1393CHAPTER 118 Traumatic Brain Injury saline as a first tier therapy to target ICP in severe pediatric TBI A number of studies also used other approaches to the administra tion of hypertonic saline,[.]
CHAPTER 118 Traumatic Brain Injury saline as a first-tier therapy to target ICP in severe pediatric TBI A number of studies also used other approaches to the administration of hypertonic saline, in over 130 patients—primarily by continuous infusion Fisher and coworkers120 compared 3% saline solution and 0.9% saline solution in children with severe TBI During the 2-hour trial, hypertonic saline solution was associated with a lower ICP The serum sodium level increased mEq/L after 3% saline therapy Khanna and associates196 reported a prospective study of 3% saline solution (514 mEq/L) given on a sliding scale to maintain ICP less than 20 mm Hg in children with resistant intracranial hypertension A reduction in ICP and an increase in CPP were noted with 3% saline solution The mean highest serum sodium level and osmolarity were about 170 mEq/L and approximately 365 mOsm/L, respectively Sustained hypernatremia and hyperosmolarity were generally tolerated Acute renal failure developed in two patients Peterson and colleagues189 reported a retrospective study on the use of a 3% saline solution infusion titrated to reduce ICP to 20 mm Hg or less in infants and children with TBI The mean daily doses of hypertonic saline solution ranged from between 11 and 27 mL/kg per day A control group was not used, but only three patients died of uncontrolled ICP and 73% of patients had a good or moderate outcome Rebound in ICP or other adverse effects were not seen Since the last edition of this textbook, support for the use of 23.4% saline as one of the level III second-tier treatment options for pediatric refractory intracranial hypertension has also emerged The suggested dose is 0.5 mL/kg, with a maximum of 30 mL.197 How hypertonic saline fits into the full spectrum of second-tier treatment options for refractory ICP is discussed later Theoretic concerns associated with use of hypertonic saline solution include development of extrapontine myelinolysis (EPM), rapid shrinking of the brain associated with mechanical tearing of bridging vessels, leading to subarachnoid hemorrhage, renal failure, and rebound intracranial hypertension.198 EPM is related to central pontine myelinolysis (CPM) but occurs with hypernatremia or its correction It is characterized by demyelination of the thalamus, basal ganglia, and cerebellum.199 Neither EPM nor CPM has been reported in human trials of hypertonic saline solution for treatment of TBI EPM has been reported in dehydrated children with serum sodium levels of 168 to 195 mEq/L, and CPM has been reported with rapid correction of chronic hyponatremia.200 Peterson and colleagues189 performed MRI evaluations in 11 patients in their study, and none had evidence of CPM However, rats with normal serum sodium levels subjected to increases of 39 mEq/L showed severe demyelinating lesions.201 Similarly, subarachnoid hemorrhage has been reported with serum sodium concentrations from 149 to 206 mEq/L within hour after injection of 9% hypertonic saline solution in normal kittens.202 Renal failure is a concern with use of hyperosmolar therapies203 but seems uncommon with hypertonic saline solution use in children after TBI, although studies have not used contemporary definitions of renal failure or renal biomarkers.189,190 Rebound intracranial hypertension has been described with use of hypertonic saline solution bolus therapy or after cessation of continuous infusion.189,204 As with mannitol therapy, if the BBB is breached, one would also expect that CSF levels of sodium would increase with prolonged therapy Patients may require progressive increases in infusion rates to control ICP Gonda and associates205 reported that serum sodium levels greater than 170 mEq/L were associated with a higher occurrence of thrombocytopenia, renal 1393 failure, neutropenia, and acute respiratory distress syndrome after controlling for key confounding variables in 88 children with raised ICP Thus, caution is indicated in refractory cases; multiple therapies to control ICP rather than advancing hypertonic saline to higher risk levels should be strongly considered Given all of the evidence, hypertonic saline solution, mannitol, and CSF drainage are first-tier therapies for raised ICP after severe TBI in infants and children Sedation Analgesia and Neuromuscular Blockade Sedation and neuromuscular blockade should be used as needed in the setting of raised ICP