Traumatic brain injury in children – clinical implications

ARTICLE IN PRESS

Experimental and Toxicologic Pathology 56 (2004) 113–125

EXPERIMENTAL ANDTOXICOLOGIC PATHOLOGY www.elsevier.de/etp

Traumatic brain injury in children – clinical implications$ Ruediger Noppens, Ansgar M. Brambrink Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Code UHS-2, Portland, OR 97239-3098, USA Received 19 March 2004; accepted 29 April 2004

Abstract Traumatic brain injury (TBI) is the leading cause of death in childhood; however only very few studies focusing on the specific pathophysiology and treatment have been published to date. Head trauma is more likely in young children than in adults given the same deceleration of the body due to their large and heavy heads and weak cervical ligaments and muscles. Resulting brain injury is more severe due to their thin, pliable skulls and the yet unfused sutures. Accordingly, children below the age of 4 years have lower chances of a full recovery after severe TBI, although in general, neurologic recovery after severe brain injury in children is better than in adults. The time course of brain injury can be divided into two steps: primary and secondary injury. Primary brain injury exclusively results from the initial impact. In contrast, adverse physiologic conditions during recovery after head trauma may account for additional brain damage, which is then referred to as secondary brain injury. As primary brain injury can only be influenced by preventive measures, all therapeutic efforts during the post-injury period focus on the reduction of secondary injury to the traumatized brain. Several mechanisms have been identified to be involved in the development of post-traumatic secondary brain injury, which render the rationale for the key treatment strategies. Three evidence based measures are of critical importance to prevent or minimize secondary brain injury: (1) avoid hypoxemia, (2) avoid post-traumatic arterial hypotension, and (3) refer the traumatized child to an experienced trauma team at a center that provides the availability of special equipment, e.g. for surgical procedures and airway management, for this age group. For several other therapeutical means, e.g. hypothermia or specific surgical interventions, clinical evidence to date is insufficient to allow recommendation as rescue treatment for children at risk of severe neurological sequelae following TBI. This review discusses the clinical implication of pathophysiologic mechanisms of TBI in the developing brain according to the recent literature and current guidelines. It follows the clinical approach to a head injured child, that can be divided into three phases, i.e. initial assessment and stabilization, followed by first tier, and if necessary second tier therapeutic interventions to assure adequate oxygenation and perfusion of the brain. r 2004 Elsevier GmbH. All rights reserved.

Introduction $

Encouraged by suggestions at the Symposium ‘‘Traumatic Injury in the Developing Brain: Biomechanical, Pathophysiological and Clinical Aspects’’ at the 4th International Congress of Pathophysiology, June 29–July 5, 2002, Budapest, Hungaria. Corresponding author. E-mail address: [email protected] (A.M. Brambrink). 0940-2993/$ - see front matter r 2004 Elsevier GmbH. All rights reserved. doi:10.1016/j.etp.2004.04.005

Trauma is the most frequent cause for death and hospital admission in childhood. In industrialized countries five times more children die from head trauma than from leukemia, the next leading cause of death in children over the age of one year (Cramer, 1995; Kasperk and Paar, 1991; Keller and Vane, 1995; Maier-Hauff et al.,

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the post-injury period focus on the reduction of secondary injury to the traumatized brain.

1993). Even though traumatic brain injury (TBI) is the leading cause of death in childhood, only very few studies focused on the specific pathophysiology and treatment have been published to this date. In Germany, each year approx. 83,000 children younger than 15 years are hospitalized after head trauma. About 80% of these children present with mild (contusion), 20% with moderate or major brain trauma (Brambrink, 2002). Children and infants have a large, heavy head; cervical ligaments and muscles are weaker than in adults. Given the same deceleration of the body, head trauma is therefore more likely in younger children. Similarly, the resulting brain injury is more severe due to the thin, pliable skull and the yet unfused sutures. The causes of TBI are different among age groups (Kraus et al., 1990). Infants mostly suffer from falls or are assaulted. Toddlers more frequently are injured as passengers in motor vehicle accidents, while falls still account for the majority of injuries. As children grow older, TBI is more often caused by traffic accidents and by accidents during sports (Table 1, Kraus et al., 1990). Neurologic recovery after severe brain injury in children is generally better than in adults (Alberico et al., 1987; Guyer and Ellers, 1990; Luerssen et al., 1988). However, the chances of a full recovery are low in children below 4 years of age (Koskiniemi et al., 1995), which may be related to the higher incidence of severe brain injury in this age group. Additionally, there is growing evidence that some of the pathophysiological mechanisms of TBI in immature brain may be different than in adult brain. However, this still is mostly related to experimental work or small clinical studies (Bauer et al., 1999; Grundl et al., 1994). The time course of brain injury can be divided into two steps: primary and secondary injury. Primary brain injury exclusively results from the initial impact. In contrast, adverse physiologic conditions during recovery after head trauma may account for additional brain damage, which is then referred to as secondary brain injury. As primary brain injury can only be influenced by preventive measures, all therapeutic efforts during

Table 1.

