Search

Discontinuation of ventilation after brain stem death {#article-title-2} Confusion among the public over the difference between brain stem death and a persistent vegetative state can make it difficult to obtain consent to withdraw ventilation. Clinicians who have been faced with this dilemma outline their strategies for coping with such a situation, and a neurologist and a neurosurgeon offer their opinions. # To whom is our duty of care? {#article-title-3} The concept of brain death is not often discussed in the public arena. According to the royal medical colleges in the United Kingdom and their faculties death of the brain stem is a component of brain death, and brain death is death.1 The criteria for brain stem death are well established,2 and their use in intensive care units enables treatment to be withdrawn from patients with brain stem death without recourse to the courts. Conversely, as a result of several high profile cases, persistent vegetative state has been reported on frequently in recent years. The application to the High Court in 1992 to discontinue life sustaining treatment for Tony Bland, who had been injured in the tragedy at Hillsborough football ground, brought the ethical debate to the front pages of the national press. Occasional stories of “miraculous recoveries” from comas are widely reported and may have led to an exaggeration of the small chances that patients have of recovering from a persistent vegetative state among a public that is increasingly well versed in this condition. This contrasts with the inevitable death from asystole which occurs within a few days for patients who are brain dead.3 We have experienced a case in which, although the patient had been declared brain stem dead, the patient's family prevented us from switching off the ventilator. On this occasion our intensive care unit was full, and maintaining this patient on a ventilator might have forced us to transfer any new …

Traumatic brain injuries (TBI) are one of the most common consequences of traffic accidents. Patients with mild, moderate or severe brain injuries suffer from physical, cognitive, behavioral, emotional and social problems. Most of these problems have been a long standing focus amongst practitioners and researchers. Only recently a development has started that took interest in the quality of life outcome of TBI patients. The international members of this consensus meeting reviewed the literature on Quality of Life assessment after TBI and discussed the applicability of different measurements to this specific patient group.During the acute phase (T1;3 month after trauma) QoL it is difficult to assess due to the reduced consciousness of TBI patients. In the phase of rehabilitation (T2;one year after trauma) and in the post-rehabilitation phase (T3) repeated assessment of QoL is recommended.Several generic and disease-specific instruments possibly relevant to TBI patients or specifically developed for this group were assessed according to the existing evidence in the literature. Criteria for the evaluation of these instruments were: feasibility, specificity, validity, comprehensiveness, international availability, existence of norms, and psychometric quality. The cognitive impairment and the existential dimension were not sufficiently considered in most of the reviewed instruments.The family's and relatives' view of the patient's QoL should not be used as a proxy but provides an additional source of information in the acute phase. At T2 and T3, assessment of the patient's quality of life should include a generic as well as a disease specific instrument. Among the generic instruments the SF-36, the EuroQol and the WHO-QoL should be considered. The literature about specific instruments for patients with TBI like the EBIC is scarce. Therefore, the group could hardly give an empirically based recommendation. The need for further investigation on QoL instruments in TBI patients is strongly emphasized.

In most surgical specialties there are wide variations in what surgeons do for the same kinds of patient. Reporting studies of surgical variations between adjacent counties of New England, and between New England and old England and other European countries, Wennberg concluded that these differences reflected the practice styles or surgical signatures of different surgeons [6]. In his view wide variations in practice indicate professional uncertainty about the effectiveness of, or necessity for, those interventions that are used at very different rates.