once appropriate monitoring has been established and thus have been integrated into first-tier treatment Narcotics, benzodiazepines, or small doses of barbiturates are generally recommended for routine use However, since the last edition of this textbook, Shein et al.195 reported that for ICP crises (.20 mm Hg), bolus administration of 3% saline outperformed bolus fentanyl administration Welch et al.206 studied 31 children with severe TBI and noted that bolus administration of fentanyl, midazolam, or their combination all failed to reduce ICP and noted a paradoxical increase The current guidelines recommendation is thus against bolus dosing of these agents as the first choice for raised ICP—recognizing, however, that the results of those studies assumed that adequate analgesia and sedation were in place An ICP spike may result from inadequate analgesia or sedation; in that setting, additional analgesics or sedatives are indicated Hsiang and colleagues207 reported on 514 adults with severe TBI and suggested that prophylactic neuromuscular blockade was associated with increased length of ICU stay and nosocomial pneumonia However, the study was not prospective and should not preclude the use of neuromuscular blockade in pediatric TBI A systematic review on the use of neuromuscular blockade in adults identified a number of small studies showing benefit on various aspects of ICP care, including preventing increases in ICP during tracheal suctioning or on spontaneous ICP spikes Thus, use of neuromuscular blockade is at the discretion of the treating physician.3,4,208 Careful assessment of ongoing indication is essential Finally, intermittent doses of barbiturates or lidocaine may be needed to blunt excessive rises in ICP resulting from routine patient care maneuvers, such as suctioning Additional studies are urgently needed Head Position Feldman and colleagues209 conducted a prospective RCT of the effect of head position on ICP, CPP, and CBF in 22 adults after severe TBI Both ICP and carotid pressure were reduced in the 30-degree versus 0-degree position CPP and CBF did not change with this intervention In general, the 30-degree head-elevated position reduced ICP without deleterious effects on CPP and thus is preferred.3 Head elevation and midline position improve jugular venous and possibly CSF drainage and reduce the contributions of these components to ICP Treatment of Intracranial Hypertension: Second-Tier Therapies Refractory intracranial hypertension occurs in 20% to 40% of cases of severe pediatric TBI and is associated with mortality rates of 30% to 100%.169–172,175–177,193,210,211 Several second-tier therapies are available for treatment of refractory intracranial hypertension, as outlined in the latest guideline algorithm (Fig 118.12).4 Second-tier therapies include barbiturates, hyperventilation, 1394 S E C T I O N X I I Pediatric Critical Care: Environmental Injury and Trauma ↑ ICP Refractory to first tier therapies Repeat CT scan (if surgical option is being considered) Surgery as indicated YES New or expanding surgical lesion Consider additional advanced neuro-monitoring • EEG • TCD • PRx • CBF NO Surgical intervention: Remove mass lesion and/or decompressive craniectomy1 Moderate hypothermia3 32-34°C Barbiturate infusion2 Hyperventilation4 28-34 mmHg Higher levels of osmolar therapy5 1Salvageable patient and evidence of expanding mass lesion or swelling on CT EEG and no medical contraindications 3No contraindications 4Strongly consider advanced neuro-monitoring for ischemia 5Advance dose of 3% saline or mannitol, or use bolus 23.4% saline If possible, avoid serum sodium concentrations of >160 mEq/L and serum osmolarity of >360 mOsm/L 2Active • Fig 118.12 Bedside algorithm to guide second-tier therapies to treat refractory intracranial hypertension in severe pediatric traumatic brain injury (TBI).4 This evidence- and consensus-based document that accompanied the third edition of the guidelines represents the treatment options when tier approaches are inadequate These therapies may be applied singly, serially, or in combinations In addition, as shown, management of refractory intracranial hypertension in the second-tier phase may be aided by advanced monitoring CBF, Cerebral blood flow; CT, computed tomography; EEG, electroencephalogram; ICP, intracranial pressure; PRx, pressure reactivity index; TCD, transcranial Doppler ultrasonography hypothermia, decompressive craniectomy, and advancing osmolar therapy to higher levels.4 Barbiturates Barbiturates reduce ICP via a decrease in cerebral metabolic rate Although an RCT of