RECAPEM

Secondary Brain Injury: “Time is the Brain”

October 15, 2020, by Mojtaba Chardoli

CONTENTS

Preface

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Acute neurologic disease is bound to get worse. Since the neuronal function is the essence of human existence, preventing the loss of any neural element is a major goal of perioperative anesthesia and critical care management. Traditionally the pathophysiology of brain injuries occurring due to neuroemergencies, such as stroke or head trauma, have been broadly classified into primary brain injury and secondary brain injury. Brain damage that occurs at the onset or immediately after injury (primary brain damage) is simple (in terms of pathology) brain damage caused by a disease or an injury. However secondary brain injury is not a simple condition, rather its a general term for a variety of pathologies wherein the ongoing brain tissue damage is caused by later reaction of the brain either to the primary injury or to other extracranial causes.1 While secondary brain injury was described in the context of head trauma in the past, this concept is now further expanded to involve other nontraumatic systemic critical conditions wherein the same molecular cascade events can result in brain damage.

As “Time Is The Brain”, It is of paramount importance that frontline providers promptly identify patients with neurologic emergencies and implement appropriate therapeutic and preventive measures to ameliorate the impact of secondary insults to the brain tissue. In the following discussion the pathophysiology of secondary brain injury and its clinical implication for preventive and therapeutic measures will be covered.

Cerebral physiology

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Intracranial pressure: More than two centuries ago, the Monro-Kellie doctrine characterized the cranial vault as a fixed space comprising 3 components: blood, cerebrospinal fluid (CSF), and brain tissue (figure 1).2 They defined that the sum of volumes of brain, CSF, and intracranial blood is constant and, therefore, that an increase in volume in one compartment results in a compensatory decrease in the volume of another. If compensatory mechanisms become exhausted, the intracranial pressure (ICP) increases (figure 2). Increase in ICP above a critical level is not tolerated because it results in a decrease in the CPP of the brain and can also cause local compression of brain tissue against the tentorium, falx, and foramen magnum and ultimately herniation.3

Cerebral blood flow (CBF): Although the brain constitutes only 2% of body mass (1400 g), it receives a large proportion (12–15%) of the resting cardiac output in the adult. CBF has a direct relationship with cerebral perfusion pressure and has an inverse relationship with cerebral vascular resistance (CVR).

CBF = CPP/CVR

CBF will thus improve if the CPP increases and the cerebral vasculature is vasodilated (↓CVR). 2 4

Autoregulation of CBF refers to the property of the brain to maintain relatively constant blood flow and oxygen supply in the face of changes in CPP. In normotensive adults with intact autoregulation,CBF is maintained at a constant rate of about 50 mL/min/100 g when CPP varies within a classically described range of 50 to 150 mmHg.2

The key mechanism of myogenic autoregulation is change in cerebrovascular resistance by vasoconstriction and vasodilation in response to changes in CPP. With intact autoregulation, when a decrement in CPP approaches the lower limit of autoregulation, vasodilation occurs to maintain CBF but, as CPP decreases below the lower limit of autoregulation, maximum cerebral vasodilation arises. This initially associates with a proportional CBF decrement as oxygen extraction increases to meet metabolic demand as a secondary compensation. However, further CBF decrease produces anaerobic cerebral ischemia and, ultimately, infarction. Conversely, elevated CPP within the autoregulatory range induces cerebral vasoconstriction. When autoregulation is intact, an increase in CPP above its upper limit produces dysregulated elevated CBF.5

Other parameters which can affect vascular tone and therefore contribute to vasodilation and hyperemia include metabolic factors (e.g. hypercapnia, hypoxemia, anemia, hypoglycemia) and neuronal activation (e.g. seizure, fever, noxious stimuli(e.g. Suctioning, endotracheal intubation, paroxysmal sympathetic hyperactivity).5

Cerebral perfusion pressure(CPP): Perfusion pressure is the difference in the pressures between the arterial and venous circulation which dictates the blood flow to the organ. In the brain, the perfusion pressure or the CPP is affected by another pressure within the skull i.e. intracranial pressure.

