Br. J. clin. Pharmac. (1992), 34, 396-401
Introducing NMDA antagonists into clinical practice: why head injury trials? R. BULLOCK University Department of Neurosurgery, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF
1 Head injury is the major cause of death and severe disability in young adults. Evidence from clinical studies shows ischaemic brain damage to be the major determinant of bad outcome, and that a proportion of this (perhaps up to 40%) is delayed, thus offering an opportunity for 'prophylactic' therapy. 2 Laboratory studies in several relevant animal models of human head injury (fluid percussion, subdural haematoma, and focal ischaemia by middle cerebral occlusion) indicate that excitatory amino acids are important mediators of brain damage. Pretreatment with NMDA antagonists has shown that the extent of ischaemic damage may be dramatically reduced in these models (68% reduction in the cat MCA occlusion model, 54% in the rat subdural haematoma model). 3 Trials of NMDA antagonists in human head injury are therefore strongly indicated.
Keywords head injury ischaemic brain damage
competitive NMDA antagonists
the last 15 years (Bullock & Teasdale, 1990; Graham et al., 1968, 1989). This may be because the pathophysiological processes which damage the brain during and after severe head injury have hitherto been uninfluenced by conventional therapy and a variety of experimental drug treatments which have been tried. There is clear evidence from both clinical and neuropathological studies that a substantial proportion - up to 40% of those patients who die after severe head injury have spoken at some stage after the impact (Blumberg et al., 1989; Graham et al., 1968). This suggests that secondary processes occurring while the patient is under medical care are responsible for this brain damage. This provides the opportunity for pretreatment by means of prophylactic drug therapy, at least in a proportion of head injured patients. There are now converging lines of evidence from several animal studies to suggest that 'excitotoxic' damage to neurons and glia may develop as a consequence of excessive release of excitatory amino acids after primary impact injury, ischaemic events, and haematoma (Becker et al., 1989; Bullock et al., 1991a,b,c; Faden et al., 1989; Inglis et al., 1990; Kawamata et al., 1992). There is now, therefore, great enthusiasm that the potent neuroprotec-
Head injuries are currently the most important cause of death for young adults in the United States (Goldstein, 1990). Throughout Western society, a high proportion of young chronically disabled individuals become dependent on care because of the effects of head injury. In contrast to stroke and coronary heart disease, the incidence of head injury is increasing (Bullock & Teasdale, 1990; Goldstein, 1990). After a severe head injury (coma for more than 6 h) around 40% of patients will die (Adams et al., 1983; Bullock & Teasdale, 1990). Of the remainder, 15 to 20% remain disabled - the disabilities may range from cranial nerve palsies to hemiparesis and impairment of higher mental function. Of these, memory and personality impairment are the most frequent, and the most distressing for the patient and his family. Over the last 15 years major advances have been made in the management of head injury: unfortunately, these have not translated into widespread improvement in outcome (Goldstein, 1990; Graham et al., 1989). In spite of improved access to better quality of intensive care, and wider usage of CT scanning, neither the mortality rate nor the incidence of 'preventable' brain damage at post mortem have decreased more than 5 to 10% over
Correspondence: Mr. R. Bullock, Department of Neurosurgery, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF This paper is based on a presentation at a symposium on 'Cerebral vascular disease-new therapeutic opportunities, sponsored by the Clinical Section of the British Pharmacological Society, held to the University of Glasgow, July 1991.
NMDA antagonists in clinical practice tive effects which have been shown for NMDA antagonist drugs in the laboratory can be translated into clinical benefits, particularly for head injured patients. The pathophysiological mechanisms which cause brain damage after severe head injury
Techniques for both dynamic imaging and monitoring the brain after acute cerebral insults such as head injury are still relatively insensitive and non-specific. It is currently seldom possible to clearly detect or differentiate between the various processes which may damage the living brain after head injury. The best data available regarding these forms of damage comes from the detailed neuropathological studies performed by Adams and Graham, in 1978 and in 1989 (Adams et al., 1983; Graham et al., 1968, 1989). The four major mechanisms which damage the brain are shown in Figure 1. Many of these pathophysiological processes can co-exist in the same patient and there is good evidence from animal studies that the effects of diffuse axonal injury and ischaemic brain damage may be synergistic (see below) (Jenkins et al., 1989).
