Postgrad Med J: first published as 10.1136/pgmj.45.526.523 on 1 August 1969. Downloaded from Postgracl. med. J. (August 1969) 45, 523-527. Sympatho-adrenal hyperactivity-the key to irreversible shock? M. H. IRVING* Dudley Road Hospital, Birmingham Summary of agreement has been obtained by workers who There would appear sound evidence on which to have investigated plasma adrenaline and noradrena- incriminate sustained sympatho-adrenal hyper- line levels in states of hypovolaemic and endotoxic activity as a deleterious factor of prime importance shock. Walton et al. (1959) recorded a mean adrena- in hypovolaemic shock. The use of sympatho- line level of 64 ,ug/l in dogs subjected to haemor- mimetics in the treatment of shock of this type is rhagic shock which corresponded with findings irrational and deleterious. Their rational use in subsequently published by Rosenberg et al. (1961). those few cases of clinical shock where they are A similar rise occurs in noradrenaline levels but indicated will have to await knowledge of plasma these invariably constitute a lesser fraction (20-40 Y.) catecholamine levels in such cases. of the total catecholamine content (Lund, 1951). Experimental studies involving a- and P-adrenergic In certain instances the level of catecholamine in blockade, unilaterally and in combination, have shock reaches exceptionally high values. Walton et revealed that, contrary to previous theories, deteriora- al. (1959) observed an adrenaline level of 220 ,ug/l in tion is mediated through both receptor types. a case of experimental haemorrhagic shock whilst Many of the current concepts of the pathophysio- Rosenberg et al. (1959) recorded an adrenaline level logy of shock will need reassessment in the light of as of 457 2 Fg/l in a case of experimental endotoxin by copyright. yet unappreciated facets of catecholamine activity. shock. Sequential studies of catecholamine levels in Introduction experimental haemorrhagic shock have demon- Of all the homeostatic mechanisms initiated by strated that they become maximal soon after haemor- most important rhage commences and remain high throughout the acute hypovolaemic hypotension the of & Bragg, 1957), only would appear to be an intense activation of the sym- period hypotension (Watts patho-adrenal system. Outpourings of adrenaline falling on correction of hypovolaemia or at the onset from the adrenal medulla and noradrenaline from of the 'irreversible' stage. con- The question of whether this fall in catecholamine the post-ganglionic sympathetic nerve-endings http://pmj.bmj.com/ just prior to the irreversible stage, stitute the most immediate and most effective pro- levels, occurring represents an exhaustion of the sympatho-adrenal tective mechanism and are responsible for the majority of the physical signs observed in clinical system and is responsible for death remains contro- shock. versial. In support of such reasoning Hift & Campos This activation of the sympatho-adrenal system (1962) demonstrated the depletion of the myocardial has the of extensive experimental in- noradrenaline stores in dogs dying from irreversible been subject et vestigation, the results of which have led to the in- haemorrhagic shock. On the other hand Walker al. (1959) and Glaviano, Bass & Nykiel (1960) have corporation into current clinical therapy of tech- on September 28, 2021 by guest. Protected niques involving both adrenergic stimulation and shown that plasma catecholamine levels are still blockade. higher in dogs dying from irreversible haemorrhagic adrenergic in animals. It is the purpose of this communication to discuss shock than healthy control stimulate the increased output of some facets of sympatho-adrenal function in shock The factors that to its place in the development of catecholamines and maintain the elevated levels and consider both likewise been the subject of the so called 'irreversible' state and its relationship observed in shock have to clinical therapy. much investigation. The initial stimulus is un- doubtedly neurogenic, hypotension causing reflex The extent of adrenergic activity in experimental autonomic activity which is conveyed to the adrenal shock states medulla via the greater splanchnic nerves (Beck & Dontas, 1955). The adrenomedullary response in Despite the relative unreliability of methods used such circumstances is thus largely abolished by for measuring plasma catecholamines a broad level section of the greater splanchnic nerves (Tachi, *Present address: North Middlesex Hospital, London. 