Primary brain injury The structural damage the brain suffers at the time of the actual trauma usually is referred to as the ‘‘primary brain injury’’. Brain injury can either be caused by penetration of a foreign body (focal injury) or by shearing forces that stem from acceleration/deceleration and may cause contusions, lacerations, diffuse axonal injury and dural tears (Bruce et al., 1979). Shearing forces are greatest at the junction of tissue of different rigidity, e.g. between skull/dura mater, dura mater/brain or gray and white matter (Gentry et al., 1988). As stated above, injury in young children tends to be more severe as a result of the specific biomechanics of head trauma in this age group (Ommaya et al., 2002). The degree of elasticity of the skull as well as the characteristics of skull sutures influences the extent of TBI. About half of the children die within the first minutes after head trauma for extensive primary injury. Preventive measures, e.g. bike helmets or child restrain systems, are currently viewed as the most important means to avoid disability and death secondary to head injury in children (Feldmann, 2002).

Secondary brain injury In contrast, secondary brain injury occurs hours or even days after the initial trauma and may therefore be a target for therapeutic interventions (Stein and Spettell, 1995). Neurologic deterioration after head trauma may be seen as an indicator for secondary brain injury and has been reported to be present in up to 90% of patients (Jones et al., 1994). Several mechanisms have been identified to be involved in the development of posttraumatic secondary brain injury, which will be reviewed briefly below.

Causes of traumatic brain injury in children (Kraus et al., 1990)

Age groups (years)

Motor vehicle accident (%)

Falls (%)

Assaults (%)

Sports (%)

Other (%)

o1 1–4 5–9 10–14 15–19

7 22 31 24 55

69 51 31 18 9

17 5 1 5 17

2 16 32 43 10

6 6 5 10 10

Total

37

24

10

21

8

Infants mostly suffer from falls or are assaulted. Toddlers more frequently are injured as passengers in motor vehicle accidents, while falls still account for the majority of injuries. As children grow older, traumatic brain injury is more often caused by traffic accidents and by accidents during sports.

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Central nervous energy failure may occur as a direct consequence of impaired regional cerebral blood flow (CBF) in the recovering brain after severe head trauma. Scattered reductions in blood flow may result from regional edema and hemorrhage within the primary damaged brain regions or from elevation of the intracranial pressure (ICP). Among others, this might lead to a dysfunction of cellular ion pumps in the respective areas, which is exacerbated by an excessive release of excitatory amino acid neurotransmitters (i.e. glutamate and aspartate). This initiates a cellular sodium and calcium overload which then may initiate a cascade of cellular destruction, e.g. free radical formation, proteolysis and lipid peroxidation. Additionally, TBI may also trigger inflammatory mechanisms (Danton and Dietrich, 2003). This may ultimately lead to secondary rapid (necrotic) or slow (apoptotic) neuronal death (Martin et al., 1998). Thus, secondary brain injury presents the morphologic correlate of the delayed deterioration observed hours or days after severe TBI. Certain clinical conditions which are associated with the risk of a decreased CBF have also been identified to result in a detrimental long-term outcome after TBI, i.e. (1) arterial hypotension; (2) hypoxemia; (3) intracranial hemorrhage and malignant brain edema; and (4) hyperthermia.

Arterial hypotension Cell death is initiated within minutes of the interruption of substrate delivery to neurons (cerebral ischemia). Arterial hypotension involving a mean arterial blood pressure (MAP) below the cerebral autoregulation threshold results in a decreased cerebral perfusion pressure (CPP=MAP—ICP [or CVP, which ever is greater]). This may cause brain ischemia after head trauma, e.g. during periods of increased ICP. Additionally, the traumatized brain often loses its ability to autoregulate CBF. CBF then becomes exclusively dependent on MAP. Hypotensive episodes have been shown to worsen survival and neurologic outcome in pediatric patients after TBI (Adelson et al., 2003c; Gabriel et al., 2002; Pigula et al., 1993). In fact, some studies suggest that hypotension is the leading cause for mortality in children, who initially survived severe head trauma (Luerssen et al., 1988; Pigula et al., 1993). Because physiologic limits of blood pressure change with age, the cut-off values for arterial hypotension need to be determined for the individual pediatric patient. As a guideline, the lower limit of the systolic blood pressure for a given child should not be less than the 5th percentile of the normal systolic blood pressure for this age. This value can be estimated by the formula: 70 mm Hg+(2  age in years) (Adelson et al., 2003b). However, it should be noted that to our knowledge this

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formula has never been validated for a specific age group, and therefore cannot serve as a substitute for the careful determination of the appropriate post-traumatic CPP in an individual pediatric patient.

Arterial hypoxemia and hypercarbia Brain stem injuries or airway obstruction can possibly result in hypoventilation leading to hypoxemia and hypercarbia. Even brief post-traumatic episodes of hypoxemia have been associated with secondary brain injury and increased mortality and morbidity in both adults and children (Gabriel et al., 2002). Hypercarbia is known to increase CBF due to direct cerebral vasodilatation. As a result of cerebral vasodilation intracerebral blood volume increases, which subsequently raises in ICP. Elevated ICP further reduces CPP, increasing the risk for brain ischemia. This may then ultimately trigger or exacerbate secondary brain injury.

