Management of intracranial hypertension

Symposium on Neurological Disorder–Advances in Management-II

Management of Intracranial Hypertension Sunit C Singhi and Lokesh Tiwari Pediatric Emergency and Intensive Care Units, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

ABSTRACT Raised intracranial pressure (ICP) is a life threatening condition that is common to many neurological and non-neurological illnesses. Unless recognized and treated early it may cause secondary brain injury due to reduced cerebral perfusion pressure (CPP), and progress to brain herniation and death. Management of raised ICP includes care of airway, ventilation and oxygenation, adequate sedation and analgesia, neutral neck position, head end elevation by 200 -300, and short-term hyperventilation (to achieve PCO2 32- 35 mm Hg) and hyperosmolar therapy (mannitol or hypertonic saline) in critically raised ICP. Barbiturate coma, moderate hypothermia and surgical decompression may be helpful in refractory cases. Therapies aimed directly at keeping ICP 20 mm Hg as threshold to define intracranial hypertension requiring treatment. Sustained ICP values of greater than 40mm Hg indicate severe, lifethreatening intracranial hypertension.2 There have been some suggestions that lower threshold values for younger children may be used, although there are no data to support this. 3 A surge in ICP normally occurs with activities such as suctioning, painful stimuli, and coughing and does not warrant intervention unless it does not return to baseline within about 5 minutes. It is important to distinguish “normal” or expected increases in ICP vs intracranial hypertension because the latter requires immediate intervention. CEREBRAL PRESSURE DYNAMICS

Intracranial pressure: Normal values The normal range for ICP varies with age. Values for children are not as well established as for adults. Normal values are less than 10 to 15mmHg for adults and older children, 3 to 7 mm Hg for young children, and 1.5 to 6 mm Hg for term infants. ICP can be sub-

Correspondence and Reprint requests : Dr Prof. Sunit Singhi, Head, Department of Pediatrics, Advanced Pediatric Centre, Chandigarh, 160012, India. Phone No. Office: 91-172-275 5301and 5302; Residence: 91-172-2715619; Fax: 91172 2744401, 2745078 [Received March 17, 2009; Accepted March 17, 2009]

Indian Journal of Pediatrics, Volume 76—May, 2009

Monro-Kellie doctrine Intracranial pressure is the sum total of pressure exerted by the brain, blood, and cerebrospinal fluid (CSF) in the non-compliant cranial vault. The Monro-Kellie doctrine states that sum of intracranial volume of brain (» 80%), blood (» 10%), and cerebrospinal fluid (» 10%) is constant. An increase in any one of these components must be offset by decrease in another to keep the total volume constant or else the ICP will increase. In response to increase in intracranial volume initial compensation occurs by displacement of CSF from the ventricles and the cerebral subarachnoid space to 519

Sunit C Singhi and Lokesh Tiwari spinal subarachnoid space (vertebral canal), decreased production, and increased absorption of CSF. Infants and children with open fontanels and sutures may be able to compensate better but will still be susceptible to acute increases in ICP. Compliance Compliance is an indicator of the brain’s tolerance to increases in ICP. Each patient has varying degrees of compliance even with similar injuries. When the patient’s compliance is exhausted, there is a dramatic increase in the pressure/volume curve, leading to a rapid elevation in ICP. Cerebral blood flow In an uninjured brain, cerebral blood flow (CBF) is regulated to supply the brain with adequate oxygen and substrates. Certain physiologic factors like hypercarbia, acidosis and hypoxemia cause vasodilatation, leading to increased CBF. Seizure activity and fever will increase cerebral metabolic rate and CBF. CBF in excess of tissue demand leads to hyperemia and increased ICP. Methods to decrease the cerebral metabolic rate, such as hypothermia and barbiturates, will decrease CBF and thus the ICP. Cerebral perfusion pressure Cerebral perfusion pressure (CPP) is the pressure at which brain is perfused. It is an important indicator of cerebral blood flow. CPP provides an indirect measurement of adequacy of CBF. It is calculated by measuring the difference between the mean arterial pressure (MAP) and the ICP (MAP – ICP), where MAP = 1/3 systolic pressure plus 2/3 diastolic pressure. A reduction in CPP can occur from an increase in ICP, a decrease in blood pressure, or a combination of both factors. Normal CPP values for children are not clearly established, but the values that are generally accepted as the minimal pressure necessary to prevent ischemia are: adults >70 mm Hg; children >50–60 mm Hg; infants/toddlers >40–50 mm Hg.4 CPP < 40 mm Hg is a significant predictor of mortality in children with TBI.2 Autoregulation maintains a steady cerebral blood flow (CBF) within a CPP range of 50-150 mmHg by vasoconstriction and vasodilatation of the cerebral vessels despite fluctuations in systemic blood pressure. Autoregulation is lost at CPP values less than 50 mmHg. Ability to pressure autoregulate may be impaired or lost even with a normal CPP, CBF can passively follow changes in CPP. Once autoregulation is lost, CBF and cerebral blood volume (CBV) become dependent on changes in systemic blood pressure. CAUSES OF RAISED ICP An increase in intracranial pressure is commonly 520

