Increased Intracranial Pressure in Critically Ill Cancer Patients

  • Abhi PandhiEmail author
  • Rashi Krishnan
  • Nitin Goyal
  • Marc Malkoff
Living reference work entry


Raised ICP can be seen with varied pathologies including traumatic brain injury (TBI), emergent large vessel occlusion stroke (ELVO), intracranial hemorrhage (ICH), primary versus metastatic neoplasms, diffuse brain processes such as cerebral edema, hepatic failure, inflammation and infection, hydrocephalus, and idiopathic.

ICP can be measured via an external ventricular drain (EVD) or a parenchymal bolt. Early clinical signs include headache, papilledema, nausea, stupor, and coma. Early recognition is helpful for early management to prevent cerebral hypoperfusion and brain death.

Management involves multiple tiers of therapies including head of bed up, sedation and analgesia, neuromuscular blockage, mild hyperventilation, and osmotherapy followed by barbiturate coma, therapeutic hypothermia, and aggressive hyperventilation. Last-ditch therapy involves decompressive hemicraniectomy. The use of multimodality monitoring helps in tailoring the appropriate therapy.


Intracranial pressure Cerebral herniation Osmotherapy Craniectomy Indices indicated in green color 


The history behind ICP dates back to 1800s when Magendie discovered a small foramen in the floor of the fourth ventricle and pointed out the connection between the ventricular system and arachnoid spaces in the brain and spinal cord. In the later part of the century, Quincke discovered the use of lumbar puncture for diagnostic and therapeutic purposes which was later on used by many including. The use of lumbar puncture widely for measuring intracranial or CSF pressures fell out of favor due to the possibility of tonsillar herniation and death [26]. Intracranial pressure is defined as pressure within the intracranial vault and is measured in mm Hg.

Lundberg et al. did extensive research on approach to direct cannulation of the ventricular system especially lateral ventricle and connected to the fluid-filled transducer system [30]. He also described that spontaneous changes in ventricular fluid pressure (VFP) curve were of two types i.e., plateau waves and rhythmic oscillations [31]. These especially, the former could cause both transient and persistent damage to brain and therefore earlier diagnosis and prevention are of critical importance. Rhythmic fluctuations can be normal at a frequency of 1/min but the incidence increases with pathology and represent cerebral dysfunction.

The waves described by Lundberg include the following:
  • A waves/plateau waves – high amplitude, i.e., 50–100 mm Hg, lasting 5–20 min. These waves are always pathological. Patients with these waveforms usually show early signs of herniation as well including bradycardia and hypertension. As the cerebral perfusion pressure (CPP) drops [CPP = MAP – ICP], cerebral vasodilation occurs which increases the cerebral blood volume. This leads to a vicious circle with eventual decrease in CPP.

  • B waves – oscillating waves with frequency of 0.5–2/m and amplitude up to 50 mmHg likely while still in lower limits of pressure autoregulation.

  • C waves – oscillating waves with frequency of 4–8/min and amplitude of up to 20 mmHg. These have been documented in healthy individuals as well.

    Both A and B waves require intervention to reduce ICP and increase CPP, thus mandating the need for continuous monitoring of ICP.

Monroe and Kellie Doctrine

This doctrine stated by Professor Monroe and Kelly from Scotland (Monro et al.; [41, 69]) which states that in a closed system (i.e., when fontanelles and sutures are closed), the intracranial pressure-volume relationship can be represented as follows: VT = Vb+Vcsf+Vvasc (where Vt is the total intracranial volume, i.e., 1700 cc; Vb is brain volume, i.e., 1400 cc; Vcsf is 30 cc in ventricles; and Vvasc is circulatory volume, i.e., arteries and veins around 150 cc) [53]. When a central nervous system pathology occurs, a new volume Vx is added, such that now VT = Vb+Vcsf+Vvasc+Vx. To maintain the ICP constant, one of the other components must be displaced, which most commonly, CSF is the first one to egress from cerebral convexities through arachnoid granulations into the cerebral venous sinuses. With further increase in Vx, other reserves are exhausted and eventually leading to even rise in ICP and compression of intracranial structures including brain (Vb) or vasculature (Vvasc), causing brain ischemia and infarction.

Avezaat and Van Eijdhoven in the 1800s significantly contributed toward understanding of raised ICP which involves an interplay between intracranial volume and compliance of cranio-spinal axis. In Fig. 1, in the physiological range, i.e., near the origin of the x-axis on the graph (point a), intracranial pressure remains normal in spite of small additions of volume until a point of decompensation (point b), after which each subsequent increment in total volume results in an ever larger increment in intracranial pressure (point c) [53].
Fig. 1

Pressure volume curve

Etiologies of Increased ICP [35]

  • Brain neoplasm: due to mass effect and vasogenic edema with symptoms of headache, blurred vision, decreased alertness, vomiting, and focal symptoms occasionally

  • Traumatic brain injury (TBI): due to either diffuse axonal injury or focal cerebral edema, intracranial hemorrhage, or contusions with mass effect

  • Large vessel ischemic stroke (could be internal carotid artery/middle cerebral artery occlusion) leading to large volume cytotoxic edema with mass effect causing secondary cerebral herniation and vascular occlusion of nearby arteries

  • Intracranial hemorrhage (ICH): mass effect due to the space-occupying lesion within closed system, which could be either of subdural hematoma or epidural hematoma or intracerebral hemorrhage, subarachnoid hemorrhage with or without hemorrhage