CPP= MAP – (CVP+ICP)

In normal adults, the CPP is variable, usually ranging between 70 and 90 mm Hg and the CBF is constant. When the CPP decreases below 50 mm Hg, there is an increased risk of brain ischaemia. In pathological conditions, if the ICP is increased, the flow through the cerebral blood vessels can be restricted.If ICP increases to the level of critical closing pressure, CBF, ordinarily continuous throughout the cardiac cycle, becomes discontinuous and there is no flow during diastole. If ICP exceeds systolic blood pressure, intracranial circulatory arrest may occur(Figure 4).5

Primary and secondary brain injury

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Primary brain injury is the direct result of a disease or an injury (neurotrauma) to the brain tissue. However secondary brain damage is not a simple condition but is a general term for secondary brain injury that occurs as a result of primary brain injury.1 The main pathologies of secondary brain injury include elevated ICP, brain hypermetabolism, neuroinflammation, and secondary damage to areas surrounding brain damage (Figure 5). Depending on the severity, and type of the primary insult, the brain tissue is vulnerable and is exposed to variable degree and extent of a secondary hit prompted by a series of molecular cascade events.

Pathologic specific factors for secondary brain injury

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ICP elevation

Increased intracranial pressure can be a surrogate of secondary brain injury, as high ICP has been correlated with high mortality and poor neurological outcome.6 ICP monitoring and control have thus been the cornerstones of the neurocritical care management of brain-injured patients.Methods for ICP monitoring can be divided into invasive and non-invasive approaches.

  • Invasive methods include fluid-based systems and implantable micro-transducers. Of the invasive methods, ICP monitoring using an EVD is considered as the gold standard (figure 6), not only for its accuracy but also because it additionally serves a therapeutic purpose by allowing CSF drainage. ICP waveform is shown below (figure7).3
  • Non-invasive method: Invasive method is the gold standard for assessing ICP. However it is not always feasible. Non-invasive methods can be used to screen patients for elevated ICP in situations where invasive interventions cannot be promptly accessed, such as in the field or where there are no neurosurgeons.Additionally, non-invasive screening can be done in patients in whom there is relatively low suspicion of elevated ICP, but the possibility needs to be ruled out. This may decrease the placement of invasive monitors in patients who, in retrospect, did not need them.3
    • Transcranial Doppler (TCD)
      • In the neuro-critical setting, TCD is most commonly used as a tool to monitor changes in cerebral blood flow (CBF) in the setting of subarachnoid hemorrhage-associated vasospasm. A number of models using TCD-derived data have shown correlation with invasively-measured ICP; these models have used measurements of flow velocity (FV) in the middle cerebral artery, arterial blood pressure and pulsatility index (PI).7 This technology may be incorporated into clinical practice sooner as a neuro-monitoring adjunct rather than an ICP sensor. 8
    • Optic Nerve Sheath Diameter (ONSD)
      • Several studies have demonstrated a correlation between invasively measured ICP and ultrasonographic ONSD measurements, with overall sensitivity and specificity of 0.90 and 0.85, respectively. A recent prospective study suggested a diameter of 5.6 mm as the optimal cut-off for diagnosing elevated ICP.9
    • Imaging-Based Methods including CT, MRI
      • There are a variety of gross anatomic changes associated with elevated ICP that can be detected using CT and MRI.For instance, the presence of a mass occupying lesion can cause compression of the ventricles and midline shift. Similarly, enlarged ventricles can be indicative of hydrocephalus, and cerebral edema can cause a loss of differentiation of grey and white matter junctions.10 While imaging continues to be used qualitatively, at present, these methods are not independently reliable enough as screening tools for elevated ICP.11

Interpretation of elevated ICP is not straightforward as multiple dissimilar pathophysiological processes may concurrently contribute to the observed numerical ICP value. Arguably, etiologic contributors to elevated ICP and its physiological consequences should be major factors in developing rational therapeutic strategies.

Treatment strategies used in one cause of ICP elevation,for example hyperemia, may be ineffective or even harmful if applied in others, for example edema producing ischemia, or hydrocephalus. Therefore a more individualized approach to intracranial hypertension based on pathophysiologic processes is deserved.5

Intracranial hypertension can be caused by increased blood volume, increased brain tissue volume (masses, and edema), and increased cerebrospinal fluid (figure 8).While these pathophysiological subsets provide a conceptual framework for approaching intracranial hypertension,it is important to be cognizant these processes seldom arise in isolation, but often in combination. For example, a hyperemic process may initially increase ICP but then contribute to subsequent edema or hemorrhage with further increases in ICP, but now with oligemia.

Increased blood volume

As explained above, in the normal state, physiological increases in cerebral blood volume do not increase ICP unless the compensatory capacitive mechanisms were exhausted. Increased intravascular blood volume can be related to cerebral arterial and cerebral venous hypervolemia.

