Practical Approach to Posttraumatic Intracranial Hypertension According to Pathophysiologic Reasoning

P r a c t i c a l A p p ro a c h t o P o s t t r a u m a t i c In t r a c r a n i a l H y p e r t e n s i o n A c c o rd i n g t o Pathophysiologic Reasoning Daniel Agustín Godoy, Mario Di Napoli, MDe,f

MD

a,b,

*, Walter Videtta,

MD

c,d

,

KEYWORDS  Intracranial pressure  Intracranial hypertension  Acute brain injury  Cerebral perfusion pressure  Multimodal monitoring  Traumatic brain injury KEY POINTS  Intracranial hypertension (ICH) is major damage pathway of acute brain injury.  ICH is a potentially life-threatening secondary brain insult.  The causes of ICH are varied and multiple and, sometimes, the origin of ICH is outside the cranial cavity.  Homeostasis of basic physiologic variables (physiologic neuroprotection) and avoiding secondary insults are important steps to control ICH.  The correct management of ICH should be based on appropriate pathophysiologic analysis and multidisciplinary work.

Do what you can, with what you have, where you are —Theodore Roosevelt INTRODUCTION

An increase in intracranial pressure (ICP) can be a medical or surgical emergency.1 Both intracranial and systemic events contribute to increased ICP after traumatic brain injury (TBI) and other acute or chronic neurologic conditions (ischemic stroke, Disclosures: The authors declare no conflict of interest and received no funding to write this article. a Intensive Care Unit, San Juan Bautista Hospital, Catamarca, Argentina; b Neurointensive Care Unit, Sanatorio Pasteur, Chacabuco 675, Catamarca 4700, Argentina; c Intensive Care Unit, National Hospital, Alejandro Posadas, Buenos Aires, Argentina; d Intensive Care Unit, Eva Peron Hospital, Merlo, Buenos Aires, Argentina; e Neurological Service, San Camillo de’ Lellis General Hospital, Rieti, Italy; f Neurological Section, SMDN—Center for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Sulmona, L’Aquila, Italy * Corresponding author. Neurointensive Care Unit, Sanatorio Pasteur, Chacabuco 675, Catamarca 4700, Argentina. E-mail address: [email protected] Neurol Clin 35 (2017) 613–640 http://dx.doi.org/10.1016/j.ncl.2017.06.002 0733-8619/17/ª 2017 Elsevier Inc. All rights reserved.

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subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, tumors).1,2 Intracranial hypertension (ICH) can be life threatening by mechanical or vascular effects. Mechanical effects are mediated through different types and degrees of cerebral displacement and herniation. Vascular effects result from reducing cerebral perfusion pressure (CPP), which is defined as mean arterial blood pressure (MABP) minus ICP. The CPP is the driving force of cerebral blood flow (CBF). As the CPP decreases, CBF may become insufficient for adequate brain-tissue perfusion and oxygenation.3,4 The adequate level of CBF and CPP vary among patients and the optimal CPP value changes over time and is linked to cerebrovascular reactivity. Increased ICP and low CPP are associated with mortality and poor long-term outcome.5–9 DEFINITIONS

Normal ICP varies with age, body position, and clinical condition.1,10 In healthy individuals in supine position it is between 7 and 15 mm Hg; while standing, it becomes negative with an average of about 10 mm Hg.1,2,10 In term infants, 1.5 to 6 mm Hg is considered normal, whereas in children these values range between 3 and 7 mm Hg.11 ICP can be increased transiently in physiologic situations such as a coughing or sneezing. Critically ill patients, occasional increases can be observed with changes in position, aspiration of secretions, asynchrony with mechanical ventilation, and physiotherapy.1,2,5 ICH is traditionally considered present in adults when ICP values are greater than 20 mm Hg for more than 5 to 10 minutes.12,13 Initiating or intensifying treatment is generally indicated above this threshold. In other situations, such as decompressive craniectomy (DC) or contusions close to the midbrain (temporal, basal region of frontal lobes), it may be advisable to use a threshold of 15 mm Hg to start therapy.14 However, the ICP threshold and the optimal time to initiate or intensify treatment are subjects of debate.13–17 In addition, this threshold can change over time in individual patients. A recent review of the Brain Trauma Foundation guidelines suggests initiating treatment when ICP is greater than 22 mm Hg.17 BASIC PHYSIOLOGY Unicompartment Model

Monro and Kellie18 postulated that, in a rigid and inextensible structure such as the skull, ICP is the result of the sum of pressures exerted by each component of the cranial compartment. The components are parenchyma (70%), cerebrospinal fluid (CSF) (15%), and cerebral blood volume (CBV) contained in veins and arteries (15%).18 This overall intracranial volume must remain constant. CSF and blood can act as a buffer, so they are displaced from the cranial compartment when a new volume is added. ICP 5 Brain tissue (parenchyma) 1 CSF 1 CBV Intracranial volumes

 Brain tissue Glia: 700 to 900 mL 5 45.5% Neurons: 500 to 700 mL 5 35.5%  Blood: 100 to 150 mL 5 7.5%  CSF: 100 to 150 mL 5 7.5%  Extracellular fluids: 50 to 70 mL 5 3.5% From an anatomic point of view, the supratentorial space is responsible for 50% of the ICP, whereas the infratentorial is responsible for 30% and the spinal space comprises the remainder (20%).2,15