Ischaemic neuronal damage is seen in at least 88% of patients who come to post mortem (Graham et al., 1989). It is commonly induced by raised intracranial pressure because of haematomas and brain swelling. It is probably focal or multi-focal in distribution (Table 1) and it is always present as a 'halo' around a haemorrhagic contusion (Figure 2). Diffuse axonal injury
Although histological evidence of diffuse axonal shearing injury (in the form of retraction balls and microglial stars) is only seen in about a quarter of the patients who die after severe head injury, a minor degree offunctional axonal disruption is likely in all patients who sustain significant head injury - the severity of this functional axonal disruption probably determines both the depth
Figure 1 Venn diagram to depict the major causes of brain damage after fatal head injury note that ischaemic damage is seen in 88-92% of patients who die. -
Table 1 Ischaemic brain damage (IBD) after severe head injury
Number of post-mortems Overall incidence Incidence of associated haematomas in patients with IBD Incidence of brain swelling in in patients with IBD Raised ICP Pattern - Focal - Multi-focal 'Boundary zone' Diffuse (Modified after Graham et al., 1989).
151 92% 21%
112 88% 46%
26% 32% 8% 9%
49% 59% 8% 24%
and duration of loss of consciousness (Adams et al., 1983; Erb & Povlishock, 1988; Kawamata et al., 1992). Almost all our understanding of the early axonal events which occur after an impact has been obtained through the study of animal models. Numerous studies using the fluid percussion injury model have shown that impact is immediately followed by massive release of neurotransmitter substances including acetylcholine, catecholamines, and glutamate (Becker et al., 1989; Faden et al., 1989; Kawamata et al., 1992). This is accompanied by a cessation of impulse transmission and unconsciousness for a variable period. Recent studies have shown a marked increase in cerebral metabolism (measured by the glucose utilisation technique) in the first few minutes after a severe injury: cerebral metabolism then becomes depressed for several hours (Kawamata et al., 1992). This early increase in metabolism associated with widespread depolarisation of axonal membrane and release of excitatory neurotransmitters suggest that diffuse axonal injury may be briefly excitatory (Becker et al., 1989; Faden et al., 1989; Katayama et al., 1990). This may provide a mechanism to explain the delayed structural damage to neurons and glia which is seen in EM studies (Erb & Povlishock, 1988). This hypothesis provides a rational basis for the use of NMDA antagonists to limit 'excitotoxic' damage, after axonal 'shear' injury of this type (Faden et al., 1989; Kawamata et al., 1992). Previously, diffuse axonal injury was thought to have been an 'instantaneous' event in which both physical and chemical functional disruption of axons, widespread over large parts of the nervous system, occurred at the moment of impact (Adams et al., 1983). Recent histological studies by the Povlishock group have shown that structural axonal disruption only develops later (Erb & Povlishock, 1988). This may be a consquence of widespread depolarisation with ingress of sodium and calcium ions and efflux of potassium into the extracellular space (Katayama et al., 1990). This then results in swelling of axoplasm and glia, which may eventually proceed to cause mechanical disruption in some axons, eventually causing 'retraction balls'. Further evidence for this consequential damage hypothesis has been provided by the careful clinical studies of Blumberg etal. (1989), who have shown that 30% of patients with histological evidence of diffuse axonal injury at post mortem had spoken at some time after impact during their clinical course.
Figure 2 Cerebral blood flow mapping using 99mTc HMPAO single photon emission computed tomography, after a severe head injury, with an acute subdural haematoma in situ. Right: MRI (T2 weighted) scan: The haematoma appears as a bright band over the right cortical surface, and at the tip of the contused frontal lobe. Note the corresponding severe reduction in cerebral blood flow in the right hemisphere, under the haematoma, on the blood flow scan (left).