  • Cerebral arterial hypervolemia: Arterial vasodilation can happen in the face of preserved cerebral autoregulation wherein metabolic and neurogenic factors can cause active vasodilation; or when autoregulatory mechanism is disrupted such as in malignant hypertension. In the latter situation, passive arterial vasodilation can contribute to cerebral arterial hypervolemia.
    • Active vasodilation in the presence of intact autoregulatory mechanism
      • Neuronal activation: Conditions of abnormally increased metabolic demand can increase CBF, with an ICP elevation if compliance is abnormal. These include increased seizure12, noxious stimuli (e.g. laryngoscopy, endotracheal intubation, suctioning)13, lung recruitment maneuver14, fever15 and paroxysmal sympathetic hyperactivity16.
      • Metabolic mediators: Hypercapnia17, hypoxemia18,hypoglycemia19, and anemia20, are all normally associated with hyperemic responses linked to maintenance of nutrient supply and removal of waste products from the brain (figure 9).These physiological responses to metabolic mediators associated with hyperemia are normally well tolerated, but can increase ICP in certain situations such as a poorly compliant brain in the case of neurotrauma.

Decreasing Blood Pressure-related Vasodilation: In the presence of heterogeneous autoregulation wherein a traumatic brain injury has caused dysautoregulation in the corresponding side, whereas the intact part of the brain is functioning normally (intact autoregulation); a drop in blood pressure can cause ICP elevation (figure 10).21

  • Dysregulated Passive Arterial Vasodilation: Encompasses conditions wherein primarily the cerebral autoregulation of blood flow is disrupted resulting in dilated poorly reactive vascular beds and capillary leakage. These conditions are associated with endothelial and BBB injury and can be caused by brain injury (ischemic or traumatic)22, acute liver failure23, hyperperfusion states24 such as malignant hypertension/PRES25, Arteriovenous malformation (AVM) resection with subsequent normal perfusion pressure breakthrough26, and post carotid endarterectomy 27or endovascular thrombectomy with successful restoration of CBF28. In addition, secondary disruption of autoregulation can arise in extremes of hypercapnia, hypoxemia, anemia, hypotension, and hypoglycemia, by which brain edema may be exacerbated. In all of these cases of extreme vasodilation, CBF is expected to vary directly with systemic blood pressure.5
  • Cerebral venous hyperemia: Increased cerebral venous or dural venous sinus pressures may increase brain tissue hydrostatic pressure and thereby contribute to vasogenic edema..5 Primary factors contributing to increased cerebral venous volume include:
    • Functional Starling resistor type venous outflow obstruction
      • Increased ICP, from whatever etiology, can also produce a direct constriction of venous outflow at the level of thin-walled cerebral veins. This venous obstruction produces an increase in internal venous pressure, which maintains vein patency such that flow continues. However, it also increases tissue hydrostatic pressure, which then presents the potential to produce or exacerbate cerebral edema which further increases ICP with a positive feedback cycle thus produced.29 30
        • The Starling resistor concept, sometimes referred to as the vascular waterfall phenomenon, describes the situation where external tissue pressure is greater than internal vascular pressure. In such a situation hollow tubes such as blood vessels collapse and flow then become dependent on the difference between proximal upstream pressure and distal external extravascular pressure at the point of constriction.
    • Mechanical outflow obstruction, such as with venous thrombosis31 32
      • Given that CSF reabsorption occurs at arachnoid granulations in the cerebral venous sinuses, thrombosis of dural sinuses can impair CSF reabsorption resulting in increased CSF volume. This can cause communicating hydrocephalus and increased ICP.
      • Cerebral venous sinus thrombosis is believed to produce an increase in local venular and capillary pressures from venous outflow obstruction. This produces or exacerbates BBB disruption with consequent vasogenic edema and oligemia/ischemia
      • Venular and capillary disruption can also result in intraparenchymal hemorrhage to increase ICP. If the hemorrhage includes the ventricular system, the process may be further complicated by noncommunicating hydrocephalus.
      • Vasogenic edema with worsened intracranial hypertension can result in further venous outflow obstruction by a Starling resistor effect, further exacerbating the pathophysiological process.
    • Very high extracranial venous press
      • Anything that increases venous pressure sufficient to fall within the range of ICP at the level of the cranium carries a theoretical risk of increased intracranial venous volume. Such situations may include high airway pressure33, acute superior vena cava syndrome, right heart failure or obstruction, or Trendelenburg head-down position.

