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INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION
Traumatic brain injury is not a simple event entirely accomplished at the time of insult but an ongoing and gradual phenomenon. The reactions are progressive and involve brain tissue progressively via vicious circle and feed forward processes. Traumatic brain injury includes two distinct sets of disorders: first, worsening of the primary lesions which may take place from local and systemic causes, and, second, brain may suffer secondary insults.
Protection essentially means prevention and mitigation of a foreseeable insult highly likely to occur in given circumstances. The area of unstable hemodynamic conditions around traumatic lesions can be described as a “traumatic penumbra”. This portion of brain tissue is at risk and cerebral protection endeavors to prevent its progression to complete destruction. Similarly a ‘therapeutic window’ exists during which perifocal tissues may be salvaged by reperfusion or by use of pharmacological agents that support cells at risk over a critical period. Brain protection essentially attempts to salvage tissues in this “traumatic penumbra” within this therapeutic window1,^.
PATHOPHYSIOLOGY OF BRAIN INSULTSPATHOPHYSIOLOGY OF BRAIN INSULTSPATHOPHYSIOLOGY OF BRAIN INSULTS PATHOPHYSIOLOGY OF BRAIN INSULTSPATHOPHYSIOLOGY OF BRAIN INSULTS
A) Primary impact and related changes
Primary impact injuries include macroscopic injuries like brain contusions, axial and extra-axial hematomas and microscopic insults like axonal dysfunction, ischemic cytotoxic edema, astrocyte swelling, blood-brain barrier disruption with vasogenic edema, and phasic inflammatory cell recruitment.
B) Secondary biochemical reactions
Secondary reaction can be considered as a three-step event. The first step is a disruption of calcium hemostasis, which immediately follows trauma. A sudden rise of intracellular calcium occurs. Excessive intracellular calcium activates a number of enzymes reactions, which eventually destroy cell structures. The outburst of highly destructive
Cerebral protection – Current concepts
Girish Menon M Ch, DNB, S Nair M Ch, RN Bhattacharya M Ch
Department of Neurosurgery Sree Chitra Tirunal Institute for Medical Sciences &Technology, Trivandrum, INDIA
free radical mediated peroxidation is the second major mechanism of damage. Acidosis is the third major mechanism of tissue disruption.
i). Calcium Damage, Excitotoxic Mechanism and
related therapies
Calcium enters the cell via two types of specific channels: those opened by membrane depolarisation (voltage operated channels VOC) and those opened by the action of a specific ligand on a receptor (receptor operated channel ROC). The VOC was initially considered to be the main route for calcium influx following energy failure. Later on emphasis was placed on the role of excitatory amino acid particularly glutamates and thus the concept of excitotoxicity – excitotoxic theory was proposed. In both, calcium overload is ultimately responsible for cell damage and that is the pivotal concept. However where as calcitoxicity may concern all cells, excitotoxicity concerns only cells equipped with EAA(excitatory amino acids) linked receptor channels which are essentially neurons. According to the excitotoxic concept a rise in the EAA concentration is the main cause of calcium entry via specific glutamate operated calcium channels. The immediate consequence of extracellular glutamate elevation is an enhanced stimulation of post-synaptic receptors. Different types of these receptors are currently described. These are: a) the ionotropic receptors : NMDA b) the quisqualate or AMPA receptors and c) the kainate receptors. In pathological conditions with high extracellular glutamate concentration , two processes take place: an immediate entry of sodium via the quisqualate kainite receptor accompanied by chloride and water which creates a sudden intracellular edema and can kill neurons very rapidly, and entry of calcium via the NMDA receptor associated channel which is a slower process and would be responsible for a delayed type of neuronal death 1,2.
ii) Perioxidative damage
Free radical reactions production is the consequences of the arachidonic acid cascade triggered by calcium-activated
Address for Correspondence: Dr. Girish Menon R Associate Professor, Department of Neurosurgery, SCTIMST, Trivandrum, INDIA, 695011, Email: [email protected]
Review Article Indian Journal of Neurotrauma (IJNT)
2005, Vol. 2, No. 2, pp. 67-
phospholipase A2. In brain tissue, arachidonic acid and other PUFAS (polyunsaturated fatty acids) induce the production of superoxide anion and provoke a parallel swelling of the tissue. The activation of nitric oxide (NO) synthetase is another possible calcium-dependent mechanism of free radical production. It has been postulated that liberation of NO could account in part for glutamate- mediated neurotoxicity. NO produced in excess functions as a powerful neurotoxin. NO combines with superoxide anion O 2 -^ produced by xanthine oxidase activation to yield the peroxynitrite anion, which is an extremely potent free radical.