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In order to keep ICP within the normal range, any change in the volume of one of the components must be accompanied by a similar change in the opposite direction of the other components.18–20 This adaptation mechanism is limited, and, when it is exhausted, the ICP increases.2,18–20 CSF and blood contained in the cerebral veins (75% of total blood volume) are the only components capable of rapidly and effectively reducing ICP levels when moved to the spinal compartment.1,2,18–20 CSF is produced by the choroid plexus at a constant rate of 20 mL/h, circulating through the ventricular system and then being absorbed by the arachnoid villi and venous granulations. Changes in CSF production or absorption usually do not play an important role in the compensation of ICP increases.21 The arterial vascular compartment (25% of the total blood volume) has an approximate volume of 23 mL. This volume can be reduced by 35% (15 mL) or increased by 172% (68 mL), depending on whether the vessels decrease (vasoconstriction) or increase their diameter (vasodilation) through the autoregulatory mechanism of the small vessels of the cerebral parenchyma. Normally, CBF remains constant despite changes in the CPP in the physiologic range between 50 and 150 mm Hg19,22–24 (Fig. 1). The cerebral veins are not compressible (except in the presence of ICH), and they do not react to the same stimuli as the arterial bed. However, the venous flow is one of the main determinants of intracranial dynamics because, from its origin to the right atrium, the system is continuous and free of valves.22,24,25 An aspect to remember is that the brain is compartmentalized because of folds of the dura forming the interhemispheric falx and the cerebellar tentorium. In this way, the ICP is not uniform throughout the skull, especially in pathologic states in which gradients can develop from one space to another.26 REGULATORY SYSTEMS OF THE BRAIN

CPP equals MABP minus ICP.1,19,23–25 Basic information obtained from multimodality monitoring (MMM) provides the ICP and CPP calculations, both of which might trigger intervention. The current guideline recommendation is to use ICP and CPP to guide therapy.17

Fig. 1. Cerebral autoregulation curve.

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CPP 5 MABP – ICP If CPP is less than 50 mm Hg or greater than 150 mm Hg, CBF passively follows CPP: that is, if the CPP is less than 50 mm Hg, the CBF decreases; if the CPP is more than 150 mm Hg, the CBF increases.2,19,23–25 The normal brain has several mechanisms for regulating pressure and volume.27–29 The goal is to keep a continuous and adequate CBF and oxygen supply, despite changes in both MABP and cerebral metabolic requirements.27–29 The key mechanism is the change in cerebrovascular resistance through vasoconstriction and dilatation mediated by various mechanisms.22,23,29 Cerebral Pressure Reactivity

Cerebral pressure reactivity is one of the critical systems in cerebral autoregulation and allows smooth vascular muscle response to changes in mean arterial pressure (MAP). Under physiologic conditions, an increase in MAP causes a compensatory increase in cerebrovascular resistance, thus keeping the CBF constant.29,30 VASODILATION AND VASOCONSTRICTION CASCADE

Many factors can initiate vasodilation and vasoconstriction cascades, including MABP, volemia, temperature, blood viscosity, oxygen delivery/metabolism, hypocapnia/hypercapnia, and pharmacologic agents (Fig. 2). Stimulating a vasoconstriction cascade can sometimes be strategically useful for ICH control.30–32 An increase in MABP or an increase in CBV can activate the vasoconstriction cascade, thereby reducing ICP.30,31 Cerebral vasodilation can be a response to decreased MABP, leading to increased CBV and ICP. If the MABP remains low, CPP decreases further, accelerating the vasodilation cascade until maximum dilatation is attained or the MABP can be stabilized. The cascade could also be initiated by hypoxemia, dehydration, seizures, fever, or hypercapnia.30,31 In about half of the cases, the physiologic phenomenon of autoregulation is damaged.23–26 This damage can be focal or diffuse, transient or permanent. Abnormal autoregulation is associated with poor outcome. Assessment of the autoregulation can be performed at the bedside, simply by observing the changes of ICP in relation to changes in MABP or by using transcranial Doppler and determination of the pressure-reactivity index (PRx) which correlates changes in ICP with spontaneous or pharmacologically induced changes in MABP.19,23–25,33,34 The index ranges from 1 to 11. A negative value, including zero, indicates that ICP does not change in changes in MABP, so the autoregulation mechanism is conserved, whereas if the value is positive, ICP follows changes in MABP, so autoregulation is damaged.34 PRx has prognostic and therapeutic value because many drugs used to control ICP (osmotherapy, barbiturates) work only if this physiologic mechanism is intact.34 In addition, PRx can help to achieve optimal CPP values.34 CEREBRAL RESPONSE TO CO2 (REACTIVITY)

PaCO2 significantly influences ICP. For each 1 mm Hg change in PaCO2, there is a blood volume change of approximately 0.04 mL/100 g of brain tissue.20,23–25 Thus, vessel dilatation caused by an increase in PaCO2 may induce an increase in CBV and worsen ICH and brain swelling.27 In contrast, when PaCO2 decreases, vasoconstriction occurs and leads to a decrease in CBV and ICP. However, if the PaCO2 value decreases to

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Fig. 2. Vasodilatory (A) and vasoconstrictor (B) cascades. SABP, systolic arterial blood pressure; CMRO2; cerebral metabolic rate for oxygen.

20 mm Hg or less, the CBF might decrease to half, thus compromising cerebral perfusion and potentially causing brain ischemia.35–38 Therefore, hyperventilation therapy should be avoided, especially during the first 24 hours after a severe injury.38–40 Loss of reactivity to CO2 is most often a terminal event associated with catastrophic outcomes.20,23–25 CEREBRAL COMPLIANCE

Cerebral compliance reflects the changes in ICP that follow changes in intracranial volume Fig. 3.23–25 The relationship between intracranial volume and ICP is exponential. Initially, when volume increases because of edema or a new lesion (eg, hematoma), the ICP increases slightly, but when the buffering capabilities of the system are exceeded, ICP increases steeply. In decompensated states, changes in CBV of

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Fig. 3. Volume/pressure curve.