caused by an increase in volume of brain (cerebral edema), blood (intracranial bleeding), space occupying lesion, or CSF (hydrocephalous). These mechanisms could be operative singly or in various combinations. Cerebral edema is the most important cause of raised ICP in non-traumatic brain injuries such as central nervous system (CNS) infections, and systemic and metabolic encephalopathies. It can be vasogenic, cytotoxic, or interstitial. Vasogenic cerebral edema is due to injury to blood brain barrier and increased capillary permeability around the area of injury or inflammation particularly in CNS infections. It can be local or diffuse and occurs around mass lesions and inflammatory processes (e.g., meningitis, encephalitis). Interstitial cerebral edema is due to an increase in the hydrostatic pressure of CSF and is often seen in patients with obstructive hydrocephalus or excessive CSF production. Cytotoxic cerebral edema (Cellular swelling) occurs following cerebral ischemia and hypoxia causing irreversible cell damage and death. Osmolar swelling may occur because of increased local osmolar load around necrotic foci caused by infarction or contusion, and possibly because of increased cerebral blood volume (hyperemia) in CNS infections. Patients with cerebral edema may have a combination of all 3 mechanisms operating. The primary etiology could be intracranial or extracranial (Table 1). When primary cause of increased ICP is intracranial, normalization of ICP depends on rapidly addressing the underlying brain disorder. Intracranial hypertension due to an extracranial or systemic process is often remediable. Increased ICP can also occur after a neurosurgical procedure. TABLE 1. Causes of Intracranial Hypertension Intracranial (primary) • CNS infections – meningitis, encephalitis, brain abscess, cerebral malaria, neurocysticercosis, • Trauma (epidural and subdural hematoma, cerebral contusions and edema) • Brain tumor • Intracranial bleed – intracerebral and intraventricular hemorrhage • Others – ischemic stroke, hydrocephalous, idiopathic or benign intracranial hypertension. • Status epilepticus. Extracranial (secondary) • Hypoxic Ischemic Injury - airway obstruction, hypoventilation, shock. • Metabolic – hyperpyrexia, hepatic failure, lead intoxication. • Drug (e.g., tetracycline, rofecoxib) • Others – hypertensive encephalopathy Postoperative • Mass lesion (hematoma) • Cerebral edema • Increased cerebral blood volume (vasodilation) • CSF obstruction.

Indian Journal of Pediatrics, Volume 76—May, 2009

Management of Intracranial Hypertension Following traumatic brain injury (TBI), intracranial hypertension is multifactorial: • Trauma induced epidural or subdural hematomas, hemorrhagic contusions, and depressed skull fractures • Cerebral edema (most important cause after hematomas).5 • Hyperemia due to loss of autoregulation • Hypoventilation leading to hypercarbia and consequently cerebral vasodilation • Hydrocephalus resulting from obstruction of the CSF pathways or its absorption • Increased intrathoracic or intra-abdominal pressure as a result of mechanical ventilation, posturing, agitation, or Valsalva maneuvers. A secondary increase in the ICP is often observed 3 to 10 days after the trauma, mainly as a result of a delayed formation of epidural or acute subdural hematoma, or traumatic hemorrhagic contusions with surrounding edema, sometimes requiring evacuation. Other potential causes of delayed increases in ICP are hypoventilation, and cerebral vasospasm, 6 hyponatremia. INTRACRANIAL PRESSURE MONITORING Acute raised ICP is an important cause of secondary brain injury hence at–risk patients should have close monitoring of systemic parameters, including temperature, heart rate, blood pressure, electrocardiogram, blood glucose, ventilation, oxygenation, and fluid intake and output. They should be on continuous monitoring with pulse oximetry and capnography to avoid unrecognized hypoxemia and hypoventilation or hyperventilation. A central venous catheter should be placed to evaluate volume status, and a Foley catheter for accurate urine output. Patients with suspected intracranial hypertension should have monitoring of ICP. Monitoring of cerebral oxygen extraction with jugular bulb oximetry is desirable, if available. Indications Clinical symptoms of increased ICP, such as headache, nausea, and vomiting, are impossible to elicit in comatose patients. Papilledema, though a reliable sign of intracranial hypertension, is uncommon after acute events, even in patients with documented elevated ICP. On the other hand, signs such as pupillary dilation and decerebrate posturing can occur in the absence of intracranial hypertension. CT scan signs of brain swelling, such as midline shift and compressed basal cisterns, are predictive of increased ICP, but intracranial hypertension can sometimes occur without those findings. 7 Indian Journal of Pediatrics, Volume 76—May, 2009