Cerebral contusion - mechanisms of neuronal damage
Early histological studies have shown that a zone of pyknotic neuronal damage and death extends up to a centimetre around the haemorrhagic zone in a cerebral contusion (Lindenberg & Freytag, 1957). Cerebral contusions may be widespread and involve extensive areas of the subfrontal and temporal cortex so that large areas of brain may be functionally decorticated by this damage mechanism (Bullock et al., 1991). Regional cerebral blood flow mapping studies in Glasgow have recently shown that a contusion is always accompanied by a zone of profoundly reduced cerebral blood flow, probably sufficient to cause death of neurons (Wyper et al., 1991). It is uncertain, however, whether this is a primary or a secondary mechanism. Ultrastructural studies in patients who have undergone removal of their contusion have shown extensive perivascular astrocytic foot process swelling and massive swelling of astrocytes in general as the dominant ultrastructural feature (Bullock et al., 1991). In many areas perivascular foot process swelling was sufficiently advanced to compress and occlude the lumen of capillaries. It thus appears that a primary process which initiates astrocyte swelling may cause the profoundly reduced cerebral blood flow which we have seen. This swelling may be a response to the same ion flux phenomena which have been described for diffuse axonal (fluid percussion) injury. Cerebral contusion and intracerebral haematoma may also damage the brain by mechanical disruption - with tearing of the pia arachnoid and underlying neuropil.
Recently, we have performed pilot studies which invite the speculation that the millimolar concentrations of glutamate present in the haemolysed blood of an acute haematoma or contusion may also exacerbate neurotoxic damage in already ischaemic tissue.
Evidence for excitotoxic mechanisms after head injury animal studies
Fluid percussion injury in rats Several authors have demonstrated a large increase in extracellular excitatory amino acids following impact injury associated with widespread depolarisation (Becker et al., 1989; Faden et al., 1989; Katayama et al., 1990). This has led to outcome studies with NMDA antagonists, particularly MK801 and phencyclidene. Hayes et al. (1992) have demonstrated that pretreatment with MK801 in rats after fluid percussion results in a dose dependent improvement in mortality (severe FPI) and memory and motor tasks (moderate FPI) as assessed using the Morris water maze and beam walking tasks. Similar improvements have been demonstrated for phencyclidene also. Subdural haematoma in the rat In our studies with the rat subdural haematoma model, we have demonstrated a sevenfold increase in glutamate
NMDA antagonists in clinical practice
by ischaemia when the subdural haematoma is induced (Figure 3). This process is associated with an increase in glucose metabolism both in the 'peri-ischaemic' zone around the infarct, and also in hippocampus (up to 142% increase) (Kuroda et al., 1992a). This hypermetabolic process is transient, persisting for somewhere between 2 and 4 h suggesting that this may be the 'window of opportunity' during which glutamate release is activating and damaging cerebral tissue (McCulloch et al., 1991). An interesting feature of this subdural haematoma model has been noticed in the hippocampus. The increase in metabolism associated with a surge in excitatory amino acids appears to induce mild ultrastructural changes in neurons particularly in the CA3 sector which in a few cells - (2 to 3%) leads to subsequent neuronal death (Bullock et al., 1991). This occurs in spite of the fact that blood flow is preserved at levels well above the thresholds for ischaemia - around 90-100 ml lOOg-1 min-' in this model - a phenomenon similar to the 'delayed neuronal death' of Kirino et al. (1984). Pretreatment with the competitive NMDA antagonist D-CPP-ene in high doses (15 mg kg-') has been able to abolish the hypermetabolism for glucose at 2 h and significantly reduce the size of the infarction occurring underneath the haematoma (by 54%) (Figure 3) (Chen et al., 1991; Inglis et al., 1991).
Neuroprotective effects of NMDA antagonists in models of 'pure' cerebral ischaemia c
Figure 3 a) H + E stained brain section (x 10) after subdural haematoma in the rat. Solid arrow haematoma, open arrow zone of underlying infarction. (b) Changes in glucose metabolism two hours after subdural haematoma, in a similar hippocampal section to the above. Note the large zone of severely reduced metabolism and adjacent 'peri'-ischaemic zone of increased metabolism. Glucose metabolism is increased up to 142% in the hippocampus bilaterally. (c) Changes in glucose metabolism 2 h after subdural haematoma in a rat pretreated with the competitive NMDA antagonist D-CPP-ene (15 mg kg-). Note that the 'infarct' zone is significantly reduced, and the hippocampal and periischaemic hypermetabolism are markedly attenuated. -
within the extracellular space after induction of the haematoma (Bullock et al., 1990; Miller et al., 1990). This was most marked in the ischaemic area beneath the haematoma, but a threefold increase in glutamate release was also seen in the hippocampus a zone unaffected -
Numerous studies have now been performed to test the ability of both competitive and non-competitive NMDA antagonists, (and non-NMDA glutamate antagonists) to reduce brain damage after an ischaemic insult. Table 2 summarises those studies performed with focal ischaemia models. NMDA antagonists have been most effective when administered before the insult, in permanent focal ischaemia, such as middle cerebral artery occlusion in the rat, and cat. MK801 has also been effective when given up to 2 h after the ischaemic event. The consistency and magnitude of this neuroprotective effect exceeds that which has been seen for any other category of 'neuroprotective' agent. The effects of NMDA antagonists after global transient ischaemic insults are much less certain. Although a few studies have yielded positive results, the majority have been negative (Meldrum, 1990, for review). Clinical characteristics which favour the use of NMDA antagonist drugs after human head injury Most severely head injured patients are hospitalised within a few hours of their injury and they are usually managed by intensive monitoring in an intensive care unit. Most patients will nowadays be paralysed and ventilated from the time of arrival in hospital so that the use of potentially psychotomimetic or psychoactive drugs should pose fewer problems than in conscious patients. Concomitant use of sedating drugs such as benzodiazepines and opiates should prevent potentially unpleasant psychomimetic side-effects.