1 mL can increase ICP by 7 to 8 mm Hg.1,2,19,23–25 This relationship explains the rapid deterioration that is frequently seen in patients with acute traumatic intracranial hematomas (see Fig. 3). Two factors are not expressed in the pressure/volume relationship: the rate and the timing.2,19,20,23–25 A slow-growing tumor allows the full development of compensatory mechanisms, which explains why many individuals are asymptomatic until the tumor has reached a critical growth, when further compensation becomes impossible. In contrast, an acute spontaneous intraparenchymal hematoma or a fast-growing traumatic contusion does not give time for the compensatory mechanisms to be fully effective, and consequently the ICP increases faster. Cerebral compliance 5 DV/DP INTRACRANIAL PRESSURE: BEYOND A SINGLE NUMBER

ICP waves are the result of pulse transmission of arterial pressure via the choroid plexuses to the CSF and brain parenchyma.41 Intracranial compliance can be assessed by ICP waveform analysis and the correlation coefficient between the ICP waveform amplitude and the mean ICP (RAP index).42–44 This relationship between ICP and MABP fluctuations can provide vital information pertaining to the underlying status of the cerebrovascular reactivity and autoregulation.45,46 Attempts have been made to identify loss of compensation using ICP waveform analysis: the normal ICP waveform has 3 components (P1>P2>P3), but is altered when pressure increases, resulting an increase in the P2 component compared with P1 (Fig. 4); the ICP pulse amplitude (difference between systolic and diastolic values) also tends to increase.47,48 However, this feature depends on the CPP and on the physical properties of the measuring system, and therefore should be interpreted with caution.43 As ICP increases, the morphology of the waves changes, adopting a pyramidal form with a gradual disappearance of P1 and P3, and the marked ascent of P2.42,43,47

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Fig. 4. ICP waves registered at 25 mm per second showing the 3 components (P1, P2, and P3). (A) Normal pattern; (B) pattern of reduced compliance.

Sometimes the ICP waveform changes before any major increase in the ICP measurement. If P2 is greater than or equal to P1, even with ICP values within the range usually considered normal, this indicates that compliance is reduced42,43,47 (see Fig. 4). Thus, the analysis of the ICP wave is a useful tool to gauge the intracranial compliance.42,43,47,48 There are also other waves, called Lundberg waves, that are seen in the slow register (50 mm/h). There are 3 types: A, B, and C. A and B waves (Fig. 5) are pathologic, reflect poor compliance, and demand treatment (particularly A waves).47–49 Multicompartment Model

Pressure increase in extracranial body compartments can affect ICP. Treatment of patients with TBI can be optimized with the knowledge of the multiple compartment syndrome (MCS).50 MCS is a condition in which pressure in one body compartment, or treatment of pressure in one body compartment, can affect pressure in another body compartment.51 In patients with a TBI, the result of MCS can be ICH, which has been associated with poor neurologic outcomes.50–52 ICP has been shown to have a complex relationship with both intra-abdominal pressure (IAP) and intrathoracic pressure (ITP).50,51,53,54 The true physiologic interplay between IAP, ITP, and ICP in MCS is not well elucidated. Increased IAP directly compresses the thoracic cavity through diaphragm elevation, inducing higher peak airway pressures while decreasing functional residual capacity, lung volume, and chest wall compliance.55 Positive pressure causes an increase in intrapleural

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Fig. 5. Lundberg waves.

pressure, which in turn increases pulmonary artery occlusion pressure and right ventricular afterload.56,57 Increased IAP also decreases cardiac compliance and cardiac output,55 all of which could potentially decrease CPP and exacerbate ICP increase if the venous return is limited.50,51,55 Fluid resuscitation may also contribute to MCS development.50 Thus, increases in ITP or IAP can compromise ICP and CPP the by 2 different mechanisms:  Cerebral venous drainage compromise  Decreased MAP and cardiac output (Fig. 6) PATHOPHYSIOLOGY OF INCREASED INTRACRANIAL PRESSURE

Table 1 lists the causes of increases of ICP by applying a pathophysiologic reasoning. INTRACRANIAL HYPERTENSION EVALUATION

The clinical signs and symptoms of ICH (headache, vomiting) are nonspecific and unreliable, whereas the classic triad described by Harvey Cushing (arterial hypertension, irregular breathing, bradycardia) occurs late.1,2,22,23 Papilledema is most prominent when ICH develops slowly and its absence does not rule out ICH. Pupillary asymmetry is also a poor marker of ICH. Space-occupying lesions larger than 25 mL only cause pupillary asymmetry of more than 1 mm in 40% of cases, whereas only one-third of individuals with pupillary asymmetry greater than 3 mm have ipsilateral focal lesions.58

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ICP = BPP + CSFP + VP CPP = MABP - ICP Cerebral Edema

Brain Parenchyma

VasodilataƟon

New occuping space Mass lesion

CSF dynamics AlteraƟon

Hydrocephalus

C S F

C B V

Venous drainage ObstrucƟon

CPP

MABP

Cardiac Output decrease

ITP

Stroke volume decrease Preload Decrease

CBV increase

IAP

Fever Hypotension Hypoxemia Hypercapnia Hyperemia Seizures Drugs

Inadequate Head posiƟon Venous Compression ITP increase IAP increase

Mechanical VenƟlaƟonPEEP Airway obstrucƟon Pneumothorax Hemothorax HyperinflaƟon ARDS Atelectasis PaƟent-VenƟlator asynchrony Gastroparesis Ileus Fluid therapy Pneumoperitoneum Hemoperitoneum

Fig. 6. Multicompartment model showed the relationship between ICP, ITP, and IAP. ARDS, acute respiratory distress syndrome; BPP, brain parenchyma pressure; CSFP, CSF pressure; PEEP, positive end-expiratory pressure; VP, vascular pressure.

The presence of a clinical picture compatible with cerebral herniation (abnormal motor postures, depression of the state of consciousness, nonreactive mydriasis) demands immediate and aggressive therapy even before neuroimaging and ICP monitoring.

Computed tomography (CT) scan is the initially diagnostic modality of choice in patients with acute brain injury. Scans should be carefully reviewed for the presence of new space-occupying lesions associated with parenchyma distortions or displacements, hydrocephalus, midline shift, or the state of basal cisterns and convexity sulcus (absent, compressed).59,60

Intraventricular or intraparenchymal invasive ICP monitoring is the gold standard for ICH evaluation.

Noninvasive systems for ICP evaluation (transcranial Doppler, pupillometry, determination of the diameter of the optic nerve sheath) remain investigational and currently should not be considered reliable alternatives to invasive ICP monitoring.61 INTRACRANIAL HYPERTENSION MANAGEMENT Therapeutic Modalities

Based on pathophysiologic reasoning, different ways to achieve ICH control have been developed (Fig. 7).

