Perioperative management of traumatic brain injury

Parichat Curry,1 Darwin Viernes,1 and Deepak Sharma1,2

Author information Copyright and License information This article has been cited by other articles in PMC.

Go to:

Abstract
Traumatic brain injury (TBI) is a major public health problem and the leading cause of death and disability worldwide. Despite the modern diagnosis and treatment, the prognosis for patients with TBI remains poor. While severity of primary injury is the major factor determining the outcomes, the secondary injury caused by physiological insults such as hypotension, hypoxemia, hypercarbia, hypocarbia, hyperglycemia and hypoglycemia, etc. that develop over time after the onset of the initial injury, causes further damage to brain tissue, worsening the outcome in TBI. Perioperative period may be particularly important in the course of TBI management. While surgery and anesthesia may predispose the patients to new onset secondary injuries which may contribute adversely to outcomes, the perioperative period is also an opportunity to detect and correct the undiagnosed pre-existing secondary insults, to prevent against new secondary insults and is a potential window to initiate interventions that may improve outcome of TBI. For this review, extensive Pubmed and Medline search on various aspects of perioperative management of TBI was performed, followed by review of research focusing on intraoperative and perioperative period. While the research focusing specifically on the intraoperative and immediate perioperative TBI management is limited, clinical management continues to be based largely on physiological optimization and recommendations of Brain Trauma Foundation guidelines. This review is focused on the perioperative management of TBI, with particular emphasis on recent developments. Keywords: Anesthesia, perioperative management, traumatic brain injury Go to:

INTRODUCTION
Traumatic brain injury (TBI) is a major public health problem and the leading cause of death and disability worldwide.[1] Approximately 1.7 million people sustain TBI every year in the United States, leading to 275,000 hospitalizations and 52,000 deaths.[1] TBI is a contributing factor in about 30.5% of all injury-related deaths in the United States.[1] TBI occurs most often in children aged 04 years, adolescents aged 1519 years and elderly aged 65 years and more.[1] In all age groups, males have a higher rate of TBI than females.[1] Falls and motor vehicletraffic injury are the leading causes of TBI in the United States.[1] In the recent

years, prehospital and intensive care of patients with TBI has improved substantially and evidence-based guidelines for management have been developed.[213] However, despite the modern diagnosis and treatment, the prognosis for patients with TBI remains poor, emphasizing the need for further research and improvement in care. This review will focus on the perioperative management of TBI, with particular emphasis on recent developments, and is based on extensive Pubmed and Medline search on various aspects of perioperative management of TBI, followed by review of research focusing on intraoperative and perioperative period. Go to:

PATHOPHYSIOLOGY OF TRAUMATIC BRAIN INJURY

Pathophysiology of TBI involves primary and secondary injuries to the brain. Primary injury is the damage caused by the initial trauma involving mechanical impact to the brain tissue and skull due to accelerationdeceleration or rotational forces, resulting in skull fracture, brain contusion, expanding intracranial hematoma or diffuse axonal injury.[14] The primary injury then initiates inflammatory process, edema formation and excitotoxicity, resulting in further increase in intracranial pressure (ICP) and reduced cerebral perfusion pressure (CPP).[14,15] Severity of primary injury is the major factor determining the outcome of TBI patients. Secondary injury is a consequence of physiological insults that develop over time after the onset of the initial injury, causing further damage to the brain tissue and worsening the outcome in TBI patients.[14,15] Two major factors that cause secondary injury are hypotension [systolic blood pressure (SBP) < 90 mmHg] and hypoxemia (PaO2 < 60 mmHg).[16] A study analyzing data from the Traumatic Coma Data Bank demonstrated that hypotension and hypoxemia were independently associated with increased morbidity and mortality from severe TBI.[17] A single episode of hypotension was associated with increased morbidity and mortality.[17] A meta-analysis of 8721 patients (IMPACT study) also suggested that hypotension and hypoxia were significantly associated with unfavorable 6-month outcome.[18] A study on the association between intraoperative hypotension and outcome demonstrated that patients who had intraoperative hypotension had over three times increased mortality than normotensive patients.[19] Moreover, the duration of intraoperative hypotension was also inversely associated with functional outcome.[19] Other factors implicated in secondary injury include hypoglycemia, hyperglycemia, hypercarbia and hypocarbia, and raised ICP.[2025] Go to:

THE IMPORTANCE OF PERIOPERATIVE PERIOD

Given the poor outcomes of TBI and impact of secondary insults, current TBI management focuses on prevention of primary injury and avoidance of secondary

injuries. Thus, the cornerstones of modern TBI management are field resuscitation, expeditious triage, emergent surgical evacuation of mass lesions, control of ICP, and support of CPP, multimodal monitoring and optimization of physiological environment. Perioperative period may be particularly important in the course of TBI management for numerous reasons. First, despite the aggressive interventions to rapidly correct hypoxemia, hypotension, hypo and hypercarbia, and hypo and hyperglycemia in the emergency department, it is not unusual for one or more of these complicating factors to persist or remain undetected as the patient is emergently transported to the operating room. Hence, perioperative period may provide an opportunity to either continue ongoing resuscitation or to correct the pre-existing secondary insults. Secondly, surgery and anesthesia may predispose the patient to new onset secondary injuries (such as intraoperative hypotension due to surgical blood loss or effect of anesthetic agents, new onset hyperglycemia due to stress response, etc.), which may contribute adversely to outcomes. Since secondary injury is largely preventable/treatable, the perioperative period may be a potential window to initiate interventions that may improve the outcome of TBI. Perioperative management involves rapid evaluation, continuation of resuscitation (cerebral and systemic), early surgical intervention, intensive monitoring and anesthetic planning.
Initial Assessment and Ongoing Resuscitation

The initial assessment and stabilization is usually achieved in the emergency department and resuscitation initiated before the patient is transported to Computed Tomography (CT) scanner and then to the operating room. Nevertheless, it is important for the anesthesia team to perform another rapid assessment as the patient is received in the operating room. The assessment should always begin with airway, breathing and circulation, followed by a rapid assessment of neurological status and associated extracranial injuries and attention to specific secondary injury mechanisms and ongoing treatment thereof. Information about time and mechanism of injury can be valuable. Brief neurological assessment is performed by using Glasgow Coma Scale (GCS)[26] score and pupillary responses. Associated thoracic, abdominal, spinal and long bone injuries may be stable or evolve during the perioperative period and must be considered in differential diagnosis of new onset hypotension, anemia, hemodynamic instability or hypoxemia during anesthesia and surgery. As the patient is transported to the operating room, all resuscitative measures should continue.
Airway Management

Patients with TBI requiring surgery will invariably require tracheal intubation. In fact, most patients are likely to arrive in the operating room already intubated. However, some patients, particularly those with extradural hematoma, may be conscious and breathing spontaneously. The indwelling tracheal tube can possibly migrate during transport, leading to endobronchial intubation or even

dislodgement, and hence, adequate position of the tube must always be confirmed. In the select patients who may not be already intubated, airway management is complicated by a number of factors, including urgency of situation (because of preexisting/worsening hypoxia), uncertainty of cervical spine status, uncertainty of airway (due to presence of blood, vomitus, debris in the oral cavity or due to laryngo-pharyngeal injury or skull base fracture), full stomach, intracranial hypertension and uncertain volume status. All TBI patients requiring urgent surgery must be considered to have full stomach and airway management must account for possible underlying cervical spine injury. Although it has been reported that patients with craniocerebral trauma had an incidence of cervical spine injury (CSI) similar to that of the general trauma population,[27] emerging evidence suggests a higher incidence of cervical injury in patients who have experienced craniocerebral trauma, especially among those with increasing severity of craniocerebral injury as determined by low GCS score and unconsciousness.[28,29] The choice of technique for tracheal intubation is determined by urgency, individual expertise/skills and available resources and generally incorporates rapid sequence intubation with cricoid pressure and manual in-line stabilization.[27] The anterior portion or cervical collar may be removed when manual in-line stabilization is established to allow greater mouth opening and facilitate laryngoscopy. Newer airway devises, particularly Glidescope videolaryngoscope, have gained popularity in recent years for use in trauma victims and may be useful in difficult airway scenarios. However, the intubation time using Glidescope may be longer due to difficulty in passing the tracheal tube through the glottis despite easier visualization.[30] Nasal intubation should be avoided in patients with base of skull fracture, severe facial fractures or bleeding diathesis. In any case, it is advisable to have a back-up plan ready in case of difficult intubation, given the significant risk of intracranial hypertension resulting from increased cerebral blood volume (CBV) because of hypoxemia and hypercarbia. Choice of induction agents and muscle relaxants is important for successful uncomplicated airway management. Sodium thiopental, etomidate and propofol are commonly used to induce anesthesia before intubation. All these agents decrease the systemic hemodynamic response to intubation, blunt increases in ICP, and decrease the cerebral metabolic rate for oxygen (CMRO2). However, propofol and thiopental may cause cardiovascular depression leading to hypotension, especially in the presence of uncorrected hypovolemia. Etomidate may be advantageous due to little change in blood pressure during induction despite reduction of CMRO2.[31] However, it may lead to adrenal insufficiency causing delayed hypotension and requiring vasopressor use.[32] Ketamine, which causes limited cardiovascular compromise, has been associated with increased cerebral blood flow (CBF) and increased ICP, and as such, may be relatively contraindicated for intubating patients with risk for or pre-existing increased ICP.[33] The choice of muscle relaxant for rapid sequence induction is between succinylcholine and rocuronium.[34] Succinylcholine may contribute to increased ICP[35,36] which can

be blunted by administration of an adequate dose of an induction agent such as thiopental.[37] While the clinical significance of the effect of succinylcholine on ICP is questionable,[37,38] increases in ICP secondary to hypoxia and hypercarbia are well documented and much more likely to be clinically important. Hence, in patients with TBI, clinicians may not avoid using succinylcholine.[38]
Anesthetic Management

The major goals of anesthetic management of TBI are to

maintain CPP; treat increased ICP; provide optimal surgical conditions; avoid secondary insults such as hypoxemia, hyper and hypocarbia, hypo and hyperglycemia; and provide adequate analgesia and amnesia.

Anesthetic technique

Important pharmacodynamic and pharmacokinetic differences exist between intravenous and volatile anesthetic agents. Intravenous agents including thiopental, propofol and etomidate cause cerebral vasoconstriction and reduce CBF, CBV, CMRO2and ICP.[39] Opioids have no direct effects on cerebral hemodynamics in the presence of controlled ventilation.[40] All volatile anesthetic agents (isoflurane, sevoflurane, desflurane) decrease CMRO2 and may cause cerebral vasodilation, resulting in increasing CBF and ICP. But at concentration less than 1 minimum alveolar concentration (MAC), the cerebral vasodilatory effects are minimal and hence they may be used in low concentrations in patients with TBI.[41] Nitrous oxide can increase CMRO2 and cause cerebral vasodialation and increased ICP and should be avoided.[42] Importantly, the effects of anesthetic agents (inhalation vs. total intravenous anesthesia) on outcome of TBI have not been demonstrated. In the absence of conclusive evidence, either anesthetic technique may be employed judiciously. However, more importantly, the principles of anesthetic management should adhere to the current guidelines for the management of severe TBI [Table 1].[213]

Table 1 Recommendations from the 2007 guidelines for management of severe traumatic brain injury[213]

Ventilation

Ventilation should be adjusted to ensure adequate oxygenation and gas exchange. Inspired oxygen concentration is adjusted to maintain PaO2 >60 mmHg.2Monitoring arterial PCO2 is recommended since end-tidal CO2 may not be reliable. Hypercarbia should be avoided but hypocarbia must not be used indiscriminately.[12] Excessive hyperventilation may cause cerebral vasoconstriction leading to ischemia.[12] Hence, hyperventilation should be used judiciously for short-term control of ICP and to facilitate surgical exposure during craniotomy. Normocarbia should be restored before dural closure to avoid development of tension pneumocephalus. Monitoring cerebral oxygenation is recommended when utilizing hyperventilation for prolonged periods. In the intraoperative period, this may be accomplished by jugular venous oximetry[9,43] and in the postoperative period by brain tissue oxygenation (PbtO2) or CBF monitoring (e.g. using Transcranial Doppler ultrasonography).[9]
Monitoring

In additional to standard American Society of Anesthesiology (ASA) monitors, arterial catheterization is recommended for beat-to-beat blood pressure monitoring and for blood gas analysis and blood glucose monitoring during craniotomy. Central venous pressure (CVP) may be useful, particularly for resuscitation and when vasopressors are administered. However, it is advisable not to delay surgical evacuation of expanding intracranial hematoma because of institution of invasive monitoring. According to the current guidelines, ICP monitoring is recommended in all salvageable patients with a severe TBI (GCS < 9) and an abnormal CT scan (hematomas, contusions, swelling, herniation or compressed basal cistern), and in patients with severe TBI with a normal CT scan if two or more of the following features are noted at the admission: age > 40 years, unilateral or bilateral motor posturing, or SBP < 90 mmHg.[5] The use of multimodal monitoring for postoperative and intensive care of patients with TBI is increasing and monitoring cerebral oxygenation (global or focal) or CBF and metabolism parameters may be helpful in making important treatment decisions.[9]
Intravenous Fluids, Blood Pressure Management and Vasopressor Use

Hypotension following TBI can compromise cerebral hemodynamics and cause cerebral ischemia. Therefore, blood pressure management, including choice of fluids and vasopressors, is of paramount importance. Brain Trauma Foundation guidelines for the management of TBI recommend avoiding hypotension (SBP < 90 mmHg) and maintaining CPP between 50 and 70 mmHg.[2,8] Warm, non-glucose containing isotonic crystalloid solution is preferable for TBI patients. The role of colloid is controversial. A post-hoc analysis of the Saline versus Albumin Fluid Evaluation (SAFE) study demonstrated that resuscitation with albumin was associated with higher mortality rate and unfavorable neurological outcome at 24 months.[44] Hypertonic saline may be beneficial resuscitation fluid for TBI patients

because it increases intravascular fluid and decreases ICP. Prehospital hypertonic saline resuscitation has been shown to be associated with a reduction in serum biomarker levels (S100B, Neuron Specific Enolase and Membrane Basic Protein) which correlated with better outcome.[45] However, a double-blind randomized controlled trial comparing prehospital resuscitation of hypotensive TBI patients with hypertonic saline with standard fluid resuscitation protocols found no difference in neurological outcome at 6 months.[46] Vasopressors are commonly administered to treat hypotension or to augment CPP. However, there are only a few studies comparing the effectiveness of commonly used vasopressors in TBI and results of these studies are conflicting. Human data explicitly comparing vasopressors are limited to three small prospective, randomized, crossover trials comparing sequential effectiveness between norepinephrine and dopamine. Despite there being no differences in mean cerebral flow velocity[47,48] and cerebral oxygenation or metabolism[49] between the two vasopressors, norepinephrine had more predictable and consistent effect[48] while dopamine use led to higher ICP.[47] A recent single-center retrospective study of patients with severe TBI who received phenylephrine, norepinephrine or dopamine reported maximum increase in MAP and CPP from baseline with phenypephrine use.[50] There was no difference in ICP between the treatment groups after initiating the vasopressor although it was unclear whether improved MAP/CPP with vasopressor use translated into improved CBF or oxygenation.[50] Current evidence does not support preference of one vasopressor over the other.
Blood Transfusion

Anemia is associated with increased in-hospital mortality[51] and poor outcome in TBI.[52,53] Yet, there is little evidence to support packed red blood cell (PRBC) transfusion practice standards to correct anemia in TBI. While some have suggested that patients with TBI may not benefit from a higher transfusion threshold than other critically ill patients,[52] others have cautioned against the liberal use of blood transfusion in TBI.[53] Potential mechanisms of cerebral injury due to anemia include tissue hypoxia, injury caused by reactive oxygen species, inflammation, disruption of blood-brain barrier (BBB) function, vascular thrombosis and anemic cerebral hyperemia.[54] However, a number of cerebroprotective physiological mechanisms become effective with anemia which include aortic chemoreceptor activation, increased sympathetic activity leading to increased heart rate, stroke volume and cardiac index, reduced systemic vascular resistance, and enhanced oxygen extraction. Moreover, a number of cellular mechanisms of cerebral protection become effective in acute anemia. These include Hypoxia Inducible Factor (HIF), increased nitric oxide synthetase and nitric oxide in the brain (nNOS/NO), erythropoietin and vascular endothelial growth factor (VEGF) mediated angiogenesis and vascular repair.[54] Although increase in CBF during acute anemia can improve oxygen delivery, high hematocrit after PRBC transfusion may potentially decrease CBF and increase the risk of cerebral

ischemia.[55] However, anemia due to hemodilution may impair cerebral autoregulation.[56] The overall effects of anemia on the brain might, therefore, depend on the relative balance between these competing protective and harmful factors of anemia and PRBC transfusion, and it is unclear whether transfusion trigger in patients with TBI should be any different from other critically ill patients and whether the injured brain is more susceptible to deleterious effects of anemia. In the absence of defined optimal hemoglobin (Hb) levels, it has been suggested that neurophysiologic criteria for RBC transfusion may be more rational and may progressively replace arbitrary Hb-based transfusion triggers in neurocritical care.[57] RBC transfusion may influence cerebral oxygenation through a number of potential mechanisms in patients with TBI. Besides increasing the oxygen-carrier capacity of blood, RBC transfusion increases the circulating volume and can increase CBF in patients with impaired cerebral autoregulation secondary to the TBI. Transfusion also increases the blood viscosity to which the circulatory network responds with the release of nitric oxide, leading to vasodilatation and increasing functional capillary density (which quantifies capillary perfusion).[58] In recent years, there has been growing interest in the effect of RBC transfusion on brain tissue oxygenation (PbtO2) in patients with TBI and it seems an interesting possibility that PbtO2 values may be developed into potential transfusion triggers. However, most studies evaluating the effect of transfusion on PbtO2 in neurosurgical patients are limited by small sample size and have failed to demonstrate a consistent response to transfusion or elucidate predictors of PbtO2 response to transfusion.[59,60] The potential role of brain tissue oxygenation in deciding transfusion thresholds has been discussed elsewhere.[61,62] Existing evidence suggests that both anemia and RBC transfusion are associated with poor neurological outcome in TBI.[52,53] While anemia is associated with increased in-hospital mortality[51] and lower hospital discharge GCS score, discharge Glasgow outcome score and Ranchos Los Amigos scores,[52] RBC transfusion is associated with acute lung injury, longer intensive care unit and hospital stay, and mortality.[6365] The optimal Hb level in TBI patients is still unclear but there is no benefit of a liberal transfusion strategy (transfusion when Hb <10 g/dl) in moderate to severe TBI patients and it is not recommended.[53]
Coagulopathy and Factor VII

