1129

below 20

EDITORIALS

ml/100 g per min a hierarchy of functional

disruption starts. First there is failure of neuronal electrical (and therefore clinical) function; at flows below 15 ml/ 100 g per min there is progressive failure of the energy-dependent ionic pumps that maintain the internal milieu of the neurons; and below 10 ml/100 g per min there is a dramatic flux of ions across the neuronal membrane and a cascade of destructive events leading to irreversible cell death. Oxygen deficiency via ischaemia prevents oxidative phosphorylation, which curtails ATP production, thereby impairing ion or neurotransmitter transport across cell membranes and protein biosynthesis. ATP poverty is especially destructive in its effects on the intricate control over calcium ion entry and distribution within cells.’ The uncontrolled calcium entry into neurons and their mitochondria associated with homoeostatic failure activates destructive lipases, proteases, and endonucleases. During this calciumtriggered cascade, highly reactive free-radical species (atoms or molecules with an unpaired electron in their outer

Treatment for stroke? Outcome after an ischaemic stroke is related to the volume of infarction measured by computed tomographic (CT) scanning.1 If a treatment achieved the modest aim of reducing this volume by even 20 %, a substantial amount of disability would be prevented. This is the ultimate goal of researchers seeking to unravel the pathophysiology of cerebral infarction. Hopes for salvaging ischaemic brain after cerebral artery occlusion depend on the perception of cerebral infarction as a process rather than an event. In studies of cerebral blood flow and metabolism in cerebrovascular disease, notably with positron emission tomography (PET), a series of compensatory mechanisms follow reduction of cerebral perfusion pressure.2Initially vasodilatation (demonstrable as focally increased cerebral blood volume) prevents any fall in cerebral blood flow. Areas of brain with exhausted vascular reserves may be recognised by nuclear medicine methods that are not

dependent on PET technology--eg, single photon emission tomography. Other isotopic methods that measure mean cerebral transit time depend on still more widely available equipment and may be more applicable in clinical trials.33 Even when the cerebrovascular reserve is exhausted and cerebral blood flow falls, adequate energy supplies may be provided by increased oxygen extraction, maintaining the cerebral metabolic rate for oxygen until further falls of cerebral perfusion pressure overcome homoeostatic mechanisms and the ischaemic process

begins. Our understanding of cerebral ischaemia is founded the concept of ischaemic thresholds and the "ischaemic penumbra" developed by Astrup and colleagues.4At various levels of cerebral blood flow

on

orbit)

are

released, probably contributing

to

ischaemic damagesIf there is supply of glucose to ischaemic brain, some ATP can be produced by anaerobic metabolism, but this process generates hydrions. Acidosis exacerbates the ischaemic process, including free-radical generation. Hydrogen ion extrusion via a Na + !H antiporter is one regulator of intracellular pH, but consequent entry of sodium ions exacerbates cell swelling if it is accompanied by failure of the energy-dependent sodium pumps. Hydrogen ion entry into neurons probably also displaces calcium from intracellular binding sites, further enhancing cellular damage. The role of the excitatory neurotransmitter glutamate in the ischaemic process excited much interest after the observation that in ischaemia there is an increase in extracellular glutamate. This increase may be caused by inappropriate entry of calcium into presynaptic terminals, probably with impairment of the ATP-requiring reuptake of glutamate into neurons and astrocytes. On the postsynaptic membrane are three main subtypes of glutamate receptor, activated selectively by N-methyl-Daspartate (NMDA), kainate (K), and quisqualate (Q), respectively. The K and Q receptors operate a conductance channel for monovalent ions that allows Nato enter in exchange for K +. The NMDA receptor operates a Ca + channel which is blocked by Mag+in a voltage-dependent manner. This receptor is also subject to inhibitory modulation by glycine. Depolarisation of the neuron allows calcium entry via the NMDA gated channel and amplifies the ischaemic cascade. Neurons that are especially sensitive to ischaemia--eg, the cornu Ammonis 1 pyramidal cells of the hippocampus-have a high density of glutamate receptors. If the cause of ischaemic stroke is cerebral arterial occlusion, why not open up the vessel, either

surgically

or

with

thrombolysis? Unfortunately

this

1130

haemorrhagic transformation

of bland infarctions in which the vascular endothelium is made leaky by ischaemia. Furthermore, after ischaemia of some duration, swelling and local thrombosis activated during the ischaemic cascade may prevent reflow.8 Opening up vessels--eg, with the thrombolytic agent human tissue-type plasminogen activator-might help if patients are at the critical stage of cerebrovascular reserve exhaustion before the ischaemic process has started. Ischaemic brain may need additional protective therapy before blood flow is restored; restoration occurs spontaneously in many arterial occlusions.9 How much time is there to salvage ischaemic brain before cell death becomes inevitable? Some brain tissue in the territory of an occluded artery may receive enough blood via anastomotic channels to maintain flow above the level of complete ionic pump failure but below that required for electrical function. This is the ischaemic penumbra. Experimental evidence suggests that metabolic failure may occur if this precarious flow is not reversed within 3-4 hours. 10 The central zone of the arterial territory is densely ischaemic and infarction will occur within 60 minutes, probably before therapy could be initiated. At the edge of the territory (probably more patchily than the expression penumbra suggests) tissue may be salvageable. Therapeutic intervention needs to be well organised since it is unusual for patients with stroke to be assessed in hospital within 6 hours, although Fieschi et al9 have shown that this is possible. Are there any agents that might halt the ischaemic process before infarction becomes inevitable? Among the possibilities are. NMDA receptor blockers, calcium ion channel blockers such as nimodipine, other calcium overload blockers such as flunarizine, and free radical scavenging agents (eg, NMDA 21-aminosteroids). Non-competitive antagonists such as MK-801 reduce the size of ischaemic lesions in laboratory animals with middle cerebral artery occlusion. Trials of NMDA antagonists in stroke will be organised if side-effects can be overcome." Results of small trials with nimodipine in cerebral infarction have been