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Table 1 Pathophysiologic causes of intracranial hypertension Localization

Pathophysiology

Cause

Occupying space mass lesions Water content increase

Hematoma, contusions, tumors Cellular (ischemia), vasogenic edema (BBB rupture, permeability increase). Others: osmotic edema; hyponatremia

Vasodilatation

Hypoxemia, hypercapnia, hyperthermia, seizures, drugs (nitroglycerine, sodium nitroprusside) Hyperemia, SIRS, sepsis Severe arterial hypertension (autoregulation lost) Jugular compressed or thrombotic, inadequate head position. ITP or IAP increase

1. Intracranial a. Brain parenchyma

b. Vascular i. Arterial

CBF increase

Drainage obstruction. Venous return to heart decrease

ii. Venous

CSF dynamics alteration Production increase Absorption decrease

Choroid plexus tumor

Circulation obstruction

Obstructive hydrocephalus: mass lesions, intraventricular blood, SAH, tumors

a. Intrathoracic pressure increase

Cerebral venous drainage decrease

Airway obstruction, pneumothorax, hemothorax, asynchronous ventilation, inadequate PEEP, ARDS, lung hyperinflation

b. IAP increase

IAP increase 5 ITP increase 5 ICP increase

Fluid therapy, pneumoperitoneum, hemoperitoneum, ascites, ileus, gastroparesis

c. CSF

Communicating hydrocephalus: SAH, meningitis

2. Extracranial

Abbreviations: ARDS, acute respiratory distress syndrome; BBB, brain blood barrier; PEEP, positive end-expiratory pressure; SAH, subarachnoid hemorrhage; SIRS, systemic inflammatory response syndrome.

General Measures. Physiologic Neuroprotection

Whatever the therapeutic modality selected, they all have 2 premises in common:  Create a suitable microenvironment to facilitate the recovery of injured brain tissue through the maintenance of basic physiologic parameters.  To avoid, recognize, and promptly treat secondary systemic insults (fever, hypotension, hypoxemia, hypercapnia or hypocapnia, hyperglycemia/hypoglycemia, coagulopathies, infections, inflammation).12,62,63

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Fig. 7. Therapeutic modalities for ICP control.

Physiologic neuroprotection is the set of measures designed to maintain the equilibrium or homeostasis of basic physiologic variables that, if altered, negatively affect ICP64,65 (Fig. 8).

Central Temperature <37.5oC Normal

Na+ 135–145 mEq/L

Volemia

SaO2 >92%

Physiologic NeuroprotecƟon Hemoglobin

PaO2 >90 mm Hg

7–10 gr/dL

PaCO2 35–40 mm Hg

Fig. 8. Physiologic neuroprotection.

Glycemia 110–150 mg/dL

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Escalating Therapy

The usual measures for ICP control lack solid supporting scientific evidence.66–68 However, there is empirical proof of their usefulness that has been accumulating for more than 6 decades. ICH management requires order and systematization. Measures should be implemented in a sequential and stepwise manner, from the least to the most aggressive in terms of their potential to generate undesirable effects.1,12,14 The measures must be additive, meaning that when the decision is taken to implement one, the previous one is not abandoned. It is also important to take a time, usually 20 to 30 minutes, to evaluate the effectiveness of the measures taken before proceeding to the next step1,12,14 (Fig. 9). The goals to achieve are: CPP between 60 and 70 mm Hg and ICP not greater than 22 mm Hg.

Determining the cause of the ICH should be the first priority. Emergency evacuation of mass lesions and CSF drainage in cases of hydrocephalus are the most effective strategies and should therefore be considered first. First-level measures should also include placing the head in neutral position (neither flexed nor extended), aligned with the rest of the body, and raised to 30 from the horizontal.1,2,12,14,25 Check for orotracheal tube restraints or cervical collars in order to ensure that they do not compress jugular veins. With these measures the venous drainage of the brain is facilitated, which reduces the CBV, whereas CSF is distributed from the cranial cavity to the spinal canal, thereby reducing ICP.12,14,19,25 In addition, this position helps to prevent microaspirations of gastric contents, which may reduce the risk of pneumonia.14 At all times, it’s essential to detect and to correct secondary insults (physiologic neuroprotection) and look for extracerebral causes of ICP increase.64,65 Agitation, anxiety, and pain significantly increase blood pressure and ICP. In addition, these patients are under mechanical ventilation, which requires good synchrony; therefore,

Fig. 9. Escalating approach to ICH control.