Coagulation disorder is a common problem after TBI. Coagulation disorder could result from TBI and cause secondary brain injury. A recent review reported that the overall prevalence of coagulopathy was 32.7% after TBI and more than 60% in severe TBI and that the presence of coagulopathy was associated with an increased mortality and poor outcome.[66] According to a recent prospective study, the independent risk factors for coagulopathy in TBI are GCS 8, Injury Severity Score (ISS) 16, presence of cerebral edema, subarachnoid hemorrhage and midline shift.[67] When brain is injured, tissue factor (TF) is released. Subsequently, procoagulant factors are activated resulting in thrombin formation and conversion of

fibrinogen to fibrin. Normally, antithrombotic mechanisms are also activated to counter fibrin formation. Disseminated intravascular coagulation (DIC) inhibits the antithrombotic mechanism, causing imbalance of coagulation and fibrinolysis. Currently, there are no guidelines for management of coagulopathy in TBI. Hemostatic drugs including antifibrinolytic agents such as tranexamic acid and pro-coagulant drugs such as recombinant activated factor VII (rFVIIa) are sometimes used in treatment of coagulopathy after TBI. A Cochrane review found two randomized controlled trials that evaluated the effects of rFVIIa, but both the trails were too small to draw a conclusion regarding the effectiveness of rFVIIa for TBI patients.[68] The Clinical Randomization of Antifibrinolytics in Significant Hemorrhage (CRASH-2) trial, a large international placebo-controlled trial evaluating the effect of tranexamic acid on death, vascular occlusion events and blood transfusion in adult trauma patients, demonstrated that tranexamic acid was associated with a reduction of mortality (RR: 0.91, 95% CI: 0.85-097, P = 0.0035).[69] The risk of death from bleeding was also lower in tranexamic acid group (RR: 0.85, 95% CI: 0.760.96, P = 0.0077).[69]
Hyperosmolar Therapy

Mannitol is the standard agent used in hyperosmolar therapy. The recommended dose of mannitol is 0.251 g/kg body weight. Due to osmotic diuresis which can result in hypovolemia and hypotension, mannitol is recommended only when there are signs of transtentorial herniation or progressive neurological deterioration not attributable to extracranial causes.[3] In patients with severe TBI and elevated ICP refractory to mannitol treatment, 7.5% hypertonic saline administered as second tier therapy can increase cerebral oxygenation and improve cerebral and systemic hemodynamics.[70]
Glycemic Control

Hyperglycemia after TBI is associated with increased morbidity and mortality.[71 73] It may reflect the extent of injury severity,[74] reflecting a normal response to stress due to a rise in circulating counter-regulatory hormones or may worsen outcome after TBI.[74,75] Secondary brain injury from hyperglycemia can ensue, leading to an increase in glycolytic rates as shown by increased lactate/pyruvate ratio, resulting in metabolic acidosis within brain parenchyma, overproduction of reactive oxygen species, and ultimately neuronal cell death.[7477] In 2001, Van den Berghe et al. reported that intensive insulin therapy (target blood glucose 80 110 mg/dl) in critically ill patients was associated with lower mortality.[78] However, more recent studies not only failed to demonstrate the mortality benefit of intensive insulin therapy but also found an increased risk of hypoglycemia.[79,80] Billotta et al. randomized 97 severe TBI patients to intensive insulin therapy group targeting blood glucose at 80-120 mg/dl or conventional insulin therapy group targeting blood glucose below 220 mg/dl and found that both the groups had similar mortality and neurological outcome at 6 months.[80]

Although the intensive insulin therapy group had shorter ICU stay, infection rates were similar between both the groups and episodes of hypoglycemia (glucose < 80 mg/dl) were significantly higher in the intensive insulin therapy group.[80] Hence, tight glucose control with intensive insulin therapy remains controversial. While a number of studies have investigated hyperglycemia in adult TBI in different contexts (admission vs. ICU, transient vs. persistent, early vs. late, etc.), none has specifically addressed the intraoperative period and the prevalence of intraoperative hyperglycemia, and its relation to preoperative glycemic patterns in adult TBI is not known. Since hyperglycemia is attributed to a stress response from the initial injury[74,75] and blood glucose levels are known to increase under anesthesia even in non-diabetic patients,[81] it is possible that added stress during general anesthesia and surgery may worsen hyperglycemia and contribute to poor outcome. Moreover, individual anesthetic agents have been shown to have differential effects on blood and brain glucose levels.[82,83] The only perioperative study in children with TBI demonstrated that intraoperative hyperglycemia is common, hypoglycemia in the absence of insulin treatment is not rare, and TBI severity and the presence of subdural hematoma (SDH) predict intraoperative hyperglycemia.[73] In the author's experience in adult patients undergoing craniotomy for TBI, intraoperative hyperglycemia (glucose > 200 mg/dl) was common (15%) and hypoglycemia (glucose < 60 mg/dl) was not observed (unpublished data). We also found that the independent risk factors for intraoperative hyperglycemia were severe TBI, SDH, preoperative hyperglycemia, and age 65 years, and the in-hospital mortality was higher in patients with intraoperative hyperglycemia. Given the current evidence for glucose control for TBI in perioperative period, a target glucose range of 80180 mg/dl seems reasonable.
Therapeutic Hypothermia and Steroids

Hypothermia reduces cerebral metabolism during stress, reduces excitatory neurotransmitters release, attenuates BBB permeability, and has been used for brain protection in TBI patients for decades. However, clinical evidence in terms of mortality and functional outcomes is still inconclusive. A recent meta-analysis reported statistically insignificant reduction in mortality and increased favorable neurological outcome with hypothermia in TBI.[84] The benefits of hypothermia were greater when cooling was maintained for more than 48 hours, but the potential benefits of hypothermia may likely be offset by a significant increase in the risk of pneumonia.[84] These observations support previous findings that hypothermic therapy constitutes a beneficial treatment of TBI in specific circumstances. Accordingly, the BTF/AANS guidelines task force has issued a Level III recommendation for optional and cautious use of hypothermia for adults with TBI.[4] Steroids have not been shown to improve outcomes or lower ICP in TBI.[13] In fact, findings from a randomized multicenter study on the effect of corticosteroids (MRC

CRASH trail) showed that administration of methylprednisolone within 8 hours of TBI was associated with higher risk of death, and the risk of death or severe disability was more compared to placebo.[85] Therefore, the use of high-dose methylprednisolone is contraindicated in patients with moderate or severe TBI.[13] Go to:

SUMMARY
Perioperative period may be important in TBI management. While it may predispose the patient to new onset secondary injuries which may contribute adversely to outcomes, it is also an opportunity to detect and correct the undiagnosed pre-existing secondary insults. It may also be a potential window to initiate interventions that may improve the outcome of TBI. While research focused specifically on the intraoperative and perioperative TBI management is awaited, clinical management will continue to be based on physiological optimization. Level I recommendations are based on the strongest evidence for effectiveness, and represent principles of patient management that reflect high degree of clinical certainty. Level II recommendations reflect a moderate degree of clinical certainty. For level III recommendations, the degree of clinical certainty is not established. Go to:

Footnotes
Source of Support: Nil Conflict of Interest: None declared.

Go to:

REFERENCES
1. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: Emergency department visits, hospitalizations, and deaths. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010. 2. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartle R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury Blood pressure and oxygenation. J Neurotrauma. 2007;24:S713. [PubMed] 3. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartle R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury II. Hyperosmolar therapy. J Neurotrauma. 2007;24:S1420. [PubMed]

4. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury III Prophylactic hypothermia. J Neurotrauma. 2007;24:S215. [PubMed] 5. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma. 2007;24:S3744.[PubMed] 6. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. VII. Intracranial pressure monitoring technology. J Neurotrauma. 2007;24:S4554.[PubMed] 7. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. VIII. Intracranial pressure thresholds. J Neurotrauma. 2007;24:S55 8. [PubMed] 8. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. IX. Cerebral perfusion thresholds. J Neurotrauma. 2007;24:S59 64. [PubMed] 9. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. X. Brain oxygen monitoring and thresholds. J Neurotrauma. 2007;24:S65 70.[PubMed] 10. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. XI. Anesthetics, analgesics, and sedatives. J Neurotrauma. 2007;24:S71 6. [PubMed]

11. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma. 2007;24:S836. [PubMed] 12. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. XIV. Hyperventilation. J Neurotrauma. 2007;24:S8790. [PubMed] 13. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Guidelines for the management of severe traumatic brain injury. XV. Steroids. J Neurotrauma. 2007;24:S915. [PubMed] 14. Greve MW, Zink BJ. Pathophysiology of traumatic brain injury. Mt Sinai J Med.2009;76:97104. [PubMed] 15. Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth.2007;99:49. [PubMed] 16. Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993;34:21622. [PubMed] 17. Marshall LF, Becker DP, Bowers SA, Cayard C, Eisenberg H, Gross CR, et al. The National Traumatic Coma Data Bank. Part 1: Design, purpose, goals, and results. J Neurosurg. 1983;59:27684. [PubMed] 18. McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, et al. Prognostic value of secondary insults in traumatic brain injury: Results from the IMPACT study. J Neurotrauma. 2007;24:28793. [PubMed] 19. Pietropaoli JA, Rogers FB, Shackford SR, Wald SL, Schmoker JD, Zhuang J. The deleterious effects of intraoperative hypotension on outcome in patients with severe head injuries. J Trauma. 1992;33:4037. [PubMed] 20. Liu-DeRyke X, Collingridge DS, Orme J, Roller D, Zurasky J, Rhoney DH. Clinical impact of early hyperglycemia during acute phase of traumatic brain injury.Neurocrit Care. 2009;11:1517. [PubMed] 21. Jeremitsky E, Omert LA, Dunham CM, Wilberger J, Rodriguez A. The impact of hyperglycemia on patients with severe brain injury. J Trauma. 2005;58:47 50.[PubMed]

22. Griesdale DE, Tremblay MH, McEwen J, Chittock DR. Glucose Control and Mortality in Patients with Severe Traumatic Brain Injury. Neurocrit Care.2009;11:3116. [PubMed] 23. Sharma D, Jelacic J, Chennuri R, Chaiwat O, Chandler W, Vavilala MS. Incidence and risk factors for perioperative hyperglycemia in children with traumatic brain injury. Anesth Analg. 2009;108:819. [PMC free article] [PubMed] 24. Warner KJ, Cuschieri J, Copass MK, Jurkovich GJ, Bulger EM. The impact of prehospital ventilation on outcome after severe traumatic brain injury. J Trauma.2007;62:13306. [PubMed] 25. Dumont TM, Visioni AJ, Rughani AI, Tranmer BI, Crookes B. Inappropriate prehospital ventilation in severe traumatic brain injury increases in-hospital mortality.J Neurotrauma. 2010;27:123341. [PubMed] 26. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2:814. [PubMed] 27. Crosby ET. Airway management in adults after cervical spine trauma.Anesthesiology. 2006;104:1293318. [PubMed] 28. Holly LT, Kelly DF, Counelis GJ, Blinman T, McArthur DL, Cryer HG. Cervical spine trauma associated with moderate and severe head injury: Incidence, risk factors, and injury characteristics. J Neurosurg (Spine 3) 2002;69:285 291. [PubMed] 29. Demetriades D, Charalambides K, Chahwan S, Hanpeter S, Alo K, Velmahos G, et al. Nonskeletal cervical spine injuries: Epidemiology and diagnostic pitfalls. J Trauma.2000;48:7247. [PubMed] 30. Platts-Mills TF, Campagne D, Chinnock B, Snowden B, Glickman LT, Hendey GW. A comparison of GlideScope video laryngoscopy versus direct laryngoscopy intubation in the emergency department. Acad Emerg Med. 2009;16:866 71.[PubMed] 31. Dearden NM, McDowall DG. Comparison of etomidate and althesin in the reduction of increased intracranial pressure after head injury. Br J Anaesth.1985;57:3618. [PubMed] 32. Cohan P, Wang C, McArthur DL, Cook SW, Dusick JR, Armin B, et al. Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study. Crit Care Med. 2005;33:235866. [PubMed] 33. Schulte am Esch J, Pfeifer G, Thiemig I, Entzian W. The influence of intravenous anaesthetic agents on primarily increased intracranial pressure. Acta Neurochir (Wien) 1978;45:1525. [PubMed]

34. Perry JJ, Lee JS, Sillberg VA, Wells GA. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev. 2008;2:CD002788.[PubMed] 35. Minton MD, Grosslight K, Stirt JA, Bedford RF. Increases in intracranial pressure from succinylcholine: Prevention by prior nondepolarizing blockade. Anesthesiology.1986;65:1659. [PubMed] 36. Stirt JA, Grosslight KR, Bedford RF, Vollmer D. Defasciculation with metocurine prevents succinylcholine-induced increases in intracranial pressure. Anesthesiology.1987;67:503. [PubMed] 37. Kovarik WD, Mayberg TS, Lam AM, Mathisen TL, Winn HR. Succinylcholine does not change intracranial pressure, cerebral blood flow velocity, or the electroencephalogram in patients with neurologic injury. Anesth Analg. 1994;78:46973. [PubMed] 38. Clancy M, Halford S, Walls R, Murphy M. In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review.Emerg Med J. 2001;18:3735. [PMC free article] [PubMed] 39. Turner BK, Wakim JH, Secrest J, Zachary R. Neuroprotective effects of thiopental, propofol, and etomidate. AANA J. 2005;73:297302. [PubMed] 40. Schregel W, Weyerer W, Cunitz G. Opioids, cerebral circulation and intracranial pressure. Anaesthesist. 1994;43:42130. [PubMed] 41. Engelhard K, Werner C. Inhalational or intravenous anesthetics for craniotomies? Pro inhalational? Curr Opin Anaesthesiol. 2006;19:504 8. [PubMed] 42. Schulte am Esch J, Thiemig I, Pfeifer G, Entzian W. The influence of some inhalation anaesthetics on the intracranial pressure with special reference to nitrous oxide. Anaesthesist. 1979;28:13641. [PubMed] 43. Schaffranietz L, Heinke W. The effect of different ventilation regimes on jugular venous oxygen saturation in elective neurosurgical patients. Neurol Res.1998;20:S6670. [PubMed] 44. Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N, et al. SAFE Study Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group; Australian Red Cross Blood Service; George Institute for International Health. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007;357:87484. [PubMed] 45. Baker AJ, Rhind SG, Morrison LJ, Black S, Crnko NT, Shek PN, et al. Resuscitation with hypertonic saline-dextran reduces serum biomarker levels and

correlates with outcome in severe traumatic brain injury patients. J Neurotrauma.2009;26:122740. [PubMed] 46. Cooper DJ, Myles PS, McDermott FT, Murray LJ, Laidlaw J, Cooper G, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: A randomized controlled trial. JAMA. 2004;291:1350 7.[PubMed] 47. Ract C, Vigu B. Comparison of the cerebral effects of dopamine and norepinephrine in severely head-injured patients. Intensive Care Med. 2001;27:1016.[PubMed] 48. Steiner LA, Johnston AJ, Czosnyka M, Chatfield DA, Salvador R, Coles JP, et al. Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients. Crit Care Med. 2004;32:104954. [PubMed] 49. Johnston AJ, Steiner LA, Chatfield DA, Coles JP, Hutchinson PJ, Al-Rawi PG, et al. Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.Intensive Care Med. 2004;30:7917. [PubMed] 50. Sookplung P, Siriussawakul A, Malakouti A, Sharma D, Wang J, Souter MJ, et al. Vasopressor Use and Effect on Blood Pressure After Severe Adult Traumatic Brain Injury. Neurocrit Care. 2010 [PMC free article] [PubMed] 51. Alvarez M, Nava JM, Ru M, Quintana S. Mortality prediction in head trauma patients: Performance of Glasgow Coma Score and general severity systems. Crit Care Med. 1998;26:1428. [PubMed] 52. Carlson AP, Schermer CR, Lu SW. Retrospective evaluation of anemia and transfusion in traumatic brain injury. J Trauma. 2006;61:56771. [PubMed] 53. Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, et al. Role of anemia in traumatic brain injury. J Am Coll Surg. 2008;207:398406. [PubMed] 54. Hare GM, Tsui AK, McLaren AT, Ragoonanan TE, Yu J, Mazer CD. Anemia and cerebral outcomes: Many questions, fewer answers. Anesth Analg. 2008;107:1356 70.[PubMed] 55. Pendem S, Rana S, Manno EM, Gajic O. A review of red cell transfusion in the neurological intensive care unit. Neurocrit Care. 2006;4:637. [PubMed] 56. Ogawa Y, Iwasaki K, Aoki K, Shibata S, Kato J, Ogawa S. Central hypervolemia with hemodilution impairs dynamic cerebral autoregulation. Anesth Analg.2007;105:138996. [PubMed] 57. Leal-Noval SR, Moz-Gmez M, Murillo-Cabezas F. Optimal hemoglobin concentration in patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Curr Opin Crit Care. 2008;14:15662. [PubMed]