  • Hydrocephalus: could be either non-communicating or communicating. Former a.k.a. obstructive hydrocephalus with mass effect/lesions obstructing the major CSF pathways or drainage. Latter a.k.a nonobstructive can be due to blockage of arachnoid granulations or microscopic CSF drainage from cells (e.g., meningitis, subarachnoid hemorrhage) or due to high proteins (such as Guillain-Barre syndrome)

  • Diffuse edematous process such as acetaminophen overdose with hepatic failure and with or without hyperammonemia, acute on chronic live failure, encephalitis, vasogenic or other forms of cerebral edema

  • Jugular venous obstruction or elevated right-sided cardiac venous pressure: could be due to central line insertion leading to jugular thrombosis or superior vena cava syndrome or severe congestive heart failure or chronic obstructive pulmonary disease (COPD) with clinically significant papilledema

  • Idiopathic edema: pseudotumor cerebri (risk factors include female sex, obesity, and use of oral contraceptives)

Effect of Increased ICP

In a closed system (within the skull and split by dural membranes into anterior middle and posterior fossae), when an intracranial mass effect occurs (such as temporal lobe hematoma), it can encroach and extend into tentorium cerebelli causing displacement of adjacent intracranial structures, like third cranial nerve and subsequent ipsilateral pupil dilatation. If the mass effect extends across the brainstem to cause it to abut the contralateral tentorium, this can cause contralateral third nerve injury and pupillary dilatation (i.e., Kernohan’s notch phenomenon) [13]. The initial mechanisms of reserve include CSF egress into ventricular system and compression of space between cortical sulci and CSF spaces. After that, brain tissue itself becomes compressed and shifts in path of least intracranial resistance, leading to mechanical movement of brain tissue, described as cerebral herniation. Examples include the following: (1) uncal herniation is defined as temporal lobe uncus shifting medially from middle cranial fossa into tentorium and medially downward toward lower posterior cranial fossa; (2) subfalcine herniation, when a part of frontal lobe moves under falx cerebri to the contralateral side which can cause compression of anterior cerebral artery and potential cerebral infarction from mechanical occlusion of these arteries (ipsilaterally and contralaterally if severe); (3) tonsillar herniation occurs when cerebellar tonsils herniate downward through foramen magnum; (4) diencephalic herniation, when diencephalon herniates downward through tentorium into posterior fossa, from bilateral cerebral edema or mass effect; and (5) external herniation occurs when part of calvarium is removed (surgically or by trauma) and brain herniates outside cranial vault [13].

Intracranial Pressure Monitoring

ICP can be measured at different sites in the brain – intraventricular and intraparenchymal measurements are more common, while extradural and subdural sensors are used occasionally. Intraventricular catheters are still the “gold standard” as they allow direct measurement by insertion of a catheter into one of the lateral ventricles, which is connected to an external pressure transducer [40, 63]. Benefits include that clinician can check for zero drift and sensitivity of the measurement system in vivo as well as excess CSF drainage when the pressure rises. Drawbacks include difficulty or failure to insert in patients with advanced brain swelling with slit ventricles. Another risk of infection is directly proportional to the amount of time catheter is in place, with rates up to 10% [3]. Antibiotic-coated tips (Codman Bactiseal® external ventricular drain catheter) that may reduce infection rates are available, but more studies are required before their use in clinical practice can be supported.

Intraparenchymal catheters are inserted through a support bolt or tunneled subcutaneously from a burr hole. These have a microminiature strain gauge pressure sensor side-mounted at the tip (Codman) or a fiber-optic catheter (Camino, InnerSpace). These have a low infection rate compared to intraventricular catheters [32]. Drawback includes small drift of the zero line and doesn’t allow the in vivo pressure calibration. Some technical difficulties including kinking of the cable and dislocation of the sensor have been reported.

Subdural catheters are easily inserted following craniotomy, but measurements are unreliable because when ICP is elevated they are likely to underestimate the true ICP. They are liable to blockage as well. Extradural probes are even more unreliable compared to the former as the relationship between ICP and pressure in the extradural space is not certain. But both of these have lower risk of infection, epilepsy, and hemorrhage than ventricular catheters [15, 51].

Determination of cerebral perfusion pressure (CPP): ICP is an important determinant of CPP, i.e., CPP = MAP – ICP, which in turn affects CBF and CBV. Most of the studies recommend CPP in the range of 50–70 mm Hg with some variation through studies [11]. Treating ICP above the range of 20–25 is recommended as it is shown to decrease mortality and improve outcomes [25].

Measurement of intracranial pressure: ICP zero point is defined as center of the head or at the level of foramen of Monro, which is anatomically close to the tragus of the outer ear. When lying in lateral recumbent, the intrathecal pressure is equivalent to ICP, assuming craniocaudal axis is intact without any blockages [56, 64]. Performing a lumbar puncture in the sitting position makes measuring ICP problematic and may be inaccurate unless the tubing system is long enough to extend above the tragus. Normal ICP is usually less than 15–20 mm Hg. Conversion from Hg mm to cm H2O requires division by 1.35.

Assessment of Intracranial Compliance and Elastance

When ICP is normal, the shape of the ICP waveform has three distinct waves, sometimes called P1, P2, and P3. As additional intracranial volume is added, ICP increases precipitously, shown as P2 higher than P1 in Fig. 2.
Fig. 2

Intracranial pressure waveform

A simple bedside test to measure intracranial compliance is jugular venous compression (either unilateral or bilateral) while monitoring ICP. This is done by applying gentle pressure over each jugular while observing ICP under continuous monitoring. This is important for comatose patients who can’t give a history or participate in Valsalva testing. Jugular pressure would raise the ICP similar to doing Valsalva, and after removal of pressure, it should decrease. The degree of ICP elevation in patients with high elastance/low compliance intracranial states can be striking and provide useful information to guide treatment.

