Maximizing Survival from Severe Traumatic Brain Injury: Applying Guidelines to Clinical Practice: Part II

This issue is the second part of a discussion about severe traumatic brain injury (TBI). This topic carries some resonance with me. In addition to my professional experience, I have a personal connection to this topic. At age 16, my oldest son was in a serious motor vehicle collision. He was a passenger in the front seat of a large SUV that collided head-on with a large oak tree at more than 55 mph. Fortunately, he was wearing his three-point restraint (seat and shoulder belt) and was small in stature at the time, so as the front of the car collapsed and he was trapped, his body was not crushed. He was dazed by the events and reluctant to move, so that when the EMS arrived on scene and the paramedics were assessing the occupants (eight in total), they judged his lack of spontaneous verbal response and movement as a serious TBI. My son distinctly remembers the phrase "this one is an organ donor" being expressed regarding his condition. Thankfully, first impressions at the scene are not always predictive.

However, another occupant was more severely injured. He was unrestrained and located in the middle seat. During the collision, he was thrown forward and sustained a serious TBI. I remember that night in the ED. All eight kids were taken to my hospital because it was the regional trauma center. The 16-year-old boy with the serious head injury had diffuse axonal injury on his initial head CT and was coagulopathic on the initial prothrombin time test; both bad signs. But with aggressive care, based on evidence derived from clinical studies discussed in this series, he made a remarkable recovery over several months. Thus, I have seen recovery from severe TBI. I know it works.

And, my son sustained a clavicle and elbow fracture, escaping serious neurologic or internal injury. I used to think my teenagers did not listen to me, but somehow, in this circumstance, he did; he remembered to wear his seatbelt. Miracles, or at least pleasant surprises, do happen.

—J. Stephan Stapczynski, MD, Editor

ED Management

The prevention of secondary brain injury by correction of hypoxia and hypotension and the rapid diagnosis and evacuation of an expanding intracranial hematoma are critical determinants of outcome.1

Airway. Patients with severe TBI have a GCS of 8 or less, and serious consideration should be given to definitive airway protection. A GCS of 8 or less, however, should not in itself dictate intubation. As was previously mentioned, every permutation of GCS of 8 or less is not the same, and Davis et al. have demonstrated that a number of patients with a GCS of 8 or less do not have a head injury, but rather intoxication as the cause of their altered mental status.2-4 Davis et al. also demonstrated that a high percentage of GCS 8 or less patients without ETI are oxygenating and ventilating adequately upon hospital arrival.2,4 The issues of airway protection and control of the patient for diagnostic testing remain. As such, the decision to perform ETI should be based on the specifics of the individual case. Care should be taken to maintain cervical spine precautions when performing ETI.

ETI can lead to an elevation in ICP by a reflex sympathetic response to laryngoscopy and a cough reflex from airway manipulation.5 There are no ideal studies evaluating the effectiveness of empiric lidocaine to blunt the aforementioned reflexes, to minimize elevations in ICP, or to improve neurologic outcomes in head-injured patients. There are, however, numerous studies that suggest a benefit. Lidocaine prior to ETI has been associated with a significant reduction in catecholamine release.6 Two studies have shown that lidocaine has a positive impact on ICP during suctioning by blunting the cough reflex, and one small study evaluated ICP during elective intubations for brain surgery and concluded that lidocaine reduced the ICP by 12 mmHg.7-9 There is little evidence that lidocaine causes harm and, as such, it should be administered as a pretreatment before RSI.5 Administration should be at least 3 minutes prior to laryngoscopy at a dose in 1.5 mg/kg IV with a maximum dose of 100 mg.10 Fentanyl has been shown to diminish the rises in heart rate and blood pressure associated with laryngoscopy and intubation. Its use should be considered at a dose of 3 mcg/kg IV.11,12 Defasciculating doses of nondepolarizing neuromuscular blocking agents (e.g. vecuronium 0.01 mg/kg or rocuronium 0.06 mg/kg) prior to administration of succinylcholine blunt fasciculation-induced increases in ICP. These agents have been shown to be effective in the neurosurgical population but have not been evaluated in TBI patients.13

A number of different sedatives can be given as part of RSI, but the hemodynamic effects of these agents should be considered. The barbiturates and benzodiazepines are well known to cause hypotension.14,15 Propofol also has been associated with hypotension.16 Etomidate is an attractive option in the unstable trauma patient at a dose of 0.3 mg/kg IV as it is hemodynamically neutral. Recognition should be given to its association with vomiting, myoclonus, and adrenal insufficiency.16,17

Succinylcholine at a dose of 1.5 mg/kg IV is the most frequently used paralytic with its rapid onset and short duration of action. The use of succinylcholine is contraindicated with allergy, history of malignant hyperthermia, denervation syndromes, and patients who are 24-48 hours after burn or crush injury.18 Rocuronium at a dose of 1 mg/kg IV is an alternative when succinylcholine is contraindicated.18 The physician should be aware that it produces prolonged paralysis. A recommended RSI strategy is demonstrated in Table 1.19

In children, the dosing of RSI medications should be done using a resuscitation aid such as the Broselow- Luten system. Succinylcholine remains the first-line paralytic despite reports of hyperkalemic cardiac arrest. Rocuronium is an alternative. Given the lack of evidence and the potential risks associated with lidocaine and fentanyl use in children, these medications are not recommended in children younger than 10 years. Finally, atropine use in parallel with succinylcholine should be reserved for special circumstances, such as in infants younger than 1 year.20