58. Martini J, Carpentier B, Chvez Negrete A, Cabrales P, Tsai AG, Intaglietta M. Beneficial effects due to increasing blood and plasma viscosity. Clin Hemorheol Microcirc. 2006;35:517. [PubMed] 59. Leal-Noval SR, Rincn-Ferrari MD, Marin-Niebla A, Cayuela A, Arellano-Orden V, Marn-Caballos A, et al. Transfusion of erythrocyte concentrates produces a variable increment on cerebral oxygenation in patients with severe traumatic brain injury: A preliminary study. Intensive Care Med. 2006;32:173340. [PubMed] 60. Zygun DA, Nortje J, Hutchinson PJ, Timofeev I, Menon DK, Gupta AK. The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med. 2009;37:10748. [PubMed] 61. Sharma D, Vavilala MS. Transfusion improves cerebral oxygenation. but not always. Crit Care Med. 2009;37:11667. [PubMed] 62. Sharma D, Vavilala MS. Should brain tissue oxygenation be the transfusion trigger in traumatic brain injury? Pediatr Crit Care Med. 2010;11:4201. [PubMed] 63. Chaiwat O, Lang JD, Vavilala MS, Wang J, MacKenzie EJ, Jurkovich GJ, et al. Early packed red blood cell transfusion and acute respiratory distress syndrome after trauma. Anesthesiology. 2009;110:35160. [PubMed] 64. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, et al. ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499507. [PubMed] 65. Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma. 2003;54:898905. [PubMed] 66. Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien) 2008;150:16575. [PubMed] 67. Talving P, Benfield R, Hadjizacharia P, Inaba K, Chan LS, Demetriades D. Coagulopathy in severe traumatic brain injury: A prospective study. J Trauma.2009;66:5561. [PubMed] 68. Perel P, Roberts I, Shakur H, Thinkhamrop B, Phuenpathom N, Yutthakasemsunt S. Haemostatic drugs for traumatic brain injury. Cochrane Database Syst Rev.2010;1:CD007877. [PubMed] 69. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet. 2010;376:23 32. [PubMed] 70. Oddo M, Levine JM, Frangos S, Carrera E, Maloney-Wilensky E, Pascual JL, et al. Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with

severe traumatic brain injury and refractory intracranial hypertension. J Neurol Neurosurg Psychiatry. 2009;80:91620. [PubMed] 71. Liu-DeRyke X, Collingridge DS, Orme J, Roller D, Zurasky J, Rhoney DH. Clinical impact of early hyperglycemia during acute phase of traumatic brain injury.Neurocrti Care. 2009;11:1517. [PubMed] 72. Jeremitsky E, Omert LA, Dunham CM, Wilberger J, Rodriguez A. The impact of hyperglycemia on patients with severe brain injury. J Trauma. 2005;58:47 50.[PubMed] 73. Sharma D, Jelacic J, Chennuri R, Chaiwat O, Chandler W, Vavilala MS. Incidence and risk factors for perioperative hyperglycemia in children with traumatic brain injury. Anesth Analg. 2009;108:819. [PMC free article] [PubMed] 74. Young B, Ott L, Dempsey R, Haack D, Tibbs P. Relationship between admission hyperglycemia and neurologic outcome of severely brain-injured patients. Ann Surg.1989;210:46672. [PMC free article] [PubMed] 75. Lipshutz AK, Gropper MA. Perioperative glycemic control: An evidence-based review. Anesthesiology. 2009;110:40821. [PubMed] 76. Rovlias A, Kotsou S. The influence of hyperglycemia on neurological outcome in patients with severe head injury. Neurosurgery. 2000;46:33542. [PubMed] 77. Bilotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, et al. Intensive insulin therapy after severe traumatic brain injury: A randomized clinical trial. Neurocrit Care. 2008;9:15966. [PubMed] 78. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med.2001;345:135967. [PubMed] 79. Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, et al. NICE-SUGAR Study Investigators, Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;306:128397. [PubMed] 80. Billotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, et al. Intensive insulin therapy after severe traumatic brain injury: A randomized clinical trial. Neurocrit Care. 2008;9:15966. [PubMed] 81. Bower WF, Lee PY, Kong AP, Jiang JY, Underwood MJ, Chan JC, et al. Perioperative hyperglycemia: A consideration for general surgery? Am J Surg.2010;199:2408. [PubMed] 82. Diltoer M, Camu F. Glucose homeostasis and insulin secretion during isoflurane anesthesia in humans. Anesthesiology. 1988;68:8806. [PubMed]

83. Kitamura T, Ogawa M, Kawamura G, Sato K, Yamada Y. The effects of sevoflurane and propofol on glucose metabolism under aerobic conditions in fed rats.Anesth Analg. 2009;109:147985. [PubMed] 84. Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: A systematic review and meta-analysis. J Neurotrauma. 2008;25:62 71.[PubMed] 85. Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B, et al. CRASH trial collaborators. Final results of MRC CRASH, a randomised placebocontrolled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365:19579. [PubMed]

Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury outcomes at 6 months
CRASH trial collaborators
*

Summary
MRC CRASH is a randomised controlled trial (ISRCTN74459797) of the effect of corticosteroids on death and disability after head injury. We randomly allocated 10 008 adults with head injury and a Glasgow Coma Scale score of 14 or less, within 8 h of injury, to a 48-h infusion of corticosteroid (methylprednisolone) or placebo. Data at 6 months were obtained for 9673 (967%) patients. The risk of death was higher in the corticosteroid group than in the placebo group (1248 [257%] vs 1075 [223%] deaths; relative risk 115, 95% CI 107 124; p=00001), as was the risk of death or severe disability (1828 [381%] vs 1728 [363%] dead or severely disabled; 105, 099110; p=0079). There was no evidence that the effect of corticosteroids differed by injury severity or time since injury. These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury.

J Neurotrauma. 2008 Jan;25(1):62-71. doi: 10.1089/neu.2007.0424.

Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis.
Peterson K, Carson S, Carney N. Source

Oregon Evidence-Based Practice Center, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, Oregon 97239, USA. peterski@ohsu.edu

Abstract
In this study, we conducted an updated meta-analysis of the effects of hypothermia therapy on mortality, favorable neurologic outcome, and associated adverse effects in adults with traumatic brain injury (TBI) for use by Brain Trauma Foundation (BTF)/American Association of Neurological Surgeons (AANS) task force to develop evidence-based treatment guidelines. Our data sources relied on handsearches of four previous good-quality systematic reviews, which all conducted electronic searches of primarily MEDLINE (OVID), EMBASE, and Cochrane Library. An independent, supplemental electronic search of MEDLINE was undertaken as well (last searched June 2007). Only English-language publications of randomized controlled trials of therapeutic hypothermia in adults with TBI were selected for analysis. Two reviewers independently abstracted data on trial design, patient population, hypothermia and cointervention protocols, patient outcomes, and aspects of methodological quality. Pooled relative risks (RR) and associated 95% confidence intervals (CIs) were calculated for each outcome using random-effects models. In the current study, only 13 trials met eligibility criteria, with a total of 1339 randomized patients. Sensitivity analyses revealed that outcomes were influenced by variations in methodological quality. Consequently, main analyses were conducted based on eight trials that demonstrated the lowest potential for bias (n = 781). Reductions in risk of mortality were greatest (RR 0.51; 95% CI 0.33, 0.79) and favorable neurologic outcomes much more common (RR 1.91; 95% CI 1.28, 2.85) when hypothermia was maintained for more than 48 h. However, this evidence comes with the suggestion that the potential benefits of hypothermia may likely be offset by a significant increase in risk of pneumonia (RR 2.37; 95% CI 1.37, 4.10). In sum, the present study's updated meta-analysis supports previous findings that hypothermic therapy constitutes a beneficial treatment of TBI in specific circumstances. Accordingly, the BTF/AANS guidelines task force has issued a Level III recommendation for optional and cautious use of hypothermia for adults with TBI.

Anesth Analg. 2009 Jan;108(1):81-9. doi: 10.1213/ane.0b013e31818a6f32.

Incidence and risk factors for perioperative hyperglycemia in children with traumatic brain injury.
Sharma D, Jelacic J, Chennuri R, Chaiwat O, Chandler W, Vavilala MS. Source
Department of Anesthesiology, Harborview Medical Center, University of Washington, Seattle, Washington 98104, USA.

Abstract
BACKGROUND: Hyperglycemia after traumatic brain injury (TBI) is associated with poor outcome. In this study, we examined the incidence and risk factors for perioperative hyperglycemia in children with TBI. METHODS: A retrospective cohort study of children <or=13 yr who underwent urgent or emergent craniotomy for TBI at Harborview Medical Center (level I Adult and Pediatric Trauma Center) between 1994 and 2004 was performed. Preoperative (emergency department to general anesthesia start), intraoperative (during general anesthesia), and immediate postoperative (first 24 h after surgery) glucose values for each patient were retrieved. The incidence of hyperglycemia (glucose >or=200 mg/dL) and hypoglycemia (glucose <60 mg/dL) was determined. Persistent hyperglycemia was defined as hyperglycemia during any 2/3

(preoperative, intraoperative, and immediate postoperative) study periods, whereas transient hyperglycemia was defined as hyperglycemia during any one study period. Multivariate logistic regression analysis was used to determine the independent predictors of perioperative hyperglycemia. Data are presented as adjusted odds ratio (AOR) (95% CI) and P < 0.05 reflects significance. RESULTS: At least one serum glucose value was recorded during each study period: preoperative (86 [82%]), intraoperative (94 [89%]), and postoperative (101 [97%]). Sixty-four percent of children had less than one glucose recorded per anesthetic hour. Forty-seven (45%) children had hyperglycemia during at least one study period. Transient hyperglycemia occurred in 29 (28%) and persistent hyperglycemia occurred in 18 (17%) children. Independent predictors of perioperative hyperglycemia were age <4 yr (AOR [95% CI]; 3.5 [1.2-10.6]), Glasgow Coma Scale <or=8 (AOR 95% CI; 7.2 [2.4-21.5]) and the presence of multiple lesions including subdural hematoma (AOR 95% CI; 34.7 [2.3-525.5]). Six children were treated with insulin, and two children had hypoglycemia, unrelated to insulin treatment. CONCLUSIONS: Perioperative hyperglycemia was common and intraoperative hypoglycemia was not rare, but more frequent intraoperative glucose sampling may be needed to better determine the incidence of hypo and hyperglycemia during the perioperative period. Age <4 yr, severe TBI and the presence of multiple lesions, including subdural hematoma, were risk factors for perioperative hyperglycemia.

Anesth Analg. 2009 Nov;109(5):1479-85. doi: 10.1213/ANE.0b013e3181b8554a.

The effects of sevoflurane and propofol on glucose metabolism under aerobic conditions in fed rats.
Kitamura T, Ogawa M, Kawamura G, Sato K, Yamada Y. Source
Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. tyy-kitamura@m7.dion.ne.j

Abstract
BACKGROUND: Recent studies reported that intraoperative hyperglycemia is an independent risk factor for mortality and morbidity related to surgery. Volatile anesthetics, such as sevoflurane, impair glucose use, suggesting their possible contributions to intraoperative hyperglycemia. However, the effects of IV anesthetics, such as propofol, on glucose metabolism are poorly understood. Thus, we compared the effects of sevoflurane and propofol on glucose metabolism under aerobic conditions in fed rats. METHODS: We first examined changes in blood glucose levels in rats undergoing sigmoid colostomy under sevoflurane, sevoflurane/buprenorphine, propofol, and propofol/buprenorphine anesthesia. We then examined changes in blood glucose levels after glucose administration using awake rats, rats under sevoflurane anesthesia, and rats under propofol anesthesia. RESULTS: Blood glucose levels increased markedly after sigmoid colostomy under sevoflurane anesthesia; the marked increases could not be prevented by the coadministration of buprenorphine. Under propofol anesthesia, blood glucose levels did not change after sigmoid colostomy at the highest dose, but increased slightly at the lowest and intermediate doses; the slight increases were completely prevented by the coadministration of buprenorphine. Whereas

changes in blood glucose levels after glucose administration in rats under sevoflurane anesthesia were significantly greater than those in awake rats, the changes in rats under propofol anesthesia were similar to those in awake rats. CONCLUSIONS: During surgery, hyperglycemia was observed under sevoflurane and sevoflurane/buprenorphine anesthesia, but blood glucose levels were relatively stable under propofol and propofol/buprenorphine anesthesia. Whereas sevoflurane exaggerates glucose intolerance, propofol has no significant effects on glucose tolerance. We speculate that this feature of propofol contributes, at least in part, to the stable glucose metabolism during surgery observed in this study. The results of this study confirm the marked difference in the effects of sevoflurane and propofol on glucose metabolism.

Anesthesiology. 1988 Jun;68(6):880-6.

Glucose homeostasis and insulin secretion during isoflurane anesthesia in humans.

Diltoer M, Camu F. Source
Department of Anesthesiology, Flemish Free University of Brussels Medical School, Belgium.

Abstract
The effect of isoflurane-air anesthesia on glucose tolerance in humans was investigated using two successive intravenous glucose tolerance tests (IVGTT). After a first IVGTT while awake, patients received a second IVGTT either while awake (group I), during anesthesia with isoflurane-air and pancuronium without surgical stimulation (group II), or during the same anesthetic technique but combined with surgery (group III). Isoflurane seemed to induce glucose intolerance (glucose disappearance rate K10-60 min = 1.628 +/- 0.462% min-1 [control] versus 1.086 +/- 0.920% min-1 [anesthesia], P less than 0.05) partly due to a decreased glucose induced insulin response. Growth hormone and norepinephrine levels were also increased during anesthesia. Epinephrine levels were lowered by isoflurane anesthesia. Although glucose intolerance was marked during surgery (K10-60 min = 0.892 +/- 0.286% min1), the glucose-induced insulin response remained similar to that observed in patients in group II, while growth hormone, cortisol, epinephrine, and norepinephrine concentrations increased significantly. These known stress factors thus seemed to enhance glucose intolerance through a diminished response to insulin action and/or an enhanced hepatic glucose output, rather than by further impairing pancreatic insulin secretion.

Abstract
Background
Intraoperative hyperglycemia in cardiac and neurosurgical patients is significantly associated with morbidity. Little is known about the perioperative glycemic profile or its impact in other surgical populations or in nondiabetic patients.

Methods
A systematic review of blood glucose values during major general surgical procedures reported since 1980 was conducted. Data extracted included blood glucose measures, study sample size, gender distribution, age grouping, study purpose, surgical procedure, anesthetic details, and infusion regime. Excluded studies were those with subjects with diabetes insipidus, insulin-treated diabetes, renal or hepatic failure, adrenal gland tumors or dysfunction, pregnancy, and emergency or trauma surgery.

Results
Blood glucose levels rose significantly with the induction of anesthesia ( P < .001) in nondiabetic patients. At incision, 2 hours, 4 hours, and 6 hours, 30%, 40%, 38%, and 40% of studies, respectively, reported hyperglycemia.

Conclusions

Factors that confound or protect against significant rises in perioperative glycemic levels in nondiabetic patients were identified. The findings facilitate investigating the impact of hyperglycemia on general surgical outcomes.

Anesthesiology. 2009 Feb;110(2):408-21. doi: 10.1097/ALN.0b013e3181948a80.

Perioperative glycemic control: an evidence-based review.

Lipshutz AK, Gropper MA. Source
Department of Medicine, Stanford University Medical Center, USA.

Abstract
Hyperglycemia in perioperative patients has been identified as a risk factor for morbidity and mortality. Intensive insulin therapy (IIT) has been shown to reduce morbidity and mortality among the critically ill, decrease infection rates and improve survival after cardiac surgery, and improve outcomes in acute neurologic injury and acute myocardial infarction. However, recent evidence of severe hypoglycemia and adverse events associated with IIT brings its safety and efficacy into question. In this article, we summarize the mechanisms and rationale of hyperglycemia and IIT, review the evidence behind the use of IIT in the perioperative period, and discuss the implications of including glycemic control in national quality benchmarks. We conclude that while avoidance of hyperglycemia is clearly beneficial, the appropriate glucose target and specific subpopulations who might benefit from IIT have yet to be identified. Given the potential for harm, inclusion of glucose targets in national quality benchmarks is premature.

Anesthesiology. 2009 Feb;110(2):408-21. doi: 10.1097/ALN.0b013e3181948a80.

Perioperative glycemic control: an evidence-based review.

Lipshutz AK, Gropper MA. Source
Department of Medicine, Stanford University Medical Center, USA.

Abstract
Hyperglycemia in perioperative patients has been identified as a risk factor for morbidity and mortality. Intensive insulin therapy (IIT) has been shown to reduce morbidity and mortality among the critically ill, decrease infection rates and improve survival after cardiac surgery, and improve outcomes in acute neurologic injury and acute myocardial infarction. However, recent evidence of severe hypoglycemia and adverse events associated with IIT brings its safety and efficacy into question. In this article, we summarize the mechanisms and rationale of hyperglycemia and IIT, review the evidence behind the use of IIT in the perioperative period, and discuss the implications of including glycemic control in national quality benchmarks. We conclude that while avoidance of hyperglycemia is clearly beneficial, the appropriate glucose target and specific subpopulations who might benefit from IIT have yet to be identified. Given the potential for harm, inclusion of glucose targets in national quality benchmarks is premature.

Ann Surg. 1989 Oct;210(4):466-72; discussion 472-3.

Relationship between admission hyperglycemia and neurologic outcome of severely brain-injured patients.
Young B, Ott L, Dempsey R, Haack D, Tibbs P. Source
Division of Neurosurgery, University of Kentucky Medical Center, Lexington 40536-0084.

Abstract
Severe head injury is associated with a stress response that includes hyperglycemia, which has been shown to worsen outcome before or during cerebral ischemia. To better define the relationship between human head injury and hyperglycemia, glucose levels were followed in 59 consecutive brain-injured patients from hospital admission up to 18 days after injury. The patients who had the highest peak admission 24-hour serum glucose levels had the worse 18day neurologic outcome (p = 0.01). Patients with peak 24-hour admission glucose levels greater than 200 mg/dL had a two-unit increase in Glasgow Coma Scale score while patients with admission peak 24-hour serum glucose levels less than or equal to 200 mg/dL had a four-unit increase in Glasgow Coma Scale score during the 18-day study period (p = 0.04). There was a significant relationship between 3-month and 1-year outcome and peak admission 24-hour serum glucose level (p = 0.02 and p = 0.02, respectively). Those patients with admission peak 24-hour serum glucose levels less than or equal to 200 mg/dL had a greater percentage of favorable outcome at 18 days, 3 months, and 1 year than those with admission peak 24-hour glucose levels greater than 200 mg/dL (p = 0.0007, p = 0.03, and p = 0.005, respectively). A significant relationship between admission peak 24-hour Glasgow Coma Scale score and 18day, 3-month, and 1-year outcomes was found (p = 0.0001, p = 0.0002, and p = 0.0002, respectively). Patients with mean admission peak 24-hour Glasgow Coma Scale scores of 3.5, 6, and 10 had mean admission 24-hour peak serum glucose levels of 252 +/- 23.5, 219.1 +/- 19, and 185.8 +/- 21, respectively (p = 0.05). These relationships were not significantly altered when confounding variables such as the amount of glucose given over the initial 24-hour postinjury period, the presence of diabetes or multiple injuries, and whether patients were given steroids, dilantin, or insulin were statistically incorporated. These data suggest that admission hyperglycemia is a frequent component of the stress response to head injury, a significant indicator of severity of injury, and a significant predictor of outcome from head injury. Neurocrit Care. 2008;9(2):159-66. doi: 10.1007/s12028-008-9084-9.