barbiturate therapy for severe TBI in adults did not show an outcome benefit,212 it can be effective in the setting of refractory raised ICP.213 Goodman and coworkers214 reported an improvement in brain interstitial concentration of lactate and glutamate accompanying a reduction of ICP in adults treated with barbiturates for refractory intracranial hypertension Mellion and colleagues215 published additional supportive data for the use of high-dose barbiturates after severe TBI in 36 children with refractory raised ICP Of the 36 patients, 10 responded with control of ICP (,20 mm Hg) Control of refractory ICP was associated with better long-term outcome If either frequent dosing or barbiturate infusion is used, an electroencephalogram (EEG) should be used to assess the response to treatment The end point of barbiturate coma is generally burst suppression Pentobarbital often is infused to achieve a burst suppression response on EEG However, that goal should only represent the maximal barbiturate dose used for ICP control because (1) smaller doses— those still associated with EEG activity—may be adequate to control ICP, and (2) indiscriminate use can be associated with undesirable adverse effects, such as hypotension, which should be prevented.216 Patients should be carefully monitored for reduced cardiac output or inadequate systemic perfusion, as clinically indicated Hyperventilation Hyperventilation has been used to manage pediatric patients with severe TBI since the 1950s.217 Bruce and colleagues24 suggested that hyperemia was the predominant mechanism involved in the development of raised ICP in children Until the mid-1980s, prophylactic hyperventilation was the standard of care In addition to reducing postinjury hyperemia, hyperventilation was suggested to reduce brain acidosis and restore CBF autoregulation Subsequently, studies in experimental models suggested that hyperventilation had deleterious effects Prophylactic hyperventilation depletes brain interstitial bicarbonate buffering capacity and is accompanied by a gradual loss of local vasoconstrictor effects.218 In an RCT in adults after severe TBI, prophylactic hyperventilation for days to a Paco2 of about 25 mm Hg versus about 35 mm Hg was associated with worse outcome.219 Skippen and colleagues220 reported that hyperventilation to a Paco2 of about 25 mm Hg reduced CBF to levels less than 18 mL/100 g per minute in 73% of infants and children with severe TBI (Fig 118.13) Coles and associates154 found similar results in adults However, neither of these studies assessed the effect of hyperventilation on regional cerebral metabolism or neurologic outcome In experimental TBI CHAPTER 118 Traumatic Brain Injury CBF 1395 CBF • Fig 118.13 Xe-enhanced cerebral blood flow (CBF) maps from a child with severe traumatic brain injury before (left) and after (right) escalation of hyperventilation (a second-tier therapy) in the scanner Intact reactivity of CBF to change in partial pressure of arterial carbon dioxide is demonstrated by an obvious reduction in flow CBF ranges from lowest (darkest image) to highest (brightest image) in rats, aggressive hyperventilation (Paco2 ,20 mm Hg) early after injury increased hippocampal cell death The most recent pediatric guidelines recommend that prophylactic hyperventilation (Paco2 ,30 mm Hg) should be avoided in the initial 48 hours after injury, and that if it is used to control refractory intracranial hypertension, advanced neuromonitoring may be considered.3 Supporting this approach in infants and children, early after severe TBI, hypoperfusion rather than hyperemia is associated with poor outcome.25 However, the risks of hyperventilation are still somewhat controversial Diringer and colleagues163 reported that, between and 14 hours after severe TBI in adults, hyperventilation (Paco2 ,30 mm Hg) reduced CBF but did not further reduce CMRO2 as assessed using PET This suggests that in TBI, after the acute hypermetabolic phase, hypometabolism follows and hyperventilation may be a relatively safe means to reduce ICP This study did not evaluate outcome In contrast, several reports in adults suggest deleterious effects of hyperventilation after TBI, including increases in brain interstitial levels of glutamate and lactate221 and higher ischemic brain volumes.222 Based on these data, there is waning support for the use of hyperventilation At Pittsburgh Children’s Hospital, with the addition of PbtO2 monitoring, when ICP is controlled but PbtO2 is less than 20 mm Hg, we have found that careful limitation of even mild hyperventilation can, in some cases, promptly