Breathing. Pulse oximetry should be used for continuous oxygen monitoring, given the deleterious effects of hypoxia.21,22 Supplemental oxygen should be provided as needed. As mentioned in the prehospital section, hyperventilation has been associated with an increase in morbidity and mortality and must be avoided.23-25 After arrival in the ED, patients who are kept in a range of PaCO2 of 30-39 mmHg have a significantly better outcome than those who remained outside of this range.26 Continuous ETCO2 monitoring should be used.27

Circulation. The goal is maintenance of cerebral perfusion and avoidance of ischemia. Hypotension occurs mainly due to blood loss and shock and is associated with significantly worse outcomes.21,28 A single episode of hypotension is associated with increased morbidity and mortality, and the aggressive correction of hypotension improves outcomes.21,29-31 While the type of fluid that provides optimal resuscitation still is not established, there is no question as to the need for adequate resuscitation for hypotension.32 Intravascular volume should be maintained at a central venous pressure of 5-10 mmHg when such monitoring is available.33 The use of pressors as supplemental agents to maintain adequate brain perfusion after volume resuscitation has been supported given the sensitivity of the injured brain to even transient episodes of hypotension. Alpha agonists such as phenylephrine are preferred. They should be used with close monitoring and be discontinued as soon as possible.27

Sustained hypertension in patients with TBI may indicate an underlying serious medical condition, and treatment may be warranted. Hypertension should not be treated before ICP monitoring is initiated unless the MAP is > 120 mmHg. Short-acting agents should be used. Analgesics and anxiolytics should be used with caution, as they can precipitate hypotension.32

Brain Trauma Foundation

The following section will be organized largely in parallel with the third edition of the BTF's Guidelines for the Management of Severe Traumatic Brain Injury.23 It will be organized with emphasis on the issues most germane to emergency physicians.

Airway and Breathing. Oxygenation should be monitored and hypoxia avoided. As was mentioned in the previous section, hypoxia (PaO2 < 60 mmHg or O2 sat < 90%) should be avoided. Data from the large prospectively collected TCDB has shown that hypoxemia has a significant adverse effect on morbidity and mortality.21

Prophylactic hyperventilation is not recommended. Hyperventilation during the first 24 hours should be avoided while cerebral blood flow often is critically reduced. Hyperventilation is recommended as a temporizing measure for the reduction of ICP, and it should be done in the setting of brain oxygen monitoring. Brain swelling and an elevation of ICP develop in 40% of patients with severe TBI, and high ICP is a major cause of disability and death.34-37 The assumption follows that because hyperventilation lowers ICP, it should be good for patients with severe TBI. Unfortunately, hyperventilation decreases ICP by causing cerebral vasoconstriction with a resultant decrease in CBF, and histologic studies have shown that cerebral ischemia is found in most TBI victims who die.38-44 A randomized trial found significantly worse outcomes at 3 and 6 months when prophylactic hyperventialion was used compared to when it was not.25

It is not clear how the use of short-term hyperventilation in the setting of acute herniation impacts outcome.23 Hyperventilation will reduce ICP by 25%, with an onset of effect within 30 seconds.45 It should be viewed as a short-term life-saving intervention, should be performed to a level of PCO2 30-35 mmHg, and should only be used by an emergency medicine physician when a patient experiences signs and symptoms associated with herniation.46 It should be discontinued when symptoms improve. Hyperventilation to PCO2 levels below 30-35 mmHg should be considered second-tier therapy.27

Circulation. Blood pressure should be monitored and hypotension avoided. Both prehospital and in-hospital hypotension (SBP < 90 mmHg) have been implicated in poor outcomes.28 Data from the TCDB shows that a single prehospital episode of hypotension was among the most powerful predictors of outcome and was associated with a doubling of mortality as compared to matched controls.21 Jones et al. showed that total duration of in-hospital hypotensive episodes was a significant predictor of both morbidity and mortality.22

Cerebral Perfusion. Aggressive attempts to maintain CPP > 70 with fluids and pressors should be avoided because of the risk of adult respiratory distress syndrome. A CPP < 50 should be avoided. Adequate CPP is important for sufficient oxygenation of the brain following TBI. However, maintaining a CPP > 70 mmHg using fluids and vasopressors (induced hypertension) has been shown to increase the risk of adult respiratory distress syndrome.47 The BTF counsels against induced hypertension as an alternative to reducing ICP.23,33 The CPP should be maintained between 50–70 mmHg, and the ICP at or below 20 mmHg.23 The routine treatment of acute hypertension in TBI is not recommended.23,33 Successful management of severe TBI patients will involve managing ICP, CPP, and MAP to achieve optimal levels of each throughout the course of treatment.

Monitoring. ICP should be monitored in all salvageable patients with a severe TBI and an abnormal CT scan. ICP monitoring is indicated with a normal CT scan if the patient has two or more of the following: age > 40, motor posturing, or SBP < 90. The objective of monitoring is to maintain optimal cerebral perfusion and oxygenation and avoid secondary injury while the brain recovers. The recommended means of monitoring ICP is via an intraventricular catheter.23 While ICP monitoring typically is performed in the ICU, with ED boarding becoming increasing prevalent, emergency physicians should be aware of the recommendation. Treatment for elevated ICP should commence with an ICP > 20 mmHg.37,48-50

Jugular venous saturation and brain tissue oxygen monitoring measure cerebral oxygenation. The aforementioned devices enable measuring oxygen delivery to the brain. ED physicians should, at minimum, be aware of the use of these devices.23