may

cause

encouraging. 12 Various simple aspects

of treatment help to reduce the size of cerebral infarction after stroke. Lactic acidosis in the ischaemic penumbra can be diminished by maintaining normal blood glucose concentrations. There is clinical evidence that hyperglycaemia may increase the size of cerebral infarction and impair outcome." Most experimental evidence suggests that hyperglycaemia increases the size of cerebral infarction, although there is some confusion relating in part to the type of ischaemia studied. In end-artery occlusion the osmotic effects of hyperglycaemia (reducing cerebral swelling) may outweigh the adverse effects of lactic acidosis. In ischaemic areas that are still partly supplied by anastomotic circulation, the lactic acidosis produced by hyperglycaemia worsens the

any osmotic advantage. 14 There is evidence from work on a rat forebrain ischaemia model that insulin infusion to maintain low normal glucose levels protects brain function.15J6 Blood pressure is usually high after an ischaemic stroke but falls during the first weeks In the ischaemic penumbra, pressure-flow autoregulation fails and flow is related linearly to pressure, so it is wise to leave the blood pressure high. However, more work is required to examine the behaviour of blood pressure after stroke and the effects of its manipulation. If the blood pressure is low through hypovolaemia, it can be restored by colloid replacement. Colloids may also confer some rheological benefit, improving blood viscosity (and therefore flow at low shear rates) in the ischaemic penumbra, although trials of haemodilution therapy have been disappointing.18 What of the swelling of ischaemic brain which further jeopardises flow in the ischaemic penumbra? Ischaemic oedema is a complex mixture of cytotoxic oedema (part of the ischaemic cascade) and vasogenic oedema from loss of integrity of the blood brain barrier at endothelial tight junctions. That the vasogenic component of ischaemic oedema is pressure driven but peaks later than cytotoxic oedema may be important for early blood pressure management. Trials of hyperosmolar agents have in general been

infarction, outweighing

disappointing, though one study of glycerol suggested some effect on survival. 19 Steroids, even in high doses, have no beneficial effect20 and may have adverse effects upon ischaemic neurons.21 All therapies for stroke care require careful yet prompt assessment of patients. Many countries will have to improve their systems of stroke care considerably if the potential of any of these new therapies is to be fulfilled. seem to

1. Allen CMC.

Predicting outcome after acute stroke: role of computed tomography. Lancet 1985; ii: 464-65. 2. Powers WJ, Press GA, Grubb RL, et al. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Intern Med 1987; 106: 27-35. 3. Gibbs JM, Wise RJS, Leenders KL, Jones T. Evaluation of cerebral perfusion reserve in patients with carotid artery occlusion. Lancet 1984; i: 310-14. 4. Astrup J, Siesjo BK, Symon L. The state of penumbra in the ischemic brain: viable and lethal threshold in cerebral ischemia. Stroke 1981; 12: 723-25. 5. Siesjö BK, Bengtsson F. Calcium fluxes, calcium antagonists and calcium related pathology in brain ischemia, hypoglycemia and spreading depression: a unifying hypothesis. J Cereb Flow Metab 1989; 9: 127-40. 6. Schmidley JW. Free radicals in central nervous system ischemia. Stroke 1990; 25: 7-12. 7. Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 1986; 19: 105-11. 8. Hossman KA. Haemodynamics of post-ischemic reperfusion of the brain. In: Weinstein PR, Faden AI, eds. Protection of the brain from ischemia. Baltimore: Williams & Wilkins, 1990: 21-36. 9. Fieschi C, Agentino C, Lenzi GL et al. Clinical and instrumental evaluation of patients with ischaemic stroke within the first six hours. J Neurol Sci 1989; 91: 311-22. 10. Collins RC, Dobkin BH, Choi DW. Selective vulnerability of the brain new insights into the pathophysiology of stroke. Ann Inter Med 1988; 110: 992-1000. 11. Albers GW, Golderg MP, Choi DW. N-methyl-D-aspartate antagonists: ready for clinical trial in brain ischemia? Ann Neurol 1989; 25: 398-403. 12. Gelmers HJ, Gorter K, de Weerdt CJ, Wiezer HJ. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med 1988; 318: 203-07