increase PbtO2 In the last edition of this textbook, several studies indicated that, despite two editions of the pediatric TBI guidelines recommending against prophylactic hyperventilation in the management early after injury, its use was still commonplace It was suggested that it may be time to set the alarm threshold for Paco2 in the management of severe TBI in children or for a practice bundle.223–226 However, results of the recent Pediatric Guideline Adherence and Outcomes (PEGASUS) study suggest that adherence to this recommendation is improving.227 Nevertheless, its use as adjunct treatment of refractory raised ICP, particularly during the delayed postinjury phase, continues to be supported as a second-tier therapy in the guidelines.3,4 Based on the current state of knowledge, if hyperventilation (Paco2 ,30 mm Hg) is used to manage refractory ICP, advanced neuromonitoring—such as assessment of PbtO2, CBF, or jugular venous oxygen saturation—is recommended to prevent iatrogenic ischemia Finally, the optimal approach to ventilation is one of the aims of the ADAPT comparative effectiveness trial Thus, additional information should be forthcoming from that important multicenter investigation Hypothermia In experimental models of TBI and in some clinical trials in adults after TBI, hypothermia improved outcome, presumably via multiple mechanisms, and meta-analyses supported its use in adults with severe TBI.228–230 However, unlike the case in hypoxicischemic encephalopathy (HIE) in newborns, RCTs of hypothermia targeting a temperature of about 33°C for 24 or 48 hours in children225,231 failed to show benefit Hutchison and colleagues,225 in a study of 225 children randomly assigned to hypothermia versus normothermia for 24 hours, observed a trend toward worse outcomes and increased mortality with hypothermia treatment A subsequent trial by Adelson and colleagues of 48 hours of moderate hypothermia with slow rewarming was stopped because of futility.231 These trials indicate that prophylactic hypothermia should not be routinely used as a first-tier therapy for severe TBI in infants and children, which is a new level II recommendation in the guidelines.3 In contrast, hypothermia remains useful as a second-tier therapy for the management of refractory intracranial hypertension after severe TBI, which level III guidelines support.3,4,232,233 Unlike studies showing benefit from transient use (12–24 hours) of mild hypothermia (33°C) or targeted temperature management in adults after cardiac arrest,234–236 a variety of temperature ranges are necessary to control ICP Thus, a titrated approach to use of 1396 S E C T I O N X I I Pediatric Critical Care: Environmental Injury and Trauma hypothermia in this setting is suggested.232,233 Rewarming should be carried out carefully, at a rate no faster that 1°C every hours— or even more slowly—and great care should be taken to monitor and treat hypotension that can occur with peripheral vasodilation during rewarming Finally, hyperthermia is extremely deleterious in experimental models of TBI, exacerbating neuronal death This effect is seen even when a brief 3-hour period of clinically relevant hyperthermia (39°C) is applied Natale and colleagues237 supported the clinical relevance of this work by showing that early hyperthermia (38.5°C within the first 24 hours of admission) occurred in 29.9% of pediatric TBI patients and was associated with poor outcome and increased length of stay The most definitive clinical study on this matter is in the area of perinatal HIE, where just 1°C of hyperthermia after HIE was associated with a deleterious effect on long-term outcome.238 Care should be taken to treat or prevent hyperthermia after severe TBI Decompressive Craniectomy Another controversial area in the management of both adults and children with refractory intracranial hypertension is the use of decompressive craniectomy Cushing239 initially described this modality in 1905 Decompressive craniectomy is a therapy that is based on the complex metabolic demands of the brain and the equally complex but poorly understood adverse effects of many of the therapies used to treat refractory intracranial hypertension (ischemia, hyperosmolality, metabolic suppression, and hypotension) This simplistic approach may have merit Several pediatric studies have been performed Cho and colleagues240 reported on the use of decompressive craniectomy versus medical management for treatment of infant victims of AHT with refractory intracranial hypertension Although the series was small, they reported an improved outcome compared