Pharmacotherapeutics. (See Table 2.) Hypersomolar Therapy (Mannitol and Hypertonic Saline). Mannitol is effective for control of raised ICP. Arterial hypotension should be avoided. Restrict mannitol use prior to ICP monitoring to patients with signs of transtentorial herniation or progressive neurological deterioration (i.e., signs of elevated ICP and impending herniation) not attributable to extracranial causes. If a herniating patient is not responding to acute hyperventilation (ETCO2 30-35 mmHg), mannitol should be considered.46 Mannitol at a dose of 0.25-1.0 g/kg has become the standard for control of elevated ICP in severe head injury patients. The benefits are derived from three factors. Mannitol increases cardiac output (thereby improving CPP), it causes diuresis, and it decreases CSF production.46 The osmotic effects occur within minutes and peak about 60 minutes after administration. The duration of effect is six to eight hours.51,52 Mannitol occasionally causes a profound diuresis with subsequent systemic hypotension, and it is thought to cause rebound hypertension and increases in ICP.33 As such, other hyperosmolar agents have been evaluated to treat elevations in ICP.

Hypertonic Saline (HTS). Unfortunately, there have been few well-designed human clinical studies assessing outcomes, and at this point the impact of HTS appears to be both modest and inconclusive. In its most recently published guidelines, the BTF stated, "Current evidence is not strong enough to make recommendations on the use, concentration and method of administration of HTS for the treatment of traumatic intracranial hypertension."23 Routine use in the emergency department should be reserved for situations when it is directed by the neurosurgical team as part of local protocol.

Anesthetics, Analgesics, and Sedatives. High-dose barbiturate therapy is indicated to control elevated ICP refractory to standard medical and surgical treatment. Maintenance of hemodynamic stability is critical during barbiturate therapy. Propofol is recommended for control of ICP, but it does not improve mortality or 6-month outcome, and high-dose propofol can increase mortality. It has long been considered beneficial to control pain and agitation in TBI patients, as they might contribute to elevations in ICP. The recent BTF guidelines recognize that analgesics are commonly used for ICP control, but the guidelines caution that analgesics have not been shown to improve outcomes and that consideration must be given to the undesirable side effects.23 The use of fentanyl has been associated with decreases in MAP and rises in ICP; morphine provides limited sedation and has been associated with tachycardia and rebound rises in ICP.23,53-55

Benzodiazepines are routinely used for sedation in patients with severe TBI. It should be noted, however, that Papazian et al. found that bolus dosing of midazolam was associated with decreases in MAP and rises in ICP. CPP fell to below 50 mmHg in 33% of patients. The authors advise that midazolam should be used with great caution in patients with severe TBI.56 The BTF recommends high-dose barbiturates for ICP control when other standard medical and surgical therapies have failed, but it cautions that the potential complications mandate that its use be limited to critical care providers.23

Propofol has become widely used as a neurosedative in adults. It suppresses seizure activity and has been shown to depress cerebral metabolism and oxygen consumption, producing a theoretical neuroprotective effect. While propofol has been associated with hypotension, several studies in the brain injury population have found no significant changes in MAP and ICP with propofol infusions.57-59 It should be noted that high-dose propofol (> 83 mcg/kg/min) has been associated with increased rates of propofol infusion syndrome (lactic acidosis, arrythmias, rhabdomyolysis) and subsequent cardiovascular collapse.60

Steroids. The use of steroids is not recommended for improving outcome or reducing ICP. In patients with severe TBI, high-dose methylprednisolone is associated with an increased mortality and is contraindicated. The BTF guidelines are very clear that the majority of evidence indicates that steroids have a deleterious effect and should not be used. They go on to say there is little interest for future study.23

Prophylaxis. Seizure Prophylaxis. Anticonvulsants are indicated to decrease the incidence of early post-traumatic seizures (within 7 days of injury). The reported incidence of early post-traumatic seizures has ranged from 4-25%.23,61 In the acute phase, seizures may precipitate secondary brain injury by impacting ICP, oxygenation, and neurotransmitter release. Additionally, experimental studies have suggested that early seizures might generate a permanent seizure focus precipitating chronic epilepsy. Several retrospective studies have demonstrated the efficacy of phenytoin in preventing post-traumatic seizures.62,63 Haltiner et al. have shown that the incidence of side effects during the first two weeks of anticonvulsant therapy with phenytoin is low.64 Temkin et al. found a similar incidence of early post-traumatic seizures with both phenytoin and valproic acid, but valproic acid-treated patients had a trend toward increased mortality.65 There is no evidence that the use of anticonvulsant therapy to prevent early post-traumatic seizures improves neurologic recovery or survival.23 Given the side effect profiles of commonly used seizure medications, it is reasonable to limit their use to situations in which a seizure might compromise tenuous ICP control.27 Patients with penetrating TBI should receive early prophylaxis given the high incidence of seizures in this group.66 Benzodiazepines remain the mainstay in the management of acute seizures.67

Infection Prophylaxis. Periprocedural antibiotics should be administered to reduce the incidence of pneumonia. This recommendation is based on a single study, and there is no support for a prolonged course of prophylactic antibiotics.23 Sirvent et al. randomized 100 critically ill patients (86 of whom had severe TBI) to receive either two doses of 1.5 g IV cefuroxime within 6 hours of intubation or no antibiotics. The incidence of pneumonia in the treated group was 23% vs. 64%. There was no impact on mortality.68

While there is limited data to support the specific antibiotic type and duration of therapy, broad-spectrum prophylactic antibiotics (e.g., vancomycin and ceftriaxone) should be administered for open skull fractures, basilar skull fractures with CSF leaks, and penetrating brain injuries.27

