blood pressure

It is essential to correct hypotension postinjury, as prolonged episodes are associated with a higher risk for morbidity and mortality. Under normal circumstances, cerebral autoregulation manages pressure regulation via cerebral vasoconstriction or dilation to ensure homeostasis. Disruption of cerebral autoregulation can be catastrophic as changes in systemic arterial pressure can result in passive increases in cerebral blood flow (CBF) and cerebral blood volume due to fixed, compensatory vasodilation and vaso collapse of the important regulatory pial arterioles. If concurrent damage to the blood–brain barrier occurs, there is further risk of brain edema and irreversible intracranial hypertension.

The Brain Trauma Foundation (BTF) Guidelines for the Management of Severe TBI currently recommend maintaining systolic blood pressure (SBP) at or above 100 mm Hg for those between the ages of 50 and 69 years and 110 mm Hg or greater for patients aged 15 to 49 years or over 70 years of age. Several recent studies have suggested that maintaining SBP as close to 120 mm Hg as possible leads to better outcomes when compared to lower pressure levels. Spaite and colleagues showed in a large cohort (n = 3844) that patients had a higher likelihood of death when prehospital SBP decreased below 120 mm Hg; for every 10 mm Hg decrease in SBP, there was an increase in adjusted odds of death.

Fuller and colleagues reported that the probability of survival following sTBI increased when admission SBP was maintained between 120 and 140 mm Hg, and poorer outcomes were associated with BP at the lower level of 110 mm Hg. Brenner and colleagues reported similar associations between mortality and SBP below both the 110 and 120 mm Hg levels. In this prospective study, hypotension was predictive of morbidity and mortality within the first 48 hours of hospital/intensive care admission following sTBI. Researchers at Massachusetts General Hospital posit that the threshold for hypotension should be set above 110 mm Hg for all comers with sTBI. In this retrospective study including over 150,000 patients, those aged between 50 and 69 years showed lower in-hospital mortality when SBP was maintained above the 110 to 119 mm Hg range.

Loss of autoregulation after sTBI can lead to significant drops in CBF with even the slightest reduction in SBP. On the other hand, elevated SBP can increase CBF leading to edema, small vessel damage, and poor neurologic outcomes. Unfortunately, there is scant literature to guide management of postinjury hypertension and antihypertensive therapy must be avoided until intracranial hypertension has been ruled out as the etiology. A retrospective study from 2012 looked at the German Society for Trauma Surgery database and found those with SBP greater than 160 mm Hg in the prehospital setting had significantly higher mortality rates than those who were normotensive (13.5% vs 25.3%, P < .001). A rare case report of Posterior Reversible Encephalopathy Syndrome demonstrated the phenomenon to occur with severe hypertension in the setting of impaired or lost autoregulation (Lynch DG, Bensam B, Aljabari A, et al. Posterior reversible encephalopathy syndrome in severe traumatic brain injury: illustrative case. Manuscript submitted for publication. n.d).

Catecholamine-induced hypertension can also increase the likelihood of secondary ischemic injury by further precipitating vasogenic edema and elevating ICP. A 2020 randomized controlled trial (RCT) looked at the effect of beta-blocker therapy on survival and functional outcomes in patients with isolated sTBI. Hemodynamically stable patients (SBP >100 mm Hg) not requiring vasopressor support or blood transfusions received 20 mg of propranolol every 12 hours for up to 10 days, commencing 24 hours after injury. Patients receiving beta-blockade demonstrated lower in-hospital mortality rates ( P = .012) and improved functional outcome at 6 months on the Glasgow Outcome Scale Extended (GOS-E) when compared to the control group ( P = .02). It is speculated that beta-blockade therapy attenuates the catecholamine surge, preventing aggravation of vasogenic edema and intracranial hypertension.

Cerebral perfusion pressure

CPP is the net pressure gradient driving oxygen delivery to brain parenchyma, reflected as the difference between mean arterial pressure (MAP) and ICP. CPP can be reduced in the early postinjury period and requires maintenance at a threshold that ensures adequate perfusion to prevent secondary ischemic damage. Several studies support maintaining postinjury CPP values between 60 and 75 mm Hg. ^{, , , ,}