3) Acidotic damage
In anerobic conditions not only is there a breakdown of ATP production but also intracellular acidosis. Main features of acidosis related brain damage include edema, widespread neuronal necrosis and complete tissue destruction. In the anerobic conditions, the cell sacrifices its volume to save its pH. Acidosis is inevitably linked to ischemia and it is not possible to prevent acidosis if ischemia itself cannot be avoided^4.
There is, however, new and emerging interest in the role of cerebral inflammation following acute brain injury from a variety of causes^5. There is good evidence now that there is a local inflammatory response in the human brain following a variety of insults, with production of pro- inflammatory cytokines (including IL-6 and IL-8) and adhesion molecule up regulation (including ICAM-1, ICAM-2 and Eselectin). These changes result in early neutrophil influx, and later recruitment of lymphocytes and macrophages and a chronic inflammatory response which may be associated with the laying down of amyloid. Indeed, head injury is a recognised risk factor for amyloid deposition in the brain and for Alzheimer’s disease. Further, the risk of these outcomes is related to an individual’s apolipoprotein E (ApoE) genotype, with an increased risk conferred by possession of the ApoEe4 genotype^6. Even more intriguingly, the ApoEe4 genotype has been shown to affect outcome directly in patients admitted with a severe head injury. This may be the first recognition of many genotypic influences that modulate the severity of secondary neuronal injury mechanisms, and elucidation of these processes may enable us, in the future, to select high risk patients for intensive neuroprotection strategies.
C.Change in cerebrovascular hemodynamics
Following head injury, cerebral blood flow (CBF) is shows a triphasic behaviour 2,3. Early after head injury (within 12 hours), global CBF is reduced, sometimes to ischemic levels. Between 12 and 24 hours post injury, CBF increases and
the brain may exhibit supranormal CBF (while many reports refer to this phenomenon as hyperemia, the absence of consistent reductions in cerebral oxygen extraction suggest that metabolism and blood flow often remain coupled, and a more appropriate label would be hyperperfusion). Thereafter CBF values begin to fall several days following head injury, and, in some patients, these reductions in CBF may be associated with marked increases in large vessel flow velocity on transcranial Doppler ultrasound that suggest vasospasm. Immediately after head injury there is no vascular engorgement and, though a transient blood- brain-barrier (BBB) leak has been reported in the immediate period after impact in animals, there is no evidence of BBB disruption at this stage in humans. Apart from surgical lesions ( e.g. intracranial haematomas), ICP elevation during this phase is commonly the consequence of cytotoxic oedema, usually secondary to cerebral ischemia. Increases in CBF and cerebral blood volume (CBV) from the second day post injury onward make vascular engorgement an important contributor to intracranial hypertension. The BBB appears to become leaky between the second and fifth days post trauma, and vasogenic edema then contributes to brain swelling.
MONITORING IN ACUTE HEAD INJURYMONITORING IN ACUTE HEAD INJURYMONITORING IN ACUTE HEAD INJURY MONITORING IN ACUTE HEAD INJURYMONITORING IN ACUTE HEAD INJURY
Monitoring modalities are selected based on their ability to measure physiological endpoints that have been shown to influence outcome as well those which can be modulated by therapeutic interventions^2.
Monitoring systemic physiology
Monitoring of direct arterial blood pressure along with measurement of ICP is essential for calculating and manipulating CPP. The need to manipulate mean arterial pressure will also require the measurement of central venous pressure, or left atrial pressure using pulmonary artery catheterization, wherever appropriate. Similarly, the maintenance of systemic oxygenation requires the continuous monitoring of this variable (by pulse oximetry, supported by arterial blood gas measurement). The need to measure core body temperature and regular blood sugar estimation cannot be overemphasized.
Intracranial pressure monitoring
The need to optimise CPP predicates the requirement of monitoring ICP in all patients with severe head injury. Clinical signs of intracranial hypertension are late, inconsistent and non-specific. Further, it has been shown that episodic rises in intracranial pressure may occur even in patients with a normal X-ray and CT scan. Majority of the devices used to monitor ICP can be placed under local anesthesia at the bedside. A ventriculostomy with an intraventricular catheter
Girish Menon, S Nair, RN Bhattacharya
insults). In addition to insights into brain physiology, this technique may provide a method of measuring local pharmacokinetics of drugs in head injury.
Cerebral blood flow measurement
Global cerebral blood flow measurements in acute head injury have commonly used 133 Xe washout techniques at the bedside and documented the phasic changes in CBF after head injury.