A second test is by placing the head of the bed 0° (head flat test) from the common 30–40° elevation used in ICU. The ICP is first assessed at 30 or 40° position and then at head of bed flat (in case of EVD in place, EVD would need to be clamped and rezeroed after head position change). Increased ICP with the head of bed at 0° indicates poor intracranial compliance and demands caution, particularly when planning transportation outside of the intensive care unit or testing with the head in a flat position (e.g., radiology or procedures). This may be detrimental in case of patients with refractory intracranial hypertension, where being laid flat for the 20–30 min necessary can potentially lead to CPP crisis states (less than 60 mm Hg) and secondary brain injury [46, 47].

Another method is by injecting a small amount of saline into the ventricular catheter or lumbar drain followed by mathematical analysis of patient’s elastance curve, which is still a topic of research.

Pressure Autoregulation (Fig. 3)

Cerebral blood flow (CBF) equation is important to know in the management of patients with increased ICP as the former is dependent on ICP values [56]:
$$ \mathrm{CBF}=\mathrm{CPP}/\mathrm{CVR} $$
where CVR is cerebrovascular resistance.
Fig. 3

CBF and CPP relationship

CBF is kept constant through a range of CPP values through mechanisms called cerebrovascular autoregulation. In normal states, as CPP increases, CVR increases as well and vice versa. Autoregulation is an energy-dependent process and starts to fail in case of an acute brain injury (i.e., stroke, TBI, or hemorrhage). When it fails, CBF becomes linearly proportional to CPP values. This presents as a challenge as low CPP may drop CBF below critical thresholds. Thus, these patients have two sets of problems: (1) compromised CPP from ICP elevation with or without preserved autoregulation and (2) loss of autoregulation (leading to linear correlation between CBF and CPP), either or both leading to exacerbation of secondary injury. The ICP monitor can measure ICP, and multimodality monitoring helps in detection of failure or preservation of autoregulation [10, 71].

ICP and Outcome

ICP, as a simple numeric value, is not an independent outcome predictor, i.e., when used to predict outcome, the ICP data should be interpreted with clinical and demographic characteristics, CT findings, and other physiologic data. Recent studies suggest that individualized or patient-specific targets may provide a more robust relationship [27, 28, 68] retrospectively analyzed data from 327 TBI patients and defined individualized ICP thresholds and observed that individualized doses of intracranial hypertension were stronger predictors of death than doses derived from universal thresholds of 20 and 25 mm Hg [27]. Multiple modalities including physiologic monitors being used today, e.g., brain oxygen, microdialysis, and PET among others, demonstrate that brain energy dysfunction may occur even when ICP is normal or that the brain could be healthy despite an elevated ICP, thus advocating the concept of permissive intracranial hypertension, i.e., even if ICP is raised, other parameters such as the above should be looked at simultaneously [39].

Management of Increased ICP

The following are goals of therapy: (a) avoid sustained intracranial hypertension >20 mm Hg which predicts poor outcomes; (b) maintain CPP of 60 mm Hg (55–70) – higher CPP can predispose to acute respiratory distress syndrome (ARDS), and low CPP produces a fall in brain tissue PO2 [29].

General resuscitation involves appropriate cardiopulmonary support, ABCs, to maintain oxygenation [keep SaO2 >92–95% with ventilator settings with adjusting PEEP (no effect on ICP up to 15 cm H2O), FiO2 to improve hypoxia if any], adequate blood pressure (MAP >70, augmented with fluids or pressor support as well as blood transfusions as needed) and airway protection (rapid sequence intubation (RSI) for anyone with GCS <8), and fever treatment especially if >39 °C in first 24 h and immediate treatment of seizures if any [54].

Initial neurological exam should be undertaken along with history (signs of increased ICP including headache, stupor, nausea, vomiting, papilledema) early on to determine if patient is stable enough for further testing including neuroimaging. CT is preferred (alternatively MRI brain) in emergent setting to rule out life-threatening causes including TBI, ICH, brain herniation, malignant stroke, and hydrocephalus, and further as indicated, neurosurgical consultation is obtained for surgical decompression versus ICP monitor versus EVD placement [7, 16]. If cancer is suspected, then MRI brain with and without contrast is recommended.

Specific Therapy

First-Tier Therapies

This includes the first line of treatment for reducing raised ICP. Patient’s head of bed should be raised up to 30° position and maximum of 45°, instead of keeping flat which can precipitate ICP crisis or higher than 45 which can drop the CPP [48]. Adequate sedation and pain control can reduce ICP somewhat by reducing Valsalva and jugular venous pressure elevation, but this comes at the cost of suppression of respiratory drive and clouding of sensorium and thus neurological examination. Subcutaneous route for analgesia is preferred at times if intractable vomiting [13]. Neuromuscular blockade is employed in these group of patients who are intubated to prevent coughing which can cause spikes of raised ICP. This approach is associated with clouding of neurological examination as well as increased risk of pneumonia and critical illness myopathy/polyneuropathy [49]. If EVD is in place, and ICP is raised, CSF can be drained as a temporizing measure [16]. Hyperventilation can be used temporarily or as a bridge therapy but avoided as a prolonged treatment modality. Latter can be associated with ischemia due to vasoconstriction. The suggested treatment plan includes mild hyperventilation (with PaCO2 of 32–34 mmHg) followed by a return to normocapnia (PaCO2 35–40 mmHg) [42].