BTF guidelines currently recommend that CPP be maintained between 60 and 70 mm Hg; aggressive attempts at maintain CPP above 70 mm Hg should be avoided due to the risk of acute respiratory distress syndrome (ARDS). This risk was reinforced by Robertson and colleagues who sought to evaluate whether CPP-guided therapy was superior to ICP-guided therapy with respect to patient outcomes. In this study, CPP-guided therapy maintained CPP at 70 mm Hg, whereas the ICP-guided therapy maintained CPP at 50 mm Hg and ICP at 20 mm Hg. While they found no significant difference in outcome, the risk for ARDS increased 5 fold in the CPP-guided group compared to the ICP-guided group. This group also reported an increased duration of epinephrine use, as well as a higher dose of dopamine to manage ARDS. Wettervick and colleagues looked at whether a fixed CPP between 60 and 70 mm Hg was more beneficial to clinical outcome than CPP levels close to autoregulatory targets. CPP values closer to normal autoregulatory target were more strongly associated with less cellular damage when compared to maintaining CPP fixed at 60 to 70 mm Hg. They suggested that autoregulatory CPP targets may correlate with optimal CBF.

The pressure reactivity index (PRx) can be determined by observing the dynamics that exist between arterial blood pressure (ABP) and ICP. PRx can be used to calculate the optimal CPP (CPPopt) target to tailor individual patient needs and has been found to correlate with outcomes following TBI. If PRx is compromised, ICP will rise passively with increases in ABP. Riemann and colleagues discovered a clear association between higher mean PRx and higher mortality rates. A 2019 study by Kramer and colleagues looked at the impact of sTBI on PRx and autoregulation, finding that those with higher PRx values and lower average CPP during the first week following TBI had poorer outcomes. Those with preserved autoregulation had better outcomes. Continuous monitoring of CPP and ICP made the calculation of PRx possible.

The goal of manipulating CPP is to restore sufficient perfusion and oxygen delivery to re-establish the brain’s normal regulatory capacity. In 2011, Rosenthal and colleagues described the MAP challenge, with the goal of establishing a bedside test to determine if cerebral autoregulation is preserved in sTBI. The challenge involves titration of phenylephrine to increase MAP by 10 mm Hg. To assess autoregulation, the researchers calculated cerebrovascular resistance (CVR) at baseline and following the MAP challenge. CVR was calculated as the ratio of CPP to CBF. If ICP eventually decreases with increases in MAP, then autoregulation is preserved. If ICP rises passively with MAP elevation, then autoregulation is impaired or lost.

Intracranial pressure

Significant increases in ICP following sTBI are typically considered a poor prognostic sign. The increase is due to brain edema and/or mass effect from hemorrhage within a rigid, fixed skull cavity. Increased ICP may cause ischemic damage and brainstem compression from herniation. Donnelly and colleagues examined patients with sTBI who had an initial ICP of less than 25 mm Hg, with a subsequent increase to greater than 40 mm Hg for a minimum of 1 hour. They found that raised ICP impaired cerebral autoregulation, CPP, PRx, and overall brain oxygenation. Current BTF guidelines recommend efforts to reduce ICP when elevated above 22 mm Hg. Correcting ICP allows the brain to normalize related parameters.

The role of decompressive craniectomy (DC) in reducing refractory elevated ICP is important to discuss. Bone removal permits expansion of the swollen brain beyond the cranial margins, avoiding brainstem compression. BTF guidelines currently suggest that a large unilateral (frontotemporoparietal) DC is more beneficial in reducing mortality and improving outcomes than a bifrontal or smaller unilateral DC. A prospective study reported significant immediate postcraniectomy decreases in ICP (from 37 ± 17 to 20 ± 13 mm Hg, P = .0003). Of 26 patients, only 19% had persistent refractory ICP postoperatively, and 51% had favorable 6 month outcomes. They also noted an increase in CPP coincident with the decrease in ICP.

The Decompressive Craniectomy (DECRA) trial determined that early bifrontal craniectomy for diffuse injury was beneficial in reducing postoperative ICP but was associated with worse 6 month outcomes compared to those treated with medical management alone. At 12 months, however, there was no difference in outcome between the groups. They also reported a greater number of vegetative survivors among the craniectomy group compared to those who did not undergo DC.

RESCUEicp (Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of ICP) recruited 408 patients (aged 10–65 years) with TBI and severe refractory raised ICP over a 10 year period spanning 2004 to 2014. Participants were randomly assigned to DC or continued medical management. The surgical group demonstrated lower rates of mortality (by approximately 22%), a higher rate of vegetative state, and varying levels of disability when compared to those who were medically managed as measured by GOS-E at the 6 months. However, at 12 and 24 months, the proportion of favorable outcomes increased significantly in the DC group compared to medical management, indicating the need for longer term follow-up to evaluate the effects of treatment on recovery.