Intensive insulin therapy after severe traumatic brain injury: a randomized clinical trial.
Bilotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, Santoro A, Rosa G. Source
Department of Anesthesiology, Critical Care and Pain Medicine, La Sapienza University of Rome, Viale Somalia 81, Rome, 00199, Italy. bilotta@tiscali.it

Abstract
INTRODUCTION: To investigate the risks and possible benefits of routine versus intensive insulin therapy, assessed by the frequency of hypoglycemic events defined as a glucose concentration less than 80 mg/dl (<4.44 mmol/l) in patients admitted to the intensive care unit (ICU) after severe traumatic brain injury (TBI).

METHODS AND RESULTS: Ninety-seven patients admitted after severe TBI, were enrolled and randomly assigned to two groups of target glycemia. Insulin was infused at conventional rates when blood glucose levels exceeded 220 mg/dl (12.22 mmol/l) or at intensive rates, to maintain glycemia at 80-120 mg/dl (4.44-6.66 mmol/l). The following primary and outcome variables were measured during followup: hypoglycemic episodes, duration of ICU stay, infection rate, and 6-month mortality and neurologic outcome measured using the Glasgow Outcome Scale (GOS). Episodes of hypoglycemia (defined as blood glucose <80 mg/dl or 4.44 mmol/l) were significantly higher in patients receiving intensive insulin therapy: median (min-max) conventional insulin therapy 7 (range 0-11) vs. intensive insulin therapy 15 (range 6-33); P<0.0001. Duration of ICU stay was shorter in patients receiving intensive insulin therapy (7.3 vs. 10.0 days; P < 0.05); while infection rates during ICU stay (25.0% vs. 38.8%, P = 0.15), and GOS scores and mortality at 6 months were similar in the two groups. CONCLUSIONS: Intensive insulin therapy significantly increases the risk of hypoglycemic episodes. Even though patients receiving intensive insulin therapy have shorter ICU stays and infection rates similar to those receiving conventional insulin therapy, both groups have similar follow-up mortality and neurologic outcome. Hence if intensive insulin therapy is to be used, great effort must be taken to avoid hypoglycemia.

N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24.

Intensive versus conventional glucose control in critically ill patients.

NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hbert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Collaborators (203) Abstract
BACKGROUND: The optimal target range for blood glucose in critically ill patients remains unclear. METHODS: Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization. RESULTS: Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control

group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39). CONCLUSIONS: In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.) 2009 Massachusetts Medical Society

N Engl J Med. 2001 Nov 8;345(19):1359-67.

Intensive insulin therapy in critically ill patients.

van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Source
Department of Intensive Care Medicine, Catholic University of Leuven, Belgium. greta.vandenberghe@med.kuleuven.ac.be

Abstract
BACKGROUND: Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. METHODS: We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). RESULTS: At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multipleorgan failure with a proven septic focus. Intensive insulin therapy also reduced overall inhospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. CONCLUSIONS: Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.

Neurocrit Care. 2009;11(2):151-7. doi: 10.1007/s12028-009-9228-6. Epub 2009 May 29.

Clinical impact of early hyperglycemia during acute phase of traumatic brain injury.
Liu-DeRyke X, Collingridge DS, Orme J, Roller D, Zurasky J, Rhoney DH. Source
Orlando Regional Medical Center, 1414 Kuhl Ave, MP 180, Orlando, FL 32806, USA. xi.liu@orlandohealth.com

Abstract
INTRODUCTION: While tight glucose control has been widely adopted in the critical care setting, the optimal target glucose level following acute traumatic brain injury (TBI) remains debatable. This observational study was conducted to delineate the relationship between glucose levels and clinical outcomes during acute phase (first 5 days) of TBI. METHODS: We retrospectively identified 429 TBI patients admitted to the intensive care unit (ICU) from January 2005 to December 2006. Of those, 380 patients were retained for final analysis. Collected data included demographics, admission Glasgow Coma Scale (GCS), and APACHE II, glucose on admission and during the first 5 days of admission, and insulin use. Clinical outcomes included mortality, ICU, and hospital length of stay. RESULTS: The overall hospital mortality was 13.2% (n = 50). Demographics were similar between survivor and nonsurvivor groups; however, nonsurvivors were older and had worse disease severity on admission. Nonsurvivors also had significantly higher glucose levels at admission and during the first 24 h of admission (P < 0.001). Based on the receiver operating characteristic (ROC) curve, admission and day-1 peak glucose were better predictors for mortality compared to hospital days 2-5 glucose levels, with day-1 peak glucose being the best predictor of mortality (AUC = 0.820). A Kaplan-Meier survival analysis also showed that patients with glucose <160 mg/dl during the first day of ICU admission had a significantly better survival rate compared to those with glucose > or =160 mg/dl (P < 0.001). Two glucose bands, <60 and > or =160 mg/dl, were identified to be associated with increased mortality irrespective of injury severity (OR = 1.130; 95% CI 1.034-1.235; P = 0.007; OR = 1.034; 95% CI 1.021-1.047, P < 0.001; respectively). CONCLUSIONS: Findings from our study suggest a glucose level > or =160 mg/dl within the first 24 h of admission following TBI is associated with poor outcomes irrespective of severity of injury, and this presents a timeframe for which active therapeutic interventions may improve clinical outcomes. Prospective efficacy trials are needed to corroborate these findings.

J Neurol Neurosurg Psychiatry. 2009 Aug;80(8):916-20. doi: 10.1136/jnnp.2008.156596. Epub 2009 Mar 16.

Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension.
Oddo M, Levine JM, Frangos S, Carrera E, Maloney-Wilensky E, Pascual JL, Kofke WA, Mayer SA, LeRoux PD.

Source
Neurointensive Care Unit, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.

Abstract
BACKGROUND: The impact of osmotic therapies on brain oxygen has not been extensively studied in humans. We examined the effects on brain tissue oxygen tension (PbtO(2)) of mannitol and hypertonic saline (HTS) in patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension. METHODS: 12 consecutive patients with severe TBI who underwent intracranial pressure (ICP) and PbtO(2) monitoring were studied. Patients were treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP (>20 mm Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with mannitol. PbtO(2), ICP, mean arterial pressure, cerebral perfusion pressure (CPP), central venous pressure and cardiac output were monitored continuously. RESULTS: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), were analysed. HTS treatment was associated with an increase in PbtO(2) (from baseline 28.3 (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min; all p<0.01) while mannitol did not affect PbtO(2) (baseline 30.4 (11.4) vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p>0.1). Compared with mannitol, HTS was associated with lower ICP and higher CPP and cardiac output. CONCLUSIONS: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.

Lancet. 2010 Jul 3;376(9734):23-32. doi: 10.1016/S0140-6736(10)60835-5. Epub 2010 Jun 14.

Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S,Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Meja-Mantilla J, Miranda J, Morales C, Olaomi O,Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. Collaborators (570) Source
Clinical Trials Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

Abstract
BACKGROUND: Tranexamic acid can reduce bleeding in patients undergoing elective surgery. We assessed the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients.

METHODS: This randomised controlled trial was undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other. All analyses were by intention to treat. This study is registered as ISRCTN86750102, Clinicaltrials.govNCT00375258, and South African Clinical Trial RegisterDOH-27-0607-1919. FINDINGS: 10 096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10 060 and 10 067, respectively, were analysed. All-cause mortality was significantly reduced with tranexamic acid (1463 [14.5%] tranexamic acid group vs 1613 [16.0%] placebo group; relative risk 0.91, 95% CI 0.85-0.97; p=0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI 0.76-0.96; p=0.0077). INTERPRETATION: Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients. FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.

Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007877. doi: 10.1002/14651858.CD007877.pub2.

Haemostatic drugs for traumatic brain injury.

Perel P, Roberts I, Shakur H, Thinkhamrop B, Phuenpathom N, Yutthakasemsunt S. Source
Cochrane Injuries Group, London School of Hygiene & Tropical Medicine, Keppel Street, London, UK, WC1E 7HT.

Abstract
BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability. Intracranial bleeding is a common complication of TBI, and intracranial bleeding can develop or worsen after hospital admission. Haemostatic drugs may reduce the occurrence or size of intracranial bleeds and consequently lower the morbidity and mortality associated with TBI. OBJECTIVES: To assess the effects of haemostatic drugs on mortality, disability and thrombotic complications in patients with traumatic brain injury. SEARCH STRATEGY:

We searched the electronic databases: Cochrane Injuries Group Specialised Register (3 February 2009), CENTRAL (The Cochrane Library 2009, Issue 1), MEDLINE (1950 to Week 3 2009), PubMed (searched 3 February 2009 (last 180 days)), EMBASE (1980 to Week 4 2009), CINAHL (1982 to January 2009), ISI Web of Science: Science Citation Index Expanded (SCIEXPANDED) (1970 to January 2009), ISI Web of Science: Conference Proceedings Citation Index - Science (CPCI-S) (1990 to January 2009). SELECTION CRITERIA: We included published and unpublished randomised controlled trials comparing haemostatic drugs (antifibrinolytics: aprotinin, tranexamic acid (TXA), aminocaproic acid or recombined activated factor VIIa (rFVIIa)) with placebo, no treatment, or other treatment in patients with acute traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two review authors independently examined all electronic records, and extracted the data. We judged that there was clinical heterogeneity between trials so we did not attempt to pool the results of the included trials. The results are reported separately. MAIN RESULTS: We included two trials. One was a post-hoc analysis of 30 TBI patients from a randomised controlled trial of rFVIIa in blunt trauma patients. The risk ratio for mortality at 30 days was 0.64 (95% CI 0.25 to 1.63) for rFVIIa compared to placebo. This result should be considered with caution as the subgroup analysis was not pre-specified for the trial. The other trial evaluated the effect of rFVIIa in 97 TBI patients with evidence of intracerebral bleeding in a computed tomography (CT) scan. The corresponding risk ratio for mortality at the last follow up was 1.08 (95% CI 0.44 to 2.68). The quality of the reporting of both trials was poor so it was difficult to assess the risk of bias. AUTHORS' CONCLUSIONS: There is no reliable evidence from randomised controlled trials to support the effectiveness of haemostatic drugs in reducing mortality or disability in patients with TBI. New randomised controlled trials assessing the effects of haemostatic drugs in TBI patients should be conducted. These trials should be large enough to detect clinically plausible treatment effects.

J Trauma. 2009 Jan;66(1):55-61; discussion 61-2. doi: 10.1097/TA.0b013e318190c3c0.

Coagulopathy in severe traumatic brain injury: a prospective study.

Talving P, Benfield R, Hadjizacharia P, Inaba K, Chan LS, Demetriades D. Source
Department of Surgery, Division of Trauma and Critical Care at the Los Angeles County, University of Southern California Medical Center, Los Angeles, California 90033, USA.

Abstract
BACKGROUND: The incidence and risk factors for traumatic brain injury (TBI)-associated coagulopathy after severe TBI (sTBI) and the effect of this complication on outcomes have not been evaluated in any large prospective studies. METHODS: Prospective study of all patients admitted to the surgical intensive care unit (ICU) of an urban, Level I trauma center from June 2005 through May 2007 with sTBI (head Abbreviated Injury Scale score of >or=3). Criteria for TBI-coagulopathy included a clinical condition consistent with coagulopathy, i.e. sTBI, in conjunction with a platelet count <100,000 mm3 and/or elevated

international normalized ratio and/or activated partial thromboplastin time. The following potential risk factors with p < 0.2 on bivariate analysis were included in a stepwise logistic regression analysis to identify independent risk factors for TBI coagulopathy and its association with mortality: age, mechanism of injury (blunt [B] or penetrating [P]), presence of hypotension upon admission, Injury Severity Score (ISS), Glasgow Coma Scale (GCS), head and other body area Abbreviated Injury Scale, isolated head injury, diffuse axonal injury, cerebral edema, intracranial hemorrhage (intraventricular, parenchymal, subarachnoid, or subdural), pneumocephalus, and presence of midline shift. RESULTS: A total of 436 patients (392 blunt, 44 penetrating) met study criteria, of whom 387 patients had isolated SHI. TBI coagulopathy occurred in 36% of all patients (B: 33%, P: 55%; p < 0.0075) and in 34% of patients with isolated head injury (B: 32%, P: 54%; p = 0.0062). Independent risk factors for TBI-coagulopathy in isolated sTBI were found to include a GCS score of <or=8, ISS >or=16, presence of cerebral edema, subarachnoid hemorrhage, and midline shift. ICU lengths of stay were significantly longer in SHI patients who developed TBI coagulopathy (12.7 vs. 8.8 days; p = 0.006). The development of TBI coagulopathy in SHI was associated with increased mortality, adjusted odds ratio (95% confidence interval): 9.61 (4.06-25.0); p < 0.0001. CONCLUSION: The incidence of TBI coagulopathy in SHI is high, especially in penetrating injuries. Independent risk factors for coagulopathy in isolated head injuries include GCS score of <or=8, ISS >or=16, hypotension upon admission, cerebral edema, subarachnoid hemorrhage, and midline shift. The development of TBI coagulopathy is associated with longer ICU length of stay and an almost 10-fold increased risk of death.

Acta Neurochir (Wien). 2008 Feb;150(2):165-75; discussion 175. doi: 10.1007/s00701-0071475-8. Epub 2008 Jan 2.

Coagulation disorders after traumatic brain injury.

Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI. Source
Department of Neurosurgery, Erasmus MC, Rotterdam, The Netherlands. b.s.harhangi@erasmusmc.nl

Abstract
BACKGROUND: Over the past decade new insights in our understanding of coagulation have identified the prominent role of tissue factor. The brain is rich in tissue factor, and injury to the brain may initiate disturbances in local and systemic coagulation. We aimed to review the current knowledge on the pathophysiology, incidence, nature, prognosis and treatment of coagulation disorders following traumatic brain injury (TBI). METHODS: We performed a MEDLINE search from 1966 to April 2007 with various MESH headings, focusing on head trauma and coagulopathy. We identified 441 eligible English language studies. These were reviewed for relevance by two independent investigators. A meta-analysis was performed to calculate the frequencies of coagulopathy after TBI and to determine the association of coagulopathy and outcome, expressed as odds ratios. RESULTS: Eighty-two studies were relevant for the purpose of this review. Meta-analysis of 34 studies reporting the frequencies of coagulopathy after TBI, showed an overall prevalence of 32.7%.

The presence of coagulopathy after TBI was related both to mortality (OR 9.0; 95%CI: 7.3-11.6) and unfavourable outcome (OR 36.3; 95%CI: 18.7-70.5). CONCLUSIONS: We conclude that coagulopathy following traumatic brain injury is an important independent risk factor related to prognosis. Routine determination of the coagulation status should therefore be performed in all patients with traumatic brain injury. These data may have important implications in patient management. Well-performed prospective clinical trials should be undertaken as a priority to determine the beneficial effects of early treatment of coagulopathy.

Crit Care Med. 1998 Jan;26(1):142-8.

Mortality prediction in head trauma patients: performance of Glasgow Coma Score and general severity systems.
Alvarez M, Nava JM, Ru M, Quintana S. Source
Intensive Care Unit, Hospital Mtua de Terrassa, Barcelona, Spain.

Abstract
OBJECTIVE: To assess the performance of general severity systems (Acute Physiology and Chronic Health Evaluation [APACHE] II, Simplified Acute Physiology Score [SAPS] II, and Mortality Probability Models [MPM] II) for head trauma patients and to compare these systems with the Glasgow Coma Score, in order to obtain a good estimate of severity of illness and probability of hospital mortality. DESIGN: Inception cohort. SETTING: Adult medical and surgical intensive care units in 12 European and North American countries. PATIENTS: Patients (n = 401) who were diagnosed with head trauma (with/without multiple trauma), leading to intensive care unit admission, and who were not brain dead at the time of arrival. INTERVENTIONS: Statistical analysis to assess the performance of general severity systems. MEASUREMENTS AND MAIN RESULTS: Vital status at the time of hospital discharge was the outcome measure. Performance of the severity systems (SAPS II, MPM II0 [MPM at admission], MPM II24 [MPM at 24 hrs], and APACHE II) was assessed by evaluating calibration and discrimination. Logistic regression was used to convert the Glasgow Coma Score into a probability of death. The MPM II system (either MPM II0 or MPM 1124) provided an adequate estimation of the mortality experience in patients with head trauma. SAPS II and APACHE II systems did not calibrate well, although they showed high discrimination (area under the receiver operating characteristic curve 0.95 for SAPS II, 0.94 for APACHE II, and 0.90 for MPM II0 and MPM II24). The logistic regression model containing the Glasgow Coma Score as an independent variable and developed in this group of patients was not as well calibrated as MPM II. The discrimination of this model was very high, in the range observed for the APACHE II, SAPS II, and MPM II systems. CONCLUSIONS: The MPM II system performs better than APACHE II, SAPS II, and Glasgow Coma Score for head trauma patients. If our results are supported by other studies, MPM II would be an

appropriate tool to assess severity of illness in head trauma patients, with applications to clinical practice and clinical research.

J Am Coll Surg. 2008 Sep;207(3):398-406. doi: 10.1016/j.jamcollsurg.2008.03.013. Epub 2008 May 19.

Role of anemia in traumatic brain injury.

Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, Margulies DR. Source
Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Abstract
BACKGROUND: Few studies have investigated the effects of anemia in patients with traumatic brain injury (TBI). The objective of this study was to examine the role of anemia and blood transfusion on outcomes in TBI patients. STUDY DESIGN: We performed a retrospective review of all blunt trauma patients with TBI admitted to the ICU from July 1998 to December 2005. Admission and daily ICU blood hemoglobin (hemoglobin) levels and blood transfusions during the first week of hospitalization were measured. Anemia was defined as a hemoglobin<9 g/dL occurring on 3 consecutive blood draws. The role of anemia and blood transfusion was investigated using logistic regression adjusting for factors, with p<0.2 from the bivariate analysis. RESULTS: During the study period, 1,150 TBI patients were admitted to the ICU. When both anemia and blood transfusion were included in the full model, blood transfusion was significantly associated with higher mortality (adjusted odds ratio [AOR], 2.19 [95% CI, 1.27, 3.75]; p=0.0044) and more complications (AOR, 3.67 [95% CI, 2.18, 6.17]; p<0.0001), but anemia was not. But when transfusion was not included in the full model, anemia was a significant risk factor for mortality (AOR, 1.59 (95% CI, 1.13, 2.24); p=0.007) and for complications (AOR, 1.95 [95% CI, 1.42, 2.70]; p<0.0001). CONCLUSIONS: Blood transfusion is associated with significantly worse outcomes in traumatic brain injured patients. In addition, blood transfusion is a major contributing factor to worse outcomes in TBI patients who are anemic. We caution against the liberal use of blood in TBI patients.

J Trauma. 2006 Sep;61(3):567-71.

Retrospective evaluation of anemia and transfusion in traumatic brain injury.

Carlson AP, Schermer CR, Lu SW. Source

Department of Neurosurgery, University of New Mexico, Albuquerque, New Mexico 871310001, USA.

Abstract
BACKGROUND: Despite clear evidence in critical care that blood transfusion has an adverse impact on outcome, neurosurgical textbooks still recommend transfusion of patients with traumatic brain injury (TBI) to a hematocrit (HCT) of 30%. There is little empirical evidence to support this practice. The current study addresses transfusion requirements in TBI in terms of neurologic outcome. METHODS: Retrospective record review of patients with severe TBI. Outcome measures were Glasgow Coma Scale score (GCS), Glasgow Outcome Score (GOS), and Ranchos Los Amigos Score (RLA) at hospital discharge (D/C); and GOS and Functional Independence Measures at followup. Association of outcomes with the number of days the HCT <30% and lowest measured HCT were evaluated. RESULTS: In all, 169 patients reviewed; 150 with D/C outcome data and 72 with long-term follow-up data. Univariate analysis showed that lowest measured HCT was associated with lower D/C GCS, D/C GOS, and RLA scores. Linear regression showed that more days with HCT <30% were associated with improved neurologic outcomes measured by GOS (R2 = 0.424, p < 0.001), GCS (R2 = 0.381, p < 0.001) and RLA (R2 = 0.392, p < 0.001) scores on D/C. Both transfusion and lowest measured HCT were significantly associated with all lower outcome scores on D/C. Additional factors with adverse impact on outcome were head Abbreviated Injury Score (AIS), Injury Severity Score, hyperglycemia, and hypotension. Long-term outcomes were only significantly associated with head AIS. CONCLUSIONS: Patients with severe TBI should not have a different transfusion threshold than other critical care patients. Prospective studies are needed to evaluate the effects of anemia in TBI.

Comment in
Evaluating anemia as a risk factor for worse neurologic outcome after traumatic brain injury (TBI). [J Trauma. 2007]

Crit Care Med. 2009 Mar;37(3):1074-8. doi: 10.1097/CCM.0b013e318194ad22.

The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury.
Zygun DA, Nortje J, Hutchinson PJ, Timofeev I, Menon DK, Gupta AK. Source
Department of Anaesthesia, University of Cambridge, Cambridge, United Kingdom.

Abstract
OBJECTIVE: There is evidence to suggest that anemia after severe traumatic brain injury (sTBI) is detrimental. However, there is a paucity of evidence supporting the use of transfusion of packed red blood cells in patients with sTBI. To understand the acute effect of packed red blood cell transfusion on cerebral oxygenation and metabolism in patients with sTBI.

DESIGN: Prospective clinical study. SETTING: Addenbrooke's Neurosciences Critical Care Unit, a 21-bed tertiary academic unit. PATIENTS: Thirty patients with sTBI. INTERVENTIONS: Patients were randomized by computer random number generator to one of three transfusion thresholds: 8, 9, or 10 g/dL. When the patients' hemoglobin concentration fell below their assigned threshold, two units of packed red blood cells were transfused over 2 hours. A 1-hour period of stabilization was observed before final data collection. MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in brain tissue oxygen (Pbto2). Secondary outcomes included dependence of baseline hemoglobin concentration and baseline Pbto2 on the relationship of transfusion and Pbto2, and the effect of transfusion on lactate pyruvate ratio (LPR) and brain pH as markers of cerebral metabolic state. Fifty-seven percent of patients experienced an increase in Pbto2 during the course of the study, whereas in 43% of patients, Pbto2 either did not change or decreased. Multivariable generalized estimating equation analysis revealed change in hemoglobin concentration to significantly and positively associated with change in Pbto2 [0.10 kPa/(g/dL) 95% confidence interval 0.03-0.17, p = 0.003]. Improvement in Pbto2 was not associated with baseline hemoglobin concentration or low Pbto2 (<1 kPa). Fifty-six percent of patients experienced an increase in LPR. No significant relationship between change in LPR or transfusion on pHbt and change in hemoglobin could be demonstrated. CONCLUSIONS: Transfusion of packed red blood cells acutely results in improved brain tissue oxygen without appreciable effect on cerebral metabolism.

Intensive Care Med. 2006 Nov;32(11):1733-40. Epub 2006 Sep 22.

Transfusion of erythrocyte concentrates produces a variable increment on cerebral oxygenation in patients with severe traumatic brain injury: a preliminary study.
Leal-Noval SR, Rincn-Ferrari MD, Marin-Niebla A, Cayuela A, Arellano-Orden V, Marn-Caballos A, Amaya-Villar R, Ferrndiz-Milln C,Murillo-Cabeza F. Source
Neurotrauma Critical Care, Hospital Universitario "Virgen del Roco", Avda/ Manuel Siurot, s/nr, 41013, Seville, Spain. sramon@cica.es

Abstract
OBJECTIVE: To investigate the long-term influence of erythrocyte transfusion on cerebral oxygenation in patients with severe traumatic brain injury. DESIGN: Prospective and observational study. SETTING: Neurotrauma intensive care unit of trauma center level I.

PATIENTS: Sixty consecutive, hemodynamically stable patients with severe traumatic brain injury, pretransfusion hemoglobin<100g/l, non-bleeding and monitored through intracranial pressure and brain tissue partial pressure of oxygen (PtiO(2)) catheters were included. INTERVENTIONS: Transfusion of 1-2 units of red blood cells. MEASUREMENTS AND RESULTS: Ten sets of variables (pretransfusion, end of transfusion, and 1, 2, 3, 4, 5, 6, 12 and 24h after transfusion) were recorded, including: PtiO(2), cerebral perfusion pressure (CPP), end-tidal CO(2), peripheral saturation of oxygen, temperature, hemoglobin, lactate and PaO(2)/FiO(2) ratio. Transfusion was associated with an increase in PtiO(2) during a 6-h period, with a peak at 3h (26.2%; p=0.0001) in 78.3% of the patients. No relationship was observed between PtiO(2), CPP and hemoglobin increments. The relative increment in PtiO(2) at hour 3 was only correlated with baseline PtiO(2) (r(2) 0.166; p=0.001). All of the patients with basal PtiO(2)<15mmHg showed an increment in PtiO(2) versus 74.5% of patients with basal PtiO(2)>or=15mmHg (p<0.01, hour 3). CONCLUSIONS: Erythrocyte transfusion is associated with a variable and prolonged increment of cerebral tissue oxygenation in anemic patients with severe traumatic brain injury. Low baseline PtiO(2) levels (<15mmHg) could define those patients who benefit the most from erythrocyte transfusion.

Clin Hemorheol Microcirc. 2006;35(1-2):51-7.

Beneficial effects due to increasing blood and plasma viscosity.

Martini J, Carpentier B, Chvez Negrete A, Cabrales P, Tsai AG, Intaglietta M. Source
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. jmartini@bioeng.ucsd.edu

Abstract
Increased plasma and blood viscosity are usually associated with pathological conditions; however there are several situations in which the elevation of both parameters results in increased perfusion and the lowering of peripheral vascular resistance. In extreme hemodilution blood viscosity is too low and insufficient to maintain functional capillary density, a problem that in experimental studies is shown to be corrected by increasing plasma viscosity up to 2.2 cP. This effect is mediated by Nitric oxide (NO) production via restoration of shear stress at the endothelium as shown by microelectrode perivascular measurements of NO concentration. Moderate elevations of blood viscosity by increasing hematocrit (approximately 10% of baseline) result in reductions of blood pressure by 10 mmHg of baseline. This effect is also NO mediated since it is absent after N-nitro-L-arginine methyl ester (L-NAME) treatment and in endothelial NO synthase deficient mice. These results show that the rheological properties of plasma affect vessel diameter in the microcirculation leading to counterintuitive responses to the increase in viscosity.

Curr Opin Crit Care. 2008 Apr;14(2):156-62. doi: 10.1097/MCC.0b013e3282f57577.

Optimal hemoglobin concentration in patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury.
Leal-Noval SR, Moz-Gmez M, Murillo-Cabezas F. Source
Neurocritical Care Division, Hospital Universitario Virgen del Roco, Seville, Spain. sramon@cica.es

Abstract
PURPOSE OF REVIEW: The review outlines recent clinical and experimental studies regarding the effects of red bloodcell transfusion on clinical outcome in neurocritical patients, including patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Optimal hemoglobin transfusion trigger and the role of other transfusion indicators for neurocritical patients are discussed. RECENT FINDINGS: Acute anemia (hemoglobin levels near 7 g/dl) is well tolerated by healthy subjects, but extreme anemia might negatively affect clinical outcome of neurocritical patients. Conversely, high hemoglobin levels, attained by means other than red blood-cell transfusion, improve clinical outcome, whereas red blood-cell transfusion is associated with poorer clinical outcome (mortality, length of stay and disability) in patients presenting subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Studies defining the optimal hemoglobin concentration in neurocritical patients are lacking, but a restrictive transfusion policy seems to be safe and is often recommended. In the near future, signals coming from the brain, such as brain tissue oxygen tension and regional cerebral oxygen saturation, might potentially be developed into transfusion triggers. SUMMARY: Both severe anemia and red blood-cell transfusion may negatively influence clinical outcome in neurocritical patients. Acceptance of low hemoglobin concentrations may be justified by avoiding negative transfusion effects. No evidence-based transfusion trigger in neurocritical patients can be recommended.

Anesth Analg. 2007 Nov;105(5):1389-96, table of contents.

Central hypervolemia with hemodilution impairs dynamic cerebral autoregulation.

Ogawa Y, Iwasaki K, Aoki K, Shibata S, Kato J, Ogawa S. Source
Department of Hygiene and Space Medicine, Nihon University School of Medicine, Tokyo, Japan.

Abstract
BACKGROUND: Frequent changes in the perioperative central blood volume could affect cerebral autoregulation through alterations in sympathetic nerve activity, cardiac output, blood viscosity, and cerebral vasomotor tone. However, the effect of dynamic cerebral autoregulation has not been studied during acute wide-ranging changes in central blood volume, especially with respect to central hypervolemia with hemodilution.

METHODS: We evaluated dynamic cerebral autoregulation during central hypovolemia and central hypervolemia with hemodilution using spectral and transfer function analysis between mean arterial blood pressure (MBP) and cerebral blood flow (CBF) velocity variability in 12 individuals. Rapid changes in central blood volume were achieved using two levels of lower body negative pressure (-15 and -30 mm Hg) and two discrete infusions of normal saline (15 mL/kg and total 30 mL/kg). We then estimated changes in central blood volume as central venous pressure (CVP) and/or cardiac output using impedance cardiography. RESULTS: Steady-state CBF velocity and cardiac output decreased at -30 mm Hg lower body negative pressure (changes of CVP approximately -4 mm Hg) or were increased by each saline infusion (changes of CVP 4-6 mm Hg), without a significant change in MBP. However, transfer function gain (magnitude of transfer) between MBP and CBF velocity variability significantly increased only after saline infusion, suggesting an increased magnitude of transfer from MBP oscillations to CBF fluctuations during central hypervolemia with hemodilution. CONCLUSION: Our results suggest that, although steady-state CBF velocity changes under both central hypervolemia and hypovolemia, only hypervolemic hemodilution impairs dynamic cerebral autoregulation.

Neurocrit Care. 2006;4(1):63-7.

A review of red cell transfusion in the neurological intensive care unit.

Pendem S, Rana S, Manno EM, Gajic O. Source
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Abstract
The treatment of anemia in critically ill patients has changed significantly in the past decade with a major shift toward restrictive blood-transfusion strategy. There is a paucity of studies regarding the approach toward anemia in the neurological critical care population. Anemia is a complex problem in this group of patients because of the extreme sensitivity of brain tissue to changes in the cerebral perfusion pressure and oxygen deficit. Most of the evidence regarding management of anemia and optimal hematocrit threshold is based on animal experiments and observational studies. Recent studies have shown a mixed response in the local oxygen saturations and patient outcomes after blood transfusion in neurological critically ill patients. Although there is little reason to suspect that restrictive transfusion protocols would be detrimental, further studies are needed to determine optimal transfusion threshold in this population.

Anesth Analg. 2008 Oct;107(4):1356-70. doi: 10.1213/ane.0b013e318184cfe9.

Anemia and cerebral outcomes: many questions, fewer answers.

Hare GM, Tsui AK, McLaren AT, Ragoonanan TE, Yu J, Mazer CD. Source

Department of Anesthesia, University of Toronto, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. hareg@smh.toronto.on.ca

Abstract
A number of clinical studies have associated acute anemia with cerebral injury in perioperative patients. Evidence of such injury has been observed near the currently accepted transfusion threshold (hemoglobin [Hb] concentration, 7-8 g/dL), and well above the threshold for cerebral tissue hypoxia (Hb 3-4 g/dL). However, hypoxic and nonhypoxic mechanisms of anemiainduced cerebral injury have not been clearly elucidated. In addition, protective mechanisms which may minimize cerebral injury during acute anemia have not been well defined. Vasodilatory mechanisms, including nitric oxide (NO), may help to maintain cerebral oxygen delivery during anemia as all three NO synthase (NOS) isoforms (neuronal, endothelial, and inducible NOS) have been shown to be up-regulated in different experimental models of acute hemodilutional anemia. Recent experimental evidence has also demonstrated an increase in an important transcription factor, hypoxia inducible factor (HIF)-1alpha, in the cerebral cortex of anemic rodents at clinically relevant Hb concentrations (Hb 6-7 g/dL). This suggests that cerebral oxygen homeostasis may be in jeopardy during acute anemia. Under hypoxic conditions, cytoplasmic HIF-1alpha degradation is inhibited, thereby allowing it to accumulate, dimerize, and translocate into the nucleus to promote transcription of a number of hypoxic molecules. Many of these molecules, including erythropoietin, vascular endothelial growth factor, and inducible NOS have also been shown to be up-regulated in the anemic brain. In addition, HIF-1alpha transcription can be increased by nonhypoxic mediators including cytokines and vascular hormones. Furthermore, NOS-derived NO may also stabilize HIF-1alpha in the absence of tissue hypoxia. Thus, during anemia, HIF-1alpha has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions. Experimental studies have demonstrated that HIF-1alpha may have either neuroprotective or neurotoxic capacity depending on the cell type in which it is up-regulated. In the current review, we characterize these cellular processes to promote a clearer understanding of anemia-induced cerebral injury and protection. Potential mechanisms of anemia-induced injury include cerebral emboli, tissue hypoxia, inflammation, reactive oxygen species generation, and excitotoxicity. Potential mechanisms of cerebral protection include NOS/NO-dependent optimization of cerebral oxygen delivery and cytoprotective mechanisms including HIF-1alpha, erythropoietin, and vascular endothelial growth factor. The overall balance of these activated cellular mechanisms may dictate whether or not their up-regulation leads to cytoprotection or cellular injury during anemia. A clearer understanding of these mechanisms may help us target therapies that will minimize anemia-induced cerebral injury in perioperative patients.

J Am Coll Surg. 2008 Sep;207(3):398-406. doi: 10.1016/j.jamcollsurg.2008.03.013. Epub 2008 May 19.

Role of anemia in traumatic brain injury.

Salim A, Hadjizacharia P, DuBose J, Brown C, Inaba K, Chan L, Margulies DR. Source
Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Abstract
BACKGROUND: Few studies have investigated the effects of anemia in patients with traumatic brain injury (TBI). The objective of this study was to examine the role of anemia and blood transfusion on outcomes in TBI patients.

STUDY DESIGN: We performed a retrospective review of all blunt trauma patients with TBI admitted to the ICU from July 1998 to December 2005. Admission and daily ICU blood hemoglobin (hemoglobin) levels and blood transfusions during the first week of hospitalization were measured. Anemia was defined as a hemoglobin<9 g/dL occurring on 3 consecutive blood draws. The role of anemia and blood transfusion was investigated using logistic regression adjusting for factors, with p<0.2 from the bivariate analysis. RESULTS: During the study period, 1,150 TBI patients were admitted to the ICU. When both anemia and blood transfusion were included in the full model, blood transfusion was significantly associated with higher mortality (adjusted odds ratio [AOR], 2.19 [95% CI, 1.27, 3.75]; p=0.0044) and more complications (AOR, 3.67 [95% CI, 2.18, 6.17]; p<0.0001), but anemia was not. But when transfusion was not included in the full model, anemia was a significant risk factor for mortality (AOR, 1.59 (95% CI, 1.13, 2.24); p=0.007) and for complications (AOR, 1.95 [95% CI, 1.42, 2.70]; p<0.0001). CONCLUSIONS: Blood transfusion is associated with significantly worse outcomes in traumatic brain injured patients. In addition, blood transfusion is a major contributing factor to worse outcomes in TBI patients who are anemic. We caution against the liberal use of blood in TBI patients.

J Trauma. 2006 Sep;61(3):567-71.

Retrospective evaluation of anemia and transfusion in traumatic brain injury.

Carlson AP, Schermer CR, Lu SW. Source
Department of Neurosurgery, University of New Mexico, Albuquerque, New Mexico 871310001, USA.