Table 2 The effects of excitatory amino acid antagonists in experimental focal cerebral ischaemia
Pretreatment! Species Cat
MCA (Temp) MCA MCA ACA/CC (temp)
MCA MCA MCA/SHR MCA MCA MCA MCA
Magnitude of neuroprotection %
Pre and Post
MK 801 Ifrenprodil/SL 82-715 D-CPP-ene Dextrorphan Dextromethorphan MK 801 MK 801 MK 801 MK 801 MK 801 BW 1003 C87
Post Post Pre and Post Pre and Post
Pre and Post Pre Pre Pre Pre Post
Mg ++ MK 801 MK 801 MK 801 MK 801
Post Post Pre Pre Post
MCA/CC MCA/CC/SHR MCA For details of references see McCulloch et al. (1991).
NMDA antagonists - particularly the high affinity competitive antagonist D-CPP-ene have sedative properties which may reduce the need for opiates and benzodiazepines in head injured patients - a potentially beneficial effect (Inglis et al., 1991). Studies in our laboratory have shown that the NMDA antagonists D-CPP-ene, CGS 19755, and MK801 do not raise intracranial pressure in rats with an intracranial mass lesion and controlled ventilation with a constant Paco2 (Kuroda et al., 1992b).
Competitive NMDA antagonists in high doses may induce hypotension (McCulloch, 1990). This may be a problem in clinical use particularly in patients who have recently sustained multiple injuries (Jenkins et al., 1989). In such patients, careful monitoring of arterial and central venous pressure and concomitant pressor agents (inotropes such as dopamine) may be needed. The sedative effects of these drugs in high doses may induce problems with CO2 retention, and a consequent rise in intracranial pressure in those patients who are not paralysed and ventilated. It is thus our view that these agents should be reserved
-41 -40 -15 -54 - 19 (NS) Significant reduction
Investigators Ozyurt et al. (1988) Park et al. (1988) Uematsu et al. (1990) Gotti et al. (1988) Bullock et al. (1990) Steinberg etal. (1988, 1989) Park et al. (1988) Tamura et al. (1988) Coyle (1989) Bielenberg (1989) Panetta et al. (1989) Meldrum (1991)
-32 -73 -23 -44
Buchan et al. (1990) Dirnagl et al. (1990) Hatfield et al. (1990)
(at least initially) for those patients managed by artificial ventilation. Recent laboratory studies with competitive NMDA antagonists suggest that these agents may have characteristics which make them in some respects an ideal agent for 'neuroprotection' after severe head injury. If a reduction in the incidence of mortality and morbidity in this heterogeneous condition can be demonstrated with these agents, then further studies should be undertaken in those patients at high risk of delayed brain damage after a subarachnoid haemorrhage, and also in carefully selected patients diagnosed and monitored early after an occlusive stroke where intensive care treatment and possibly concomitant ventilator therapy can be justified. NMDA antagonists may find an indication as adjuncts to anaesthesia, a role which would optimise their sedative ('neuroleptic'?) properties and their neuroprotective role. A major logistical challenge for clinicians, however, remains: the delivery of 'neuroprotective' drugs to brain damaged patients must be acheived as soon as possible after the event because all the available evidence suggests that excitotoxic processes probably occur predominantly within the first 1 to 3 h after the onset of ischaemia, although delayed 'bursts' of damage may occur, even days later.
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(Received 27 March 1992, accepted 8 April 1992)