Deep Dive into the Evidence: Monitoring and Management of Elevated Intracranial Pressure in Severe Traumatic Brain Injury

Elevated ICP is an emergent complication associated with injury to the brain. In this Deep Dive, we summarize the existing evidence regarding the monitoring and management of elevated intracranial pressure in the setting of traumatic brain injury.

Pathophysiology

The Monro-Kellie doctrine states that the intracranial compartment contains a fixed total volume determined by the rigid skull. Blood, brain, and CSF are the main components contributing to the intracranial volume. Thus, an increase in the volume of one component will result in a rise in intracranial pressure (ICP) unless buffered by displacement or a decrease in one of the other compartments. When the buffering capacity is exhausted, there is poor intracranial compliance, and thus, small physiologic changes can result in relatively significant changes in ICP.

Normally, the ICP values should be between 7 to 15 mmHg for adults and between 3 to 6 mmHg in children, and the guidelines recommend keeping ICP less than 22 mmHg in the setting of traumatic brain injury (TBI).¹ Elevated ICP can cause brain herniation and brainstem compression via regional injury or by reduction of cerebral perfusion leading to global brain ischemia.² Cerebral perfusion pressure (CPP) is defined as the difference between mean arterial pressure (MAP) and ICP. In states of cerebral hypoperfusion, which is frequently seen in the setting of TBI, the normal physiologic response is cerebral vasodilation. However, if a patient has poor intracranial compliance, cerebral vasodilation will increase intracranial blood volume and thus increase ICP, resulting in a paradoxical drop in CPP. Therefore, the management of ICP in patients with TBI requires close neurological monitoring and careful adjustment of hemodynamics to optimize CPP.³

Diagnosis and Monitoring 

Clinical signs of elevated ICP vary and depend on the underlying etiology. While there are commonly discussed clinical signs and imaging findings to suggest elevated ICP–such as pupillary changes, altered level of consciousness, motor posturing, effacement of the ventricles, narrowing of the basal cisterns, and midline-shift on neuroimaging–no single physical examination or imaging finding is sufficiently sensitive or specific to diagnose elevated ICP.⁴ Sonography, specifically the measurement of optic nerve sheath diameter (ONSD), has also been cited as a non-invasive method to detect elevated ICP. However, the variable performance of this method precludes its use as a definitive diagnostic method.⁴

Invasive methods are still the gold standard to monitor ICP. One commonly used device is the external ventricular drainage (EVD) system, a system made up of a catheter placed into one of the lateral ventricles. This allows for drainage of CSF and ICP monitoring via connection to an external pressure transducer. An intracranial transducer device is another option, and it can be inserted into the parenchyma via a less invasive procedure; however, unlike an EVD, it cannot be recalibrated or used to drain CSF (see Devices Series: EVD and ICP Monitors for more information).⁵ The BEST-TRIP RCT showed that in patients with severe TBI, management guided by invasive ICP monitoring did not improve outcomes compared with management based on clinical and exam findings, though there may be methodological issues with the study, including inadequate sample size and low generalizability to other clinical settings.⁶ The SYNAPSE-ICU observational study showed significant variability in the use of ICP monitoring devices between different centers and countries, and showed that invasive ICP monitoring leads to a more aggressive therapeutic approach and lower 6-month mortality in more severe cases of acute brain injury.⁷ 

The 2020 Seattle International Brain Injury Consensus Conference (SIBICC) expressed support for a protocol that included brain tissue oxygen (PbtO₂) monitoring as well as ICP monitoring.⁸ While utilizing brain tissue oxygen monitoring has been shown to reduce the proportion of time with brain tissue hypoxia after severe TBI, it did not seem to reduce the proportion of patients with poor neurologic outcome at six months when compared to an ICP-only monitoring protocol.^9,10 However, the Brain Oxygen Optimization in Severe Traumatic Brain Injury (BOOST-3) trial and Brain Oxygen Neuromonitoring in Australia and New Zealand Assessment (BONANZA) trial are ongoing multicenter RCTs to evaluate functional outcomes after management guided by ICP monitoring alone versus both ICP and PbtO₂ monitoring and will provide further data on the topic.^11,12 