We have shown previously that acetaldehyde forms stable covalent adducts with tubulin, resulting in impaired microtubule formation. The present study explored the mechanism responsible for impaired microtubule formation caused by the substoichiometric stable binding of acetaldehyde to tubulin. The free tubulin dimer was much more reactive with acetaldehyde than microtubules, binding more than twice as much aldehyde. The dimer also formed nearly twice as many stable adducts on its alpha-chain as on its beta-chain, whereas microtubules exhibited an equal distribution of adducts between the two subunits. These data confirm that the alpha-chain of free tubulin, but not microtubules, has an accessible highly reactive lysine (HRL) residue that is a preferential target of acetaldehyde binding. Adduct formation with the HRL residue also correlated with impaired tubulin polymerization, and only 0.08 moles of acetaldehyde bound per mole of HRL was required for complete inhibition; however, adducts with other lysine residues (bulk adducts) did not affect assembly. Adducts to microtubule-associated proteins (MAPs) also impaired the assembly of tubulin, but were much less effective than HRL adducts. In a copolymerization assay, HRL-adducted tubulin, in addition to being itself assembly incompetent, also interfered with polymerization of normal (unadducted) tubulin. Bulk adducts did not alter assembly and were incorporated normally into the growing polymer. When tubulin was cleaved by the proteolytic enzyme, subtilisin, microtubule formation could readily take place in the absence of MAPs. In this polymerization system, HRL adducts, but not bulk adducts, still markedly inhibited assembly. When low concentrations of acetaldehyde (50 microM) were used to generate HRL adducts, an adduct on only 1 out of 20 tubulin molecules was sufficient to totally block polymerization. These findings indicate that substoichiometric amounts of acetaldehyde bound to HRL of tubulin can markedly inhibit microtubule formation via direct interference of dimer-dimer interactions, and further suggest that low concentrations of acetaldehyde could generate sufficient amounts of HRL adducts in cellular systems to alter microtubule formation and function.

Treatment that results in death or survival with unacceptable disability should be minimized. A decision to limit treatment can sometimes be made within 48 hours. Failure to decide may deny intensive care to other patients who could benefit.

In most Westernised countries injury is the leasing cause not only of death under the age of 45, but also of years of life lost between the ages 1 and 65 years. By these measures injury is ahead of heart disease, stroke and cancer in the UK, West Germany, France, the US and Japan. The proportion of all deaths that are due to accidents varies considerably between countries, higher in Australia and Canada than in the USA and West Germany, and less common in the UK. Road accidents account for about a half of accidental deaths in North America, Australia and West Germany but for only a third in England and Scotland. Road accident deaths per 100000 population vary from 30 in West Germany, Australia, and Canada, through 22 for the USA, to only about 15 in the UK (WHO 1987).

The strategy of head injury management should be to minimize avoidable mortality and morbidity by reducing secondary brain damage. Patients with severe injuries are a minority, and their main needs are maintenance of the airway and nutrition. Some patients with less severe injuries are at risk for developing intracranial hematoma, and these need CT scanning. Pharmacological interventions may improve the outlook for patients with diffuse injuries associated with brain swelling.

Features of patients transferred to a regional neurosurgical unit in coma after recent head injury were compared with a similar audit seven years previously. There were fewer avoidable adverse factors in the recent series, but some patients received inadequate care of the airway, while in some others major extracranial injuries were overlooked or poorly managed. Only 42% of the comatose patients had had an endotracheal tube inserted; half those in whom neither a tube nor an oral airway had been inserted were transported supine. Systemic hypoxia or hypotension [corrected] were associated with a poor outcome. Even when computed tomography scanners become available in more hospitals, many patients who are unconscious after head injury will still need to be transferred to a neurosurgical unit. Detailed guidelines should be agreed locally to minimise the hazards of transfer of unconscious patients between hospitals. A rota of experienced doctors and nurses at the sending hospital should be responsible for deciding how each individual patient should be managed during transfer, according to the guidelines. Continuing audit of such cases is needed to indicate whether revision of local practice is needed.

The ability to predict outcome in the early stages of severe head injury would have several uses. A computerized system which has been developed in Glasgow to assist clinicians in this task, based on information from over 2500 severely head-injured patients, is described, with particular attention to the testing of the statistical properties of the system, and, more importantly, the assessment of its clinical impact.