with medical therapy, with some survivors showing good outcome This is one of the few studies of treatments in patients with AHT Polin and associates241 reported on the use of extensive bifrontal decompressive craniectomy to treat 35 adults and children with severe TBI and either refractory intracranial hypertension or diffuse edema on CT scan They reported a favorable percentage of survivors with good or moderate disability (improved outcome versus retrospectively matched cases from the Traumatic Coma Data Bank) and suggested a 48-hour time window for successful use However, the patients in this report generally were not treated with either CSF drainage or barbiturates Taylor and colleagues242 reported on an RCT of early decompressive craniectomy versus standardized medical management alone Although the sample size was limited (n 27 children), strong trends toward reduced ICP and improved long-term outcome were seen with decompressive craniectomy Jagannathan and coworkers243 reported 81% favorable outcome in 23 children with severe TBI treated with decompressive craniectomy Cooper and associates244 reported on an RCT of decompressive craniectomy in 155 adults with diffuse TBI and intracranial hypertension refractory to first-tier therapy—the DECRA trial Although craniectomy reduced intracranial hypertension versus standard care, surprisingly, it was associated with more unfavorable outcomes Patients with mass lesions were excluded in this trial; thus, it informs us only on patients with diffuse injury Nevertheless, it certainly argues against prophylactic decompressive craniectomy in that population In 2016, the results of the RESCUEicp trial were published.245 RESCUEicp targeted testing of the impact of the application of decompressive craniectomy offered as a second- or last-tier therapy RESCUEicp, unlike the DECRA trial, included patients with intracranial hematoma (evacuated or nonevacuated) and included unilateral decompression as one of the surgical options In RESCUEicp, decompressive craniectomy in adults with refractory intracranial hypertension after severe TBI reduced mortality by 22% but resulted in higher rates of vegetative state and severe disability than medical management Unfortunately, in addition, the rates of moderate disability and good recovery did not differ between groups Decompressive craniectomy thus remains a second-tier treatment option with level III evidence that is used with varying frequency depending on local experience and the discretion of the management team.3,4 Other Therapies for Refractory Intracranial Hypertension There are several other approaches to treating refractory intracranial hypertension that did not have sufficient support to include in the most recent guidelines but are occasionally used.3 Lumbar CSF drainage was supported at a level III of evidence in the second edition of the guidelines but was not recommended in the third edition If it is used, to avoid the risks of herniation, the patient must have open basal cisterns and no mass effect or shift and a functional ventriculostomy already in place.246,247 A second controversial approach is the use of induced hypertension—that is, raising CPP to a higher level with pressor support Whether pressure autoregulation of CBF is intact or defective, arterial hypotension or inadequate CPP must be avoided If pressure autoregulation is impaired, CBF is directly related to CPP and hypotension reduces flow If pressure autoregulation is intact, as CPP is reduced, reflex cerebral vasodilation occurs (to maintain flow), which increases CBV and ICP.248 This latter phenomenon occurs as CPP is reduced within the autoregulatory range Based on the relationship among CPP, vessel diameter, CBV, and ICP in selected adults with refractory intracranial hypertension, induced arterial hypertension (CPP increased in adults to between 100 and 140 mm Hg via infusion of phenylephrine) reduced ICP.248 However, arterial hypertension reduces ICP only when pressure autoregulation of CBF is intact because a hypertension-mediated reduction in vessel caliber reduces CBV (to maintain a constant flow) and thus reduces ICP Use of this intervention is complex in pediatric TBI because a single general threshold value of CPP is not applicable Management must be tailored to each individual patient It is possible that the aforementioned PRx approach could help guide this intervention.72 Also, the effect of the greater hydrostatic pressure on the development of cerebral edema is unclear Optimal management of blood pressure after severe TBI requires both monitoring of the involved