Monitoring of ICP is an invasive technique and has some associated risks. The aim of monitoring is prevention of cerebral ischemia and secondary brain injury. For a favorable risk-to-benefit ratio, therefore, ICP monitoring is indicated only in selected at-risk patients. 8 These include patients with Glasgow Coma Scale of 8 or less and patients with TBI who have an abnormal admission head CT scan. 9 Patients who are able to follow commands have a low risk for developing raised ICP and can be followed with serial neurologic examinations. Patients with a Glasgow Coma Scale score greater than 8 also might be considered for ICP monitoring if they require a treatment that might increase ICP, such as positive end-expiratory pressure (PEEP). Other, less common indications include patients with multiple systemic injuries with altered level of consciousness and subsequent to removal of an intracranial mass (e.g., hematoma, tumor). ICP monitoring also must be considered in nontraumatic conditions in which an intracranial mass lesion is present (e.g., cerebral infarction) and has a likelihood of expansion leading to intracranial hypertension and clinical deterioration. The duration of monitoring is until ICP has been normal for 24 to 48 hours without a need for therapy to reduce ICP. Although ICP monitoring has never been subjected to randomized controlled studies to evaluate its effectiveness, its use has been associated with decreased morbidity and mortality, and improved outcome in patients with TBI, intracerebral hemorrhages, and CNS infections.8,10-12 ICP monitoring is crucial to identify rapidly increasing pressure and to institute appropriate therapy to prevent cerebral herniation and preserve cerebral perfusion. It is also necessary to monitor ICP in order to calculate the CPP. Sites for ICP monitoring The most common sites used for ICP monitoring are intraventricular and intra-parenchymal. Intraventicular catheter remained the preferred device for monitoring ICP and the standard against which all newer monitors are compared.13 These days the use of intraventricular catheter placement, preferably with an implantable micro-transducer (fiberoptic or strain-gauge) 14 allows simultaneous monitoring of ICP and management of increased ICP by CSF drainage.The advantages of the ventriculostomy are its relatively low cost, the option to use it for therapeutic CSF drainage, and its ability to recalibrate to minimize errors owing to measurement drift. Disadvantages are difficulties with insertion into compressed or displaced ventricles, risk of infection, inaccuracies of the pressure measurements because of obstruction of the fluid column, and the need to maintain the transducer at a fixed reference point relative to the patient’s head. The system should be checked for proper functioning at least every 2 to 4 hours, and any time there is a change in the ICP, 521

Sunit C Singhi and Lokesh Tiwari neurologic examination, and CSF output. This check should include assessing for the presence of an adequate waveform, which should have respiratory variations and transmitted pulse pressure. When the ventricle cannot be cannulated, intraparenchymal site can be used. Other alternatives for monitoring ICP include subdural, subarachnoid, and epidural catheter placement using microsensor transducer and fiberoptic transducer tipped catheters. The main advantages of micro-transducers are the ease of insertion, especially in patients with compressed ventricles. However, none of the micro-transducer- tipped catheters can be recalibrated after they are inserted into the skull. They also exhibit measurement drift over time15 and must be replaced if monitoring is in excess of several days. Intracranial pressure waveforms