Intracranial hematoma and brain edema Traumatic intracranial hemorrhage, e.g. epidural, subdural or intracerebral hematoma, may induce ischemia by a pressure related critical impairment of substrate supply to the affected area. Epidural hematoma is rare in infants and young children, possibly because of the firm adherence of the dura mater and the calvarium. However, in affected children surgery is frequently indicated to evacuate the hematoma, but initial diagnosis may be difficult since most children with epidural hematoma clinically present with a lucid interval (Choux, 1986). More children present with acute subdural hemorrhage after TBI, and their long-term outcome appears to be poor independent to the therapeutical intervention (Ewing-Cobbs et al., 1998; Herrera et al., 2000). A study conducted in the UK showed a frequent correlation of subdural hemorrhage with child abuse (the so-called ‘‘shaken-baby-syndrome’’). Subdural hemorrhage in young children should therefore always prompt a closer investigation of the circumstances of injury (Jayawant et al., 1998). Finally, intracerebral hematoma is rarely seen in children. It is caused mostly by motor vehicle accidents or falls (3%, Zimmerman and Bilaniuk, 1981). Another characteristic of pediatric TBI is the high incidence of brain edema formation after head trauma in infants and small children. Recent studies suggest that both, cytotoxic and vasogenic edema contributes to the development of diffuse brain swelling after head injury in children. Blood brain barrier disruption after head trauma has been attributed to oxidative stress. The more severe disruption observed in traumatized children may therefore in part be related to the smaller antioxidative capacity of the immature brain. Other mechanisms,

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e.g. an increased risk of sustained cerebral hypoperfusion or relative overexpression of NMDA receptors might also result in a higher susceptibility of children to develop severe brain edema after TBI (Bauer et al., 1999; Merten and Osborne, 1983; Ommaya et al., 2002).

Cerebral hyperthermia Thermoregulation is impaired by TBI, frequently causing fever in the early phase of recovery after head injury (Rumana et al., 1998). Elevated temperature is known to raise ICP via cerebral vasodilation. For every 1 1C increase in body temperature there is a 5% increase in cerebral metabolic rate, leading to a respective increase of CBF (Baughman, 2002). Experimental studies suggested that an increased demand for oxygen and other metabolic substrates caused by elevated temperature worsens functional damage after TBI (Brambrink et al., 1999a; Dietrich et al., 1996). In contrast, a mild reduction in brain temperature seems to render protective effects and was shown in adults to be associated with a better outcome after various brain insults. This is supposed to be due to a reduction of brain metabolic needs during recovery (Hypothermia after Cardiac Arrest Study Group, 2002; Hendrick, 1959).

Clinical implications Initial assessment and stabilization Management of the head injured child in general should be optimized to prevent secondary brain injury. To date, only a few therapeutic recommendations can be based on clinical evidence. Most of therapeutic strategies that are commonly used are adapted from recommendations for the treatment of adults. However, the different pathophysiology involved in pediatric TBI might be targeted with specific treatment concepts. Therefore, more clinical trials centered on treatment of children are needed to develop optimal strategies for this age group. For initial resuscitation basic and advanced pediatric life support guidelines should be applied (Fig. 1). Control of the airway and sufficient ventilation and oxygenation must be achieved immediately to avoid hypoxemia (Noppens and Brambrink, 2002). The threshold to apply endotracheal intubation and controlled mechanical ventilation should be low when managing severely injured children. Initially normocarbia should be established as more aggressive hyperventilation and resulting hypocarbia (PaCO2533 mm Hg) may cause further damage to the brain after TBI

(Adelson et al., 2003g). Hypocarbia results in cerebrovascular constriction, which may further worsen regional cerebral perfusion in already impaired primarily traumatized brain regions. However, for the acute treatment of severely increased ICP moderate hyperventilation may be considered, if appropriate monitoring is provided by using, e.g. capnometry, jugular venous oxygen saturation monitors or transcranial Doppler-sonography. As outlined above, cardiovascular stability is essential to maintain cerebral perfusion. However, additional extra cranial injuries beside the head injury may be present in pediatric trauma victims, which may cause arterial hypotension, or even shock, due to, e.g. significant blood loss. Children below the age of 4 years have a higher incidence of hypotensive episodes, compared to other age groups (Berger et al., 1985). In order to prevent brain injury secondary to arterial hypotension, blood pressure should always be kept within physiologic limits for the individual child (formula shown above) or slightly above these limits. Treatment of hypotension may include the use of crystalloids, hypertonic saline, colloids and, if necessary, vasopressors such as norepinephrine (Bayir et al., 2003; Brambrink, 2002; Doyle et al., 2001).