Imaging physiology and metabolism in head
injury
The best established technique for physiological imaging is the use of stable xenon CT studies for measurement of regional CBF (rCBF). Positron emission tomography (PET) and magnetic resonance imaging have been also used for the purpose. In addition, PET provides the opportunity to image cerebral glucose and oxygen utilization, and radio ligand binding. Recent interest has focused on increased uptake of the PET tracer 18F-deoxyglucose around contusions and adjacent to hematomas, which are probably unaccompanied by increases in oxygen metabolism.
Multimodality monitoring
While individual monitoring techniques provide information regarding specific aspects of cerebral function, the correlation of data from several modalities has several advantages in head injury management. Integration of monitored variables allows cross validation and artifact rejection, better understanding of pathophysiology and the potential to target therapy.
While individual monitoring techniques provide information regarding specific aspects of cerebral function, the correlation of data from several modalities has several advantages in head injury management. Integration of monitored variables allows cross validation and artifact rejection, better understanding of pathophysiology and the potential to target therapy.
I. GENERAL MEASURESI. GENERAL MEASURESI. GENERAL MEASURES I. GENERAL MEASURESI. GENERAL MEASURES
A. Brain oriented life support:
Basic physiological premises suggest the benefit of maintaining cerebral blood flow and oxygenation, and these assumptions are confirmed by data from the Traumatic Coma Data Bank (TCDB) and from other sources which demonstrate the detrimental effects of hypotension (systolic blood pressure below 90 mmHg) and hypoxia (PaO 2 levels below 60mmHg [8 kPa]) in the early and later phases of head injury on outcome^8. Hypotension and low cardiac output are deleterious to an already compromised brain. CVP should be maintained within 8–10 cms of water,
and hypotension should be treated expeditiously by administering IV fluids, blood or ionotropes as appropriate in a given situation. Hypoxia and hypercapnia cause further cerebral injury and need to be strictly avoided. Mechanical ventilation and PEEP is generally required to optimize oxygenation. Normal acid base balance is desirable. Metabolic acidosis and respiratory alkalosis are the common disturbances that need to be treated. Normovolemia should be maintained: hypervolemia increases brain edema while excessive dehydration decreases CBF. Normal serum osmolality and oncotic pressure should be maintained. Hyponatremia aggravates brain edema and precipitates seizures and should be promptly corrected. Hyperglycemia is associated with worsening of neurological injury in head injury 9. Normothermia should be achieved by measures such as cold sponging, cooling blankets and antipyretics, since hyperthermia aggravates neurological injury. Systemic infections should be appropriately treated^8.
B. Fluid therapy
Fluid replacement should be guided by clinical and laboratory assessment of volume status and by invasive hemodynamic monitoring, but generally involves the administration of 30–40 ml/kg of maintenance fluid per day. The choice of hydration fluid is largely based on inconclusive results from animal data. Unlike other vascular beds, capillaries in the brain are impermeable to most small molecules, and fluid flux across the normal BBB is governed by osmolarity rather than oncotic pressure. Consequently, hypotonic fluids are avoided and serum osmolality is maintained at high normal/levels (290–300 mosm/l in our practice) to minimise fluid flux into the injured brain. Dextrose containing solutions are avoided since the residual free water after dextrose metabolism can worsen cerebral edema, and because the associated elevations in blood sugar may worsen outcome^10. Hypertonic saline has been shown to raise plasma sodium and osmolality with reduction in ICP and reduction of midline shift in head injuries11,12. Simma et al reported that 1.6% saline, when compared to lactated Ringer’s solution as maintenance fluid in head injured children, resulted in lower ICP values, less need for barbiturate therapy, a lower incidence of acute lung injury, fewer complications and a shorter ICU stay^13. Maintenance of oncotic pressure with albumin supplements is one of the cornerstones of the Lund protocol, and other authors have discussed the advantages of colloid use in this setting 13. Both albumin and gelatins have been used, but hetastarch should be used with caution, since its effects on hemostasis may potentiate intracranial haemorrhage. There is some evidence indicating that certain colloids (pentastarch) may be effective in reducing the
Girish Menon, S Nair, RN Bhattacharya
cerebral oedema associated with cerebral ischaemic and reperfusion injury 10,14^. Agents which ‘plug leaks’ by acting as oxygen free radical scavengers and or by inhibiting neutrophil adhesion may be the resuscitation fluids of the future.
C.Nutrition
Head injured patients have high nutritional requirements and feeding should be instituted early (within 24 h), aiming to replace 40% of resting metabolic expenditure (with 15% of calories supplied as protein) by the seventh day post trauma 15. Enteral feeding is preferred as it tends to be associated with a lower incidence of hyperglycemia and because of its protective effect against gastric ulceration, the incidence of which may be increased in these patients. Impaired gastric emptying is a common finding in head injury, and can be treated with prokinetic agents. In those who cannot be fed enterally, parenteral nutrition should be considered together with some form of prophylaxis against gastric ulceration (H2 antagonists or sucralfate) and rigorous blood sugar control.