Tidal (redbound) P2

Complications of ICP monitoring(13) The most common complication of ventricular catheter placement is infection (incidence of 5% to 14%); colonization of the device is more common than clinical infection. 17 There was a nonlinear increase of risk during 10 to 12 days, after which the risk diminished.17 Use of antibiotic-coated ventricular catheters has been shown to reduce the risk of infection from 9.4% to 1.3%.18 Other complications of ventricular catheters are hemorrhage (incidence 1.4%), malfunction, obstruction, and malposition. MANAGEMENT OF INCREASED ICP

The normal ICP waveform contains three phases (Fig. 1A) • P1 (percussion wave) represents arterial pulsations. • P2 (rebound wave) reflects intracranial compliance. • P3 (dichrotic wave) represents venous pulsations. Percussion (arterial) P1

waveform, but high amplitude. C waves may be superimposed on plateau waves.16

Low pressure wave, non-compliant cranium Dichrotic P3 (venous)

Fig. 1A. Normal ICP wave forms

As the ICP increases, cerebral compliance decreases, arterial pulses become more pronounced, and venous components disappear. Pathologic waveforms include Lundberg A, B, and C types (Fig. 1B). Lundberg A waves or plateau waves are ICP elevations to more than 50 mm Hg lasting 5 to 20 minutes. These waves are accompanied by a simultaneous increase in MAP, but it is not clearly understood if the change in MAP is a cause or effect. Lundberg B waves or pressure pulses have amplitude of 50 mm Hg and occur every 30 seconds to 2 minutes. Lundberg C waves have amplitude of 20 mmHg and more and a frequency of 4 to 8 per minute; they are seen in the normal ICP

High pressure wave, non-compliant cranium

In patient with raised ICP in addition to treatment of primary cause-whether intracranial or extracranial, the main focus of treatment is to prevent and minimize secondary injury. Secondary brain injury refers to the processes that occur within hours to days after the primary injury that can be prevented or minimized— such as cerebral ischemia, cerebral edema, and neurochemical alterations including excitatory neurotransmitters, the formation of free radicals, and increased levels of intracellular calcium and potassium. 19 Factors that are known to worsen secondary injury are hypoxia and hypotension.20 The neurological devastation caused by the secondary injury is often worse than the underlying primary disorder. Most of the current treatment recommendations are based on consensus and clinical experience. Few specific treatment options have been subjected to randomized trials. Since there are limited outcome studies to support the current management of children with increased ICP from etiologies other than TBI it is the knowledge gained from treating TBI that is often applied to treat raised ICP of other etiologies also. Goals of therapy • Maintain ICP less than 20 to 25 mm Hg. • Maintain adequate CPP usually greater than 60 mm Hg, by maintaining adequate MAP. • Avoid factors that aggravate or precipitate elevated ICP. An overall approach to the management of intracranial hypertension is presented in fig. 2. Airway, Breathing, and Circulation

Fig. 1B. High ICP wave forms

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The initial management of the child with suspected increased ICP includes assessment of airway, breathing, and circulation. Even prior to a thorough Indian Journal of Pediatrics, Volume 76—May, 2009

Management of Intracranial Hypertension

Head midline elevated 20-30o

Fig. 2. Approach to the management of intracranial hypertension Abbreviations : ICP – Intracranial Pressure, GCS – Glargow coma score, HTS – Hypertonic saline

neurological exam, if the patient is unarousable, has a GCS 60 mm Hg, an oxygen saturation > 92%, and physiologic positive end expiratory pressure (PEEP) of 5 cm H2O. Blood pressure must be maintained at levels appropriate for age or restored to ensure adequate CPP and prevent further ischemia. Fluid boluses should be given to the hypotensive neurologically injured child in the same way as any other child presenting in shock. Vasopressor support is initiated if the child remains hypotensive despite appropriate fluid resuscitation. General measures Prevention or treatment of factors that may aggravate or precipitate intracranial hypertension should be undertaken. Specific factors that may aggravate intracranial hypertension include obstruction of venous return (head position, agitation), respiratory problems (airway obstruction, hypoxia, hypercapnia), fever, severe hypertension, hyponatremia, anemia, and seizures. Head elevation and position Elevation of the head-end of the bed and keeping the head in a neutral position are standard recommendations to minimize resistance to venous outflow and promote displacement of CSF from the intracranial compartment to the spinal compartment. Elevation of the head up to 30o reduces ICP and increases CPP, but does not change brain tissue oxygenation. 21 The reduction in ICP resulting from 15 o to 30 o of head elevation is probably advantageous and safe for most patients. The child must be euvolemic prior to placing in this position to avoid orthostatic hypotension. When head elevation is used, the pressure transducers for blood pressure and ICP must be zeroed at the same level (at the level of the foramen of Monro) to assess CPP accurately. Management of Respiratory failure Comatose patients often have respiratory dysfunction requiring mechanical ventilation, pneumonia and pulmonary insufficiency, or periodic episodes of hypoventilation. Resultant hypoxia and hypercapnia can increase ICP dramatically, and mechanical ventilation can alter cerebral hemodynamics. Controlled ventilation may be needed for optimal management and to maintain normal carbon dioxide . During mechanical ventilation high PEEP can increase ICP by impeding venous return and increasing cerebral venous pressure, and by decreasing blood pressure leading to a reflex increase of cerebral blood volume. The effects of PEEP on ICP also depend on lung compliance; minimal effect is seen when lung compliance is low.22 524