Neurologic assessment Initially injury should be assessed using a minimal neurologic examination and results should be well documented. Neurologic status should be reassessed frequently during the immediate post-injury period and observations should always be noted in a timely manner. This may allow the rapid identification of changes in neurologic status over time. Each assessment should apply the Glasgow Coma Scale (GCS), test the corneal reflex, check size of pupils and their reaction to light, examine gross motor and sensory function as well as reflexes. For young children and infants an age adapted Pediatric GCS has been suggested (Table 2, Tasker et al., 1996). Severe head injury is indicated by a GCS of 8 or less, whereas moderate injuries are usually associated with scores between 9 and 12. Children with minor head injuries usually present with a GCS between 13 and 15. In approximately 3% of children with a mild head injury (GCS 13–15) the neurologic status will further deteriorate and individuals may than require neurosurgical intervention (Dacey et al., 1986). With moderate head injury (GCS 9–12) the patient’s status can deteriorate quickly during the first hours, and about 50% of the children will develop moderate to severe disability within 3 months of the trauma (Rockswold et al., 1987). Accordingly, a single initial neurologic assessment to identify patients with a developing

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Traumatic Brain Injury

GCS < 8

apply Pediatric Advanced Life Support: A–Airway → rapid sequence intubation B–Breathing → oxygenation, controlled ventilation C–Circulation → maintain CPP, MAP (according to age using fluid resuscitation,vasopressors) D–Drugs → adequate sedition / analgesia → consider neuromuscular blockade

In case of sudden changes in neurostatus (e.g. GCS, pupils) consider immediate CT-scan to determine cause and appropriate treatment

– elevate upper part of body to approx. 30° (MAP according to age specific range) evidence for ICP ↑

no

yes -ICP Monitoring suggested -consider CSF drainage -neurosurgical intervention as indicated

evidence for ICP ↑

no

Intensive Care: - comprehensive monitoring (e.g. ICP-measurement, MAP, SjO2, TCD, EEG)

- frequent reevaluation - adjustment of therapy

yes - drain CSF - consider osmotherapy (mannitol, hypertonic saline) - mild hyperventilation (PaCO2 30-35 mmHg)

ICP resistant to therapy ?

no

yes consider: - moderate hypothermia (32-34°C) - hyperventilation (PaCO2 < 30 mmHg; TCD, CBF,SjO2, AjDO2 should be monitored)

- barbiturate coma - decompressive craniectomy

Fig. 1. Suggested algorithm for the clinical management of infants and children suffering from severe traumatic brain injury. After initial resuscitation and stabilization therapeutic strategy is targeted to tightly control ICP and provide adequate CPP for the respective age to prevent secondary brain injury. During subsequent intensive care frequent re-evaluation of the patients status is indicated, using both clinical and apparative means, e.g. computer tomography, and treatment needs to be adjusted accordingly. (GCS, Glasgow Coma Scale; CCT, cranial computer tomography; CPP, cerebral perfusion pressure; MAP, mean arterial blood pressure; ICP, intracranial pressure; CSF, cerebrospinal fluid; EEG, electroencephalography; CBF, cerebral blood flow; SjO2, jugular venous oxygen saturation; AjDO2, arterial-jugular venous difference in oxygen content. Modified according to Adelson et al. (2003k), and Brambrink et al. (1999a).)

intracranial pathology after TBI is not sufficient. Especially young children are prone to a delayed deterioration of their neurologic status, most likely due to their elevated risk for brain edema formation.

Additional information can be gathered from frequent evaluation of both eyes. The importance of this diagnostic tool cannot be over-emphasized as it allows determining the need for immediate therapeutical

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Table 2.

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Glasgow coma scale (GCS) for adults and older children, adapted for infants and small children (Tasker et al., 1996)

Response

Adults and children

Infants

Points

Eye opening

No response To pain To voice Spontaneous

No response To pain To voice Spontaneous

1 2 3 4

Verbal

No response Incomprehensible Inappropriate words Disoriented Conversation

No response Moans to pain Cries to pain Irritable Coos, babbles

1 2 3 4 5

Motor

No response Decerebrate posturing Decorticate posturing Withdraws to pain Localizes pain Obeys commands

No response Decerebrate posturing Decorticate posturing Withdraws to pain Withdraws to touch Normal spontaneous movement

1 2 3 4 5 6

Total score

intervention, especially in the unconscious child. First, pupil size and reaction to light should be assessed. For example, a subthalamic lesion may cause moderate miosis, whereas bilateral maximal miosis might be rather indicative of a pons lesion. One should always be aware of the miotic effects of therapeutic doses of opioids. Mydriasis after TBI may indicate severe midbrain injury and/or critically increased ICP, due to e.g. brain edema or ICB. Anisochorous is commonly associated with an impairment of one oculomotoric nerve, e.g. due to an ipsilateral intracranial hematoma or regional edema. Second, the assessment should focus on the corneal reflex and the bulbar position. Bulbar divergence or bulbar deviation as well as spontaneous oscillation (nystagmus) are frequently associated with post-traumatic lesions of the brainstem or pons. Vertical bulbar oscillation appears to be associated with an unfavorable neurologic outcome. Any deterioration of the neurologic status of the child needs to be documented and appropriate diagnostic (e.g. CT-scan) and therapeutic means (e.g. surgical intervention) need to be initiated immediately. A CT-scan is always indicated in patients with a GCS below 9, but also with onset of clinical signs, indicating a deterioration of the neurologic status, e.g. changes in pupil size and reaction to light. A prolonged impairment of neurologic status, even if it is only mild, for example, a GCS of less than 14 for more than 8 h, similarly requires further diagnostic evaluation (e.g. CT-scan). While treating a child with head injury one must keep in mind that 2–5% of pediatric patients with head injuries have an associated cervical spine fracture, mostly between C1 and C3 (Skellett et al., 2002). This is related to the relatively large head combined with weak neck muscles. Rarely, children may also have