Another method of reducing ICP is the use of hyperosmolar therapy. Although the BTF Guidelines do not offer formal recommendations for its use due to the lack of qualifying evidence, several studies have looked at the use of mannitol and hypertonic saline (HS). A small-sample study looked at 22 patients with sTBI treated with either 23.4% HS or mannitol to reduce ICP. They found that the mean reduction in ICP was more significant in those who received a dose of HS in comparison to those who received mannitol 1 hour after administration (9.3 ± 7.37 mm Hg vs 6.4 ± 6.57 mm Hg respectively; P =.0028x ² ). The study concluded that 23.4% HS is more efficacious in reducing ICP when compared to mannitol. Huang and colleagues investigated the comparative effectiveness of 20% mannitol versus 10% HS, reporting no significant difference in absolute ICP reduction, time to reduction, or duration of effect. Although commonly used as standard care, further studies are necessary to determine the role of hyperosmolar agents and therapy in sTBI.

Serum sodium

Under normal circumstances, the human body maintains strict physiologic regulation of sodium concentrations via water homeostasis. The generally accepted normal range for serum sodium is between 135 and 145 mmol/L. Following sTBI, bimodal variation—with both hypernatremia and hyponatremia—may occur, each associated with increased mortality. Severe hyponatremia may result in confusion, seizures, and even death. There are 2 common causes of hyponatremia in the setting of brain injury: syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting (CSW). The diagnostic criteria for SIADH include hypo-osmolality, inappropriate urinary concentration, clinical euvolemia, elevated urinary sodium, and exclusion of hypothyroidism/glucocorticoid deficiency. CSW is less common and is characterized by natriuresis and diuresis, with subsequent hyponatremia and blood volume depletion. Acute, symptomatic hyponatremia may result in cerebral edema and can manifest as nausea, fatigue, seizures, loss of consciousness, and respiratory arrest if serum sodium concentrations rapidly decline. Symptomatic hyponatremia should be treated immediately but cautiously, correcting by no more than 10 to 12 mEq/L in a 24 hour period to reduce the risk of osmotic demyelination syndrome.

Li and colleagues determined that hypernatremia was an independent risk factor with a significant odds ratio for death in patients with TBI admitted to the intensive care unit. Among those with sTBI and severe hypernatremia, 40.7% experienced acute renal failure, likely secondary to negative water balance. None of the patients diagnosed with acute kidney failure survived. These patients had significantly higher use of desmopressin acetate (or 1-deamino-8-D-arginine vasopressin) (DDAVP) and vasoactive drugs. Additionally, 91.5% of patients who died also had central diabetes insipidus (DI). DI, often seen in end-stage sTBI, results from damage to the hypothalamic antidiuretic hormone (ADH)-producing neurons sometime after the initial traumatic insult. DI causes abnormally low secretion of ADH that may be transient, or in severe cases, permanent. The result may be severe hypernatremia, with subsequent increased mortality in patients with TBI. Another study found that desmopressin could be used safely to reduce serum sodium slowly, without significant change in ICP.

An international, multicenter cohort study of patients with sTBI found that sodium variability was greatest during the first 2 days after hospital admission, leveling out thereafter. Of the 240 patients, 64% had hypernatremia and 24% had hyponatremia; hospital mortality was 28%. Any perturbation of serum sodium, whether above or below goal range, was associated with an increased risk for mortality, even when adjusted for confounding factors such as TBI severity, use of osmotherapy, and DI. Keeping this in mind, hyperosmolar therapy endpoints should be limited to a maximum serum sodium of 155 mEq/L and serum osmolality of 320 mEq/L.

It is important to manage both sides of the imbalance and maintain serum sodium within its normal range. Hyponatremia with its potential devastating effects on brain swelling should be identified with frequent electrolyte evaluations.

Temperature

Brain temperature may be 0.5°C to 2°C higher than core temperature after TBI. Hyperthermia, in the context of neurotrauma and stroke, is associated with worse outcomes ; a rise in brain and bodily temperature precipitates further neuronal damage, in turn, contributing to secondary injury. A retrospective study of 1626 patients demonstrated a strong correlation between poor outcome and duration/degree of hyperthermia. A prospective multicenter study examined the effects of elevated brain temperature on both ICP and CPP, reporting an association among brain temperature exceeding 37.5 ^o C (99.5 ^o F), a subsequent rise in ICP, and decreased CPP.

A study by Weng and colleagues in 2019 looked at the effects of both spontaneous hyperthermia and hypothermia in patients over the first 24 hours following TBI. They concluded that those who endured brain temperature extremes (less than 37C [98.6F] or greater than 39C [102.2F]) experienced more severe injury, as well as worse 6 month outcomes.