Second-Tier Therapies: Osmotherapy

Mannitol: intravenous hyperosmolar agent which can be administered via peripheral line. It causes an increase in serum osmolality and an osmotic gradient between the serum and intracranial compartment with subsequent removal of brain water to reduce ICP. It has a reflection coefficient of 0.9, thus a theoretically increased risk of extravasating through blood-brain barrier into damaged brain tissue and exacerbating brain damage. The side effects associated with it include hypovolemia and secondary hypernatremia, thus mandating frequent electrolyte and serum osmolality monitoring. It can also precipitate hypokalemia and if sever enough can cause EKG changes as well. It can potentially worsen fluid status in patients with severe congestive heart failure or end-stage renal disease (contraindicated in latter as can’t excrete mannitol out of body). It could be used a bolus therapy or even scheduled for patients with refractory ICP until the surgical therapy [61].

Hypertonic saline: comes in various concentrations including 1.5% vs. 3% vs. 10% vs. 14.6% vs. 23.4%. It requires a central venous access for administration to prevent peripheral thrombophlebitis. Similar to mannitol, it creates an osmotic gradient between serum and intracranial compartment to reduce ICP, but it doesn’t have a diuretic effect and increases total body sodium and chloride concentrations and helps increase CPP. Patients who develop salt and volume overload due to the above can be given mannitol and hypertonic saline alternatively. It has a reflection coefficient of 1, thus lower theoretical risk of extravasation across blood-brain barrier and into damaged tissue. Caution exerted in using in patients with congestive heart failure. Frequent monitoring of electrolytes and osmolality is recommended to watch for signs of iatrogenic hypernatremia hyperchloremia and non-anion gap metabolic acidosis. Latter can be treated with enteral water pushes or infusions. Infusions of hypotonic solutions are generally avoided as they can increase the brain edema and ICP. Lastly, patients who develop high urine output and hypernatremia regardless of osmotherapy should be monitored for development of diabetes insipidus that can be a complication of the underlying severe brain injury. The clinical picture can be confused even with diuresis produced due to mannitol [14, 16, 28].

Third-Tier Therapy

Therapeutic hypothermia: hypothermia reduces brain metabolism and brain blood flow, thus reducing ICP. Mild to moderate hypothermia (32–34 °C) is effective in reducing ICP. NABIS II (National Acute Brain Injury Study: Hypothermia II) study was a randomized controlled trial comparing normothermia with hypothermia and didn’t demonstrate a difference in outcomes between two groups at 6 months [37]. A study by Jiang et al. demonstrated favorable outcomes with longer use of hypothermia up to 48–72 h [19]. Eurotherm 3235 trial provides evidence against therapeutic hypothermia to lower intracranial pressure but no clear guidance on its use for refractory intracranial hypertension [1].

The use of this modality has been associated with increased risk of infections and prolonged effects of sedatives and analgesics due to alteration in their metabolism. For patients who are febrile, normothermia is targeted as high temperatures are associated with worse outcomes. Controlled normothermia with cooling devices is being studied as well [34].

Barbiturate coma: includes pentobarbital and thiopental. The use of barbiturate in the setting of high ICP works in the following ways: (a) decreased cerebral metabolic rate (CMRO2), caused by decrease in synaptic transmission which is due to its effect on GABA transmission; (b) decrease in cerebral blood volume and flow and thus ICP due to increased cerebrovascular resistance because of vasoconstriction; (c) induction of hypothermia; (d) increase in intracranial glucose, glucagon, and phosphocreatine energy store; (e) decrease in nitrogen excretion following acute head injury; (f) anticonvulsant effect; (g) stabilization of lysosomal membranes; (h) decrease in excitatory neurotransmitters and intracellular calcium; and (i) free radical scavenging. Adverse effects of barbiturate therapy include (1) direct myocardial depressant, (2) impaired gastrointestinal motility, (3) direct CNS depressant, and (4) possible allergic reaction [20].

Aggressive hyperventilation: used as a last-ditch therapy. The details of hyperventilation are discussed above in first-tier therapy.

Role of steroids: use of steroids as temporizing measures for reducing vasogenic edema in primary and metastatic cancers. Patient is initially given dexamethasone 8 mg IV. If the patient responds and is stable and not vomiting, then continue with dexamethasone oral 4 mg four times daily. If the patient remains unwell or continues to vomit, then continue with IV dexamethasone; doses of up to 8 mg three to four hourly can be given IV for up to 2–3 days if needed. Consider prophylactic gastroprotection while the patient is on high-dose corticosteroids (omeprazole oral 20 mg daily or lansoprazole oral 30 mg daily). However, steroid use has been associated with worse outcomes in patients with high ICP and related brain edema [52, 55, 57, 59].

ICP and Malignancy

As stated above, steroids are sued for high ICP due to primary or metastatic malignancy. For intractable vomiting, cyclizine SC can be used. If the patient doesn’t respond to the above regimen of steroids, then mannitol IV may be considered. Long-term mannitol is contraindicated.

Therefore, unless there is a rapidly acting therapeutic maneuver likely to provide longer-term stabilization of ICP (usually this requires surgery), mannitol should not be used. Mannitol total dose is 1 g/kg. First give 100 ml of a 20% solution (20 g mannitol) over 15 min. Then give the remainder over approximately 45 min. Repeat the following day if required but not long term [22].