3–15

spinal cord injury without radiographic abnormality (Ergun and Oder, 2003). Therefore, a spine injury must be always suspected even if a conventional X-ray appears normal. Spinal injury in children is usually diagnosed based on clinical signs only. Unless CT-/ MRI-images or dynamic X-ray images are evaluated, it is not possible to exclude spinal damage or instability of vertebra. Therefore, special care should be taken to avoid exacerbation of a potential spinal cord injury during, e.g. endotracheal intubation (in-line stabilization) and positioning for therapeutic or diagnostic procedures (e.g. CT-scan, placement of central venous line). The child’s neck should always be immobilized using an appropriately sized collar until cervical spine injury is definitely excluded.

Treatment strategies after traumatic brain injury Clinical evidence (Adelson et al., 2003b; Gabriel et al., 2002; Ong et al., 1996; Pigula et al., 1993) has identified three therapeutical measures, which are of critical importance to prevent or minimize secondary brain injury: (1) avoid hypoxemia (PaO2o60 mmHg), (2) avoid post-traumatic arterial hypotension (see formula above for age dependent limits), and (3) refer the traumatized child to a trauma team consisting of professionals experienced in the emergency treatment of children, at a center that provides the availability of special equipment, e.g. for the potentially necessary surgical procedures and airway management, for this age group (Adelson et al., 2003b; Gabriel et al., 2002; Ong et al., 1996; Pigula et al., 1993). For many other therapeutical means, e.g. hypothermia and specific surgical intervention, which intuitively seem to be

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beneficial, clinical evidence to date is insufficient to allow conclusions about their superiority to effectively rescue children at risk for severe neurological sequelae following TBI. The following sections review the key strategies for the treatment of infants and children after TBI, suggested by the current guidelines. The review follows the clinical approach to a head injured child, that can be divided into three phases, i.e. initial assessment and stabilization, followed by first tier, and if necessary second tier therapeutic interventions to assure adequate oxygenation and perfusion of the brain. First tier therapeutic interventions are means to control ventilation, circulation and ICP, including appropriate surgical intervention if necessary. Second tier therapeutic interventions may be considered if initial management fails to stabilize ICP and to achieve adequate CPP. At all times the patients status needs to be re-evaluated frequently and therapeutic interventions need to be adjusted accordingly.

First tier therapeutic interventions Means to provide oxygen and blood flow to the brain Mechanical ventilation is used to control PaCO2 and to maintain good cerebral oxygenation in order to prevent secondary brain injury (Fig. 1). Hypoxemia (PaO2o65 mm Hg) should be identified and corrected as soon as possible after the trauma (Adelson et al., 2003a; Chesnut et al., 1993; Gabriel et al., 2002; Pigula et al., 1993). Early and adequate oxygenation increases survival by 2–4-fold after TBI in childhood (Ong et al., 1996; Pigula et al., 1993). Hyperventilation applied as a standard treatment for all patients with suspected increased ICP has been shown to worsen outcome in adult patients with severe brain injury (Muizelaar et al., 1991). The possibility of a critical reduction of CBF causing ischemia in already injured brain areas and the short therapeutic effects of hyperventilation (max. 6 h), raised serious concerns about the value of prophylactic hyperventilation (Coles et al., 2002; Stringer et al., 1993). Moreover, a small study in 20 adult patients with severe TBI showed that episodes of hyperventilation during early recovery after brain injury are associated with an increased release of extracellular neuroexcitatory aminoacids, known to trigger secondary brain damage (Marion et al., 2002). Accordingly, the current guidelines suggest normoventilation for infants or children after TBI (Fig. 1). However, mild hyperventilation (PaCO2=30–35 mm Hg) may indeed be considered in an emergency situation, e.g. in the prehospital setting, where no other means are available to treat apparent ICP elevation. It should be applied only for short periods of time and should be controlled tightly, e.g. by online measurement of the