Miscellaneous. Hypothermia. Prophylactic hypothermia is not significantly associated with decreased mortality when compared with normothermic controls. Prophylactic hypothermia is associated with higher Glasgow Outcome Scale scores when compared to scores for normothermic controls. Despite the above statement, the BTF Guidelines offer that preliminary data suggest hypothermia might positively impact mortality when it is continued for greater than 48 hours. Importantly, the guidelines also note that induced hypothermia increases the risk of infection and bleeding, a particularly important issue in the multi-trauma patient.23 Since the publication of the guidelines, a meta-analysis of eight clinical trials of adult TBI by Peterson et al. has shown a significant reduction in mortality (relative risk 0.51) and improved neurologic outcomes in patients treated for more than 48 hours with moderate hypothermia (32-33 °C). The authors note an increased risk of pneumonia (relative risk, 2.37).69 Prolonged moderate hypothermia requires further research but offers promise to prevent neuronal injury in the treatment of severe TBI.

Figure 1 is an algorithm for the management of severe TBI that incorporates the latest BTF guideline recommendations and emphasizes emergency department care.

Additional Therapies

There are several additional therapies that are not addressed by the BTF guidelines. The following section will briefly discuss these therapies.

Antipyretics. Fever is an independent predictor of poor outcome from TBI and, as such, fevers should be lowered rapidly.22,70 In patients with fever and ICH, acetaminophen typically is the agent of choice.27 Consideration should be given to cooling blankets and a fan.27 Care should be taken to determine the source of the fever and not to assume that it is neurologic in origin.

Anticoagulation Reversal Agents. Several studies have shown that anticoagulated TBI patients with a high INR have worse outcomes, and others have shown that anticoagulation reversal improves outcomes in patients with spontaneous intracranial hemorrhage.5,71-75 A prospective cohort study of 82 TBI patients treated with a warfarin reversal protocol found a lower mortality than in historical controls who were not reversed.76 Of note, follow-up work by the same authors failed to show a benefit.77 In an analysis of warfarin-associated ICH, Aguilar et al. were unable to reach consensus on the means of warfarin reversal, with experts varying in their support for fresh frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa (rFVIIa). The authors were clear that anticoagulation must be reversed and that vitamin K was inadequate.74,78-83 In summary, anticoagulation typically should be reversed, but on a case-by-case basis based on local protocol.

Great interest has developed over the use of rFVIIa for the treatment of traumatic hemorrhages. To date, there has not been a randomized controlled trial examining the efficacy of rFVIIa for the treatment of severe TBI with hemorrhage.5 A phase IIb study examined the use of rFVIIa for the treatment of spontaneous intracranial hemorrhage and showed a significant reduction in hematoma growth and mortality with improved neurologic recovery. Unfortunately, the phase III trial failed to confirm these findings.83 A subsequent subset analysis of a trial evaluating the effectiveness of rFVIIa in 143 multi-trauma patients showed no impact on standard outcomes in the 30 patients with TBI.84 There are numerous ongoing trials evaluating the utility of rFVIIa in the treatment of patients with severe TBI.5 Given its high cost and uncertain efficacy, the use of rFVIIa should be made on a case-by-case basis according to local policies and procedures.

Neuroprotective Agents. During the past 25 years, more than 20 agents have been studied in phase III clinical trials of severe TBI. As of 2007 none of these agents had shown efficacy in the overall study population.85-88

A recent review of published preclinical and epidemiological studies summarized evidence for the neuroprotective effects of progesterone following TBI.89 Animal studies show that progesterone infused shortly after TBI reduces cerebral edema, prevents neuronal loss, and improves functional outcomes.5 The ProTECT study is the first human trial (double-blind, placebo-controlled) of progesterone as a treatment in early TBI and showed no harmful effects compared to placebo and showed a nonsignificant trend toward improved outcomes.90 A more recent randomized controlled trial of progesterone has shown a beneficial effect by decreasing mortality compared to placebo.91 Ongoing studies evaluating progesterone undoubtedly will contribute significantly to our understanding of progesterone's effects following TBI.

Glucose Control. In patients with severe TBI, optimal glycemic control is indicated as in other critically ill patients. It should be noted that the injured brain does not tolerate hypoglycemia.92

Head of Bed Elevation. Head of bed (HOB) elevation to 30 degrees is recommended to lower ICP by facilitating venous drainage as well as CSF drainage through the foramen magnum. Reverse Trendelenberg can be used prior to spine clearance.27 Several studies demonstrate a reduction in ICP with the HOB elevated.5,93-96 Raising the HOB to greater than 30 degrees should be avoided prior to ICP monitoring because it can increase ICP via the effects of increased intra-abdominal pressure.27 Caution should be used in raising the HOB prior to resuscitation as it can lower blood pressure and subsequently CPP.27

Burr Holes. Burr hole drainage might be life-saving in patients herniating from an EDH. The mechanics of the procedure are considered simple enough to be performed by the willing emergency physician.27 Before operating, the emergency physician should contact a neurosurgeon for consultation and definitive care. The ultimate decision to perform this procedure clearly depends on the experience and training of the provider, the clinical situation, and the availability of neurosurgical back-up.27

Special Populations

The Pediatric Patient. During the first two years of life, abusive or nonaccidental head trauma is a leading cause of morbidity and mortality, accounting for nearly one-quarter of all pediatric hospital admissions for head injuries.97-99 Child abuse must be seriously considered in any child younger than age 4 with severe TBI.46,100 Age-related values always should be used to determine treatment parameters.103 Moderate hypothermia (32-33°C) has shown early promise as a potential therapy for pediatric TBI, but more research is needed before it should be considered standard of care.104 At present there is an ongoing Phase III randomized controlled trial called Cool Kids.105 For more details on the management of pediatric TBI, the reader is referred the Guidelines for Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children and Adolescents.106