1928). Once hypotension is established other factors Postgrad Med J: first published as 10.1136/pgmj.45.526.523 on 1 August 1969. Downloaded from 524 M. H. Irving develop which stimulate further secretion. Amongst The second observation, stimulated to a large these are said to be metabolic acidosis (Malm et al., extent by the knowledge that infusion of adrenaline 1966), anoxia (Walton et al., 1959) and hypovolaemia caused irreversible hypotension, was that surgically (Fowler, Shabetai & Holmes, 1961). Catecholamine sympathectomized animals, although reduced to a levels remain high throughout shock because of lower level of blood pressure by a measured blood continued release of hormones from the adrenal loss compared with intact animals, did not become medulla and not because of interference with the as acidotic nor did they as readily relapse into irrever- mechanisms that remove them from the plasma. sible shock (Freeman et al., 1938). Other workers Adrenalectomy during hypovolaemia causes the using varying techniques to achieve sympathetic complete disappearance of adrenaline from the denervation subsequently verified these observations plasma (Watts, 1965). (Kleinberg et al., 1942; Eversole et al., 1944). Knowledge of plasma catecholamine levels in The immediate assumption was that the benefit in clinical shock and preterminal states is remarkably these cases was obtained by prevention of compen- scanty. Rhoads & Howard (1963) have, however, satory vasoconstriction with consequent main- documented urinary adrenaline and noradrenaline tenance of tissue perfusion and tissue nutrition. levels in man after trauma and demonstrated that Thus parallel to these somewhat crude surgical the levels are highest 8 hr after injury and may experiments the more refined method of pharma- remain high for several days. cologically induced vasodilatation was investigated. Beginning with ergot, and progressing to dibenamine Adrenergic hyperactivity in shock: is it deleterious? and phenoxybenzamine, considerable investigation It is obvious that the initial adrenergic response of the effects of vasodilator therapy upon experimen- to acute hypovolaemic hypotension is a vital homeo- tally induced haemorrhagic and endotoxin shock static mechanism without which the organism is less was undertaken. able to tolerate the stresses to which it is subjected. Indeed the inhibition of this compensatory response Mechanisms in catecholamine-induced deterioration in an incompletely resuscitated patient, e.g. by Although Ahlquist (1948) who laid the founda-by copyright. anaesthesia, may precipitate a cardiovascular col- tions of the modern adrenergic receptor concept had lapse. clearly nominated two receptor types (cx and D) as Two principal observations however, aroused the the mediators for adrenergic activity, the question suspicion that sustained sympatho-adrenal activity of adrenergic mechanisms in shock has been domi- in such circumstances could be deleterious. The first nated by the role of the cx receptor. Deterioration has, resulted from investigations ofthe effect ofprolonged apparently quite logically, been attributed to the adrenaline and noradrenaline infusion into healthy vasoconstriction - tissue-underperfusion - tissue- animals. Using this technique several workers, hypoxia cycle (Fig. 1). notably Bainbridge & Trevan (1917), Freeman (1933) Blood loss and Watts & Westfall (1964), produced states of http://pmj.bmj.com/ irreversible hypotension comparable with those seen after protracted haemorrhagic hypotension. The Faol in cardiac output Compensatory sympotho- odrenal similarities between haemorrhagic and adrenaline- induced vasoconstriction infusion shock are noteworthy. In both a profound metabolic acidosis occurs, due principally to a rise in lactic acid, together with anuria and a paralytic ileus. Tissue underperfusion In dogs both stimuli cause portal hypertension, haemorrhagic necrosis of the intestine and a pro- on September 28, 2021 by guest. Protected gressively rising haematocrit in the irreversible stage, Tissue hypoxia said to be the result of plasma loss. The similarity between the two conditions stimu- lated Watts & Westfall (1964) to compare the cate- Metobolic acidosis and cellular damage cholamine levels in each. They found that a con- FIG. 1 tinuous infusion of 3-4 ,ug/kg/min of adrenaline sustained a plasma adrenaline level of 39 ,ug/l and It followed that to prevent or reverse the vaso- produced a state of irreversible hypotension cul- constrictive element would be a logical supportive minating in death. They commented that if this measure in improving the tolerance to shock- plasma level of adrenaline alone was enough to cause inducing stimuli. Support for this concept was forth- a fatal outcome then surely the level of 46 1 pcg/l of coming from Wiggers et al. (1947), who found that endogenous catecholamine observed in haemor- the oc-blocking agent, dibenamine, gave protection rhagic hypotension must in itself be of significance. against the development of irreversible