D.Antiepileptic therapy
Seizures occur early (before 7 days) or late (after 7 days) following head injury, with a reported incidence of between 4–25% and 9–42%, respectively^15. Seizure prophylaxis with phenytoin or carbamazepine can reduce the incidence of early post-traumatic epilepsy, but has little impact on late seizures, neurological outcome or mortality. The incidence of posttraumatic seizures is greatest in patients with a GCS below 10, and in the presence of an intracranial haematoma, contusion, penetrating injury or depressed skull fractures. Since it is important to balance the possible benefit from seizure reduction against the side effects of anti epileptic drugs, such patients may form the most appropriate subgroup for acute (days to weeks) seizure prophylaxis following head injury8,16.
II.II.II.II.II. CEREBRAL BLOOD FLOW PROMOTIONCEREBRAL BLOOD FLOW PROMOTIONCEREBRAL BLOOD FLOW PROMOTIONCEREBRAL BLOOD FLOW PROMOTIONCEREBRAL BLOOD FLOW PROMOTION
TECHNIQUESTECHNIQUESTECHNIQUESTECHNIQUESTECHNIQUES
The ultimate object is to provide brain cells with the amount of oxygen and glucose which covers their energy requirements for both functional needs and to circumvent the crisis. Against energy failure we have two lines of protection: hemodynamic and metabolic. Hemodynamic protection composes attempts at restoring circulation or at improving its efficiency via manipulation of blood pressure, vasoreactivity and blood rheology 17,18^. The alternative strategy is to reduce the needs by lowering CMRO 219.
Available oxygen = CBF x Hb x sO 2 /100.
Available oxygen can thus be improved by
a) Increasing CBF essentially by improving CPP b) Improving Hb c) Improving sO2 : Intentional hyperoxia has been documented to reverse the cerebral oxygen desaturation and anerobic metabolism in head injured patients20,^.
A. MAP Targeted treatment : CPP = MAP - ICP
When cerebral autoregulation is intact the cerebral blood flow is kept constant despite changes in CPP between 60 mm and 140 mm. The controversy centers on the minimum level of CPP that is adequate in TBI. Most centres would agree on the need to maintain cerebral perfusion by keeping CPP well above 60–70 mmHg, either by decreasing ICP or by increasing MAP. Despite this large body of data that supports the maintenance of high CPP values in head injury, there is some concern that relatively high perfusion pressures may contribute to oedema formation post head injury. A recent study comparing CBF targeted management (CPP more than 70, pCO 2 = 35) with ICP targeted therapy (ICP below 25, pCO 2 upto 25, CPP below 50) found no difference in the outcome^5. There are however, data that show that ICP is an independent, albeit weaker, determinant of outcome in severe head injury. A recent study in fact concluded that CPP has correlation with outcome only when CPP was below 60 mm; above 60 mm CPP had no correlation with outcome suggesting that higher CPP does not always translate itself into better outcome 1,2,18^. The different schools of thought on CPP targeted therapy can be summarized as follows Optimising cerebral perfusion by CPP management 22 : This approach is based on the concept that normal autoregulatory response to reduced CPP causes dilatation of the cerebral blood vessels .This results in an increase in ICP causing further reduction in CPP, thus setting up a cycle that leads to ever reducing CPP. Under these circumstances an increase in arterial blood pressure would break the cycle and reduce ICP. This approach is widely practiced and recommended. Lund Therapy approach2,18,22,23: This approach centers on reduction in microvascular pressures to minimize edema formation in the brain. Colloid osmotic pressure is maintained near normal values using infusion of albumin and erythrocytes and capillary hydrostatic pressure is decreased by reducing systemic blood pressure using betablockers and clonidine. In addition, low dose thiopental and dihydroergotamine are used to reduce cerebral blood volume by contricting precapillary resistance vessels. Miller et als balanced approach 23,24^ : This approach attempts to direct the treatment to the underlying
Cerebral protection – Current concepts
Neuromuscular blockade in the head injured patient receiving intensive care is currently the subject of much debate. The use of neuromuscular blockers can play an important role in the head injured patient. Coughing and ‘bucking on the tube’ can result in an increase in ICP, and the administration of non-depolarising muscle relaxants prevents such rises in ICP. However, despite facilitation of ICP control, use of these agents is not associated with better outcomes, perhaps because of increased respiratory complications. Further, long term use of neuromuscular blockade has been associated with continued paralysis after drug discontinuation and acute myopathy, especially with the steroid-based medium to long acting agents. However, atracurium is non-cumulative and has not been associated with myopathy, and theoretical concerns about the accumulation of l audanosine, a cerebral excitatory metabolite of atracurium, in head injured patients have not been shown to be clinically relevant2,18.