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endtidal CO2-pressure. Moderate hyperventilation (PaCO2o30 mm Hg), in contrast, may be considered as a second tier therapeutic intervention in cases presenting with prolonged intracranial hypertension, which is refractory to other treatment strategies, e.g. cerebrospinal fluid drainage or hyperosmolar therapy (Adelson et al., 2003g). Moderate hyperventilation should only be applied in the clinical setting and should be accompanied by extensive physiologic monitoring of, e.g. jugular venous oxygen saturation, brain arterial/venous oxygen content differences, brain tissue oxygenation or regional CBF, to prevent additional brain damage due to generalized cerebral hypocarbic hypoperfusion (Fig. 1) (Adelson et al., 2003g). Supporting arterial blood pressure Hypotensive episodes are common in patients after TBI (Pigula et al., 1993). Especially in severely traumatized children, one should always consider blood loss and hypovolemic shock as reasons for unexplained hypotension. Infants may even develop hypovolemic shock because of blood loss due to an intracranial hemorrhage. Children with TBI are more vulnerable to hypotension than adults, resulting in a higher mortality rate (Luerssen et al., 1988). Therefore, blood pressure should be monitored closely, e.g. by using an intraarterial catheter, to allow immediate detection and treatment of hypotension. MAP should be kept within normal limits, and mild systemic hypertension might be helpful to maintain adequate perfusion of the brain (White et al., 2001). As outlined above, in children physiologic blood pressure limits vary with age. Thus, the recently suggested formula to estimate systolic blood pressure in children older than one year of age [90+(2  age in years); Adelson et al., 2003b] appears to be particularly helpful for the clinical practice. Arterial hypotension should always be treated immediately using infusion therapy and if necessary vasopressor agents such as norepinephrine. Fluid resuscitation should usually be started with an isotonic crystalloid solution (e.g. Ringer’s). Colloid solutions (e.g. albumin, hetastarch) can be added if hypotension persists. Hypertonic saline might be useful for fluid resuscitation in children with hypovolemic shock. However, further clinical data are needed before the use of hypertonic saline in children can be recommended (Doyle et al., 2001). In contrast, hypotonic solutions, e.g. 5% glucose or Ringer’s lactate may increase the risk of cerebral edema due to intracellular fluid accumulation thereby worsening neurologic outcome after TBI in children (Kaieda et al., 1989). Management of the ICP ICP can increase due to formation of brain edema, intracerebral hemorrhage, or as a result of cerebrospinal fluid stasis. Increased ICP presents a major complication

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after TBI and significantly raises mortality among patients (Adelson et al., 2003c; Alberico et al., 1987). An elevated ICP compromises CBF and increases the risk of brain ischemia, especially in injured areas after TBI. Thresholds describing critically elevated ICP, which requires therapeutic interventions, have not been determined for children so far. Physiologic ICP in children is usually lower than in adults. It is considered adequate to start treatment in infants with an ICP above 15 mm Hg, in young children ICP intervention is indicated when ICP raises above 18 mm Hg, and in all other children if ICP is higher than 19 mm Hg (Adelson et al., 2003c). This approach is supported by clinical studies, indicating that the neurologic outcome after TBI in children is improved if ICP is kept below 20 mm Hg (Esparza et al., 1985; Sharples et al., 1995). Nevertheless, the decision to therapeutically lower ICP always has to be based on appropriate clinical evaluation, taking into account the entire data set available, e.g. the calculated CPP (Adelson et al., 2003c). Therefore, it is strongly suggested to perform ICP monitoring in all children at risk for ICP increase as a result of a severe head injury. Drainage of venous blood from the head can be improved by elevating the upper part of the body including the head up to about 301 with the head in a neutral position (Fig. 1). As a result ICP may be lowered, due to a decreased intracranial blood volume. Elevation of the head by more than 301, in contrast, might compromise arterial CBF and even cause brain ischemia in adults (Feldmann, 2002). Care should be taken to maintain adequate MAP when the patient’s position is changed, especially in hypovolemic patients or in patients under the influence of vasodilating drugs, e.g. volatile anesthetics during surgical intervention. Additionally, there is no published evidence to suggest a specific level of upper body elevation that is both, effective and safe for the use in traumatized children. In general, elevation of the head should be regulated according to the actual CPP. Arterial blood pressure modules should always be calibrated to the level of the skull base in patients with upper body elevation, to ensure measurements reflecting actual arterial blood pressure to the brain. All children with severe head injury should receive sedation and analgesia to reduce stimulation of the sympathetic nervous system during therapeutical manipulations, e.g. surgery, or positioning (Fig. 1) (Adelson et al., 2003d). Sympathetic stimulation may result in hypertension and an increasing ICP. Painful or stressful stimulation can increase cerebral metabolic rate (Rehncrona and Siesjo, 1981). Muscle paralysis should be considered in order to avoid coughing at any time. Coughing may rapidly increase ICP, thereby imposing a significant risk of herniation of the brain, especially when ICP is already critically elevated. However, the

