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Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16. Acute Interventions for Acquired Brain Injury Matthew J Meyer PhD (Candidate), Robert Teasell MD FRCPC, Joseph Megyesi MD PhD FRCSC, Nestor Bayona MSc ERABI Parkwood Hospital 801 Commissioners Rd E, London ON 519-685-4292 x42630 Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Table of Contents 16.1 Management of Intracranial Pressure (ICP) ............................... 10 16.1.1 Non-Pharmacological Treatments ................................................................ 11 16.1.1.1 Head Posture ............................................................................................... 11 16.2.1.2 Hypothermia ................................................................................................ 16 16.1.1.3 Hyperventilation .......................................................................................... 32 16.1.1.4 Cerebrospinal Fluid Drainage ...................................................................... 36 16.1.1.5 Decompressive Craniotomy ........................................................................ 41 16.1.1.6 Continuous Rotational Therapy and Prone Positioning .............................. 50 16.1.2 Pharmacological Treatments ........................................................................ 52 16.1.2.1 Osmolar Therapies....................................................................................... 52 16.1.2.1.1 Hypertonic Saline .......................................................................................................... 52 16.1.2.1.2 Mannitol........................................................................................................................ 61 16.1.2.2 Propofol ....................................................................................................... 66 16.1.2.3 Midazolam ................................................................................................... 69 16.1.2.4 Opioids ......................................................................................................... 71 16.2.2.5 Barbiturates ................................................................................................. 74 16.1.2.6 Cannabinoids ............................................................................................... 81 16.2.2.7 Corticosteroids ............................................................................................ 83 16.1.2.8 Progesterone ............................................................................................... 87 16.1.2.9 Bradykinin Antagonists ................................................................................ 89 16.1.2.10 Dimethyl Sulfoxide..................................................................................... 92 16.2 Prompting Emergence from Coma ............................................ 95 16.2.1 Non-Pharmacological ................................................................................... 95 16.2.1.1 Sensory Stimulation ..................................................................................... 95 16.2.1.2 Music Therapy ........................................................................................... 102 16.2.1.3 Electrical Stimulation ................................................................................. 103 Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.2.2 Pharmacological Interventions ................................................................... 105 16.2.2.1 Amantadine ............................................................................................... 105 16.4 Summary ................................................................................ 111 16.5 References ............................................................................. 115 Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Table Directory Table 16.1 Head Posture for the Management of Elevated Intracranial Pressure post-ABI Table 16.2 Hypothermia for the Acute Management of Elevated ICP Post ABI Table 16.2a Summary of RCT Studies of Acute Hypothermia Post ABI Table 16.2b Summary of non-RCT Studies of Acute Hypothermia Post ABI Table 16.3 Hyperventilation for the Treatment of Elevated ICP Post ABI Table 16.4 Cerebrospinal Drainage for Treatment of Elevated ICP Post ABI Table 16.5 Decompressive Craniectomy to Control Refractory Elevated ICP Post ABI Table 16.6 Continuous Rotational Therapy and Prone Positioning in Acute Care Management Post ABI Table 16.7 Hypertonic Saline for the Management of ICP Hypertension Post ABI Table 16.8 Mannitol for the Management of ICP and Hypertension Post ABI Table 16.9 Propofol for the Management of Acute ABI Table 16.10 Midazolam for the Management Acute ABI Table 16.11 Opioids for the Management Acute ABI Table 16.12 Barbiturates for the Management of Elevated Intracranial Pressure Post ABI Table 16.13 Cannabinoids as an Acute Therapeutic Strategy Post ABI Table 16.14 Corticosteroids for the Management of Elevated Intracranial Pressure and Neuro-protection Post ABI Table 16.15 Progesterone for Treatment of Acute ABI Table 16.16 Bradykinin Antagonist as an Acute Therapeutic Strategy Post ABI Table 16.17 DMSO as an Acute Therapeutic Strategy Post ABI Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Table 16.18 Sensory Stimulation for the Management of Patients in a Coma or Vegetative State Post ABI Table 16.18a Summary of Studies of Sensory Stimulation to Promote Emergence from Coma or Vegetative State Post ABI Table 16.19 Music and Musicokinetic Therapy for Patients with Coma or Vegetative State Post ABI Table 16.20 Electrical Stimulation Post ABI Table 16.21 Amantadine for Arousal from Post ABI Coma Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Key Points Study findings suggest a 30° head elevation reduces ICP and improves CPP post TBI. Elevating the head of the bed post TBI is effective at lowering intracranial pressure in children, although the impact on CPP was minimal. Although hypothermia has been shown to reduce elevated ICP by some researchers there is no solid evidence to support its effectiveness post ABI. More research needs to be done. Systemic hypothermia increases the risk of pneumonia post ABI. Tromethamine counteracts the detrimental effects of prolonged hyperventilation for the control of ICP leading to better outcomes post-ABI. Hyperoxia may counteract the adverse effects of prolonged hyperventiliation for the control of ICP post-ABI. Hyperventilation below 34 torr PaCO2 may cause an increase in hypoperfused brain tissue. CSF drainage has been found to reduce ICP and increase CPP in those who have sustained an ABI. In adults standard trauma craniectomy leads to better control of ICP and better clinical outcomes at 6 months when compared with limited craniectomy Resection of a larger bone flap during craniectomy may lead to a greater reduction in ICP, better patient outcomes and fewer post-surgical complications Although decompressive cranectomy does reduce ICP in children more research needs to be conducted investigating its impat on the long term clinical outcomes. Continuous rotational therapy may not worsen intracranial pressure in severe brain injury patients Prone position may increase oxygenation and cerebral perfusion pressure in patients with acute respiratory insufficiency. Hypertonic saline reduces ICP more effectively than mannitol. Hypertonic saline and Ringer’s lactate solution are similar in lowering elevated ICP and result in similar clinical outcomes and survival up to 6 months post-injury. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury In children, use of hypertonic saline in the ICU setting results in a lower frequency of early complications and shorter ICU stays compared with Ringer’s lactate in children. Saline results in decreased mortality rates compared to albumin. Hypertonic saline may reduce elevated ICP uncontrolled by conventional ICP management measures. Hypertonic saline may aid in resuscitation of brain injured patients by increasing cerebral oxygenation. Sodium lactate is more effective than mannitol for reducing acute elevations in ICP. High dose mannitol results in lower mortality rates and better clinical outcomes compared with conventional mannitol. Early out of hospital administration of mannitol does not negatively affect blood pressure. Mannitol may only lower ICP when initial ICP values are abnormally elevated. Propofol may help to reduce ICP and the need for other ICP and sedative interventions when used in conjunction with morphine. Infusions of propofol greater than 4mg/kg per hour should be undertaken with extreme caution. Midazolam has no effect on ICP but may result in systemic hypotension. Bolus opioid administration results in increased ICP. There is conflicting evidence regarding the effects of opioid infusion on ICP. Remifentanil results in faster arousal compared to hypnotic based sedation. There are conflicting reports regarding the efficacy of pentorbarbital for the control of elevated ICP. Thiopental is beter than pentobarbital for controlling unmanageable refractory ICP. Pentobarbital is not better than mannitol for the control of elevated ICP. Barbiturate therapy plus hypothermia may improve clinical outcomes. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Patients undergoing barbiturate therapy should have their immunological response and systemic blood pressure monitored. Dexanabinol is not effective in controlling ICP or in improving clinical outcomes post-ABI. Methylprednisolone increases mortality rates in ABI patients and should not be used. Triamcinolone may improve outcomes in patients with a GCS<8 and a focal lesion. Dexamethasone does not improve ICP levels and may worsen outcomes in patients with ICP > 20mmHg Glucocorticoid administration may increase the risk of developing first late seizures. Progesterone decreases 30-day mortality rates. Progesterone improves GOS and modified FIM scores at 3 and 6 months post-injury. Some bradykinin antagonists prevent acute elevations in ICP but their effects on long-term clinical outcomes are uncertain. Dimethyl sulfoxide may cause temporary reductions in ICP elevations post-ABI. Sensory stimulation provided by family members improves consciousness for patients with GCS 6-8. Sensory stimulation may help to promote emergence from coma or vegetative state post ABI. Music therapy might be useful in promoting emergence from coma post ABI. Median nerve electrical stimulation does not improve emergence from coma post-ABI. Amantadine may improve consciousness and cognitive function in comatose ABI patients. Dopamine enhancing drugs may facilitate rate of recovery post traumatic brain injury in children; however, due to the small sample sizes more definitive research is needed. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury List of Common Abbreviations AANS ABI BTF CBF CBV CMRO2 CPP DRS EBIC GCS GOS ICP mmHg PEDro RLA TBI American Association of Neurological Surgeons Acquired Brain Injury Brain Trauma Foundation Cerebral Blood Flow Cerebral Blood Volume Cerebral Metabolic Rate for Oxygen consumption Cerebral Perfusion Pressure Disability Rating Scale European Brain Injury Consortium Glasgow Coma Scale Glasgow Outcome Scale Intracranial Pressure mm of mercury Physiotherapy Evidence Database rating scale Rancho Los Amigos scale Traumatic Brain Injury Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16. Acute Interventions for Acquired Brain Injury During the initial stages of a brain injury, there are variable degrees of irreversible damage to the central nervous system commonly known as the primary injury. Subsequently, a chain of events is put into motion leading to ongoing injury to the brain caused by edema, hypoxia, and ischemia which occurs as a result of increased ICP, the release of toxic amounts of excitatory neurotransmitters like glutamate, and impaired ionic homeostasis (2007). Acute brain injury treatment therefore focuses on preventing or minimizing the extent of secondary injury by targeting intracranial hypertension, oxygenation and ion homeostasis in order to reduce cellular injury. 16.1 Management of Intracranial Pressure (ICP) High intracranial pressure (ICP) is one of the most frequent causes of death and disability following severe head injury. It is defined as an ICP reading greater than 20 mmHg within any intracranial space (subdural, intraventricular, extradural, or intraparenchymal compartments) (Sahuqillo & Arikan, 2006). Mortality and morbidity following severe brain injury are strongly associated with increased ICP. Since the consequences of primary brain injury cannot be reversed, post-injury management primarily focuses on prevention and reversal of secondary insults to improve outcomes. Following a brain injury, the brain is extremely vulnerable to secondary ischemia due to systemic hypotension or diminished cerebral perfusion resulting from elevations in intracranial pressure (Doyle et al., 2001). For these reasons, the acute care of TBI patients includes the maintenance of adequate blood pressure and management of anticipated rises in ICP. Elevated ICP after ABI is generally due to edema or inflammation within the cranial cavity. There are different physiological mechanisms responsible for the production of this excess fluid resulting in vasogenic, cytotoxic and interstitial edema (Rabinstein, 2006). Vasogenic edema results from disruption of the blood brain barrier causing increased permeability and release of fluid into the extravascular space. Cytotoxic edema is due to failure of cellular ionic pumps causing increases in intracellular water content. Finally, interstitial edema is the forced flow of fluid from intraventricular compartments to the parenchyma generally due to an obstruction in drainage. Control of ICP is extremely important in patients with traumatic brain injuries (TBI), and multiple therapies tend to be used to manage ICP. To be effective, treatments need to target the specific form of edema that is problematic. The degree and timing of ICP elevation are also important determinants of clinical outcome, so it is important for ICP interventions to act rapidly to be effective. Non-surgical therapy includes the use of osmotic and loop diuretics, hypothermia, sedation and paralysis, controlled hyperventilation and barbiturates. Surgical therapies include Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury ventriculostomy with therapeutic drainage, evacuation of mass lesions, as well as decompressive craniectomy. Interest in the promise of potential neuroprotective agents has also begun to spark new research initiatives. The negative effects associated with cellular level post-traumatic stress may be a potential target for future therapies. Traditional therapies have included sedatives such as barbiturates and opiates in an attempt to down regulate cellular metabolism. Newer initiatives have begun to target free radical production and oxidative stresses, which affect membrane viability. Some neuroprotective agents that have been suggested include sedatives, steroids and anti-oxidant solutions. Guideline Recommendations In an attempt to standardize acute management of acquired brain injury, several consensus guidelines of care have been developed. The two most prominent sets of guidelines are those developed by the American Association of Neurological Surgeons initially in 1995 and most recently in 2007 (Carney & Ghajar, 2007), and by the European Brain Injury Consortium (EBIC) in 1997 (Maas et al., 1997). These guidelines, which have gained credibility worldwide, are widely recognized as influencing clinical practice. With this in mind, we have chosen to add recommendations made by either organization into our evaluation of each intervention. However, the conclusions presented here are based on our methodology and have not been influenced by guideline recommendations. Although, the EBIC provides descriptive guidelines, they do not incorporate levels of evidence (Maas et al., 1997). The AANS make recommendations based on levels of evidence as follows (Carney & Ghajar, 2007): Level I - Good quality Randomized Control Trial (RCT) Level II - Moderate quality RCT, good quality cohort, good quality case-control Level III - Poor quality RCT, moderate or poor quality cohort, moderate or poor quality casecontrol, case-series, databases or registries 16.1.1 Non-Pharmacological Treatments 16.1.1.1 Head Posture The standard practice in most head injury intensive care units is to elevate the head above the level of the heart in an effort to reduce intracranial pressure by facilitating venous outflow without compromising cerebral perfusion pressure (CPP) and cardiac output (Ng et al., 2004). It has been suggested that head elevation may even slightly improve CPP (Schulz-Stiibner and Thiex 2006). Placing patients in an elevated head posture also facilitates early provision of enteral nutrition while at the same time reducing the risk for gastric reflux and pulmonary aspiration when compared with patients kept in the supine position (Ng et al., 2004). Ng et al. (2004) note that nursing individuals who sustain a TBI remaining in a flat position reduces the Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury risk for systemic hypotension inherent in a semi-recumbent posture. Furthermore, some authors argue that a horizontal body position increases cerebral perfusion pressure improving cerebral blood flow (Winkelman 2000). The European Brain Injury Consortium stated that no consensus existed regarding the benefits of head elevation to 30 degrees when compared to the recumbent position (Maas et al., 1997). The AANS has not referred to head position in their most recent guidelines (Carney and Ghajar 2007). Individual Studies Table 16.1 Head Posture for the Management of Elevated Intracranial Pressure post-ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Adult Population Winkelman (2000) RCT PEDro = 4 N=8 Non-vascular, non-penetrating severe brain injury (GCS < 8) patients were randomly assigned to be placed either with the backrest elevated at 30 degrees or flat (0 degree elevation). Patients remained in the initial position for 65-75 min after which they were placed in the alternative position. ICP and CPP were assessed at 5, 15, 30 and 60 min after the change in position. No other interventions occurred during the 60 min observation period. Use of backrest elevation of 30 degrees resulted in significant improvements in both ICP and CPP immediately after changes in backrest position from 0 to 30 degrees (p=0.001) and during equilibrium at the 30 degree position (p=0.003). March et al., (1990) USA RCT PEDro = 3 N=4 Head injury patients started laying flat and No significant changes noted on any of the underwent backrest manipulation into 3 measures among the 4 backrest positions. different positions: 30 degree head elevation, 30 degree head elevation with knee gatch raised, and flat to reverse Trendelenburg position. Subjects were initially placed in the flat position for 15 minutes, followed by 15 minutes in one of the 3 randomly assigned alternate backrest positions. All subjects were assessed under all 4 backrest positions for changes in ICP, CPP and CBF. Ledwith et al., (2010) USA Quasi-RCT N=30 All participants had sustained either a TBI or SAH. Each participant was placed in one of 12 body positions, which were randomly ordered. Positions included, the supine, supine with knee bent, left lateral position and right lateral position. In each position the HOP was elevated to 15, 30 or 45 degrees. Individuals remained in each position for 2 hours. Thirty of the 33 participants completed the study. Results indicate that ICP was significantly reduced when individuals were placed in the supine with HOB 45° (p=0.002 – decrease), left lateral with HOB 15° (p=0.026 – increase), right lateral with HOB 15° (p=0.002 increase) and the knee elevation with HOB 30° (p=0.039 - decrease). Oxygenation of brain tissue also increased while in 4 of the positions: supine with HOB 30° (p= 0.006 - Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome decrease), supine with HOB 45° (p=0.004 – decrease), left lateral with HOB 30° (p=0.046, decrease and right lateral with HOB 30° (p=0.028 - decrease). Schulz-Stiibner & Thiex (2006) Case Series N=10 Study participants had sustained either a severe TBI (n=5) and SAH (n=5). Participants had their head elevated to 30°. Positive end expiratory pressure (PEEP) of 5cmH20. PEEP was increased to 10 and 15cmH20. When participants had their heads lowered to a flat position, ICP was increased and CPP was reduced. Increase in PEEP from 5 to 10 cmH 20 increased ICP without dropping CPP significantly. When the head was elevated to 30° PEEP was found to increase from 5 to 10 cmH20. Ng et al., (2004) Singapore Case Series N=38 The effect of head elevation on ICP, CPP, mean arterial pressure, global cerebral oxygenation, and regional cerebral oxygenation were compared in a group of closed head injury patients (GCS ≤ 8) when the head was elevated 30 degrees or when the head was lowered to 0 degrees. Patients acted as their own controls. ICP was significantly lower at 30 degrees than at 0 degrees of head elevation (p=0.0005). Mean arterial pressure remained unchanged. CPP was slightly but not significantly higher at 30 degrees (p=0.412). Of note those who had lower ICP at the start of the study were found to have the greatest decrease in ICP when the head was elevated 30°. Global cerebral oxygenation and regional cerebral oxygenation were not affected significantly by head elevation. Meixensberger et al., (1997) Germany Case Series N=22 Acute brain injury patients were initially placed in a 30 degree body position and baseline values were collected for 10 min, then body position was changed to 0 degrees and values were noted after reaching steady state conditions (10-15 min). ICP, tissue pO2 (ti-pO2), and CPP were assessed in both head positions. Compared with the 30 degree head position ICP was significantly higher (p<0.001) and CPP significantly lower (p<0.01) at the 0 degrees head position. ti-pO2 and mean arterial blood pressure were unaffected by head position. Feldman et al., (1992) USA Case Series N=22 Patients were treated within 72 hours after injury. In the first 13 patients the head was initially elevated to 30 degrees. In the subsequent 9 patients the head was initially set at 0 degrees of elevation. Head elevation was changed to the alternate position after 45 minutes. Cerebral blood flow (CBF), mean carotid pressure (MCP), ICP, CMRO2, oxygen saturation in the jugular bulb, cerebrovascular resistance (CVR), PaCO2, PaO2, arteriovenous difference of lactate, mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were compared in both head positions. MCP and ICP were significantly lower at 30 degrees of head elevation than at 0 degrees of elevation (p=0.085 and p=0.0079 respectively). Furthermore, patients with the highest ICP at the horizontal position experienced the greatest reductions in ICP at 30 degree of head elevation (r= -05890). All of the other physiological parameters were not significantly affected by the change in head elevation. Lee N=30 Changes in ICP were measured in severe Compared with the supine 0º position, ICP Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome (1989) China Case Series head injury patients (GCS < 8) with patients in four different positions: head at 0º; supine with head of the bed down 30º; three fourths supine; and three fourths prone without turning the head. increased significantly for head down 30º (p<0.01), three fourths supine (p<0.01) and three fourths prone (p<0.01) positions, although there were individual differences in ICP in response to position changes. Durward et al., (1983) Canada Case Series N=11 Severe brain injury patients (GCS < 8) with associated intracranial hypertension were subjected to 4 positions of head elevation: 0 (baseline), 15, 30 and 60º. Each position was maintained for 5-10 minutes and ICP and CPP) were assessed. ICP decreased significantly with elevation of the head from 0º to 15º (p<0.001). This decrease in ICP was maintained at 30º (p<0.001) but was not significantly different from the ICP at 15º. ICP at head elevation of 60º was not significantly different from 0º of elevation. Furthermore, CPP was not significantly affected by 15º or 30º of head elevation, whereas elevation of the head to 60º caused a significant reduction of CPP compared with baseline (0º, p< 0.02). Pediatric Population Agbeko et al. (2012) United Kingdom RCT PEDro = 5 N=38 The effect of head elevation on ICP, CPP, mean arterial pressure, global cerebral oxygenation, and regional cerebral oxygenation were compared in a group of closed head injury patients (GCS ≤ 8) when the head was elevated 30 degrees or when the head was lowered to 0 degrees. Patients acted as their own controls. ICP was significantly lower at 30° than at 0 degrees of head elevation (p=0.0005). Mean arterial pressure remained unchanged. CPP was slightly but not significantly higher at 30 degrees (p=0.412). Of note those who had lower ICP at the start of the study were found to have the greatest decrease in ICP when the head was elevated 30°. Global cerebral oxygenation and regional cerebral oxygenation were not affected significantly by head elevation. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In an earlier RCT Winkelman (2000) reported that head elevation of 30 degrees resulted in significant improvements in both ICP and cerebral perfusion pressure when compared to a flat position. This finding was also supported by several other studies (Ng et al., 2004; Lee et al., 1989; Durward et al.,1983; Feldman et al., 1992). In each of these elevating the head to 30° significantly decreased ICP, while increasing CPP. Again, in a 2006 study, Schulz-Stiibner noted that ICP decreased and CPP increased when participants’ heads were elevated to 30°. The findings of Durward et al. (1983) also suggest that a head elevation of 15 to 30° may yield the best result. Further they found an elevation of 60° did not lead to changes in ICP but did increase CPP when compared to not elevating the head. Although these studies lack randomization, their findings support the work of Winkelman. Despite these positive findings, March et al. (1990) reported that head elevation to 30° did not improve ICP or CPP compared to Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury no head elevation. Due to the small sample size (n=4) in the March study, it is unclear as to the benefits of elevating the head to 30° post ABI. More recently Ledwith et al. (2010) have suggested that no single position is optimal for improving neurodymanic parameters in those who sustain an ABI. In this study authors placed individuals who had sustained an ABI (n=33) into one of 12 positions, that were randomly assigned. Positions included the supine, supine with knee bent, left lateral position and the right lateral position. While in each of these positions the head of the bed was elevated to 15, 30, or 45 degrees. The level of brain tissue oxygen was significantly affected, notably a decrease was seen, when participants were placed in the following positions: supine with the head of be elevated to 45 º, Supine with head of be elevated to 45º, when placed in the right or left lateral position with the head of the bed elevated to 30º. Further ICP was found to decrease significantly when placed in the supine position with the head of the bed elevated to 45º (p<0.002) and when the knee was elevated and the head of bed was elevated to 30º (p<0.039). Increases in ICP were seen when placed in the left lateral position with the head of the bed elevated to 15º (p<0.026), the right lateral position with a head of bed elevation of 15º (p<0.002). Only one position had a significant effect on CPP, the left lateral position with the head of the bed elevated to 30º (Ledwith et al., 2010). In one paediatric study examining the benefits of elevating the head of bed by 10 cm increments in children who had sustained a TBI, ICP was found to decrease (Agbeko et al., 2012). If the head of bed (HOB) was lowered ICP was found to increase. Cerebral perfusion pressure (CPP) was not found to change significantly as a result of adjusting the HOB. In total study authors presented individuals with 66 HOB challenges. Study authors also noted that the age and height of individuals is necessary when considering the HOB effect on ICP (Agbeko et al., 2012). Conclusions There is Level 2 evidence suggesting a 30° head elevation reduces intracranial pressure with concomitant increments in CPP. There is Level 2 evidence to suggest head elevation does reduce ICP in children post TBI; however, it was not found to have a significant impact of CPP. Study findings suggest a 30° head elevation reduces ICP and improves CPP post TBI. Elevating the head of the bed post TBI is effective at lowering intracranial pressure in children, although the impact on CPP was minimal. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.2.1.2 Hypothermia Mild to moderate hypothermia is a neuroprotective strategy that has been explored as a measure to reduce secondary brain injury. It was first proposed as a possible treatment for ABI more than a half a century ago (Fay 1945) and early reports suggested that hypothermia might improve clinical outcomes. It is believed that hypothermia is initiated to control for 1) elevated intracranial pressure (ICP) and 2) it limited the biochemical cascade believed to result in secondary brain injury (Clifton 2004). Neuroprotective effects include reducing cerebral metabolism, decreasing the inflammatory response, and decreasing the release of excitotoxic levels of glutamate and free radicals post-ABI (Marion et al., 1997; Alderson et al, 2004; Globus et al., 1995). Many studies looking at the benefits of hypothermia report on the impact it has on ICP (Clifton, 2004). It should also be noted that prolonged hypothermia is believed to be associated with various adverse effects including arrhythmias, coagulopathies, sepsis and pneumonia which could ultimately lead to a poorer clinical outcome (Alderson et al., 2004; Gadkary, and Signorini2004; Schubert 1995). It has also been suggested that there may be a threshold during re-warming above which pressure reactivity may reach damaging levels (Lavinio et al., 2007) and that there is a critical window beyond which hypothermia may be ineffective (Clifton et al., 2009). Several methods of hypothermic intervention have been suggested. Systemic hypothermia involves cooling the entire body with cooling blankets (Qiu et al., 2007) and occasionally a gastric lavage (Marion et al., 1993), while selective hypothermia aims to target the head specifically using a cooling cap and neckband (Liu et al, 2006). The AANS noted that prophylactic hypothermia showed no significant association with improved outcomes relative to normothermic controls but preliminary findings suggested that mortality risks may be seen when target temperatures were maintained for more than 48 hrs. They also suggested that hypothermia was associated with significantly higher GOS scores (Bratton et al., 2007a). Currently there are no EBIC recommendations for hypothermia. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.2 Hypothermia for the Acute Management of Elevated ICP Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Hypothermia in the Adult Population Clifton et al., (2011) USA/Canda RCT PEDro=9 N=92 Participants was stratified by centre (6 centres participated) to either the hypothermia or normothermia. Those in the hypothermia groups had their core body temperatures maintained to 35° C, while those in the normothermia groups were maintained at 37° C. Those receiving hypothermia treatment by intravenous instillation of up to 2L of cold crystalloid and received wet sheets or gel packs to help lower their core body temp. Those in the normothermia group were given cooling blankets to maintain their core body temperature at 37° C. Overall there were no significant differences in there number of individuals between the two groups who developed complications (mortality rates and long term outcomes). For those in the hypothermia groups there were episodes of increased intracranial pressure. This resulted in an increase in the total rate of complications for the hypothermia group. Surgical patients in the hypothermia group had poorer outcomes then those in the normothermia group (p=0.09). Further those in the diffuse brain injury group had more episodes of raised intracranial pressure then those in the normothermia group. Lee et al., (2010) China RCT D&B=19 N=45 Participants were randomly assigned to one of 3 groups, after undergoing a craniotomy. Those assigned to group A participated in intracranial pressure/cerebral perfusion pressure guided management only, those in group B received mild hypothermia and ICP/CPP guided management and group C received hypothermia and brain tissue oxygen (Pti O2) with guided ICP/CPP management Overall no significant findings were noted between the 3 groups. Favourable outcomes were noted in 50% of the normothermia group, 60% on the hypothermia only group and 71.4% in the Pti O2, and hypothermia group. Mortality was highest in the normothermia groups (12.5%) while in the hypothermia groups it was 6.7% and in the Pti O2, 8.5%. Yan et al., (2010) China RCT PEDro = 6 N=148 Participants were randomized between normothermia (37±.05°C) and hypothermia (32-34°C). All had sustained a a severe TBI (GCS 3-8). Those in the hypothermia group were placed on a cooling bed. Treatment colling lasted 3 to 5 days. Following this patients were rewarmed, until normal body temperature was reached. While on the cooling bed the pressure of the oxygen in the brain tissue (PbrO2) and cerebral oxygen saturation (rSaO2) was monitored. Neuroelectrophysiological For those with a GCS of 7-8, the PbrO2 levels were significantly greater for hypothermia group compared to the normotherapy group. Further the levels were significantly higher for hypothermia group, and the shortlatency somatosensory evoked potential (SLSEP) wave amplitude was significantly higher for hypothermia group. For GCS 5-6, PbrO2 levels were significantly greater for hypothermia group, rSaO2 levels were significantly greater for hypothermia group, short- Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome monitoring was also completed. latency somatosensory evoked potential (SLSEP) wave amplitude was significantly higher for hypothermia group. There were no significant differences for the GCS 3-4 on any measurements. GOS for those with a GCS of 7-8 indicated more in the hypothermia group made either a good or moderate receovery (n=17) compared to the normotherapy group (n=13). For those with a GCS of 3-4 no significant differences were noted on the GOS at follow-up. Harris et al., (2009) USA RCT PEDro = 7 N=21 Severe TBI patients (GCS ≤8) were randomized to receive either localized hypothermia treatment (target 33°C) via a cooling cap or normothermia. Patients were monitored for brain and systemic temperature with clinical outcomes of mortality, GOS and FIM. Beyond the first 3 hours of treatment, the mean intracranial temperature was significantly lower in the treatment group than in the control group (p<0.05), except at the 6 hour (p=0.08) and 4 hour (p=0.08) point. The target temperature of 33°C was rarely achieved however and no significant differences were noted on any of the clinical outcomes between groups. Qiu et al., (2007) China RCT PEDro = 7 N=80 Patients with severe TBI after unilateral craniotomy were randomized into a hypothermia group with brain temperature of 33-35°C maintained for 4 days and a normothermia group. Vital signs, intracranial pressure, serum superoxide dismutase levels, GOS scores and complications were prospectively analyzed. Mean ICP of therapeutic group at 24, 48 and 72 hours was lower than control. (23.49±2.38, 24.68±1.71, and 22.51±2.44 vs 25.87±2.18, 25.90±1.86, and 24.57±3.95 mmHg; p = 0.000, 0.000, and 0.003). Mean serum superoxide dismutase levels were higher at days 3 and 7 in the intervention group (533.0±103.4 and 600.5±82.9 vs 458.7±68.1 and 497.0±57.3 microg/L; p=0.000). Percentage of favourable neurological outcome at 1 year was 70% vs 47.5% respectively (P=0.041).Complication, including pulmonary infection were higher in the therapeutic group (57.5% vs 32.5%; p=0.025). Liu et al., (2006) China RCT PEDro = 5 N=66 Brain injured patients (GCS ≤ 8) were randomly allocated to one of three groups: 22 to selective brain cooling SBC, 21 to mild systemic hypothermia MSH and 23 to control. SBC consisted of Both hypothermia groups showed a significant decrease in ICP levels relative to the control group at 24, 48 and 72 hours post injury (p<0.05). Superoxide dismitase levels were significantly Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome cooing of the head and neck to 33-35°C using a cooling cap and neckband with circulating 4°C water. MSH was achieved using a cooling blanket and refrigerated ice bags to a rectal temperature of 3335°C. Control received the same conventional treatment minus the hypothermia. higher in the hypothermia groups at 3 and 7 days post injury(p<0.01). The percentage of patients with good GOS scores 2 years post injury were 72.7%, 57.1% and 34.8% in the SBC, MSH and control groups respectively. Clifton et al., (2001) USA RCT PEDro = 6 N=392 Severe (GCS 3-8) comatose nonpenetrating head injury patients were randomly assigned to be treated with hypothermia (33ºC) which was initiated within 6 hours after injury and maintained for 48 hours or normothermia (37 ºC). GOS outcome 6 months post-injury was assessed as the primary outcome. Poor GOS outcome (severe disability, vegetative state, death) were reported in 57% of patients in both groups. Mortality was not significantly different between groups (28% in the hypothermia group and 27% in controls, p=0.79). Patients in the hypothermia group had more hospital days with complications than those in the normothermia group. Fewer patients in the hypothermia group had high ICP compared with those in the normothermia group. Jiang et al., (2000) China RCT PEDro = 6 N=87 Severe TBI patients (GCS ≤ 8) were randomly assigned to prolonged mild hypothermia (33-35ºC for 3-14 days. Rewarming started when ICP returned to normal levels) or normothermia (3738ºC). Acute changes in ICP between groups were compared. Mortality rates and clinical outcome using the GOS were assessed 1 year later. Mortality rate was 25.58% and the rate of favourable outcome on the GOS (good recovery/mild disability) was 46.51% in the hypothermia group while in the normothermia group the mortality rate was 45.45% and the rate of favourable outcome was 27.27 % (p<0.05). Hypothermia caused a significant reduction in ICP (p<0.01) and inhibited hyperglycemia (p<0.05). Shiozaki et al., (1999) Japan RCT PEDro=5 N=16 Following randomization participants in the treatment group mild hypothermia was begun by cooling the body surface. Intracranial temperature was maintained at 33.5 to 34.5°C. This was continued for the first 48 hours, at which time the participants were slowly warmed to 37° C. During the warming period, all were placed on barbiturates. Those in the normothermia group had their intracranial pressure maintained at 36.5 to 37.5° C by surface cooling for 5 days. Barbiturates were infused every 6 to 8 hours during the first 48 hours. Overall there were no significant changes in cerebrospinal fluid (CSF) concentrations between the two groups when looking at the presence of excitatory amino acids or cytokines. Nor was any difference in cardiac arrhythmia between the two groups. Study results indicate no significant changes between the groups regardless of the group participants were randomized to. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Marion et al., (1997) USA RCT PEDro = 5 N=82 Severe closed head injury patients (GCS 3-7) were randomized to a hypothermia group (33ºC using cooling blankets and cold saline gastric lavage within a mean of 10 hours after injury and maintained for 24 hours. Patients were then rewarmed to 37-38.5ºC over 12 hours at a rate of 1 ºC/hour) or to a normothermia group (37-38.5ºC). GOS outcomes at 3, 6 and 12 months after injury were compared. At 3 months, the hypothermia group had a significantly more patients with favorable outcome (good outcome/moderate disability) on the GOS than the normothermia group (38% vs. 17%, p=0.03). At 12 months, a similar difference in favorable GOS outcome between groups was observed (62% vs. 38%, p=0.05). Patients with an initial GCS of 3-4 did not benefit from hypothermia, whereas those with scores of 5-7 did. Among patients with an initial GCS score of 5-7, significantly more patients in the hypothermia group had a favorable GOS outcome at 6 months than those in the normothermia group (73% vs. 35%, p=0.008). During the cooling period, the hypothermia group had significantly lower ICP (p=0.01), CBF (p=0.05) and heart rate (p<0.001) and higher CPP (p=0.05) compared with controls. Resnick et al., (1994) USA RCT PEDro = 5 N=36 Severe head injury patients (GCS ≤ 8) were randomly assigned to therapeutic hypothermia (cooled within 6 hours of injury to a brain temperature of 32-33 ºC for 24 hours using cooling blankets and cold saline gastric lavage. Patients were then rewarmed over 12 hours) or to a normothermia group (brain temperature of 37-38 ºC). At admission and again 24 hours after admission, the development of delayed traumatic intracerebral hematoma (DTICH) and the most common tests of coagulation function: prothrombin times, partial thromboplastin times, and platelet counts were used as outcome measures. There were no significant differences between groups in measured coagulopathy, or in any of the coagulation parameters. The incidence of DTICH was not increased by the use of moderate hypothermia (6/20 of the patients in the hypothermia group developed DTICH compared with 5/16 patients in the normothermia group). The short-term use of hypothermia does not appear to increase the risk of intracranial hemorrhage complications in head injury patients. Marion et al., (1993) USA RCT PEDro = 6 N=40 Severe closed head injury patients (GCS 3-7) were randomized to hypothermia (using cooling blankets and cold saline gastric lavage within 10 hours after injury and maintained for 24 hours. Patients were rewarmed to 37-38ºC over 12 hours) or normothermia (37-38ºC). ICP, CBF, and CMRO2 were assessed as Hypothermia significantly reduced ICP (p<0.004) and CBF (p<0.021) during the cooling period. Mean CMRO2 in the hypothermia group was significantly lower during cooling and higher 5 days after injury compared with the normothermia group (p<0.001). There was a trend toward a better outcome 3 Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome well as the DRS and the GOS scales 3 months after the injury. months post-injury in the hypothermia group as 12 patients in this group showed moderate, mild or no disability (GOS score 3-4) whereas only 8 patients in the normothermia group had improved to this level (p<0.24). DRS scores reflected the same trend, with more patients in the hypothermia group achieving a better outcome. Shiozaki et al., (1993) Japan RCT PEDro = 5 N=33 Severe head injury patients (GCS ≤ 8) in whom ICP remained > 20 mmHg despite high dose barbiturate therapy were randomly assigned to mild hypothermia (33.5 –34.5 ºC via surface cooling using water circulating blankets for 2 days. Patients were then rewarmed slowly and core temperature maintained between 35.5 –36.5 ºC for 24 hours. If ICP again became elevated, patients were re-cooled to 34 ºC) or no hypothermia. ICP, CPP and GOS were assessed. In the control group 12/17 died from ICP hypertension, while mild hypothermia significantly reduced ICP (p<0.01) and increased CPP (p<0.01). Fifty percent of the patients in the hypothermia group survived compared with only 18% in the control group (p<0.05), while 31% in the hypothermia group and 71% in the control group died from uncontrollable ICP (p<0.05). Thirty-eight percent of the patients in the hypothermia group had good GOS outcome (good recovery/mild disability) at 6 months compared with only 6% in the control group. Tokutomi et al., (2009) Japan Non-RCT N=61 Patients treated with hypothermia to 35 ºC were compared to those treated with hypothermia to a target temperature of 33 ºC. Patients were monitored for ICP levels, CPP, serum potassium levels, c reactive protein, mortality and complications. Patients in both groups exhibited decreases in ICP below 20 mmHg with no differences in the incidence of intracranial hypertension or low CPP. Patients cooled to 35 ºC showed significant improvements in serum potassium concentrations and Creactive protein levels with a trend toward decreased mortality and fewer complications. Qiu et al., (2006) China Non-RCT N=90 Severe TBI patients (GCS ≤ 8) were divided between selective brain cooling (SBC) group (cooling cap at 4ºC and a neck band with ice straps) and a control group. Patients were treated for 3 days and monitored for ICP. They were then followed up on at 6 months post-injury. At 24, 48 and 72 hours ICP was lower for the SBC group compared to the normothermia group (19.14 ± 2.33 vs 23.41 ± 2.51, 19.72 ± 1.73 vs 20.97 ± 1.86 and 17.29 ± 2.07 vs 20.13 ± 1.87 mmHg respectively. P<0.01). There was also significant difference in GOS good neurological outcome rates 6 months after injury (68.7% SBC vs 46.7% Control, P<0.05) Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Carhuapoma et al., (2003) USA Case Series N=6 Acute brain injury patients (GCS 5-9) who experienced fever (≥ 38.0 ºC) that was refractory to conventional pharmacological antipyretic treatment were treated with hypothermia (36.5ºC). Prophylactic hand warming using instant Hot Packs was used to prevent shivering at the time of cooling. Fever was significantly reduced to 36.9 ºC after 120 min (p<0.001). Core temperature remained controlled and unchanged during the remainder of the treatment (36.6 ºC, p = 0.5; 36.6 ºC, p=0.09, and 36.5 ºC, p=0.09 at 180, 300 and 600 minutes respectively). Tokutomi et al., (2003) Japan Case series N=31 Severe brain injury patients (GCS ≤ 5) were cooled to 33 ºC. Hypothermia was induced by surface cooling with water-circulating blankets. Patients were slowly rewarmed after 48-72 hours of hypothermia. Changes in ICP and CPP were assessed. Incidence of elevated ICP decreased significantly with hypothermia (p>0.0001). ICP decreased significantly at brain temperatures < 37 ºC and decreased more sharply at 35-36 ºC, but no differences were observed at temperatures < 35 ºC. CPP peaked at 35-35.9ºC and decreased with further decreases in temperature. Yamamoto et al., (2002) Japan Non-RCT N=84 Severe TBI patients (GCS 3-7) were assigned to receive mild therapeutic hypothermia (33-35 ºC) for at least 36 hours to a maximum of 7 days according to the severity of brain injury or to a group which was treated without hypothermia. GOS outcome 3 months after the injury was compared between groups. The hypothermia group was subdivided into 2 subgroups according to their GOS outcome: GOOD (good recovery/mild disability) and POOR (severe disability/vegetative/death). The mild hypothermia group had significantly better outcome and significantly lower mortality compared with the control group (p<0.05). The patients in the good outcome subgroup were significantly younger, and their cerebral perfusion pressure was significantly higher during hypothermia compared with the poor outcome subgroup (p<0.05). Polderman et al., (2002) Netherlands Non-RCT N=136 Severe (GCS ≤ 8) head injury patients in whom intracranial pressure ICP remained > 20 mmHg despite conventional therapy were assigned to be treated with moderate hypothermia (32-34 ºC) using water-circulating blankets (n=64) or no hypothermic treatment (n=72). If ICP remained ≤ 20 mmHg for 24 hrs, the patient was slowly rewarmed (1ºC per 12 hrs). If ICP increased to > 20 mmHg, the temperature was again decreased until ICP decreased below 20 mmHg. Mortality and neurological outcome were assessed at 6 months using the GOS. The average duration of hypothermia was 4.8 days (range 1-21 days). ICP decreased markedly in all patients during cooling. Actual mortality rates were significantly lower in the hypothermia group compared with the control group (62% vs. 72%, p<0.05). The number of patients with good neurological outcome on the GOS was also higher in the hypothermia group (15.7% vs. 9.7%, p<0.02). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Gal et al., (2002) Czech Republic Non-RCT N=30 Severe head injury patients (GCS 38) were assigned to a hypothermic group (core temperature reduced to 34 ºC within 15 hours of injury and maintained for 72 hours using forced air cooling combined with circulating water mattress cooling) or a normothermic group (36.537.5 ºC). Changes in ICP, CPP, and GOS outcome at 6 months were assessed. The 2 groups were similar in terms of injury severity, age, sex ratios, and CT findings. There was a significant reduction in ICP in the hypothermia group compared with the normothermia group (p=0.0007). Significant increase in CPP during hypothermia (p=0.0007) with unchanged (p=0.90) systolic arterial pressure values compared with normothermia. No significant differences between groups in GOS outcome 6 months post-injury (p=0.084) although 87% of patients in the hypothermia group reached good neurological recovery (GOS 4-5) compared with only 47% in the control group. Chen et al., (2001) China Non-RCT N=30 Severe head injury patients were assigned to moderate hypothermia (3335 ºC over 10 hours for 3-10 days) or routine treatment. Mortality, endothelin (ET) in serum, neuron-specific enolase (NSE) in serum, free radical scavenger superoxide dismutase (SOD) was compared between groups. Mortality was significantly lower in the hypothermia group than in the control group. Hypothermia greatly reduced ET and NSE and increased SOD. No obvious differences found in arterial pH, pO2, + + pCO2, serum K , Na , or Cl between groups. Tateishi et al. (1998) Japan Case Series N=9 Severe brain injury patients (GCS ≤ 8) with ICP ≥ 20 mmHg despite conventional therapeutic measures were subjected to a maximum of 6 days of mild hypothermia induced by repeated intragastric cooling using a nasoduodenal tube of iced half-saline infused during 15 – 30 min supplemented with surface cooling. This process was repeated if necessary to reduce and maintain ICP < 20 mm Hg. Changes in ICP and jugular venous oxygen saturation at baseline and 3 hours after beginning of hypothermia were assessed. Platelet count, C-reactive protein, and GOS at 6-12 months after discharge were also evaluated. Hypothermia was induced within 24 hours of admission and continued for 20 – 118 hours (mean = 68 h). Lowest brain temperature obtained ranged from 33 – 35 ºC. Significant reduction in ICP 3 hours after cooling (p<0.05), however 4 patients experienced systemic infection complications. Increased C-reactive protein and decreased platelet count were observed in all patients during hypothermia. 7/9 patients showed good recovery or moderate disability according to the GOS 6 – 12 months after discharge. Hypothermia in the Pediatric Population Adelson et al., (2013) N=77 Children were randomly assigned to either the hypothermia group or the When looking at the main outcome, mortality at 3 months, researchers Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome USA RCT D&B=27 normothermia group. Children in the hypothermia group were cooled with iced saline to 34-45° c then surfaced cooled to 32-33° C. This was maintained for a 48 hour period at which time all were rewarmed. Those in the nomothermia group had their temperatures maintained at 36.5-37.5°C. If temperature rose to 38°C cooling blankets and rectal acetaminophen was given. found no difference between the groups. Six of 39 in the hypothermia group died and 2 of 38 in the normothermia group died. When looking at global functioning no significant differences were found between the two groups. Due to the lack of significant findings between the two groups, the study was halted much earlier then planned. Hutchison et al., (2013) Canada RCT N=205 Children with TBI were randomized to receive either hypothermia (32.5±0.5°C) or normothermia (37±0.5°C) treatment. Patients 7 or older showed more unfavorable outcomes in the hypothermia group than in the normothermia group (P=0.06). Patients with intracranial pressure lower than 20 mm Hg also showed a higher risk of unfavorable outcomes when receiving hypothermia treatment as opposed to normothermia. No benefits were noted in either intermediate or long-term outcomes after hypothermia treatment. Bayir et al., (2009) USA RCT PEDro = 6 N=28 Infants and children with severe TBI (GCS ≤8) were randomized to receive either hypothermia (32-33°C) or normothermia (36.5-37.5°C). Patients were monitored for measures of oxidative stress. When looking at the total antioxidant reserve, those in the normothermai group showed reduction reduction vs those in the hypothermia group post injury. An inverse relationship between cerebrospinal fluid (CSF) total antioxidant reserve and temperature after injury (p=0.022) was found. Glutathione concentration in CSF and temperature were inversely related after injury (p=0.002). The effect of temperature was not significant on CSF prot-SH (p=0.104) or CSF F2-isoprostane levels (p=0.104). Li et al., (2009) China RCT PEDro = 6 N=22 Children (6-108 months) who were severely brain injured (GCS ≤8) were randomized to either localized hypothermia treatment using a cooling cap (34.5±0.2°C) or normothermia (38.0±0.5°C). Hypothermia treated group showed lower ICP values which were statistically significant at 8, 24, 48 and 72 hours (P<0.05). In the hypothermia group, neuron-specific enolase levels were lowered (P<0.05), S-100 levels were lowered (P<0.01) and creatine kinase-BB levels were also lowered (P<0.0001) in comparison with the normothermia Follow-up to the 2008 study Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome group. Hutchison et al., (2008) RCT Canada PEDro= 9 N=225 Children aged 1-17 years with a TBI were randomly assigned to either a hypothermia (n=108) or nonhypothermia group (n=117). The intervention group maintained a mean temperature of 31.9-34.3 degrees while the control group maintained a normal temperature (36.5-37.4 degrees). At 6 months, 22% of the nonhypothermia group had only sustained unfavorable outcomes in comparison to 31% of the hypothermia group. A total of 23 deaths were recorded among the hypothermia group in contrast to the 14 deaths among the non-hypothermia group. A total of 205 children completed the study. Adelson et al., (2005) USA RCT PEDro = 6 N=48 Children aged 0-13 yrs within 6 hours of injury, GCS < or = 8, abN CT. Hypo 1: Phase II multicenter, randomized controlled trial. HYPO 32- 33deg vs NORM 36.5-37.5 deg. Hypo 2: single institution > 6 hours post injury, unknown time of injury or 13-18 years. Mortality, coagulopathy, arrhythmia, infection, intracerebral hemorrhages, mean ICP or CPP no significant difference. Glascow Outcome Score (GOS), Vineland Adaptive Behaviour Scale and Child Health Questionnaire at 3 and 6 months no significant difference (*study designed as a safety trial). Phase III clinical trial required to determine efficacy. Biswas et al., (2002) USA RCT PEDro = 7 N=21 Children who met study inclusion criteria were randomly assigned to either the hypothermia group or the normothermia group. All were administered sedative, analgesics and neuromuscular blocking agents during the first 48 hrs of hospital admission. Those assigned to the hypothermia group began the cooling process immediately following enrollment into the study. Rectal temperature was lowered and maintained at 32° to 34°C. This temperature was maintained for a period of 48 hrs, at which time participants were slowly rewarmed. Those in the normothermia group received standard treatment. Results indicate there were no statistically significant differences between the groups when looking at ICP changes (p=0.73), nor was there any significant differences were looking the overall ICP levels between the two groups (p=.77). A trend in lower ICP levels was noted in the hypothermia th th group during the 13 to the 28 hour during treatment. CPP levels for each group decreased slowly during the first 60 hrs, then began to increase. The rate of increase was not significant for either group. ICP levels were within the normal range for approximately 90% (or more) of the time each day for the hypothermia group compared to the normothermia group. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al. 2002) Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Table 16.2a Summary of RCT Studies of Acute Hypothermia Post ABI Authors Methods Results Adult Population Clifton et al., N=97 Hypothermia (35°C) vs - Results of the GOS indicate poor outcomes (2011) Normothermia 37°C) were higher in the hypothermia group compared to the normothermia group. Lee et al., N=45 study consisted of 3 groups: A) -Groups B and C had lower ICP levels than (2010) ICP/CPP guided management, B) Group A. ICP/CPP guided management with mild + fewer deaths were noted in Group B hypothermia and C) mild hypothermia + PtiO2. increased as ICP levels decreased. and PtiO2. Yan et al., N=148 Hypothermia (32-34°C) vs. + oxygenation & electrophysiologic (2010) normothermia (37±.05°C) measures (GCS 5-6 and 7-8) ND oxygenation or electrophysiologic measures (GCS 3-4) ND clinical outcomes (GOS 1-7 years) Harris et al., N=21 Hypothermia via cooling cap vs. + cerebral temperature (2009) normothermia ND mortality, FIM, GOS Qiu et al., N=80 Mild hypothermia (33-35°C) for 4 + for decreased ICP (2007) days after decompressive craniotomy. + for increased superoxide dismutase + for better GOS outcomes at 1 year + for increased pulmonary complications Liu et al., N=66 Mild Hypothermia (33-35°C), + for reduced ICP relative to control (2006) Selective brain cooing (33-35°C brain + for increased SOD relative to control temp) + for better outcomes 2 years post injury relative to control Jiang et al., N=87 Mild hypothermia (33-35ºC) for + lower mortality (2000) up to 14 days vs. normothermia. + for favourable GOS + for reduction in ICP Clifton et al., N=392 Mild hypothermia (33 ºC) within ND for GOS outcome (2001) 6 hrs of injury and maintained for 48 ND for mortality hrs vs. normothermia. - for medical complications + for number of patients with elevated ICP Marion et al., N=82 Mild hypothermia (33ºC for 24 + favorable GOS only for patients with initial (1997) hours) vs. normothermia. GCS of 5-7. + reduction in ICP, CBF and HR and higher CPP. Marion et al., N=40 Mild hypothermia (32-33ºC) for < + for reduction in ICP and CBF and CRMO2 (1993) 24 hours vs. normothermia. ND for favorable GOS or DRS outcome Resnick et al., N=36 Mild hypothermia (32-33 ºC) for ND for caugolopathy parameters (1994) 24 hours vs. normothermia. Shiozaki et al., N=33. Mild hypothermia (33.5 –34.5 + for reduction in ICP and increase in CPP (1993) ºC) for 2 days vs. normothermia. + for survival Pediatric population Adelson et al., N=77 Hypothermia (34-35°C) vs ND between groups when looking at (2013) Normothermia (36.5-37.5°C) mortality or global function (GOS) at 3 months Hutchinson et N=205 Hypothermia (32.5±0.5°C) vs - >7 more unfavorable outcomes in those al., (2013) normothermia (37±0.5°C) over 7 ND in either intermediate or long-term Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Authors Bayir et al., (2009) Hutchison et al., (2008) Li et al., (2008) Methods N=28 Infants and children. Hypothermia (32-33°C) vs. normothermia (36.5-37.5°C). N=225 Children (1-17) Hypothermia (32.5°C for 24 hr) vs. normothermia (37°C). N=22 Children (6 to 108 months) Hypothermia via cooling cap (34.5±0.2°C) vs. normothermia (38.0±0.5°C) N=21 Hypothermia vs. normothermia Results outcomes after hypothermia treatment. + attenuation of oxidative stress ND unfavorable outcome at 6- months + ICP reduction + CSF biochemical markers Biswas et al., No differences between groups (2002) ND = No difference between groups; + = Improvement compared with control; - = Impairments compared with control Table 16.2b Summary of non-RCT Studies of Acute Hypothermia Post ABI Authors Methods Results Tokutomi et al., N=61 Hypothermia to 35 ºC vs. + serum potassium levels and C-reactive (2009) hypothermia to 33 ºC protein levels ND ICP control, mortality, complications Qiu et al., N=90 Selective brain cooling (33-35 + lower ICP (2006) ºC) for 3 days vs control. + for positive GOS outcome 6 months post injury Carhuapoma et al., N=6 Mild hypothermia (36.5ºC). + for reduction in fever after 120 min of (2003) hypothermia Tokutomi et al., N=31 Moderate hypothermia (33ºC) + for reduction in ICP at brain temperatures (2003) of 35-37ºC. ND at temperatures < 35ºC. CPP peaked at 35-35.9ºC and decreased with lower temperatures. Gal et al., N=30 Mild hypothermia (34ºC) for + for reduction in ICP and increase in CPP (2002) 72 hours vs. normothermia. ND for systolic BP ND in GOS outcome at 6 months ND for favourable GOS or DRS outcome Polderman et al., N=136 Mild hypothermia (32-34ºC) + for reduction in ICP (2002) vs. no hypothermia. + for lower mortality + for good GOS outcome Yamamoto et al., N=84 Mild hypothermia (33-35 ºC) + for GOS outcome (2002) for 36 hrs – 7 days according to + for lower mortality severity of injury vs. no + for CPP in patients with good GOS hypothermia. outcome Chen et al., N=30 Mild hypothermia (33-35ºC) + lower mortality (2001) for 3-10 days vs. routine treatment. + for reduction in ET and NSE and increased SOD Tateishi et al., N = 9. Mild hypothermia (33-35 ºC) + for reduction in ICP 3 hrs after cooling (1998) for up to 6 days. + for increased C-reactive protein and decreased platelet counts + for favourable GOS outcome 6-12 months post-discharge Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury ND = No difference between groups; + = Improvement compared with control Discussion Due to the inconsistent findings in a variety of clinical trails, Clifton and colleagues (2011) revisited the treatment effects of hypothermia post TBI. In this RCT patients (n=97) were randomized to either a hypothermia group (n=52) or a normothermia group (n=45). Participants ranged in age from 16 to 45 years and all had sustained a non-penetrating brain injury and had a GCS <8. Overall no significant findings were noted between the two groups. Study findings lead authors to conclude that early hypothermia induction did not act as a neuroprotectant in those with a diffuse brain injury. Lee et al., 2010 investigated the efficacy of hypothermia on ICP and CPP in 45 individuals post TBI. Participants in this study were randomly assigned to one of 3 groups: group A (n=16) received intracranial pressure/cerebral perfusion (ICP/CPP) pressure guided management only (normothermia group); group B (n=15) received mild hypothermia and ICP/CPP guided management; group C (n=14) received mild hypothermia and PtiO2 guided with ICP/CPP management. Body temperature was monitored throughout the study. ICP levels were lower for those in groups B and C compared to group A. Overall mean GOS was highest for those in group C while mean ICP was lowest for this group. There were not significant differences in the number of deaths in each group. Study authors concluded that mild hypothermia coupled with PtiO2 was beneficial post TBI (Lee et al., 2011). In the study conducted by Yan and colleagues 148 participants were randomized to hypothermia or normothermia. Participants were divided into three groups by GCS (3-4, 5-6, 78) prior to randomization. Cerebral oxygenation and electrophysiological markers were monitored. They noted that both oxygenation and electrophysiological outcomes were improved in patients who received hypothermia and had initial GCS 7-8, but not in the group who had a GCS of 3-4. Those with GCS of 5-6 the effect was unclear (Yan et al., 2010). Harris et al. (2009) conducted a randomized clinical trial to evaluate the impact of selective brain cooling using a cooling cap on cerebral temperature and clinical outcomes. Although they reported that cerebral temperatures were indeed decreased by hypothermia, no differences were noted between groups on mortality, FIM gain, or GOS outcome. Qiu et al. (2007) conducted an RCT of mild hypothermia in severe TBI patients who had undergone craniotomy. Mean ICP of therapeutic group at 24, 48 and 72 hours was lower than controls. Mean serum superoxide dismutase levels were higher at days 3 and 7 in the intervention group (P=.000). Percentage of favourable neurological outcome on the GOS scale at 1 year was 70% vs 47.5% in the therapeutic group and control group respectively (P=.041). Complications, including pulmonary infection were higher in the therapeutic group (57.5% vs 32.5%; p=.025). Qiu et al. (2007) reported that complications were managed without severe sequelae and they noted that mild hypothermia was an effective treatment after decompressive craniotomy. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Liu et al. (2006) performed a randomized controlled study to assess the use of selective brain cooling relative to mild systemic hypothermia and a control group. Decreased ICP levels and increased superoxide dismutase levels post injury were found in both hypothermia groups compared to the control group. Patients Results of the GOS scale, 2 years post intervention, indicated selective brain cooling was likely to improve patient outcomes compared to other groups. While the study was limited by the small sample number, the authors recommended selective brain cooling as a safe and effective treatment post TBI (Liu et al., 2006). In an RCT conducted by Clifton et al. (2001) participants were randomly assigned to either the hypothermia group (treatment group) or the normothermia group (control group). Cooling for both groups began approximately 4 hours post injury. Outcomes of the treatments revealed no differences in the number of individuals who died in each group (28% for the hypothermia group compared 27% for the normothermia group)and there were not significant differences in the results of the neurobehavioral and neuropsychological tests conducted 6 months post treatment. Further more medical complications were reported in those over 45 years of age in the hypothermia group only. Despite these negative findings, the authors reported that hypothermia was associated with significant reductions in elevated ICP during the first 96 hours of treatment (Clifton et al., 2001). The study authors concluded that hypothermia treatment was “not effective in improving outcomes in those with a severe TBI”. Jiang et al. (2000) investigated the effects of prolonged mild hypothermia (33-35ºC) for up to 14 days in severe TBI patients. The authors reported that compared with patients randomized to normothermia (control group), the hypothermia group exhibited significantly lower mortality rates, and considerably more patients with favorable outcomes on the GOS 1 year post-injury. Moreover, the study authors reported that after 7 days of treatment, hypothermia was successful in significantly reducing elevated ICP compared with patients in the control group. Contrary to common clinical beliefs, the authors found that 1 year post-injury, patients who underwent prolonged hypothermia did not experience a higher number of complications: including pneumonia, arrhythmias, hypotension, than those in the normothermia group (Jiang et al., 2000). Marion et al. (1993) reported on the results of early short-duration (<24 hours) mild (32-33ºC) hypothermia. Their findings indicated during the cooling period, patients randomized to the hypothermia group demonstrated significant declines in ICP, CBF and cerebral metabolism compared with patients in the normothermia group. Although there was a trend favoring the hypothermia group, there were no significant differences in favourable outcomes on the GOS and the DRS 3 months post-injury. In a subsequent study by the same researchers using the same treatment paradigm and general methodology, the previous findings were further elucidated (Marion et al., 1997). The authors reported that patients with more severe injuries (initial GCS of 3-4) did not benefit from hypothermia. However, among patients with an initial GCS of 5-7, significantly more patients in the hypothermia group had a favorable GOS outcome at 6 months compared to those in the normothermia group. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury In a related study of mild short duration hypothermia, Resnick et al. (1994) aimed to investigate the incidence of potential adverse coagulation effects associated with hypothermia. They reported that hypothermia did not increase the incidence of coagulopathy as measured by differences in coagulation parameters 24 hours post-treatment (Resnick et al., 1994). However, their findings did not exclude the possibility that hypothermia could lead to increased hemorrhagic complications in the long-term. Shiozaki et al. (1993) conducted an RCT to investigate the efficacy of mild hypothermia (33.5 – 34.5 ºC for 2 days) for the treatment of uncontrollable elevation in ICP. They reported that hypothermia significantly reduced ICP while at the same time increasing cerebral perfusion pressure. Furthermore, treatment with hypothermia was associated with a significantly lower level of mortality and a higher incidence of favourable GOS outcome than normothermia at 6 months. Each of the remaining studies utilized non-randomized research designs. All of these studies indicated that hypothermia markedly reduced elevation in ICP. Furthermore, this reduction was associated with a concomitant increase in CPP, which may explain the lower mortality rates in those treated with hypothermia. The findings of Chen et al. (2001) also suggested that the favorable effects of hypothermia could arise from reductions in mediators of secondary brain injury while at the same time increasing the levels of some free radical scavengers. When looking at the pediatric literature results were less favourable. In a large clinical trial, Hutchison et al. (2008) reported that a period of hyporthermia for 24hrs post injury resulted in no difference in favourable outcomes at 6 months on the GOS among children aged 1-17. In fact, they noted several trends towards worse outcomes among patients who received hypothermia. In another much smaller trial, Bayir et al. (2009) noted that among infants and children, hypothermia helped to attenuate oxidative stress when compared to normothermia. Similarly, Li et al. (2008) noted that in children 6-108 months, selective brain cooling with a cooling cap reluted in decreased ICP and improved CSF biochemical markers. Unfortunately, neither of these two trials evaluated differences in clinical outcomes. A 2004 Cochrane review noted that there was no evidence that hypothermia is beneficial in the treatment of TBI (Alderson et al., 2004). They reported that although early studies on the subject suggested that hypothermia may be beneficial, there have been no larger trials which have repeated these results. They also point out that the increased risks of pneumonia and other potentially harmful side-effects make its use inappropriate unless clear benefits are suspected. Another RCT identified by our review reported similar findings to those of this metaanalysis (Clifton et al., 2001). However, several studies have been released since these reviews were published and research continues into the benefits of hypothermia in ABI management. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Extensive research has been conducted looking at the impact of hypothermia on clinical outcomes post ABI in both the adult and pediatric populations. Despite the number of studies conducted and the methods used, more research appears to be needed. Meta-Analysis Results As part of this current update we decided conduct a meta-analysis looking at the efficacy of hypothermia treatment post-acute ABI with an adult population. We looked at the impact on mortality rates, intracranial pressure and Glasgow Outcome Scores. Results from the metaanalysis indicate there were no significant differences between the hypothermia groups and the normothermia groups when looking at the mortality rate post treatment (see Figure 1). However results from the meta-analysis looking at the long term outcomes as measured by the GOS, those receiving hypothermia were found to have better outcomes (see Figure 2). Figure 1: Hypothermia Treatment and Mortality post ABI Study name Statistics for each study Odds ratio and 95% CI Odds Lower Upper ratio limit limit Z-Value p-Value Wu et al., 2006 Qiu et al., 2009 Jiang et al., 2000 Clifton et al., 2001 Harris et al., 2009 Qiu et al., 2007 Resnick et al., 1994 Clifton et al., 2011 Marion et al., 1993 Lee et al., 2010 0.325 0.282 0.413 1.048 2.250 0.603 0.917 1.472 0.180 0.519 0.750 0.112 0.947 0.107 0.748 0.167 1.021 0.663 1.657 0.439 11.522 0.223 1.630 0.315 2.671 0.578 3.747 0.008 4.009 0.066 4.083 0.560 1.006 -2.059 -2.545 -1.915 0.199 0.973 -0.997 -0.159 0.811 -1.082 -0.624 -1.921 0.039 0.011 0.055 0.842 0.330 0.319 0.873 0.417 0.279 0.533 0.055 0.5 1 hypothermia 2 normothermia Meta Analysis Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Figure 2: Hypothermia Treatment and Glasgow Outcome Scores Post-Acute ABI. Study name Statistics for each study Odds ratio and 95% CI Odds Lower Upper ratio limit limit Z-Value p-Value Yan et al., 2010 Qiu et al., 2007 Lee et al., 2010 Qui et al., 2007 Jiang et al., 2000 Marion et al., 1993 Liu et al., 2006 1.171 2.579 0.550 2.579 2.319 2.250 3.500 1.914 0.605 2.267 1.030 6.457 0.106 2.860 1.030 6.457 0.948 5.669 0.635 7.973 1.209 10.131 1.338 2.738 0.469 2.023 -0.711 2.023 1.844 1.256 2.310 3.552 0.639 0.043 0.477 0.043 0.065 0.209 0.021 0.000 0.1 0.2 0.5 1 hypothermia 2 5 10 normothermia Meta Analysis Conclusions There is Level 2 evidence to suggest hypothermia treatment helps to improve long term outcomes post ABI. There is conflicting evidence regarding hypothermia’s effect on mortality. There is Level 1b evidence that systemic hypothermia is associated with an increased incidence of pneumonia. Although hypothermia has been shown to reduce elevated ICP by some researchers there is no solid evidence to support its effectiveness post ABI. More research needs to be done. Systemic hypothermia increases the risk of pneumonia post ABI. 16.1.1.3 Hyperventilation Controlled hyperventilation to achieve a PaCO2 of 30-35 mmHg during the first few days following an ABI has been reported to improve outcomes. Hyperventilation causes cerebral vasoconstriction, thus leading to a decrease in cerebral blood flow and cerebral blood volume and hence leading to a decrease in ICP (Muizelaar et al., 1991). During mild hyperventilation, increased oxygen extraction mechanisms allow compensation for decreases in blood flow and volume allowing normal cellular metabolism to continue (Diringer et al., 2000). There is concern Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury that intense or prolonged hyperventilation may increase metabolic acidosis, which is common following brain injury. Depletion of oxygen supplies forces the injured brain to turn to anaerobic metabolism and an increase in lactic acid which has been correlated with poor outcomes (DeSalles et al., 1986; DeSalles et al., 1987). Since hyperventilation decreases cerebral CO2, this leads to an increase in pH diminishing the detrimental effects of acidosis. However, this process depends on the availability of bicarbonate in the cerebral spinal fluid. Thus, prolonged hyperventilation may not be an appropriate therapeutic measure since this may deplete bicarbonate levels favoring ischemia and leading to poorer outcomes. Several studies have also discussed concerns related to pre-hospital intubation leading to inappropriate hyperventilation (Warner et al., 2007; Lal et al., 2003). Targeted hyperventilation to within 30-45 mmHg have been associated with decreased mortality rates but both precise regulation and proper training are recommended. The AANS make Level II recommendations that prophylactic hyperventilation not be used. They make Level III recommendations that hyperventilation be used as a temporizing measure for reduction of elevated ICP but that it should be avoided within the first 24 hours after injury when CBF is often critically low. They recommend that jugular venous oxygen saturation or brain tissue oxygen tension measurements be performed when hyperventilation is used (Bratton et al., 2007f) The EBIC recommend hyperventilation to manage high ICP and CPP in association with sedation and analgesia. They recommend mild to moderate hyperventilation initially to a PaCO2 of 30-35 mmHg. If this fails to control ICP along with osmotic therapy and CSF drainage, then intensive hyperventilation to <30 mmHg is recommended with jugular oxymetry monitoring of cerebral oxygenation to detect ischemia (Maas et al., 1997). Individual Studies Table 16.3 Hyperventilation for the Treatment of Elevated ICP Post ABI Author/Year/ Country/Study design/PEDro Scores Muizelaar et al., (1991) USA RCT PEDro = 20 Methods N=113 Patients with a severe brain injury (GCS < 6) were randomly assigned into 3 groups. Groups were given the following: 1) those in the control group received normal ventilation PaCO2 35 ± 2 mmHg; 2) those in the hyperventilation (HV) group received PaCO2 25 ± 2 mm Hg; or 3) those in the hyperventilation plus buffer tromethamine (THAM) received PaCO2 25 ± 2 mm Hg + THAM (0.3 M IV solution. This was initially administered as bolus and then as continuous infusion Outcome At 3 and 6 months after injury, the number of patient with favorable outcome (good or moderately disabled) on the GOS was significantly lower (p < 0.03 and p < 0.05 respectively) in the HV group compared with control and HV + THAM group. This occurred only in patients with a motor score of 4-5 but not 3 or less. The interaction effect of treatment group and motor score was found to be significant (p < 0.02) indicating that the detrimental effect of hyperventilation was limited to patient with better prognosis at admission. At 12 months post-injury, this Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Scores Methods Outcome for 5 days to achieve an arterial pH of difference in outcome between groups was 7.6. The GOS at 3, 6 and 12 months was no longer significant (p = 0.13). There were no used to assess outcomes. significant differences in GOS outcome at any of the 3 time points between the HV + THAM treated group and the control group (no p value provided). Coles et al., (2002) UK Case Control N=33 TBI patients (GCS 3-13) underwent PET imaging of cerebral blood flow at baseline and after reduction to 29±1 torr PaCO2. Jugular venous saturation (Sjv O2) and arteriovenous oxygen content differences (AVDO2) were monitored in 25 patients and related to PET variables. The volume of critically hypoperfused (hypoBV) and hyperperfused (hyperBV) brain were calculated based on thresholds of 10 and 55 mL/100g/min respectively. Only hypoBV values were significantly higher in hyperventilated patients compared to controls (p<0.05). Hyperventilation decreased ICP (p<0.001) and increased CPP (p<0.0001). Despite this improvement, hyperventilation decreased global cerebral blood flow (31±1 to 23±1 mL.100g/min; p<0.0001) and increased hypoBV (p<0.0001). Hyperventilation induced increases in hypoBV were non-linear with a threshold between 34 and 38 torr. Diringer et al., (2000) US Case Control N=9 Severe brain injury patients (GCS < 9) were studied a mean of 11.2±1.6 hrs after TBI and compared to 10 healthy normocapnic controls. Patients were hyperventilated to 30±2 mmHg PaCO2 for 30 mins. Measurement of CBF, CBV, CMRO2, oxygen extraction factor (OEF), and cerebral venous oxygen content (CvO2) were taken before and after 30 mins of hyperventilation. Global CBF, CBV and CvO2 did not differ between groups but in the TBI patients, CMRO2 and OEF were reduced (1.59±0.44 ml/100g/min (p<0.01) and 0.31±0.06 (p<0.0001) respectively). During hyperventilation, global CBF decreased to 25.5±8.7 ml/100g/min (p<0.0009), CBV fell to 2.8±0.56 ml/100g (p<0.001), OEF rose to 0.45±0.13 (p<0.02), and CvO2 fell to 8.3±3 vol% (p<0.02). CMRO2 remained the same. Thiagarajan et al., (1998) India Case Series N=18 Severe brain injury patients (GCS ≤ 9) undergoing hyperventilation (PaCO2 25 mmHg) for the management of ICP received concurrent hyperoxia (PaO2 200-250 mmHg) to determine if this prevents the deleterious effects of hyperventilation. Jugular venous bulb oxygen saturation (SJvO2) and arteriovenous oxygen content difference (AVDO2) which provide indirect evidence of the adequacy of cerebral blood flow and global oxygenation were evaluated. SJvO2 decreased significantly during hyperventilation (PaCO2 25 mmHg) and returned to baseline when PaCO2 was restored to 30 mmHg (p<0.0001) or when hyperoxia (PaO2 200-250 mmHg) was induced. Similarly AVDO2 increased significantly when hyperventilation was induced (PaCO2 25 mmHg at a PaO2 of 100-150 mmHg) and recovered to baseline values when the PaCO 2 was restored to 30 mm Hg (p<0.001) or when PaO2 was increased to 200-250 mmHg (P<0.001). PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Discussion Muizelaar et al. (1991) conducted an RCT in which patients received prolonged hyperventilation for 5 days. As expected, the authors reported that prolonged hyperventilation alone lead to poor clinical outcomes. This is likely due to a depletion of cerebral bicarbonate supplies. Study authors found that the combination of hyperventilation and tromethamine, a weak base and buffer that crosses the blood brain barrier, resulted in significantly better outcomes than hyperventilation alone (Muizelaar et al., 1991). This suggests that the deleterious effects of prolonged hyperventilation may be overcome by the addition of a buffer system capable of taking over once cerebral bicarbonate levels are depleted. Muizelaar et al. (1991) suggest that “the use of THAM seem to counteract the deleterious effect of prolonged hyperventilation and, therefore, its use would be beneficial when sustained hyperventilation is required for ICP control.” A UK study performed in 2002 found that despite the benefits of hyperventilation on ICP and CPP, the volume of severely hypoperfused brain tissue increased (Coles et al., 2002). The authors used PET scans to assess cerebral blood flow during hyperventilation and discovered decreases in regional perfusion that are not detectable using global monitors of oxygen such as saturation of jugular oxygen and arterial-venous differences in oxygenation. The authors identified a threshold of 34 torr below which patients become vulnerable to regional hypoperfusion. Future studies that more accurately assess patient outcomes are needed (Coles et al., 2002) A study by Diringer et al. (2000) found that early, brief, moderate hyperventilation does not impair global cerebral metabolism in patients with severe TBI and, thus, is unlikely to cause further neurological injury .The authors call for the assessment of more severe hyperventilation and the effects of hyperventilation in the setting of increased ICP. The findings of Thiagarajan et al. (1998) suggest that increasing the partial pressure of oxygen above normal (hyperoxia) may also offset the deleterious effects of hyperventilation in head injured patients. However, this study used a single group intervention design, and thus the strength of such conclusions is limited until further studies using controlled randomized designs are performed to corroborate these findings. Conclusions There is Level 2 evidence that the use of tromethamine, a weak base and buffer that crosses the blood brain barrier, can offset the deleterious effects of prolonged hyperventilation and lead to better outcomes than hyperventilation alone. There is Level 4 evidence that hyperoxia can counteract the deleterious effects of hyperventilation for the control of ICP following brain injury. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury There is Level 4 evidence that hyperventilation below 34 torr arterial CO 2 can cause an increase in regionally hypoperfused tissue. Tromethamine counteracts the detrimental effects of prolonged hyperventilation for the control of ICP leading to better outcomes post-ABI. Hyperoxia may counteract the adverse effects of prolonged hyperventiliation for the control of ICP post-ABI. Hyperventilation below 34 torr PaCO2 may cause an increase in hypoperfused brain tissue. 16.1.1.4 Cerebrospinal Fluid Drainage In an attempt to control ICP, ventricular CSF drainage is a frequently used neurosurgical technique. Catheters are generally inserted in to the anterior horn of a lateral ventricle and attached to an external strain gauged transducer (March 2005; Bracke et al., 1978). This allows for concurrent pressure monitoring and fluid drainage. Generally, a few milliliters of fluid are drained from the ventricle at a time resulting in an immediate decrease in ICP (Kerr et al., 2000). However, ventricular space is often compressed due to associated brain swelling, which limits the potential for drainage as a stand alone therapy for ICP control (James 1979). When ventricular drainage is not possible, lumbar CSF drainage has been proposed as another method for reducing elevated ICP. Standard practice has been to avoid lumbar drainage for fear of transtentorial or tonsillar herniation, however, technological improvements have renewed interest in its potential for reducing ICP in patients refractory to other treatments (Tuettenberg et al., 2009). Cerebrospinal fluid drainage use is predicated on the belief that increased ICP may result in worse outcomes for ABI patients. However, empirical evidence regarding its direct effect on improved outcomes is limited. It has been generally accepted that complications arising from increased ICP are deleterious and that any intervention that improves ICP levels is therefore worth exploring. Criticisms of ventricular drainage generally surround the intrusiveness of the procedure and the complication of potential infections (Hoefnagel et al., 2008; Zabramski et al., 2003). In the most recent AANS guidelines no mention was made regarding indications for use of CSF drainage. However if used, prophylactic antibiotic use and routine catheter exchange are not recommended for reduction of nosocomial infection rates (Bratton et al., 2007d). CSF drainage is listed as an acceptable treatment for ICP reduction according to the EBIC (Maas et al., 1997). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.4 Cerebrospinal Drainage for Treatment of Elevated ICP Post ABI Author/Year/ Country/Study design/PEDro Scores Methods Outcome Kerr et al., (2001) USA RCT PEDro = 7 N=58 Severe TBI patients (GCS ≤ 8) were randomly assigned to one of three drainage protocols (1ml, 2ml, or 3ml volume of CSF drained) each time an intervention was required (ICP > 20 mmHg). Patients were monitored for ICP, CPP, cerebral blood flow velocity, nearinfrared-spectroscopy-determined regional cerebral oxygenation. Physiological variables were time averaged in 1-minute blocks from base-line to 10 minutes after drainage cessation. Significant dose-time interactions were seen in all three drainage protocols with relation to decreases in ICP (p=0.0001). There was a significant difference in CPP depending on the amount of CSF drained (p=0.04). A 3ml withdrawal of CSF resulted in a 10.1% decrease in ICP and a 2.2% increase in CPP that were sustained for 10 min. Murad et al., (2012) USA Pre-Post N=15 All participants underwent lumbar drainage when their ICP levels reached or exceeded >20 mm Hg and medical management of symptoms was complete. Lumbar drains were placed approximately 3.5 days post admission. Results indicate ICP was reduced significantly following the placement of the lumbar drain (p<0.01), CPP increased, although not significantly, from 76.7 mm Hg to 81.2 mm Hg. MAP levels decreased from 96.8 mm Hg to 91.4 mmHg, again this decrease was not found to be significant. When looking at the administration of sedates, mannitol, hypertonic saline, or paralysis, post treatment only one individual required additional boluses. Prior to treatment 12 of 15 required additional boluses. Llompart-Pou et al., (2011) Spain Case Series (Retrospective Review) N=30 External lumbar drainage (ELD) was used to reduce elevated ICP levels. ELD placement was completed in those with elevated ICP and ICP was not responding to other measures or due to the risk of cardiorespiratory failure other measures were not an option. Once implanted, the CSF was drained continuously when ICP was 20 mm HG or higher. When ICP levels dropped to 10 mm Hg the system was closed and only reopened if ICP levels began to increase and were once again above 15 mm Hg. ICP significantly decreased following ELD (p<0.0001). Results of the GOS found 30 % of participants had a good recovery or moderate disability following treatment upon ICU discharge. Further long term follow up noted 62% had a good recovery or moderate disability. Study authors reported few ELD complications. Tuettenberg et al., (2009) Germany Pre-Post N=100 Patients were prospectively evaluated for changes in refractory ICP after initiation of lumber CSF drainage. Patient outcomes were also assessed 6 Initiation of lumbar CSF drainage led to significant reductions in ICP (32.7 ± 10.9 to 13.4 ± 5.9 mmHg, p<0.05) and increases in CPP (70.6 ± 18.2 to 86.2 ± Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Scores Methods Outcome months after treatment. 15.4 mmHg, p<0.05). Cerebral herniation with lethal outcome occurred in 6 patients. Thirty-six had favorable outcomes (on GOS), 12 were severely disabled, 7 remained in a persistent vegetative state, and 45 died. Timofeev et al., (2008b) UK Pre-Post N=24 TBI patients requiring mechanical ventilation, neuromonitoring, and ventriculostomy due to uncontrollable ICP were monitored for ICP and related parameters post drainage. Free drainage was allowed and limited only by the height of the collecting reservoir. Drainage led to a decrease in ICP in all patients with sustained reduction past 24 hrs in 13 of 24 patients. When ICP reduction remained stable, significant improvements in craniospacial compensation, CPP, and PbtO2 were also seen. Murad et al., (2008) USA Case Series N=8 Patients with brain injury and high ICP refractory to medical management underwent controlled lumbar drainage. Patients were monitored for reductions in ICP, ICP levels were significantly reduced (27±7.8 to 9±6.3 mmHg, p<0.05) after drainage. In the 24 hrs post-drainage, reductions were seen in the need for hypertonic saline, mannitol, and sedation. No complications were noted. Kerr et al., (2000) USA Case Series N=31 Severe TBI patients (GCS ≤ 8) underwent cerebrospinal fluid drainage where 6 ml of fluid was removed. Patients were monitored for CPP, cerebral blood flow velocity, and regional cerebral oximetry before, during and after drainage. There was a significant change in ICP immediately after drainage which remained significant up until 10 minutes post treatment (p=0.0001). A significant increase in CPP was also seen immediately after drainage but was not maintained (p=0.0001). Fortune et al., (1995) USA Case Series N=22 Patients with a severe brain injury (GCS < 8) were treated with hyperventilation, intravenous mannitol, or CSF drainage based on the attending physicians discretion when ICP became > 15 mHg. Patients were continuously monitored for SjvO2, ICP, BP, arterial O2 saturation, and end tidal CO2 during treatment. After drainage from ventriculostomy ICP fell in 90% of the observations by 8.6±0.7 mmHg. In patients where ICP dropped, SjvO2,only increased by 0.39±0.4% saturation PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In an RCT conducted by Kerr et al. (2001) a group of patients were randomized to one of 3 protocols. Those in the first had 1 ml of CSF drained, while those in the second had 2 ml of CSF drained and those in the third had 3 ml drained. All underwent CSF drainage when their ICP was found to be >20mm Hg. Continuous monitoring of ICP, CPP, cerebral blood flow velocity, and near-infrared-spectroscopy-determined regional cerebral oxygenation was performed and Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury analyzed to assess the dose response to CSF drainage. Results indicate all experienced significant decreases in ICP and increases in CPP regardless of the amount of fluid drained; however, ICP levels began to increase toward within 10 minutes of treatment. Despite this reduction in ICP, there were no improvements in cerebral blood flow velocity or regional oxygenation. Also, the short duration of follow up limits the accurate measurement of the effect of CSF drainage on ICP or any long term outcome measure. In a recent study, Murad and his fellow researchers (2011) placed a lumbar drain in 15 patients, following the medical management of all symptoms. In this study patients had sustained either a TBI (n=10) and SAH (n=5). Following the placement of the lumbar drain, patients were found to have a significant decrease in the ICP and a non-significant increase in their CPP. Post treatment there was a significant decrease in the number of patients who required additional boluses treatments (p<0.05). The need for sedative and paralytics was also decreased following the insertion of the lumbar drain (p<0.05). Further no CSF infections were noted. Overall the study found lumbar CSF drainage to be effective in lowering ICP post injury. In a retrospective review of patient charts, Llompart-Pou et al. (2011) found that draining CSF through external lumbar drainage was successful in improving ICP and long-term patient outcomes. ICP decreased from 33.7 mm Hg pre treatment to 21.2 mm Hg post treatment. Initial results from the GOS found 9 participants scored a 4 or 5 when discharged from the ICU. This increased to 18 at the long-term evaluation. In three case series, the effects of ventricular CSF drainage on ICP were also assessed. Timofeev et al. (2008) found reductions in ICP were maintained at the end of the initial 24 hour period for 13 of the 24 particiapants, resulting in a reduction in the need for alternative treatments. Kerr et al. (2000) treated 36 participants with CSF drainage after ICP levels reached >20 mmHg. They noted a significant increase in CPP immediately after treatment and a decrease in ICP levels. Of note those diagnosed with a subdural hematoma (SDH) ICP levels were not as likely to respond to CSF drainage. In the study conducted by Fortune and colleagues (1995), individuals who had sustained a closed head injury were treated with mannitol, CSF drainage or hyperventilation with their ICP levels exceeded 15mmHg. Physiological changes were documented continuously. Change noted 20 minutes post interventions was compared to the initial ICP, jugular venous saturation and MAP levels. Although ICP levels decreased following treatment, fluid accumulation allowed ICP to increase steadily once treatment was stopped. They also noted only slight improvements in oxygenation based on jugular vein O2 saturation associated with the drop in ICP. These results suggested only minimal improvements in cerebral blood flow (Fortune et al., 1995). Two studies were located that evaluated the effects of lumber drainage on refractory ICP (Murad et al., 2008; Tuettenberg et al., 2009). In the study conducted by Tuettenberg and colleagues the safety and efficacy of lumbar drainage in patients with TBI (n=45) or SAH (n=55) was evaluated. Study authors noted a significant reduction in ICP and a significant increase in Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury CPP (p<0.05) following lumbar drainage. Twelve patients experienced cerebral herniation with unilateral mydriasis. Six of these 12 experienced lethal herniation. At the 6th month follow up, results from the GOS indicated 36 patients had favorable outcomes, 12 were severely disabled, 7 remained in a persistent vegetative state and 45 had died (Tuettenberg et al., 2009). Study authors concluded their findings with the suggestion that lumbar drainage should be considered in instances when ICP is refractory to other treatments and basal cisterns are clearly discernible. In the previous year, Murad et al. (2008) also conducted a study investigating the effectiveness of performing lumbar CSF drainage on a group of eight individuals who had sustained a severe TBI. Study results indicate ICP was reduced in all participants and the use of hypertonic saline or mannitol boluses was not needed to control ICP 24 hours post intervention. Based on these two studies, lumber drainage appears to be a potential option when ICP remains refractory to other interventions, ventricular drainage is not possible, and basal cisterns are clearly discernible. Conclusions Results from one RCT suggest there is Level 1b evidence that CSF drainage decreases intracranial pressure in the short term. There is Level 4 evidence from several studies that suggest CSF drainage does decrease ICP in individuals post ABI. CSF drainage has been found to reduce ICP and increase CPP in those who have sustained an ABI. 16.1.1.5 Decompressive Craniotomy Removal of skull sections has been suggested as a drastic measure for the management of elevated ICP unresponsive to other therapies. It is thought that surgical decompression could improve the damage caused by secondary injury (delayed brain damage) such as high ICP and reduced oxygenation of the brain. In a recent meta-analysis by Sahuquillo and Arikan (2006), the authors identified two types of surgical decompression: prophylactic or primary decompression and therapeutic or secondary decompressive craniectomy. The former involves performing the surgical procedure as a preventive measure against expected increases in ICP while the latter is performed to control high ICP “refractory to maximal medical therapy” (Sahuquillo & Arikan, 2006). However, debate regarding if and when to perform these surgeries continues. Factors such as age and initial GCS score have been proposed as potential prognostic factors (Guerra et al., 1999; Munch et al., 2000). Of course, any surgical procedure is associated with inherent risks. The majority of decompressive techniques are therefore precipitated by evacuation of a mass lesion (Compagnone et al., 2005). Once decompression is decided upon, resection of a larger bone fragment is generally recommended to allow for Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury greater dural expansion with less risk of herniation (Compagnone et al., 2005; Skoglund et al.,2006; Csokay et al., 2001) Therapeutic decompressive craniectomy is only performed after other therapeutic measures (CSF drainage, moderate hypocapnia, mannitol, barbiturates, hyperventilation, hypothermia etc.) have failed to control ICP (Morgalla et al., 2008). The AANS make no recommendations regarding decompressive craniectomy in their most recent recommendations. The EBIC suggest that decompressive craniectomy be considered in “exceptional situations” (Maas et al., 1997). Individual Studies Table 16.5 Decompressive Craniectomy to Control Refractory Elevated ICP Post ABI Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome Adults and Decompressive Craniectomy Post TBI Cooper et al., (2011) Australia RCT PEDro=9 N=155 In this RCT participants were randomly assigned to receive either standard care (n=82) or decompressive craniectomy (n=73) within the first 72 hours of hospitalization. Participants received treatment for intracranial hypertension if intracranial pressure exceeded >20mmHg. When second tier options were needed, participants received mild hypothermia, barbiturates or both. For those receiving standard care, decompressive craniectomy was used post >72 hours if needed. GOS was used to assess participants 6 months post intervention. Although there was no significant difference between the groups, those in the decompressive craniectomy group had both shorter duration of mechanical ventilation and stay in ICU. Medical complications and hydrocephalus were noted more often in those in the decompressive craniectomy group compared to the standard care group. Results from the GOS showed those in the standard care group had better long term outcomes then those in the decomprssive craniectomy group. Of note unfavourable outcomes were noted in 70% in the decompressive group. Only 51% had unfavourable outcomes in the standard care group. Qiu et al., (2009) China RCT PEDro = 7 N=74 Severely brain injured patients (GCS ≤ 8) with midline shift > 5 mm were randomized to receive either unilateral decompressive craniectomy (DC) or unilateral routine temporoparietal craniectomy (control). ICP levels were significantly lower in the DC group at 24, 48, 72 and 96 hours post-operation in comparison to controls. Mortality rates were reduced from 57% to 27% in DC group with respect to controls (p=0.01) and GOS score 4 or 5 was 56.8% vs. 32.4% among controls. Jiang et al., (2005) China RCT PEDro = 5 N=486 Adult patients with severe TBI (GCS ≤ 8) with refractory intracranial hypertension were randomized to receive standard trauma craniectomy (STC) with a unilateral frontotemporoparietal bone flap At 6 months follow up, more patients in the STC group showed favourable (good recovery/moderate disability) GOS outcome compared with the LC group (p<0.05). In addition, the incidence of Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome (12 x 15 cm) or limited craniectomy (LC) with a routine temporoparietal bone flap (6 x 8 cm). In both groups, bone flaps were removed and cranioplasty was performed 3-6 months after injury. GOS outcome at 6 months was compared between groups. some secondary complications (delayed intracranial hematoma, incisional hernia, and CSF fistula) was lower in the STC group (p<0.05). ICP fell more rapidly and to a lower level in the STC group than in the LC group (p<0.05). Flint et al., (2008) USA Pre-Post N=40 Computed Tomography scans for patients with non-penetrating severe TBI who underwent decompressive hemicraniectomy were analyzed. Size of contusions were measured on initial, last pre-operative, and first post-operative scans. Mortality and 6 month GOS scores were recorded. New or expanded hemorrhagic contusions of ≥ 5cc were observed after hemicraniectomy in 58% of patients. The mean volume of increase hemorrhage in these patients was 37.1 ± 36.3 cc. Rotterdam CT score was associated with total volume of expanded contusion. Contusions expanded >20cc post hemicraniectomy were strongly associated with mortality and poor outcome on the GOS at 6 months even after controlling for age and initial GCS. Howard et al., (2008) USA Database Review N=40 A retrospective review of patient data for patients with severe TBI managed with decompressive craniectomy was performed. Outcomes were measured using the GOS-E. DC effectively lowered ICP (p=0.005). Twenty two patients died in hospital. Initial GCS score and pupil reactivity were associated with outcomes while age and ISS score did not. Of the survivors, 12 of 18 had good outcomes on the GOSE. Ho et al., (2008) Singapore Case series N=16 Patients with isolated TBI and elevated ICP refractory to maximal medical therapy underwent decompressive craniectomy. Patients were evaluated for clinical outcomes using the GOS and were then retrospectively divided into favourable and poor outcome groups and compared for ICP, CPP, pressure reactivity, cerebral oxygenation, and cerebral microdialysis. Only 5 patients had a favourable outcome at 6-month follow up and one made a good recovery. Significant reductions in ICP and pressure reactivity were seen in both groups. Patients with favourable outcomes saw significant improvements in oxygenation and a reduction in cerebral ischemia compared to no improvements in biochemical indices for patients with poor outcomes. Aarabi et al., (2006) USA Retrospective Chart Review N=50 Patients with diffuse brain swelling secondary to TBI who underwent decompressive craniectomy without removal of clots or contusion were retrospectively evaluated for ICP reductions and GOS > 3 months later. Craniectomy reduced ICP below 20 mmHg in 85% of cases. Forty percent of patients experience a good outcome on discharge and 17/50 after 3 months. Outcomes were independent of abnormal papillary response, timing of DC, brain shift, and patient age. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome Huang et al., (2008) Taiwan Retrospective Chart Review N=54 Patients with GCS ≤ 8, a frontal or temporal hemorrhagic contusion greater 3 than 20 cm , and a midline shift > 4mm or cisternal compression were studied. 16 underwent standard craniotomy with hematoma evacuation and 38 underwent craniectomy as the primary surgical treatment. Mortality, reoperation rate, GOS-E scores, and LOS were compared. Reoperation rates (7.9% vs. 37.5%, p<0.05) and GOS-E scores at 6 months (5.55 vs. 3.56, p<0.01) improved in the craniectomy group whereas LOS and mortality was similar between groups. Yang et al., (2008) China Retrospective Chart Review N=108 A retrospective review of patients who underwent decompress craniotomy was performed to establish the incidence of secondary complications and associated risk factors. Twenty-five patients died within the first month. Lower GCS was associated with poorer outcomes. Complications secondary to surgery occurred in 50% of patients, 28% of which developed more than one complication. Initially, herniation through the cranial defect was the most common complication followed by subdural effusion. “Syndrome of the trephined” and hydrocephalus were common after 1 month. Older patients and more severe injuries were associated with more complications. Li et al., (2008) China Non-RCT N=263 Data from patients with severe TBI (GCS≤8) was retrospectively reviewed to compare large decompressive craniectomy to routine craniectomy. 71.1% of cases in the large craniectomy group obtained satisfactory outcomes (GOS 3-5) compared to 58.6% of routine craniectomy patients (p<0.05). Large craniectomy was even more efficient in treating very severe TBI (p<0.01). Large craniectomy was also associated with a lesser need for recurrent surgery and fewer complications. Salvatore et al., (2008) USA Chart Review N=80 Patients with severe closed head injury (GCS <8) who underwent selective uncoparahippocamparectomy and tentorial edge incision with wide decompressive craniectomy were reviewed. GOS was measured on follow-up (mean 30 months). 75% of patients had a favourable outcome. Younger age, and earlier operations were associated with better outcomes. Preoperative GCS and papillary reactivity had no effect on outcome. Olivecrona et al., (2007) Sweden Chart review N=93 All patients treated for severe TBI during 1998-2001 who had a GCS<9 at intubation and sedation, first recorded CPP >10mmHg, arrival within 24 h of trauma, and in need of intensive care for >72 h were included. Craniectomy was performed Craniectomy patients showed a decrease in average ICP from 36.4 mmHg to 12.6 mmHg directly after the procedure. There was an increase in ICP to 20 mmHg 8-12 h after surgery leveling off at around 25 mmHg within Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome when the ICP could not be controlled by evacuation of hematomas, sedation, ventriculostomy, or low-dose pentothal infusion. Twenty-one patients underwent craniectomy and were compared to the non-craneiectomy group for ICP, CPP and GOS scores. 72 h. The GOS scores did not significantly differ from the noncraniectomy patients. Skoglund et al., (2006) Sweden Chart review N=19 Charts for all patients receiving decompressive craniectomy between 1997 and 2002 were drawn. Patients were assessed for ICP decrease, survival rates, and GOS scores. The size of craniectomy was also assessed for its relation to ICP decrease. ICP was reduced from 29.2±3.5 to 11.1±6.0 mmHg after decompression and 13.9±9.7 mmHg 24h after surgery (both p<0.01). Sixty eight percent of patients had favorable outcomes at least one year post surgery. A significant correlation was seen between the size of craniectomy and decrease in ICP. Ucar et al., (2005) Turkey Chart review N=100 Patients with severe brain injury (GCS<9) who received decompressive craniectomy were retrospectively divided into two groups; groups I (GCS 4-5,N=60) and group II (GCS 6-8,N=40). Prognosis was evaluated based on GOS scores at 6 months and a backwards regression analysis was used to assess age, GCS, timing of surgery, and the presence of mass lesions as indicators. After regression analysis, only age (p=0.046) and belonging to GCS group II (p<0.05) were significantly related to having a “favorable” final outcome (GOS 4-5). A paired t-test showed a significant decrease in ICP after decompression from 29.8±5.2 to 23.9±4.9 mmHg (p<0.001). Morgalla et al., (2008) Germany Case Series N=33 Patients with severe TBI (Grades III and IV) and subsequent swelling underwent decompressive craniectomy. Patients were assessed three years post surgery using the Barthel Index. Twenty percent of patients died and 20% remained in a vegetative state. Thirteen of the surviving patients made a full recovery (BI 90-100). Five patients returned to a previous job and 4 found new work. Williams et al., (2009) USA Retrospective Chart Review N=171 Patients with severe TBI (AIS 4-5) treated with decompressive craniectomy were identified from the Trauma Registry. Patients were assessed for GOS-E scores and mortality rates on follow-up. Multiple regression was used to identify factors associated with good outcomes. 