The effects of phenobarbital on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Phenobarbital (2 mM) decreased [14C]glucosamine and [14C]leucine incorporation into liver proteins and markedly inhibited their incorporation into medium (secretory) proteins. The inhibitory effect of phenobarbital was dose dependent and not reversible under the conditions of this study. In the presence of cycloheximide, an inhibitor of peptide synthesis, phenobarbital still inhibited the release of glycoproteins into the medium; however, the specific activity of liver glycoproteins was increased. The effects of phenobarbital on hepatic macromolecular secretion, independent of its effects on synthesis, were determined by prelabeling proteins in a liver slice system with either [14C]leucine or [14C]glucosamine. When phenobarbital was present, the secretion of these prelabeled proteins into the medium was inpaired. 12 h after intraperitoneal injections of phenobarbital, glycoprotein secretion was inhibited from liver slices prepared from the pretreated rats. This inhibition of secretion occurred even though protein synthesis was stimulated and intracellular glycosylations unaffected. The results of this study indicate that phenobarbital impairs the secretion of glycoproteins by the liver.

The regulatory protein, calmodulin, undergoes major conformational changes in response to changes in intracellular calcium concentration. Furthermore, calmodulin has been reported to have lysine residues which markedly increase their reactivity toward electrophilic substances in the calcium-loaded state. We found that calmodulin formed two or three times more stable adducts with acetaldehyde in the calcium-loaded state as compared to the calcium-free state. Competition-binding studies showed that calmodulin could preferentially compete with albumin for acetaldehyde in the presence, but not in the absence, of calcium. When calmodulin was in the calcium-loaded state, trifluoperazine, an inhibitor of calmodulin activity, significantly decreased the stable binding of acetaldehyde to the protein, whereas in the calcium-free state, minimal effects on binding were observed. Since calmodulin is involved in regulation of multiple important processes in the cell, it is possible that acetaldehyde-calmodulin adducts could contribute to liver injury by perturbation of calcium-dependent homeostatic mechanisms within the hepatocyte.

The effects of ethanol on the synthesis and secretion of serum glycoproteins and albumin, a nonglycosylated protein, were studied in rat liver slices. Serum glycoproteins and albumin were determined by immunoprecipitation from either the incubation medium or from the washed slices. When ethanol (10 mM) was present in the incubation medium, [14C]glucosamine incorporation in secretory glycoproteins was decreased. This inhibitory effect was, however, much greater in the secretory proteins released into the medium than in those retained in the liver slices. Similar inhibitions by ethanol were also observed when leucine or valine were used as a label for either total export proteins or albumin. Since ethanol impaired protein synthesis, and inhibitor of protein synthesis, cycloheximide, was used so that both the control and ethanol-treated slices had identical pools of protein acceptors available for glycosylation. When cycloheximide alone was added to the slices, glucosamine radioactivity of secretory glycoproteins was equally reduced in both the medium and the liver. When cycloheximide and ethanol were both present, decreased appearance of glucosamine-labeled proteins in the medium was observed when compared to the slices containing cycloheximide alone; however, radioactivity of secretory glycoproteins retained in the liver was elevated. Ethanol also decreased the appearance of fucose-labeled glycoproteins in the medium without altering fucose incorporation into the total pool of secretory glycoproteins. The effects of ethanol on hepatic protein secretion independent of its effect on synthesis were further determined by prelabeling proteins with either [14C]leucine or [14C]fucose. Ethanol impaired the secretion of these prelabeled proteins into the medium. The results of this study show that ethanol impairs both the synthesis and secretion of secretory glycoproteins and albumin.