III.REDUCING CEREBRAL METABOLISMIII.REDUCING CEREBRAL METABOLISM III.REDUCING CEREBRAL METABOLISMIII.REDUCING CEREBRAL METABOLISMIII.REDUCING CEREBRAL METABOLISM
1. Hypothermia
One of the interventions which has never lived up to the theoretical promise it offered is the reduction of brain metabolism in order to reduce the production of cytotoxic radicals, penumbral ischemia and brain swelling. The well designed National Acute Brain Injury study (NABIS) trial in conjunction with the similar Japanese trial seems to settle the matter and has shown fairly conclusively that mild hypothermia applied following head injury does not reduce mortality or dysfunction. It is important however not to entirely dismiss the role of hypothermia in achieving cerebral protection and may still be used in patients with cardiac arrest, pediatric head injury etc1,2,18,29,^.
Hypothermia progressively depresses the cerebral metabolism which has been reported to decrease linearly from 6 to 10% for each one degree decrease in temperature in the range 35 to 25º. The protective mechanism may not entirely be due to decrease in metabolism but also due to its membrane stabilization action, influence on blood flow, reduction in excitatory amino acids and sustained suppression of cytokines, particularly interleukin^1.
One of the early studies on hypothermia, the NABIS study by Clifton et al 29 in 1994 was halted after 392 patients as the treatment was not effective. Some important points from the study are that older patients not only do not benefit from the hypothermia , they also do worse than normothermics. Also if patients are hypothermic on admission it is not advisable to warm them to normothermia. The timing of initiation might also be important with early induction of hypothermia giving better results. Similarly it
was shown that hypothermia did have a beneficial effect on the proportion of patients with high intracranial pressure. The Cochrane review analyzing 12 trials with 812 patients could not find a statistical reduction in mortality in patients receiving mild hypothermia either early or deferred. The patients receiving hypothermia seemed to give an increase in ventilator associated pneumonia, which negate any beneficial effect. Two ongoing trials (IHAST) and (HyP – HIT) should however provide information on the role of hypothermia in post SAH and pediatric head injury respectively.
2. Barbiturate narcosis
Intravenous barbiturates have been used in the setting of acute head injury for ICP reduction since 1937 when the utility of barb narcosis in decreasing ICP was described by Shapiro^31. Among the other possible indications were, control of ICP intraoperatively , focal and global ischemia and in decreasing the incidence of neuropsychiatry complications following cardiopulmonary bypass. Barbiturate can reduce the rate of energy depletion (ATP depletion and lactate accumulation), and prolong the time for energy failure in case of ischemic injuries. Deep barbiturate anesthesia can reduce cerebral metabolic rate to the same extent as hypothermia to 30ºC. Barbiturate therapy would be expected to reduce CMRO 2 , which limits cell energy demand at a time when blood flow may be compromised. In these patients, barbiturates may increase perfusion pressure through reduction of ICP (CPP = MAP
- ICP). Other potential beneficial effects of barbiturates are reduction of elevated intracranial hypertension, producing favorable redistribution of blood towards ischemic tissue by constricting the vessels in the non-ischemic cortex and suppression of abnormal or seizure-like activity. It has also been suggested that barbiturates exert neuroprotective effects through anti-oxidant or free radical scavenging actions. Barbiturates may also reduce ischemia induced neurotransmitter release. Dosage: Pentobarbital may be used for elective induction of barbiturate coma. It has a serum half-life (elimination) of about 30 hours. It is administered by a loading dose (3 to 10 mg/kg) at 1 mg/kg/min, followed by continuous infusion at 1 to 2 mg/kg/hour. Monitoring of blood level and maintaining it at 25 to 40 mg/ml range may prevent excessive recovery times from barbiturate coma. Thiopentone is a rapidly acting barbiturate, which is often used if the desired effect is necessary immediately. In this context, doses of 3 to 5 mg/kg intravenously will produce transient burst suppression and blood thiopentone levels of 10 to 30 mg/ ml. Following are the various regimens used:
Cerebral protection – Current concepts
High initial dose to produce burst suppression on EEG, which may or may not be followed by an infusion. This use is applicable to situations of focal ischemia. Loading dose consists of 25 to 50 mg/kg. This is followed by an infusion 2 to 10 mg/kg/hr to give plasma concentration of 10 to 50 mg/L. Accumulation occurs and recovery may be prolonged over a period of days before neurological assessment can be made.