benefits of long-term muscle paralysis (424 h) must be balanced against potential detrimental effects, e.g. the increased risk of pulmonary infection and the deterioration of compliance of the respiratory system in ventilated children after TBI (Biswas et al., 2002; Schindler et al., 1996). Surgical intervention Today, direct ICP-monitoring using designated intracranial measurement devices is considered of paramount importance for an individualized treatment regime based on pathophysiologic rationale in children after severe TBI. A catheter placed into the lateral ventricle in addition may allow continuous drainage of cerebrospinal fluid, thereby providing a direct means to reduce ICP, as well as early detection of intracranial hemorrhage in some cases prior to the appearance of neurological symptoms (Adelson et al., 2003e). The benefits of recently introduced techniques to determine local brain tissue oxygen content or local brain metabolism by, e.g. intracranial placement of specifically designed O2-probes or microdialysis catheters, is still under debate (Hutchinson et al., 2002a; Steiner et al., 2003). The respective data collected with these techniques only reflect very limited areas of the brain, and therefore may be not able to indicate detrimental conditions in other regions at risk for secondary brain injury (Hutchinson et al., 2002a, b). However, less invasive and more global monitoring techniques, e.g. jugular catheters to measure the oxygen saturation in the venous outflow of the whole brain (SjO2), may not be sensitive enough to allow identification of regional cerebral ischemia, which typically occurs after TBI and, if untreated, results in secondary brain injury (Gupta et al., 1999; Steiner et al., 2003). Subdural hematoma has an incidence of about 25% in children after TBI and presents the most common type of post-traumatic intracranial hemorrhage. While small hemorrhages can usually be treated conservatively under close monitoring, larger bleedings that may result in critically increased ICP typically require immediate surgical evacuation to protect the child from excessive secondary brain injury. However, clinical evidence showed that the long-term neurologic outcome after post-traumatic acute subdural hemorrhage is poor (Ewing-Cobbs et al., 1998; Herrera et al., 2000), but even in children without intracranial bleeding long-term neurological outcome is still poor and mortality is high, despite advances in different pharmacological strategies to lower ICP (Adelson et al., 2003i; Hejazi et al., 2002; Koskiniemi et al., 1995). Most children benefit from initial therapy after severe TBI, but in some of them neurologic status suddenly deteriorates dramatically due to excessive brain edema formation, which does not respond to any conservative

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treatment strategy. Clinical as well as experimental evidence suggest that in these children a decompressive craniectomy (DC) may be considered to prevent acute herniation and subsequent brain death (Adelson et al., 2003i; Hejazi et al., 2002; Kontopoulos et al., 2002). A few studies have suggested a trend towards a better longterm neurological outcome when DC was performed in children after severe TBI (Hejazi et al., 2002; Kontopoulos et al., 2002; Taylor et al., 2001). At present, the optimal time window for DC is still undetermined. Clinical evidence, although very limited as of today, suggests that performing DC as early as possible, but no later than 12–24 h after TBI may result in a more favorable outcome in infants and small children compared to a delayed approach (Adelson et al., 2003i; Gaab et al., 1990; Hejazi et al., 2002). However, DC is a rather aggressive intervention and carries significant risks as it may, e.g. result in further increase of cerebral edema, upward cerebral herniation (especially after circumferential craniectomy) and venous compression at the edge of the craniectomy (Clark et al., 1968; Hejazi et al., 2002). According to the limited clinical experience with DC at present, the most recent guidelines for the treatment of infants and children with severe TBI (Adelson et al., 2003i) suggest to consider this intervention in patients with secondary diffuse brain swelling and an evolving cerebral herniation syndrome, who prior to surgery did not present with sustained ICP elevation (440 mm Hg) or evidence of profound brain damage (GCS=3). Osmotherapy Today, mannitol is considered the gold standard for the treatment of elevated ICP in children with TBI (Adelson et al., 2003f; Segal et al., 2001). Effective doses range from 0.25 to 1 g/kg body weight (Adelson et al., 2003f). Surprisingly, despite its wide acceptance mannitol has not yet been subjected to large controlled clinical trials (Adelson et al., 2003f). Mannitol increases serum osmolality, shifting fluid from the extracellular space into the blood vessels, thus decreasing tissue volume. Subsequently, fluid is eliminated from the circulation due to osmotic diuresis. This mechanism allows reducing brain edema within 15–30 min after administration. Mannitol can be applied at 4–6 h intervals or as necessary to treat increased ICP levels. However, use of mannitol in patients after TBI may need to be re-evaluated. In a recent retrospective study on 136 children, admitted with TBI, therapeutical application of mannitol was associated with a prolonged hospital stay. Survival was not ameliorated, nor was neurologic outcome improved with application of mannitol (White et al., 2001). Furthermore, mannitol may accumulate in injured brain regions after prolonged administration. This may induce a reverse osmotic shift with fluid shifting from the intravascular compartment

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into brain parenchyma, causing edema and possibly increasing ICP (Kaieda et al., 1989). Hypertonic saline has recently been introduced to treat elevated ICP in adult patients with severe head injury (Doyle et al., 2001). Unfortunately, data from controlled clinical studies in young children with TBI are not available at present. Hypertonic saline solutions appear to be equal to, if not more effective then mannitol in controlling ICP (Doyle et al., 2001). Similar to mannitol, hypertonic saline creates an osmotic gradient between intra- and extracellular spaces, which results in a mobilization of water into blood vessels. Other benefits include improved hemodynamic stability through enhancement of cardiac output, a decrease in overall fluid requirements, improvement in CBF and immunomodulatory effects (Angle et al., 1998; Doyle et al., 2001; Noppens et al., 2002). However, a rebound phenomenon has been reported when hypertonic saline was mixed with other hypertonic fluids such as mannitol. It has been suggested that an accumulation of these molecules in the extravasal space, may create a reversed osmotic gradient. Other possible side effects include central pontine myelinolysis and subarachnoid hemorrhage (Doyle et al., 2001; Qureshi and Suarez, 2000). Even though recent studies showed a promising effect of hypertonic solutions in reducing elevated ICP and these solutions are already used on a routine base during resuscitation of adult patients with hemorrhagic shock and TBI in several countries (Doyle et al., 2001), they cannot yet be considered a first line treatment in children and should only be used with great caution in pediatric patients with increased ICP after TBI (Adelson et al., 2003f).