Management

Management algorithms for severe TBI are often presented as a tiered approach that weighs the benefits and efficacy of each intervention against its risks. In practice, there may be differences in the organization of the tiered algorithm depending on the clinical setting and the presence of invasive ICP monitoring to guide management. The lowest tier generally consists of basic neuroprotective interventions, which include optimizing venous outflow from the brain (ie, avoid IJ central venous catheters, keep neck midline, avoid over-tightening of cervical collar), avoiding hyponatremia, temperature management to prevent fever, and head of bed elevation to 30-45°.⁸ Higher tiers represent more aggressive therapy in response to clinical decompensation or rising ICP. One should attempt to use the lowest tier possible to achieve the appropriate clinical goal; however, there is no need to exhaust all treatment modalities of one tier before moving on to the next if a patient would benefit from a different therapy or has failed to benefit from a lower tiered therapy.

Ventilation Therapies
Decreasing PaCO₂ will induce cerebral vasoconstriction, which will lower ICP and improve CPP (CPP = MAP—ICP). However, as PaCO₂ is a powerful driver of cerebral blood flow, prolonged or inappropriate hyperventilation may result in too dramatic a decrease in cerebral flow and thus inadequately match the brain's metabolic demands. 

For this reason, most patients will benefit from keeping PaCO₂ in the normal range (35-45 mmHg) and avoiding significant hypocapnia (<25 mmHg). While the existing Brain Trauma Foundation (BTF) guidelines do not provide specific recommendations on how hyperventilation should be used as a treatment, in practice it may be used briefly as a temporizing measure in response to acutely elevated ICP. It is important to note that due to lower cerebral blood flow in the initial 24 hours after TBI, there is concern about an increasing risk of ischemia with prolonged hyperventilation during this period.¹³

Lastly, care must also be taken to slowly taper back to normocapnia over 4-6 hours to avoid a rebound increase in ICP, which is possible with rapid discontinuation of hyperventilation.¹⁴

Sedation
Sedation in the patient with TBI is a balancing act. At a minimum, sedation should minimize discomfort, agitation, and ventilator dyssynchrony. However, care must be taken not to over-sedate these patients as this can lead to prolonged unreliable neurological exams, cognitive dysfunction, increased incidence of ventilator-associated pneumonia (VAP), and increased risk of hemodynamic instability.¹⁵ Some common sedatives used in the neurocritical care unit include propofol, opioids, dexmedetomidine, benzodiazepines, and barbiturates.

Propofol increases sedation in a dose-dependent manner and has been shown to depress cerebral metabolism and oxygen consumption.¹⁶ However, younger patients and patients on prolonged (>48 hours) or high dose (> 5 mg/kg/hour) infusions of propofol are at an increased risk of developing propofol infusion syndrome, characterized by lactic acidosis, rhabdomyolysis, and cardiovascular instability.¹⁷ Although midazolam has less hemodynamic effect than propofol, it can cause prolonged sedation due to accumulation in adipose tissue.¹⁸ Though the topic requires more rigorous research, a pilot study comparing midazolam and propofol as sedation for patients with severe TBI found that plasma markers of neurological injury were similar between the two groups.¹⁹ Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that can cause sedation without substantial respiratory depression. A recent review concluded that while dexmedetomidine is a safe and efficacious strategy in TBI patients, more work needs to be done to understand how its associated risks of bradycardia and hypotension may affect cerebral hemodynamics and how it compares with other sedative strategies alone or as an adjunct.²⁰ Fentanyl and other opioids are commonly used to treat pain and agitation post-TBI. Recent review articles examining existing data on the effect of opioids on cerebral physiology in TBI found that, in general, opioids administered as an infusion resulted in no significant effect on ICP, CPP, or MAP, whereas high-dose boluses were associated with increases in ICP with associated decreases in CPP and MAP.^21,22