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adequate analgesia and sedation are essential for the control of ICH.12,14,69–71 To our knowledge, there is no analgesia/sedation scheme that has been shown to be superior to others. The authors prefer short-acting agents that allow brief interruptions to perform neurologic examinations. Maintaining euvolemia is useful to avoid negative hemodynamic effects of these drugs.12,14,69–71 In general, benzodiazepines reduce CBF and metabolic rate for oxygen in a coupled manner, without affecting ICP; opioids do not modify CBF or metabolism, but ICP increases have been reported.69–71 Prolonged infusion of benzodiazepines, may significantly delay wakefulness because of reduced clearance, especially in the elderly.69–71 Because of its short half-life, the authors prefer midazolam at 2 to 15 mg/h.69–71 For analgesia, morphine (3–5 mg/h) is a reasonable option unless the patient has cardiac disease or severe hemodynamic compromise, in which case fentanyl is preferred, at a rate of 50 to 200 mg/h.69–71 Fentanyl has more potent analgesic activity than morphine. Fentanyl accumulates in the fatty tissue and its redistribution after suspension can cause a rebound effect and respiratory depression.69–71 Sufentanil is more potent than fentanyl and its half-life is much shorter, averaging 60 minutes. It has sedative action.69–71 Remifentanil has pharmacokinetic properties that bring it closer to the ideal drug. Its volume of distribution is lower and its half-life is very short (6–15 minutes). It undergoes plasma metabolism through esterases, which allows its rapid elimination. ICP may decrease without substantial changes of the CPP, but the exact effect on cerebral hemodynamics remains to be elucidated.69–71 Propofol is a sedative agent of short half-life (2–4 minutes), allowing clinical examination when necessary. It reduces ICP and has an anticonvulsive effect. It does not have analgesic effect and should therefore be combined with opioids. Long-term administration of high doses may lead to propofol infusion syndrome, especially in high-risk individuals, characterized by rhabdomyolysis, metabolic acidosis, hypertriglyceridemia, and cardiac toxicity (malignant ventricular arrhythmias), so it has been recommended not to exceed 4 mg/h and to avoid its continuous infusion over multiple days as much as possible if high doses are required.69–71 Dexmedetomidine, a central a2 receptor agonist, can be used as an alternative to traditional sedatives. It has a short half-life (2 hours), allows a quick and comfortable arousal, and does not compromise ventilation.72,73 It attenuates sympathetic activity and may lead to bradycardia, hypotension, and decrease in CPP, especially in the presence of hypovolemia. It does not affect ICP. Usual doses are 0.2 to 0.7 mg/kg/h.72,73 Ketamine (1–5 mg/kg/h) can be used as an adjunct to standard sedatives to reinforce their effects and limit excessive drug requirement. Ketamine is less prone to causing arterial hypotension.72,73 The approach to sedation should consider the severity of the injury and the cerebral physiologic state, especially ICP. Attention should be given to adequately controlling pain and agitation and promoting ventilator synchrony. MMM is an important tool to optimize ICP. The implementation of protocols may limit excessive sedation.71–74 In deeply sedated patients and in those treated with neuromuscular blocking agents, the role of electroencephalogram (EEG) to monitor sedation has been a topic of clinical investigation. Simplified EEG tools providing quantitative bispectral index have shown good correlation with the Richmond Agitation Sedation Scale and Sedation-Agitation Scale scores.74 The Nociception Coma Scale has recently emerged as a valid tool to assess pain in patients with disorders of consciousness.74 The determination of the adequacy of analgesia for these patients still relies on the observation of indirect signs of pain; for example, tachycardia, systemic hypertension, and ICP increase during painful interventions.71–74

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Neuromuscular paralysis

Neuromuscular paralysis is not routinely indicated for ICP control except for specific situations, such as intubation, shivering (hypothermia, controlled normothermia), unconventional or difficult ventilation (acute respiratory distress syndrome [ARDS]), in which oxygenation and adequate CO2 levels are crucial. In addition, neuromuscular blockers (NMBs) can be used during a dangerous increase of ICP; for example, secondary to severe and refractory agitation or cough crisis.12,14,69–78 In contrast, NMBs prevent neurologic examination; mask seizures; and predispose to infections, deep venous thrombosis, and decubitus ulcers.12,14,69–78 NMBs are linked to prolonged mechanical ventilation and, if used in conjunction with aminoglycosides, corticosteroids, or in septic patients, they can predispose to critical illness myoneuropathy.12,14,69–78 If NMBs need to be used, short-acting agents that do not cause histamine release, such as vecuronium or cisatracurium, are preferred.12,14,69–78 Cerebrospinal fluid drainage

Intraventricular catheter is the gold standard for ICP monitoring.12 The ventricular catheter is attached to a fluid-filled external drainage system and a transducer, so ICP monitoring or CSF drainage are possible. External ventricular drainage systems allow only 1 mode of operation at a time. Although ICP decreases immediately following CSF drainage, this effect is transient and usually does not modify ICP wave morphology.41 This system requires frequent calibration and manipulation and is therefore subject to complications such as obstruction and infection.12,14 Overdrainage is associated with hemorrhages and the generation of pressure gradients that favor parenchymal displacement, so it is recommended not to drain more than 20 mL/h.12,14 Complications related to ventricular catheters include infection (1%–10%) and bleeding (1%–2%).12,14 Ventricular catheters may be difficult to place when there is compression or shift of the ventricles. In cases of a misplaced catheter, the ICP waveform may be dampened and the ICP values inaccurate.12,14 Osmotherapy

For more than 30 years, osmotic therapy has been the cornerstone for the control of ICH.14,25,79 Osmotic agents work by creating gradients causing fluid mobilization from the interstitium to the intravascular space.14,25,79 They also improve the rheological properties of the blood, increasing CBF and thereby causing vasoconstriction, which contributes to ICP decrease. The most commonly used agents are mannitol and hypertonic saline solutions (HSSs). Both share pharmacologic properties: low molecular weight, same distribution in the extracellular space, and similar half-life.12,14,25,79 Mannitol

Mannitol is a mannose-derived sugar, inert, not metabolized by the body, and eliminated by the renal route without reabsorption. Maximum effects are reached after 30 to 40 minutes and its duration of action varies between 2 and 12 hours. Mannitol bolus (15%) generates an osmolality of 1150 mOsm/L and the usual doses range from 0.25 to 1 g/kg. The optimal dose and regimen of administration of mannitol (continuous or bolus) remain uncertain.1,12,14,79 The use of mannitol as well as HSS requires monitoring of osmolality and volemia. Mannitol provokes intense diuresis and it is important to replace fluids to maintain normovolemia.2,12,14,79 It can trigger hydroelectrolytic disorders, particularly of sodium and potassium. It has been arbitrarily established that 320 mOsm/L is the maximum tolerable serum osmolality,2,12,14,79 although this cutoff is strictly a safety measure; mannitol can continue to be effective in reducing ICP at much higher osmolalities as long as the osmolar gap is not markedly increased. Mannitol works best

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in situations of low CPP with preserved autoregulation and intact blood-brain barrier (BBB). If there is increased permeability of BBB, mannitol may accumulate in the interstitium with the theoretic risk of causing rebound increase of ICP. Mannitol may precipitate in renal tubules, causing acute kidney injury.2,12,79 Hypertonic saline solutions

