Angeles Marcos

Breder

Bruno Allolio

Esteban Martínez

GilbertR Park

Gleadle

Martin Reincke

Michie

Niraj Varma

Park

Peter Vadas

Schein

Sibbald

Vadas

Varma

Voerman

Waldemar Pruzanski

Werner Winkelmann

English

Reincke, Martin

Allolio, B.

Winkelmann, W.

Universität München: Elektronischen Publikationen

Cortisol response to corticotropin and survival in septic shock

Crossref

Open Access LMU ( Ludwig-Maximilians-Univ. München)

1230calcipotriol has been used in higher concentrations than calcitriol.Long and Marks seem unaware of controlled studies showing thatcalcipotriol ointment 50 pg/g is better than vehicle control.’ Nowthat calcipotriol has been shown to compare favourably withbetamethasone 17-valerate, it may be possible to replace topicalcorticosteroids with calcipotriol in many patients with psoriasis. Weshould soon know how calcipotriol compares with dithranol: morethan 400 patients have entered a multicentre trial designed tocompare the efficacy and tolerability of the two agents.Calcipotriol is by far the best studied vitamin KD analogue. Theresults obtained in more than 3000 patients with psoriasis haveshown calcipotriol to be both effective and well-tolerated. Itrepresents a breakthrough in the topical treatment of psoriasis.Department of Dermatology,University of Aarhus,Marselisborg Hospital,DK-8000 Aarhus C, Denmark KNUD KRAGBALLE1. Van de Kerkhof PCM, van Bokhoven M, Zultak M, Czarnetzki. A double-blind studyof topical 1, 25-dihydroxy-vitamin D3 in psoriasis. Br J Dermatol 1989; 120:661-64.2. Henderson CA, Papworth-Smith J, Cunliffe WJ, Highet AS, Shamy HK,Czarnetzki BM. A double-blind, placebo-controlled trial of topical1,25-dihydroxycholecalciferol in psoriasis. Br J Dermatol 1989; 121: 493-96.3. Binderup L, Bramm E. Effect of a novel vitamin D analogue calcipotriol on cellproliferation and differentiation in vitro and calcium metabolism in vivo. BiochemPharmacol 1988; 37: 889-95.4. Kragballe K. Treatment of psoriasis by the topical application of the novelcholecalciferol analogue calcipotriol (MC 903). Arch Dermatol 1989; 125: 1647-52.Inhibition of hepatitis B virus by antisenseoligodeoxynucleotidesSIR,-Hepatitis B virus (HBV) infection is a major cause ofchronic liver disease and hepatocellular carcinoma world wide. 1Although interferon alpha is effective in about one-third ofpatients,2 other therapeutic strategies need to be explored.We analysed the effect of antisense oligodeoxynucleotides onHBV gene expression and replication. Transfection of humanhepatoma cells with HBV-DNA3 (control) results in the synthesisand secretion of hepatitis B surface antigen (HBsAg) and hepatitis Be antigen (HBeAg). Cotransfection of HBV-DNA with anoligodeoxynucleotide of antisense polarity (ATC-40) completelyblocked HBsAg and HBeAg synthesis as well as HBV replication(figure). The same oligodeoxynucleotide of sense polarity(GAT-40) had no effect on viral antigen production or replication.vara rtot <<a&laquo;a)et;nunInhibition of viral antigen synthesis by HBV-specific antisenseoligodeoxynucleotide.Detection of HBsAg (left) and HBeAg (right) in cell culture mediumafter transfection of human hepatoma cells (HuH-7) with HBV-DNAalone (&mdash;&mdash;&mdash;&mdash; control), HBV-DNA plus an antisenseoligodeoxynucleotide (w.w ATC-40), or HBV-DNA plus a senseoligodeoxynucleotide (---A--- GAT-40). Analyses were completed withcommercially available radioimmunoassays (Centocor, Malvern, andAbbott, Chicago, USA).These data show that HBV-specific antisenseoligodeoxynucleotides can block viral gene expression andreplication. Inhibition of both human immunodeficiency virusinfection4 and lymphoma growths will have to await a clearerdefinition of the role of antisense oligodeoxynucleotides, eitheralone or in combination with other strategies.Massachusetts General Hospital,Harvard Medical School,MGH Cancer Center,Charlestown,Massachusetts 02129, USAH. E. BLUME. GALUNF. V. WEIZS&Auml;CKERJ. R. WANDS1. Hoofnagle JH. Chronic hepatitis B. N Engl J Med 1990; 323: 337-39.2. Perillo RP, Schiff ER, David GL, et al A randomized, controlled trial of interferonalfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitisB. N Engl J Med 1990; 323: 295-301.3. Blum HE, Galun E, Liang TJ, v Weizsacker F, Wands JR. Naturally occurringmissense mutation in the polymerase gene terminating hepatitis B virus replication.J Virol 1991; 65: 1836-42.4. Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990;249: 1533-44.5. McManaway ME, Neckers LM, Loke SL, et al. Tumour-specific inhibition oflymphoma growth by an antisense oligodeoxynucleotide. Lancet 1990; 335: 808-11.Cortisol response to corticotropin andsurvival in septic shockSIR,&mdash;Dr Rothwell and colleagues (March 9, p 582) show a poorresponse to corticotropin in 13 patients with septic shock, all ofwhom died. They state that "the cause of this apparent adrenalimpairment is unclear". We offer a possible explanation.Cortisol plasma concentrations are usually raised in severe sepsis.Interleukin-1 and tumour necrosis factor are lymphokines that playan important part in endotoxin-mediated septic shock. It has beensuggested that these cytokines stimulate the ACTH-cortisol axis.lThe degree of rise in blood cortisol tends to reflect the severity ofsepsis. In Rothwell and colleagues’ report, total blood cortisol afterstimulation shows no significant difference between survivors andnon-survivors (1174 and 963 nmol/l, respectively). In ourexperience, the stimulation from already stimulated adrenal glandsmay result in a smaller difference between the basal concentrationand the 30-60-minute concentration than expected for the shortcorticotropin stimulation test. In addition, we do not agree that atrial of steroid replacement in severe sepsis with physiological dosesof cortisol might be of value because cortisol plasma concentrationsare already high in severe sepsis, as Rothwell et al recognise.Departments of Internal Medicine and Microbiology,Hospital de la Santa Creu i Sant Pau,08025 Barcelona, SpainESTEBAN MART&Iacute;NEZANGELES MARCOS1. Michie HR, Manogue KR, Spnggs DR, et al. Detection of circulating tumor necrosisfactor after endotoxin administration. N Engl Med 1988; 318: 1481-86.2. Breder CD, Dmarello CA, Saper CB. Interleukin-1: Immuno-reactive innervation ofthe human hypothalamus. Science 1988; 240: 321-23.SIR,-Dr Rothwell and colleagues state that "relative"adrenocortical insufficiency may be observed often in patients withseptic shock. However, in our opinion, their data do not support thisconclusion.The response of cortisol to corticotropin is known to bedependent on baseline cortisol concentrations. In patients with highbasal concentrations, an attenuated response would be expected. 6of the 13 reported patients with adrenocortical impairment hadstrikingly increased baseline cortisol concentrations up to above1500 nmol/1, which reflected the severity of the underlying disorder.Lack of a cortisol response to corticotropin may be because thepituitary-adrenal axis is already maximally stimulated in thesepatients.Rothwell et al do not comment on plasma ACTH concentrationsin their patients. Adrenocortical impairment of whatever origin in acomplex setting such as septic shock cannot be established withoutcomplete biochemical investigation of the pituitary-adrenal axis.Did patients with a poor response to corticotropin have higherACTH concentrations than patients with a "normal" response?Since cortisol is bound to steroid binding globulin, did Rothwell etal exclude the possibility that low total serum concentrations of1231cortisol in their patients were merely due to protein (steroid bindingglobulin) loss in the interstitial space as is common in septic shock?If protein loss were an important factor, free cortisol concentrationscould have been normal.Rothwell et al also suggest a relation between a low cortisolresponse to corticotropin and mortality. Was the poor cortisolresponse reproducible? Was corticotropin given in the same way inall patients (via a peripheral vein or a central line)? How wasmortality defined ? Furthermore, histopathological data on theadrenal cortex are not given. Did patients