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EDITORIALS Neurohumoral responses to thermal injury Trauma and sepsis cause substantial changes in fuel and fluid metabolism. During the past decade there has been increasing interest in the hormonal control of metabolism and in the neuroendocrine responses to physical stress of which severe thermal injury

example, often associated with high morbidity and mortality. The hypermetabolic state that usually persists for many weeks after acute injury is related not only to substantial changes in the hormones which mediate the metabolic response3,5 but also to changes in other neurohumoral factors not directly involved in metabolic control. For example, concentrations of circulating prolactin remain increased for up to 4 weeks after thermal injury,66 and plasma gonadotropins (particularly follicle stimulating hormone) which are raised for the few days following injury, subsequently decline to subnormal values for several weeks.6 Investigations of the pituitarythyroidal axis have shown the characteristic pattern of hormonal changes associated with non-thyroidal illness.7 In thermal injury, it seems that the greater the suppression of plasma thyroxine the worse the prognosis.8 The precise physiological and metabolic importance of these endocrine responses has not been

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clarified. Attention has lately turned to the neurohumoral responses involved in the maintenance of fluid homoeostasis. Burn injury can result in the loss of large quantities of fluid. Moreover, there is a considerable shift of fluid from the intravascular compartment to the interstitium, leading to oedema, vascular volume depletion, and electrolyte disturbances.9,1O Consequently, severe vasoconstriction and depression of cardiac function often arise despite vigorous therapeutic attempts to replenish fluid losses. The documented neurohumoral responses that accompany the insult to the vascular system include big alterations in circulating concentrations of catecholamines, aldosterone, angiotensin II, vasopressin, and atrial natriuretic peptide.11-14 Although many of these neuroendocrine consequences might seem entirely appropriate to the severe intravascular hypovolaemia, work by Crum and colleagues14 challenges this assumption. In a study of 12 badly burned adult patients (burn area

30-66% of total body surface), they looked at changes in cardiac output, stroke volume, pulmonary capillary and central venous pressures, systemic vascular resistance, and mean arterial pressure in relation to

plasma concentrations of vasopressin, angiotensin II, atrial natriuretic peptide, the catecholamines noradrenaline and adrenaline, and neuropeptide Y. During the first few days after thermal injury there were no changes in mean arterial pressure, the values remaining about 94 mm Hg. On the day of injury systemic vascular resistance was extremely high and cardiac function was considerably impaired; both these abnormalities returned

over the hormone circulating angiotensin II and atrial natriuretic peptide were increased immediately after injury. Crum et al emphasise the observation that plasma vasopressin concentration was 50 times greater than normal (about 100 pmol/1) and remained high for 4 days despite apparently adequate fluid replacement with both hypertonic and isotonic lactated Ringer’s solutions. Surprisingly, plasma levels of angiotensin II and atrial natriuretic peptide, the latter not especially low immediately after injury despite the hypovolaemia, both rose to supranormal values by days 3-5 post injury. Catecholamines were increased initially after injury but fell to near normal levels by 5 days. The researchers highlight the remarkably high plasma vasopressin concentrations and suggest that vasopressin is responsible for the vascular complications and depressed cardiac function. There is strong evidence that vasopressin reduces cardiac output, the magnitude of the effect being species dependent.15 In man, plasma vasopressin concentrations of the order of 50 pmol/1 cause a 20% fall in cardiac output.15," As the vasopressin concentration approaches 100 pmol/1 total peripheral resistance increases by 25%, but there is little change in arterial blood pressure because human beings have an extremely efficient vasoactive buffering system.16,17 If the reduction in cardiac output and the increase in systemic vascular resistance reported by Crum et al in thermal injury are mainly attributable to high circulating vasopressin concentrations, blockade of the vasopressin Vi (pressor) receptor might prove beneficial. Such Vi receptor antagonists have been synthesised, and have little if any Vz (antidiuretic) activity .18 More important is the fact that they have no agonist activity. The therapeutic use of these agents to

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the cardiovascular complications of thermal injury might well lead to a fall in arterial pressure, which should respond readily to infusion of colloidal solutions to fill the expanded vascular compartment. Thus, one could predict improvements in cardiac output, renal function, and skin blood flow. Careful study of complex clinical events often yields treat

inexplicable data, thereby posing more questions about the underlying pathophysiology; the results described by Crum et al are no exception. The normal initial plasma angiotensin II values, which increased four-fold in 3 days, and the three-fold rise in plasma atrial natriuretic peptide despite very slight changes in central venous pressure are two examples in this study. Unravelling such complexities of the stress mechanisms in major thermal trauma may eventually lead to rational therapeutic strategies to reduce the mortality and morbidity of bum injury. 1.

Frayn KN. Hormonal control of metabolism in trauma and sepsis. Clin Endocrinol 1986; 24: 577-99.

EA. The effects of stress on salt and water balance. Clin Endocrinol Metab 1987; 1: 375-90. 3. Alberti KGMM, Batstone GF, Foster KJ, et al. Relative role of various hormones in mediating the metabolic response to injury. J Parenteral Enteral Nutr 1980; 4: 141-46. 4. Vaughan GM, Becker RA, Allen JP, Goodwin CW, Pruitt BA, Mason AD. Cortisol and corticotropin in burned patients. J Trauma 1982; 22:

2. Espiner

263-73. 5. Dolecek R, Adamkova M, Sotornikova T. Endocrine response after burn. Scand J Plast Reconstr Surg 1979; 13: 9-16. 6. Brizio-Molteni L, Molteni A, Warpeha RL, Angelats J, Lewis N, Fors EM. Prolactin, corticotropin, and gonadotrophin concentrations following thermal injury in adults. J Trauma 1984; 24: 1-7. 7. Becker RA, Wilmore DW, Goodwin CW, et al. Free T4, free T3 and reverse T3 in critically ill, thermally injured patients. J Trauma 1980; 20: 713-19. 8. Vaughan GM, Mason AD, McManus WF, Pruitt BA. Alterations of mental status and thyroid hormones after thermal injury. J Clin Endocrinol Metab 1985; 60: 1221-25. 9. Demling RH, Kramer G, Harms B. Role of thermal injury-induced hypoproteinemia on fluid flux and protein permeability in burned and non-burned tissue. Surgery 1984; 95: 136-43. 10. Aulick LH, Wilmore DW, Mason AD, Pruitt BA. Influence of the burn wound on peripheral circulation in thermally injured patients. Am J Physiol 1977; 233: H520-26. 11. Griffiths RW, Millar JGB, Albano J, Shakespeare PG. Observations on the activity of the renin-angiotensin-aldosterone (RAA) system after low volume colloid resuscitation for burn injury. Ann R Coll Surg 1983; 65: 212-15. 12. Shirani KZ, Vaughan GM, Robertson GL, et al. Inappropriate vasopressin secretion (SIADH) in burned patients. J Trauma 1983; 23: 217-24. 13. Becker RA, Vaughan GM, Goodwin CW. Plasma norepinephrine, epinephrine and thyroid hormone interactions in severely burned patients. Arch Surg 1980; 115: 439-43. 14. Crum RL, Dominic W, Hansbrough JF, Shackford SR, Brown MR. Cardiovascular and neurohumoral responses following burn injury. Arch Surg 1990; 125: 1065-69. 15. Cowley AW, Liard JF, Skelton MM, Quillen EW, Osborn JW, Webb RL. Vasopressin-neural interactions in the control of cardiovascular function. In: Schrier RW, ed. Vasopressin. New York: Raven, 1985: 1-10. 16. Ebert TJ, Cowley AW, Skelton MM, Smith JJ. Physiologic vasopressin infusion in man alters resting hemodynamics and reflex responses to low level lower body negative pressure. Fed Proc 1984; 43: 896. 17. Cowley AW, Barber BJ. Vasopressin vasculature and reflex effects—a theoretical analysis. Prog Brain Res 1983; 60: 415-24. 18. Burnier M, Waeber B, Nussberger J, Nicod P, Brunner HR. Cardiovascular effects of vascular antagonists (V1) to the action of vasopressin in health and disease. In: Cowley AW, Liard J-F, Ausiello DA, eds. Vasopressin: cellular and integrative functions. New York: Raven, 1988: 473-85.

NOW WE UNDERSTAND ANTIPSYCHOTICS?

Many antipsychotic drugs act by blocking brain receptors for the neurotransmitter dopamine. In common with most neurotransmitters there are multiple receptors for dopamine; physiological, pharmacological, and biochemical studies have provided evidence’ for two receptor subclasses, D1 and Dz. Dz receptors are blocked by the antipsychotic drugs in eliciting their clinical effects-there are excellent correlations between the affinities of such drugs for Dz receptors and the average daily dose used to treat

schizophrenia.z,3 Dz receptors are found in several regions of the brain and it is believed that blockade of receptors in limbic and cortical is responsible for the antipsychotic effects of the drugs. Many antipsychotic agents are also associated with adverse reactions, especially with extrapyramidal (parkinsonian) motor side-effects that are thought to result from blockade of D receptors in the striatum (a typical motor region of the basal ganglia). Some antipsychotic drugs-the so-called atypical antipsychotics such as clozapine, sulpiride, and thioridazine-are less likely to induce extrapyramidal sideeffects, whereas typical antipsychotics such as haloperidol and spiperone are more often associated with such complications. This difference has been explained in several ways: the atypical drugs may preferentially block limbic! cortical Dz receptors;4they may penetrate more effectively into limbic/cortical brain regions;4or they may have a stronger blocking action on muscarinic acetylcholine receptors,thereby suppressing the side-effects. None of these explanations is entirely satisfactory. The discovery of a third dopamine receptor, by means of gene cloning techniques,6 has provided new insights into the typical atypical dichotomy and also into the mechanisms of the antipsychotic effect. In the past five years gene cloning techniques have considerably advanced the study of neurotransmitter receptors. Isolation of the genes encoding several receptors shown that has pharmacological studies have underestimated receptor diversity. Availability of cloned gene sequences for receptors has also opened the way for localisation of these receptor subclasses to be achieved by in-situ hybridisation. By expressing a unique receptor gene in a clonal animal cell line, highly specific screening systems for new drugs are now available. The D1 and Dz receptors have been cloned ;7,8 these receptors, when expressed, have properties that were predicted from earlier pharmacological studies. However, cloning of a third receptor, D3,6showed that it had properties unlike those of the D1 or Dz receptors. Pharmacologically and structurally the D3 receptor more closely resembles the Dz than the D1 receptor. Most dopamine antagonists, including antipsychotic drugs, have high affinities for the D3 receptor, although the affmities are generally lower than their corresponding affinities for the Dz receptor. By contrast, affinities of dopamine agonists are often higher at D3 than Dz receptors. Of special interest is that typical antipsychotic drugs show a 10-20-fold preference for Dz over D3 receptors whereas the atypical antipsychotics show only a 2-3-fold preference. Localisation of the D3 and Dz receptors also differs-the Dz receptor is found in motor (striatal), limbic, and cortical brain regions whereas the D3 receptor is largely confined to limbic and cortical regions. These regions of the brain are typically associated with the antipsychotic effect of these drugs, so it is of great interest to find a pharmacologically different areas

Neurohumoral responses to thermal injury.

1221 EDITORIALS Neurohumoral responses to thermal injury Trauma and sepsis cause substantial changes in fuel and fluid metabolism. During the past de...
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