HSSs were introduced into clinical practice more than 20 years ago for the treatment of traumatic shock.80–89 They are used in different concentrations and dosages. They generate greater osmolality than mannitol. For example, the infusion of 7.5% solution (equimolar to 15% mannitol) gives 2560 mOsm/L. Thus, to achieve the same effect as mannitol it is necessary to infuse a smaller volume of HSS.80–89 HSS rapidly expands the intravascular space and can be effective even when autoregulation is compromised.80–89 In relation to mannitol, it seems to have a more profound and lasting effect (18–24 hours). In addition, it has been postulated that HSS has inotropic, antiinflammatory, and immunomodulatory properties, and might improve hepatic and splanchnic blood flow.80–89 HSS can be used in continuous infusion or in boluses. Concentrations range from 3.5% to 23.4%. Our usual practice is to use boluses at 7.5% at 1.5 to 4 mL/kg. Monitoring of serum sodium is necessary and it is advisable to avoid levels higher than 160 mEq/L.80–89 Undesirable effects include phlebitis (which requires the administration through a central venous catheter, unlike mannitol), pulmonary edema, coagulopathy, hyperosmolar states, and pontine myelinolysis.80–89 Hypertonic lactate (0.5 M)

Hypertonic lactate (0.5 M) has emerged as an alternative osmotic agent.90,91 From the point of view of its mechanism of action and the osmolality achieved after its infusion, it resembles HSS at 3% (1020 mOsm/L).90,91 Hypertonic lactate also exerts sufficient expansion of the intravascular space to improve systemic hemodynamics with less volume than the usual crystalloids. Its effects may last longer than those of equimolar mannitol or hypertonic saline.90,91 Two additional properties of this solution make it extremely attractive. First, hypertonic lactate solution does not have chloride and therefore it does not generate hyperchloremic metabolic acidosis. In addition, lactate can help to mitigate the increase in energetic demands caused by the injury because it can be used as fuel by astrocytes and neurons.90,91 Hyperventilation

It is well known that hypocapnia can have significant detrimental effects by inducing or exacerbating cerebral ischemia.12,14,92,93 Hyperventilation decreases PaCO2, which can induce vasoconstriction by alkalinizing CSF. The resulting reduction in CBV decreases ICP.92,93 Hyperventilation has limited use in the management of ICH because this effect on ICP is brief, and the risk of ischemia limits the duration of its use.92,93 The vasoconstrictive effect lasts only 11 to 20 hours because the pH of the CSF rapidly equilibrates to the new PaCO2 level. As the CSF pH equilibrates, the cerebral arterioles increase in diameter, possibly reaching a larger caliber than at baseline, which can cause increased CBV and ICP (rebound hyperemia).93 When hypocapnia is induced and maintained for several hours, it should be reversed slowly, to minimize this risk.12,14,92,93 Hyperventilation can be easily induced by increasing tidal volume or respiratory rate, the latter being preferred because it is less likely to induce alveolar injury. The usual PaCO2 target is 30 to 35 mm Hg.2,14,92,93 For hyperventilation to work, it is

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necessary that the reactivity to CO2 is preserved.2,14,92,93 Hyperventilation should not be used prophylactically or in a prolonged manner. It should be limited to emergency management of life-threatening ICH, such as herniation syndromes or during A or B plateau waves.2,14,92,93 Normocapnia should be the standard of care for braininjured patients.17 During hyperventilation, continuous monitoring of expired CO2 (end-tidal CO2) and measures of regional or global cerebral oxygenation are recommended.2,14,92,93 Maintaining adequate cerebral perfusion pressure

Maintaining adequate CPP is as vital as controlling ICP.10,17 Regardless of the type of injury, arterial hypotension should be avoided.94,95 The first step in achieving and maintaining normal volemia is volume expansion with either isotonic or hypertonic fluids. If the desired MABP is not achieved, vasopressors and/or inotropes should be used according to hemodynamic monitoring and the pathophysiology of the situation. Refractory intracranial hypertension

Refractory ICH is defined by the failure of first-level therapies to control ICP, a situation that occurs in approximately 10% to 15% of cases10,14,17 (Fig. 10). Refractoriness denotes a poor prognosis, with mortality higher than 80%. In this situation, it’s necessary the utilization of the so-called second-level therapeutic measures, characterized by their complexity and potentially lethal undesirable effects.10,14,17 Barbiturates at high doses

Barbiturates (BBTs) at high doses are an option to treat refractory ICH.12,14,17,96,97 The most commonly used agents are thiopental and pentobarbital. BBTs decrease cerebral metabolism, causing vasoconstriction and CBF decrease.12,14,17,96,97 They purportedly have neuroprotective properties, acting as scavengers of free oxygen radicals, attenuating the release of fatty acids, and preventing calcium entry into the cells.12,14,17,96,97 Thiopental has a half-life of 9 to 27 hours, and is administered in a loading dose of 300 to 500 mg, which can be repeated every 30 minutes until the desired effect is achieved, followed by continuous infusion at the rate of 1 to 6 mg/kg/h.12,14,17,96,97 Pentobarbital requires an initial bolus of 5 to 10 mg/kg, which can be repeated every 15 to 20 minutes. Usual doses for continuous infusion are between 1 and 8 mg/kg/h.12,14,17,96,97

Fig. 10. Refractory ICH definition.