Role of Surgery: Last Resort Therapy

Decompressive craniectomy (DC) involves removal of a part of the skull to let the swollen brain expand out. It is done to for cases of refractory intracranial hypertension [23] especially in operable cases such as posterior fossa hemorrhage with mass effect or large posterior fossa stroke (>3 cm) with effacement or midline shift or extra-axial hematomas [16, 24]. Replacement of original bone flap versus cranioplasty can be done typically within 6–12 weeks. If the follow-up surgery gets delayed beyond 12 weeks, then patients may develop severe headaches, tinnitus, dizziness, behavioral or emotional symptoms, sensorimotor or autonomic deficits, and cognitive impairments, which collectively can be referred to as syndrome of trephined, which gets reversed after the surgery [66].

DECRA (decompressive craniectomy) trial was conducted in Australia, New Zealand, and Saudi Arabia and included 155 adults randomized to medical management or medical management plus DC. After 6 months, the craniectomy group patients had worse outcomes with more complications than former [8]. In comparison, Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) trial included 408 patients with severe TBI and refractory elevated intracranial pressure and found that even though 6-month mortality was lower in the DC group, the risk of vegetative state or severe disability was higher as compared to the medical management group [18].

The following recommendations regarding DC have been proposed:
  • Brain Trauma Foundation (BTF) guidelines, 2017: Bifrontal DC is not recommended to improve outcomes in severe TBI patients with diffuse injury and with ICP elevations to >20 mm Hg for more than 15 min duration in an hour period that are refractory to first-tier therapies. But it does reduce ICP and days in the ICU [5].

  • American College of Surgeons (ACS) 2015: Recommended as third-tier treatment after positioning, sedation, ventricular drainage, osmotherapies, and neuromuscular paralysis have been tried [9].

  • Joint Trauma System Clinical Practice guidelines (JTS CPG), 2017: DC should be strongly considered following penetrating combat brain trauma [36].

  • Recent systematic review and meta-analysis by Zhang et al. included multiple RCTs as well as several retrospective and observational studies and concluded that the mortality was reduced with DC compared to medical arm, but no significant difference found for the functional outcomes (except if DC was done within 36 h of the injury) [70]. Determination of whether an individual patient should undergo DC rests on clinical judgment and surrogate engagement.

Surgery has a role in elevated ICP and intracranial malignancy including removal or debulking of tumor to target symptom relief or management of focal resistant epilepsy, biopsy of the lesion especially if near or surrounding eloquent areas of the brain, as well as a definitive therapy for increased intracranial pressure [38].

Supportive Care

Mechanical DVT prophylaxis should be instituted right away, whereas chemical DVT prophylaxis should be started within 1–2 days of injury, sometimes at the discretion of the treating physician [16].

Nutrition: early feeding is important because of high metabolic requirement.

Supportive care also includes providing for anxiolysis, treatment of withdrawal syndromes, and seizure control [5].

Role of Multimodality Monitoring

No one method can provide complex information about the brain’s functioning thus a combination of monitors or multimodality monitoring (MMM) has evolved in recent years.

Why do we need it?
  • Detects damage caused by primary and secondary brain injury (SBI), before patient shows signs of clinical deterioration. SBI is seen sometimes hours to days after the injury and can be due to alteration in neurochemical mediators, glutamate-mediated influx of calcium/sodium leading to swelling and death, and alterations in glucose utilization such as mitochondrial dysfunction [39, 60, 67].
    • Evidence of microvascular injury and metabolic failure precedes an increase in ICP; thus detection of ICP (or CPP) may not always detect ingoing dysfunction/damage [12, 44].

    • Earlier detection can potentially lead to prompt intervention and better outcomes.

  • Clinical indications include (a) GCS < or = 8 + abnormal CT head and (b) GCS < or =8 + normal CT head +2 of the following (hypotension or age >40 years or posturing)

  • Diagnostic indications – TBI, subarachnoid hemorrhage (SAH), ICH, anoxic injury, cerebral edema, and status epilepticus.

MMM tools include the following:
  • ICP monitoring

  • Brain tissue oxygen monitoring (PbtO2) or Licox monitoring

  • Cerebral microdialysis (CMD)

MMM can help guide various therapies including hyperventilation, osmotherapy, glycemic control, transfusion, CPP augmentation, and therapeutic temperature modulation while making sure not to cause significant side effects from one type of therapy [21, 44]. It can also help differentiate between different pathologies causing similar clinic radiological picture as well as more accurate assessment of perfusion pressure compared to ICP/CPP monitoring alone [2] including those with diffuse brain damage. Some of the monitoring modalities including microdialysis and Licox monitoring, i.e., PbtO2, are associated with mortality and morbidity outcomes [33, 43, 65].

Monitoring by itself does not alter outcome. Instead, it is how the information is used that contributes to patient outcomes. RCT done by Chesnut et al. [6] revealed that patients undergoing MMM had 50% decrease in use of ICP lowering treatments but in fact ended up spending more days in ICU [6].

Study by Ponce et al. suggests that outcome is better when both PbtO2 and ICP/CPP therapy rather than ICP/CPP-only-based therapy are used in severe TBI [45]. BOOST 2 trial showed physiological efficacy and a trend toward improved outcomes in the population randomized to PbtO2 monitoring-based therapy [50]. The next phase, BOOST 3, is currently enrolling. The use of pressure reactivity (PRx) has been employed to determine an optimum CPP in a severe TBI group, but a study by Howell et al. found that CPP-targeted approach showed to be more successful in patients with preserved pressure reactivity and in contrast ICP-targeted approach was better when pressure reactivity was impaired [17].