The Elderly Patient. There is another peak in the incidence of TBI in the elderly, and falls now are the leading cause of TBI in this country.107 Preexisting conditions are common in the elderly, and injuries are more likely to be complicated by anticoagulation. Elderly patients have worse outcomes, with annual death rates of 50.6 per 100,000 population as compared to 18.1 per 100,000 in the general population.5,108,109

The Intoxicated Patient. Intoxicated patients are difficult to manage in the prehospital setting and in the emergency department. They have been shown to undergo potentially unnecessary field intubations, but care also must be taken not to attribute the entirety of their altered mental status to intoxication rather than underlying injury.2,4,110,111 Alcohol-intoxicated patients are more likely to have delays in care and worse outcomes.5,111,112 Golan, et al. demonstrated a delay of more than two hours to ICP monitoring in intoxicated patients, and Gurney, et al. demonstrated that intoxicated patients were more likely to develop pneumonia.111,112

Disposition

Patients with severe TBI should be admitted to the intensive care unit and to the neurocritical care unit when available. If your hospital does not have a trauma response system, trauma surgery and neurosurgery should be consulted early. If trauma and neurosurgical support are not available, the patient should be transported to an institution capable of providing these services.24 Transport to a level I trauma center for specialized care and the early detection and treatment of surgical lesions has been associated with a mortality benefit in multi-trauma patients and specifically in those with TBI.86,113-116 Patel and colleagues showed a doubling of the odds of death for patients with severe TBI treated in non-neurosurgical centers vs. neurosurgical centers.117 Other analyses support these findings.118-120

Summary/Bottom Line

Severe TBI is common and is associated with profound morbidity and mortality. Guideline-based care has resulted in remarkable improvements in outcomes.121-125 In order to continue to optimize outcomes, TBI guidelines must continue to evolve in accordance with the latest scientific evidence and be effectively translated into clinical practice.

References

1. Dunn J, Smith M. Critical care management of head injury. Anesthesia and Intensive Care Medicine 2008;9:197-201.

2. Davis DP, Hoyt DB, Ochs M, et al. The effect of paramedic rapid sequence intubation on outcome in patients with severe traumatic brain injury. J Trauma 2003;54:444-453.

3. Teoh LS, Gowardman JR, Larsen PD, et al. Glasgow Coma Scale: Variation in mortality among permutations of specific total scores. Intensive care medicine. 2000;26:157-161.

4. Davis DP, Vadeboncoeur TF, Ochs M, et al. The association between field Glasgow Coma Scale score and outcome in patients undergoing paramedic rapid sequence intubation. J Emerg Med 2005;29:391-397.

5. Bhat R, Hudson R, Sabzevari T. An evidence-based approach to severe traumatic brain injury. Emerg Med Practice 2008; 10:1-24.

6. Robinson N, Clancy M. In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature. Emerg Med J 2001;18: 453-457.

7. Yano M, Nishiyama H, Yokota H, et al. Effect of lidocaine on ICP response to endotracheal suctioning. Anesthesiology 1986;64:651-653.

8. Donegan MF, Bedford RF. Intravenously administered lidocaine prevents intracranial hypertension during endotracheal suctioning. Anesthesiology 1980;52:516-518.

9. Bedford RF, Winn HR, Tyson G. Lidocaine prevents increased ICP after endotracheal intubation. In: Schulman K, Mamorou I, Miller JD, eds. Intracranial Pressure. Germany: Springer-Verlaf-Berlin; 1980:595-598.

10. Wang YM, Chung KC, Lu HF, et al. Lidocaine: the optimal timing of intravenous administration in attenuation of increase of intraocular pressure during tracheal intubation. Acta Anaesthesiologica Sinica 2003;41:71-75.

11. Kautto UM, Heinonen J. Attenuation of circulatory response to laryngoscopy and tracheal intubation: a comparison of two methods of topical anaesthesia. Acta Anaesthesiol Scand 1982;26:599-602.

12. Adachi YU, Satomoto M, Higuchi H, et al. Fentanyl attenuates the hemodynamic response to endotracheal intubation more than the response to laryngoscopy. Anesthesia and Analgesia 2002;95:233-237, table of contents.

13. Schramm WM, Strasser K, Bartunek A, et al. Effects of rocuronium and vecuronium on intracranial pressure, mean arterial pressure and heart rate in neurosurgical patients. Br J Anaesth 1996;77:607-611.

14. Schneider R, Caro D. Sedative and Induction Agents. In: Walls R, Luten R, Murphy M, Schneider R, eds. Manual of Emergency Airway Management. Philadelphia: Lippencott, Williams & Wilkins; 2004:189-199.

15. Jagoda AS, Bruns J. Increased Intracranial Pressure. In: Walls R, Luten R, Murphy M, Schneider R, eds. Manual of Emergency Airway Management. Philadelphia: Lippincott, Williams and Wilkins; 2004:262-269.

16. Darrouj J, Karma L, Arora R. Cardiovascular manifestations of sedatives and analgesics in the critical care unit. Am J Therapeutics 2009.

17. Cohan P, Wang C, McArthur DL, et al. Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study. Crit Care Med 2005;33:2358-2366.

18. Walls R. Rapid Sequence Intubation. In: Walls R, Murphy M, eds. Emergency Airway Management. 3rd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008:23.

19. Jagoda AS, Bruns J. Elevated Intracranial Pressure. In: Walls R, Murphy M, eds. Emergency Airway Management. 3rd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008:353-350.