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BBT infusion requires strict hemodynamic monitoring, because it causes arterial hypotension, myocardial depression, and potentially severe reductions of CPP. In addition, BBTs have immunosuppressant properties so they increase the susceptibility to infections, especially respiratory. During BBT infusion, continuous electroencephalographic monitoring is recommended.12,14,17,96,97 The target is ICP control and not burst suppression pattern in EEG.12,14,17 Indomethacin

Indomethacin is a nonsteroidal antiinflammatory drug, unique for its vasoactive properties at the level of resistance vessels, causing vasoconstriction, decreased CBV, and ICP.98,99 After indomethacin bolus, CBF decreases on average around 30%. In theory, this effect can induce cerebral ischemia, but this effect has never been shown, possibly because the cerebral metabolic rate of oxygen decreases in a coupled manner with CBF.98–100 The mechanism of action is still unclear, although it has been postulated to be related to modulation of prostaglandin levels.98–103 Other beneficial actions of indomethacin include decrease of CSF production, improvement in cerebrovascular autoregulation, edema reduction, and antipyretic effect.98–103 A recent review examined studies that used indomethacin for ICH control.104 Some important points were identified. First, indomethacin seems to reduce ICP in a significant manner in almost all patients (Oxford 2b, grade C). Second, the ICP reduction occurred with boluses ranging between 15 and 50 mg and the infusion rates from 0.3 to 0.8 mg/kg/h. Third, the ICP effect seemed to be sustained for the duration of the infusion. No serious complications related to indomethacin were identified.104 Potential side effects of indomethacin are cerebral ischemia (never shown), renal failure, bleeding disorders, and peptic ulcerations.98,99 Abrupt discontinuation is not recommended because ICP can increase suddenly (rebound effect).98–103 Tromethamine

Cerebral acidosis in the setting of brain injury is a known predictor of poor outcome. Acidosis leads to excitotoxicity and mitochondrial dysfunction. Furthermore, cerebral acidosis leads to glial swelling, through modulation of aquaporin channels, contributing to ICP increase.105–107 The attenuation of acidosis provides a potential mechanism for edema reduction and improved cell viability.105–107 The non–CO2-generating buffer capacity of tromethamine (THAM) affords it potential advantages in the setting of hypercapnic acidosis.105–107 The use of sodium bicarbonate as a buffer in the setting of acidosis leads to CO2 generation, which carries the potential of ICP increase. Thus, THAM offers a unique solution to this problem. THAM is a buffer solution that causes CSF alkalosis, which prolongs the time of vasoconstriction induced by hyperventilation.105–107 After TBI, THAM reduced the incidence of ICP values more than 20 mm Hg, but no differences in the final outcome were observed.105 THAM should be infused only by central venous access. If the initial bolus of 1 mmol/kg is effective in decreasing ICP, it can then be administered continuously, titrating the infusion to achieve blood pH between 7.5 and 7.55.105–107 THAM can induce arterial hypotension.105–107 Controlled lumbar drainage

Controlled lumbar drainage is an option under investigation.108–112 Lumbar CSF drainage may reduce ICP by decreasing CSF volume, and reducing craniocaudal resistance to CSF flow. In addition, cerebral venous outflow improves, contributing to decreasing ICP.108–112 Spinal space is not compressible and lumbar drainage is less likely to induce hemorrhagic or infectious complications.108–112 However, lumbar

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drainage is contraindicated when there are space-occupying lesions, midline shift greater than 10 mm, or effacement of the basal cisterns.108–112 Hypothermia

Hypothermia has been shown to be an excellent measure of neuroprotection in experimental studies.113–116 It reduces metabolic demands, protein degradation, oxidation, lactate accumulation, and calcium toxicity, and it stabilizes cell membranes. It also inhibits cortical spreading depolarizations, and reduces apoptosis and inflammation.113–116 All these effects should contribute to lower ICP and reduce the formation of edema. However, large clinical trials, especially in severe TBI, have not shown favorable results.113–116 Implementation requires complexity and a dedicated multidisciplinary team. Pending points to elucidate are the optimal manner of its implementation, the best method to achieve the cooling, temperature target, duration of hypothermia, and pace of rewarming.113–116 At present, hypothermia should be considered as an alternative to metabolic suppression (such as barbiturate coma) in patients with refractory ICH. Decompressive craniectomy

Decompressive craniectomy (DC) consists of removing part of the skullcap and opening of the dura mater to increase the capacity of the cranial cavity to tolerate increases in cerebral volume. Its effectiveness is directly proportional to its size.117,118 It can be performed preemptively (eg, during the evacuation of an acute subdural hematoma associated with brain swelling) or as a rescue measure when traditional measures for the control of ICH have failed. DC can be bifrontal or frontotemporoparietooccipital, and unilateral or bilateral.117–120 DC decreases ICP, and increases CPP, CBF, and cerebral oxygenation. It also allows de-escalating the intensity of other interventions to control ICH.117–120 Two large trials were recently published.121,122 The DECRA trial showed no benefit from the surgery,121 but the RESCUE ICP trial showed marked reduction in mortality in the surgery group as well as a trend toward better functional outcomes.122 BRAIN TRAUMA FOUNDATION GUIDELINES

In the fourth edition of the Brain Trauma Foundation’s Guidelines for the Management of Severe Traumatic Brain Injury some recommendations were modified based on new evidence17:  ICP monitoring: management of patients with severe TBI using information from ICP monitoring is recommended to reduce in-hospital and 2-week postinjury mortality.  ICP thresholds: treating ICP greater than 22 mm Hg is recommended because values above this level are associated with increased mortality.  CPP monitoring: management of patients with severe TBI using guideline-based recommendations for CPP monitoring is recommended to decrease 2-week mortality.  CPP thresholds: the recommended target CPP value for survival and favorable outcomes is between 60 and 70 mm Hg. Whether 60 or 70 mm Hg is the minimum optimal CPP threshold is unclear and may depend on the autoregulatory status of the patient.  Blood pressure threshold: maintaining systolic blood pressure (SBP) at 100 mm Hg for patients 50 to 69 years old or at 110 mm Hg or more for patients 15 to 49 years old or more than 70 years old may be considered to decrease mortality and improve outcomes. The interrelationship between SBP, MAP, and CPP should

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be kept in mind as the threshold recommendations in these guidelines are considered. Cerebral Perfusion Pressure–directed Therapy

In the early 1990s, a theory for ICH control based on vasodilator and vasoconstrictor cascades emerged30,31 (see Fig. 2). This so-called CPP-directed therapy holds that increasing CPP in a brain with intact autoregulatory mechanism would result in vasoconstriction, which in turn would cause CBV and ICP to decrease.30,31 Although this hypothesis is attractive from a pathophysiologic point of view, it requires an intact autoregulation mechanism throughout all cerebral territories, a situation that does not occur in almost half of patients with severe brain injury.30,31 This theory has not stood the test of clinical studies and it can induce potentially lethal complications, such as ARDS and renal injury.12 Consequently, its use is not recommended. Therapy Based on Intracranial Volume Control (Lund Concept)