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13. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med 1983; 74: 540-44. 14. Ginberg MD. Glycolytic metabolism in brain ischemia. In: Weinstein PR, Faden AI, eds. Protection of the brain from ischemia. Baltimore: Williams & Wilkins, 1990: 21-36. 15. Voll CL, Whishaw IQ, Auer RN. Post-ischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke 1989; 20: 646-51. 16. Strong AJ, Fairchild JE, Monteiro E, et al. Insulin protects cognitive function in experimental stroke. J Neurol Neurosurg Psychiatry 1990;

53: 847-53. 17. Britton M, Carlsson A, de Faire U. Blood pressure course in patients with acute stroke and matched controls. Stroke 1986; 17: 861-64. 18. Italian Acute Stroke Study Group. Haemodilution in acute stroke: results of the Italian haemodilution trial. Lancet 1988; i: 318-21. 19. Bayer AJ, Palhy MS, Newcombe R. Double blind randomised trial of intravenous glycerol in acute stroke. Lancet 1987; i: 405-08. 20. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J 1986; 292: 21-23. 21. Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 1985; 229: 1397-1400.

Growth hormone therapy in elderly

people (GH) release in childhood is necessary for linear growth; the hormone continues to Growth hormone

be secreted in adult life but for what purpose is unclear. GH secretion is pulsatile but decreases with age-integrated GH levels are 30% lower after the age of 55 than they are during the third decade. This decline in GH is matched by a decline in circulating levels of insulin-like growth factor 1 (IGF-1), which mediates many of the actions of GH.1 Is this decline in GH and IGF-1 important in human ageing? Ageing is associated with a decrease in metabolic rate and changes in body composition--eg, decrease in muscle mass, relative increase in adipose tissue, and decrease in skin thickness. Exercise performance declines. GH deficiency in early life leads to some of these changes.2 Thus lean body mass and skin thickness are decreased and adipose tissue mass is increased in GH-deficient children; body composition returns towards normal with GH

therapy. Studies of GH deficiency have

replacement in adults with GH provided information on the physiological role of the hormone once linear growth is complete. GH was replaced by daily subcutaneous injection at doses of 0-07 units/kg body weight or 2 units/m2 in patients with either isolated GH deficiency or GH deficiency as one of the components of hypopituitarism.-"-6 As in GH-treated children, therapy in adults resulted in an increase in lean body mass and a decrease in adipose tissue mass. Total body weight was unchanged. Waist: hip ratio decreased. Muscle volume assessed by computed tomography increased, isometric muscle strength improved, and exercise capacity on a cycle ergometer increased. Resting metabolic rate rose, as would be expected from the increase in muscle

mass. Bone mineral has been to increase after GH density reported for 12 months in one study,although no therapy significant change was observed after 6 months’ treatment in another.8

These beneficial effects of GH in GH-deficient adults and the fact that secretion of the hormone declines with normal ageing aroused hopes that GH supplementation might reverse some of the effects of old age. Short-term experiments in elderly patients showed that GH led to a positive nitrogen balance and an increase in circulating concentrations of osteocalcin, a marker of bone synthesis. In the first major trial of supplementation in normal elderly people,1O GH at a daily dose of 0-03 mg/kg subcutaneously three times weekly for 6 months to individuals with initially low IGF-1 concentrations resulted in circulating IGF-1 values in the young adult normal range. Lean body mass increased by 9%, adipose tissue decreased by 14%, and there was a small (7%) though statistically insignificant increase in skin thickness. Bone density of the lumbar vertebrae increased by 1-6%. These effects of GH supplementation will undoubtedly stimulate more studies of its role in elderly people. Nevertheless, it is as well to remember that low GH levels are a feature of and not the cause of human ageing. Young adults with GH deficiency are not the same as old people. Complications of GH supplementation in adult life remain to be clarified. Short-term side-effects of existing replacement regimens in GH-deficient adults include ankle oedema, arthralgia, hypertension, and carpal tunnel syndrome. Lower doses or a slow increase in dosage may help to lessen these complications. The thrice weekly regimen used in normal elderly people seemed to be free of short-term side-effects, but data on long-term effects will require years to accrue. The relation between GH status and vascular disease is complex. Long-term hypopituitarism is associated with an increased risk of death from premature vascular disease, to which GH deficiency may be a contributory factor.11 Increased serum triglyceride and cholesterol and an increase in waist: hip ratio, which occur in GH deficiency, are risk factors for vascular disease. GH replacement may therefore be beneficial and serum cholesterol decreases with GH replacement in deficient adults. However, over-treatment may be harmful. Acromegaly is associated with hypertension, cardiomyopathy, and a four-fold increased risk of premature death from vascular disease."," For normal elderly people, optimum treatment regimens and doses and means of monitoring therapy (total circulating IGF-1 concentrations are far from perfect), and even the best injection sites are unknown.

The possibility that GH treatment may increase the risk of cancer also needs long-term investigation. IGF-1 has mitogenic properties in addition to its stimulatory effects on growth. Patients with hypopituitarism have a lower than average risk of death from cancer (although deaths overall are raised), whereas acromegaly in both men and women is associated with an increased risk of malignant