20. Luten RC, McAllister JD. Approach to the Pediatric Airway. In: Walls R, Murphy M, eds. Emergency Airway Management. 3rd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008:263-281.

21. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34:216-222.

22. Jones PA, Andrews PJ, Midgley S, et al. Measuring the burden of secondary insults in head-injured patients during intensive care. J Neurosurg Anesthesiol 1994;6:4-14.

23. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2007;24 Suppl 1:S1-106.

24. Badjatia N, Carney N, Crocco TJ, et al. Guidelines for prehospital management of traumatic brain injury 2nd edition. Prehosp Emerg Care 2008;12 Suppl 1:S1-52.

25. Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized clinical trial. J Neurosurg 1991;75:731-739.

26. Warner KJ, Cuschieri J, Copass MK, et al. The impact of prehospital ventilation on outcome after severe traumatic brain injury. J Trauma 2007;62:1330-1336; discussion 1336-1338.

27. Chesnut RM. Care of central nervous system injuries. Surg Clin North Am 2007; 87:119-156, vii.

28. Fearnside MR, Cook RJ, McDougall P, et al. The Westmead Head Injury Project outcome in severe head injury. A comparative analysis of pre-hospital, clinical and CT variables. Br J Neurosurg 1993;7:267-279.

29. Gentleman D. Causes and effects of systemic complications among severely head injured patients transferred to a neurosurgical unit. International Surgery 1992; 77:297-302.

30. Hill DA, Abraham KJ, West RH. Factors affecting outcome in the resuscitation of severely injured patients. Aust NZ J Surg 1993;63:604-609.

31. Vassar MJ, Perry CA, Holcroft JW. Prehospital resuscitation of hypotensive trauma patients with 7.5% NaCl versus 7.5% NaCl with added dextran: a controlled trial. J Trauma 1993;34:622-632; discussion 632-623.

32. Shutter LA, Narayan RK. Blood pressure management in traumatic brain injury. Ann Emerg Med 2008;51(3 Suppl):S37-38.

33. Helmy A, Vizcaychipi M, Gupta AK. Traumatic brain injury: Intensive care management. Br J Anaesth 2007;99:32-42.

34. Becker DP, Miller JD, Ward JD, et al. The outcome from severe head injury with early diagnosis and intensive management. J Neurosurg 1977;47:491-502.

35. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I: The significance of intracranial pressure monitoring. J Neurosurg 1979;50:20-25.

36. Miller JD, Becker DP, Ward JD, et al. Significance of intracranial hypertension in severe head injury. J Neurosurg 1977; 47:503-516.

37. Narayan RK, Kishore PR, Becker DP, et al. Intracranial pressure: To monitor or not to monitor? A review of our experience with severe head injury. J Neurosurg 1982;56: 650-659.

38. Warner KJ, Bulger EM. Does pre-hospital ventilation effect outcome after significant brain injury? Trauma 2007;9:283-289.

39. van Hulst RA, Haitsma JJ, Lameris TW, et al. Hyperventilation impairs brain function in acute cerebral air embolism in pigs. Intensive Care Med 2004;30:944-950.

40. Sheinberg M, Kanter MJ, Robertson CS, et al. Continuous monitoring or jugular venous oxygen saturation in head-injured patients. J Neurosurg 1992;76:212-217.

41. Muizelaar JP, van der Poel HG, Li ZC, et al. Pial arteriolar vessel diameter and CO2 reactivity during prolonged hyperventilation in the rabbit. J Neurosurg 1988;69: 923-927.

42. Graham DI, Adams JH. Ischaemic brain damage in fatal head injuries. Lancet 1971;1:265-266.

43. Graham DI, Lawrence AE, Adams JH, et al. Brain damage in fatal non-missile head injury without high intracranial pressure. J Clin Pathology 1988;41:34-37.

44. Ross DT, Graham DI, Adams JH. Selective loss of neurons from the thalamic reticular nucleus following severe human head injury. J Neurotrauma 1993;10:151-165.

45. Greenberg M. Handbook of Neurosurgery. Lakeland (FL): Greenberg Graphics; 1997.

46. Heegaard W, Biros M. Traumatic brain injury. Emerg Med Clin North Am 2007; 25:655-678, viii.

47. Contant CF, Valadka AB, Gopinath SP, et al. Adult respiratory distress syndrome: A complication of induced hypertension after severe head injury. J Neurosurg 2001;95: 560-568.

48. Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988; 69:15-23.

49. Ratanalert S, Phuenpathom N, Saeheng S, et al. ICP threshold in CPP management of severe head injury patients. Surgical Neurology 2004;61:429-434; discussion 434-425.

50. Saul TG, Ducker TB. Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. J Neurosurg 1982;56:498-503.

51. Gaab MR, Hollerhage HG, Walter GF, et al. Brain edema, autoregulation, and calcium antagonism. An experimental study with nimodipine. Advances in Neurology 1990;52:391-400.

52. Gaab MR, Seegers K, Smedema RJ, et al. A comparative analysis of THAM (Tris-buffer) in traumatic brain oedema. Acta Neurochir Suppl (Wien). 1990;51:320-323.

53. Albanese J, Durbec O, Viviand X, et al. Sufentanil increases intracranial pressure in patients with head trauma. Anesthesiology 1993;79:493-497.

54. de Nadal M, Ausina A, Sahuquillo J, et al. Effects on intracranial pressure of fentanyl in severe head injured patients. Acta Neurochirurgica 1998;71:10-12.