Low initial dose followed by infusion: this regimen is used to control ICP. A dose of 1 to 3 mg/kg intravenously is followed by an infusion of 0.06 to 0.2mg/kg/min. This regimen is useful in head injuries to decrease raised ICP. Intermittent low doses of thiopentone (1 to 3 mgkg-1) will lower ICP and brain bulk during intracranial operations.
Small bolus dose for short-term protection. A dose of 4 mg/kg over 3 minutes produces EEG burst suppression for about 6 minutes.
Duration of therapy: When used prophylactically, therapy is usually discontinued when the period of potential or actual insult is over. The duration of therapy when instituted after an insult is controversial and has varied from bolus doses to infusions for 24 to 72 hours or more. The long duration has been advocated because post-insult injury may last for this period & cerebral edema peaks at 48 hours after an ischemic injury.
Problems during barbiturate therapy
Barbiturate therapy may cause depression of cardiac output and cerebral perfusion pressure, and even frank cardiovascular collapse in poorly hydrated patients as well as in those with a reduced cardiac function.
The profound respiratory depressant effect of barbiturates makes controlled mechanical ventilation mandatory.
Long-term barbiturate therapy is associated with hypothermia & depression of immune responses. This introduces the risk of pulmonary infectious complications.
Neurologic evaluation of the patient in barbiturate coma is difficult.
Ninety nine percent of administered thiopental is metabolized in the liver. Therefore special attention is required inpatients with hepatic dysfunction.
A sophisticated intensive care setting is required to support patients who are going to benefit from this mode of therapy.
Two randomized control trials compared barbiturate narcosis to mannitol as initial therapy in head injury patients with GCS less than 8. The important message form the Schwartz and Ward studies were i) Barbiturate narcosis is associated with a high incidence of hypotension. ii) As a first line of therapy mannitol is superior to pentobarbital in ICP control. iii) In some case barbiturate narcosis can cause oligemic hypoxia to the brain because of decrease in CPP. Nordstorms group from Sweden suggested that response to barbiturate narcosis in severe head injures may be related to the response of cerebral circulation to PaCO 2. Patients who responded to hypocarbia with decrease in CBF and ICP are the ones who respond to barbiturate narcosis with decrease in ICP. In these patients (intact cerebral vasoreactivity), 50% had a good outcome and 25% died. In patients with absent cerebral vasoreactivity barbiturate narcosis was associated with a mortality of 64%. The best source of review for this subject is the guidelines for the management of severe traumatic brain injury patients – a joint venture of the BTF, AANS and the joint section of the neurotrauma and critical care. The guidelines say that “high dose barbiturate therapy can be considered in hemodynamicaly stable salvageable severe head injury with increased ICP, refractory to conventional medical/surgical management”. Two laboratory studies and one clinical study have clarified the role of barbiturate in ischemia once and for all – barbiturate narcosis is of no benefit in global ischemia and may be of variable use in some cases of focal ischemia and in reducing neuropsychitaric complications in CPB1,2,18,32,^.
3) Etomidate
Like barbiturates, etomidate produces EEG burst suppression and reduces CMR for glucose and oxygen. Clinically, etomidate decreases CBF, CMRO 2 and ICP whereas carbon-dioxide reactivity, hemodynamic stability and cerebral perfusion pressure (CPP) are maintained. It inhibits release of excitatory neurotransmitters. Etomidate has a low incidence of hemodynamic instability at doses sufficient to depress the EEG. In this respect, it has a major advantage over thiopental. However, etomidate has been associated with significant adrenocortical suppression, even when administered as a single injection. This effect of the drug has greatly limited its utility in usual anesthetic care but not its utility in neurosurgical cases in which patients are routinely administered high doses of steroids^32.
Girish Menon, S Nair, RN Bhattacharya
B. Non-anesthetic agents as neuroprotectants
In the past ten years , published reports of clinical trials on the treatment of head injury have included one large trial on the use of a corticostreoid (triamcinolone ), three trials on the use of nimodipine , three trials on the use of free radical scavenging agents (PEGSOD and tirilazad) and three trials on the use of NMDA antagonists. Four of these studies were halted prematurely, and only six were completed.