factors and an in-depth understanding of the mechanisms.248 Induced hypertension is a controversial last-ditch therapy that is not addressed in either version of the pediatric guidelines.3 Finally, a few groups managing adults with severe TBI have adopted a very different therapeutic approach to blood pressure and ICP management termed the Lund concept This includes aggressive control of ICP with the unusual combination of b-blockade, a2-receptor agonists, ergotamine, and barbiturates, with avoidance of systemic hypertension.249 In some sense, this represents a form of chemical hyperventilation— that is, a pharmacologically controlled reduction in CBV Remarkably, this approach has produced good outcome data and no exacerbation of ischemia, as assessed using intracerebral microdialysis in adults.250 A report of this approach to ICP control in children with TBI is available.251 This approach requires additional study in children CHAPTER 118 Traumatic Brain Injury Miscellaneous Seizures should be treated aggressively because excessive metabolic demands in the setting of hypoperfusion could result in a second insult to an already compromised brain Vespa and colleagues252 in 20 adults with severe TBI showed that posttraumatic subclinical status epilepticus was associated with a considerable burden in raised ICP and long-lasting increases in the brain interstitial lactate/pyruvate ratio—a marker of ischemia This finding has heightened interest in this area and suggests the consideration of continuous EEG monitoring in pediatric TBI We use continuous EEG in all severe TBI patients in our center in Pittsburgh The pediatric guidelines support the use of prophylactic levetiracetam or fosphenytoin as a treatment option to prevent early posttraumatic seizures in severe TBI with level III evidence.3 Prophylactic anticonvulsant use, however, has not been shown to improve outcome either acutely or in the prevention of the late development of epilepsy Additional anticonvulsants are recommended to be given as needed to treat seizures Even if hypertonic saline solution is not used as a therapy, careful attention should be paid to the serum sodium level It should be monitored at least twice daily in children with severe TBI To prevent the development of hyponatremia, we recommend using 0.9% normal saline solution as the initial intravenous fluid for children with severe TBI For infants, 5% dextrose normal saline solution can be used Hyponatremia that develops while only isotonic fluids are being administered generally can be attributed to either syndrome of inappropriate antidiuretic hormone secretion or cerebral salt wasting.253 Care should be taken to determine the correct cause of hyponatremia because the management of syndrome of inappropriate antidiuretic hormone secretion involves fluid restriction, whereas that of cerebral salt wasting involves the administration of isotonic or hypertonic saline solution Hyperglycemia exacerbates experimental ischemic brain injury; threshold values greater than 200 mg/dL are generally considered as the target Similarly, countless studies have shown associations between hyperglycemia and poor clinical outcome after various CNS insults Most textbooks of adult neurocritical care recommend withholding glucose in intravenous fluids for at least 24 hours unless hypoglycemia is seen Supporting this concept, Van den Berghe and colleagues254 reported that insulin administration to control blood glucose at less than 110 mg/dL in 63 adults with isolated brain injury from various causes produced benefits with regard to ICP, CPP, and seizures However, more recent trials of tight glucose control in pediatric critical care have not been positive.255 In severe pediatric TBI, Smith and associates256 reported that exogenous glucose could be safely withheld for 48 hours after injury (mimicking the approach generally taken in cases of severe TBI in adults) with careful monitoring and the addition of dextrose if blood glucose was less than 70 mg/dL With that approach, hyperglycemia in the initial 48 hours was not associated with unfavorable outcome However, Vespa and associates,257 using intracerebral microdialysis in adults with severe TBI, reported that tight glucose control (serum glucose 90–119 mg/dL) produced a metabolic crisis in the brain (increases in glutamate and lactate/pyruvate ration) versus less rigorous glucose control (serum glucose 119–150 mg/dL) Controversy remains as to the optimal management strategy for glucose administration and control after severe TBI Glucose management is another hypothesis being addressed