55. Sperry RJ, Bailey PL, Reichman MV, et al. Fentanyl and sufentanil increase intracranial pressure in head trauma patients. Anesthesiology 1992;77:416-420.

56. Papazian L, Albanese J, Thirion X, et al. Effect of bolus doses of midazolam on intracranial pressure and cerebral perfusion pressure in patients with severe head injury. Br J Anaesth 1993;71:267-271.

57. McCollum JS, Dundee JW. Comparison of induction characteristics of four intravenous anaesthetic agents. Anaesthesia 1986; 41:995-1000.

58. Farling PA, Johnston JR, Coppel DL. Propofol infusion for sedation of patients with head injury in intensive care. A preliminary report. Anaesthesia 1989;44:222-226.

59. Pinaud M, Lelausque JN, Chetanneau A, et al. Effects of propofol on cerebral hemodynamics and metabolism in patients with brain trauma. Anesthesiology 1990;73: 404-409.

60. Kang TM. Propofol infusion syndrome in critically ill patients. Ann Pharmacotherapy 2002;36:1453-1456.

61. Pechadre JC, Lauxerois M, Colnet G, et al. [Prevention of late post-traumatic epilepsy by phenytoin in severe brain injuries. 2 years' follow-up]. Presse Med 1991;20: 841-845.

62. Wohns RN, Wyler AR. Prophylactic phenytoin in severe head injuries. J Neurosurg 1979;51:507-509.

63. Young B, Rapp R, Brooks WH, et al. Posttraumatic epilepsy prophylaxis. Epilepsia 1979;20:671-681.

64. Haltiner AM, Newell DW, Temkin NR, et al. Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis. J Neurosurg 1999;91:588-592.

65. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: A randomized trial. J Neurosurg 1999;91:593-600.

66. Aarabi B, Alden TD, Chesnut R. Guidelines for the management of penetrating brain injury. J Trauma 2001;51(2 Suppl):S1-86.

67. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792-798.

68. Sirvent JM, Torres A, El-Ebiary M, et al. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Resp Crit Care Med 1997;155: 1729-1734.

69. Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: A systematic review and meta-analysis. J Neurotrauma 2008;25:62-71.

70. Freeman WD, Brott TG. Modern treatment options for intracerebral hemorrhage. Current Treatment Options in Neurology 2006;8:145-157.

71. Pieracci FM, Eachempati SR, Shou J, et al. Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients. J Trauma 2007;63:525-530.

72. Mina AA, Knipfer JF, Park DY, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma 2002;53:668-672.

73. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: Comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006;37:1465-1470.

74. Makris M, Greaves M, Phillips WS, et al. Emergency oral anticoagulant reversal: The relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemostasis 1997;77:477-480.

75. Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992;23: 972-977.

76. Ivascu FA, Howells GA, Junn FS, et al. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma 2005;59:1131-1137; discussion 1137-1139.

77. Ivascu FA, Janczyk RJ, Junn FS, et al. Treatment of trauma patients with intracranial hemorrhage on preinjury warfarin. J Trauma 2006;61:318-321.

78. Siddiq F, Jalil A, McDaniel C, et al. Effectiveness of Factor IX complex concentrate in reversing warfarin associated coagulopathy for intracerebral hemorrhage. Neurocritical Care 2008;8:36-41.

79. Freeman WD, Aguilar MI. Management of warfarin-related intracerebral hemorrhage. Expert Review of Neurotherapeutics 2008; 8:271-290.

80. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: Literature review and expert opinion. Mayo Clinic Proc 2007;82:82-92.

81. Martinowitz U, Kenet G, Segal E, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001;51:431-438; discussion 438-439.

82. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clinic Proc 2004;79:1495-1500.

83. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-785.

84. Kluger Y, Riou B, Rossaint R, et al. Safety of rFVIIa in hemodynamically unstable polytrauma patients with traumatic brain injury: Post hoc analysis of 30 patients from a prospective, randomized, placebo-controlled, double-blind clinical trial. Critical Care (London, England). 2007;11:R85.

85. Moppett IK. Traumatic brain injury: Assessment, resuscitation and early management. Br J Anaesth 2007;99:18-31.

86. Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurology 2008;7: 728-741.

87. Maas AI, Steyerberg EW, Murray GD, et al. Why have recent trials of neuroprotective agents in head injury failed to show convincing efficacy? A pragmatic analysis and theoretical considerations. Neurosurgery 1999;44:1286-1298.

88. Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma 2002;19:503-557.

89. Stein DG, Wright DW, Kellermann AL. Does progesterone have neuroprotective properties? Ann Emerg Med 2008;51: 164-172.

90. Wright DW, Kellermann AL, Hertzberg VS, et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007;49:391-402, 402 e391-392.

91. Xiao G, Wei J, Yan W, et al. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Critical Care (London, England) 2008;12:R61.

92. Vespa P, Boonyaputthikul R, McArthur DL, et al. Intensive insulin therapy reduces microdialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury. Crit Care Med 2006;34:850-856.

93. Feldman Z, Kanter MJ, Robertson CS, et al. Effect of head elevation on intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in head-injured patients. J Neurosurg 1992;76:207-211.

94. Ng I, Lim J, Wong HB. Effects of head posture on cerebral hemodynamics: Its influences on intracranial pressure, cerebral perfusion pressure, and cerebral oxygenation. Neurosurgery 2004;54:593-597; discussion 598.

95. Winkelman C. Effect of backrest position on intracranial and cerebral perfusion pressures in traumatically brain-injured adults. Am J Crit Care 2000;9:373-380; quiz 381-372.