Upcoming Therapies

Currently a trial is enrolling for possibility for use of hyperbaric oxygen for reducing brain injury in patients with severe TBIs. ProTeCT trial is currently underway as well studying the role of progesterone as a possible neuroprotective agent in moderate to severe TBI. The role of magnesium has been studied in TBI patients with variable results. Study by Temkin et al. [62] showed that serum concentration of 1.25–2.5 mmol/L was associated with increased mortality [62]. Review by Sen et al. suggested that a combination of magnesium and mannitol with dexanabinol and progesterone and interventions with hyperoxia or hypothermia could be a safe and clinically successful neuroprotective regimen for the treatment of TBI [58].

Specifically, for increased ICP and intracranial malignancies, various studies are underway in the field of regenerative medicine with the use of administration of healthy, functioning exogenous oligodendrocyte progenitor cells (OPCs) which maintain their normal function upon implantation into a previously irradiated brain migrating widely and generating oligodendrocytes and remyelinating lesioned area [4].


Increased ICP on critically ill patients can be multifactorial and can be monitored while in ICU with various modalities including external ventricular drain, intracranial bolt, multimodality monitoring. Various therapies available include positioning, sedation, analgesia, hypothermia, and medical management with steroids (specifically for increased intracranial pressure related to primary or secondary neoplasms) as well as osmotherapy. Surgical therapies as detailed above have been tried as a last resort to manage medically refractory ICP as well as for diagnostic purposes in case of suspicious lesions. The role of multimodality monitoring including PbtO2 or Licox monitoring, PRx, and CMD is being studied extensively in various studies as outlined above. Various neuroprotective agents including hyperbaric oxygen, magnesium, selenium, and progestin analogues have been studied as well as the use of OPCs for previously irradiated brain in the setting of a malignancy.