Mass and edema

In contrast to increased intravascular blood volume subsets of elevated ICP, masses and edema can directly produce oligemic intracranial hypertension and have immediate deleterious effects.

  • Brain tissue edema: Diffuse brain tissue edema is an important cause of intracranial hypertension and is commonly entwined with other causes of increased ICP. Brain edema is an abnormal accumulation of fluid within the brain parenchyma and is subdivided into two major categories; vasogenic and cytotoxic edema.34 35
    • Vasogenic edema: It encompasses conditions associated with BBB breakdown, allowing movement of intravascular proteins, solutes, and water through the damaged microvascular endothelial cells into the extracellular space. Etiologies of vasogenic edema are numerous and include TBI, brain tumor, radiation necrosis, acute demyelination, dysregulated hyperemia, venous obstruction, and inflammatory/infectious process. When brain edema overcomes the compensatory mechanisms, ICP, following an exponential relationship with volume of an intracranial compartment, can increase dramatically resulting in compromise of CBF with widespread ischemia or in herniation (figure 2 above).36
    • Cytotoxic edema: It develops following processes that arise and cause intracellular fluid translocation. In the case of hypoxia-ischemia, a primary insult leads to failure of ATP-dependent sodium-potassium and calcium pumps resulting in intracellular sodium (or other metabolite) accumulation, an osmotic gradient, fluid shift from extracellular to intracellular compartments, and eventual cellular swelling. Other syndromes may increase different intracellular osmoles to produce the same effect. Calcium can also accumulate within the cell, triggering an inflammatory cascade that recruits microglia and leads to free radical formation that ultimately results in the destruction of the BBB and concurrent vasogenic edema.37 Causes of cytotoxic edema include hypoxic-ischemic brain injury,TBI, central nervous system infections, drug overdoses, renal and liver failure, spreading depolarization38, ornithine transcarbamylase deficiency39, and osmolar gradient syndromes as may be seen with hyperglycemia and hyponatremia.
  • Masses: Pathologic intracranial masses can increase ICP, eventually culminating in oligemia. Masses can be in the form of hematoma or neoplasm, abscess. The more rapid the growth of said mass, the more acute and profound the rise in ICP.

Increased CSF volume:

In brief, CSF is produced mainly by epithelial cells of the choroid plexus lining the cerebral ventricles using active transport, largely dependent on the enzyme carbonic anhydrase. CSF then circulates unidirectionally through the ventricular system,from the lateral ventricles to the foramen of Monro, into

the third ventricle, aqueduct of Sylvius, the fourth ventricle, and finally exiting into the spinal subarachnoid space through the foramina of Luschka and Magendie. The spinal subarachnoid space is in direct communication with the intracranial subarachnoid space from where CSF is passively absorbed down a pressure gradient through the arachnoid villi of dural venous sinuses into venous sinuses.40 In order for this process to occur, CSF pressure must exceed sagittal sinus venous pressure. From the

venous sinuses, CSF eventually enters into the systemic venous circulation. This classic description of CSF dynamics has recently been enhanced to incorporate the glymphatic system, a perivascular intraparenchymal pathway for CSF egress from the brain. 41

Hydrocephalus is a disruption of CSF formation, flow, or absorption characterized by excessive accumulation of CSF within the cerebral ventricular system and/or subarachnoid space. Regardless of cause, this can result in ventriculomegaly and intracranial hypertension. Hydrocephalus was historically classified by Dandy into 2 types; communicating and noncommunicating.42

  • Communicating hydrocephalus: occurs due to excess CSF production or, more commonly, ineffective CSF absorption. For example, it can be a result of scarring or fibrosis in the subarachnoid space after infection, inflammation, or hemorrhage.
  • Noncommunicating hydrocephalus: occurs from obstruction of CSF flow within the ventricular system or its outlets, resulting in dilation of the ventricular system proximal to the point of obstruction.