The Swedish school of Lund proposes that the control of ICP should be based on the strict regulation of intracerebral volume.123,124 The proposal argues that posttraumatic cerebral edema is the main reason for ICP increase in a brain with absent or severely compromised autoregulatory mechanisms, associated with increases in the permeability of the BBB. In this situation, if CPP is increased, vasogenic edema becomes worse.123,124 Therefore, Lund therapy is based on strict MABP control (permissive hypotension) by the use of a-blockers and b-blockers, ergotamine for venous vasoconstriction to decrease CBV, and infusion of albumin to attract fluid to the intravascular space. CPP remains close to 55 mm Hg and some degree of hypertonicity is allowed (serum sodium level around 150–155 mEq/L).123,124 This theory does not take into account that the origin of posttraumatic brain edema is not always hydrostatic-vasogenic, and that the BBB is not always damaged. In addition, cerebral autoregulation remains unchanged in half of the cases, and permissive hypotension is dangerous because of the risk of cerebral ischemia.123,124 Clinical studies are limited to small and heterogeneous populations and this therapeutic strategy has never been validated in prospective, multicenter, randomized, large-scale trials. Escalating Versus Targeted Therapy

During the past 30 years, management of increased ICP has evolved toward standardized strategies that use algorithms and escalating treatment intensity.1,2,12,14,25 The fundamental flaw in this approach has been the application of strict universal management strategies regardless of patient-specific or disease-specific considerations. The Brain Trauma Foundation guidelines recommend a universal approach.12,17 The escalating approach is strictly based on the ICP measurement. This scheme is simple but does not provide for individualization of therapy.1,2,12,14,17 A weakness of the current classification of TBI is the failure to capture the underlying heterogeneous injury patterns.17,74,125 A diverse range of pathophysiologic processes occurs in TBI, and there are several mechanisms of secondary brain injury at play (eg, microvascular dysfunction or alterations in glucose use) that cannot be detected using an ICP monitor.17,74,125–128 In these patients, MMM can add pathophysiologic information and potentially improve management and outcome.125 There is a wide range of therapeutic options, few of which have proven efficacy. This raises the question of which interventions are best used at different stages following head injury.74,125–128 MMM can better guide the use of specific interventions. Available monitoring

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modalities include ICP, CPP, assessment of autoregulation using PRx, brain tissue oxygenation (PbtO2), continuous EEG, and cerebral microdialysis.74,125–128 An individually targeted therapy seems to be a more rational approach to severe acute brain injury after the initial general measures have been implemented.125–128 Targeted therapy guided by the use of an MMM platform has recently been recommended in a consensus statement on neuromonitoring.74 The target is to administer individual therapies for specific pathophysiologic processes. Examples are the use of hyperventilation in the presence of hyperemia, HTS, or mannitol for vasogenic cerebral edema when autoregulation is preserved or the use of blood pressure increase in the presence of B waves and nonoptimal CPP.74,125 Although this approach is intellectually appealing, it is hindered by the pathophysiology usually being mixed, and global monitors of brain physiology may miss critical focal abnormalities, whereas focal monitors may miss areas of ongoing damage. In practice, many established management protocols represent a hybrid approach. Initial baseline monitoring and therapy (eg, analgesia, sedation, mechanical ventilation) are applied to all patients, and refractory problems are dealt with by therapy escalation, with the choice of intervention determined by clinical presentation and physiologic monitoring125–128 (Fig. 11). Treatment of Intracranial Hypertension Without Intracranial Pressure Monitoring

Some treatments can be used in specific settings with the availability of MMM, but not in environments with more constraints.125–128 In these environments, clinical examination and serial CT scans are used routinely to guide the management.129 A recent

Fig. 11. Targeted therapy based in multimodal monitoring. p50, oxygen arterial pressure at 50% saturation (normal value 27 mm Hg); PtiO2, brain parenchyma oxygen saturation; SajO2, jugular venous oxygen saturation; SIRS, systemic inflammatory response syndrome; TCD, transcranial Doppler.

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randomized controlled trial conducted in general intensive care units in Bolivia and Ecuador introduced ICP monitoring to an environment in which they had not been used previously to evaluate 2 management protocols of ICH management in severe TBI.129 In the arm without ICP monitoring, treatment was driven by a protocol based in clinical and CT signs in a staircase escalating approach. The outcome was similar in the two treatment groups.129 HOW AND WHEN TO STOP INTRACRANIAL HYPERTENSION THERAPY

There are no widely validated guidelines to answer this question. Box 1 outlines recommendations based on more than 2 decades of experience. Box 1 Recommendations for how and when to stop ICH therapy 1. ICH cause resolved. 2. At least 48 hours of clinical-neurologic stability. Check MMM values. 3. CT scan showing no new mass lesions, no midline shift, and open basal cisterns. 4. Stepwise decrease of therapy, from the most to the least aggressive, contrary to how they were used. 5. Suspension is slow, avoiding ICP rebound. 6. Monitoring during the withdrawal process.

SUMMARY

ICH is one of the leading causes of mortality after acute brain injury. Its cause is variable and insults can originate from inside or outside of the cranial cavity. An adequate approach should be based on detailed analysis of the underlying pathophysiology. There are different therapeutic modalities to control increased ICP, but all share the objective of normalizing basic physiologic variables. ICP control should be combined with the simultaneous achievement of adequate CPP. The classic approach to ICH control is escalating intensity in a sequential form and systematically. The first therapeutic level includes sedation, analgesia, and mechanical ventilation; an adequate position of the body and head; drainage of CSF; osmotherapy; and mild hyperventilation. Refractoriness to first-level therapy is associated with high mortality. Multimodal monitoring has emerged as a useful tool for these complex refractory cases. REFERENCES

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