have adrenalitis, adrenalhaemorrhage, adrenal necrosis, or normal adrenal histology? Webelieve that further data are required before a final conclusion can bedrawn. We remain unconvinced that adrenocortical impairment is amajor difficulty in patients with septic shock.National Institute of Child Healthand Human Development,Bethesda, MD 20892, USAUniversity Clinic of Medicine II,Krankenhaus Merheim,5000 Koeln 91, GermanyMARTIN REINCKEWERNER WINKELMANNBRUNO ALLOLIOSIR,-Absolute adrenal insufficiency in overwhelming infectionis rare. The notion of absolute adrenal insufficiency as a cause ofrefractory shock is gradually being replaced by the idea of relativeadrenal insufficiency.1 Dr Rothwell and colleagues noted a clearstratification of stimulated cortisol release between survivors andnon-survivors, although basal cortisol concentrations were similar.We have studied the interaction between the hypothalamic-adrenal axis and phospholipase A2 in septic shock. Circulatingphospholipase A2 (PLA2) has been implicated in the pathogenesisof cardiopulmonary changes in septic shock, and serumconcentrations of PLA2 correlate with outcome.2 Twoglucocorticoid-suppressible cytokines, tumour necrosis factor andinterleukin-1, are signals for PLA2 synthesis and extracellularrelease.3 We measured ACTH, cortisol, and PLA2 concentrationsin a prospective study of ten episodes of septic shock.4 Serumcortisol concentrations in individual patients varied up to four-fold,although peak values were similar in survivors (mean [SD] 1397[314] nmol/l, range 662-2480) and non-survivors (1232 [328]nmol/1, range 450-2320). There was a complete discordancebetween serum cortisol and ACTH concentrations in all patients,irrespective of outcome. However, serum cortisol and PLA2 valueswere concordant in all survivors (r > 069, p < 00001), but werediscordant in non-survivors (r = 0-26). These data, together withthose of Rothwell et al, suggest that adrenocortical responsiveness,whether assessed by ACTH challenge or by concordance withserum PLA2, is an important prognostic determinant of septicshock.Inflammation Research Group,Wellesley Hospital,University of Toronto, Canada M4Y 1J3PETER VADASWALDEMAR PRUZANSKI1 Schein RMH, Sprung CL, Marcial E, Napolitano L, Chernow B. Plasma cortisollevels m patients with septic shock. Crit Care Med 1990; 18: 259-63.2 Vadas P, Pruzanski W, Mustard R, et al. The pathogenesis of hypotension in septicshock. correlation of circulating phospholipase A2 levels with circulatory collapse.Crit Care Med 1988; 16: 1-7.3 Pruzanski W, Vadas P. Phospholipase A2&mdash;a mediator between proximal and distaleffectors of inflammation. Immunol Today (in press).4 Vadas P, Pruzanski W, Stefanski E, et al. Concordance of endogenous cortisol andphospholipase A2 levels in gram-negative septic shock: a prospective study. J LabClin Med 1988; 111: 584-90.SIR,-Our experience is similar to that of Rothwell et al.However, their report does not mention whether glucocorticoidreplacement was given to patients who were "adrenocorticallydeficient"; if so, were any improvements seen, and did thosepatients still have a poor final outcome? We found that replacementwas associated with both haemodynamic and clinicalimprovement.’ Other workers have reported similar fmdings toOurs.2,3We have also shown that a blunted adrenocortical response tocorticotropin may take place in critically ill patients who do not haveestablished sepsis, and that treatment with steroids is associatedwith an improved haemodynamic and clinical state.’ Our findingssuggest that adrenocortical deficiency is not specific to septicaemiabut may also occur in critically ill patients with other disorders(Rothwell et al include one patient in their series with acutepancreatitis who may have been in this category). The cause of thiseffect is uncertain, but several inflammatory mediators such astumour necrosis factor are implicated, although these cytokines arereleased in critically ill patients who are not septic.5 Adrenal failuremay be an under-recognised component of multiorgan failure inpatients who are critically ill, and should be sought actively.Rothwell et al noted that all patients who failed to increase theircortisol by at least 250 nmol/1 died. This group includes cases with awide range of basal cortisol concentrations. Although it is possiblethat those with high baseline cortisol concentrations are "relativelyadrenocortically deficient", the more likely explanation is synthetichyperactivity. Such a response probably does not merit adjunctivesteroid therapy.What does an impaired response to corticotropin mean? Is it amarker of poor outlook, or does it imply that adrenal syntheticfunction is impaired to a point where adverse effects result? Littleinformation is available on adrenal activity in critically ill patients.Endogenous ACTH activity, delivery of ACTH to the adrenalcortex, synthetic function in the gland, hormone release and plasmabinding, and cortisol breakdown are all factors that need to beaccounted for before concluding that a blunted response toexogenous corticotropin implies adrenal exhaustion.We agree that evidence exists to suggest that some crtitically illpatients may merit adjunctive corticosteroid therapy as assessed bythe short ’Synacthen’ test, but such benefits may have beenobscured in large clinical trials in which high doses of steroid havebeen given irrespective of endogenous adrenal function.John Farman Intensive Care Unit,Addenbrookes Hospital,Cambridge CB2 2QQ, UKNIRAJ VARMAGILBERT R. PARK1. Park GR, Raggatt P. Diagnosis of adrenal insufficiency. Br Med J 1989; 298: 669-70.2. Voerman HJ, Strack van Schijndel RJM, Thijs LG. Endocrine disturbances in thecritically ill: the role of growth hormone and cortisol. In: Vincent JL, ed. Update mintensive care and emergency medicine 10. Berlin: Springer Verlag, 1990: 809-20.3. Sibbald WJ, Short A, Cohen MP, Wilson RF. Variations in adrenocorticalresponsiveness during severe bacterial infections. Ann Surg 1977; 186: 29-33.4. Gleadle J, Varma N, Raggatt P, Park GR. Adrenal insufficiency in critically ill patients.Clin Int Care 1991; 2: 104-05.5. Varma N, Park GR. Adrenal dysfunction in the critically ill. Clin Int Care 1991; 2:68-70.Painful clitoral tumescence duringbromocriptine therapySIR,&mdash;Bromocriptine, a dopaminergic agonist, is used tosuppress lactation and prolactin secretion. We report a woman whohad clitoral tumescence during bromocriptine therapy.A healthy woman, aged 28, was delivered of a normal male childafter an uneventful pregnancy. She was given paracetamol (500 mgthrice daily on the day of delivery). Because she chose not tobreast-feed, she was given bromocriptine (2-5 mg twice dailystarting one day after delivery). Three days after treatment wasbegun she had painful episodes of clitoral tumescence, lasting a fewminutes and arising about ten times a day when she was upright.These episodes were not related to sexual arousal but an overallincreased libido was noticed. The patient temporarily discontinuedbromocriptine and had no futher episodes. However, she was againgiven the drug for breast congestion and the episodes reappeared1-2 h after dosing. Bromocriptine treatment was discontinued 19days after delivery. The side-effects disappeared in the next fewdays. The patient denied previous similar episodes. No otherside-effects were noted.In an assessment by French workers of unexpected or toxic drugreactions, the role of bromocriptine was regarded as convincing.lWe are not aware of other reports of clitoral tumescence as aside-effect of this drug. As seen in our patient, increased libido canbe induced by levodopa2 and dopaminergic agonists,3 but not bysingle-dose treatment.4 Dopaminergic agents induce erection, acentral nervous system effect mediated by dopamine, oxytocin, andadrenocorticotropin hormone in animals and man.4-6

http://epub.ub.uni-muenchen.de/7023/1/Reincke_Martin_7023.pdf

Cortisol response to corticotropin and survival in septic shock

Abstract

Similar works

Full text

Available Versions

Universität München: Elektronischen Publikationen

Crossref

Open Access LMU ( Ludwig-Maximilians-Univ. München)