Sedation and analgesia Children with acute brain injury, especially those who are mechanically ventilated, should be appropriately sedated and given adequate analgesia to prevent pain and anxiety, both of which increase the cerebral metabolic rate and ICP. There are no randomized controlled studies comparing sedation methods in children with acute neurological injury. In general, benzodiazepines have no effect on ICP, whereas the opiates have been reported to increase ICP in adult patients with TBI. 23 One consideration in the choice of sedative should be to minimize effects on blood pressure because most available agents can decrease blood pressure. Hypovolemia predisposes to hypotensive side effects and should therefore be corrected before administering sedatives. Selection of a shorter acting agent (midazolam) may have the advantage of allowing brief interruption of sedation to examine neurologic status. Propofol is not approved for sedation in PICU as its safety is not established by US FDA and UK committee on safety of Medicine. Fever Fever increases metabolic rate by 10% to 13% per degree Celsius and is a potent vasodilator. Fever-induced dilation of cerebral vessels can increase CBF and may increase ICP. In patients at risk of intracranial hypertension, fever should be controlled with antipyretics and hydrotherapy. Etiology of fever must be sought and treated appropriately. A significant relationship has been seen between fever and a poor neurologic outcome in head injury patients.24 Hypertension Elevated blood pressure is seen commonly in patients with raised ICP. Characteristically systolic blood pressure increase is greater than diastolic increase. It is unwise to reduce elevated blood pressure associated with untreated raised ICP, especially in patients with intracranial mass lesion, because the high blood pressure maintains cerebral perfusion. In the absence of an intracranial mass lesion, the decision to treat elevated blood pressure has to be individualized. When autoregulation is impaired, which is common after TBI, systemic hypertension may increase CBF and ICP, may exacerbate cerebral edema and increase the risk of postoperative intracranial hemorrhage. Systemic hypertension may resolve with sedation. If the decision is made to treat systemic hypertension, vasodilating drugs, such as nitroprusside, nitroglycerin, and nifedipine, should be avoided; these increase ICP, which may be deleterious to the marginally perfused injured brain. Sympathomimetic-blocking antihypertensive drugs, such as beta-blocking drugs (labetalol, esmolol) or central acting alfa-receptor agonists (clonidine), are preferred because they reduce blood Indian Journal of Pediatrics, Volume 76—May, 2009

Management of Intracranial Hypertension pressure without affecting the ICP. Agents with a short half-life have an advantage when the blood pressure is labile. Treatment of anemia Patients with severe anemia have been reported to present with symptoms of increased ICP and signs of papilledema, which resolve with treatment of the anemia.25 The mechanism is thought to be related to the marked increase in CBF that is required to maintain cerebral oxygen delivery when anemia is severe. Although anemia has not been clearly shown to exacerbate ICP after TBI, a common practice is to maintain hemoglobin concentration around 10 g/dL. A large randomized trial of critically ill patients showed better outcome with a more restrictive transfusion threshold of 7 g/dL.26. The issue of optimal hemoglobin concentration in patients with raised ICP needs further study. Prevention of seizures Seizures occur commonly in association with raised ICP irrespective of etiology, be it meningitis, encephalitis or severe head injury. Seizures increase cerebral metabolic rate and lead to a dramatic rise in ICP, but there is no clear relationship between the occurrence of early seizures and a worse neurologic outcome. In patients with severe TBI as well as in those with nontraumatic coma, seizures may be subclinical and can be detected only with continuous electroencephalographic monitoring. Prophylactic anti-seizure therapy may be considered for prevention of early posttraumatic seizures (PTS) in children at high risk of seizure following TBI. However, prophylactic use of anti-seizure therapy is not recommended for children for prevention of late post-traumatic seizure.27 If a late PTS occurs, the patient should be managed in accordance with standard approaches to patients with new-onset seizures.27 MEASURES FOR REFRACTORY INTRACRANIAL HYPERTENSION For patients with sustained ICP elevations of greater than 20 to 25 mm Hg, additional measures are needed to control the ICP. Hyperosmolar therapy Mannitol is the most commonly used hyperosmolar agent for the treatment of intracranial hypertension.28 More recently, hypertonic saline has also been used. A few studies have compared the relative effectiveness of these two hyperosmotic agents, but more work is needed. Indian Journal of Pediatrics, Volume 76—May, 2009