Abstract
BACKGROUND: Despite clear evidence in critical care that blood transfusion has an adverse impact on outcome, neurosurgical textbooks still recommend transfusion of patients with traumatic brain injury (TBI) to a hematocrit (HCT) of 30%. There is little empirical evidence to support this practice. The current study addresses transfusion requirements in TBI in terms of neurologic outcome. METHODS: Retrospective record review of patients with severe TBI. Outcome measures were Glasgow Coma Scale score (GCS), Glasgow Outcome Score (GOS), and Ranchos Los Amigos Score (RLA) at hospital discharge (D/C); and GOS and Functional Independence Measures at followup. Association of outcomes with the number of days the HCT <30% and lowest measured HCT were evaluated. RESULTS: In all, 169 patients reviewed; 150 with D/C outcome data and 72 with long-term follow-up data. Univariate analysis showed that lowest measured HCT was associated with lower D/C GCS, D/C GOS, and RLA scores. Linear regression showed that more days with HCT <30% were associated with improved neurologic outcomes measured by GOS (R2 = 0.424, p < 0.001), GCS (R2 = 0.381, p < 0.001) and RLA (R2 = 0.392, p < 0.001) scores on D/C. Both transfusion and lowest measured HCT were significantly associated with all lower outcome scores on D/C. Additional factors with adverse impact on outcome were head Abbreviated Injury Score (AIS),

Injury Severity Score, hyperglycemia, and hypotension. Long-term outcomes were only significantly associated with head AIS. CONCLUSIONS: Patients with severe TBI should not have a different transfusion threshold than other critical care patients. Prospective studies are needed to evaluate the effects of anemia in TBI.

Crit Care Med. 1998 Jan;26(1):142-8.

Mortality prediction in head trauma patients: performance of Glasgow Coma Score and general severity systems.
Alvarez M, Nava JM, Ru M, Quintana S. Source
Intensive Care Unit, Hospital Mtua de Terrassa, Barcelona, Spain.

Abstract
OBJECTIVE: To assess the performance of general severity systems (Acute Physiology and Chronic Health Evaluation [APACHE] II, Simplified Acute Physiology Score [SAPS] II, and Mortality Probability Models [MPM] II) for head trauma patients and to compare these systems with the Glasgow Coma Score, in order to obtain a good estimate of severity of illness and probability of hospital mortality. DESIGN: Inception cohort. SETTING: Adult medical and surgical intensive care units in 12 European and North American countries. PATIENTS: Patients (n = 401) who were diagnosed with head trauma (with/without multiple trauma), leading to intensive care unit admission, and who were not brain dead at the time of arrival. INTERVENTIONS: Statistical analysis to assess the performance of general severity systems. MEASUREMENTS AND MAIN RESULTS: Vital status at the time of hospital discharge was the outcome measure. Performance of the severity systems (SAPS II, MPM II0 [MPM at admission], MPM II24 [MPM at 24 hrs], and APACHE II) was assessed by evaluating calibration and discrimination. Logistic regression was used to convert the Glasgow Coma Score into a probability of death. The MPM II system (either MPM II0 or MPM 1124) provided an adequate estimation of the mortality experience in patients with head trauma. SAPS II and APACHE II systems did not calibrate well, although they showed high discrimination (area under the receiver operating characteristic curve 0.95 for SAPS II, 0.94 for APACHE II, and 0.90 for MPM II0 and MPM II24). The logistic regression model containing the Glasgow Coma Score as an independent variable and developed in this group of patients was not as well calibrated as MPM II. The discrimination of this model was very high, in the range observed for the APACHE II, SAPS II, and MPM II systems. CONCLUSIONS: The MPM II system performs better than APACHE II, SAPS II, and Glasgow Coma Score for head trauma patients. If our results are supported by other studies, MPM II would be an appropriate tool to assess severity of illness in head trauma patients, with applications to clinical practice and clinical research.

Neurocrit Care. 2011 Aug;15(1):46-54. doi: 10.1007/s12028-010-9448-9.

Vasopressor use and effect on blood pressure after severe adult traumatic brain injury.
Sookplung P, Siriussawakul A, Malakouti A, Sharma D, Wang J, Souter MJ, Chesnut RM, Vavilala MS. Source
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.

Abstract
BACKGROUND: We describe institutional vasopressor usage, and examine the effect of vasopressors on hemodynamics: heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygenation (PbtO(2)), and jugular venous oximetry (SjVO(2)) in adults with severe traumatic brain injury (TBI). METHODS: We performed a retrospective analysis of 114 severely head injured patients who were admitted to the neurocritical care unit of Level 1 trauma center and who received vasopressors (phenylephrine, norepinephrine, dopamine, vasopressin or epinephrine) to increase blood pressure RESULTS: Phenylephrine was the most commonly used vasopressor (43%), followed by norepinephrine (30%), dopamine (22%), and vasopressin (5%). Adjusted for age, gender, injury severity score, vasopressor dose, baseline blood pressure, fluid administration, propofol sedation, and hypertonic saline infusion, phenylephrine use was associated with 8 mmHg higher mean arterial pressure (MAP) than dopamine (P = 0.03), and 12 mmHg higher cerebral perfusion pressure (CPP) than norepinephrine (P = 0.02) during the 3 h after vasopressor start. There was no difference in ICP between the drug groups, either at baseline or after vasopressor treatment. CONCLUSIONS: Most severe TBI patients received phenylephrine. Patients who received phenylephrine had higher MAP and CPP than patients who received dopamine and norepinephrine, respectively.

Intensive Care Med. 2004 May;30(5):791-7. Epub 2004 Mar 27.

Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.
Johnston AJ, Steiner LA, Chatfield DA, Coles JP, Hutchinson PJ, Al-Rawi PG, Menon DK, Gupta AK. Source
Department of Anaesthetics, University of Cambridge, Addenbrooke's Hospital, Box 93, Cambridge CB2 2QQ, UK. ajj29@cam.ac.uk

Abstract
OBJECTIVE: To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury.

DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP. INTERVENTION: Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period. MEASUREMENTS AND RESULTS: The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine. CONCLUSIONS: If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.

Crit Care Med. 2004 Apr;32(4):1049-54.

Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients.

Steiner LA, Johnston AJ, Czosnyka M, Chatfield DA, Salvador R, Coles JP, Gupta AK, Pickard JD, Menon DK. Source
Academic Neurosurgery, Addenbrooke's Hospital, Cambridge, UK. lsteiner@uhbs.ch

Abstract
OBJECTIVE: To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DESIGN: Prospective randomized crossover trial. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg.

INTERVENTIONS: Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p <.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. CONCLUSIONS: Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.

Intensive Care Med. 2001 Jan;27(1):101-6.

Comparison of the cerebral effects of dopamine and norepinephrine in severely head-injured patients.
Ract C, Vigu B. Source
Ranimation Mdicale, CHU Broussais, Paris, France.

Abstract
OBJECTIVE: To compare the cerebral effects of dopamine and norepinephrine after severe head injury. DESIGN: Prospective, clinical study. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Nineteen patients with severe head-injuries already requiring vasopressor therapy. Group 1: patients receiving dopamine (n = 9); group 2: patients receiving norepinephrine (n = 10). INTERVENTION: Vasopressor therapy was switched from dopamine to norepinephrine in group 1 and from norepinephrine to dopamine in group 2, maintaining the same mean arterial pressure (MAP). MEASUREMENTS AND RESULTS: MAP, intracranial pressure (ICP), jugular venous oxygen saturation (SjvO2), transcranial Doppler mean velocity in the middle cerebral artery (Vm), and transoesophagal Doppler aortic output (AO) were evaluated under dopamine and norepinephrine. Means for each group were compared with the paired Student's t-test. For the same MAP, ICP was significantly higher with dopamine than norepinephrine in both groups (respectively, group 1: 26 +/- 11 vs 23 +/- 11

mmHg, P < 0.005; group 2: 39 +/- 13 vs 31 +/- 9 mmHg, P < 0.005). SjvO2, Vm, and AO did not change significantly between treatments. The ICP variation between treatments was not correlated with the variation of any other measured parameter. The ICP variation between treatments was significantly higher in group 2 than group 1, which could be explained by autoregulation mechanisms. CONCLUSIONS: For the same MAP, ICP was significantly higher with dopamine than norepinephrine with no argument supporting an increase of cerebral blood flow.

JAMA. 2004 Mar 17;291(11):1350-7.

Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial.
Cooper DJ, Myles PS, McDermott FT, Murray LJ, Laidlaw J, Cooper G, Tremayne AB, Bernard SS, Ponsford J; HTS Study Investigators. Source
Department of Intensive Care, Alfred Hospital, Monash University, Melbourne, Victoria, Australia. j.cooper@alfred.org.au

Abstract
CONTEXT: Prehospital hypertonic saline (HTS) resuscitation of patients with traumatic brain injury (TBI) may increase survival but whether HTS improves neurological outcomes is unknown. OBJECTIVE: To determine whether prehospital resuscitation with intravenous HTS improves long-term neurological outcome in patients with severe TBI compared with resuscitation with conventional fluids. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized controlled trial of 229 patients with TBI who were comatose (Glasgow Coma Scale score, <9) and hypotensive (systolic blood pressure, <100 mm Hg). The patients were enrolled between December 14, 1998, and April 9, 2002, in Melbourne, Australia. INTERVENTIONS: Patients were randomly assigned to receive a rapid intravenous infusion of either 250 mL of 7.5% saline (n = 114) or 250 mL of Ringer's lactate solution (n = 115; controls) in addition to conventional intravenous fluid and resuscitation protocols administered by paramedics. Treatment allocation was concealed. MAIN OUTCOME MEASURE: Neurological function at 6 months, measured by the extended Glasgow Outcome Score (GOSE). RESULTS: Primary outcomes were obtained in 226 (99%) of 229 patients enrolled. Baseline characteristics of the groups were equivalent. At hospital admission, the mean serum sodium level was 149 mEq/L for HTS patients vs 141 mEq/L for controls (P<.001). The proportion of patients surviving to hospital discharge was similar in both groups (n = 63 [55%] for HTS group and n = 57 [50%] for controls; P =.32); at 6 months, survival rates were n = 62 (55%) in the HTS group and n = 53 (47%) in the control group (P =.23). At 6 months, the median (interquartile range) GOSE was 5 (3-6) in the HTS group vs 5 (5-6) in the control group (P =.45). There was no significant

difference between the groups in favorable outcomes (moderate disability and good outcome survivors [GOSE of 5-8]) (risk ratio, 0.99; 95% confidence interval, 0.76-1.30; P =.96) or in any other measure of postinjury neurological function. CONCLUSION: In this study, patients with hypotension and severe TBI who received prehospital resuscitation with HTS had almost identical neurological function 6 months after injury as patients who received conventional fluid.

J Neurotrauma. 2009 Aug;26(8):1227-40. doi: 10.1089/neu.2008.0868.

Resuscitation with hypertonic saline-dextran reduces serum biomarker levels and correlates with outcome in severe traumatic brain injury patients.
Baker AJ, Rhind SG, Morrison LJ, Black S, Crnko NT, Shek PN, Rizoli SB. Source
Brain Injury Laboratory, Cara Phelan Centre for Trauma Research, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. BakerA@smh.toronto.on.ca

Abstract
In the treatment of severe traumatic brain injury (TBI), the choice of fluid and osmotherapy is important. There are practical and theoretical advantages to the use of hypertonic saline. S100B, neuron-specific enolase (NSE), and myelin-basic protein (MBP) are commonly assessed biomarkers of brain injury with potential utility as diagnostic and prognostic indicators of outcome after TBI, but they have not previously been studied in the context of fluid resuscitation. This randomized controlled trial compared serum concentrations of S100B, NSE, and MBP in adult severe TBI patients resuscitated with 250 mL of 7.5% hypertonic saline plus 6% dextran70 (HSD; n = 31) versus 0.9% normal saline (NS; n = 33), and examined their relationship with neurological outcome at discharge. Blood samples drawn on admission (<or=3 h post-injury), and at 12, 24, and 48 h post-resuscitation were assayed by ELISA for the selected biomarkers. Serial comparisons of biomarker concentrations were made by ANOVA, and relationships between biomarkers and outcome were assessed by multiple regression. On admission, mean (+/-SEM) S100B and NSE concentrations were increased 60-fold (0.73 +/0.08 microg/L) and sevenfold (37.0 +/- 4.8 microg/L), respectively, in patients resuscitated with NS, compared to controls (0.01 +/- 0.01 and 6.2 +/- 0.6, respectively). Compared with NS resuscitation, S100B and NSE were twofold and threefold lower in HSD-treated patients and normalized within 12 h. MBP levels were not significantly different from controls in either treatment arm until 48 h post-resuscitation, when a delayed increase (0.58 +/- 0.29 microg/L) was observed in NS-treated patients. Biomarkers were elevated in the patient group showing an unfavorable outcome. HSD-resuscitated patients with favorable outcomes exhibited the lowest serum S100B and NSE concentrations, while maximal levels were found in NS-treated patients with unfavorable outcomes. The lowest biomarker levels were seen in survivors resuscitated with HSD, while maximal levels were in NS-resuscitated patients with fatal outcome. Prehospital resuscitation with HSD is associated with a reduction in serum S100B, NSE, and MBP concentrations, which are correlated with better outcome after severe TBI.

N Engl J Med. 2007 Aug 30;357(9):874-84.

Saline or albumin for fluid resuscitation in patients with traumatic brain injury.

SAFE Study Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group; Australian Red Cross Blood Service; George Institute for International Health, Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N, Kai Lo S, Vallance S. Source
ANZICS Clinical Trials Group, Level 3, 10 Ievers Terrace, Carlton, VIC 3053, Australia. j.myburgh@unsw.edu.au

Abstract
BACKGROUND: The Saline versus Albumin Fluid Evaluation study suggested that patients with traumatic brain injury resuscitated with albumin had a higher mortality rate than those resuscitated with saline. We conducted a post hoc follow-up study of patients with traumatic brain injury who were enrolled in the study. METHODS: For patients with traumatic brain injury (i.e., a history of trauma, evidence of head trauma on a computed tomographic [CT] scan, and a score of < or =13 on the Glasgow Coma Scale [GCS]), we recorded baseline characteristics from case-report forms, clinical records, and CT scans and determined vital status and functional neurologic outcomes 24 months after randomization. RESULTS: We followed 460 patients, of whom 231 (50.2%) received albumin and 229 (49.8%) received saline. The subgroup of patients with GCS scores of 3 to 8 were classified as having severe brain injury (160 [69.3%] in the albumin group and 158 [69.0%] in the saline group). Demographic characteristics and indexes of severity of brain injury were similar at baseline. At 24 months, 71 of 214 patients in the albumin group (33.2%) had died, as compared with 42 of 206 in the saline group (20.4%) (relative risk, 1.63; 95% confidence interval [CI], 1.17 to 2.26; P=0.003). Among patients with severe brain injury, 61 of 146 patients in the albumin group (41.8%) died, as compared with 32 of 144 in the saline group (22.2%) (relative risk, 1.88; 95% CI, 1.31 to 2.70; P<0.001); among patients with GCS scores of 9 to 12, death occurred in 8 of 50 patients in the albumin group (16.0%) and 8 of 37 in the saline group (21.6%) (relative risk, 0.74; 95% CI, 0.31 to 1.79; P=0.50). CONCLUSIONS: In this post hoc study of critically ill patients with traumatic brain injury, fluid resuscitation with albumin was associated with higher mortality rates than was resuscitation with saline. (Current Controlled Trials number, ISRCTN76588266 [controlled-trials.com].).

Neurol Res. 1998;20 Suppl 1:S66-70.

The effect of different ventilation regimes on jugular venous oxygen saturation in elective neurosurgical patients.
Schaffranietz L, Heinke W. Source
Department of Anaesthesiology and Intensive Care Medicine at the University of Leipzig, Germany.

Abstract

Since the concept of hyperventilation on neurosurgical and neurotraumatological patients has been contested, our analysis was aimed at its scrutiny on the basis of easily accessible parameters of perisurgical monitoring. Furthermore, the influence of an improved oxygen supply was tested on hyperventilationally induced cerebral changes and to what extent recommendations could be derived for clinical application. In 50 patients (normoventilation FiO2 = 0.4, 0.6; moderate hyperventilation up to a value of paCO2 = 31 mmHg and FiO2 = 0.4, 0.6 and 0.8), who underwent an elective neurosurgical operation at the central nervous system, a fiberoptical catheter was inserted into the bulb of the jugular vein for the continuous monitoring of the jugular venous oxygen saturation (sjvO2), additionally to the regular measures of perioperative monitoring. Approval for this study was given by the Ethics Committee of the University of Leipzig. At five defined times an analysis of arterial and jugular venous blood gas samples was made and their lactate and glucose concentration determined: 1. Immediately after inducing anesthesia; 2. After dura opening; 3. Sixty minutes after dura opening; 4. At dura closing; 5. Sixty minutes after the end of the operation. The lactate oxygen index (LOI) as well as the cerebral oxygen extraction (CEO2) were calculated from primary data. Hyperventilation with a value of FiO2 = 0.4 leads to a significant decrease of the jugular venous oxygen saturation below 55%. It can be positively influenced by increasing the inspiratory oxygen concentration from 40% to 60%. The CEO2 increases, above values of 42% under a hyperventilation of FiO2 = 0.4. This effect can be reversed by increasing the FiO2 value up to 0.6. Under hyperventilation the LOI reaches 'pre-ischemic' values (LOI > 0.03) prior to dura opening. Further decrease of FiO2 to 0.8 has no positive additional effect. Normoventilation with FiO2 = 0.6 induces a decrease of sjvO2 but also a decrease of LOI. Hyperventilation as a routine procedure during elective neurosurgery shall be applied critically and be combined with an increased inspiratory oxygen concentration if necessary. A longterm normoventilation with increased FiO2 should be avoided.

Anaesthesist. 1979 Mar;28(3):136-41.

[The influence of some inhalation anaesthetics on the intracranial pressure with special reference to nitrous oxide (author's transl)].
[Article in German]

Schulte am Esch J, Thiemig I, Pfeifer G, Entzian W. Abstract

The influence of inhalation anaesthetics on intracranial pressure (ICP), arterial blood pressure and cerebral perfusion pressure (CPP) was investigated on 12 unconscious patients with head injury having an initial ICP of about 20 mm Hg. Halothane, enflurane and nitrous oxide induced a considerable rise of ICP during a 15 to 25 minute period of observation. The moderate fall in blood pressure caused by halothane and enflurane enhanced the reduction of the calculated CPP. Besides, a regular fall in blood pressure of about 16% was observed under the influence of nitrous oxide, subsequently reducing the CPP in some cases under 40 mm Hg. Inhalation anaesthetics, including nitrous oxide, should therefore not be used in patients with decreased intracranial compliance before the increased ICP is treated.