96. Moraine JJ, Berre J, Melot C. Is cerebral perfusion pressure a major determinant of cerebral blood flow during head elevation in comatose patients with severe intracranial lesions? J Neurosurg 2000;92:606-614.

97. Hymel KP, Makaroff KL, Laskey AL, et al. Mechanisms, clinical presentations, injuries, and outcomes from inflicted versus noninflicted head trauma during infancy: Results of a prospective, multicentered, comparative study. Pediatrics 2007;119:922-929.

98. Duhaime AC, Christian CW, Rorke LB, et al. Nonaccidental head trauma in infants: The "shaken baby syndrome." N Engl J Med 1998; 338:1822-1829.

99. DiScala C, Osberg JS, Savage RC. Children hospitalized for traumatic brain injury: Transition to postacute care. J Head Trauma Rehabil 1997;12:1-10.

100. Greenwald BD, Burnett DM, Miller MA. Congenital and acquired brain injury. 1. Brain injury: epidemiology and pathophysiology. Arch Physical Med Rehab 2003;84(3 Suppl 1):S3-7.

101. Feickert HJ, Drommer S, Heyer R. Severe head injury in children: Impact of risk factors on outcome. J Trauma 1999;47: 33-38.

102. Weiner H, Weinberg J. Head injury in the pediatric age group. In: Cooper P, Golfinos J, eds. Head Injury. 4th ed. New York: McGraw-Hill; 2000:419-456.

103. Horan MJ, Sinaiko AR. Synopsis of the Report of the Second Task Force on Blood Pressure Control in Children. Hypertension 1987;10:115-121.

104. Adelson PD. Hypothermia following pediatric traumatic brain injury. J Neurotrauma 2009;26:429-436.

105. Cool Kids Trial. Children's Hospital of Pittsburgh. Available at: http://www.coolkidstrial.org/. Accessed September 2, 2009.

106. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Chapter 1: Introduction. Pediatr Crit Care Med 2003;4(3 Suppl):S2-4.

107. Kraus J, McArthur D. Epidemiology of Brain Injury. In: Cooper P, Golfinos J, eds. Head Injury. 4th ed. New York: McGraw-Hill Publishers; 2000:1-26.

108. Morris JA Jr., MacKenzie EJ, Edelstein SL. The effect of preexisting conditions on mortality in trauma patients. JAMA 1990;263:1942-1946.

109. Rozzelle CJ, Wofford JL, Branch CL. Predictors of hospital mortality in older patients with subdural hematoma. J Am Geriatr Soc 1995;43:240-244.

110. Sperry JL, Gentilello LM, Minei JP, et al. Waiting for the patient to "sober up": Effect of alcohol intoxication on glasgow coma scale score of brain injured patients. J Trauma 2006;61:1305-1311.

111. Gurney JG, Rivara FP, Mueller BA, et al. The effects of alcohol intoxication on the initial treatment and hospital course of patients with acute brain injury. J Trauma 1992;33:709-713.

112. Golan JD, Marcoux J, Golan E, et al. Traumatic brain injury in intoxicated patients. J Trauma 2007;63:365-369.

113. Trunkey DD. Trauma centers and trauma systems. JAMA 2003;289:1566-1567.

114. MacKenzie EJ, Rivara FP, Jurkovich GJ, et al. A national evaluation of the effect of trauma center care on mortality. N Engl J Med 2006;354:366-378.

115. Heros RC. Case volume and mortality. J Neurosurg 2003;99:805-806; discussion 806.

116. Hannan EL, Farrell LS, Cooper A, et al. Physiologic trauma triage criteria in adult trauma patients: Are they effective in saving lives by transporting patients to trauma centers? J Am Coll Surgeons 2005;200: 584-592.

117. Patel HC, Bouamra O, Woodford M, et al. Trends in head injury outcome from 1989 to 2003 and the effect of neurosurgical care: An observational study. Lancet 2005;366:1538-1544.

118. Varelas PN, Conti MM, Spanaki MV, et al. The impact of a neurointensivist-led team on a semiclosed neurosciences intensive care unit. Crit Care Med 2004;32: 2191-2198.

119. Visca A, Faccani G, Massaro F, et al. Clinical and neuroimaging features of severely brain-injured patients treated in a neurosurgical unit compared with patients treated in peripheral non-neurosurgical hospitals. Br J Neurosurg 2006;20:82-86.

120. Suarez JI, Zaidat OO, Suri MF, et al. Length of stay and mortality in neurocritically ill patients: Impact of a specialized neurocritical care team. Crit Care Med 2004;32:2311-2317.

121. Vukic M, Negovetic L, Kovac D, et al. The effect of implementation of guidelines for the management of severe head injury on patient treatment and outcome. Acta Neurochir (Wien) 1999;141:1203-1208.

122. Palmer S, Bader MK, Qureshi A, et al. The impact on outcomes in a community hospital setting of using the AANS traumatic brain injury guidelines. Americans Associations for Neurologic Surgeons. J Trauma 2001;50:657-664.

123. Lu J, Marmarou A, Choi S, Maas A, et al. Mortality from traumatic brain injury. Acta Neurochirurgica 2005;95:281-285.

124. Fakhry SM, Trask AL, Waller MA, et al. Management of brain-injured patients by an evidence-based medicine protocol improves outcomes and decreases hospital charges. J Trauma 2004;56:492-499; discussion 499-500.

125. Faul M, Wald MM, Rutland-Brown W, et al. Using a cost-benefit analysis to estimate outcomes of a clinical treatment guideline: Testing the Brain Trauma Foundation guidelines for the treatment of severe traumatic brain injury. J Trauma 2007;63: 1271-1278.