Colchicine-binding properties of the total cytoplasmic pool of tubulin from rat liver were evaluated in tubulin-stabilizing (TS) supernates. Microtubules were separated from free tubulin using a microtubule-stabilizing solution (MTS) and ultracentrifugation. [3H]Colchicine-binding properties of microtubule-derived tubulin were investigated in supernates prepared after resuspension of MTS pellets in TS. In TS buffer at 37 °C the colchicine-binding activity of the total cytoplasmic pool of tubulin decayed with T 1 2 of 3.39 h. Resuspended pellet tubulin decayed much more rapidly under the same conditions with a T 1 2 of 0.72 h. This rapid time decay of microtubule-derived tubulin was found to be at least partially attributable to prior microtubule-stabilizing solution exposure. Since tartrate has been reported to increase the rate of colchicine binding to tubulin, sodium tartrate (150 m m ) was added to our colchicine-binding system. This addition increased the detectable [3H]colchicine binding by 10% in the total cytoplasmic preparation and by 85% in the resuspended pellet preparation. Addition of tartrate (150 m m ) also resulted in a 105% increase in the T 1 2 for total cytoplasmic tubulin and a 412% increase for microtubule derived tubulin. Total cytoplasmic supernates of liver bound [3H]colchicine linearly over a wide range of tissue concentrations. However, resuspended microtubule-stabilizing solution pellet supernates in tubulin-stabilizing solution showed some increase in colchicine binding per tissue weight in the more dilute samples. Our data which demonstrate differences in colchicine-binding properties for total cytoplasmic and microtubule-derived pools of tubulin suggest that present assays for hepatic tubulin polymerization which assume identical binding properties should be interpreted with caution.

Ethanol, acetaldehyde, and acetate were investigated for their effects on bovine neurotubulin polymerization. Ethanol at concentrations as high as 50 mM did not affect the rate or extent of tubulin polymerization. Acetyldehyde inhibited tubulin polymerization in a concentration-dependent manner, with complete inhibition at 10 mM and slight inhibition at 1 mM. Sodium acetate caused a concentration-dependent increase in tubulin polymerization, however sodium chloride showed a similar effect. These data indicate that ethanol and acetate were not inhibitors of microtubule formation while acetaldehyde exhibited weak inhibitory activity.

Accident is now the commonest cause of death under the age of 45 years in developed countries. Head injuries contribute to many fatal accidents, and are the only common cause of persisting disability in survivors. In Britain, which has less than half the head injury death rate (per unit of population) that prevails in North America, Australia, West Germany or France, there are a million patients attending British hospitals each year with head injury. Many of these are mildly injured, but even so there may be minor sequelae for weeks or months. There are about 7000 deaths each year, and at least 1500 patients leave hospital with permanent brain damage, half of them never to work again; as the average age of these severely injured survivors is under 30 years, they face many years of disability.

When the brain is examined within a few days of injury it can be surprisingly difficult to establish what has been the cause of death, or to determine with certainty which lesions are primary and which are secondary, apart from clear-cut complications such as intracranial haematoma or infection. Recent reports of continuous measurements of intracranial pressure after head injury (Lundberg, Troupp, and Lorin, 1965; Troupp, 1965 and 1967) suggest that many patients who die after head injury develop very high intracranial pressure before death without necessarily having a focal expanding lesion. The effect of a generalized increase in intracranial pressure on the brain is ultimately to produce a reduced perfusion of blood and the brain will then suffer hypoxic damage. In the belief that this may be one of the mechanisms contributing to brain damage after head injuries (and other lesions causing raised pressure) we have explored various aspects of the relationships between intracranial pressure and cerebral blood flow. The oxygen supply to the brain depends, as in any other tissue, on the equation: available oxygen = haemoglobin x oxygen saturation x blood flow. A reduced oxygen content of the blood is not uncommon after head injury, which makes the brain much more critically dependent on blood flow. Blood loss from associated injuries, which occurs in a third of all cases of head injury admitted to hospital, commonly gives a low haemoglobin. Respiratory difficulties are also frequent after head injury, either due to the unconscious state or to associated chest injuries, and as a result of ventilatory insufficiency the oxygen saturation is then reduced. Blood flow in the brain has a characteristic peculiar to its situation within a rigid closed cavity, namely, its susceptibility to surrounding tissue pressure. Indeed the supply of blood to the brain depends on cerebral perfusion pressure, which is the difference between systemic arterial pressure and intracranial pressure. Cerebral perfusion may be altered not only by systemic hypotension but also by raised intracranial pressure. Whilst hypotension is uncommon in patients suffering from head injury alone, the