Cerebral hypermetabolism

The brain consumes 20% of the body’s total oxygen supply. Brain metabolism is dependent on glucose and oxygen transported by the blood. In neurological emergencies (e.g. head trauma and stroke, etc) the blood supply does not fit to the demand and this will cause relative ischemia and anaerobic metabolism in which lactic acid is produced , and secondary brain damage is promoted. This condition leads to further worsening of brain damage when accompanied by convulsive seizures, systemic hypoxia, decreased CPP due to reduced blood pressure, reduced oxygen-carrying capacity due to decreased hemoglobin, and the onset of other factors. Hyperglycemia is also known to promote secondary brain damage. Hyperglycemia promotes anaerobic glycolysis that causes lactic acid accumulation, resulting in lactic acidosis, which is considered a cause of aggravated secondary brain damage.

Neuroinflammation

Blood cells do not naturally reside within the brain tissue. Cerebral blood vessels are separated from the brain by the blood–brain barrier (BBB) and are normally isolated from the systemic immune system.43 44Disruption of the BBB has been discovered to be involved in different primary brain injuries such as neurotrauma, stroke, and Alzheimer’s disease.45 The vascular endothelial dysfunction and dysfunction of nearby astrocytes in the cerebral blood vessels surrounding the site of injury cause the tight junctions of the BBB to break down, resulting in disruption of the BBB.This results in the so-called neuroinflammation, in which negative cross talk occurs between local inflammation in the brain and systemic inflammation.46

Almost immediately after the occurrence of a brain injury, microglia are activated and produce active oxygen and inflammatory cytokines, which engulf nerve cells and other cells that can cause cell death.47

In addition to macrophages migrating to the brain and acting as inflammatory cells due to disruption of the BBB, circulating inflammatory cytokines in the body penetrating the BBB to act on the brain are one of the many important actions resulting in the spread of systemic inflammation to the brain.48 This promotes an inflammatory response in the damaged part of the brain and exacerbates secondary brain injury.49

This inflammatory response is mediated by multiple different molecular cascade events, which is beyond the scope of this discussion. Of note, hyperglycemia caused by disease-related stress can also exacerbate neuroinflammation.50 51

Secondary brain damage in the surrounding injured area

Many of the aforementioned secondary brain damage pathologies will expand to involve adjacent areas of the primary brain damage which if not prevented and suppressed leads to higher brain dysfunction e.g. paralysis. In particular, the penumbra area in ischemic stroke, an area of decreased blood flow, exists from the start surrounding the area of brain injury, which causes irreversible dysfunction when secondary brain damage develops in this area. Thus, acute treatment through neurocritical care is vital regardless of the severity of injury.52

Treatment of secondary brain injury

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As mentioned earlier, different types of pathologies (figure 5) that contribute to secondary brain injury warrants different treatment. The various pathways of cellular injury have been the focus of extensive preclinical work into the development of neuroprotective treatments to prevent secondary brain injury. At this time; no clinical trials of these strategies have demonstrated clear benefit in patients.

However, a critical aspect of ameliorating secondary brain injury is the avoidance of secondary brain insults (e.g. optimizing CPP, avoiding hypotension, hypoxia, hyperglycemia, etc) and resolution of the primary brain injury (e.g. evacuation of a blood clot, resection of a tumor, CSF diversion in the setting of hydrocephalus, or treatment of an underlying metabolic disorder).

Resuscitation:

The emergent assessment and support of the airway, oxygenation, organ perfusion are applicable to all patients. If intubation is indicated, resuscitate before intubate. Optimize BP, arterial oxygenation before proceeding to intubation as hypotension, especially in conjunction with hypoxemia, can induce reactive vasodilation and elevations in ICP.

There’s no good clinical evidence supporting the use of systemic lidocaine to prevent ICP rise before intubation. Topical lidocaine is more effective than intravenous routes. For full lecture on this visit:

The Neurocritical Care Intubation(EMCrit RACC)

In the following discussion therapeutic options for main pathologies of secondary brain injury are listed.

A.Control of ICP: Elevated ICP is not a homogenous entity and each different pathophysiologic mechanisms responsible for ICP elevation may require a unique treatment strategy. Keep in mind that the treatment goal is to protect cerebral perfusion pressure (figure1) and the only way to reliably determine CPP is to continuously monitor both ICP and blood pressure. Therefore, while initial empiric therapy to control presumed elevated ICP may be performed without the benefit of ICP monitoring, an important early goal in management of the patient with presumed elevated ICP is close monitoring of both ICP (via placement of an ICP monitoring device) and BP (via arterial line).

Elevated ICP is a medical emergency and treatment should be undertaken promptly.In addition to definitive treatment, there are measures that can be employed to reduce ICP acutely (though their therapeutic effect might be transient).