Current BTF guidelines do not recommend prophylactic hypothermic treatment to improve patient outcomes. A 2018 study by Cooper and colleagues concluded that prophylactic hypothermia did not improve 6 month GOS as compared with normothermia. A multicenter RCT hypothesized that mild hypothermia (34 ^o C–35 ^o C, 93.2 ^o F–95 ^o F for 5 days) might mitigate brain swelling associated with elevated ICP, concluding that hypothermia is helpful in reducing ICP exceeding 30 mm Hg. Despite inconsistent results in the literature, targeting normothermia within the first week of sTBI seems prudent.

Brain oxygenation

Secondary ischemic damage can occur after sTBI if hypoxemia occurs. A post hoc analysis explored the relationship between early arterial oxygenation and long-term outcome in patients with sTBI. Oxygenation thresholds of 150 to 200 mm Hg were associated with better functional outcomes and improved cognition at 6 months.

Monitoring the delivery of oxygen to the brain after sTBI is crucial as reduced delivery is associated with worse functional outcomes and potentially, death. Spiotta and colleagues compared outcomes for patients with sTBI managed by ICP and brain tissue oxygen (PbtO ₂ ) monitors versus ICP monitor alone. Patients with dual monitoring demonstrated lower rates of mortality and more favorable outcomes. The researchers noted a tendency to implement corrective measures more rapidly with a PbtO ₂ monitor, potentially improving outcomes. Okonkwo and colleagues reported similar results for multimodal monitoring with respect to mortality and outcomes in the (Brain Oxygen Optimization in Severe Traumatic Brain Injury [BOOST-2]) trial. The recently published (Oxygen Pressure Monitoring for Severe Traumatic Brain Injury [OXY-TC]) trial—again comparing multimodality versus ICP monitoring alone—found no difference in outcome in 300 patients at 6 months. BOOST-3, a phase 3 RTC is slated to study the same in 1094 patients and is currently underway.

Based upon the literature, there is benefit to monitoring PbtO ₂ in conjunction with other modalities to assist in normalizing function and mitigating the risk of hypoxic injury. ^{, ,} These studies suggest that with the addition of a PbtO ₂ monitor, any deviations from the normal range are discovered sooner and addressed more quickly. This seemingly translates to a more favorable recovery for patients by normalizing cerebral function.

Normocapnia

Hyperventilation after sTBI has previously been shown to cause hypocapnic, vasoconstriction with resultant reduced CBF. The BTF guidelines advise that prophylactic hyperventilation to maintain PCO ₂ below 25 mm Hg should be avoided. Hyperventilation is also not recommended in the first 24 hours following sTBI if CBF is significantly reduced. However, hyperventilation can be used as a temporizing measure to reduce ICP.

A prospective study by Rangel-Castilla and colleagues explored the effects of hyperventilation/hyperoxia on cerebral hemodynamics after sTBI. Patients with sTBI underwent cerebral hemodynamic monitoring (ICP, BP, PbtO ₂ , end-tidal carbon dioxide, and jugular venous oxygen saturation [SjvO ₂ ]) for the first 10 days after injury. Dynamic pressure autoregulation was also measured during that period. Hyperventilation and hyperoxia resulted in vasoconstriction as well as decreased ICP and flow velocity. Hyperventilation caused a decrease in PbtO ₂ and SjvO ₂ , while hyperoxia caused a significant increase in both PbtO ₂ and SjvO ₂ . A slight but consistent improvement was noted in autoregulatory index (ARI) with hyperoxia. The researchers theorize that the observed improvement in ARI reflected hypocapnic vasoconstriction and a subsequent increase in CPP.

A retrospective study by Wettervik and colleagues looked at the effects of mild hyperventilation (PCO ₂ 30–34 mm Hg) and its association with clinical outcomes in patients with TBI. Lower PCO ₂ was significantly associated with better pressure autoregulation, including in a multiple linear regression, suggesting mild hyperventilation may be safe and improve cerebrovascular reactivity. Mild hyperventilation was associated with a slight increase in ICP but did not result in disrupted cerebral energy metabolism or worse clinical outcomes. Higher ICP was associated with poor autoregulation in the first 3 days following injury, as was older age. Lower PCO ₂ did not impact clinical outcome as measured by the GOS-E.

It is important to note that while mild hyperventilation can be beneficial, excessive hyperventilation induces vasoconstriction, resulting in decreased CBF and ultimately, ischemia. Alternatively, a slight increase in PCO ₂ triggers vasodilation, an increase in ICP and subsequent cerebral swelling. Initial management should include maintaining normocarbia. A published consensus-based algorithm supported the use of mild hyperventilation in the range of 32 to 35 mm Hg in later-tier treatment of intracranial hypertension if close monitoring is performed to evaluate the effect on ICP and PbtO ₂ to avoid compromise to CBF.