Barbiturates, namely pentobarbital or thiopental, also work to decrease ICP by suppressing brain metabolism. However, they have a significant risk of hemodynamic instability, decreased cerebral perfusion, and leukopenia. A Cochrane systematic review found that barbiturate therapy in patients with severe TBI did not improve outcomes but did result in a fall in blood pressure in a quarter of the patients.²³ While some disagreement remains on the true utility of a barbiturate coma, the BTF still maintains a level IIb recommendation of high-dose barbiturate therapy for elevated ICP of traumatic etiology that is refractory to standard medical and surgical therapy.¹

Hyperosmolar Therapy
The two agents commonly employed for hyperosmolar therapy in elevated ICP are mannitol and hypertonic saline. Briefly, both agents create osmotic disequilibrium between the intra and extracellular compartments and can draw free water out of brain tissue and into systemic circulation. In addition, these agents reduce red blood cell viscosity by decreasing cell rigidity, thus increasing the ease of passage of blood cells through small blood vessels.¹³

Mannitol is typically dosed between 0.25 and 1.0 g/kg and administered IV over 30-60-minute infusions. The target serum osmolality in mannitol therapy is between 310 and 320 mOsm/l. Hypertonic saline has various concentrations and dosing options. A 250mL bolus of 3% normal saline is often used for bolus therapy. If using higher concentrations, such as 23.4% saline, it should be administered through a central line.

Certain situations may preclude the use of one of these agents due to side-effect profiles. For example, hypertonic saline may be dangerous to a hyponatremic patient due to rapid shifts of serum sodium concentration, whereas the diuretic effect of mannitol may make it undesirable in a hemodynamically unstable patient. Overall, there is no strong evidence to suggest one may be more optimal than the other due to the heterogeneity between existing trials and varying statistical methods in existing meta-analyses, and the guidelines reflect this uncertainty.^24,25,26 The BFT guideline did not make specific recommendations on the use of hyperosmolar therapy, and while the Neurocritical Care Society made a conditional recommendation of using hypertonic saline over mannitol based on the former’s putative advantages of quicker onset and possibly more durable ICP reduction, it notes that mannitol is comparably safe and efficacious. Neither agent has been associated with improvement in neurologic outcomes.^1,27,28 There is an ongoing large RCT that directly compares hypertonic saline and mannitol in terms of their effect on neurologic outcomes in patients with severe TBI and may provide more definitive evidence on the topic in the near future.²⁹

Another topic that requires further investigation is the continuous infusion of hypertonic therapy. While a systematic review notes that prophylactic initiation of continuous hypertonic saline was associated with improved 90-day survival, the COBI RCT demonstrated that, compared to intermittent boluses of mannitol or hypertonic saline, there was no significant benefit in continuous administration of 20% hypertonic saline for 48 hours in terms of neurologic outcome.^30,31

Hypothermia
Hypothermia affects cerebral blood flow and ICP by decreasing cerebral metabolism. While there is no strong data to support its neuroprotective effects in TBI, physicians were operating under the assumption that hypothermia could be beneficial as it can decrease ICP and they had seen its utility in patients with cardiac arrest from acute coronary syndrome. However, the intervention also has risks, including hypokalemia, atrial and ventricular arrhythmias, hypotension, coagulopathies, and an increased risk of ventilator-acquired infections.

Most ICP protocols that incorporate induced hypothermia use 32°C-35°C as a target, and it can be initiated before ICP elevation, referred to as prophylactic hypothermia, or as a treatment in response to refractory ICP elevation, referred to as therapeutic hypothermia. Based on existing evidence, hypothermia, compared to normothermia, has not been shown to improve neurologic outcomes as a prophylactic intervention or as a therapeutic intervention.^32,33