32% of patients died in hospital. Of the survivors, 82% achieved good outcomes (5-8 on the GOS-E) Patients who experienced good outcomes were younger (26 vs. 43, p=0.0028) and experienced a greater reduction in ICP post-surgery (23mmHg vs. 10 mmHg, p<0.0001). Immediate predecompression GCS in survivors was higher (7 vs. 5, p<0.0001). Polin et al., (1997) USA N=35 Patients undergoing decompressive craniectomy were each matched to 4 patients from the Traumatic Coma Data Postoperative ICP was significantly lower in craniectomy patients compared to preoperative levels (p=0.0003). A Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome Cohort control Bank as a control based on sex, age, GCS scores and maximum preoperative ICP. Mortality rates and discharge GOS scores were compared between groups. significant increase in favorable outcomes was seen in patients who underwent craniectomy compared to the matched controls (p=0.014). Patients who did not exhibit ICP > 40Torr and underwent surgery less than 48 h after injury revealed a 60% favorable outcome rate and did better than control patients (p=0.0001). Meier et al., (2008) Germany Chart Review N=131 Clinical records for patients treated with decompressive craniectomy were reviewed. Outcomes were compared to patient and radiographic factors to identify trends. Outcomes were correlated with initial GCS as well as the patients age, condition of the basal cisterns, the degree of midline shift, pupil reactivity on admission, established clotting disorders, post-traumatic hydrocephalus internus, hyperglycemia and initial acidosis. Bao et al., (2010) China Retrospective cohort N=37 Patients who had received a bilateral decompressive craniectomy (BDC) were retrospectively reviewed. Patients were between the ages of 18-69 and 67.6% were male. Pre and post surgical ICP and CPP were compared and 6-month GOS was assessed. Mean ICP was reduced from 37.7 +/- 7.5 mm Hg pre surgery to 27.4 +/- 7.3 mm Hg (p<.05) after bone removal and 11.2 +/- 7.1 mm Hg (p<.05) after dura mater opening and enlargement. Mean ICP was 16.3 +/- 5.9 mm Hg 1 day post surgery, 17.4+/- 6.3 mm Hg 3 days post surgery and 15.5 +/- 4.6 mm Hg at 7 days post surgery. Mean CPP was increased from 57.6 +/- 7.5 mm Hg pre surgery to 63.3 +/- 8.4 mm Hg (p<.05) after bone removal and 77.8 +/- 8.3 mm Hg (p<.05) after durameter opening and enlargement. At 6-months, 54.1% of patients made moderate (GOS=4, 32.5%) or good (GOS=5, 21.6%) recoveries on the GOS. Daboussi et al., (2009) France Prospective Observational N=26 Patients undergoing decompressive craniectomy were prospectively tracked. Neurological outcomes and mortality rates were evaluated. ICP was reduced from 37 +/- 17 to 20 +/13 mm HG (P=.0003) and mean cerebral perfusion pressure was increased from 61 +/- 22 to 79 +/- 19 (P<.05) immediately post surgery and remained significant 48 hours post. Middle cerebral artery blood flow velocity was also significantly increased as measured by Transcranial Doppler Ultrasonoghraphy. Mortality rate was 27% and among those that survived 53% Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome had favourable neurologic outcomes. Aarabi et al., (2009) USA Retrospective Cohort N=54 All patients undergoing DC along with removal of a mass lesion were retrospectively divided into 2 groups for comparison; patients who had DC performed without ICP monitoring (n=27, Group A) and patients underwent ICP monitering from day 1 to 14 before DC (n=27, Group B). No difference was noted between groups for survival or outcome. Twelve patients died in group A and 10 in group B, while 11 had good recovery in group A and 8 in group B. Adamo et al., (2009) USA Case Series N=7 Charts were reviewed of infants (2-24 months) with a severe TBI who underwent a decompressive craniectomy. All patients developed epidural and subural empyemas that required debridement and surgical drainage. KOSCHI scores at 1-year follow up ranged from 3b to 4b. Timofeev et al., (2008a) UK Retrospective chart review N=27 Charts of moderately to severely brain injured patients who underwent decompressive craniectomy were reviewed. Reductions in ICP immediately post surgery as well as pressure reactivity were evaluated. Mean ICP levels were reduced from 21.2 mm Hg pre-operation to 15.7 mm Hg post-operation (P=0.01). ICP exceeded 25 mm Hg 28.6% of the time preoperation and only 2.2% of the time post-operation. Pressure reactivity post-surgery was significantly associated with favourable outcome (GOS 4 or 5) 6months post (p=0.02) but pre-surgical reactivity was not (p=0.462) Otani et al., (2010) Japan Cohort N=80 Patients with acute epidural hematomas were treated with either hematoma evacuation (HE) or HE as well as an external decompression (ED). Significant differences in patient characteristics were noted between groups. A favorable outcome was noted in 78.2% of patients in the HE group, while only in 55.8% of the HE plus ED group. Children and Decompressive Craniectomy Post ABI Taylor et al., (2001) Australia RCT PEDro = 6 N=27 Children >12 who had sustained a TBI and had a functioning intraventricular catheter, and sustained intracranial hypertension during the first day after admission (ICP 20-24 mmHg for 30 min, 25-29 mmHg for 10 min, 30 mmHg or more for 1 min) or had evidence of herniation (dilation of one pupil or the presence of bradycardia) were randomized to conventional medical management (control group) or decompressive craniectomy plus Significantly lower ICP in the decompression group following craniectomy compared with control group (p=0.057). There was a trend towards shorter time in intensive care in the decompression group than in the control group (p=0.12). The median stay in hospital was 26.8 days (range 13.8-73.3) in the decompression group and 47.7 days (range 21.9-73.1) in the control group (p=0.33) More children in the decompression group obtained a Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome conventional medical management favourable outcome 6 months after the (decompression group). A decompressive injury on the GOS and HSU compared with bitemporal craniectomy was performed the control group (p=0.046) at a median of 19.2 hr (range 7.3-29.3 hr) from the time of injury. Control of ICP and GOS and the Health State Utility (HSU) index (Mark 1) 6 months after injury were assessed. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In a recent RCT, Cooper et al. (2011) assigned a group of individuals to receive either decompressive craniectomy or standard care (n=73) or standard care alone (n=82). Six months after recovery all were evaluated using the GOS. Those in the decompressive group had a shorter stay in ICU and did not require mechanical ventilation as long as those receiving standard care. However despite this according to the results of the GOS, those in the decompressive group had worse outcomes. Fifty-one of the 73 participants had unfavorable outcomes compared to 42 of the 82 in the standard care group. Overall study authors did not find, as has been previously reported, decompressive craniectomy was effective in reducing poor outcomes in participants. In two separate adult RCTs, Jiang et al. (2005), and Qiu et al. (2009) assessed randomly assigned patients with refractory intracranial hypertension to receive standard trauma craniectomy with a unilateral frontotemporoparietal bone flap (12 x 15 cm) or limited craniectomy with a routine temporoparietal bone flap (6 x 8 cm). In both studies, the authors reported that significantly more patients in the standard (larger) craniectomy group showed favourable GOS outcomes than those who received limited craniectomy at 6-months (Jiang et al., 2005) and 1-year post surgery (Qiu, 2009). Moreover, ICP fell more rapidly and to a lower level in the standard craniectomy group than in the limited craniectomy group and one month mortality was also reduced (Qiu, 2009). In the first of three non-randomized control trials, Polin et al. (1997) used patients from the Traumatic Coma Data Bank who had not received decompressive craniectomy as a matched control for 35 patients who had been surgically decompressed. Averages of four control patients (matched for age, sex, preoperative GCS and maximum preoperative ICP) were used as controls for each decompressed patient. Operative patients showed decreased ICP post-surgery and improved ICP compared to late stage control measures. The rate of favorable outcome in the decompressed group was significantly higher than the control group. Patients who received decompression before ICP levels reached 40 Torr and within the first 48 hours post trauma showed the most significant improvement compared to controls. Polin et al., (1997) suggest Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury that decompressive craniectomy be considered as early as possible when routine ICP management measures fail. In the second non-RCT, Li et al. (2008) retrospectively reviewed clinical data for 263 patients treated with either large decompressive craniectomy (n=135) or routine craniectomy (n=128). They report that patients who underwent larger resections showed significantly higher rates of satisfactory outcomes on the GOS. Similar results were seen for severe TBI patients. Patients who underwent larger craniectomies were also less likely to require further operations and presented fewer complications. In the third non-RCT, Aarabi et al. (2009) retrospectively assessed differences in outcome on the GOS between patients who had ICP monitoring 1-14 days before DC and those who did not. They found no difference between the two groups. In all, 18 chart reviews were located. Of these reviews, nine explicitly reported decreases in ICP associated with decompressive craniectomy (Howard et al., 2008; Aarabi et al., 2006; Olivecrona et al., 2007; Skoglund et al., 2006; Ucar et al., 2005; Tuettenberg et al., 2009; Ho et al., 2008; Bao et al., 2010; Daboussi et al., 2009; Timofeev et al., 2008). Of these nine, only 1 reported an association between decreased ICP and improved outcomes (Williams et al., 2009). Other factors that were reported to correlate with long-term outcomes included: initial GCS; (Meier et al., 2008; Ucar et al., 2005; Yang et al., 2008; Howard et al., 2008) age; (Salvatore et al., 2008; Ucar et al., 2005; Williams et al., 2009; Meier et al., 2008) pupil reactivity; (Howard et al., 2008; Meier et al., 2008) and earlier operations (Salvatore et al., 2008). Larger decompressions were also associated with better reduction in ICP (Skoglund et al., 2006) and decompressive craniectomy was reported to be more effective for improving outcomes after removal of hemorrhagic contusions than craniotomy (Huang et al., 2008). In a more recent study Salvatore et al. (2008) performed uncoparahippocampectomy with tentorial edge incision followed by decompressive craniectomy on 80 patients and reported 75% favorable outcomes. They also suggested that younger age and earlier operations were associated with better outcomes. In a well designed observational study, Flint et al. (2008) evaluated the effects of post-operative expansion of hemorrhagic contusions on patient outcomes. They report that new or expanded contusions >5cc were found in 58% of patients after decompressive hemicraniectomy and that contusions greater than 20cc were significantly associated with poorer outcomes and mortality. This represents a serious concern that must be monitored in patients undergoing decompressive procedures. A 2006 Cochrane review found no evidence to recommend routine use of decompressive craniectomy to reduce unfavorable outcomes in adults with uncontrolled ICP (Sahuquillo & Arikan, 2006). However, they do recommend that decompressive craniectomy may be a useful option in the pediatric population when maximal medical treatment has failed to control ICP. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury In a study of pediatric TBI patients Taylor et al. (2001), children with intracranial hypertension were randomized to receive decompressive craniectomy or to continue conventional medical management (control group). The authors reported that children who received craniectomy showed significantly lower ICP and more achieved a favourable outcome on the GOS and the Health State Utility index at 6 months Conclusions There is Level 1b evidence that in adults, standard trauma craniectomy is more effective than limited craniectomy in lowering elevated ICP and leading to better GOS outcomes at 6 months. There is conflicting evidence supporting the use of decompressive craniectomies in adults post TBI. There is Level 3 evidence that resection of a larger bone flap results in greater decreases in ICP reduction after craniectomy, better patient outcomes and leads to fewer post-surgical complications. There is Level 1b evidence that in children, decompressive craniectomy reduces elevated ICP. There is Level 4 evidence from several studies does reduce ICP in children post severe TBI. In adults standard trauma craniectomy leads to better control of ICP and better clinical outcomes at 6 months when compared with limited craniectomy. Resection of a larger bone flap during craniectomy may lead to a greater reduction in ICP, better patient outcomes and fewer post-surgical complications. Although decompressive cranectomy does reduce ICP in children more research needs to be conducted investigating its impat on the long term clinical outcomes. 16.1.1.6 Continuous Rotational Therapy and Prone Positioning The concept of continuous rotational therapy has been used for the prevention of secondary complications resulting from immobilization. These include bedsores and ulcers, pneumonia, atelectasis, deep vein thrombosis, pulmonary emboli, muscle atrophy, contracture and others. There are some indications that continuous rotational therapy may be useful in managing elevations in intracranial pressure. We identified a single study that evaluated the efficacy of this intervention post ABI. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Use of the prone position has been shown to be an effective treatment for patients with acute respiratory insufficiency in the ICU (Pelosi et al., 2002). However, many studies have excluded patients with ABI due to fears of increasing ICP during the turning process and in the prone position itself (Johannigman et al., 2000). We found two studies that showed increased oxygenation in the prone position in patients with TBI and reduced intracranial compliance. Neither the EBIC nor the AANS make any recommendations regarding continuous rotational therapy or prone positioning. Individual Studies Table 16.6 Continuous Rotational Therapy and Prone Positioning in Acute Care Management Post ABI Author/Year/ Country/Study design Methods Outcome Tillet et al., (1993) USA Case Series N=58 Severe brain injury patients (GCS ≤ 9) received continuous rotational therapy within 24 hours of injury onset with side-to-side rotation maintained at 40º (rotation of body to prevent pressure ulcers and other complications). Differences in ICP during rotation and non-rotation periods were compared. No significant differences in the ICP during rotation compared to nonrotation periods during any of the time periods examined (day 2, 3, 4 and 5 post-admission). Highest ICP reported in patients with unilateral injuries when rotated to the side of their lesions. These findings showed a statistically significant difference on ICP when patients were rotated to the side of the lesion (p = 0.025). Nekludov et al., (2006) Sweden Case Series N=8 Patients with TBI (5 with GCS ≤ 8) or Sub-arachnoid Hemorrhage were studied in the Supine and Prone positions. Hemodynamics, arterial oxygenation, respiratory mechanics, ICP and CPP were measured. A significant improvement in arterial oxygenation was observed in the prone position (P=0.02). Both ICP (P=0.03) and MAP (P=0.05) increased in the prone position as well. MAP however, increased to a greater extent resulting in improved CPP (P=0.03). Thelandersson et al., (2006) Sweden Case Series N=11 Patients admitted to the neuro intensive care unit due to TBI or intracerebral hemorrhage. Patients were monitored for ICP, CPP, HR, mean arterial blood pressure (MABP), arterial partial pressure of oxygen (PaO2 )and carbon dioxide, and respiratory system compliance. Measurements were taken before, three times during and two times after being placed in the prone position. No significant changes were demonstrated in ICP, CPP or MABP. PaO2 and SaO2 were significantly increased in the prone position and after 10 minutes in the supine post-prone position (P<0.05). Respiratory system compliance was increased 1h in the supine post-prone position (P<0.05). Discussion We identified a single study examining the effects of continuous rotational therapy on intracranial pressure. This study utilized a single group pre-post intervention comparative Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury design lacking a true control group (Tillett et al.,1993). This study failed to find any direct benefit of continuous rotational therapy for the management of elevated ICP. However, continuous rotational therapy did not worsen ICP. Study authors suggest that care should be taken not to rotate patients with unilateral brain injuries towards the side of the lesion to avoid further increments in ICP. Two studies, Thelandersson et al., (2006) and Nekludov et al., (2006), discussed the effects of the prone position on oxygenation rates in ABI patients. Both studies were case series’ with no control group using a prospective pre-post design. Both studies showed increased pO2 levels in the prone position. However, only one study showed increased oxygenation after return to the supine position (Thelandersson et al., 2006).The other study showed increased CPP associated with increased MAP while in the prone position (Nekludov et al., 2006). Of note, in this study, ICP also significantly increased in the prone position. Due to the small numbers associated with both papers, the authors recommend further studies be performed to verify the efficacy of prone positioning. Conclusions There is Level 4 evidence that continuous rotational therapy does not worsen intracranial pressure in severe brain injury patients. There is level 4 evidence that the prone position may increase oxygenation and CPP in ABI patients with acute respiratory insufficiency. Continuous rotational therapy may not worsen intracranial pressure in severe brain injury patients Prone position may increase oxygenation and cerebral perfusion pressure in patients with acute respiratory insufficiency. 16.1.2 Pharmacological Treatments 16.1.2.1 Osmolar Therapies Osmolar therapy is a major treatment approach in controlling intracranial hypertension and edema following an ABI. Although mannitol is the drug most widely used in this regard, hypertonic saline has gained popularity and some studies have called for examination of hypertonic saline as a primary measure for ICP control (Horn et al., 1999; Ware et al., 2005). 16.1.2.1.1 Hypertonic Saline Hypertonic saline exerts its effect mainly by increasing serum sodium and osmolarity thereby establishing an osmotic gradient. This allows water to passively diffuse from the cerebral Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury intracellular and interstitial space into blood capillaries causing a reduction in water content and a subsequent reduction in ICP (Khanna et al., 2000). Although mannitol works similarly, sodium chloride has a better reflection coefficient (1.0) than mannitol (0.9) (Suarez 2004) meaning that the blood-brain barrier is better able to keep out sodium chloride, making it a more ideal osmotic agent. It has also been proposed that hypertonic saline normalizes resting membrane potential and cell volume by restoring normal intracellular electrolyte balance in injured cells (Khanna et al., 2000). The AANS or EBIC made no recommendations for the use of hypertonic saline. Individual Studies Table 16.7 Hypertonic Saline for the Management of ICP Hypertension Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Adult Studies Rhind et al., (2010) Canada RCT Pedro = 7 N=65 TBI patients were randomized to receive either 250mL of 0.9% normal saline (NS) or an equal dose of 7.5% hypertonic saline mixed with 6% dextran70 (HSD) pre-hospital and then compared to each other and normal controls for immunologic and coagulation markers. The authors note a number of differences between NS and HSD, & note that in many cases, HSD is beneficial in modulating inflammatory response, and may help ameliorate secondary brain injury. Baker et al., (2009) Canada RCT Pedro = 10 N=64 Severe head injured patients were randomized to receive either a 250 mL intravenous infusion of 7.5% hypertonic saline in 6% dextran 70 (HSD) or an equivalent dose of 0.9% isotonic normal saline (NS) and compared to control patients. Variation in levels of several serum biomarkers was conducted. No differences in patient survival or neurocognitive outcomes were noted between groups. However, peak levels of biomarkers were significantly correlated with unfavorable outcomes measured by the GOS and GOSE. Myburgh et al., (2007) NZ/Aus RCT PEDro = 10 N=460 Severely brain injured patient (GCS3-12) information was accessed from a previous study of saline vs albumin in a heterogeneous population of ICU patients. Mortality and 24 month GOS-E scores were used as outcome measures. Overall, there was a significant increase in mortality rates in the albumin group (p=0.003) after 24 months. Also, there was a significant increase in mortality rates in patients with severe TBI (GCS<9) treated with albumin (p<0.001). No differences were seen between groups on GOS-E scores. Battison et al., (2005) UK RCT PEDro = 5 N=9 Brain injury patients who required an ICP monitor as part of their management due to ICP > 20 mm Hg for > 5 min which was not related to a transient external noxious stimulus or systemic derangement Both mannitol and HSD were effective in reducing ICP, however HSD caused a significantly greater decrease in ICP than mannitol (p=0.044). HSD had a longer duration of effect than mannitol Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods + Outcome (low serum Na , low PaO2, increased PaCO2) received equimolar rapid intravenous infusions of either 200 mL of 20% mannitol or 100 mL of 7.5% saline and 6% dextran-70 solution (HSD) over 5 min in a cross over fashion. The order of the treatments was randomized. (p=0.044). Cooper et al., (2004) Australia RCT PEDro = 9 N=229 Severe brain injury patients (GCS < 9) were randomized to receive 250 mL intravenous infusion of either 7.5% hypertonic saline (HTS) or 250 mL of Ringer’s lactate solution (controls) in addition to standard intravenous resuscitation fluids. GOS score, FIM and Rancho Los Amigos score at 3 and 6 months post-injury were compared between groups. Proportion of patients surviving was similar in both groups at hospital discharge (55% in HTS group and 50% in control, p=0.32) and at 6 months postinjury (55% in HTS group and 47% in control, p=0.23). There were no significant group differences at 6 months in median (interquartile range) GOS score (HTS group 5 (3-6) vs. control group 5 (5-6), p=0.45). There was no significant difference between groups in favorable outcomes (GOS 5-8, p=0.96) or in any other measure of post-injury neurological function. Vialet et al., (2003) France RCT PEDro = 7 N=20 Severe head injury patients (GCS < 8) who experienced persistent coma requiring ICP monitoring and infusion of an osmotic agent to correct refractory episodes of ICP that were resistant to standard modes of therapy were randomized to either 20% mannitol (1160 mOsm/kg/H20) or 7.5% hypertonic saline (2400 mOsm/kg/H2O). Infused volume was the same for both medications (2 ml/kg body weight in 20 min). Number and duration of episodes of ICP hypertension per day, failure rate of each treatment (defined as the persistence of ICP hypertension despite two successive infusion of the same osmotic agent), mortality rate and GOS score at 90 days were compared. The mean number (6.9 ± 5.6 vs. 13.3 ± 14.6 episodes) of ICP hypertension episodes per day and the daily duration (67 ± 85 vs. 131 ± 123 min) of ICP hypertension episodes were significantly lower in the hypertonic saline group (p<0.01). The rate of clinical failure was also significantly lower in the hypertonic saline solution group (1 of 10 patients vs. 7 of 10 patients, p<0.01). Mortality rate and GOS outcome did not differ between the two groups. Shackford et al., (1998) USA RCT PEDro = 5 N=41 ABI patients (GCS < 13) who required ICP monitoring were randomly assigned to receive 1.6% hypertonic Saline (HTS) or Lactated Ringer’s Solution (LRS). Differences in ICP, number of medical Interventions to lower ICP, and GOS at Treatment lowered ICP in both groups, and there were no significant differences between groups in ICP at any time after entry. The average total number of interventions to control elevations in ICP during the entire study Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome discharge were compared between groups. Groups were similar in age and Injury Severity Score. HTS patients had a lower admission GCS score (p=0.057), a higher initial ICP (p=0.06), and a higher initial mean maximum ICP (p <0.01) compared with the LRS group. was significantly greater in the HTS group than in the LRS group (p < 0.01). During the study, the change in maximum ICP was positive in the LRS group but negative in the HTS group (p<0.05) There were no significant differences between groups in the mean GOS at discharge from hospital. Eskandari et al., (2013) USA Prospective Cohort N=11 Participants were administered a 14.6% hypertonic saline (HTS) bolus over 15 minutes through a cent At the time of infusion of the HTS, ICP, CPP HR and SBP were recorded. Each bolus administration was considered an individual exposure. Repeated boluses were administered if, after 60 minutes the patient was found to have refractory ICP once again. Following the administration of bolus HTS participants ICP levels were reduced from 40 ± 12 mm Hg to 33 ± 10 mm Hg (p<0.05). Tem minutes post administration there was a further reduction to 28 ± 9 mm Hg (p<0.05). Similar trends were noted with looking at cerebral perfusion pressure measurements. Again these trends were found to be significant (p<0.05) Mean heart rates and systolic blood pressure were not affected by the HTS infusions. Kerwin et al., (2009) USA Cohort N=22 Severely brain injured patients were administered 23.4% hypertonic saline or mannitol to treat acute intracranial hypertension. Patient charts were retrospectively reviewed for reductions in ICP immediately after administration. Mean reduction of ICP by hypertonic saline was 9.3 ± 7.37 mm Hg and 6.4 ± 6.57 mm Hg by mannitol. Patients receiving mannitol were more likely to have an ICP reduction of <5 mm Hg whereas hypertonic saline treated patients were more likely to have a decrease of greater than 10 mm Hg. However, patients receiving hypertonic saline had statistically significantly greater ICP immediately before administration. Oddo et al., (2009) USA Chart review N=12 Patients treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP or hypertonic saline if not controlled by mannitol were retrospectively evaluated. PbtO2, ICP, MAP, CPP, central venous pressure, and cardiac output were monitored. Forty-two episodes were analysed. Compared with mannitol, hypertonic saline was associated with lower ICP, and higher CPP and cardiac output. Hypertonic saline also resulted in significant improvements in PbtO2 (p<0.01) while mannitol did not. Schatzmann et al., (1998) Germany Case Series N=6 Severe ABI patients (GCS ≤ 7) received hypertonic saline (100 ml NaCl intravenously over 5 min) after standard agents (mannitol, sorbitol, THAM) failed in reducing ICP. Changes in ICP were Following hypertonic saline infusions relative ICP decreased by an average of 43%. The corresponding pressure drop was 18 mmHg (15-17mmHg). Relaxation in ICP lasted for 93 min (64- Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome assessed. 126 min) and relative ICP minimum was reached 26 min (12-33 min) after infusion. No p values provided. Qureshi et al., (1998) USA Chart Review N=10 Head injury patients (GCS = 7.1 ± 0.8) received 3% hypertonic saline/acetate solution composed of sodium chloride and sodium acetate (50:50) at a variable rate (75 – 150 mL/hr through a central venous catheter). Changes in ICP, GCS and GOS score at 1 month were evaluated. A favorable trend toward ICP reduction correlating with increasing serum sodium concentration was observed (r2 = 0.91, p = 0.03). Mean ICP was reduced from 14.2 ± 4.2 to 7.3 ± 1.8 mmHg (no p value provided). There was reduction in lateral displacement of the brain (2.8 ± 1.4 to 1.1 ± 0.9 mm). GCS showed a slight improvement to 7.4 ± 1.3 compared with 7.1 ± 0.8 before treatment (no p value). GOS 1 month post treatment was 3.6 ± 0.4. Pascual et al., (2008) USA Chart Review N=12 Severe hypotensive TBI patients (GCS ≤ 8) in ICU received hypertonic saline (HTS) as a method for resuscitation under a guideline regulated protocol over a course of 3.5 years. Changes in ICP, CPP, hemodynamics, and PbtO2 were monitored. HTS was associated with a significant trend in decreased ICP and increases in CPP and Pbt O2. Patients were only administered HTS as an adjunct to standard protocol as a means of resuscitation. Only 6 patients survived to rehabilitation. Lescot et al., (2006) France Case Control N=14 TBI patients (GCS 4-14) were administered a 20 min infusion of 40 mL of 20% Saline. A CT scan was performed before and after to assess the volume, weight and specific gravity of contused and non-contused brain tissue. HTS significantly increased natremia from 143 ± 5 mmol/L to 146 ± 5 mmol/L and decreased ICP from 23 ± 3 to 17 ± 5 mmHg. The Volume of noncontused hemispheric areas decreased by 13 ± 8 mL whereas the specific gravity increased by 0.029 ± 0.027%. The volume of contused hemispheric tissue increased by 5 ± 5 mL without any concomitant change in density. There was wide individual variability in the response of the noncontused hemispheric tissue with changes in specific gravity varying between 0.0124% and 0.0998%. Ware et al., (2005) USA Chart Review N=13 Brain injured patients who had been administered 23.4% hypertonic saline in conjunction with mannitol to control ICP. Charts were reviewed for ICP, CPP, MAP, serum sodium values, and serum osmolarity after treatment with 23.4% sodium chloride and mannitol. Hypertonic saline was shown to significantly reduce ICP (P<0.001) and there was no significant difference between ICP reduction by hypertonic saline and mannitol (P=0.174). The mean duration of ICP reduction by HTS (96 min) was significantly longer than Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome mannitol (59min) (P=0.016). Horn et al., (1999) Germany Case control N=10 Patients with TBI or SAH and therapy-resistant elevation of ICP were given 7.5%, 2 ml/Kg b.w. intravenously at an infusion rate of 20 ml/min. Only patients with ICP > 25mmHg and plasma sodium concentration <150 mmol/L were included. Within the first hour after HSS administration ICP decreased from 33 ± 9 mmHg to 19 ± 6 mmHg (p< 0.05) and further to 18 ± 5 mmHg at the time of maximum effect. CPP rose from 68 ± 11 mmHg to 79 ± 11 mmHg after one hour (p<0.05) and 81 ± 11 mmHg at maximum effect. Rockswold et al., (2009) USA Prospective N=25 Patients with severe TBI were treated with 23.4% NaCl (30mm over 15 mins). Patients were evaluated on intercranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2). For each evaluation, patients were divided into either a low, medium or high risk group. Mean ICP decreased by 8.3 mm Hg (P<0.0001). ICP level was positively effected for all 3 groups (P<0.05) The higher the initial ICP value, the more effective NaCl was at reducing ICP (P<0.05). The best MAP response was in the groups with the lowest initial MAP values. Most patients MAP levels were not affected by hypertonic saline. Patients above 70 mm Hg initial CPP level were unaffected by treatment, whereas patients under 70 mm Hg were shown to have significant improvement after treatment (P<0.05). PbtO2 was significantly improved at 1,3, and 4 hours post-treatment, and nearly reached significance 2 and 5 hours (p=0.06). Pediatric Studies Simma et al., (1998) Switzerland RCT PEDro = 6 N=32 Children (< 16 yrs of age) with severe traumatic brain injuries (GCS < 8) were randomly assigned to Ringer’s Lactate (sodium 131 mmol/L, 277 mOsm/L) or hypertonic saline (sodium 268 mmol/L, 598 mOsm/L) treatment over 72 hours. There was no difference between groups with respect to age, gender ratios, or initial GCS score. Changes in ICP and CPP were compared. In both groups there was a positive correlation between higher serum sodium concentrations and lower ICP and higher CPP. There was a significantly lower frequency of acute respiratory distress syndrome, shorter ICU stays and lower occurrence of more than two complications in the children receiving hypertonic saline during the first three days post injury. Khanna et al., (2000) USA Case Series N=10 Severe brain injury pediatric patients (4 months – 12 years of age, GCS ≤ 8) who failed conventional ICP therapy were treated with continuous infusion of 3% saline (514 mEq/L) to achieve a target serum sodium level. Changes in ICP, CPP There was a steady increase in serum sodium over time that was statistically significant at 24, 48, and 72 hrs (p<0.01). A significant decrease in ICP and ICP spike frequency and a significant increase in CPP at 6, 12, 24, 48 and 72 Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods and GOS outcome at discharge and at 6 months after discharge were evaluated. Outcome hrs (p<0.01) were found. Significant increase in serum osmolarity at 12 hrs (p<0.05) and at 24, 48 and 72 hrs (p<0.01) was also noted. Median 6month GOS was 4 (range 1-5). One patient died of uncontrolled ICP hypertension. If the nine remaining patients, seven had a GOS score of 4 or 5 (moderate-mild disability). Pedro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In a recent prospective cohort study, Eskandari and colleagues (2013) found the infusion of Hypertonic Saline (HTS) was effective in significantly reducing ICP in individuals who had sustained a severe TBI. Further this reduction was sustained for 12 hours following the infusion of HTS. Cerebral perfusion pressure increased within in minutes of bolus initiation. Study authors noted that once the HTS bolus was administered in combination with the various vasopressor agents, the appropriate CPP goals were met. On note mean heart rate and systolic blood pressure were not affected by HST bolus (Eskandari et al., 2013). In two studies, conducted by the same group of researchers, participants were randomly assigned to receive either hypertonic saline-dextran solution or normal saline solution (0.9% saline). The effect on the inflammatory and serum biomarker levels was assessed (Rhind et al., 2010; Baker et al., 2009). They report that hypertonic saline-dextran is superior to normal saline for controlling inflammatory and serum biomarker spikes while reducing elevated ICP. Results of these two studies suggest this may help to ameliorate the secondary brain injury after TBI but failed to show improvements in patient outcomes between groups. In a post-hoc RCT, Myburgh and colleagues (2007) performed an analysis of saline compared to albumin in 460 patients. A significant increase in mortality rates were seen in the albumin group upon 24 month follow-up (p=0.003). Patient data was then divided into sub-groups and reanalyzed. Patients with severe injury (GCS 3-8) in the albumin group were significantly more likely to have died than those in the saline group (p<0.001). However, patients with moderate injuries (GCS 9-12) showed no statistical differences in between group mortality rates (p=0.50). Overall, no differences were noted in rates of favorable outcomes as assessed by the GOS-E. In a cross-over RCT, compared the effects of mannitol and a hypertonic saline dextran solution (Battison et al., 2005). Although both mannitol and the saline solution were effective in reducing elevated ICP, saline caused a significantly greater decrease over a longer period of time. In a similar RCT conducted by Vailet et al. (2003) comparing the effects of mannitol and Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury hypertonic saline, the use of the latter resulted in significantly fewer episodes of ICP hypertension. Furthermore, treatment with hypertonic saline was associated with fewer clinical failures (defined as the persistence of ICP hypertension despite two successive infusions of the same osmotic agent). Despite these apparent differences, mortality rates and GOS outcome 90 days post-injury did not differ between groups. Another non-randomized trial also suggested that hypertonic saline was superior to mannitol for ICP reduction but baseline differences in comparison groups make their findings difficult to interpret (Kerwin et al., 2009). Cooper et al. (2004) in another RCT, examined the clinical outcomes of patients who were randomly assigned to treatments with hypertonic saline or Ringer’s lactate solution. They reported that at 6 months post-injury there was no difference between groups in survival, favorable GOS outcome, FIM or Rancho Los Amigos score. Similarly, in an RCT where patients were randomized to receive either hypertonic saline or lactated Ringer’s solution, the authors reported that both treatments lead to reductions in ICP without any significant differences between groups (Shackford et al., 1998). However, they indicated that those treated with hypertonic saline required a significantly greater number of medical interventions to lower ICP. Although this may appear contrary to the use of hypertonic saline in brain injured patients, it should be noted that the hypertonic saline group had a significantly greater number of more severe brain injury patients. As such, it is plausible that with increasing severity of brain injury, patients would require a greater number of medical interventions to control ICP. Despite this disparate randomization of more severe brain injury patients, the study found that at discharge from the hospital, there were no significant differences between groups in GOS scores. Pascual et al. (2008) demonstrated that hypertonic saline improved cerebral oxygenation and therefore may be a valuable component in resuscitation of brain injured patients. The authors caution that due to the small sample size (n=12), further study is necessary. These finding were confirmed by in a study conducted by Oddo et al. (2009). Here hypertonic saline was found to significantly improve oxygenation. Lescot et al. (2006) applied CT technology to assess the effectiveness of hypetonic saline on volume, weight and specific gravity of contused and non-contused brain tissue.Three days after TBI, the blood brain barrier remained semi-permeable in non-contused areas but not in contused areas. Contused tissue was shown to increase in volume after administration of hypertonic saline. The authors recommend that further study be done to assess the effects of hypertonic saline on different tissue types so that contusion site and size might be appropriately factored into clinical decisions (Lescot et al., 2006). In a study of severely head injured children, Simma et al. (1998) compared the effects of hypotonic resuscitation with Ringer’s Lactate versus hypertonic saline during the first three days post head injury. There was an inverse relationship between sodium concentration and intracranial pressure. Increased serum sodium concentration correlated with lower ICP and higher CPP. The children treated with hypertonic saline were reported to have a significantly lower frequency of acute respiratory distress syndrome, a lower frequency of two or more Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury complications and significantly shorter ICU stay. This study suggests that hypertonic saline is superior to ringer’s lactate for early fluid resuscitation in children following TBI. The remaining six studies identified on this topic (Qureshi et al., 1998; Khanna et al., 2000; Schatzmann et al., 1998; Horn et al., 1999; Ware et al., 2005; Rockswold et al., 2009) reported positive results indicating that treatment with hypertonic saline resulted in significant reduction in ICP with appreciable improvements in cerebral perfusion pressure. Furthermore, two of these studies demonstrated that the reductions in ICP were mediated by concomitant increments in serum sodium concentrations (Qureshi et al., 1998; Khanna et al., 2000). Conclusions There is Level 1b evidence (from 2 RCTS) to suggest that hypertonic saline reduces ICP more effectively than mannitol. There is Level 1 evidence that treatment with hypertonic saline results in similar clinical outcome and survival when compared with treatment with Ringer’s lactate solution up to 6 months post-injury. There is Level 1b evidence that saline solution results in decreased rates of mortality compared with albumin. There is Level 4 evidence that treatment with hypertonic saline reduces elevated ICP refractory to conventional ICP management measures. There is Level 2 evidence that hypertonic saline is similar to Ringer’s lactate solution in lowering elevated ICP. There is Level 4 evidence that hypertonic saline may be useful as a component of a resuscitation algorithm by increasing cerebral oxygenation. There is Level 1b evidence that in children, use of hypertonic saline in the ICU setting results in a lower frequency of multiple early complications and a shorter ICU stay compared with Ringer’s lactate. There is Level 4 evidence to suggest HTS is effective in decreasing ICP levels in children post TBI. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Hypertonic saline reduces ICP more effectively than mannitol. Hypertonic saline and Ringer’s lactate solution are similar in lowering elevated ICP and result in similar clinical outcomes and survival up to 6 months post-injury. In children, use of hypertonic saline in the ICU setting results in a lower frequency of early complications and shorter ICU stays compared with Ringer’s lactate in children. Saline results in decreased mortality rates compared to albumin. Hypertonic saline may reduce elevated ICP uncontrolled by conventional ICP management measures. Hypertonic saline may aid in resuscitation of brain injured patients by increasing cerebral oxygenation. 16.1.2.1.2 Mannitol Rapid administration of mannitol is among the first-line treatments recommended for the management of increased ICP. However, this treatment is reported to be associated with significant diuresis and can cause acute renal failure, hyperkalemia, hypotension, and in some cases rebound increments in ICP (Battison et al. 2005;Doyle et al. 2001). For these reasons, the Brain Trauma Foundation recommends that mannitol should only be used if a patient has signs of elevated ICP or deteriorating neurological status. Under such circumstances the benefits of mannitol for the acute management of ICP outweigh any potential complications or adverse effects (AANS1995). There is also some evidence that with prolonged dosage, mannitol may penetrate the blood brain barrier thereby exacerbating the elevation in ICP (Wakai et al., 2005). Despite mannitol’s effectiveness in ICP management, recent evidence points to hypertonic saline as a potentially more effective hyperosmotic agent. The AANS make a level II recommendation that mannitol is effective for ICP control at 0.25 g/Kg to 1 g/Kg body weight but systolic BP < 90 mmHg should be avoided . They make a Level III (recommendation that mannitol use prior to ICP monitoring should be restricted in patients with signs of transtentorial herniation or progressive neurological deterioration not attributable to extracranial causes (Bratton et al., 2007e). The EBIC recommend mannitol as the preferred osmotic therapy. They recommend administration via repeated bolus infusions, or as indicated by monitoring, to a serum osmolarity of ≤ 315 (Maas et al., 1997). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.8 Mannitol for the Management of ICP and Hypertension Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Ichai et al., (2009) France RCT PEDro = 6 N=34 Patients with severe TBI (GCS ≤ 8) and intracranial hypertension were randomly allocated to receive equally hyperosmolar and isovolumetric therapy with mannitol or sodium lactate followed by cross-over rescue therapy when necessary. Outcome measures included ICP lowering at 4h and percentage of successfully treated episodes of ICP. Compared to mannitol, the effect of sodium lactate on ICP was more pronounced (7 vs. 4 mmHG, p=0.016), th more prolonged (4 hour decreases of 5.9 ±1 vs. 3.2 ± 0.9 mmHg, p=0.009) and more frequently successful (90.4% vs. 70.4%, p=0.053). Francony et al., (2008) France RCT PEDro= 6 N=20 Stable patients with a sustained ICP of >20 mmHG secondary to TBI (n=17) or stroke (n=3) were given a single equimolar infusion of either 20% mannitol or 100mL of 7.45% hypertonic saline during 20 mins of administration. A single equimolar infusion of 20% mannitol is as effective as 7.45% hypertonic saline in decreasing ICP in patients with ABI. Mannitol exerts additional effects on brain circulation through a possible improvement in blood rheology. Cruz et al., (2004) Brazil RCT PEDro = 5 N=44 Severe ABI patients with recent clinical signs of impeding brain death were randomized to receive high dose mannitol (500 ml of fast intravenous “wide open” mannitol in a total dose of approximately 1.4 g/kg) or conventional-dose mannitol (250 ml of 0.7 g/kg mannitol). Immediately after the mannitol infusion, patients in the high-dose and conventional mannitol groups received 1000 or 500 ml respectively of intravenous normal saline to prevent acute hypovolemia and possible secondary arterial hypotension. Pupillary improvement (partial or full pupillary constriction ≥ 1 mm toward the normal diameter at 5-10 min after treatment) and GOS scores at 6 months were evaluated. Improvement in bilateral abnormal papillary widening was significantly more frequent in the high-dose group than in the conventional dose group (p<0.02). At 6 months post-injury, mortality rates were 39.1% and 66.7% in the high-dose and conventional dose mannitol groups respectively. Clinical outcomes on the GOS scale were significantly better for the highdose than for the conventional dose group (p<0.02). Cruz et al., (2002) Brazil RCT PEDro = 5 N=141 Adult patients with traumatic nonmissile acute intraparenchymal temporal lobe hemorrhages (GCS 1-5) and abnormal pupillary widening (partially or fully dilated pupil with a diameter ≥ 4 mm associated with very sluggish or absent light response) were randomized to receive intravenous conventional mannitol Improvements in abnormal bilateral pupillary widening were significantly more frequent in the high dose mannitol group than in the control group (p<0.03). At 6 months after injury, mortality rates were 19.4% and 36.2% for the high dose mannitol and conventional mannitol groups respectively. Overall clinical Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome treatment (0.7 g/kg) or high dose mannitol treatment (1.4 g/kg). Immediately after the mannitol infusions both groups received normal saline infusions to compensate for mannitol-induced urine losses and to prevent arterial hypotension. Pupillary improvements (partial or full pupillary constriction ≥ 1 mm toward the normal diameter), and GOS at 6 months were assessed. outcome on the GOS were significantly better for the high dose mannitol group with a greater number of patients in this group showing a favorable outcome (good recovery/moderate disability) compared with the conventional mannitol group (p<0.005). Cruz et al., (2001) Brazil RCT PEDro = 4 N=178 Adult patients with non-missile traumatic acute subdural hematomas were randomly assigned to receive intravenous conventional mannitol treatment (0.6-0.7 g/kg) or high dose mannitol treatment (2 separate infusions of 0.6-0.7 g/kg). Both groups received normal saline infusions to compensate for mannitol-induced urine losses and to prevent arterial hypotension. In the high dose mannitol group, the second mannitol infusion began 25-30 min after the first infusion. Pupillary improvements (partial or full pupillary constriction ≥ 1 mm toward the normal diameter), and GOS at 6 months were assessed. Improvement in abnormal pupillary widening was significantly more frequent in the high dose mannitol group than in the conventional mannitol group (p<0.0001). At 6 months after injury, mortality rates were 14.3% and 25.3% for the high dose mannitol and conventional mannitol groups respectively. Overall clinical outcome on the GOS were significantly better for the high dose mannitol group with a greater number of patients in this group showing a favorable outcome (good recovery of moderate disability) compared with the conventional mannitol group (p<0.01). Smith et al., (1986) USA RCT PEDro = 4 N=80 Severe head injury patients (GCS scores ≤ 8) were randomized to receive mannitol only after ICP elevations > 25 mmHg (group I) or empirical mannitol therapy irrespective of ICP readings (group II). Mortality rates and neurological outcome were compared between groups. No significant difference in mortality between groups I and II (35% vs. 42.5%, p=0.26). There were also no significant differences in neurological outcome between groups. Mean highest ICP in nonsurvivors form both groups was significantly higher than that in survivors from both groups (p=0.0002). Sayre et al., (1996) USA RCT PEDro = 7 N=41 Moderate to severe (GCS < 12) head injury patients who were being transported to a hospital’s level 1 trauma centre by helicopter within 6 hours of injury and who had IV access, had airway control with an endotracheal tube and were being hyperventilated were. randomized to receive either saline (5 mL/kg of 0.9% saline solution; 308 mOsmol/L) or mannitol (5 mL/kg of 20% mannitol; 1,098 mOsmol/L) within the Systolic BP or pulse rates did not change significantly throughout the 2 hours observation period and there were no significant differences between groups indicating that mannitol did not cause secondary hypotension. There was no difference in study volume administered to the groups. However, urine output (p<0.001) was significantly greater and serum sodium (p<0.00001) was significantly lower in the mannitol group Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome aircraft. Changes in systolic blood pressure compared with the placebo group. (BP) during the 2-hour observation period were compared. Hartl et al., (1997) Germany Pre-Post N=11 Severe head injury patients (GCS < 9) who were sedated, intubated and mechanically ventilated to maintain an arterial PO2 > 100 mmHg and a PaCO2 of approximately 35 mmHg received mannitol (125 ml of 20% infused over 30 min through a central vein). Changes in ICP were evaluated. When the initial ICP before mannitol infusion was below 20 mmHg, neither ICP nor any other parameter changed significantly during or after mannitol infusion. When the pre-infusion ICP was above 20 mmHg there was a significant decrease in ICP and a significant increase in CPP; however there was no change in cerebral white matter oxygenation, or jugular bulb oximetry. Sorani et al., (2008) US Case Series N=28 Patients with ABI were continuously monitored for ICP while in the NICU. Patients were administered 50g or 100g doses (or both) of mannitol for management of elevated ICP. Patient data was then retrospectively analyzed to determine the dose-response relationship of mannitol to ICP. ICP response to mannitol proved to be dose related. Every 0.1 g/Kg of mannitol administered (to a maximum of 100g) resulted in approximately 1.0 mmHG drop in ICP. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In a recent RCT conducted in France, patients were randomized to receive either mannitol or a sodium lactate solution for management of acute episodes of elevated ICP (Ichai et al., 2009) The authors report that an equimolar dose of sodium lactate had a significantly more pronounced effect on acute elevations of ICP that lasted longer that treatment and with mannitol. Sodium lactate was also successful in reducing elevated ICP more frequently. Based on these results, further research into the effectiveness of sodium lactate in reducing ICP is warranted. In another trial conducted in France, equimolar doses (255 mOsm) of mannitol and hypertonic saline were compared (Francony et al., 2008). The authors found that both interventions were comparable in reducing ICP in stable patients with intact autoregulation. Mannitol was shown to improve brain circulation through possible improvements in blood rheology, but also significantly increased urine output. The authors suggest that both treatments may be effective, but patient pretreatment factors should be considered before selection. Cruz and colleagues conducted 3 separate RCTs in ABI patients to investigate the effects of high dose mannitol on clinical outcomes 6 months post-injury (Cruz et al., 2004; 2001; 2002). All 3 trials reported positive results indicating that high dose mannitol (1.4 g/kg) was superior to Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury conventional mannitol (0.7 g/kg) in improving mortality rates, and clinical outcomes. In a retrospective case study in the US, Sorani et al. (2008) found that for every 0.1 g/Kg increase in mannitol dosage there was a 1.0 mmHG drop in ICP which support the findings put forth by Cruz and colleagues. Further study is still recommended. Most reports recommend administering mannitol only when elevated ICP is proven or strongly suspected. Some discourage the use of mannitol before volume resuscitation and stabilization of the patient due to the potential osmotic diuresis and hypotension that could result following mannitol administration. These adverse effects could further compromise cerebral perfusion. However, this approach may deprive head injured patients of the potentially beneficial effects of mannitol upon ICP. With this in mind, Sayre et al. (1996) conducted another RCT to investigate the effects or early mannitol administration in head injured patients in an out-ofhospital emergency care setting. The authors reported that compared with patients randomized to receive saline, early out-of-hospital administration of mannitol does not significantly affect blood pressure. In another RCT by Smith et al. (1986) the authors reported that compared with patients who were randomized to receive empirical mannitol irrespective of ICP measurements, those who received mannitol only after the onset of intracranial hypertension (> 25 mmHg) were not significantly different in terms of mortality rates or neurological outcomes. The findings of a single group intervention study by Hartl et al. (1997) indicate that mannitol is only effective in diminishing ICP when the initial ICP is hypertensive (>20 mmHg) and not when it is below such values. Thus, the use of mannitol as a prophylactic measure against potential elevations in ICP may not be appropriate. This was corroborated in a more recent study by Sorani et al. (2008). A 2008 Cochrane review suggests that mannitol may have beneficial effects on mortality when compared to pentobarbital but detrimental effects when compared to hypertonic saline. They also report that there is insufficient data on the effectiveness of pre-hospital administration of mannitol (Wakai et al., 2005). Conclusions There is Level 1 evidence that sodium lactate is more effective than mannitol for the management of acute elevations in ICP. There is Level 2 evidence that higher dose mannitol is superior to conventional mannitol in improving mortality rates, and clinical outcomes. There is Level 2 evidence that early out-of-hospital administration of mannitol does not adversely affect blood pressure. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury There is Level 4 evidence that mannitol is effective in diminishing intracranial hypertension only when initial ICP values are elevated. Sodium lactate is more effective than mannitol for reducing acute elevations in ICP High dose mannitol results in lower mortality rates and better clinical outcomes compared with conventional mannitol. Early out of hospital administration of mannitol does not negatively affect blood pressure. Mannitol may only lower ICP when initial ICP values are abnormally elevated. 16.1.2.2 Propofol Propofol is a fast acting sedative that is absorbed quickly and metabolized equally quickly leading to pronounced effects of short duration. Its beneficial effects occur via decreases in peripheral vascular tension resulting in potential neuroprotective effects, which may be beneficial in acute ABI care. Experimental results have shown positive effects on cerebral physiology including reductions in cerebral blood flow, cerebral oxygen metabolism, EEG activity, and ICP (Adembri et al., 2007). However, administration of high doses can result in propofol infusion syndrome (PRSI), which has been characterized by severe metabolic acidosis, rhabdomyolosis, cardiac dysrhythmias, and potential cardiovascular collapse (Corbett et al., 2006). Children are especially susceptible to PRSI (Sabsovich et al., 2007). The AANS recommend propofol use for the control of ICP but not for improvement in mortality or 6 month outcome (Carney and Ghajar 2007). They also indicate that high-dose propofol can produce significant morbidity (Bratton et al., 2007b) The EBIC recommend sedation as part of the treatment course for ABI but make no specific mention of propofol (Maas et al., 1997). Individual Studies Table 16.9 Propofol for the Management of Acute ABI Author/Year/ Country/Study design/PEDro Score James et al., (2012) USA Methods N=8 Participants were randomly assigned to receive either propofol or dexmedetomidine for the first 6 hours of the study. Outcome No significant differences were noted between the two groups on any of the physiological measure (ICP, CPP, bispectral index (BIS), Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome RCT PEDro=6 Following this participants were crossed over into the opposite treatment protocol. brain tissue oxygenation (PbtO2), lactate to pyruvate (L/P ration). Kelly et al., (1999) USA RCT PEDro = 8 N=42 Patients with a GCS 3-12 who required mechanical ventilation were randomly assigned to receive propofol (20mg/ml with 0.005% EDTA) or morphine. Patients were assessed for adverse effects, physiological response (including ICP) and 6 month GOS. Intracranial pressure therapy in the propofol group was less intensive than the morphine group (less use of neuromuscular blocking agents, benzodiazepines, pentobarbital, and CSF drainage) and ICP on day 3 was significantly lower (p<0.05). Six month GOS scores were not significantly different between groups for mortality or favorable outcome rates. Stewart et al., (1994) UK Case series N=15 Patients were sedated with either a continuous infusion of propofol (mean 232 mg/hr, range 150-400 mg/hr) or infusions of morphine (mean rate 2.3 mg/hr, range 04mg/hr) and midazolam (mean rate 2.8mg/hr, range 0-5 mg/hr). Continuous collection of AVDO2, MABP, ICP, and CPP was performed. A fall in AVDO2 after 4 hours from 6.3 ± 2.6 ml/dl to 3.0 ± 0.6 ml/dl was noted while on propofol. No significant differences were seen in any of the other measures in either group. Farling et al., (1989) Ireland Case Series N=10 Patients with severe head injuries that required sedation were given intravenous propofol infusions as a 1% solution at a rate of 2-4 mg/kg/hr. Dose was adjusted to maintain ICP below 10 mmHg and CPP above 60 mmHg. Patients were monitored for HR, MABP, ICP, CPP, pupil size and PaCO2. A mean infusion rate of 2.88 mg/kg/hr was sufficient for sedation and recovery was rapid. CPP was significantly increased at 24 hrs. Significant differences were not seen in any of the other variables. Smith et al., (2009) USA Case Study N=146 Severe TBI (GCS ≤ 8) patients who had been treated with either vasopressures or propofol were analyzed. Patients were monitered for developing symptoms of propofol infusion syndrome (PRIS) Of the 146 patients included in the study, only 3 patients on both propofol and vasopressors developed PRIS. Of note, there were no patients on either propofol or vasopressures who developed PRIS. PRIS was not linked to mortality (p>0.05) PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002) Discussion In a recent RCT, propofol and dexmedetomidine were administered to a group of 8 individuals who had sustained an ABI (James et al., 2012). In this randomized cross over trial each medication was given for a 6 hour period, at which time participants were administered the opposite medications. Medication doses were individualized. No significant differences were found between the groups. As a result of these findings, study authors recommend that the Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury “choice of sedative regimen be based on the profile of the sedative and the individual goals for a patient (pg 955)” In an earlier RCT, propofol sedation was compared to morphine for safety and efficacy (Kelly et al. 1999). Here patients were randomly assigned to either a morphine group or a propofol group where they received interventions consisting of three simultaneous injections Injection 1 contained propofol or placebo, injection 2 morphine or placebo and injection three low-dose morphine (both groups). Physicians were allowed to administer injections as regularly as every 5 minutes as needed. This particular design allowed for the comparison of propofol dosing and its effectiveness while preserving the blind experimental component. However, all patients received morphine in conjunction with propofol infusion. Propofol tended to reduce ICP generally with significance reached on day 3 (p<0.05). Patients in the propofol group also showed less need for neuromuscular blocking agents, benzodiazepines, pentobarbital, and CSF drainage. At 6 months, there were no significant differences in mortality rates or GOS scores. The authors suggest that propofol is a safe, acceptable, and possibly desirable alternative to opiate-based sedation (Kelly et al., 1999). In the studies conduced by Stewart et al (1994) and Farling and colleagues (1989) propofol was reported to provide satisfactory sedation with few side effects. Stewart et al. (1994) reported that propofol provided sedation similar to a combination of midazolam and morphine with no differences in 6 month outcomes between groups. Farling et al. (1989) also reported that propofol provided safe and effective sedation. Both of these studies were small and received poor methodological scores. Further study is warranted. There is concern regarding the potential of high-dose propofol resulting in propofol infusion syndrome. Several case studies and research synthesis articles have recently been released warning of this potentially fatal side effect. Cremer et al. (2001) provided the most comprehensive report after 5 patients in their ICU died of unexplained cardiac failure on days 45 of treatment. They retrospectively assessed all patients treated in their facility from 1996-99 and identified 7 patients who died of apparent propofol infusion syndrome. Upon logistic regression, they identified a “crude” odds ratio of 1.93 (95% CI 1.12-3.32, p=0.018) for developing propofol infusion syndrome per unit (mg/kg per h) increase in propofol dose. Smith et al. (2009) conducted a similar retrospective review and identified 3 patients (out of 146) with propofol infusion syndrome (PRIS) all of whom were receiving vasopressors and propofol infusions. They report an odds ration of 29 (95% CI, 1.5-581, p<0.05) for developing PRIS while receiving both vasopressors and propofol. The authors also noted that no patient on either propofol or vasopressors alone developed PRIS. Otterspoor et al. (2008) also released a review of case reports to assess the risk factors associated with propofol infusion syndrome. They recognized large cumulative doses, young age, acute neurological injury, low carbohydrate intake, high fat intake, catecholamine infusion, corticosteroid infusion, critical illness, and inborn errors of mitochondrial fatty acid oxidation as potential risk factors. Otterspoor et al. (2008) recommend that until further research has been conducted, “4mg/kg/hr infusions should not be exceeded in patients with severe head injury and others who are in need of Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury prolonged sedation” (pg 550) .5mg/kg/hr should never be exceeded in any patients found acceptable for sedation in the ICU. Conclusions There is Level 1 evidence that propofol may help to reduce ICP and the need for other ICP and sedative interventions when used in conjunction with morphine. Propofol may help to reduce ICP and the need for other ICP and sedative interventions when used in conjunction with morphine Infusions of propofol greater than 4mg/kg per hour should be undertaken with extreme caution. 16.1.2.3 Midazolam Midazolam is a fast-acting benzodiazepine with a short half-life and inactive metabolites (McCollam et al., 1999). It is anxiolytic and displays anti-epileptic, sedative, and amnestic properties. It is a protein-bound, highly lipid soluble drug which crosses the blood brain barrier and has a rapid onset of action within 1-5 minutes in most patients (McClelland et al.,1995). However, delayed elimination of midazolam, resulting in prolonged sedation, has been demonstrated in some critically ill patients. Studies in the operating room or intensive care unit have demonstrated Midazolam to be relatively safe in euvolemic patients or in the presence of continuous hemodynamic monitoring for early detection of hypotension (Davis et al., 2001). Midazolam has been found to reduce cerebrospinal fluid pressure in patients without intracranial mass lesions as well as decrease cerebral blood flow and cerebral oxygen consumption (McClelland et al., 1995). One RCT and two non-RCTs on midazolam use in acute ABI management were reviewed. The AANS guidelines made no evidence based recommendations regarding midazolam’s efficacy but they do suggest a 2 mg test dose followed by a 2-4 mg/h infusion if used (Bratton et al., 2007b). The EBIC recommend sedation but make no specific reference to midazolam (Maas et al., 1997). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.11 Midazolam for the Management Acute ABI Author/Year/ Country/Study design/Pedro Scores Methods Outcome Sanchez-IzquierdoRiera (1998) Spain RCT PEDro = 5 N=100 Trauma patients were randomely assigned to one of three groups. Group A: was given a continuous infusion of midazolam (0.1 mg/kg/hr to a max of 0.35 mg/kg/hr); group B was given continuous IV infusion of propofol (1.5 mg/kg/hr to a max of 6 mg/kg/hr); or group C was givencontinuous infusion of midazolam (0.1 mg/kg/hr to a max of 0.2 mg/kg/hr) and propofol (1.5-3 mg/kg/hr) only if further sedation was necessary. All patients received morphine as well. Patients were monitored for sedation, hemodynamic and oximetric variables. All three regimens achieved similar sedationand incidences of adverse effects. No differences were found in ICP, CPP, or jugular venous oxygen saturation in head trauma patients. Serum triglyceride levels were significantly higher in propofol patients but wakeup time was shorter. Papazian et al., (1993) France Case Series N=12 Patients with severe head injury (GCS ≤ 6) were given bolus doses of midazolam (0.15 mg/kg i.v.). Patients were monitored for MAP, ICP, and CPP. Significant reductions in MAP (89 mmHg to 75 mmHg, p<0.0001) and in CPP (71 mmHg to 55.8 mmHg, p<0.0001) were observed. Overall, no significant change in ICP was noted. However, patients with initial ICP ≤ 18 mmHg saw increases in ICP while those with initial ICP >18 mmHg was decreases. Davis et al. (2001) USA Case Series N=219 Patients data was retrospectively reviewed in two different regions with different pre-hospital midazolam dosing protocols. North crews used 0.1 mg/kg for every patient being intubated while south crews used 0.1 mg/kg up to 5mg. Multiple linear regression was used to assess the relationship between midazolam dose and hypotension and systolic blood pressure. A significant relationship was seen between midazolam dose and both hypotension and decreased systolic blood pressure. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion Infusions of midazolam or propofol were reported to provide similar quality sedation in patients with severe head trauma, although propofol was associated with a high incidence of hypertriglyceridemia (Sanchez-Izquierdo-Riera et al., 1998). In both studies evaluating midazolam and ICP, no significant difference was seen after midazolam administration (Sanchez-Izquierdo-Riera et al., 1998; Papazian et al., 1993). However, significant hypotension related to increased doses of midazolam (Davis et al., 2001) and decreases in MAP resulting in Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury decreased CPP (especially in patients with initial ICP ≤ 18 mmHg) (Papazian et al., 1993) were also reported. The study by Sanchez-Izquierdo-Riera et al. (1998) measured ICP, CPP and MAP in all patients and reported no between group differences. However, they did not report comparisons with baseline values making it unclear whether or not midazolam resulted in any negative effects. Based on current evidence, hypotension should be monitored as a potential side effect during midazolam administration. Conclusions There is Level 2 evidence that midazolam has no effect on ICP but conflicting evidence regarding its effect on MAP and CPP. Midazolam has no effect on ICP but may result in systemic hypotension. 16.1.2.4 Opioids Opioids are substances that have morphine-like actions. They work by binding to opioid receptors, found principally in the central nervous system and the gastrointestinal tract. Each opioid has a distinct binding affinity to group(s) of opioid receptors that then determines its pharmacodynamic response. Morphine has been the most commonly used opioid following ABI, while fentanyl and its derivatives have gained popularity owing to their more rapid onset and shorter duration of effect (Metz et al., 2000). Controversy persists regarding the effect of opioids on ICP and CPP. It has been reported that opioids can increase cerebral blood flow (CBF), which may lead to an increase in ICP, (Marx et al., 1989; de Nadal et al., 2000; Werner et al., 1995; Bunegin et al., 1989) in the presence of intracranial pathology. Despite a reexamination of the literature, nothing new was found. Individual Studies Table 16.11 Opioids for the Management Acute ABI Author/Year/ Country/Study design/Pedro Score de Nadal et al., (2000) Spain RCT PEDro = 8 Methods Outcome N=30 Severe head injury patients were randomly assigned to receive morphine (0.2 mg/kg) and fentanyl (2 μg/kg) through IV for 1 minute every 24 hours in a crossover fashion. ICP, MAP, and CPP were monitored for 1 hour after administration. Cerebral blood flood was estimated using Transcranial Doppler sonography. CO2 reactivity was maintained in all patients but 18 patients showed impaired or abolished autoregulation. Both morphine and fentanyl caused significant increases in ICP and decreases in MAP and CPP. Estimated cerebral blood flow remained the same. No difference was seen in ICP increases between patients with intact autoregulation and those without. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/Pedro Score Methods Outcome Sperry et al., (1992) USA RCT PEDro = 7 N=9 Patients with severe head trauma (mean GCS 6 ± 1) received an IV bolus of fentanyl (3μg/kg) or sufentanil (0.6 μg/kg) in a randomized masked fashion. Patients then received the other opioid 24 hrs later. MAP, HR, and ICP were recorded continuously for the first hour after administration. Both fentanyl and sufentanil resulted in significant increases in ICP (8±2 mmHg and 6±1 mmHg respectively) and statistically significant decreases in MAP (11±6 mmHg and 10±5 mmHg). No changes in heart rate were noted. Karabinis et al., (2004) Greece RCT PEDro = 5 N=161 Patients were randomized to receive analgesia-based sedation (remifentanil 9 μg/kg/h and propofol 0.5mg/kg/h (days 1-3) or midazolam 0.03mg/kg/h (days 4-5)), hypnotic-based sedation (propofol (days 1-3;midazolam days 4-5) and fentanyl), or morphine. Agents were titrated to receive optimal sedation in all three cases. Sedation with remifentanil permitted significantly faster (p=0.001) and more predictable awakening for neurological assessment (p=0.024). Lauer et al., (1997) USA RCT PEDro = 5 N=15 Severely brain injured patients (GCS ≤8) randomly received fentanyl, sufentanil or morphine titrated to a maximal decrease in MAP of 10% followed by a continuous infusion of the same opioid for 4 hours. Patients were monitored for ICP, MAP, and HR. There was no increase in ICP in any group. There was a significant decrease in MAP in the sufentanil group at 10 min (p<0.05) and 45 min after initial bolus. Albanese et al, (1999) France Pre-Post N=6 Patients randomly received a 6-min injection of either sufentanil (1μg/kg), alfentanil (100μg/kg), or fentanyl (10μg/kg) followed by an infusion of 0.005, 0.7, and 0.075 μg/kg/min respectively for 1 hr. MAP, ICP, CPP, and SjvO2 were continuously measured every minute throughout the hour. All three medications were associated with significant increases in ICP peaking before 6 minutes and returning to baseline by 15 min. Increases in ICP were accompanied by decreases in MAP and thus CPP. No evidence of cerebral ischemia was noted. Scholz et al., (1994) Germany Pre-Post N=10 Head injured patients (GCS<6) received an IV bolus of sufentanil (2μg/kg) followed at 30 min by infusion of sufentanil (150 μg/hr) and midazolam (median 9 mg/hr) over 48 hrs. Pharmacokinetic and physiological measures were recorded. Decreases in ICP (16.1±1.7 mmHg to 10.8±1.3 mmHg, p<0.05) and MAP (85.53.9 mmHg to 80.2±4.9 mmHg, p<0.05) were noted. CPP remained stable. Albanese et al.,. (1993) France Case Series N=10 Head trauma patients sedated with propofol received further sedation using an IV injection of 1 μg/kg over 6 min and infusion of 0.005 μg/kg/min. MAP, ICP and end tidal CO2 were measured every Sufentanil injection resulted in a significant increase in ICP (9±7 mmHg) that peaked after 5 min and gradually returned to baseline after 15 minutes. This was accompanied by a significant Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/Pedro Score Methods Outcome minute for 30 minutes. decrease in MAP and CPP that gradually increased but remained significant throughout the study. Engelhard et al., (2004) Germany Pre-Post N=20 Head trauma patients (GCS<8) sedated with propofol and sufentanil received an IV bolus of remifentanil (0.5 μg/kg) followed by an infusion of 0.25 μg/kg/min for 20 min. Patients were monitored for MAP, ICP, CBFV using transcranial Doppler flowmetry. No differences were noted in MAP, ICP, or CBFV after remifentanil administration. Werner et al., (1995) Germany/USA Cohort N=30 Patients with severe TBI (GCS<6) received an IV bolus of sufentanil (3 μg/kg) and were monitored for 30 min. Heart rate, arterial blood gases and esophageal temperature did not change. MAP decreased greater than 10mmHg in 12 patients. ICP was constant in patients with maintained MAP, but was significantly increased in those with decreased MAP. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion Analgesic sedation with opioids is commonly used in conjunction with hypnotic agents (i.e. midazolam, propofol) to reduce nociceptive stimulation. This makes it difficult to evaluate the effects of opioids in isolation. Five studies reported increases in ICP after opioid administration (Werner et al., 1995; de Nadal et al., 2000; Sperry et al., 1992; Albanese et al., 1993; Albanese et al., 1999), while 2 found no increase (Lauer et al., 1997; Engelhard et al., 2004) and one reported a decrease (Scholz et al., 1994). However, mode of administration has been suggested as a determining factor for increases in ICP (Albanese et al. 1999 & 1993). In those studies where patients received only bolus injections of opioids, significant increases in ICP were seen (Werner et al., 1995; de Nadal et al., 2000; Sperry et al., 1992). Fentanyl and its derivatives have been suggested as more ideally suited for sedation in patients with brain injury due to their rapid onset and short duration (Metz et al., 2000). In our review, one study found remifentanil resulted in significantly faster arousal compared to propofol or midazolam (Karabinis et al., 2004). The authors suggested that this allowed for prompt neurological assessment. However, patients in the treatment group received remifentanyl as the primary sedative agent and then a hypnotic agent, while patients in the control groups received fentanyl or morphine in conjunction with a hypnotic agent. Therefore, remifentanil’s efficacy can be compared to hypnotic based sedation but not fentanyl or morphine. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Conclusions There was Level 1 evidence that bolus opioid administration resulted in increased ICP. There was conflicting evidence regarding the effects of opioid infusion on ICP levels. There was Level 2 evidence that remifentanil results in faster arousal compared to hypnotic based sedation. Bolus opioid administration results in increased ICP. There is conflicting evidence regarding the effects of opioid infusion on ICP. Remifentanil results in faster arousal compared to hypnotic based sedation. 16.2.2.5 Barbiturates It has long been proposed that barbiturates may be useful in the control of ICP. Barbiturates are thought to reduce ICP by suppressing cerebral metabolism to reduce metabolic demands and cerebral blood volume (Roberts 2000). Early reports indicated that barbiturates reduced ICP even in patients reported to be unresponsive to rigorous treatments with conventional ICP management techniques including mannitol and hyperventilation (Marshall et al., 1979). Further studies supported the therapeutic potential of barbiturates and suggested that failure to control ICP can lead to death (Rea and Rockswold 1983; Rockoff et al., 1979). However, most of these early investigations provided only anecdotal or poor evidence as they were conducted in very small cohorts of patients lacking control comparisons. More recent studies have explored the negative side effects associated with barbiturate coma such as adrenal insufficiency (Llompart-Pou et al., 2007) and bone marrow suppression (Stover and Stocker 1998). The AANS make Level II recommendations that prophylactic administration of barbiturates to induce EEG burst suppression should not be performed. They also make Level II recommendations that high-dose barbiturate administration can be used to control elevated ICP that is refractory to maximum standard medical and surgical treatment (Bratton et al., 1007). The EBIC guidelines recommend barbiturate use to increase sedation only after sedation, analgesia, hyperventilation, osmotic therapy, and CSF drainage have failed to control ICP (Maas et al., 1997). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.13 Barbiturates for the Management of Elevated Intracranial Pressure Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Eisenberg et al., (1988) USA RCT PEDro = 4 N=73 Severe head injury patient (GCS ≤ 7) were randomized to receive either high-dose pentobarbital (loading dose 10 mg/kg over 30 min, 5 mg/kg q 1 hr x 3. Maintenance dose of 1mg/kg/hr or adjusted to achieve serum levels of 34mg%) or conventional therapy (elevation of the head, hyperventilation, morphine, pancuronium, mannitol, ventricular drainage) for the reduction of ICP). Changes in ICP and survival at 30 days and 6 months were assessed. The chance of ICP control in patients with ICP refractory to conventional management was nearly double (ratio 1.94, p=0.12) for patients in the barbiturate group compared with controls. After declaration of treatment failure, 26 of the patients randomly assigned to conventional therapy were crossed over to receive barbiturates. The likelihood of survival at 1 month was 92% for those who responded to barbiturates while 83% of the nonresponders died. 80% of all deaths in each of the groups were due to uncontrolled ICP. Last follow up examination (a median of 6 months post-injury) showed that 36% of the responders and 90% of the nonresponders were vegetative or had died. Perez-Barcena et al., (2005) Spain RCT PEDro = 5 N=20 Severe traumatic brain injury patients (GCS ≤ 8) who presented with intracranial hypertension (ICP > 20 mmHg) refractory to conventional first level measures were randomized to receive either thiopental (initial bolus of 2 mg/kg over 20 seconds to reduce ICP below 20 mm Hg. If ICP did not decrease, a second bolus injection at a dose of 3 mg/kg was administered which was subsequently increased to 5 mg/kg if ICP remained elevated. Once ICP was reduced, patients received a continuous infusion at a rate of 3 mg/kg/hr) or pentobarbital (loading dose of 10mg/kg for 30 min followed by a continuous infusion at a rate of 5 mg/kg/hr for 3 hours, and then a dose of 1 mg/kg/hr for the last hour) to control refractory elevations in ICP. Changes in ICP and mortality at discharge and 6 months later were compared between groups. Successful ICP control was defined as a drop in ICP below 20 mmHg for at least 48 hours. Thiopental was able to control ICP in 50% of patients while pentobarbital was only able to control ICP in 20% (p=0.16). 50% of patients in the thiopental group died at discharge while this figure rose to 80% in the pentobarbital group (p=0.16). Perez-Barcena et al., (2008) Spain RCT N=44 Severe traumatic brain injury patients (GCS ≤ 8) who presented with intracranial hypertension (ICP > 20 mmHg) refractory to conventional first Multivariate logistic regression resulted in an odds ratio of 5.1 (95%CI, 1.2 to 21.9, p=0.027) in favour of thiopental for control of refractory ICP compared Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome PEDro = 4 level measures (BTF guidelines) were randomized to receive either thiopental (initial bolus of 2 mg/kg over 20 seconds; if ICP remained refractory (ie. >20 mm Hg) a second bolus of 3 mg/kg was administered which was subsequently increased to 5 mg/kg if necessary, followed by continuous infusion of 3 mg/kg/hr once ICP was controlled) or pentobarbital (loading dose of 10mg/kg for 30 min followed by a continuous infusion at a rate of 5 mg/kg/hr for 3 hours, and then a dose of 1 mg/kg/hr for the last hour) to control refractory elevations in ICP. to pentobarbital. The relative risk for good control of ICP was 2.26 for thiopental vs. pentobarbital in patients with focal lesions and 3.52 in patients with difuse lesions. Schwartz et al., (1984) Canada RCT PEDro = 5 N=59 Severe brain injury patients (GCS ≤ 7) who had elevated intracranial pressure (ICP > 25 torr for more than 15 minutes) were randomized to receive mannitol (20 % with an initial dose of 1 gm/kg) or pentobarbital (initial intravenous bolus of up to 10 mg/kg, followed by continuous infusion at 0.5-3 mg/kg/hr provided that cerebral perfusion pressure remained > 50 torr) initially followed by the second drug as required by further elevation of ICP (defined as failure to control ICP by the current treatment). Subjects were stratified at the outset into two groups, those with intracranial hematomas and those without. ICP and survival at 3 months were compared between groups. No significant difference in mortality of patients with evacuated hematomas in the pentobarbital or mannitol groups (40% and 43% respectively); however, in those with evacuated hematomas twice as many patients in the pentobarbital group required the mannitol to control raised ICP than did patients starting with mannitol indicating that pentobarbital is not better than mannitol for the control of ICP (p=0.04). Patients with no hematoma treated with pentobarbital as initial therapy had 77% mortality compared to 41% mortality in those treated initially with mannitol. In these patients, there was a higher rate of failure to control ICP in the pentobarbital group than in the mannitol group indicating that pentobarbital is not better than mannitol to control ICP (p<0.001). Ward et al., (1985) USA RCT PEDro = 6 N=53 Head injury patients (GCS < 8) were randomly assigned for placement into a control group (conventional ICP management measures) or a barbiturate-treated group who received intravenous pentobarbital (loading dose at 5-10 mg/kg or enough to achieve burst suppression on the electroencephalogram. After loading dose, pentobarbital was given hourly, initially as a bolus and then as a Groups were similar in terms of age, sex distribution, cause of injury, neurological status, intracranial lesions, and initial ICP. Clinical outcome on the GOS at 1 year did not differ between groups (both groups had equal number of deaths, patients with good outcome, moderate or severe disability). During the first 4 days there was no significant difference in hourly levels of ICP levels, the number of patients dying from Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome continuous infusion to achieve a uncontrolled ICP hypertension, the maintenance dose of 1-3 mg/kg duration of ICP elevation. adjusted to maintain a serum level of 25-45 mg%). Pentobarbital was started as soon as possible after the injury regardless of the ICP and continued for at least 72 hours and was then slowly discontinued. Changes in ICP and outcome on the Glasgow Outcome scale at 1 year were compared. Fried et al., (1989) USA Non-RCT N=7 ABI patients (GCS 4-8) were involved in this study in which one group received a bolus injection of intravenous pentobarbital followed by continuous infusions to achieve a serum pentobarbital concentration of 20-40 mg/L (n=4) or received conventional therapy (n=3). Measured energy expenditure (% of predicted), 24-hour nitrogen excretion and urinary 3methylhistadine excretions were assessed. Measured energy expenditure, and 24 hours nitrogen excretion were significantly lower in the pentobarbital group compared with control (p <0.01 in both cases). There was no significant difference in urinary 3-methylhistidine excretions between groups. Llompart-Pou et al., (2007) Spain Case control N=40 Patients were prospectively studied with moderate to severe TBI. Seventeen patients were treated with barbiturate coma and 23 had their ICP controlled through tier I measures and were used as a control. Adrenal function was assessed using the high-dose corticotrophin stimulation test within 24h after brain injury and after barbiturate coma induction. Within 24h, adrenal function was similar in both groups. After barbiturate coma, patients in group A (barbiturates) presented higher insufficiency vs. control (53% vs 22%, p=0.03). Patients treated with barbiturates who developed insufficiency required higher levels of Norepinephrine to maintain CPP than the barbiturate treated individuals without insufficiency. Stover & Stocker (1998) Germany Case control N=52 Patients with sever head injury were investigated. Twenty three patients did not respond to ICP treatment and were administered Thiopental at 5-11 mg/Kg b.w. as a bolus followed by continuous infusion of 4-6 mg/Kg/h to maintain a burst suppression pattern of 4-6 bursts/min. Patients were monitored for white blood cells while their tracheobronchial secretions and urine were sampled for bacterial growth. Barbiturate coma was shown to induce reversible leukopenia and granulocytopenia as well as an increased infection rate. Several patients showed suppressed bone marrow production on histological examination. Nordby and N=38 Severe brain injury patients (GCS ≤ Better GOS outcome in the thiopental Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Nesbakken (1984) Norway Non-RCT 6, all younger than 40 years of age) experiencing a progressive rise in ICP to 40 mmHg for 25 min despite intensive therapy with hyperventilation, steroids and mannitol were assigned to receive a continuous infusion of thiopental (loading dose of 10-20 mg/kg and a maintenance dose of 3-5 mg/kg/hour) and hypothermia (32-35 ºC) or to continue conventional intensive care. GOS outcome was assessed at 9-12 months post-injury. group compared with the conventional therapy group (p=0.03). Therapy with thiopental resulted in 6 patients with good/moderate outcome, 3 severe and 7 dead/vegetative. In contrast conventional therapy resulted in 2 patients with good/moderate outcomes and 13 dead/vegetative. Thorat et al., (2008) Singapore Case Series N=12 Patients with severe TBI were managed with barbiturate coma if medical therapy failed to control elevated ICP. Patients were continuously monitored for ICP, pressure reactivity and PTiO2. No significant reductions in mean ICP, MAP, CPP, PTiO2, or PRx were reported. Eight of the patients experienced reductions in ICP but only 4 below 20 mmHg. Improved oxygenation was seen in 6 of the 8 patients with PTiO2 levels greater than 10 mmHg prior to coma. Schalen et al., (1992) Sweden Case Series N=38 Patients with severe TBI who despite conventional management developed a dangerous increase in ICP were treated with high dose intravenous thiopentone (5-11 mg/kg, followed by a continuous infusion at 4-8 mg/kg/hr to achieve and maintain a burst suppression pattern on the electroencephalogram (EEG). Treatment continued until ICP decreased and remained stable below 20 mmHg for at least 12 h, or until treatment was considered to be ineffective. Changes in ICP and CPP were assessed. After induction of treatment, a fall in mean arterial blood pressure (MABP) was seen in 31 patients, in 4 patients no change occurred and a small increase was seen 3 patients. There was a simultaneous decrease in ICP in 26 patients, no change in 3 patients, and a small increase in 2 patients. CPP decreased in 18 patients, increased in 10 patients and remained unchanged in 3 patients. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion The findings of the RCT conducted by Eisenberg et al. (1988) suggest that the use of high dose pentobarbital is an effective adjunctive therapy for the management of elevated ICP refractory to conventional therapeutic measures. However, this study only supported the use of this high dose barbiturate for a small subgroup of severe ABI patients (GCS ≤ 7). In contrast, the findings of another RCT conducted by Ward et al. (1985) suggest that pentobarbital is no better than conventional ICP management measures, which was corroborated by Thorat et al. (2008) in a smaller case series. Results of the study by Ward et al. (1985) contradict those of Eisenberg et al. (1988). Schwartz et al. (1984) compared pentobarbital and mannitol for the control of ICP in Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury another RCT. Their findings support Ward et al. suggesting that pentobarbital is not better than mannitol in the treatment of ICP. Furthermore, the latter study also reported that more than half of those treated with pentobarbital developed arterial hypotension, an adverse effect that could worsen the condition of patients with severe ABI. Similarly, Schalen et al. (1992) noted that although pentobarbital may decrease elevated ICP, it may also decrease cerebral perfusion pressure due to a decrease in arterial pressure. Results of one meta-analysis suggest that although barbiturates reduced elevated ICP, there was little evidence to link this with reductions in mortality or disability. Furthermore, barbiturate therapy was associated with substantial hypotension that may have offset any ICPlowering effect (Roberts, 2000). In accordance with recommendations made by the Brain Trauma Foundation, Perez-Barcena et al. (2008) compared the efficacy of pentobarbital and thiopental on the management of refractory ICP unmanageable by conventional measures. In two linked trials (the second an extension of the first), they reported that thiopental is superior to pentobarbital in controlling refractory ICP (Perez-Barcena et al., 2005 & 2008). In the first report, thiopental was shown to help reduce refractory ICP in a greater number of patients although these differences were not statistically different Perez-Barcena et al., 2005). In a follow-up report, the authors found statistically significant results in favour of thiopental using multivariate logistic regression (Perez-Barcena et al., 2008). Even after randomization, initial CT findings were different between groups, however, the results held for patients with both focal and difuse lesions on initial CT. Similarly, Llampart-Pou et al. (2007) found thiopental less likely to induce adrenal insufficiency when compared to pentobarbitol further supporting its use when barbiturate coma is indicated. It should be noted that in a much earlier study, Stover et al. (1998), reported that use of thiopental significantly reduced white blood cell production and could induce reversible leukopenia and granulocytopenia relative to TBI patients who did not require barbiturate sedation. The authors also noticed interactions with bone marrow suppressing antibiotics (specifically, tazobactum/piperacillin) which further exacerbated problem. Therefore, in instances where barbiturate coma is indicated, monitoring of immunological response is recommended. Fried et al. (1989) conducted a study to compare the energy expenditure and nitrogen excretion in patients treated with pentobarbital and those who received conventional ICP therapy without pentobarbital. They reported that pentobarbital essentially lowered the energy expenditure and nitrogen excretion and suggest that this in turn would better enable the brain to achieve energy and nitrogen equilibrium during metabolic support of acute head-injured patients. There is some evidence that barbiturate therapy may contribute to improvements in long-term clinical outcomes. In a prospective controlled trial conducted by Nordby and Nesbakken (1984), Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury the authors reported that thiopental combined with mild hypothermia resulted in better clinical outcomes as per the Glasgow Outcome scale 1 year post-injury when compared with conventional ICP management measures (including hyperventilation, steroids and mannitol). However, since this study used a combination of thiopental and hypothermia, it is not possible to attribute the better clinical outcomes to thiopental alone. Roberts (2000), in his meta-analysis, noted that further randomized trials are needed to determine the effects of barbiturates on clinical outcomes such as mortality and disability following severe ABI. Similarly, a 1999 Cochrane review stated that there was no evidence that barbiturate use in TBI patients improved outcomes and were reported to decrease blood pressure in one of four patients, which will offset the effect of ICP reduction on CPP (Roberts 1999). Therefore, based on current evidence, barbiturate coma should be avoided until all other measures for controlling elevated ICP are exhausted. Conclusions There is conflicting evidence regarding the efficacy of pentobarbital over conventional ICP management measures. There is Level 2 evidence that thiopental is more effective than pentobarbital for controlling unmanageable refratory ICP. There is Level 2 evidence that pentobarbital is no better than mannitol for the control of elevated ICP. There is Level 4 evidence that barbiturate therapy may cause reversible leukopenia, granulocytopenia, and systemic hypotension. Based on a single study, there is Level 4 evidence that a combination barbiturate therapy and hypothermia may result in improved clinical outcomes up to 1 year post-injury. There are conflicting reports regarding the efficacy of pentorbarbital for the control of elevated ICP Thiopental is beter than pentobarbital for controlling unmanageable refractory ICP. Pentobarbital is not better than mannitol for the control of elevated ICP. Barbiturate therapy plus hypothermia may improve clinical outcomes. Patients undergoing barbiturate therapy should have their immunological response and systemic blood pressure monitored. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.1.2.6 Cannabinoids Dexanabinol (HU-211) is a synthetic, non-psychotropic cannabinoid (Mechoulam et al., 1988), thought to act as a non-competitive N-methyl-D-aspartate receptor antagonist (Feigenbaum et al., 1989) to decrease glutamate excitotoxicity. This drug is also believed to possess antioxidant properties (Eshhar et al., 1995). Dexanabinol has shown very encouraging neuroprotective effects in animal models of TBI (Shohami et al., 1995). The AANS and the EBIC make no recommendations regarding cannabinoids. Individual Studies Table 16.13Cannabinoids as an Acute Therapeutic Strategy Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Knoller et al., (2002) Israel RCT PEDro = 22 N=67 Severe head injury patients (GCS 4-8) were randomized to receive intravenous dexanabinol (50 mg or 150 mg dexanabinol/1 mL of Cremophorethanol was diluted in 100 mL of saline) or placebo (vehicle) by fast infusion (over 15 min). ICP, cardiovascular function (HR, mean arterial BP, CPP and electrocardiogram) were compared. Galveston Orientation and Amnesia Test (GOAT), GOS and DRS scores up to 6 months post-injury were used as secondary outcome measures. There were no significant differences between drug and vehicle groups in the distribution of sex, age, injury cause, injury type (single or multiple), mean time to treatment, and GCS scores. ICP in drug treated group decreased significantly on day 2 and 3 (p< 0.02 and p<0.005 respectively). ICP control achieved without lowering systemic BP. Significant reduction percentage of time CPP was < 50 mmHg in the drug treated group on days 2 & 3 (p < 0.05). No significant differences in mortality rates between groups (p = 0.54). On the GOS, drug treated patients improved faster than controls and a significantly higher percentage achieved good recovery compared with controls at 1 month (p=0.04), with a similar trend at 3 months (p=0.1) post-injury. Similarly on the DRS, a higher proportion of drug treated patients achieved no disability compared with controls. Trend toward better scores on the GOAT in the drug treated group compared to the placebo group throughout the 6 months follow up period, although the % of patients with a GOAT score of 70 (maximum = 100) plateaued at 3 months. Maas et al., (2006) The Netherlands RCT PEDro = 10 N=861 Severe brain injury patients (GCS motor score 2-5) were randomly assigned to a single intravenous injection of 150 mg dexanabinol or placebo given within 6 hours of injury. The extended GOS scores at 6 months did not differ between groups (p=0.78): 50% of patients in the dexanabinol group and 51% of those in the placebo group had an unfavourable outcome Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Trial drug was given by infusion over 15 min. ICP and CPP were measured hourly for the first 72 hours. The primary outcome was the extended GOS at 6 months. The Barthel Index (BI) and measures of quality of life (SF36 and the community reintegration questionnaire (CIQ)) were also assessed at 6 months. (odds ratio for a favourable outcome was 1.07; 95% CI 0.83 – 1.39). There were no differences in mortality, occurrence of neuroworsening, or in events related to recovery between groups. No beneficial effects of dexanabinol for improving control of ICP and CPP, BI or on quality of life measures (SF36, CIQ). PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion Knoller et al. (2002) randomly assigned 67 severe brain injury patients to receive dexanabinol (50 or 150 mg) or placebo. Their findings were encouraging in that the active drug group showed significant improvements in ICP and CPP. However, despite showing initially significant improvements on the GOS and DRS at 1 month post-treatment, these benefits progressively lost significance over the 6-month follow-up (Knoller et al., 2002). Recently, Maas et al. (2006) conducted a large-scale multi-centre RCT to conclusively establish the efficacy of dexanabinol in the treatment of ABI. In this study, 861 severe brain injury patients admitted to 86 different centres from 15 countries were randomized to receive dexanabinol or placebo within 6 hours of injury. The authors reported that compared with placebo treatment, dexanabinol did not significantly improve outcomes on the extended GOS, mortality rates, Barthel index, or quality of life measures (SF36, CIQ) at 6-months. Moreover, dexanabinol failed to provide any acute control of derangements in ICP or CPP (Maas et al., 2006). These strongly negative findings suggest that the initial benefits reported by Knoller et al. (2002) could have simply been due to the small sample size in this earlier study. Overall, this suggests that overt generalizations made from the findings of smaller RCTs should be undertaken with caution. Conclusions Based on the findings of one large-scale multi-centre RCT, there is Level 1 evidence that treatment with dexanabinol does not provide acute improvements in ICP or long-term clinical benefits post-ABI. Dexanabinol is not effective in controlling ICP or in improving clinical outcomes postABI. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.2.2.7 Corticosteroids Numerous corticosteroids have been used in brain injury care including dexamethasone, methylprednisolone, prednisolone, betamethasone, cortisone, hydrocortisone, prednisone and triamcinolone (Alderson and Roberts 2005). Using such a broad spectrum of agents within diverse patient groups has made understanding corticosteroid efficacy difficult. Adding to this difficulty is a lack of understanding regarding the mode of steroid action. Grumme et al. (1995) report that laboratory studies have associated reductions in wet brain weight, facilitation of synaptic transmission, reduction of lipid peroxidation, enhanced blood flow, preservation of electrolyte distribution, and membrane stabilization with corticosteroid use (Grumme et al., 1995). Although it had been thought that benefits could arise from reductions in ICP as well as neuro-protective activity, several studies have suggested some limitations in the use of corticosteroid. Focal lesions seem to respond well to corticosteroid therapy while diffuse intracerebral lesions and hematomas are less responsive (Grumme et al., 1995; Cooper et al., 1979). Questions regarding the safety of corticosteroid administration have been brought to light in the wake of several large scale trials. Alderson and Roberts (1997) conducted a systematic review of corticosteroid literature and concluded that there was a 1.8% improvement in mortality associated with corticosteroid use. However, their 95% confidence interval ranged from a 7.5% reduction to a 0.7% increase in deaths. This only added to the uncertainty around corticosteroid safety and prompted a large multi-center trial. Roberts et al. (2004) studied corticosteroid use in acute brain injury with the goal of recruiting 20, 000 TBI patients; after 10,008 patients were recruited it became clear that corticosteroid use caused significant increases in mortality and the trial was halted. The AANS stated that steroid use was not recommended for improving outcomes or reducing ICP and that high-dose methylprednisolone was associated with increased mortality and was contraindicated (Bratton et al., 2007c). The EBIC state that there was no established indication for the use of steroids in acute head injury management (Maas et al., 1997). Individual Studies Table 16.14 Corticosteroids for the Management of Elevated Intracranial Pressure and Neuro-protection Post ABI Author/Year/ Country/Study design/PEDro Score Roberts et al., (2004) International RCT PEDro = 10 Methods N=10,008 Patients with head injury (GCS≤14) whose physician was uncertain about administering methylprednisolone were randomized into a treatment group (48h administration) and a control group. Patients were then monitored for death Outcome Compared with the placebo, the risk of death was higher in the corticosteroid group (relative risk 1.18, p=0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0.22) or time since injury Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome within 2 weeks and death or disability at 6 (p=0.05). months. Grumme et al., (1995) Germany/ Austria RCT PEDro = 9 N=396 Patients diagnosed with head injury were randomized to a treatment group (200mg triamcinolone acetonide within 4h of trauma, then 3x40mg/day IV for 4 days, and 3X20 mg/day for 4 days) or placebo. Outcomes were measured using the GOS at discharge and 1 year after trauma. No significant difference was seen between groups although a trend towards improved outcomes in the treatment groups was noted. A significant difference was seen in the subset of patients with GCS<8 and focal lesions compared to placebo (p=0.0145) when good outcomes were compared. Dearden et al., (1986) UK RCT PEDro = 4 N=130 Severely head injured patients were randomly allocated dexamethasone (50mg on admission, 100mg on days 1,2,3, 50mg on day 4 and 25mg on day 5), or placebo. ICP and 6 month GOS scored were measured. Patients in the placebo group with ICP > 20mmHg showed significantly poorer outcomes compared to similar patients in the placebo group (p=0.0377). No other differences were noted. Gianotta et al., (1984) USA RCT PEDro = 7 N=88 Patients with a GCS ≤ 8 6 hours after nonpenetrating head trauma were given either high dose methylprednisolone sodium succinate (30mg/kg q6h x 2, then 25o mg q6h x 6, then tapering over 8 days), low dose methylprednisolone (1.5mg/kg q6h x 2, then 25 mg q6h x 6, then tapering over 8 days) or placebo. Follow-up was performed on all surviving patients at 6 months and were graded according to the GOS. At six months, no significant differences in mortality was seen between groups. There were also no significant differences in morbidity between groups. Braakman et al., (1983) Netherlands RCT PEDro = 4 N=161 Comatose patients admitted after a No significant differences were seen in 1 non-missile related head injury were month survival rates or 6 month GOS randomized to receive high-dose scores between groups. dexamethasone or placebo. Survival at one month and 6 month GOS scores were used as assessments of effectiveness. Saul et al., (1981) USA RCT PEDro = 4 N=100 Severely brain injured patients (GCS<8) were given methylprednisolone (5mg/kg/day) or no drug. GCS was measured daily while in hospital and GOS at 6-months was used as the ultimate outcome. No significant difference was seen in proportion of “good” and “disabled” outcomes compared to “vegetative” and “dead” outcomes between groups (p=0.22). Kaktis et al., (1980) USA RCT N=76 Head injured adults who were comatose on admission were randomly allocated to a high-dose groups (dexamethasone 24mg/day), low-dose No significant differences in ICP levels were seen between groups at any point within the first 72 hours after injury. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome PEDro = 4 group (dexamethasone 16mg/day), or placebo. Patients were monitored for ICP levels in 6 hour increments up until 72 hours after injury. Cooper et al., (1979) USA RCT PEDro = 8 N=76 Patients with Grady Coma Grade 3-5 were stratified for severity of injury and then divided into high dose dexamethasone (96mg/day), low dose dexamethasone (16mg/day) or placebo for 6 days. Outcome was was assessed at 6 months post treatment with a GOS scoring system. No significant improvement in outcome was seen between groups for good outcomes at 6 months, ICP patterns, or serial neurological examinations in hospital. Watson et al., (2004) USA Cohort N=404 Patients were included if one of the following criteria was met: a cortical contusion visible on CT; subdural, epidural, or intracerebral hematoma; depressed skull fracture; penetrating head wound; seizure within 24h of injury; or a GCS ≤ 10 (n=125). After controlling for seizure risk, patients treated with glucocorticoids were compared for odds of developing first and second late posttraumatic seizures with those receiving no glucocorticoids. Patients dosed with glucocorticoids within 1 day of their TBI were more likely to develop first late seizures than were those without (p=0.04,hazard ratio = 1.74) Those receiving glucocorticoids ≥ 2 days post injury had no similar associations (p=0.66, HR = 0.77). Glucocorticoid administration was not associated with second late seizure development in any group. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In light of a series of inconclusive studies into the effectiveness and safety of corticosteroid use, a very large multinational randomized collaboration for assessment of early methylprednisolone administration was initiated in 1999 (Roberts et al., 2004). In order to achieve 90% power, recruitment of 20,000 patients in the Corticosteroid Randomization after Severe Head Injury (CRASH) trial was the goal. After the random allocation of 10,008 patients, the experiment was halted. Of 4,985 patients allocated corticosteroids, 1052 died within 2 weeks compared to 893 of 4979 patients in the placebo group. This indicated a relative risk of death equal to 1.8 in the steroid group (p=0.0001). Further analysis showed no differences in outcomes between 8 CT subgroups or between patients with major extracranial injury compared to those without. The authors also conducted a systematic review and meta-analysis of existing trials using corticosteroids for head injury. Before the CRASH trial, a 0.96 relative risk of death was seen in the corticosteroid group. Once the patients from the CRASH trial were added the relative risk changed to 1.12. The authors suggest that based on this large multinational trial, corticosteroids should not be used in head injury care no matter what the severity of injury. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Two other studies assessed methylprednisolone in ABI management. Giannotta et al. (1984) conducted an RCT of patients with GCS ≤ 8 treated with methylprednisolone. Patients were divided into one of three groups: a high dose, low dose or placebo group, then assessed at 6 months based on the GOS grading system. They reported no differences in mortality rates between groups. The authors then compressed the low dose and placebo groups and performed further analyses. They found that patients less than 40 years old in the high dose group showed significant decreases in mortality when compared to the low dose/ placebo group. However, they also found no significant differences between these groups in beneficial outcomes. Even if the decreases in death are taken into account, the authors point out that decreasing mortality without decreasing morbidity may not be valuable. Saul et al. (1981) conducted another RCT where patients received methylprednisolone or no drug at all. They noted that there were no differences between the two groups for 6 month GOS scores. Grumme et al. (1995) conducted an RCT in Germany and Austria in which GOS scores were assessed 1 year after injury in patients treated with the synthetic corticosteroid triamcinolone. While no overall effect between groups was found, further analysis was performed on subsets of patients. A significant increase in beneficial outcomes was seen in patients who had both a GCS<8 and a focal lesion. The authors suggest that in light of this evidence, patients with both GCS<8 and a focal lesion would benefit from steroid administration immediately after injury. Four randomized trials were found that assessed dexamethasone in ABI. Dearden et al. (1986) assessed consecutively admitted head injured patients treated with dexamethasone. They noted that patients experiencing ICP levels > 20mmHg showed significantly poorer outcomes on the 6 month GOS scores. Braakman et al. (1983) found no differences between patients treated with dexamethasone compared to placebo in 1 month survival rates or 6 month GOS scores. Similarly, Cooper et al. (1979) performed a double blind randomized controlled study of the effects of dexamethasone on outcomes in severe head injuries. Patients were divided into three groups and no significant differences were seen in outcomes. The authors performed several post-mortem examinations and indicate that often, patients initially diagnosed with focal lesions were in fact suffering from diffuse injuries which are not amenable to corticosteroid treatment. Finally, Kaktis & Pitts (1980) assessed the effects of low-dose (16mg/day) and highdose (14mg/day) dexamethasone on ICP levels in brain injured patients. They noted no differences in ICP at any point during the 72 hour follow-up period. In a cohort study conduced by Watson et al. (2004) patients receiving any form of glucocorticoid therapy (dexamethasone 98%, prednisone 2.4%, methylprednisone 1.6%, or hydrocortisone 1.6%) were compared too patients treated without corticosteroids for risk of development of post-traumatic seizures. Their inclusion criteria allowed for patients with only one of a list of complications to be included resulting in a diverse group of TBI patients. They noted that patients receiving glucocorticoid treatment on the first day post injury were at increased risk of developing first late seizures compared to patients receiving no treatment. They also saw no improvement in patients receiving glucocorticoids after the first day. The Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury authors suggest that this ads further strength to the argument against routine corticosteroid use in TBI (Watson et al., 2004). Conclusions There is Level 1 evidence that methylprednisolone increases mortality rates in ABI patients and should not be used. There is Level 2 evidence that triamcinolone may improve outcomes in patients with a GCS<8 and a focal lesion. There is Level 1b evidence that dexamethasone does not improve ICP levels and may worsen outcomes in patients with ICP > 20mmHg. There is Level 3 evidence that glucocorticoid administration may increase the risk of developing first late seizures. Methylprednisolone increases mortality rates in ABI patients and should not be used Triamcinolone may improve outcomes in patients with a GCS<8 and a focal lesion Dexamethasone does not improve ICP levels and may worsen outcomes in patients with ICP > 20mmHg Glucocorticoid administration may increase the risk of developing first late seizures 16.1.2.8 Progesterone Progesterone has drawn interest as a potential neuroprotective agent. Animal studies suggest that progesterone modulates excito-toxicity, reconstitutes the blood brain barrier, reduces cerebral edema, regulates inflammation, and decreases apoptosis (Stein, 2008). In the human population, Groswasser et al. (1998) observed that female TBI patients seemingly recovered better than male patients and progesterone was suggested as a possible cause of this disparity Trials are now being undertaken to accurately assess the effects of progesterone in the ABI population. The AANS and the EBIC made no recommendations regarding progesterone use in ABI treatment. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.15Progesterone for Treatment of Acute ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Wright et al. (2007) USA RCT PEDro=10 N=100 Adult TBI patients (GCS 4-12) who arrived within 11 h after injury were randomized 4:1 to IV progesterone or placebo. Treatment patients received 0.71 mg/kg progesterone at 14mL/h for 1 h, then 0.5mg/kg at 10 mL/h for 11 h, and then 10mL/h maintenance infusions every 12h to a total of 3 days treatment. Patients were assessed for adverse event rates, 30-day mortality, and 30 day GOS-E scores. Adverse event rates were similar between groups and no serious adverse events were associated with progesterone. Patients in the progesterone group had lower 30-day mortality rates (RR 0.43; 95%CI 0.18 – 0.99). Moderately severe patients (GCS 9-12) in the progesterone group were more likely to have a moderate to good recovery on GOS-E (p=0.0202). Xiao et al. (2008) China RCT PEDro=7 N=159 Patients with severe TBI (GCS3-8) were prospectively randomized to receive progesterone (1.0 mg/kg via intramuscular injection b.i.d.) or placebo. Neurological outcome was measured using the GOS. Modified FIM and mortality rates were also evaluated. Patients receiving progesterone showed more favourable outcomes on the GOS at 3 months (p=0.034) and 6 months (p=0.048). Progesterone patients also had higher mFIM scores (p<0.05 and p<0.01) and lower mortality rates (p<0.05) at 3 and 6 month follow-ups. No instances of complications were found after progesterone administration. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion Two RCTs were identified that assessed progesterone use for the treatment of acute ABI. Wright et al. (2007) conducted a phase II clinical trial of progesterone for care of moderate and severe ABI patients (GCS 4-12) in response to positive clinical observations and animal trials. As a phase II trial, the initial goal was to assess the safety of progesterone administration. For this purpose, patients were allocated 4:1 to the progesterone group compared to the placebo group. Patients were monitored for any complications so that inter-group comparisons could be made. Patients in the progesterone group showed no increase in complication rates and a decreased 30-day mortality rate. Moderately severe patients in this group also showed significantly greater rates of moderate to good GOS-E scores. The authors point to limitations in sample size and group distribution as cautioning factors but feel the results are encouraging and warrant a larger, more thorough clinical trial. More recently, Xiao et al. (2008) conducted a placebo controlled RCT of progesterone use in TBI patients in China. Patients received a 5-day course of progesterone during acute management. They reported significant improvements in GOS scores, mFIM scores at 3 and 6-month followModule 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury up and decreases in mortality rates at 6 months. They also reported no complications associated with progesterone administration. These two studies suggest that progesterone is safe and effective improving patient outcomes after ABI. Further study should be performed to verify these results and identify specific indications for its use. Conclusions There is Level 1 evidence that progesterone improves GOS and modified FIM scores, and decreases mortality rates in ABI patients. Progesterone decreases 30-day mortality rates. Progesterone improves GOS and modified FIM scores at 3 and 6 months post-injury. 16.1.2.9 Bradykinin Antagonists Pharmacological interventions for the treatment of TBI generally neglect the acute phase of the injury, which is marked by an acute inflammationi that contributes to the pathology of TBI. Research has shown that any type of tissue injury or death act as strong triggers for the initiation of an inflammatory response. The kinin-kallikrein pathway is one of the components of this acute inflammatory cascade following brain injury (Marmarou et al., 1999; Narotam et al., 1998). The generation of bradykinin from this pathway leads to a detrimental cascade of events ultimately ending in altered vascular permeability and tissue edema (Francel, 1992). Upregulation of kinins following concussive brain injury in rats and blunt trauma in humans has been reported, emphasizing their importance in the pathophysiology of brain injury. Recent animal research using BK2 receptor knockout mice has demonstrated direct involvement of this receptor in the development of the inflammatory induced secondary damage and subsequent neurological deficits resulting from diffuse TBI (Hellal et al., 2003). These findings strongly suggest that specific inhibition of the BK2 receptor could prove to be an effective therapeutic strategy following brain injury. Bradycor is a bradykinin antagonist which acts primarily at the BK2 receptor (Marmarou et al., 1999; Narotam et al., 1998) making it attractive for the management of inflammation post-ABI. Anatibant is another BK2 receptor antagonist that is believed to more strongly bind to these receptors (Marmarou et al., 2005). Animal research has suggested that anatibant dampens acute inflammation, reduces brain edema, and improves long-term neurological function (Hellal et al., 2003; Kaplanski et al., 2002; Pruneau et al., 1999; Stover et al., 2000). The AANS and EBIC make no recommendations regarding bradykinin antagonists. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Individual Studies Table 16.16Bradykinin Antagonist as an Acute Therapeutic Strategy Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Shakur et al., (2009) UK RCT PEDro = 9 N=219 Subjects with traumatic brain injury (GCS ≤12) patients aged 16-65 who had received their injury less than 8 hours prior to examination. Patients were randomly administered a placebo or anatibant in a high (30mg loading dose and 15mg/day), medium (20mg loading dose and 10mg/day) or low dose (10mg loading dose and 5mg/day). For 4 days a maintenance doses was administered. Patients were followed-up for serious adverse events (SAE), mortality and morbidity (GCS, DRS, modified Oxford Handicap Scale score) 15 days post event. Due to patients’ safety issues, the tril ended early. In patients (26.3%) treated with anatibant serious adverse side effects were noted compared to those treated with placebo (19.3%). Analyses suggested that anatibant was not significantly related to causing a serious adverse side effect within 2 weeks (p=.19). Difference in GCS and Disability Rating Scale outcomes were not statistically significant (p>0.05). Marmarou et al., (2005) USA RCT PEDro = 4 N=25 Severe head injury patients (GCS 38) were randomized to receive a single dose of anatibant (LF16-0687Ms at 3.75 or 22.5 mg), a selective and potent antagonist of the BK B2 receptor or placebo. Injections were administered within 8 hr of injury or 12 hr if surgery was required. GOS at 1, 3 and 6 months postinjury, maximum ICP during the first 5 days, and CPP were compared. Given small sample size and the fact that groups were not comparable at entry, no conclusion could be drawn with respect to the efficacy of anatibant in preventing brain edema, increased ICP or decreased CPP. More patients showed improvement and favorable outcomes (good outcome/moderate disability) on the GOS at 3 and 6 months among those treated with anatibant 22.5 mg compared with the other groups (anatibant 3.75 mg or placebos). Marmarou et al., (1999) USA RCT PEDro = 8 N=139 Patients with severe TBI (GCS 3-8) were randomized to receive either Bradycor (deltibant, CP-1027 at 3 µg/kg/min) or placebo as a continuous intravenous infusion for 5 days with the infusion beginning within 12 hrs of the injury. ICP and Therapeutic Intensity Levels (TIC – the need for therapeutic interventions to control ICP) changes were compared. Long-term outcome assessed at 3 and 6 months after injury using the GOS. Percentage of time ICP of > 15 mmHg on days 4 and 5 was significantly lower in the Bradycor group compared with placebo (p=0.035). There were fewer deaths in the Bradycor group (20% vs. 27% in placebo). Patients in the Bradycor group showed a 10.3% and 12% improvement in GOS at 3 and 6 months respectively (p=0.26). Patients treated with Bradycor required less therapy for the control of ICP (mannitol, pressors, barbiturates, ventricular drainage, hyperventilation) although Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome this effect was not statistically significant. Narotam et al., (1998) South Africa RCT PEDro = 6 N=20 Patients with focal cerebral contusions presenting within 24-96 hours of closed head injury (GCS 9-14) were randomized to receive a 7-day infusion of TM CP-0127 (Bradycor 3.0 µg/kg/min) or placebo (lactated Ringer’s solution). Therapy Intensity Level (TIC – the need for therapeutic intervention to control ICP), changes in ICP, and neurological function as measured by the GCS scores were compared between groups. No differences in age, baseline GCS, initial ICP between groups was found. However, the CP-0127 group had a longer interval from time of injury to initiation of drug infusion (p=0.027).The mean rise in peak ICP from baseline was greater in the placebo group than with CP-0127 (p=0.018). The mean deterioration in GCS score in the placebo group was significantly greater than in the CP-0127 group (p=0.002). CP-0127 had a significant effect in preventing elevation of ICP (10/11 patients in contrast to the placebo group where elevated ICP occurred in 7/9 patients, p=0.005). Clinically significant neurological deterioration (higher TIC) occurred more in the placebo group than in the CP-0127 group (77% vs. 9%, p=0.005). PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion We identified two studies that evaluated the efficacy of Bradycor in the acute treatment of ABI. In the first of these studies, Narotam et al. (1998) randomly assigned a small number of patients to receive bradycor or placebo for 7 days. They reported that treatment with bradycor resulted in a significant reduction in ICP elevations. Moreover, compared with the bradycor group, patients in the placebo group experienced a greater deterioration in GCS scores over the course of the study. Furthermore, the need for other therapeutic interventions to control ICP was markedly lower in those who received bradycor (Narotam et al., 1998). A larger RCT conducted by Marmarou et al. (1999) partially confirmed the therapeutic efficacy of bradycor for ABI. Marmarou et al. (1999) reported that compared with those assigned to a placebo group, patients in the bradycor group experienced a significant reduction in intracranial hypertension (ICP > 15 mmHg). However, despite trends favouring the bradycor treatment, there were no significant differences from those treated with the placebo in mortality rates, improvements in GOS scores at 3 and 6 months, or the intensity of therapeutic interventions needed to control ICP (Marmarou et al., 1999). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury In a more recent study by Marmarou and colleagues (2005), severe head injury patients were randomized to receive anatibant (3.75 or 22.5 mg) or placebo. Anatibant is believed to be a more potent bradykinin antagonist, and this pilot trial was likely inspired by the mixed results obtained for the therapeutic efficacy of the less potent bradycor. However, due to a small sample size and a lack of baseline comparability between groups in this study, the authors were unable to draw any conclusion to support or refute the efficacy of anatibant in preventing brain edema, or deteriorations in ICP and CPP (Marmarou et al., 2005). The authors suggested that a larger trial of anatibant is likely warranted as a greater number of patients who received the higher dose of this drug showed favourable outcomes on the GOS at 3 and 6 months compared with the other groups (Anatibant 3.75 mg or placebos) (Marmarou et al., 2005). A large-scale multi-center trial of anatibant was therefore conducted by Shakur et al. (2009). Four-hundred patients within 8 hours of experiencing a severe brain injury were to be randomized to receive one of three doses of anatibant or placebo. However, the trial was halted after randomization of 228 patients due to an elevated risk of serious adverse events among patients receiving anatibant. This study appears to have been extremely problematic. A number of treatment protocols were breached and a dispute between the sponsors and the clinical trial team were ultimately dealt with in the High Court of Justice (Shakur et al., 2009). Analysis of results from those patients who were included suggested higher levels of serious adverse events in patients receiving anatibant with no improvement in mortality or morbidity. However, the authors report that there were no SAEs suspected to be related to the study drug as judged by the investigators and call for a larger trial to be conducted. Conclusions Based on the findings of two RCTs, there is Level 1 evidence that Bradycor (a bradykinin antagonist) is effective preventing acute elevations in ICP post-ABI. There is conflicting evidence to support the use of bradykinin antagonists to improve functional clinical outcomes such as the GOS. Some bradykinin antagonists prevent acute elevations in ICP but their effects on longterm clinical outcomes are uncertain. 16.1.2.10 Dimethyl Sulfoxide Dimethyl sulfoxide (DMSO) has been suggested for the treatment of elevated ICP post-ABI. It causes a strong diuresis, protects cells from mechanical damage, reduces edema in tissue through its ability to stabilize cell membranes, and is believed to act as a free radical scavenger (Kulah et al., 1990). DMSO is also believed to increase tissue perfusion thereby improving cell oxygenation, neutralizing metabolic acidosis and decreasing intracellular fluid retention (Kulah et al., 1990). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury The AANS and the EBIC make no recommendations regarding dimethyl sulphoxide. Individual Studies Table 16.17 DMSO as an Acute Therapeutic Strategy Post ABI Author/Year/ Country/Study design Methods Outcome Kulah et al., (1990) Turkey Case Series N=10 Severe closed head injury patients (GCS ≤ 6) who presented to hospital within 6 hours of injury received an intravenous bolus infusion of DMSO (50cc DMSO in 5% dextrose) when ICP was ≥ 25 mmHg. ICP, CPP, and arterial pressure were assessed pre and post-treatment. 3 of the 10 patients died due to uncontrolled ICP. In most cases DMSO reduced raised ICP within 10 minutes after the onset of infusion with a parallel increase CPP. DMSO had no effect on systemic blood pressure. There were no cardiac or circulatory disturbances following the injection of DMSO. However, DMSO caused only a temporary decrease in ICP as continuous infusions of DMSO (up to 7 days) did not prevent the ICP from returning to elevated baseline levels. Marshall et al., (1984) USA Collection of case studies No Score N=5 Severe head injury patients and 1 patient with a cortical venous thrombosis in whom ICP could not be controlled using standard methods (head elevation, hyperventilation, ventricular drainage, mannitol, barbiturates) received a rapid infusion of 10% DMSO at a dose of 1 g/kg or 20% DMSO titrated against the ICP rather than as a bolus infusion. In both cases, an upper dose limit of 8 g/kg/day was sought. All patients showed satisfactory control of elevated ICP (defined as a reduction of ICP to < 25 mmHg for more than 15 minutes) within minutes (range 2-24 minutes) after DMSO administration. However, despite initial improvements in ICP, over time, fluid overload, severe electrolyte disturbances, and an ultimate loss of ICP control occurred. Most patients experienced significant hypernatremia as a side effect. Karaca et al., (1991) Turkey & Canada Case Series N=10 Severe head injury patients (GCS ≤ 9) with elevated ICP received DMSO every 6 hours for 1-10 days (28% solution diluted with physiological saline to give a final dose of 1.2 g/kg delivered intravenously). 4 of the 10 patients also received oxygen intermittently for the first 24 hours. Acute changes in ICP and Neurological assessment at 6 days and 3 months after were evaluated. All patients showed a reduction in ICP after 24 hours and 7 had normal ICP after 6 days of treatment. Although reductions in ICP were seen within the first 30 min after DMSO administration, the effect was not sustained and most patients required maintenance doses for 2-10 days to minimize fluctuations in ICP. Neurological assessment at 6 days showed 2 patients with severe neurological deficits, 2 with moderate impairments, and 6 patients with mild to no deficit. After a 3 month follow-up, 1 patient remained severely impaired and 7 patients showed mild to no Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design Methods Outcome deficit. Discussion We identified three studies examining the effects of DMSO in the management of ICP and brain swelling post-ABI. In a study using a single group intervention design conducted by Kulah et al. (1990) 10 severe brain injury patients with elevated ICP were treated with a single bolus injection of DMSO within 6 hours of injury. The authors reported that in the majority of cases, DMSO was effective in controlling ICP elevations within minutes of injection (Kulah et al., 1990). This was followed by a concomitant increase in CPP. Unfortunately, these benefits appear to be only transient, since continuous infusions of DMSO for up to seven days failed to control elevations in ICP. In a similar study conducted by Karaca et al. (1991) 10 severe head injury patients were treated with repeated injections of DMSO for up to 10 days. The authors reported that although reductions in ICP were seen within the first 30 min after DMSO administration, the effect was not sustained and most patients required maintenance doses for 2-10 days to minimize fluctuations in ICP. The findings of Marshall et al. (1984) similarly suggest that rapid infusions of DMSO are effective in controlling elevated ICP in patients in whom ICP cannot be controlled by standard measures. Conclusions There is Level 4 evidence that dimethyl sulfoxide transiently reduces ICP elevations. Dimethyl sulfoxide may cause temporary reductions in ICP elevations post-ABI. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.2 Prompting Emergence from Coma 16.2.1 Non-Pharmacological 16.2.1.1 Sensory Stimulation It has been reported that one in eight patients with severe closed head injury suffers from prolonged coma and vegetative state following their injury (Levin et al., 1991). It has also been estimated that 50% of vegetative survivors from severe brain injuries regain consciousness within one year of their injury with up to 40% subsequently improving to a higher level on the Glasgow Outcome Scale (Task Force 1994). The idea that sensory stimulation could enhance the speed and degree of recovery from coma has gained popularity. Early studies employed single stimuli to a single sense (unimodal stimulation), whereas more current studies have focused on sensory stimulation to all the senses using various stimuli (multimodal stimulation). Neither the AANS nor the EBIC make recommendations regarding sensory stimulation in comatose brain injured patients. Individual Studies Table 16.18 Sensory Stimulation for the Management of Patients in a Coma or Vegetative State Post ABI Author/Year/ Country/Study design/PEDro Score Methods Outcome Abbasi et al., (2009) RCT Iran PEDro = 7 N=50 Comatose head injury patients (GCS 6-8) were assigned to receive a regular family visiting program or routine care. Family visits were 15 mins long for each of 6 days and were structured to include affective, auditory and tactile stimulation by family members. Patients were evaluated using the GCS at baseline and 30 minutes after each family visit by a double blinded nurse. Patients receiving family visits showed significant increases in GCS scores on each day during the study period. After six days, GCS scores in the intervention group were significantly higher (8.8 vs. 6.8, p=0.0001) Johnson et al., (1993) RCT UK PEDro = 3 N=14 Comatose severe brain injury patients (GCS ≤ 8) were randomized (within 24 hrs of hospital admission) to one of 2 groups. The experimental group received stimulation of five senses (olfactory, visual, auditory, gustatory, tactile) for 20 min/day for all of their stay in the ICU (medium stay 8.1 days) while the control group received no stimulation. GCS, state of ventilation, spontaneous eye movements, oculocephalic response, oculovestibular response were assessed daily. 3-methoxy 4-hydroxyphenylglycol levels were significantly higher in the sensory stimulation group post-treatment (p<0.006). No significant group differences post-treatment were seen in heart rate (p<0.499), or skin conductance (p<0.092). No data was provided on changes on the main outcome measure (GCS). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Catecholamine, serotonin, acytylcholinesterase, 3 methoxy 4hydroxyphenylglycol, skin conductance, heart rate were assessed 20 min pre and post treatment periods. Mitchell et al., (1990) UK Non-RCT N=24 Comatose severe head injury patients (GCS 4-6) were assigned to 2 groups matched for age, gender, type and location of injury, and GCS score at admission. Group I received Coma Arousal Procedure (CAP) involving vigorous sensory stimulation including auditory, tactile, olfactory, gustatory, visual, kinesthetic propioceptive and vestibular stimulations in a sequential order. Each of the 5 sensory modalities were stimulated in a cyclical manner for about 1 hour 1-2 times/day. Group II acted as the control, receiving no sensory stimulation at all. Duration and degree of coma and the GCS were used to assess outcomes. Duration and degree of coma and the GCS were used to assess outcomes. The duration of coma for the CAP group was significantly shorter than the total duration for the control group (p<0.05). Davis and Gimenez (2003) USA Non-RCT N=12 Comatose severe brain injury male patients (GCS ≤ 8) who had suffered a their brain injury at least 3 days earlier and who had a Rancho Los Amigos (RLA) score between Level I and Level III (unresponsive to sensory stimuli or responding at a low or inconsistent level to sensory stimuli) were assigned to a structured auditory sensory stimulation program including 1) orientation and commands, 2) bells, blocks and claps, 3) music, 4) familiar voices, and 5) television or radio or to receive no stimulation. Participants received 5-8 stimulation sessions/day lasting 5-15 min each depending on type of stimuli for up to 7 days. Outcomes were assessed using the GCS, sensory stimulation assessment measure (SSAM), RLA scale, DRS. Mean daily GCS scores were not statistically different between groups (however, the treatment group’s were lower and rose over time, while the control group’s was higher and decreased over time). Difference between groups on SSAM scores before and after arousal was statistically significant (p = .015). RLA change score for the intervention group was 1.2, but no change was found in the control group. DRS improvements from baseline to discharge were significantly better in the intervention group compared with the control group (p = 0.0005). Kater (1989) USA Non-RCT N=30 Acute brain injury patients known to have experienced impaired cognition (cognitive functioning level < 8 in the Rancho Los Amigos scale) and hospitalized for a minimum of 2 weeks prior to entering the study were assigned to receive Patients in the experimental treatment group had a significantly improved cognitive level score 3 months post injury compared with controls (6.33 vs. 4.40, p < 0.05). Cognitive functioning level varied inversely with coma severity (based on Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome controlled structured sensory-stimulation (visual, auditory, olfactory, gustatory, tactile, and kinesthetic stimulation for 45 min 2x/day and 6days/week for 1-3 months) or nursing care that did not include planned structured sensory stimulation. Patients in both groups were matched one to one on the basis of sex, age, approximate type of injury, GCS score, and length of time since injury. The Rancho Los Amigos Scale (RLA) was used for outcome assessment 3 months post injury. initial GCS score). Subjects with moderate and deep coma severity (GCS 3-10) seemed to benefit the most from the sensory stimulation, while subjects with light coma severity showed little difference from the corresponding control subjects. The type of pre-injury environment was also correlated with outcome 3 months after treatment, with subjects coming from enriched environments showing significantly improved cognitive levels compared with subjects coming from non-enriched environments (p<0.05). Hall et al., (1992) Canada Non-RCT N=6 Comatose severe closed head injury patients (GCS ≤ 8) who acted as their own control received alternating weeks for 30 min per day of Specific Directed Stimulation (SDS) involving multisensory input at the subject’s level of responding and nondirected stimulation (NDS) involving stimulation not specific to the patient’s level of responding. Eye opening, motor movements, vocalizations/verbalization were rated using the Rader Scale. GCS, Rancho Los Amigos levels, and the Western Neuro Sensory Stimulation Profile (WNSSP) were also rated. Quality of responses was greater during the SDS condition. Subjects obtained higher Rader scores for eye movements during the SDS condition than during the NDS condition. General improvement on the WNSSP over the course of the treatment for both conditions, with subjects improving from 20% to 80% by the end of the treatment. General improvement on the GCS and Rancho Los Amigos levels under both conditions over the course of the treatment. Gruner and Terhaag (2000) Germany Pre-Post N=16 Severe head trauma patients (GCS < 8) with coma for at least 48 hours received multimodal early onset sensory stimulation (acoustic, tactile, olfactory, gustatory, and kinesthetic) administered daily in 2 units of 1 hour each. Vegetative parameters (e.g. heart and respiratory frequency) were assessed pre and post treatment. Significant changes in heart and respiratory frequencies werenoted, with the most significant changes being found following tactile and acoustic stimulation. No statistical comparisons were reported. Wilson et al., (1996) UK Pre-Post N=24 ABI patients who were in vegetative state were subjected to multimodal (stimuli to each of the senses in turn during each treatment session) and unimodal (stimuli to one sensory modality only within a treatment session) stimulation. Familiar personal items (i.e. favorite perfume, favorite sound) were also used with both multimodal and unimodal stimulation. Frequency with which eyes were observed opened increased significantly following multimodal (p<0.001) and multimodal familiar (p<0.05) stimulation; whereas no significant changes were seen following unimodal stimulation. Significant increases in the frequency of spontaneous movements with eyes opened following multimodal (p<0.005), Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome Treatments administered in 3-week blocks, (2 treatments/day) until subjects were no longer in vegetative state or until they were discharged. Behaviours pre/post treatment that suggested increased arousal were used to assess outcome: eyes shut and no body movement, eyes shut and reflexive body movement, eyes shut and spontaneous body movements, eyes open no body movement, eyes open and reflexive body movement, eyes open and spontaneous body movement, engaged in activity and vocalization. unimodal (p<0.05) and multimodal familiar stimulation (p<0.05). Significant decrease in frequency of eyes shut with no body movement following both multimodal (p<0.005) and multimodal familiar stimulation (p<0.05). Significant reduction in reflexive movements with eyes shut following multimodal stimulation (p<0.025). Greatest changes in behaviour achieved through multimodal stimulation, Wood et al., (1992) USA Non-RCT N=8 severe closed head injury patients (GCS 9-10) were divided into 2 groups matched for age, gender, type of injury, time since injury, GCS scores, and Rancho Los Amigos scores at admission. Both groups of patients were retrospectively recruited from the same rehab centre before (control group) and after (experimental group) the implementation of the specialized sensory regulation procedure (SSRP). The SSRP involved sensory stimulation with low ambient noises, regular rest intervals free from any kind of stimulation, and appropriate interstimulus intervals during therapy. The control group received standard sensory stimulation in an unregulated manner. The GCS, Rancho Los Amigos scale were assessed at baseline (4 days following admission) and before discharge (4 days before discharge). Average length of stay in the experimental group was 88.7 days compared with 125.7 days in the control group. The experimental group made greater progress on GCS and Rancho Los Amigos scores compared with the control group. All patients in the experimental group progressed into an acute rehab setting compared with only one of the control patients (the other 3 control patients returned to their families where they required total care from family, visiting nurses and care attendants). No statistical comparisons reported. Pierce et al., (1990) USA/Australia Case-Control N=31 Individuals, who has sustained a severe head injury (GCS < 6) and had a prolonged or persistent vegetative state for at least 2 weeks were included in the study. Patients were treated with a coma arousal intervention involving a sequence of vigorous multisensory stimulation (auditory. vestibular, visual and cutaneous) provided by close family relatives for up to 8 hrs/day 7 days/week continuing until the patient was accepted for conventional rehabilitation therapy. Results were compared with those of a historical group Within the various time periods, the number patients who emerged from the coma did not differ significantly between groups. No significant differences were found in reasonable recovery between coma arousal group and the historical control group (42% vs. 31%, p>0.025). No significant improvements were noted in either the time to obey simple commands (p>0.2) or in the GOS (p<0.25) Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design/PEDro Score Methods Outcome of similar patients (n=135) from a previous publication who did not receive this intervention. Duration of coma and the GOS at 10-12 months post-injury were compared. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Table 16.18a Summary of Studies of Sensory Stimulation to Promote Emergence from Coma or Vegetative State Post ABI Authors Methods Results Abbasi et al., N=50 Family visits program for tactile, + for higher GCS scores each day and overall (2009) auditory and affective stimulation 15min/day for 6 days vs. routine care. Johnson et al., N=14 Sensory stimulation to all five + for higher 3-methoxy 4(1993) senses 20 min/day for the length of hydroxyphenylglycol levels stay in the ICU (median 8.3 days) vs. no sensory stimulation. Note: No data provided on the primary outcome (i.e. GCS) Mitchell et al., N=24 Coma Arousal Sensory + for reduction in duration of coma (1990) Stimulation Procedure (auditory, tactile, olfactory, gustatory, visual, kinesthetic propioceptive and vestibular stimulations) for 1 hour 1-2 times/day for up to 4 weeks vs. no sensory stimulation at all. Davis and N=12 Structured auditory sensory ND for mean daily GCS scores Gimenez (2003) stimulation program vs. no stimulation + for SSAM scores for 5-8x/day for 7 days. + for DRS scores Kater N=30 Controlled structured sensory+ for RLA cognitive levels (1989) stimulation to all senses for 45 min 2x/day 6days/week for 1-3 months vs. standard nursing care. Hall et al., N=6 Specific Directed Stimulation (SDS) + Rader scores for eye movements (1992) involving multisensory input at the ND on the WNSSP subject’s level of responding vs. nonND on the GCS directed stimulation (NDS) involving ND on the RLA stimulation not specific to the patient’s level of responding (control) for 30 min/day. Grunner and N=16 Multimodal early onset sensory + for heart rate and respiratory changes Terhaag (2000) stimulation (acoustic, tactile, olfactory, gustatory, and kinesthetic) Note: no statistical comparisons reported for administered daily in 2 units of 1 hour this study. each. Wilson et al., N=24 Multimodal (stimuli to each of + for frequency of eye opening with Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury (1996) the senses in turn during each treatment session) and unimodal (stimuli to one sensory modality only within a treatment session) stimulation in 3-week blocks, 2 treatments/day until subjects where no longer in vegetative state or until they were discharged. Wood et al., (1992) following multimodal stimulation + for frequency of spontaneous movements following unimodal and multimodal stimulation + for reduction in eyes shut with no body movements following multimodal stimulation + for reduction in reflexive movements with eyes shut following multimodal stimulation + for shorter length of stay + for greater progress on the GCS and RLA scale N=8 Specialized sensory regulation procedure (SSRP) involving sensory stimulation with low ambient noises, regular rest intervals free from any kind of stimulation, and appropriate inter-stimulus intervals during therapy Note: no statistical comparisons reported for vs. standard sensory stimulation in an this study. unregulated manner (control). Pierce et al., N=31 Multisensory stimulation ND for number of patients emerging from (1990) (auditory. vestibular, visual and coma; ND for time to obey simple cutaneous) provided by close family commands; ND for GOS scores relatives for up to 8 hrs/day 7 days/week vs. no stimulation at all in a retrospective group. ND = No difference between groups; + = Improvement compared with control; - = Impairments compared with control Discussion One of the major challenges for sensory stimulation to promote emergence from coma is that outcome assessment measures are often qualitative and more difficult to assess. With this in mind, Rader et al. (1989) developed the Sensory Stimulation Assessment Measure (SSAM), based on the Rancho Los Amigos Levels of cognitive functioning, in an attempt to better quantify the efficacy of sensory stimulation. This measure was used in one of the studies located (Hall et al., 1992). A meta-analysis of sensory stimulation for comatose or vegetative state ABI patients found only three clinical trials that used rigid experimental designs to meet the desired inclusion criteria (Lombardi et al., 2002). The authors noted that these studies varied widely in terms of outcomes measured, treatment and experimental design making it impossible to carry out a conventional quantitative synthesis of the data. Instead, this Cochrane review provided an unconventional qualitative analysis of these studies. The authors concluded that there was no reliable evidence to support or refute the efficacy of sensory stimulation programs for patients in a coma or vegetative state post ABI. Since the release of this review, few new studies have been published in this area. However, in a well designed trial, Abbasi et al. (2009) conducted an RCT to evaluate the effect of sensory stimulation through structured family visits on consciousness as assessed by the GCS. Families received training on coma; how to provide appropriate stimulation and how to remain calm. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Patients receiving family visits showed significantly greater GCS scores on each day of the intervention and attained a mean GCS that was 2 points higher than the control group. Although no long-term outcomes were evaluated and no follow-up was reported, these results suggest that family provided stimulation may be an effective intervention for stimulating recovery from coma. In the only other RCT identified on this topic, Johnson et al. (1993) randomly assigned patients to a group that received multimodal sensory stimulation or to a group received no purposeful sensory stimulation at all. The primary outcome in this study was changes in the GCS posttreatment. However, Johnson et al. (1993) did not report any data on this measure and only presented data on biochemical and physiological parameters of questionable clinical importance. The strength of the study findings have been questioned due to the “poor” methodological score (PEDro = 3); conclusions, were not based upon the study’s findings Overall, the studies identified in this area generally show greater improvements in a variety of measures following multimodal sensory stimulation. Some studies aimed to investigate if the duration of coma could be reduced using sensory stimulation as their only objective. For example, Mitchell et al. (1990) reported that patients subjected to multimodal sensory stimulation experienced significant reductions in the duration of coma compared with controls. Again, duration of coma was their only outcome and in the absence of other measures of clinical importance, such as functional indicators (i.e. GOS or DRS scores), such results fall short in demonstrating any clinical functional benefit of sensory stimulation. A 2002 Cochrane review showed similar results stating that there was insufficient evidence to refute or support the use of multisensory programs for patients in coma or vegetative state (Lombardi et al., 2002). Sensory stimulation is usually an intervention that provided in addition to standard care and yet there have been a paucity of RCTs. However, as demonstrated by Abbasi et al. (2009) it is feasible to randomize patients to one of these two options. Further research is needed. Conclusions There is Level 1b evidence that multimodal sensory stimulation provided by family members improves consciousness of severe ABI patients with GCS 6-8. There is Level 2 evidence to suggest that sensory stimulation may improve clinical outcomes, physiological parameters, and behaviours indicative of emergence from coma post ABI. Sensory stimulation provided by family members improves consciousness for patients with GCS 6-8. Sensory stimulation may help to promote emergence from coma or vegetative state post ABI. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.2.1.2 Music Therapy Musical sounds stimulate the auditory pathway and activate emotional functions in the brain. If the music is familiar to the patient (i.e. a favorite song) then the stimuli can become meaningful for the patient. Anecdotaly, it has been noted that music therapy could specifically be used to encourage arousal from coma post-ABI. We identified two studies which used music therapy as a specific treatment to encourage emergence from coma post-ABI. The AANS and EBIC make no recommendations regarding music therapy. Individual Studies Table 16.19 Music and Musicokinetic Therapy for Patients with Coma or Vegetative State Post ABI Author/Year/ Country/Study design Methods Outcome Noda et al. (2004) Japan Pre-Post N=26 patients with persistent vegetative state (12 head trauma, 9 subarachnoid hemorrhage, 3 stroke and 2 cases of encephalopathy) received musicokinetic therapy (MKT) that involves vertical motions on a trampoline and live music in synchrony with the vertical motion. Following this, the patient lay on the trampoline and received massage therapy for 5 minutes while listening to slow music. Patients underwent these steps for 40 minutes 1/week for 3 months. Persistent Vegetative State (PVS) score was determines before and 3 months after the sessions. The PVS scoring system had been proposed by the Society for Treatment of Coma (Japan). After MKT PVS scores were significantly better compared with pre-MKT scores (p<0.001). Patients whose brain damage was caused by trauma or subarachnoid hemorrhage demonstrated larger improvements in their PVS scores compared with patients who suffered stroke or anoxic encephalopathy. Time elapsed after brain damage was not correlated to the pre-MKT scores (p=0.873), but it was negatively correlated to the post-MKT scores (p=0.029). MKT was most effective when initiated within 6 months of injury compared to when initiated > 6 months post-injury. Wilson et al. (1992) UK Collection of case studies No Score N=4 ABI patients (age ranged from 15-29) who were in vegetative state received various forms of stimulation over 23 consecutive days. Patients received one stimulation session every morning and afternoon and they received 15 sessions of each of three treatments: unimodal (one sense only), multimodal (all senses stimulated) or music therapy (well pronounced rhythm and speed in excess of 60 beats/minute from music belonging to the patient). Pre and post-treatment behaviour was scored as follows: eyes shut 2/4 patients showed significant increases in eyes opened with body movement following music therapy. 3/4 subjects also showed significant increases in activity following multimodal but not unimodal stimulation. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/Study design Methods Outcome with no body movement, eyes open with no body movement, engaging in activity. Discussion No RCTs were identified in this area and the only two studies included were generally of weaker methodological quality. Noda et al. (2004), used an innovative approach to treat patients with what they termed “musicokinetic therapy”. This involved vertical motions on a trampoline and listening to live music in synchrony with the vertical motion. The rationale for this approach was that this therapy should result in the activation of multiple pathways within the brain simultaneously to more effectively promote awareness of environmental stimuli. Outcome assessments were based on the Persistent Vegetative State (PVS) scoring system proposed by the Society for Treatment of Coma of Japan in 1997. The authors reported significantly better PVS scores post-treatment (Noda et al., 2004). Treatment was most effective when initiated within 6 months of injury compared to when initiated > 6 months post-injury (Noda et al., 2004). Despite these positive findings, the practicality of providing this therapy to multi-trauma patients is questionable. The inherent physical stress involved with jumping on a trampoline could potentially exacerbate physical injuries to other organs. The other study identified was a collection of 4 case studies of patients who received a combination of unimodal, mulitimodal and music therapy (Wilson et al., 1992). The authors reported that half of the patients showed an increased in the frequency of behaviours suggestive of emergence from coma following music therapy. Conclusions There is Level 4 evidence that music therapy as an adjunct to other modes of sensory stimulation may be used to promote emergence from coma post ABI. Music therapy might be useful in promoting emergence from coma post ABI. 16.2.1.3 Electrical Stimulation Electrical stimulation is a common therapeutic approach used in the rehabilitation of a variety of diseases of the nervous system. Some reports have proposed that electrical stimulation may be beneficial in severely brain injured patients. It is believed that electrical stimulation applied peripherally may stimulate the reticular activating centre and cortical areas responsible for consciousness and arousal (Peri et al., 2001). Stimulation of the median nerve has been shown to cause significant increments in blood flow and improved electroencephalogram activity (Cooper et al., 1999). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury The AANS and the EBIC make no recommendations regarding electrical stimulation. Individual Studies Table 16.20 Electrical Stimulation Post ABI Author/Year/ Country/Study design/ Score Methods Outcome Cooper et al., (1999) USA RCT PEDro = 4 N=6 Comatose TBI patients (GCS 4-8) were randomized to receive right median nerve stimulation (asymmetric biphasic pulses at an amplitude of 20 mA with pulse width of 300 µs at 40 Hz for 20 sec/min) or sham stimulation for 8-12 hrs/day for a period of 2 weeks. Stimulation started when the patient’s medical condition stabilized and within 1 week of admission. GCS, days spent in the intensive care unit, and GOS 1 month post-injury were compared between groups. At 1 week, the treated group improved by an average of 4.0 on the GCS compared with an average increase of only 0.7 in the controls. By 2 weeks, the treated group improved by an average of 6.4 on the GCS compared with 1.3 for the control group. The treated group stayed in the ICU for an average of 7.7 days compared with 17.0 days for the control group. The GOS for the treated group averaged III compared with II for the control group. No statistical comparisons were reported. Peri et al., (2001) USA RCT PEDro = 6 N=10 Comatose non-penetrating TBI patients (GCS 3-8) were randomized to receive median nerve electrical stimulation (300 ms intermittent pulses, 20 seconds on and 40 seconds off at 40 Hz 8 hours/day for each day in coma for up to 14 days) or sham stimulation to the patients’ dominant arm. GCS was used to assess the emergence from coma (defined as GCS ≥ 9) and was compared between groups. The GOS and the FIM/FAM were also assessed 3-months post-injury. The treatment group emerged from coma on average 2 days earlier than the control group, however this difference was not significant (p=0.31). There was no significant difference between groups in GOS or FIM/FAM scores, although there was a trend for more improvement in the electrical stimulation group. Liu et al. (2003) Taiwan Pre-Post N=6 patients (2 brain trauma, 1 aneurysm rupture, 1 hemorrhagic stroke, 2 hypoxic encephalopathy) received right median nerve stimulation (asymmetric biphasic pulses at an amplitude of 20 mA with a pulse width of 300 µs at 35 Hz for 20 sec on/50 sec off). Stimulation was performed for 10 hours (comatose patients) or 8 hours (once a patient became conscious) per day during the daytime for 3 months. Cerebral perfusion using SPECT scan and dopamine levels were evaluated before, and one and three months after electrical stimulation. Significant increase in cerebral perfusion bilaterally in all patients following stimulation. 4 patients regained consciousness within 35 days after initial stimulation. Dopamine levels were elevated in the majority of patients following stimulation. Young patients (< 40 years of age) had better results than older patients. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Discussion Three studies which investigated the efficacy of median nerve electrical stimulation in promoting emergence from coma were identified. In the first of these studies, severe TBI patients were randomized to receive right median nerve stimulation or sham stimulation for 812 hours per day for a period of 2 weeks (Cooper et al., 1999). This study lacked statistical comparisons and provided more of a qualitative analysis. The authors reported that the treated group seemed to show better improvements on the GCS, GOS and showed shorter lengths of stay in the intensive care unit compared with sham-stimulated controls (Cooper et al., 1999). The lack of statistical group comparisons weakens any conclusions that could be drawn from these findings. Peri et al. (2001) randomly assigned comatose severe TBI patients to receive radial nerve electrical stimulation or sham stimulation on their dominant arm 8 hours per day for up to 14 days. Unlike the seemingly positive findings reported by the previous study, Peri et al. (2001) reported that median nerve electrical stimulation did not significantly improve the duration of coma, GOS or FIM/FAM clinical scores. The third study employed a single group intervention design and reported that median nerve electrical stimulation caused considerable increments in cerebral perfusion which appeared to be coupled with elevations in dopamine levels (Liu et al., 2003). Dopamine has been involved in the regulation of consciousness (Krimchansky et al., 2004). However, the authors failed to demonstrate a direct correlation between dopamine levels and increased levels of consciousness. Conclusions There is Level 1b evidence that median nerve electrical stimulation does not improve emergence from coma post-ABI. Median nerve electrical stimulation does not improve emergence from coma post-ABI. 16.2.2 Pharmacological Interventions 16.2.2.1 Amantadine Amantadine is a Dopamine agonist that acts both pre and post-synaptically to up-regulate Dopamine activity (Meythaler et al., 2002). Dopamine is thought to be involved in frontal lobe stimulation and plays a role in behavior, mood, language, motor control, hypothalamic function and arousal (Sawyer et al., 2008). Amantadine was initially developed for prophylactic use as an antiviral agent in the prevention of influenza A, but is now in common use in the treatment of Parkinson’s disease. Amantadine’s properties as a potential neuro-active agent were quickly recognized (Zafonte et al., 2001) and there is now interest in its use as a potentially useful Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury treatment in the management of ABI (Schneider et al., 1999). Researchers believe that amantadine could significantly improve arousal in comatose patients. Potential side effects, which are easily reversible, include over-stimulation, peripheral edema, livido reticularis, and lowering of the seizure threshold (Schneider et al., 1999). The favorable risk-benefit profile of amantedine suggests that it may be an attractive treatment option for inducing arousal from coma (Hughes et al., 2005). Neither the AANS nor the EBIC have made recommendations regarding amantadines use in ABI management. Individual Studies Table 16.21 Amantadine for Arousal from Post ABI Coma Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome Adults Meythaler et al., (2002) USA RCT- cross-over PEDro=6 N=35 Patients with severe TBI related diffuse axonal injury (GCS <11) were randomly assigned to a placebo controlled crossover design trial. Patients were administered 200mg amantadine or placebo daily for 6 weeks and then the opposite for the next 6 consecutive weeks. Outcome measures included the Disability Rating Scale, Mini Mental Status Exam, Glascow Outcome Scale, Galveston Orientation and Amnesia Test, and the Functional Independence Measure (cognitive). In group one (amantadine first), there was an improvement in MMSE scores of 14.3 points (p=.0185), DRS of 9.8 points (p=0.0022), GOS of 0.8 points (p=0.0077), and FIM-cog of 15.1 points (p=0.0033) but no improvement in the second six weeks on placebo (p>0.05). In group two (placebo first), there was an improvement of MMSE of 10.5 points, in the DRS of 9.4 points (p=0.0006), GOS of 0.5 points (p=0.0231), and FIM-cog of 11.3 points (p=0.003, Wilcoxon signed rank) spontaneously on placebo. In the second six weeks, group two also continues to make significant gains in MMSE (6.3 points, p=0.409), DRS (3.8 points, p=0.0099), and FIM-cog (5.2 points, p=0.0173 Wilcoxon signed rank). Hughes et al., (2005) Canada Chart Review N=123 Some patients admitted over a 10year period who remained in coma after becoming medically stable were administered 100-200 mg of amantadine twice daily. Charts for these patients were compared with charts from those who did not receive amantadine and emergence from coma was reviewed. No significant difference in the number of patients emerging from coma was seen between groups (p=0.42). Somatosensory evoked potential (SSEP) was identified as a significant predictor of emergence (p=0.02). Saniova et al., (2004) N=74 Patients with severe head injury (GCS<8) were retrospectively identified Patients treated with amantadine showed significant improvement on Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores Methods Outcome Slovak Rep. Chart review as having been treated with amantadine or not. Groups were assessed for differences in discharge GCS and mortality rates. discharge GCS scores (p<0.0001) and decreased mortality (p<0.001). Whyte et al., (2005) USA Cohort N=47 In this longitudinal observational study, comatose brain injured patients (GCS 3-8) were retrospectively reviewed for exposure to amantadine and assessed for impovements in Disability Rating Score (DRS) and time until commands were followed. Patients receiving amantadine showed significant improvements in DRS scores in the first week following administration (p<0.01) which remained in the second week post treatment (p=0.06). Peadiatric Population Vargus-Adams et al., (2010) USA RCT PEDro = 6 N=7 Children aged 5-18years who were in a vegetative or minimally conscious state were involved in a study of amantadine to determine the effects on the level of consciousness post-ABIT. Participants were randomly assigned to receive either treatment or placebo. The study proceeded over 7 weeks: 3 weeks intervention, 1 week for washout followed by the same 3 week intervention. Those receiving amantadine, a maximum dose of 4mg/kg was given for the first week and during the second and third week they received a maximum daily dose of 6mg/kg. The Coma Near Coma Scale and Coma Recovery Scale Revised were used 3 times a week to assess the level of consciousness of the participants. Results found that higher doses of amatadine is well tolerated by ABI children and may be associated with improving the recovery of consciousness in ABI children who are in a vegetative or minimally conscious state. McMahon et al., (2009) USA RCT PEDro = 7 N=7 Children with ABI were randomized to receive either amantadine or placebo for 3 weeks followed by a wash-out week and three weeks of the other agent. Patients were evaluated on the coma/near-coma scale (CNCS) and the coma recovery scale-revised (CRS-R) three times per week as well as weekly subjective evaluations by arousal and consciousness weekly. No significant differences were noted in the slopes of recovery between the two agents on either of the outcome scales. Improvements in consciousness were noted by the physician during weeks when amantadine was given. Patrick et al., (2006) USA RCT N=25 Children and adolescents with severe TBI (Rancho Los Amigos Scale level <4) who remained in a low response state at least 1 month post-injury were The weekly rate of change was significantly better on all three measures on medication than off medication (p<0.05). Rancho Los Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Author/Year/ Country/ Study design/ PEDro Scores PEDro=7 Methods Outcome randomized to receive either amantadine Amigos Scale levels also improved or pramipexole. Subjects were evaluated significantly on medication (p<0.05). with the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale at baseline and weekly. PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002). Discussion In the only RCT regarding amantadine’s effectiveness for improving consciousness in adults, Meythaler et al. (2002) randomly assigned patients to receive amantadine or placebo for 6 weeks with a crossover to the other for a second 6 week period. All patients had suffered severe TBI related diffuse axonal injuries. Patients were assessed for several indicators of alertness and cognitive function. They found that patients who received amantadine initially made significant gains on all outcome measures but made no further gains when they were switched to placebo. Patients assigned to the placebo group initially made smaller but still significant gains when on the placebo but then went on to make further improvements on the Disability Rating Scale, Mini Mental Status Exam, Galveston Orientation and Amnesia Test, and the Functional Independence Measure (cognitive) in the second 6 week period after amantadine induction. The authors note that although patients who had received placebo made some natural recovery, patients receiving amantadine made more pronounced improvements. Furthermore, the improvements made by patients receiving amantadine in the second 6 week period suggests that amantadine aids in recovery no matter when it is administered. Three other studies were located which assessed amantadine. Hughes et al. (2005) conducted a chart review of all comatose brain injured patients admitted over a 10-year period in which patients who received amantadine were compared with a control group of patients who did not receive amantadine. They noted that patients receiving amandatine were no more likely to emerge from coma (p=0.42). The authors caution of potential confounders, such as potential selection bias, which may have affected the results. Also, the point at which a patient was considered to have emerged from the coma was arbitrarily assessed. Whyte et al. (2005) also conducted a retrospective review of comatose patients who received amantadine. They isolated patients who received amantadine in weeks 4-16 post injury to assess its potential in improving consciousness after medical stability was reached. They noted that patients who received amantadine showed significant improvements in DRS scores one week after administration when compared to patients treated by other methods. They also measured the time to first response to directions in which they saw no significant difference in amantadine patients. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury Results of a chart review found patients who were treated with amantadine as a component of standard therapy showed significant improvements in GCS at discharge and decreased mortality rates compared to those who did not receive amantadine (Saniova et al., 2004). While the retrospective nature of these three studies makes it difficult to draw conclusions, all three authors suggest that amantadine is a safe option with promising potential and that further study is warranted. Three randomized trials of amantadine use in children were located. In a RCT, conducted by Vargus-Adams et al. (2010) ABI children participated in a study to determine the effectiveness of amantadine to improve the level of consciousness. It was found that amantadine may be beneficial to improving the recovery of consciousness in ABI children. In an earlier study, children were administered amantadine or placebo for three weeks followed by the opposite for three weeks (McMahon et al., 2009). Although two patients drop out of the study, the authors reported no significant differences in coma recovery during amantadine administration. These two drop-outs along with the small number of subjects may have masked any potential improvements. The authors suggest that amantadine did indeed show signs of improving consciousness and should be studied further. In the second study, Patrick et al. (2006) conducted a randomized trial in which children and adolescents who remained in a low-responsive state 1 month post-injury were assigned to receive amantadine or pramipexole (both dopamine agonists). Patients in both groups made significant improvements on the Coma Near Coma Scale, the Western NeuroSensory Stimulation Profile, and the Disability Rating Scale weekly gains. Patients also improved on Rancho Los Amigos Scale level. There were no significant side effects to treatment which, combined with the positive results, suggest that dopamine agonists may be a viable option for coma arousal in children and adolescents. However, the lack of control group and small sample size warrant further study before conclusions are drawn. Conclusion There is Level 1b evidence that amantadine may improve levels of consciousness and cognitive function in patients in various stages of coma. There is Level 1a evidence that amantadine improves the level of consciousness in children post ABI. There is Level 1b evidence, from one RCT, that amantadine and pramipexole improves the levels of consciousness in TBI children and adolescents. Amantadine may improve consciousness and cognitive function in comatose ABI patients. Dopamine enhancing drugs may facilitate rate of recovery post traumatic brain injury in Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury children; however, due to the small sample sizes more definitive research is needed. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.3 Summary 1. There is Level 2 evidence suggesting a 30° head elevation reduces intracranial pressure with concomitant increments in CPP. 2. There is Level 2 evidence to suggest head elevation does reduce ICP in children post TBI; however, it was not found to have a significant impact of CPP. 3. There is Level 2 evidence to suggest hypothermia treatment helps to improve long term outcomes post ABI. 4. There is conflicting evidence regarding hypothermia’s effect on mortality. 5. There is Level 1b evidence that systemic hypothermia is associated with an increased incidence of pneumonia. 6. There is Level 2 evidence that the use of tromethamine, a weak base and buffer that crosses the blood brain barrier, can offset the deleterious effects of prolonged hyperventilation and lead to better outcomes than hyperventilation alone. 7. There is Level 4 evidence that hyperoxia can counteract the deleterious effects of hyperventilation for the control of ICP following brain injury. 8. There is Level 4 evidence that hyperventilation below 34 torr arterial CO 2 can cause an increase in regionally hypoperfused tissue. 9. Results from one RCT suggest there is Level 1b evidence that CSF drainage decreases intracranial pressure in the short term. 10. There is Level 4 evidence from several studies that suggest CSF drainage does decrease ICP in individuals post ABI 11. There is Level 1b evidence that in adults, standard trauma craniectomy is more effective than limited craniectomy in lowering elevated ICP and leading to better GOS outcomes at 6 months. 12. There is conflicting evidence supporting the use of decompressive craniectomies in adults post TBI. 13. There is Level 3 evidence that resection of a larger bone flap results in greater decreases in ICP reduction after craniectomy, better patient outcomes and leads to fewer post-surgical complications. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 14. There is Level 1b evidence that in children, decompressive craniectomy reduces elevated ICP. 15. There is Level 4 evidence from several studies does reduce ICP in children post severe TBI. 16. There is Level 4 evidence that continuous rotational therapy does not worsen intracranial pressure in severe brain injury patients. 17. There is level 4 evidence that the prone position may increase oxygenation and CPP in ABI patients with acute respiratory insufficiency. 18. There is Level 1b evidence (from 2 RCTS) to suggest that hypertonic saline reduces ICP more effectively than mannitol. 19. There is Level 1 evidence that treatment with hypertonic saline results in similar clinical outcome and survival when compared with treatment with Ringer’s lactate solution up to 6 months post-injury. 20. There is Level 1b evidence that saline solution results in decreased rates of mortality compared with albumin. 21. There is Level 4 evidence that treatment with hypertonic saline reduces elevated ICP refractory to conventional ICP management measures. 22. There is Level 2 evidence that hypertonic saline is similar to Ringer’s lactate solution in lowering elevated ICP. 23. There is Level 4 evidence that hypertonic saline may be useful as a component of a resuscitation algorithm by increasing cerebral oxygenation. 24. There is Level 1b evidence that in children, use of hypertonic saline in the ICU setting results in a lower frequency of multiple early complications and a shorter ICU stay compared with Ringer’s lactate. 25. There is Level 4 evidence to suggest HTS is effective in decreasing ICP levels in children post TBI. 26. There is Level 1 evidence that sodium lactate is more effective than mannitol for the management of acute elevations in ICP. 27. There is Level 2 evidence that higher dose mannitol is superior to conventional mannitol in improving mortality rates, and clinical outcomes. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 28. There is Level 2 evidence that early out-of-hospital administration of mannitol does not adversely affect blood pressure. 29. There is Level 4 evidence that mannitol is effective in diminishing intracranial hypertension only when initial ICP values are elevated. 30. There is Level 1 evidence that propofol may help to reduce ICP and the need for other ICP and sedative interventions when used in conjunction with morphine. 31. There is Level 2 evidence that midazolam has no effect on ICP but conflicting evidence regarding its effect on MAP and CPP. 32. There was Level 1 evidence that bolus opioid administration resulted in increased ICP. 33. There was conflicting evidence regarding the effects of opioid infusion on ICP levels. 34. There was Level 2 evidence that remifentanil results in faster arousal compared to hypnotic based sedation. 35. There is conflicting evidence regarding the efficacy of pentobarbital over conventional ICP management measures. 36. There is Level 2 evidence that thiopental is more effective than pentobarbital for controlling unmanageable refratory ICP. 37. There is Level 2 evidence that pentobarbital is no better than mannitol for the control of elevated ICP. 38. There is Level 4 evidence that barbiturate therapy may cause reversible leukopenia, granulocytopenia, and systemic hypotension. 39. Based on a single study, there is Level 4 evidence that a combination barbiturate therapy and hypothermia may result in improved clinical outcomes up to 1 year postinjury. 40. Based on the findings of one large-scale multi-centre RCT, there is Level 1 evidence that treatment with dexanabinol does not provide acute improvements in ICP or longterm clinical benefits post-ABI. 41. There is Level 1 evidence that methylprednisolone increases mortality rates in ABI patients and should not be used. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 42. There is Level 2 evidence that triamcinolone may improve outcomes in patients with a GCS<8 and a focal lesion. 43. There is Level 1b evidence that dexamethasone does not improve ICP levels and may worsen outcomes in patients with ICP > 20mmHg. 44. There is Level 3 evidence that glucocorticoid administration may increase the risk of developing first late seizures. 45. Based on the findings of two RCTs, there is Level 1 evidence that Bradycor (a bradykinin antagonist) is effective preventing acute elevations in ICP post-ABI. 46. There is conflicting evidence to support the use of bradykinin antagonists to improve functional clinical outcomes such as the GOS. 47. There is Level 4 evidence that dimethyl sulfoxide transiently reduces ICP elevations. 48. There is Level 1b evidence that multimodal sensory stimulation provided by family members improves consciousness of severe ABI patients with GCS 6-8. 49. There is Level 2 evidence to suggest that sensory stimulation may improve clinical outcomes, physiological parameters, and behaviours indicative of emergence from coma post ABI. 50. There is Level 4 evidence that music therapy as an adjunct to other modes of sensory stimulation may be used to promote emergence from coma post ABI. 51. There is Level 1b evidence that median nerve electrical stimulation does not improve emergence from coma post-ABI. 52. There is Level 1b evidence that amantadine may improve levels of consciousness and cognitive function in patients in various stages of coma. 53. There is Level 1a evidence that amantadine improves the level of consciousness in children post ABI. 54. There is Level 1b evidence, from one RCT, that amantadine and pramipexole improves the levels of consciousness in TBI children and adolescents. Module 16_Acute Interventions for Acquired Brain Injury_V9_2013 http://www.abiebr.com Updated August 2013 Evidence-Based Review of Moderate to Severe Acquired Brain Injury 16.4 References Medical aspects of the persistent vegetative state (1). The Multi-Society Task Force on PVS. N Engl J Med 1994; 330: 1499-1508. Aarabi B, Hesdorffer DC, Ahn ES, Aresco C, Scalea TM, Eisenberg HM. Outcome following decompressive craniectomy for malignant swelling due to severe head injury. J Neurosurg 2006; 104: 469-479. Aarabi B, Hesdorffer DC, Simard JM et al. Comparative study of decompressive craniectomy after mass lesion evacuation in severe head injury. Neurosurgery 2009; 64: 927-939. Abbasi M, Mohammadi E, Sheaykh RA. Effect of a regular family visiting program as an affective, auditory, and tactile stimulation on the consciousness level of comatose patients with a head injury. Jpn J Nurs Sci 2009; 6: 21-26. Adamo MA, Drazin D, Waldman JB. 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