Lactate/pyruvate ratio

An elevated lactate/pyruvate ratio (LPR) is a marker for cerebral metabolic dysfunction, predicting neurologic outcomes in trauma or cerebrovascular insults. LPR is measured by brain microdialysis; a value greater than 25 indicates impaired cerebral oxidative metabolism. This type of cellular distress precipitates impaired glucose transport to the brain, which may result in interstitial hyperglycemia.

A prospective, observational study looked at glucose, lactate, pyruvate, and LPR following sTBI and their relationship to clinical outcome as measured by the GOS at discharge. Of their 12 samples, 58.4% had bad outcomes, and 41.6% had good outcomes. The researchers reported that glucose, lactate, LPR and lactate/glucose ratio were elevated in TBI patients with GCS 3 to 6, and pyruvate levels were lower in patients with GCS 7 to 9. High glucose, lactate, and LPR were also noted in patients with GOS of 1 to 3.

Wettervik and colleagues looked at the association between arterial glucose, pressure autoregulation, and cerebral energy metabolism in patients with sTBI during the first 3 days following injury. Of the 120 participants, 68 had at least one LPR greater than 25 during that period. The mean LPR gradually increased after injury, and those with a high LPR on the third day also experienced ICP above 50 mm Hg. LPR disturbances were characterized mainly by high lactate and normal-high pyruvate, indicating mitochondrial dysfunction. Furthermore, high arterial glucose was associated with poor pressure autoregulation, high LPR, and poor clinical outcome at 6 months. While not widely used, microdialysis can be a useful adjunct in measuring metabolism to help “normalize” parameters, such as glycemic control and brain oxygen.

Summary

sTBI causes a range of physiologic abnormalities that may result in vulnerability to secondary injury. Managing sTBI is a constant battle against internal disruptions. Attempting to restore parameters to a more “normal” state during the critical days after injury should be the fundamental goal. This process requires diligent and close monitoring with thoughtful interventions. This review outlined general considerations in the neurocritical care management of sTBI, with attention to parameters—including BP, ICP, CPP, temperature, serum sodium, brain oxygen, and cerebral metabolism—that can affect outcome, either independently or in concert. Although sTBI may bring on a “new normal,” early, optimized support for brain recovery can reap benefits in the long-term.

Clinics care points

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  Early resuscitation and avoidance of hypotension

  
  
  
  
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    Maintaining SBP at minimum 110 to 120 mm Hg helps to reduce mortality.

    
    
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    SBP less than 100 mm Hg is associated with worse outcomes due to reduced cerebral perfusion. Even brief episodes of hypotension can cause secondary damage—resuscitate as early as possible.

    
    
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    Avoid overcorrecting hypertensive episodes as hypotension can decrease CBF and worsen ischemia.

  
  
  
  
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  CPP optimization

  
  
  
  
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    Aim to achieve CPP targets between 60 and 70 mm Hg while avoiding aggressive elevation (>70 mm Hg) due to risk of ARDS.

    
    
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    The PRx can be used to tailor patient-specific CPP targets.

  
  
  
  
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  ICP monitoring and management

  
  
  
  
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    ICP threshold for treatment is 22 mm Hg to prevent brain herniation. ICP monitoring should be started early in patient with a GCS of 9 or less.

    
    
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    DC can reduce ICP and mortality but does not always guarantee a favorable outcome; consider the patient’s prognosis.

    
    
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    Large unilateral craniectomy is more effective than smaller craniectomy.

  
  
  
  
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  Serum sodium management

  
  
  
  
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    Monitor closely for both hyponatremia and hypernatremia (SIADH, CSW, and diabetes insipidus).

    
    
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    Avoid rapid sodium correction (>12 mEq/L per 24 hours) to prevent osmotic demyelination syndrome.

  
  
  
  
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  Temperature control

  
  
  
  
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    Hyperthermia (>37.5°C) worsens ICP and cerebral metabolism that can affect outcome.

    
    
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    Prophylactic hypothermia is not recommended but may be used selectively to control ICP.

  
  
  
  
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  PbtO ₂ monitoring

  
  
  
  
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    Maintaining PaO ₂ greater than 150 to 200 mm Hg improves long-term functional outcomes.

    
    
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    PbtO ₂ can be helpful in addressing tissue hypoxia.

  
  

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