  1. 1.
    Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, Murray GD, Eurotherm3235 Trial Collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med. 2015;373(25):2403–12. Scholar
  2. 2.
    Bouzat P, et al. Accuracy of brain multimodal monitoring to detect cerebral hypoperfusion after traumatic brain injury. Crit Care Med. 2014;43(2):445–52.CrossRefGoogle Scholar
  3. 3.
    Bekar A, Goren S, Korfali E, Aksoy K, Boyaci S. Complications of brain tissue pressure monitoring with a fibreoptic device. Neurosurg Rev. 1998;21:254–9.CrossRefGoogle Scholar
  4. 4.
    Burns TC, Awad AJ, Li MD, Grant GA. Radiation-induced brain injury: low-hanging fruit for neuroregeneration. Neurosurg Focus. 2016;40(5):E3. Scholar
  5. 5.
    Carney N, Totten AM, O’Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Ghajar J. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. 2017;80(1):6–15. Scholar
  6. 6.
    Chesnut RM, Temkin N, Carney N, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012;367(26):2471–81. Scholar
  7. 7.
    Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(6):1711–37. Scholar
  8. 8.
    Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D’Urso P, New Zealand intensive care society clinical trials, G, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011;364(16):1493–502. Scholar
  9. 9.
    Cryer HG, Manley GT, Adelson PD, Alali AS, Calland JF, Cipolle M, Wright DW. ACS TQIP best practices in the management of traumatic brain injury. Chicago: American College of Surgeons; 2015.Google Scholar
  10. 10.
    Czosnyka M, Kirkpatrick PJ, Pickard JD. Multimodal monitoring and assessment of cerebral haemodynamic reserve after severe head injury. Cerebrovasc Brain Metab Rev. 1996;8(4):273–95.PubMedGoogle Scholar
  11. 11.
    Czosnyka M, Czosnyka Z, Pickard JD. Laboratory testing of the Spiegelberg brain pressure monitor: a technical report. J Neurol Neurosurg Psychiatry. 1997;63:732–5.CrossRefGoogle Scholar
  12. 12.
    Eriksson EA, et al. Cerebral perfusion pressure and intracranial pressure are not surrogates for brain tissue oxygenation in traumatic brain injury. Clin Neurophysiol. 2012;123:1255–60.CrossRefGoogle Scholar
  13. 13.
    Freeman WD. Management of intracranial pressure. Continuum (Minneap Minn). 2015;21(5 Neurocritical Care):1299–323. Scholar
  14. 14.
    Francony G, Fauvage B, Falcon D, et al. Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure. Crit Care Med. 2008;36(3):795–800. Scholar
  15. 15.
    Gaab MR, Heissler HE, Ehrhardt K. Physical characteristics of various methods for measuring ICP. In: Hoff JT, Betz AL, editors. Intracranial pressure VII. Berlin: Springer; 1989. p. 16–21.CrossRefGoogle Scholar
  16. 16.
    Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, Fung GL, Goldstein JN, Macdonald RL, Mitchell PH, Scott PA, Selim MH, Woo D, American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032–60. Scholar
  17. 17.
    Howells T, et al. Pressure reactivity as a guide in the treatment of cerebral perfusion pressure in patients with brain trauma. J Neurosurg. 2005;102(2):311–7.CrossRefGoogle Scholar
  18. 18.
    Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, Collaborators, R. E. T, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med. 2016;375(12):1119–30. Scholar
  19. 19.
    Jiang JY, Xu W, Li WP, et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006;26(6):771–6. Scholar
  20. 20.
    Greenberg J. Handbook of head and spine trauma. 1993. p. 230–3.Google Scholar
  21. 21.
    Johnston AJ, et al. Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury. Crit Care Med. 2005;33(1):189–95.CrossRefGoogle Scholar
  22. 22.
    Kaal EC, Vecht CJ. The management of brain edema in brain tumors. Curr Opin Oncol. 2004;16(6):593–600.CrossRefGoogle Scholar
  23. 23.
    Kahraman S, et al. Heart rate and pulse pressure variability are associated with intractable intracranial hypertension after severe traumatic brain injury. J Neurosurg Anesthesiol. 2010;22(4):296–302.CrossRefGoogle Scholar
  24. 24.
    Mostofi K. Neurosurgical management of massive cerebellar infarct outcome in 53 patients. Surg Neurol Int. 2013;4:28. Scholar
  25. 25.
    Khormi YH, Gosadi I, Campbell S, Senthilselvan A, O’Kelly C, Zygun D. Adherence to brain trauma foundation guidelines for management of traumatic brain injury patients and its effect on outcomes: systematic review. J Neurotrauma. 2018; Scholar
  26. 26.
    Langfitt TW, Weinstein JD, Kassell NF, Simeone FA. Transmission of increased intracranial pressure I: within the craniospinal axis. J Neurosurg. 1964;21: 989–97.CrossRefGoogle Scholar
  27. 27.
    Lazaridis C, et al. Patient-specific thresholds of intracranial pressure in severe traumatic brain injury. J Neurosurg. 2014;120(4):893–900.CrossRefGoogle Scholar
  28. 28.
    Lewandowski-Belfer JJ, Patel AV, Darracott RM, et al. Safety and efficacy of repeated doses of 14.6 or 23.4% hypertonic saline for refractory intracranial hypertension. Neurocrit Care. 2014;20(3):436–42. Scholar
  29. 29.
    Lou M, Xue F, Chen L, Xue Y, Wang K. Is high PEEP ventilation strategy safe for acute respiratory distress syndrome after severe traumatic brain injury? Brain Inj. 2012;26(6):887–90. Scholar
  30. 30.
    Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychiat Neurol Scand. 1960;36(suppl):149.Google Scholar
  31. 31.
    Lundberg N, Troupp H, Lorin H. Continuous recording of the ventricular fluid pressure in patients with severe acute traumatic brain injury. J Neurosurg. 1965;22: 581–90.CrossRefGoogle Scholar
  32. 32.
    Mack WJ, King RG, Ducruet AF, Kreiter K, Mocco J, Maghoub A, Mayer S, Connolly ES Jr. Intracranial pressure following aneurysmal subarachnoid hemorrhage: monitoring practices and outcome data. Neurosurg Focus. 2003;14:1–5.CrossRefGoogle Scholar
  33. 33.
    Maloney-Wilensky E, et al. Brain tissue oxygen and outcome after severe traumatic brain injury: a systematic review. Crit Care Med. 2009;37:2057–63.CrossRefGoogle Scholar
  34. 34.
    Marion DW. Controlled normothermia in neurologic intensive care. Crit Care Med. 2004;32(2 suppl):S43–5. Scholar
  35. 35.
    May K. The pathophysiology and causes of raised intracranial pressure. Br J Nurs. 2009;18(15):911–4.CrossRefGoogle Scholar
  36. 36.
    McCafferty R, et al. Joint trauma system clinical practice guideline: neurosurgery and severe head injury (CPG ID:30). 2017.Google Scholar
  37. 37.
    McCauley SR, Wilde EA, Moretti P, et al. Neurological outcome scale for traumatic brain injury: III. Criterion-related validity and sensitivity to change in the NABIS hypothermia-II clinical trial. J Neurotrauma. 2013;30(17):1506–11. Scholar