Corticosteroids
Their efficiency in reducing vasogenic peritumoral edema is well documented. Use of glucocorticoids is not recommended for improving outcome or reducing ICP in patients with severe head injury. The ability of steroids to stabilize membranes, prevent lipid peroxidation and their anti-inflammatory property can be expected to protect ischemic/ injured brain. Early studies using various types of steroids both in high and low doses did not provide any benefit. A recent trial using triamcinolone showed increase in the number of patients with good recovery and decrease in mortality. A recent Cochrane review^39 concluded that neither moderate benefit nor moderate adverse effect of steroid can be confirmed and a large randomized controlled trial is justified to explore the benefits of steroids in severe head injury. After performing a meta analysis of the results of all identified steroid trials in head injury both published and unpublished it was concluded that a 2% reduction in mortality is possible and to confirm or exclude this a prospective trial of 20000 patients is necessary 1,2,8,32.
Novel neuroprotective interventions
Although none of these have been accepted as standard therapy in acute head injury, a variety of novel pharmacological neuroprotective agents are currently under investigation. Disappointingly, none of the agents that have been tested thus far in Phase III trials have proved to provide benefit on an intention to treat basis.
a. Calcium anatagonists :
The vital role played by calcium in ischemic and traumatic injury raised the possibility of utilizing calcium entry blockers for cerebral protection37,38^. Lidoflazine was one of the first calcium entry blockers to be tried but the most studied drug is nimodipine. This drug antagonizes the entry of calcium into cells, which in turn ameliorates the lactic acidosis, which occurs during ischemia. Nimodipine probably increases CBF, particularly in regions of moderate ischemia. Major human trials in head injury also documented very limited role for nimodipine. The two major European trials HIT 1 and HIT II showed no statistically
significant improvement in favorable outcome at the end of six months with the use of nimodipine. HIT III however reported a 10% improvement in favorable outcome in a sub group of patients who had evidence of traumatic SAH. A recent Cochrane data base review on the subject of calcium blockers in head injury was uncertain about the ability of these agents to decrease death and disability. However there seems to be a trend towards improved outcome in a subgroup of patients with traumatic SAH. Treatment with Nimodipine decreases BP, decreases systemic vascular resistance and increases cardiac output. The lack of a neuroprotective effect was disappointing & may be attributable to the fact that nimodipine is a cerebral vasodilator, conferring a physiologic effect of increased embolic load and obliterating any protective effect at the cellular &biochemical level. Nicardipine, another calcium antagonist has been administered into venous reservoir before deep hypothermic circulatory arrest but has not been extensively studied in head injury b. Magnesium : By virtue of its ability to antagonize the actions of calcium , anatagonism of glutamate release and NMDA receptor blockade magnesium has been proposed to protect the ischemic brain. Though the results of small trials have not been encouraging they have provided the sample for large ongoing randomized trial (IMAGES- intravenous magnesium efficacy in Stroke), the results of which are expected. c. Glutamate antagonist : Recent microdialysis experiments have shown association between brain glutamate levels and neurological deterioration. Major effects of glutamate are mediated through NMDA receptors. Competitive NMDA antagonists, selfotel and non competitive antagonist like dizocilpine dexanibol and aptiganel have been subjected to phase III trials. The Selfotel study was prematurely terminated because of concerns relating to increased mortality 38. Human studies in head injury with non competitive NMDA antagonist dizocilpne and aptiganel also had to be prematurely terminated because of unacceptable side effects. A trend towards beneficial effect in head injury has been seen in a trial with dexanabinol. Lubeluzole is an agent that inhibits glutamate release or glutamate initiated nitric oxide toxicity. Modest beneficial effect has been reported with this drug in patients with stroke. Dextromethorphan and its metabolite dextrorphan are also non-competitive NMDA antagonists useful in focal cerebral ischemia. So is dexmedetomidine, an alpha 2 agonist, but they all need to be tried in head injury.
Girish Menon, S Nair, RN Bhattacharya
d.Antioxidants
Although initial clinical trials of polyethylene glycol conjugated superoxide dismutase (pegorgotein) were encouraging, a more recent large randomized outcome study has failed to demonstrate any benefit, and large Phase III trials of the novel antioxidant, tirilazad (which had proven efficacy in experimental models) have shown no improvement in outcome in clinical head injury.
Tirilazad mesylate (TM): Tirilazad mesylate (TM) is a 21- aminosterid (lazaroid) that was developed specifically to maximize their inhibition of lipid peroxidation by glucocorticoids such as methylprednisolone, but eliminate the unwanted glucocorticoids effects. The lazaroids are potent antioxidants, 100 times more potent than the corticosteroids, therefore may be efficacious in the clinical management of acute CNS injury. The mechanism of action appears to be cell membrane preservation by inhibition of lipid peroxidation.