in the ADAPT trial; thus, additional information on this topic should be available in the future 1397 The provision of adequate nutrition is essential during the catabolic response to critical illness; beneficial effects of early feeding (either enteral or parenteral) in the critically ill or injured patient are well described In critically ill adults, a cumulative deficit of 10,000 kcal was associated with increased mortality In the PICU, this amount can be easily surpassed in less than week.258 A study using indirect calorimetry in 13 children with severe TBI by Mtaweh and colleagues,259 however, suggests that with contemporary management, equation-based estimates of energy expenditure greatly overestimate caloric needs, which were only 70% of predictions This argues against a hypermetabolic response and suggests new nutritional targets or the use of calorimetryguided nutritional support Hyperalimentation formulations containing glutamate have been shown to increase glutamate levels, possibly exacerbating excitotoxicity.260 This thus magnifies ongoing concerns in pediatric severe TBI regarding the use of early parenteral nutrition across the PICU.261 Curiously, studies in experimental brain injury suggest that starvation for 48 hours dramatically reduces ultimate damage.262 Ketosis is suggested to confer this benefit The optimal nutritional approach in severe TBI needs to be addressed Two recent studies have begun to clarify the optimal approach to nutrition in pediatric severe TBI This is reflected in the third edition of the guidelines, which now recommends in favor of initiating enteral nutritional support within 72 hours from injury to decrease mortality and improve outcomes.3 Taha et al.263 reported on a retrospective study in 90 children with severe TBI and found that the time to both initiation of enteral nutrition and full caloric support by enteral nutrition were associated with favorable outcome Subsequent to the guidelines, in a secondary analysis of the Cool Kids Trial of hypothermia in severe pediatric TBI (NCT 00222742), Meinert et al.264 reported that initiating nutritional support before 72 hours (by any means) was associated with favorable outcome This study further supports the new recommendation to start enteral nutrition within 72 hours—or at the earliest possible time When parenteral nutrition should be started remains to be defined The ADAPT trial, once again, may also help since nutritional support is another hypothesis it addresses Routine use of glucocorticoids to treat patients with severe TBI is not recommended.3 However, hypotension in the setting of severe TBI in rare cases is associated with pituitary failure, possibly from vascular disruption.265 In addition, corticosteroid use could be indicated in the setting of adrenal suppression such as from the use of etomidate for intubation or recent steroid use.265 Alterations in autonomic function characterized by tachypnea, tachycardia, hypertension, fever, dystonia, and diaphoresis may develop after TBI Paroxysmal episodes characteristically occur in response to what is normally nonpainful stimuli and recur over or more days and at least weeks from injury Alternatively referred to as dysautonomia, autonomic or sympathetic storming, brainstem attack, and over 20 other eponyms, an international group of experts recently recommended the term paroxysmal sympathetic hyperactivity (PSH) to describe this syndrome after acquired brain injury.266 Consensus criteria established in adults to aid in the diagnosis of PSH were recently applied to a retrospective cohort of children with severe TBI Of the children in that cohort, 20% met the classification of “likelihood of PSH,” which was associated with longer length of stay and discharge to an inpatient rehabilitation facility.267 Another review found that approximately 10% of children are diagnosed with dysautonomia or similar diagnoses after severe TBI; therefore, PSH may represent an underrecognized complication.268 PSH is suspected to ... hypertension in severe pediatric traumatic brain injury (TBI).4 This evidence- and consensus-based document that accompanied the third edition of the guidelines represents the treatment options... assessed using PET This suggests that in TBI, after the acute hypermetabolic phase, hypometabolism follows and hyperventilation may be a relatively safe means to reduce ICP This study did not... neuronal death This effect is seen even when a brief 3-hour period of clinically relevant hyperthermia (39°C) is applied Natale and colleagues237 supported the clinical relevance of this work by