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Rapid circulatory clearances and half‐lives of plasma free metanephrines

To the Editor: Campbell and colleagues present data from two patients operated for phaeochromocytoma in whom plasma free metanephrines were measured at intervals following surgical removal of tumours. They conclude that the free metanephrines in plasma have half-lives of hours rather than minutes and that because of this there is no reason to sample blood in the recommended supine position. Their interpretation is, however, flawed and misses a large body of data published over 15 years ago, establishing rapid circulatory clearances of free metanephrines. Animal studies involving i.v. administration of H-labelled L-normetanephrine initially established that the circulatory clearance of the metabolite was rapid and close to that of the parent catecholamine. Disappearance kinetics indicated a bi-exponential decay, similar to that reported for noradrenaline. The half-life of the fast component was calculated at less than a minute, while that of the slow component was between 13 and 20 min. The sampling carried out by Campbell et al. missed the first rapid part of the disappearance curve, which reflects initial clearance from the relevant circulatory compartment. Review of the reported data indicates that 5 of the 6 postclamping measurements were made 2 or more hours into the post-operative recovery phase when levels were under 3 nM. At this stage, much of the fall in plasma concentrations of metanephrines likely reflected slow normalization of heightened sympathoadrenal activity associated with the surgical procedure, not decreases in metanephrines originally produced by resected tumours. Thus, in addition to entirely missing the relevant initial rapid component of disappearance curves, it appears that the half-lives of the second component of curves were overestimated. Rapid increases in plasma normetanephrine during sympathetic activation and attainment of steady-state levels of Hlabelled normetanephrine during i.v. infusions of tracer doses of H-labelled noradrenaline provided initial evidence that the circulatory half-lives of free metanephrines were short in humans. This was confirmed in another clinical study examining the regional formation of metanephrines from the parent amines. Rates of circulatory removal and plasma spillover of metanephrines (0 32–0 49 nmol/min) divided by the steady-state arterial plasma concentrations of the metabolites (0 26–0 29 nmol/l) indicated circulatory clearances of metanephrines from 1 1 to 1 9 l/min. Plasma half-lives were estimated at <4 min, also close to those of the parent catecholamines. While metanephrines are not substrates for the neuronal noradrenaline transporter, they are superb substrates for the same extra-neuronal monoamine transporters responsible for most of the circulatory clearance of catecholamines. Inhibition of these transporters dramatically decreases both circulatory clearances of catecholamines and metanephrines. Actions of monoamine oxidase and monoamine-preferring sulfotransferase are thereafter important for further metabolism of the metanephrines, but active uptake by extraneuronal monoamine transporters is primarily responsible for the rapid circulatory clearance of the metabolites. We and others have also established that plasma concentrations of normetanephrine and metanephrine, but particularly metanephrine, are much less responsive to sympathoadrenal activation as the parent amines. Nevertheless, the metabolites do show parallel changes to the parent catecholamines, which in response to some procedures are extremely transient in nature, both for the catecholamines and the blunted responses of the metanephrines. Because of the relatively blunted responses to sympathoadrenal activation of the metanephrines compared with the parent catecholamines, some have proposed that it is unnecessary to use the same precautions when sampling for measurements of plasma metanephrines as when sampling for catecholamines. In particular, it has been suggested that sampling in the supine position is not required, even though it is well established that upright posture potently stimulates sympathoneural release of noradrenaline, increasing plasma concentrations by twofold or more. We have therefore, examined the influence of posture in 60 hypertensives in whom blood samples were first taken in the seated position and then after 30 mins of supine rest. Plasma concentrations of normetanephrine showed consistent and highly significant decreases after 30 mins of supine rest, on average 30% lower than concentrations in the seated position (Fig. 1). On the basis of the above considerations, we disagree with the notion of Campbell et al. that blood sampling for measurements of plasma free metanephrines need not consider influences of posture. We, nevertheless, recognize that in clinical care settings, it is often more practical to sample in seated than in supine positions. Such conditions of sampling, however, significantly increase numbers of false-positive results. It was, therefore, recommended by a panel of experts at the first international symposium on phaeochromocytoma that blood samples should ideally be collected after 20 mins of supine rest; when this is not possible and blood sampling in the seated position returns a positive result, then sampling should be repeated in the supine position (http://www.pressor.org/ips2005/ recommendations.htm). It was also recommended that reference intervals should be established in samples of blood taken after at least 20 mins in the supine position. This latter recommendation recognizes the need to preserve diagnostic sensitivity using the lower cut-offs for reference intervals obtained in the supine rather than the higher cut-offs in the seated position (Fig. 1).