Superoxide dismutase: Superoxide dismutase (SOD) is a specific scavenger of superoxide anion. Superoxide anion is capable of producing significant biological injury. It is generated on reperfusion of post ischemic tissues. Because, superoxide dismutase (SOD) has a biological half-life of only five minutes, it has been conjugated with polyethyleneglycol (PEG-SOD) for use in humans.
e. Lidocaine
Possible mechanisms for cerebral protection by lidocaine include deceleration of ischemic transmembrane ion shifts, reduction in CMR, modulation of leukocyte activity, and reduction of ischemic excitotoxin release.
f. Furosemide
It is a sulfonamide that inhibits distal tubular reabsorption. It has been shown to decrease ICP effectively without the transient ICP increase that can be seen with mannitol. An additional action of furosemide, which may be of benefit, is its reduction of cerebrospinal fluid formation. The dose of furosemide may be upto 1 mg/kg, depending on the degree of diuresis required.
g. Tromethamine
Tromethamine (THAM), a weak base which crosses the plasma membrane and acts directly on intra cellular acidosis has been used with success in models of experimental head injury. THAM has been used in head injuries in man and is reportedly useful along with hyperventilation to reduce brain edema and intracranial pressure.
h. Perfluorocarbons
Perfluorocarbons have been mainly used in decreasing
cerebral emboli associated with cardiac surgery, and no controlled trial is available on its use following head injury. These compounds have high gas affinity, hence may decrease cerebral gaseous microemboli. They may improve flow characteristics in areas of decreased perfusion. i. Other drugs Other drugs used include high dose aprotinin and acadesine, an adenosine-regulating agent. The mechanism of action is unknown; however it is tempting to speculate that the anti-inflammatory properties of aprotinin may be responsible. Again, the possible mechanism of action of acadesine is unknown, but may involve decreased excitatory transmitter release or reduced granulocyte accumulation32,36. However despite an extensive understanding of the pathophysiology of traumatic brain injury and convincing success in experimental animals, success with pharmacological cerebral protection has been very limited.
CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION
Pathophysiology of traumatic brain injury is multifaceted, wherein multiple mechanisms are simultaneously operative. It is unlikely that a single treatment aimed at a single mechanism will be successful. The existence of these mechanisms and the relative importance of each of these mechanisms have never been satisfactorily demonstrated in human studies and most of our inference is from animal studies. Hemodynamic and physiological manipulations for cerebral protection, though theoretically sound have not been practically successful. Following the relative failure of barbiturates and hypothermia the possibilities and limits of metabolic brain protection seems to be restricted. The balance of hopes and actual achievements in pharmacological brain protection is not satisfactory. Nearly all the compounds of proven efficacy in animal models have failed to demonstrate consistent usefulness in clinical trials, To quote Cohadon 1 “The present concept of brain protection brings together in a unique piece of mechanism thinking, facts, hypothesis and hopes. The investigation of biochemical cascades allows a scientific description of facts: the assumption that specifically these biochemical events are a major aspect of the secondary evolution of brain insult is for a large part hypothesis: the proposal that appropriate drugs could oppose this evolution in a clinically meaningful manner is as yet only a hope. Such a mixture of solid data, nice ideas and dreams for a better world is typical of ideological thinking and to some extent brain protection
Cerebral protection – Current concepts
- Ramani Ramachandran. Barbiturate Narcosis –Present status. Proceedings of the 5 th^ ISNACC ; 2004:255-260.
- Kelly Daniel F, Goodale David B, Williams John, et al. Propofol in the treatment of moderate and severe head injury : a randomized , prospective double blinded pilot trial. J Neurosurg 1999; 90: 1042- 52.
- Maas A I R, Ewout W Steyerberg, Gordon D Murray et al. Why have recent trials of neuroprotective agents in head injury failed to show convincing efficacy? A pragmatic analysis and theoretical considerations. Neurosurgery 1999; 44: 1286-98.
- Bullock MR Lyeth BG, Muizelaar JP. Current status of neuroprotection trials for traumatic head injury: lessons from
Cerebral protection – Current concepts
animal models and clinical studies. Neurosurgery 1999; 45: 207-17.
- Langham J, Goldfrad C, Teasdale GM, Shaw D, et al. Calcium channel blockers for acute traumatic brain injury. Cochrane Database Syst Rev 2000 (2):CD 000565.
- Gabrielle F Morris, Ross Bullock , Sharon Bowers Marshall. Failure of competitive N – Methyl Aspartate antagonist Selfotel (CGS 19755 ) in the treatment of severe head injury : result of two phase III clinical trials. J Neurosurg ;1999; 91: 737-43.
- Philip Alderson ,Ian Roberts. Corticosteroids in acute traumatic brain injury : Cochrane Database Syst Rev 2000 ( 2): CD 000196.