Intravenous bolus administration of mannitol lowers the ICP in 1 to 5 minutes with a peak effect at 20 to 60 minutes. The effect of mannitol on ICP lasts 1.5 to 6 hours, depending on the clinical condition.29 Mannitol is usually given as a bolus of 0.25 to 0.5g/kg; when urgent reduction of ICP is needed, an initial dose of 1 g/ kg may be given. Two prospective clinical trials in adults, one in patients with subdural hematoma and the other in patients with herniation secondary to diffuse brain swelling, have suggested that a higher dose of mannitol (1.4 g/kg) may give significantly better results than a lower dose in these extremely critical situations. 30 When long-term reduction of ICP is needed, 0.25 to 0.5 g/kg can be repeated every 2 to 6 hours. Attention should be paid to replacing fluid that is lost because of mannitol-induced diuresis, or else intravascular volume depletion would result. Mannitol has rheologic and osmotic effects. 31 Infusion of mannitol increases serum osmolarity, which draws edema fluid from cerebral parenchyma. This process takes 15 to 30 minutes until gradients are established. Immediately after infusion of mannitol, therefore there is an expansion of plasma volume and a reduction in hematocrit and in blood viscosity, which may increase CBF and oxygen delivery to the brain.31 In patients with intact pressure autoregulation, infusion of mannitol induces cerebral vasoconstriction, which maintains constant CBF and causes a considerable decrease in ICP. In patients with absent pressure autoregulation, infusion of mannitol increases CBF, and hence the decrease in ICP is less pronounced. Mannitol opens the blood-brain barrier, and may cross it. Mannitol that has crossed the blood-brain barrier may draw fluid into the central nervous system, which can aggravate vasogenic edema. For this reason, when it is time to stop mannitol, it should be tapered to prevent ICP rebound.31 For optimal effect of mannitol, serum osmolality should be between 300-320 mOsm. Keeping osmolality less than 320 mOsm also helps to prevent complications such as hypovolemia, hyperosmolarity, and renal failure. The adverse effects of mannitol are more likely when it is present in the circulation for extended periods, such as in slow or continuous infusions or with repeated administration of high doses. Hypertonic saline administration appears to be a promising therapy for control of cerebral edema. Given in concentrations ranging from 3% to 23.4%, it creates an osmotic force to draw water from the interstitial space of the brain parenchyma into the intravascular compartment in the presence of an intact blood-brain barrier, reducing intracranial volume and ICP. In some studies in adults, hypertonic saline has been more effective in reducing ICP in TBI than mannitol. 32 However, variations in hypertonic solution prepara525

Sunit C Singhi and Lokesh Tiwari tions and dosing regimens, difference in inclusion and exclusion criteria, and small numbers of patients make these studies difficult to compare. Hypertonic saline is said to have advantage over mannitol in hypovolemic and hypotensive patients as it augments intravascular volume and may increase blood pressure in addition to decreasing ICP. However, use of hypertonic saline as prehospital bolus to hypotensive patients with severe TBI was not associated with improved neurologic outcomes.33 Adverse effects of hypertonic saline administration include hematologic and electrolyte abnormalities, such as bleeding secondary to decreased platelet aggregation and prolonged coagulation, hypokalemia, and hyperchloremic acidosis. Available data show only level II evidence supporting the use of continuous infusion of 3% saline for treatment of elevated ICP in pediatric TBI. 34 An effective minimum dose on a sliding scale (0.1 – 1.0 ml/kg/hour) to keep ICP