Seizure Prophylaxis
There is a relatively high incidence of seizures in patients with severe TBI as acute brain injury lowers the threshold for epileptiform discharges. Preventing seizures in the post-traumatic setting has potential benefits, such as minimizing changes to cerebral metabolism and ICP and preventing the development of chronic epilepsy. A well-powered RCT looked at the role of phenytoin in the prevention of both early (within seven days of injury) and late (after seven days) post-traumatic seizures (PTS) and found a statistically significant decrease in the rate of early PTS in the cohort who received phenytoin but no difference in mortality or occurrence of late PTS.³⁴ For this reason, the BTF recommends early initiation of phenytoin administration (within seven days) following TBI in situations when the benefits of drug administration outweigh the risks.¹ While levetiracetam has a more preferable side-effect profile, there is insufficient evidence to suggest its superiority in terms of efficacy over other antiepileptics in this setting.³⁵

CSF Drainage
Whether ICP lowering via CSF drainage improves outcomes in TBI requires further research, however its use may be considered, especially in patients with neurological decline due to ICP crisis after an injury.³⁶ External Ventricular Drainage (EVD) systems are the preferred method of CSF drainage as they mitigate the risk of transtentorial herniation seen with other methods such as serial lumbar punctures in the cases of ICP crisis.²¹ In general, a closed EVD allows for monitoring of ICP, while an open position allows for drainage of CSF. Based on a single cohort study, continuous drainage of CSF may result in a more effective lowering of ICP than intermittent drainage, with an unknown effect on neurological outcomes or mortality.³⁷

Paralysis
There is no high-quality evidence to support the routine use of neuromuscular blocking agents in patients with TBI. However, in patients with refractory elevated ICP, its use can be considered as it can decrease ICP by decreasing overall metabolism and can help with vent dyssynchrony or shivering.³⁸

Decompressive Craniectomy
As discussed earlier, the Monroe-Kellie doctrine dictates that the cranial vault has a fixed volume. Thus, a decompressive craniectomy (DC), which is the surgical removal of a portion of the skull, can help relieve elevated ICP. The most recent BTF guidelines recommend against the routine use of DC as it has not been shown to improve outcomes.¹ These recommendations are supported by the DECRA trial studying severe TBI patients with refractory elevated ICP. While early bi-frontotemporoparietal DC resulted in shorter duration of elevated ICP and decreased length of stay in the ICU, it was associated with more unfavorable outcomes at 6 months as measured by the extended Glasgow Outcome Scale (GOS-E).³⁹ The more recent RESCUE-ICP trial also evaluated DC versus medical management and found higher odds of survival in the DC group than the medical management group at 6 months. However, there was also a significantly greater proportion of survivors in the DC group who, at 6 months, were in a persistent vegetative state and severely disabled when compared to the medical management group.⁴⁰ In summary, DC is currently reserved as a higher-tier management of refractory ICP in recognition of these hazards.

Steroids
While steroids are commonly used to reduce ICP in other types of brain injury (ie, space-occupying abscess or vasogenic edema secondary to neoplasm), the CRASH multi-site RCT evaluated the effects of 48 hours infusion of methylprednisolone in TBI patients with GCS of 14 or less and found significantly higher mortality in the corticosteroid group than the placebo group.⁴¹ For this reason, the BTF recommends against the use of steroids for improving neurologic outcomes or reducing ICP in patients with severe TBI.¹

Summary

Detection and treatment of elevated ICP is essential in patients with TBI. Current guidelines and consensus group statements support a tier-based algorithm for treatment, with basic neuroprotective measures as the first tier and moving to higher tiers in response to clinical decompensations or refractory elevated ICP. While existing research has not provided robust evidence to demonstrate the efficacy of many of these treatments in improving neurologic outcomes, in practice, treatments such as hyperosmolar therapy, barbiturate coma, short-term hyperventilation, paralysis, CSF drainage, decompressive craniectomy can all be considered in response to ICP crises. In addition to further research on these known treatment modalities, the ongoing study on the use of brain oxygenation monitoring in addition to ICP monitoring in TBI will be crucial to look out for as it may lead to changes in treatment algorithms as well.

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