  38. 38.
    Macdonald DR, Cairncross JG. Surgery for single brain metastasis. N Engl J Med. 1990;323(2):132–3.CrossRefGoogle Scholar
  39. 39.
    Menon DK, et al. Diffusion limited oxygen delivery following head injury. Crit Care Med. 2004;32: 1384–90.CrossRefGoogle Scholar
  40. 40.
    Miller JD. Measuring ICP in patients: its value now and in the future. In: Hoff JT, Betz AL, editors. Intracranial pressure VII. Berlin/Heidelberg/New York: Springer; 1989. p. 5–15.CrossRefGoogle Scholar
  41. 41.
    Monro A. Observations on the structure and function of the nervous system. Edinburgh: Creech & Johnson; 1783.Google Scholar
  42. 42.
    Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg. 1991;75(5):731–9.CrossRefGoogle Scholar
  43. 43.
    Oddo M, et al. Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurgery. 2011;69:1037–45.PubMedGoogle Scholar
  44. 44.
    Oddo M, et al. Anemia and brain oxygen after severe traumatic brain injury. Intensive Care Med. 2012;38:1497–504.CrossRefGoogle Scholar
  45. 45.
    Okonkwo DO, Shutter LA, Moore C, Temkin NR, Puccio AM, Madden CJ, Andaluz N, Chesnut RM, Bullock MR, Grant GA, McGregor J, Weaver M, Jallo J, LeRoux PD, Moberg D, Barber J, Lazaridis C, Diaz-Arrastia RR. Brain oxygen optimization in severe traumatic brain injury phase-II: a phase II randomized trial. Crit Care Med. 2017;45(11):1907–14. Scholar
  46. 46.
    Peace K, Wilensky EM, Frangos S, et al. The use of a portable head CT scanner in the intensive care unit. J Neurosci Nurs. 2010;42(2):109–16. Scholar
  47. 47.
    Peace K, Maloney-Wilensky E, Frangos S, et al. Portable head CT scan and its effect on intracranial pressure, cerebral perfusion pressure, and brain oxygen. J Neurosurg. 2011;114(5):1479–84. Scholar
  48. 48.
    Pandhi A, Elijovich L. Postoperative positioning in the neurointensive care unit. In: Arthur A, Foley K, Hamm C, editors. Perioperative considerations and positioning for neurosurgical procedures. Cham: Springer; 2018. Scholar
  49. 49.
    Pandit L, Agrawal A. Neuromuscular disorders in critical illness. Clin Neurol Neurosurg. 2006;108(7): 621–7.CrossRefGoogle Scholar
  50. 50.
    Ponce LL, et al. Position of probe determines prognostic information of brain tissue pO2 in severe traumatic brain injury. Neurosurgery. 2012;70(6):1492–502.CrossRefGoogle Scholar
  51. 51.
    Raabe A, Totzauer R, Meyer O, Stockel R, Hohrein D, Schoeche J. Reliability of extradural pressure measurement in clinical practice: behaviour of three modern sensors during simultaneous ipsilateral intraventricular or intraparenchymal pressure measurement. Neurosurgery. 1998;43:306–11.CrossRefGoogle Scholar
  52. 52.
    Rangel-Castilla L1, Gopinath S, Robertson CS. Management of intracranial hypertension. Neurol Clin. 2008;26(2):521–41. Scholar
  53. 53.
    Rengachary SS, Ellenbogen RG, editors. Principles of neurosurgery. Edinburgh: Elsevier Mosby; 2005.Google Scholar
  54. 54.
    Reynolds SF, Heffner J. Airway management of the critically ill patient: rapid-sequence intubation. Chest. 2005;127(4):1397–412. Scholar
  55. 55.
    Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomized placebo-controlled trial. Lancet. 2004;364(9442):1321–8. Scholar
  56. 56.
    Rose JC, Mayer SA. Optimizing blood pressure in neurological emergencies. Neurocrit Care. 2004;1(3):287–99.CrossRefGoogle Scholar
  57. 57.
    Ryken TC, McDermott M, Robinson PD, et al. The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J Neuro-Oncol. 2010;96(1):103–14. Scholar
  58. 58.
    Sen AP, Gulati A. Use of magnesium in traumatic brain injury. Neurotherapeutics. 2010;7(1):91–9. Scholar
  59. 59.
    Shenkin HA. Steroids in treatment of high intracranial pressure. N Engl J Med. 1970;283(12):659.PubMedGoogle Scholar
  60. 60.
    Singh IN, et al. Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy. J Cereb Blood Flow Metab. 2006;26:1407–18.CrossRefGoogle Scholar
  61. 61.
    Stocchetti N, Picetti E, Berardino M, et al. Clinical applications of intracranial pressure monitoring in traumatic brain injury: report of the Milan consensus conference. Acta Neurochir. 2014;156(8):1615–22. Scholar
  62. 62.
    Temkin NR, Anderson GD, Winn HR, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol. 2007;6:29–38.CrossRefGoogle Scholar
  63. 63.
    The Brain Trauma Foundation, The American Association of Neurological Surgeons, The Joint Section on Neurotrauma and Critical Care. Recommendations for intracranial pressure monitoring technology. J Neurotrauma. 2000;17:497–506.CrossRefGoogle Scholar
  64. 64.
    The Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. VII. Intracranial pressure monitoring technology. J Neurotrauma. 2007;24(suppl 1):S45–54.Google Scholar
  65. 65.
    Timofeev I, et al. Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. Brain. 2011;134: 484–94.CrossRefGoogle Scholar
  66. 66.
    Vasung L, Hamard M, Soto MCA, Sommaruga S, Sveikata L, Leemann B, Vargas MI. Radiological signs of the syndrome of the trephined. Neuroradiology. 2016;58(6):557–68. Scholar
  67. 67.
    Vespa P, et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005;25:763–74.CrossRefGoogle Scholar
  68. 68.
    Vik A, et al. Relationship of “dose” of intracranial hypertension to outcome in severe traumatic brain injury. J Neurosurg. 2008;109(4):678–84.CrossRefGoogle Scholar
  69. 69.
    Wu OC, Manjila S, Malakooti N, Cohen AR. The remarkable medical lineage of the Monro family: contributions of Alexander primus, secundus, and tertius. J Neurosurg. 2012;116(6):1337–46. Scholar
  70. 70.
    Zhang D, Xue Q, Chen J, Dong Y, Hou L, Jiang Y, Wang J. Decompressive craniectomy in the management of intracranial hypertension after traumatic brain injury: a systematic review and meta-analysis. Sci Rep. 2017;7(1):8800. Scholar
  71. 71.
    Zweifel C, Dias C, Smielewski P, Czosnyka M. Continuous time-domain monitoring of cerebral autoregulation in neurocritical care. Med Eng Phys. 2014;36(5):638–45. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Abhi Pandhi
    • 1
    Email author
  • Rashi Krishnan
    • 1
  • Nitin Goyal
    • 1
  • Marc Malkoff
    • 1
  1. 1.Department of NeurologyUniversity of Tennessee Health Science CenterMemphisUSA

Section editors and affiliations

  • Yenny Cardenas
    • 1
  1. 1.Critical Care DepartmentUniversidad del Rosario Hospital Universitario Fundacion Santa Fe deBogotaColombia

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