SUMMARY The effects of the neuroleptanalgesic drug combinations, droperidol 5 mg+phnoperidine 1.5 mg, and droperidol 5 mg+fentanyl 0.1 mg, on the cerebrospinal fluid (c.s.f.) pressure, have been studied in patients with normal c.s.f. pathways during controlled ventilation. The influence of droperidol 5 mg+fentanyl 0.1 mg on intracranial pressure has also been investigated in patients with intracranial space-occupying lesions. In patients with normal c.s.f. pathways, droperidol and phenoperidine produced only small alterations in c.s.f. pressure in either direction, while a significant decrease in overall mean c.s.f. pressure. Similarly, in patients with intracranial space-occupying lesions, droperidol plus fentanyl produced decreases in c.s.f. pressure in all but one of the cases studied. The striking difference between the effect on c.s.f. pressure of these drugs and of the volatile anaesthetic agents could be of importance to the clinical anaesthetist dealing with head injuries or working in a neurosurgical unit, when under conditions of controlled ventilation these drugs could be used as adjuvants to nitrous oxide-oxygen anaesthesia.

Immunization of mice with acetaldehyde conjugated to human plasma proteins resulted in the production of polyclonal antibodies that reacted with erythrocyte protein-acetaldehyde conjugates, but not with control erythrocyte proteins. Such antibodies recognized erythrocyte protein-acetaldehyde conjugates prepared with 20–100 μM acetaldehyde, concentrations that exist in the blood of alcoholics. The antibodies also recognized acetaldehyde condensation products with synthetic poly-(L-lysine). Immunization with keyhole limpet hemocyanin-acetaldehyde conjugates resulted in antibodies against both plasma protein-acetaldehyde and erythrocyte protein-acetaldehyde conjugates, which did not cross-react with the respective unmodified carrier proteins. Immunization with human erythrocyte protein-acetaldehyde condensates led to the production of antibodies against both the protein moiety as well as the condensate. Monoclonal antibodies with affinities 50 times greater for the condensate than for the carrier protein were produced by hybridization of spleen cells from the immunized mice. Chronic alcohol administration to mice for 45–50 days led to the generation of antibodies that reacted against protein-acetaldehyde conjugates, suggesting that such adducts are formed in vivo and can act as neoantigens. Antibodies against acetaldehyde adducts should be of value in the identification of alcohol consumption and in the study of the biology of the adducts in relation to organ pathology.

Three weeks after admission to a maternity hospital for observation following minor antepartum haemorrhage, a primiparous patient aged 22 suffered a sudden left hemiplegia and became comatose. Congestive cardiac failure ensued and because of the subsequent severe hypoxaemia she was transferred to the hyperbaric oxygen unit at the Western Infirmary, Glasgow, where it was found possible to improve her condition by means of oxygen at increased pressure. A caesarean section was w successfully performed in the hyperbaric chamber, and a normal live female infant was delivered. Though the patient's general condition improved she never regained consciousness and died almost three months later. Necropsy confirmed the clinical diagnosis of cardiomyopathy of pregnancy with severe ischaemic changes in the brain.

In 1966 we published a preliminary communication indicating that measurements of rCBF in the operating room before and after trial occlusion of the carotid arteries in the neck might provide a better estimate of the risk of permanent ischemia of the cerebral hemisphere than methods already available. On the basis of our experience with those 10 cases it seemed that 25% reduction during trial clamping was a critical level; with a greater reduction of flow than this hemiparesis often occurred. This communication reports our experience with a further 58 patients.