Second tier therapeutic interventions Hypothermia Several studies have shown that hyperthermia can increase secondary brain injury after TBI (Selden et al., 2003), and the specific detrimental effects of increased brain temperature are discussed in more detail elsewhere in this issue of the journal (‘‘Cerebral Hyperthermia’’). In contrast, there is some evidence that hypothermia improves neurological outcome in adult patients after transient cerebral ischemia (Hypothermia after Cardiac Arrest Study Group, 2002; Polderman et al., 2002). Little is known about the effects of hypothermia in brain-injured children. There is evidence that mild hypothermia (32–34 1C) initiated within 6 h after head trauma combined with other strategies for treating intracranial hypertension may be beneficial in children (Biswas et al., 2002). However, more research is needed to determine the optimal temperature range and to further analyze efficacy and safety of therapeutic

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hypothermia in small children (for more details see Fritz and Bauer, this volume).

Barbiturate coma High-dose barbiturates have long been known to be neuroprotective because they can reduce cerebral metabolism by up to 50%, and, among other effects, were shown to reduce free radical mediated lipid peroxidation (Demopoulos et al., 1980; Kassell et al., 1980). Barbiturates have been effective in reducing elevated ICP when other therapeutic measures (e.g. hyperventilation, mannitol administration) had failed (Eisenberg et al., 1988; Pittman et al., 1989). An effective loading dose of 10–20 mg/kg is usually associated with a burst (10–20 s) suppression EEG (Nordby and Nesbakken, 1984). However, there are also reports that barbiturates worsened the clinical status of patients after TBI (Cruz, 1996). Barbiturates may induce systemic hypotension because they can cause myocardial depression. Therefore, treatment of intracranial hypertension using high-dose barbiturate is only suggested for patients that are hemodynamically stabile, when other pressure lowering strategies have failed (Adelson et al., 2003h). Online hemodynamic monitoring is highly recommended when barbiturates are used in traumatized patients. Prolonged therapy using high-dose barbiturates has also been associated with an increased rate of serious systemic infections and increased mortality (Loop et al., 2003). Once again, no clinical studies have evaluated therapeutic administration of high-dose barbiturates to children after TBI, thus, at present, this therapeutical strategy cannot be recommended without limitations.

Steroids In the past, animal studies showed a positive effect of steroids after TBI, which suggested, that these effects may also be reproducible in humans (Park, 1998). However, studies have failed to show that steroids lower ICP or improve neurologic outcome in humans (Adelson et al., 2003j; Fanconi et al., 1988; Kalkum and Gaab, 2002). Some studies even revealed an increased complication rate in adult patients after TBI that has been related to an increased rate of infection or a suppression of endogenous cortisol (Fanconi et al., 1988). Several studies were conducted in a small number of patients only and outcome parameters were not comparable. None of the clinical studies specifically addressed the use of steroids in children after TBI. Thus, further investigations are needed to clarify risks and benefits of therapeutical steroids until recommendations can be given to whether they should be included in the treatment of pediatric head trauma patients (Adelson et al., 2003j; Alderson and Roberts, 1997).

Anticonvulsants Seizures have been shown to deteriorate neurologic outcome after various insults in immature brain, possibly due to their increasing of brain metabolism at times of decreased substrate availability (Brambrink et al., 1999a, b). Anticonvulsants have been used for several years in patients with severe head injury. In children, anticonvulsant treatment is used to prevent early seizures and reduce the risk of chronic epilepsy (Ben-Ari, 1985; Chang and Lowenstein, 2003), although there is only little evidence for the latter (Iudice and Murri, 2000). So far, no study was able to demonstrate effectiveness of this prophylaxis in reducing secondary brain injury in children after TBI.

Conclusions Treatment of pediatric victims of TBI should always focus on adequate oxygenation and hemodynamic stability. If increased ICP is suspected sedation, analgesia and neuromuscular blockade are indicated and mild to moderate hyperventilation, hyperosmolar therapy (e.g. mannitol) or surgical intervention including cerebrospinal fluid drainage should be considered. If ICP elevation persists moderate hypothermia, barbiturate coma or short-term moderate hyperventilation (Fig. 1) may be applied as second tier therapeutic interventions. Intracranial bleeding resulting in elevated ICP needs to be surgically evacuated and in a situation where ICP increase is unresponsive to conventional therapeutical means, decompression craniectomy may be considered to prevent acute brain herniation. The clinical management of children with severe TBI requires a team approach in a hospital specialized for the treatment of severely injured children. The team should include specialists familiar with traumatized pediatric patients, such as pediatric neurosurgeons, pediatric anesthesiologists and specialized emergency physicians. Further studies should be initiated to establish evidence for the treatment strategies discussed in this review.

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