  • Brain edema
    • Head-up position:
      • Elevation of the head to at least 30° is advised in patients with raised ICP, with one study confirming that this degree of elevation produces consistent reduction in ICP53 (moderate elevation is safe as long as CPP is continuously maintained at > 60 mm Hg)
    • Osmotic therapy and diuresis:
      • May include hypertonic saline, mannitol and furosemide. Further trials are required to show superiority of hypertonic saline over mannitol.
  • Control of cerebral blood volume
    • Cerebral blood flow control:
      • Hyperventilation: Use of mechanical ventilation to lower PaCO2 to 26 to 30 mmHg has been shown to rapidly reduce ICP through vasoconstriction and a decrease in the volume of intracranial blood. It can be an effective urgent intervention when elevated ICP complicates cerebral edema, intracranial hemorrhage, and tumor. It should Not be used in the setting of TBI, or acute stroke, wherein vasoconstriction may cause a critical decrease in local cerebral perfusion and worsen neurologic injury, particularly in the first 24 to 48 hours54. It should be emphasized that regardless of the cause of elevated ICP, hyperventilation has a short-lived effect (1 to 24hours)55, and Following therapeutic hyperventilation, the patient’s respiratory rate should be tapered back to normal over several hours to avoid a rebound effect.
      • Blood pressure control: Both extreme hypotension and hypertension can impair cerebral perfusion pressure especially in neurologically vulnerable patients. By enlarge, BP should be controlled sufficient to keep cerebral perfusion pressure above 60mmHg but lower than 120mmHg.
    • Prevention of venous congestion: head-up position, control of intrathoracic pressure, avoidance of compression of the jugular vein
  • Control of CSF
    • CSF drainage: When hydrocephalus is identified, a ventriculostomy should be inserted. When indicated, CSF should be “Slowly” removed at a rate of approximately 1 to 2 mL/minute, for two to three minutes at a time, with intervals of two to three minutes in between until a satisfactory ICP has been achieved (ICP <20 mmHg) or until CSF is no longer easily obtained.
  • Control of mass effect
    • Control of brain edema
      • Steroids are effective only for reducing the volume of mass lesions related to abscess or neoplasm, and the mechanism is based on its effect on vasogenic edema. In cytotoxic edema processes such as acute ischemic stroke56, ICH57, TBI58; it should not be used.
    • Coagulopathy: in the presence of life threatening hemorrhage, coagulopathy should be corrected.
    • Operation (internal decompression, external decompression)

B.Control of cerebral hypermetabolism

  • Fever: fever increases brain metabolism. Elevated metabolic demand in the brain results in increased cerebral blood flow and can elevate ICP by increasing the volume of blood in the cranial vault. Acetaminophen and cooling blankets are the first line of therapy and should be instituted when temperature is sustained above 101°F (38.3°C).59
  • Seizure: Seizures can both complicate and contribute to elevated ICP. Anticonvulsant therapy should be instituted if seizures are suspected; prophylactic treatment may be warranted in some cases. There are no clear guidelines for the latter, but examples include high-risk mass lesions, such as those within supratentorial cortical locations, or lesions adjacent to the cortex, such as subdural hematomas or subarachnoid hemorrhage.
  • Agitation:
    • Agitation must be avoided because it can aggravate ICP elevation through straining (increasing thoracic, jugular venous, and systemic blood pressure) and increased brain metabolic rate. For this reason, adequate sedation must be the first pharmacologic intervention in managing an ICP crisis. Preferred agents are short acting opioids such as fentanyl (1-3 μg/kg/h) to provide analgesia and propofol (0.3-3 mg/kg/h). Compared with an opioid-based sedation regimen, in one trial propofol was associated with lower ICP and fewer ICP interventions in patients with severe TBI.60

C.Prevention of neuro-inflammation

  • Prevention of hyperglycemia
  • Control of secondary systemic inflammatory response (infection, others)
  • Other theoretical potential targets for therapy in future may include:
    • Hypothermia, measures for prevention of BBB disruption, and endothelial cell injury, suppression of glial activation, suppression of inflammatory agents production (free radicals, HMGB1, inflammatory cytokines) and antioxidant therapy.

D.Prevention of secondary brain damage in surrounding injured area

  • The basic views on secondary brain injury localized to the area of brain injury correspond to the aforementioned above points

Going further:

Post Peer Reviewed By: Shahriar Lahouti, MD. Darab Zohri, MD.

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