Prognosis depends on establishing a relationship between the patient's state in the early stages and the ultimate outcome. Both the severity of the initial damage (including early complications) and the degree of recovery need to be defined, but practical and statistical considerations impose a limit on the number of variables which can be manipulated. Variables chosen should be those likely to be relevant, and pilot studies are more reliable than intuition in indicating which items should be included. Data chosen should be of a kind likely to be readily available for most patients and should not therefore depend on complex laboratory investigation. The most reliable indicant of initial severity appears to be the depth and duration of coma or altered consciousness, and a scale has been devised for measuring these. Measures of outcome should include separate assessment of mental and physical disability as well as the overall social consequence of the brain damage. Prognosis should be expressed as the probability (mathematically expressed) that a patient will reach certain defined outcome categories, five of which are recognized in the present study. Predictions should begin only after initial resuscitative measures are complete (say six hours after ictus); they need not be limited to the early stages but can include estimates of the degree of further improvement expected in the light of progress in the early weeks after injuries. New methods of management cannot be critically assessed unless factors influencing prognosis are reliably identified and can be matched in comparative patient groups. An estimate of prognosis is also required for the selection of patients for intensive treatment, both in the acute and in the rehabilitation stage. Without such data there is a tendency to deploy an unduly high proportion of scarce resources on patients who have little prospect of recovery; this may deny the best chance of recovery to patients with severe, but less overwhelming, brain damage.

Opinions about the importance of age as a prognostic factor after head injury have varied. For instance, Carlsson et al.1 emphasized a close correlation between increasing age and a decreasing change of mental recovery; but others2 report that age has little influence on the prospects for recovery.

No apologies are needed for returning to the subject of brain death and its definition. There has been so much public discussion that it is important for public confidence that the issues should be clarified. In the following two contributions - one from a professor of neurosurgery and the other from a lawyer - an attempt is made to convince doctors (if that is needed) and lay people alike that what appears to be a new bogy is not one at all but a confusion of thought arising from the use of new technology to treat brain-damaged patients. This, however, might not be the view of Mr Skegg (Journal of medical ethics, 2, 190) who, fearful of the situation, has argued for a statutory definition of death.

The covalent binding of [14C]acetaldehyde to purified rabbit skeletal muscle actin was characterized. As we have found for other cytoskeletal proteins, actin formed stable covalent adducts under reductive and non-reductive conditions. Under non-reductive conditions, individual and competition binding studies versus albumin both showed that the G-form of actin is more reactive toward acetaldehyde than the F-form. When proteins were compared on an 'equi-lysine' basis under non-reducing conditions, G-actin was found to preferentially compete with albumin for binding to acetaldehyde. Time-course dialysis studies indicated that acetaldehyde-actin adducts become more stable with prolonged incubation at 37 degrees C. These data raise the possibility that actin could be a preferential target for adduct formation in cellular systems and will serve as the basis for ongoing studies aimed at defining the role of acetaldehyde-protein adducts in ethanol-induced cell injury.

In 1975 Jennett and Bond published an account of a Global Outcome Scale which they developed for use in the assessment of individuals who have had head injuries. The Scale has been used widely in several contries including Britain, Holland, and the United States, and familiarity with it has brought several criticisms. The main ones are, first, that it is a crude measure and not sensitive to subtle changes in patients’ status and, second, that there is little background information about the nature and extent of physical and mental handicaps which make up the first three elements of the Scale. In other words, we wish to know what constitutes good recovery, moderate disability and severe disability. Jennett and others (1978) accept the first of these criticisms, and in a response to it have expanded the categories mentioned above from three to six thereby giving increased sensitivity. In order to deal with the second criticism a careful study of the mental and physical deficits of two groups of brain injured individuals has been carried out. Four kinds of disability have been examined. In a first sample of 150 patients physical, cognitive, and personality deficits have been graded as nil, mild, moderate, or severe, and related to outcome at six months after injury by which time most of these deficits are established. In a second sample, which is still under study, in addition to the deficits examined in the first group, the social consequences of disability are being examined in detail. Results from the first study show that some deficits, albeit mild, were detectable in 97% of the patients examined. Two-thirds had personality change, two-thirds had cognitive change, and 93% had one or other of both of these mental deficits. Physical handicaps were present in 75% of patients, but were less significant than mental handicaps which dominated recovery in just over half the patients in the survey. This pattern was repeated in each of the three outcome categories examined. In more detail, in 30% of patients the only detectable deficit was a change in personality, a figure which increased to 60% in patients without physical deficits or one of only a mild degree, and to a similar extent in those with nil or mild cognitive deficits.