Curr Opin Anaesthesiol. 2006 Oct;19(5):504-8.

Inhalational or intravenous anesthetics for craniotomies? Pro inhalational.

Engelhard K, Werner C.

Source
Klinik fr Ansthesiologie, Johannes Gutenberg-Universitt, Mainz, Germany. engelhak@unimainz.de

Abstract
PURPOSE OF REVIEW: In neurosurgery, anesthesiologists and surgeons focus on the same target - the brain. The nature of anesthetics is to interact with brain physiology, leading to favorable and adverse effects. Research in neuroanesthesia over the last three decades has been dedicated to identifying the optimal anesthetic agent to maintain coupling between cerebral blood flow and metabolism, keep cerebrovascular autoregulation intact, and not increase cerebral blood volume and intracranial pressure. RECENT FINDINGS: Sevoflurane is less vasoactive than halothane, enflurane, isoflurane, or desflurane. The context sensitive half-life is short and similar to that of desflurane, which translates into fast on and offset. Compared with propofol, sevoflurane decreases cerebral blood flow to a lesser extent, while cerebral metabolism is suppressed to the same degree. Sevoflurane does not increase intracranial pressure, while propofol decreases intracranial pressure. SUMMARY: In neurosurgical patients with normal intracranial pressure, sevoflurane might be a good alternative to propofol. In patients with reduced intracranial elastance, caused by space occupying lesions, with elevated intracranial pressure or complex surgical approaches, propofol should remain first choice.

Anaesthesist. 1994 Jul;43(7):421-30.

[Opioids, cerebral circulation and intracranial pressure].

[Article in German]

Schregel W, Weyerer W, Cunitz G. Source

Klinik fr Anaesthesie und operative Intensivtherapie, Knappschaftskrankenhaus, RuhrUniversitt Bochum RUB.

Abstract
The effects of the opioids alfentanil (A), fentanyl (F), and sufentanil (S) on cerebral blood flow (CBF) and intracranial pressure (ICP) have been discussed in several recent publications. The purpose of this review is to describe the results of studies in animals, healthy volunteers, and patients with and without intracranial diseases. Clinical relevance and mechanisms of the reported ICP and CBF increases are analysed. METHODS. Approximately 70 original articles and abstracts were retrieved by a systematic literature search using the key word list at the end of this abstract. The cited studies came from computerised database systems like Silver Platter and DIMDI, the SNACC reference list, and the bibliographies of pertinent articles and books. These studies were classified into three groups: significant increase of ICP and/or CBF; no significant or clinically relevant alterations; and significant decreases of ICP and/or CBF. RESULTS. The numerical relationship was 6:7:3 for A, 7:16:9 for F, and 5:11:8 for S. Increases of previously normal or only slightly elevated ICP were registered in some studies in connection with a decrease in mean arterial pressure (MAP). On the other hand, in patients with brain injury and elevated ICP opioids did not further increase ICP despite MAP decreases. In studies monitoring ICP and/or CBF continuously, transient and moderate increases of questionable clinical relevance became apparent a few minutes after bolus injection of opioids. Alterations of systemic and cerebral haemodynamics observed after bolus application were not registered

during continuous infusion of A and S. DISCUSSION AND CONCLUSIONS. The cerebral effects of opioids are dependent on several factors, e.g., age, species, ventilation, anaesthesia before and during measurements, systemic haemodynamics, and underlying diseases. The probable mechanism of ICP increase during decreasing MAP is cerebral vasodilatation due to maintained autoregulation. With increasing severity of the cerebral lesion autoregulation is often disturbed. Therefore, ICP often remains unaltered despite MAP decreases. However, the resulting decrease in cerebral perfusion pressure makes such patients more susceptible to develop ischaemic neurological deficits. Induction of somatic rigidity or (with high doses) convulsions, exceeding the upper limit of autoregulation, histamine release, cerebral vasodilatation, increased cerebral oxygen consumption, or carbon dioxide accumulation during spontaneous breathing were discussed as mechanisms for transient ICP/CBF increases. It is concluded that opioids are often beneficial and not generally contraindicated for patients with cerebral diseases and compromised intracranial compliance. However, since negative side effects cannot be excluded, opioid effects and side effects should be monitored (MAP, ICP, cerebrovenous oxygen saturation, transcranial Doppler sonography) in patients at risk. It has to be stressed that opioids should be administered only to patients with stable haemodynamic situations and preferably in well-titrated, continuous infusions.

AANA J. 2005 Aug;73(4):297-302.

Neuroprotective effects of thiopental, propofol, and etomidate.

Turner BK, Wakim JH, Secrest J, Zachary R. Source
Anesthesiology Consultant Exchange, Chattanooga, TN, USA.

Abstract
In selecting an anesthetic agent to be used for neurosurgical procedures, the anesthesia provider must consider the agent's effects on intracranial pressure (ICP), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2). The anesthetic of choice for neurosurgical procedures for many decades has been thiopental. It meets the strict requirements for neurosurgical procedures because it protects the brain from ischemia and herniation by lowering ICP through decreases in CBF and CMRO However, new drugs, including etomidate and propofol, have been introduced that offer anesthesia providers comparable neuroprotective actions plus other positive attributes. The purpose of this course is to review current and benchmark literature on thiopental, propofol, and etomidate to compare researchers' reports of the effects on ICP, CMRO2, and CBF Literature was gathered using computer assistance to search PubMed, the Cumulative Index of Nursing and Allied Health Literature, and the World Wide Web. The literature showed that all 3 anesthetic agents provide favorable neurological protection. Each drug has some undesirable side effects. Knowledge of these side effects and the patient's medical and surgical history can help CRNAs determine the most suitable anesthetic in specific situations.

Emerg Med J. 2001 Sep;18(5):373-5.

In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review.

Clancy M, Halford S, Walls R, Murphy M. Source

Emergency Department, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. clancm@hotmail.com

Abstract
A literature search was undertaken for evidence of the effect of succinylcholine (SCH) on the intracranial pressure (ICP) of patients with acute brain injury and whether pretreatment with a defasciculating dose of competitive neuromuscular blocker is beneficial in this patient group. The authors could find no definitive evidence that SCH caused a rise in ICP in patients with brain injury. However, these studies were often weak and small. For those patients suffering acute traumatic brain injury the authors could find no studies that investigated the issue of pretreatment with defasciculating doses of competitive neuromuscular blockers and their effect on ICP in patients given SCH. There is level 2 evidence that SCH caused an increase in ICP for patients undergoing neurosurgery for brain tumours with elective anaesthesia and that pretreatment with defasciculating doses of neuromuscular blockers reduced such increases. It is unknown if this affects neurological outcome for this patient group. Anesth Analg. 1994 Mar;78(3):469-73.

Succinylcholine does not change intracranial pressure, cerebral blood flow velocity, or the electroencephalogram in patients with neurologic injury.
Kovarik WD, Mayberg TS, Lam AM, Mathisen TL, Winn HR. Source
Department of Anesthesiology, University of Washington, Seattle.

Abstract
The effect of succinylcholine (SCh) on intracranial pressure (ICP) was studied in 10 mechanically ventilated patients (Glasgow coma scale score 3-10, median 6) being treated for increased ICP in an intensive care unit. Mean arterial blood pressure (MAP), ICP, processed electroencephalogram (EEG), and mean middle cerebral artery blood flow velocity (V mca) were monitored. Baseline measurements after saline injection were obtained for 5 min. SCh (1 mg/kg) was administered intravenously and the above variables were monitored for 15 min. Neither saline nor SCh cause any significant change in cerebral perfusion pressure, MAP, V mca, EEG, or ICP. We conclude that in brain-injured patients, SCh did not alter cerebral blood flow velocity, cortical electrical activity, or ICP. Anesthesiology. 1987 Jul;67(1):50-3.

"Defasciculation" with metocurine prevents succinylcholine-induced increases in intracranial pressure.

Stirt JA, Grosslight KR, Bedford RF, Vollmer D. Abstract
In order to determine whether a small, "defasciculating" dose of metocurine could prevent increases in intracranial pressure (ICP) induced by succinylcholine (Sch), the authors studied 12 patients (ages 25-79 yr) undergoing craniotomy for excision of malignant supratentorial gliomas. After insertion of a subarachnoid bolt for ICP monitoring and a radial arterial cannula for determination of blood pressure and blood gas tensions, six patients (group I) were randomly allocated to receive MTC 0.03 mg/kg 3 min before induction of general anesthesia with thiopental 4 mg/kg and nitrous oxide 70% in O2. Six other patients (group II) received

saline 0.015 ml/kg instead of MTC, followed by the same induction sequence. After induction of anesthesia, ventilation was controlled by mask (PaCO2 = 40 mmHg +/- 2 SE), and arterial and intracranial pressures were allowed to stabilize. Four minutes after thiopental administration (7 min after MTC), after a 1-min period of relatively stable arterial pressure and ICP, Sch 1 mg/kg was administered as a bolus. ICP and blood pressure were recorded continuously until normal twitch tension was restored. In group I (MTC pretreatment), ICP did not change significantly from the mean value observed before Sch, 14 mmHg +/- 2 SE. In group II (saline pretreatment), ICP increased from 11 mmHg +/- 2 SE to 23 mmHg +/- 4 SE (P less than .05). This study not only confirms previous work showing that Sch may induce marked ICP increases in lightly anesthetized patients with intracranial mass lesions, but also indicates that pretreatment with a "defasciculating" dose of MTC can prevent these potentially deleterious ICP increases in patients known to be at risk.

Anesthesiology. 1986 Aug;65(2):165-9.

Increases in intracranial pressure from succinylcholine: prevention by prior nondepolarizing blockade.

Minton MD, Grosslight K, Stirt JA, Bedford RF. Abstract
Whether succinylcholine causes an increase in intracranial pressure (ICP) in patients with brain lesions is uncertain and, if increased ICP does occur, its pathophysiology remains unknown. The authors investigated both the effect of succinylcholine on ICP and its modification with prior neuromuscular blockade by measuring ICP (subarachnoid bolt) in 13 consecutive patients with brain tumors who received succinylcholine both before and after complete neuromuscular blockade with vecuronium. Anesthesia was induced with thiopental, 6 mg X kg-1 iv, and nitrous oxide, 70% in oxygen, while ventilation was controlled (PaCO2 = 37.2 mmHg +/- 1.7 SE). Succinylcholine, 1 mg X kg-1 iv, was administered and ICP, heart rate (HR), and blood pressure (BP) were recorded until normal twitch tension was restored. Complete neuromuscular blockade was then established with vecuronium, 0.14 mg X kg-1 iv; 3 min later, succinylcholine, 1 mg X kg-1 iv, was repeated. The resulting changes in ICP, HR, and BP were recorded for 3 min. Following the first dose of succinylcholine, mean ICP increased from 15.2 mmHg +/- 1.3 SE to 20.1 mmHg +/- 2.0 SE (P less than 0.05), with five of the patients sustaining increases in ICP of 9 mmHg or greater. In contrast, when succinylcholine was given after vecuronium-induced paralysis, no patient developed an increase in ICP greater than 3 mmHg (P less than 0.05 compared with the incidence of ICP greater than or equal to 9 mmHg observed after the first dose of succinylcholine). A second group of six patients received two doses of succinylcholine according to the same protocol but without an intervening dose of vecuronium.(ABSTRACT TRUNCATED AT 250 WORDS)

Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002788. doi: 10.1002/14651858.CD002788.pub2.

Rocuronium versus succinylcholine for rapid sequence induction intubation.

Perry JJ, Lee JS, Sillberg VA, Wells GA. Source
Clinical Epidemiology Programme, Ottawa Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada, K1Y 4E9.

Abstract
BACKGROUND: Patients requiring emergency endotracheal intubation often require a rapid sequence induction (RSI) intubation technique to protect against aspiration or increased intracranial pressure, or to facilitate intubation. Succinylcholine is the most commonly used muscle relaxant because of its fast onset and short duration; unfortunately, it can have serious side effects. Rocuronium has been suggested as an alternative to succinylcholine for intubation. This meta-analysis is an update since our initial Cochrane systematic review in 2003. OBJECTIVES: To determine if rocuronium creates comparable intubating conditions to succinylcholine during RSI intubation. Comparisons were made based on dose of rocuronium, narcotic use, emergency versus elective intubation, age and induction agent. The primary outcome was excellent intubation conditions. The secondary outcome was acceptable conditions. SEARCH STRATEGY: In our initial systematic review we searched all databases until March 2000. We have updated that search and searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2007 issue 3), MEDLINE (1966 to June Week 3 2007), EMBASE (1988 to 2007 Week 26) for randomized controlled trials or controlled clinical trials relating to the use of rocuronium and succinylcholine. We included foreign language journals and handsearched the references of identified studies for additional citations. SELECTION CRITERIA: We included all trials meeting the inclusion criteria (comparison of rocuronium and succinylcholine, main outcomes of intubation conditions). DATA COLLECTION AND ANALYSIS: Two authors (JP, JL or VS) independently extracted data and assessed methodological quality for allocation concealment. We combined the outcomes in RevMan using relative risk (RR) with a random-effects model. MAIN RESULTS: In our initial systematic review we identified 40 studies and included 26. In this update we identified a further 18 studies and included 11. In total, we identified 58 potential studies; 37 were combined for meta-analysis. Overall, succinylcholine was superior to rocuronium, RR 0.86 (95% confidence interval (95% CI) 0.80 to 0.92) (n = 2690). In the group that used propofol for induction, the intubation conditions were superior with succinylcholine (RR 0.88, 95% CI 0.80 to 0.97) (n = 1183). This is contrary to our previous meta-analysis results where we reported that intubation conditions were superior in the rocuronium group when propofol was used. We found no statistical difference in intubation conditions when succinylcholine was compared to 1.2mg/kg rocuronium; however, succinylcholine was clinically superior as it has a shorter duration of action. AUTHORS' CONCLUSIONS: Succinylcholine created superior intubation conditions to rocuronium when comparing both excellent and clinically acceptable intubating conditions.

Comment in
Evidence-based emergency medicine. Does succinylcholine maximize intubating conditions better than rocuronium for rapid sequence intubation? [Ann Emerg Med. 2011]

Acta Neurochir (Wien). 1978;45(1-2):15-25.

The influence of intravenous anaesthetic agents on primarily increased intracranial pressure.

Schulte am Esch J, Pfeifer G, Thiemig I, Entzian W. Abstract
In the choice of anaesthetics and techniques the danger of a possible progressive increase of intracranial pressure (ICP) should be considered. Therefore the influence of intravenous anaesthetic agents on mean arterial pressure, ICP, and cerebral perfusion pressure (CPP) in patients with primarily increased ICP was observed under standard conditions for 20-40 minutes. Etomidate, thiopentone, propanidid, and ketamine showed remarkable effects on ICP, even in patients with disturbed cerebro-vascular reactivity. Etomidate and thiopentone cause a fall of ICP by 26%. Because of its stabilizing effects on circulation etomidate does not induce a reduction of CPP, whereas thiopentone will do so because of its depressing effect on blood pressure. Propanidid appears to be a less suitable agent when there is raised ICP, because it induces fluctuations of ICP and blood pressure up to the third minute after injection. According to our results, monoanaesthesia with ketamine cannot be recommended when there is increased ICP because it causes a prolonged increase in ICP, and reduction of blood pressure and CPP.

Crit Care Med. 2005 Oct;33(10):2358-66.

Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study.
Cohan P, Wang C, McArthur DL, Cook SW, Dusick JR, Armin B, Swerdloff R, Vespa P, Muizelaar JP, Cryer HG, Christenson PD, Kelly DF. Source
Division of Neurosurgery, UCLA School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

Abstract
OBJECTIVE: To determine the prevalence, time course, clinical characteristics, and effect of adrenal insufficiency (AI) after traumatic brain injury (TBI). DESIGN: Prospective intensive care unit-based cohort study. SETTING: Three level 1 trauma centers. PATIENTS: A total of 80 patients with moderate or severe TBI (Glasgow Coma Scale score, 3-13) and 41 trauma patients without TBI (Injury Severity Score, >15) enrolled between June 2002 and November 2003. MEASUREMENTS: Serum cortisol and adrenocorticotropic hormone levels were drawn twice daily for up to 9 days postinjury; AI was defined as two consecutive cortisols of < or =15 microg/dL (25th percentile for extracranial trauma patients) or one cortisol of < 5 microg/dL. Principal outcome measures included: injury characteristics, hemodynamic data, usage of vasopressors, metabolic suppressive agents (high-dose pentobarbital and propofol), etomidate, and AI status. MAIN RESULTS:

AI occurred in 42 TBI patients (53%). Adrenocorticotropic hormone levels were lower at the time of AI (median, 18.9 vs. 36.1 pg/mL; p = .0001). Compared with patients without AI, those with AI were younger (p = .01), had higher injury severity (p = .02), had a higher frequency of early ischemic insults (hypotension, hypoxia, severe anemia) (p = .02), and were more likely to have received etomidate (p = .049). Over the acute postinjury period, patients with AI had lower trough mean arterial pressure (p = .001) and greater vasopressor use (p = .047). Mean arterial pressure was lower in the 8 hrs preceding a low (< or =15 microg/dL) cortisol level (p = .003). There was an inverse relationship between cortisol levels and vasopressor use (p = .0005) and between cortisol levels within 24 hrs of injury and etomidate use (p = .002). Use of high-dose propofol and pentobarbital was strongly associated with lower cortisol levels (p < .0001). CONCLUSIONS: Approximately 50% of patients with moderate or severe TBI have at least transient AI. Younger age, greater injury severity, early ischemic insults, and the use of etomidate and metabolic suppressive agents are associated with AI. Because lower cortisol levels were associated with lower blood pressure and higher vasopressor use, consideration should be given to monitoring cortisol levels in intubated TBI patients, particularly those receiving high-dose pentobarbital or propofol. A randomized trial of stress-dose hydrocortisone in TBI patients with AI is underway.

Br J Anaesth. 1985 Apr;57(4):361-8.

Comparison of etomidate and althesin in the reduction of increased intracranial pressure after head injury.
Dearden NM, McDowall DG. Abstract
The increasing use of shorter-acting hypnotic agents to control intracranial pressure (ICP) following severe head injury has prompted a prospective double-blind controlled trial comparing the efficacy of etomidate and Althesin, given by i.v. infusion. Over the dose ranges used, the two drugs appeared equipotent in decreasing ICP whilst preserving cerebral perfusion pressure. However, in two patients (one in each group) ICP did not respond to hypnotic infusion, a feature noted in other studies to occur in a minority of patients. With the cessation of Althesin manufacture and the discussion about the use of etomidate infusions, it is timely to document the effectiveness of etomidate in decreasing ICP.

Acad Emerg Med. 2009 Sep;16(9):866-71. doi: 10.1111/j.1553-2712.2009.00492.x. Epub 2009 Aug 6.

A comparison of GlideScope video laryngoscopy versus direct laryngoscopy intubation in the emergency department.
Platts-Mills TF, Campagne D, Chinnock B, Snowden B, Glickman LT, Hendey GW. Source
Department of Emergency Medicine, University of California San Francisco, Fresno, CA, USA. tplattsm@med.unc.edu

Abstract
OBJECTIVES: The first-attempt success rate of intubation was compared using GlideScope video laryngoscopy and direct laryngoscopy in an emergency department (ED).

METHODS: A prospective observational study was conducted of adult patients undergoing intubation in the ED of a Level 1 trauma center with an emergency medicine residency program. Patients were consecutively enrolled between August 2006 and February 2008. Data collected included indication for intubation, patient characteristics, device used, initial oxygen saturation, and resident postgraduate year. The primary outcome measure was success with first attempt. Secondary outcome measures included time to successful intubation, intubation failure, and lowest oxygen saturation levels. An attempt was defined as the introduction of the laryngoscope into the mouth. Failure was defined as an esophageal intubation, changing to a different device or physician, or inability to place the endotracheal tube after three attempts. RESULTS: A total of 280 patients were enrolled, of whom video laryngoscopy was used for the initial intubation attempt in 63 (22%) and direct laryngoscopy was used in 217 (78%). Reasons for intubation included altered mental status (64%), respiratory distress (47%), facial trauma (9%), and immobilization for imaging (9%). Overall, 233 (83%) intubations were successful on the first attempt, 26 (9%) failures occurred, and one patient received a cricothyrotomy. The first-attempt success rate was 51 of 63 (81%, 95% confidence interval [CI] = 70% to 89%) for video laryngoscopy versus 182 of 217 (84%, 95% CI = 79% to 88%) for direct laryngoscopy (p = 0.59). Median time to successful intubation was 42 seconds (range, 13 to 350 seconds) for video laryngoscopy versus 30 seconds (range, 11 to 600 seconds) for direct laryngoscopy (p < 0.01). CONCLUSIONS: Rates of successful intubation on first attempt were not significantly different between video and direct laryngoscopy. However, intubation using video laryngoscopy required significantly more time to complete. (c) 2009 by the Society for Academic Emergency Medicine.

Anesthesiology. 2006 Jun;104(6):1293-318.

Airway management in adults after cervical spine trauma.

Crosby ET. Source
Department of Anesthesiology, University of Ottawa, Ontario, Canada. ecrosby@sympatico.ca

Abstract
Cervical spinal injury occurs in 2% of victims of blunt trauma; the incidence is increased if the Glasgow Coma Scale score is less than 8 or if there is a focal neurologic deficit. Immobilization of the spine after trauma is advocated as a standard of care. A three-view x-ray series supplemented with computed tomography imaging is an effective imaging strategy to rule out cervical spinal injury. Secondary neurologic injury occurs in 2-10% of patients after cervical spinal injury; it seems to be an inevitable consequence of the primary injury in a subpopulation of patients. All airway interventions cause spinal movement; immobilization may have a modest effect in limiting spinal movement during airway maneuvers. Many anesthesiologists state a preference for the fiberoptic bronchoscope to facilitate airway management, although there is considerable, favorable experience with the direct laryngoscope in cervical spinal injury patients. There are no outcome data that would support a recommendation for a particular practice option for airway management; a number of options seem appropriate and acceptable.

J Trauma. 2000 Apr;48(4):724-7.

Nonskeletal cervical spine injuries: epidemiology and diagnostic pitfalls.

Demetriades D, Charalambides K, Chahwan S, Hanpeter D, Alo K, Velmahos G, Murray J, Asensio J. Source
Department of Surgery, University of Southern California School of Medicine, Los Angeles 90033, USA. demetria@hsc.usc.edu

Abstract
BACKGROUND: Cervical spine injuries are the most commonly missed severe injuries with serious implications for the patient and physician. The diagnosis of subluxations or spinal cord injuries in the absence of vertebral fractures, especially in unevaluable patients, poses a major challenge. The objective of this study was to study the incidence and type of cervical spine trauma according to mechanism of injury; identify problems and pitfalls in the diagnosis of nonskeletal cervical spine injuries. METHODS: Retrospective study of all C-spine injuries caused by traffic accidents or falls admitted over a 5year period at a large Level I trauma center. Data were obtained from the trauma registry, review of patient charts, and radiology reports. RESULTS: During the study period, there were 14,755 admissions due to traffic injuries or falls who met trauma center criteria. There were 292 patients with C-spine injuries, for an overall incidence of 2.0% (3.4% in car occupants, 2.8% for pedestrians, 1.9% for motorcycle riders, and 0.9% for falls). The incidence of C-spine injuries in patients with a Glasgow Coma Scale score of 13 to 15 was 1.4%, 9 to 12 was 6.8%, and in < or =8 was 10.2% (p < 0.05). Of C-spine injuries, 85.6% (250 patients) were a vertebral fracture, 10.6% of the injuries (31 patients) were subluxation without fractures, and 3.8% (11 patients) were an isolated spinal cord injury without fracture or subluxation. Of the 31 patients with isolated subluxations, one-third required an early endotracheal intubation before clinical evaluation of the spine, because of associated severe head injury or hypotension. Adequate lateral C-spine films diagnosed or suspected 30 of the 31 subluxations (96.8%). The combination of plain films and computed tomographic (CT) scan diagnosed or suspected all injuries. Of the 11 patients with isolated cord injury, 27.3% required early intubation before clinical evaluation of the spine. The diagnosis of cord injury was made on admission in only five patients (45.5%). In three patients, the neurologic examination on admission was normal and neurologic deficits appeared a few hours later. In the remaining three patients (two intubated, one intoxicated), the diagnosis was missed clinically and radiologically. CONCLUSIONS: Isolated nonskeletal C-spine injuries are rare but potentially catastrophic because of the high incidence of neurologic deficits and missed diagnosis. In subluxations, the combination of an adequate lateral film and CT scan was reliable in diagnosing or highly suspecting the injury. A large prospective study is needed to confirm these findings, before a recommendation is made to remove the cervical collar if the findings of these investigations are normal. However, in isolated cord injuries, the diagnosis was often missed because of associated severe head trauma and the low sensitivity of the plain films and CT scans.

J Neurosurg. 2002 Apr;96(3 Suppl):285-91.

Cervical spine trauma associated with moderate and severe head injury: incidence, risk factors, and injury characteristics.
Holly LT, Kelly DF, Counelis GJ, Blinman T, McArthur DL, Cryer HG. Source
Department of Surgery, University of California at Los Angeles Center for Health Sciences, 90095-7039, USA.

Abstract
OBJECT: Diagnosing and managing cervical spine trauma in head-injured patients is problematic due to an altered level of consciousness in such individuals. The reported incidence of cervical spine trauma in head-injured patients has generally ranged from 4 to 8%. In this retrospective study the authors sought to define the incidence of cervical injury in association with moderate or severe brain injury, emphasizing the identification of high-risk patients. METHODS: The study included 447 consecutive moderately (209 cases) or severely (238 cases) head injured patients who underwent evaluation at two Level 1 trauma centers over a 40-month period. Of the 447 patients, 24 (5.4%) suffered a cervical spine injury (17 men and seven women; mean age 39 years; median Glasgow Coma Scale [GCS] score of 6, range 3-14). Of these 24 patients, 14 (58.3%) sustained spinal cord injuries (SCIs), 14 sustained injuries in the occiput-C3 region, and 10 underwent a stabilization procedure. Of the 14 patients with SCIs, nine experienced an early hypotensive and/or hypoxic insult. Regarding the mechanism of injury, cervical injuries occurred in 21 (8.2%) of 256 patients involved in motor vehicle accidents (MVAs), either as passengers or pedestrians, compared with three (1.6%) of 191 patients with non-MVA-associated trauma (p < 0.01). In the subset of 131 MVA passengers, 13 (9.9%) sustained cervical injuries. Patients with an initial GCS score less than or equal to 8 were more likely to sustain a cervical injury than those with a score higher than 8 (odds ratio [OR] 2.77, 95% confidence interval [CI] = 1.11-7.73) and were more likely to sustain a cervical SCI (OR 5.5, 95% CI 1.22-24.85). At 6 months or more postinjury, functional neurological recovery had occurred in nine patients (37.5%) and eight (33.3%) had died. CONCLUSIONS: Head-injured patients sustaining MVA-related trauma and those with an initial GCS score less than or equal to 8 are at highest risk for concomitant cervical spine injury. A disproportionate number of these patients sustain high cervical injuries, the majority of which are mechanically unstable and involve an SCI. The development of safer and more rapid means of determining cervical spine integrity should remain a high priority in the care of head-injured patients.

ASSESSMENT OF COMA AND IMPAIRED CONSCIOUSNESS

Graham Teasdale , Bryan Jennett

Abstract

A clinical scale has been evolved for assessing the depth and duration of impaired consciousness and coma. Three aspects of behaviour are independently measured motor responsiveness, verbal performance, and eye opening. These can be evaluated consistently by doctors and nurses and recorded on a simple chart which has proved practical both in a neurosurgical unit and in a general hospital. The scale facilitates consultations between general and special units in cases of recent brain damage, and is useful also in defining the duration of prolonged coma. J Neurotrauma. 2010 Jul;27(7):1233-41. doi: 10.1089/neu.2009.1216.

Inappropriate prehospital ventilation in severe traumatic brain injury increases in-hospital mortality.
Dumont TM, Visioni AJ, Rughani AI, Tranmer BI, Crookes B. Source
Division of Neurosurgery, University of Vermont College of Medicine, Burlington, Vermont 05401, USA. Travis.Dumont@vtmednet.org

Abstract
In the setting of acute brainstem herniation in traumatic brain injury (TBI), the use of hyperventilation to reduce intracranial pressure may be life-saving. However, undue use of hyperventilation is thought to increase the incidence of secondary brain injury through direct reduction of cerebral blood flow. This is a retrospective review determining the effect of prehospital hyperventilation on in-hospital mortality following severe TBI. All trauma patients admitted directly to a single level 1 trauma center from January 2000 to January 2007 with an initial Glasgow Coma Scale (GCS) score <or=8 were included in the study (n = 77). Patients without documented or with late (>20 min) arterial blood gas at presentation (n = 12) were excluded from the study. The remaining population (n = 65) was sorted into three groups based on the initial partial pressure of carbon dioxide: hypocarbic (Pco(2) < 35 mm Hg), normocarbic (Pco(2) 35-45 mm Hg), and hypercarbic (Pco(2) > 45 mm Hg). Outcome was based on mortality during hospital admission. Survival was found to be related to admission Pco(2) in head trauma patients requiring intubation (p = 0.045). Patients with normocarbia on presenting arterial blood gas testing had in-hospital mortality of 15%, significantly improved over patients presenting with hypocarbia (in-hospital mortality 77%) or hypercarbia (in-hospital mortality 61%). Although there are many reports of the negative impact of prophylactic hyperventilation following severe TBI, this modality is frequently utilized in the prehospital setting. Our results suggest that abnormal Pco(2) on presentation after severe head trauma is correlated with increased in-hospital mortality. We advocate normoventilation in the prehospital setting.

J Trauma. 1992 Sep;33(3):403-7.

The deleterious effects of intraoperative hypotension on outcome in patients with severe head injuries.
Pietropaoli JA, Rogers FB, Shackford SR, Wald SL, Schmoker JD, Zhuang J. Source
Department of Surgery, College of Medicine, University of Vermont, Burlington.

Abstract

Prehospital or admission hypotension doubles the mortality for patients with severe head injury (SHI = Glasgow Coma Scale score less than or equal to 8). To our knowledge no study to date has determined the effects of intraoperative hypotension [IH: systolic blood pressure (SBP) less than 90 mm Hg] on outcome in patients with SHI. This study examined 53 patients who had SHI and required early surgical intervention (surgery within 72 hours of injury). All patients were initially normotensive on arrival. There were 17 patients (32%) who developed IH and 36 (68%) who remained normotensive throughout surgery. The mortality rate was 82% in the IH group and 25% in the normotensive group (p less than 0.001). The duration of IH was inversely correlated with Glasgow Outcome Scale using linear regression (R = -0.30; p = 0.02). Despite vigorous fluid resuscitation in the IH group, additional pharmacologic support was used in only 32%. These data suggest that IH is not uncommon after SHI (32%) and that it does have a significant effect on patient outcome.

J Neurotrauma. 2007 Feb;24(2):287-93.

Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study.
McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, Hernndez AV, Marmarou A, Maas AI, Murray GD. Source
Public Health Sciences, University of Edinburgh Medical School, Edinburgh, United Kingdom. Gillian.McHugh@ed.ac.uk

Abstract
We determined the relationship between secondary insults (hypoxia, hypotension, and hypothermia) occurring prior to or on admission to hospital and 6-month outcome after traumatic brain injury (TBI). A meta-analysis of individual patient data, from seven Phase III randomized clinical trials (RCT) in moderate or severe TBI and three TBI population-based series, was performed to model outcome as measured by the Glasgow Outcome Scale (GOS). Proportional odds modeling was used to relate the probability of a poor outcome to hypoxia (N = 5661), hypotension ( N = 6629), and hypothermia ( N = 4195) separately. We additionally analyzed the combined effects of hypoxia and hypotension and performed exploratory analysis of associations with computerized tomography (CT) classification and month of injury. Having a pre-enrollment insult of hypoxia, hypotension or hypothermia is strongly associated with a poorer outcome (odds ratios of 2.1 95% CI [1.7-2.6], 2.7 95% CI [2.1-3.4], and 2.2 95% CI [1.63.2], respectively). Patients with both hypoxia and hypotension had poorer outcomes than those with either insult alone. Radiological signs of raised intracranial pressure (CT class III or IV) were more frequent in patients who had sustained hypoxia or hypotension. A significant association was observed between month of injury and hypothermia. The occurrence of secondary insults prior to or on admission to hospital in TBI patients is strongly related to poorer outcome and should therefore be a priority for emergency department personnel.

J Neurosurg. 1983 Aug;59(2):276-84.

The National Traumatic Coma Data Bank. Part 1: Design, purpose, goals, and results.
Marshall LF, Becker DP, Bowers SA, Cayard C, Eisenberg H, Gross CR, Grossman RG, Jane JA, Kunitz SC, Rimel R, Tabaddor K,Warren J. Abstract

This paper describes the pilot phase of the National Traumatic Coma Data Bank, a cooperative effort of six clinical head-injury centers in the United States. Data were collected on 581 hospitalized patients with severe non-penetrating traumatic head injury. Severe head injury was defined on the basis of a Glasgow Coma Scale (GCS) score of 8 or less following nonsurgical resuscitation or deterioration to a GCS score of 8 or less within 48 hours after head injury. A common data collection protocol, definitions, and data collection instruments were developed and put into use by all centers commencing in June, 1979. Extensive information was collected on pre-hospital, emergency room, intensive care, and recovery phases of patient care. Data were obtained on all patients from the time of injury until the end of the pilot study. The pilot phase of the Data Bank provides data germane to questions of interest to neurosurgeons and to the lay public. Questions are as diverse as: what is the prognosis of severe brain injury; what is the impact of emergency care; and what is the role of rehabilitation in the recovery of the severely head-injured patient?

J Trauma. 1993 Feb;34(2):216-22.

The role of secondary brain injury in determining outcome from severe head injury.
Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, Jane JA, Marmarou A, Foulkes MA. Source
Division of Neurological Surgery, UCSD Medical Center 92103-1990.

Abstract
As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

Br J Anaesth. 2007 Jul;99(1):4-9.

Pathophysiology of traumatic brain injury.

Werner C, Engelhard K. Source
Klinik fr Ansthesiologie, der Johannes Gutenberg-Universitt Mainz, Langenbeckstrasse 1, D55131 Mainz, Germany. werner@anaesthesie.klinik.uni-mainz.de

Abstract

The knowledge of the pathophysiology after traumatic head injury is necessary for adequate and patient-oriented treatment. As the primary insult, which represents the direct mechanical damage, cannot be therapeutically influenced, target of the treatment is the limitation of the secondary damage (delayed non-mechanical damage). It is influenced by changes in cerebral blood flow (hypo- and hyperperfusion), impairment of cerebrovascular autoregulation, cerebral metabolic dysfunction and inadequate cerebral oxygenation. Furthermore, excitotoxic cell damage and inflammation may lead to apoptotic and necrotic cell death. Understanding the multidimensional cascade of secondary brain injury offers differentiated therapeutic options.

Mt Sinai J Med. 2009 Apr;76(2):97-104. doi: 10.1002/msj.20104.

Pathophysiology of traumatic brain injury.

Greve MW, Zink BJ. Source
Department of Emergency Medicine, Warren Alpert School of Medicine, Brown University, Providence, RI, USA. mgreve@lifespan.org

Abstract
Traumatic brain injury is a major source of death and disability worldwide. Significant success has been achieved in improving short-term outcomes in severe traumatic brain injury victims; however, there are still great limitations in our ability to return severe traumatic brain injury victims to high levels of functioning. Primary brain injury, due to initial injury forces, causes tissue distortion and destruction in the early postinjury period. Clinical outcomes depend in large part on mediating the bimolecular and cellular changes that occur after the initial injury. These secondary injuries from traumatic brain injury lead to alterations in cell function and propagation of injury through processes such as depolarization, excitotoxicity, disruption of calcium homeostasis, free-radical generation, blood-brain barrier disruption, ischemic injury, edema formation, and intracranial hypertension. The best hope for improving outcome in traumatic brain injury patients is a better understanding of these processes and the development of therapies that can limit secondary brain injury.