Ch. Ohmann

Definition and Classification of the Histamine-Release Response to Drugs in Anaesthesia and Surgery: Studies in the Conscious Human Subject* **

SummaryIn 2 clinical studies in 40 conscious human volunteers and 164 orthopedic patients histamine-release responses were diagnosed, defined and classified. Polygeline (Haemaccel) in its now outdated formulation [40] was chosen as a clinical histamine releaser. The main interest was not concentrated on the extreme, the “classical” anaphylactic response, but on theaverage histamine-release response found in clinical experiments with so many drugs in the last 10 years.In human volunteers 600 ng/kg histamine was i. v. injected. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, “metallic taste”, flush, congestion of head, “wet eyes” and tears, hypertension and headache. Following polygeline none of these subjects developed a life-threatening reaction, but 12 showed a systemic response, 11 a cutaneous reaction and 17 were non-responders. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were plasma histamine levels >1 ng/ml, tachycardia, wheals, sensation of heat, narrowness of throat, hypertension, headache and wet eyes or tears.In a prolective, cohort study in the orthopedic patients 3 subjects with life-threatening reactions, 27 with systemic response, 96 with cutaneous reaction and 38 non-responders were included. Indicants with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, erythema and wheals, cough, flush, stuffy nose and facial oedema. With this trial the indicants for diagnosing a systemic histamine release response in volunteers were validated in patients to a large extent.Thus the average histamine-release response was defined by clinical signs such as tachycardia and mild hypertension, scattered hives such as spots of erythema and wheals, respiratory symptoms in the laryngeal and nasal region, such as cough, narrowness in the throat, stuffy nose and sneezingand by pathological plasma histamine levels (>1 ng/ml). In addition histamine-release responses were differentiated as cutaneous responses, systemic responses and life-threatening responses by clinical and operational criteria and by plasma histamine levels. Using clinical trials and medical decision making procedures the incidence of systemic histamine-release responses in patients higher by two orders of magnitude than in other studies reported hitherto.ZusammenfassungIn 2 klinischen Studien bei 40 wachen Freiwilligen und 164 orthopädischen Patienten wurde versucht, Histaminfreisetzungsreaktionen zu diagnostizieren, zu definieren und zu klassifizieren. Haemaccel in einer heute klinisch nicht mehr verwendeten Zubereitung [40] wurde als klinischer Histaminfreisetzer verwendet. Das Hauptinteresse galt nicht der extremen, der klassischen anaphylaktischen Reaktion, sondern einer durchschnittlichen Histaminfreisetzung, die in klinischen Untersuchungen der letzten 10 Jahre mit so vielen Arzneimitteln gefunden wurde.Bei den Freiwilligen wurden 600 ng/kg Histamin intravenös verabreicht. Indikatoren für eine systemische anaphylaktoide Reaktion mit der höchsten Inzidenzrate waren Tachykardie, Plasmahistaminspiegel über 1 ng/ml, metallischer Geschmack, Flush, Kopfdruck, feuchte Augen oder Tränen, Hypertension und Kopfschmerzen. Nach Haemaccel-Infusion zeigte keiner der Probanden eine lebensbedrohliche Reaktion, aber 12 eine systemische und 11 eine Hautreaktion, während bei 17 keine Symptome gefunden werden konnten. Indikatoren mit der höchsten Inzidenzrate waren wiederum Plasmahistaminspiegel über 1 ng/ml, Tachykardie, Quaddeln, Hitzegefühl, Enge im Hals, Hypertension, Kopfschmerzen und Tränen.In einer prolektiven Cohortstudie wurden aus 600 orthopädischen Patienten 164 ausgewählt: 3 hatten eine lebensbedrohliche Reaktion, 27 eine systemische und 96 eine Hautreaktion, 38 Patienten zeigten keine Symptome. Indikatoren mit der höchsten Inzidenzrate waren wiederum Tachykardie, Plasmahistaminspiegel über 1 ng/ml, Erytheme und Quaddeln, Husten, Flush, verstopfte Nase und Gesichtsödem. Damit wurden durch die Patientenstudie die Indikatoren für eine systemische Histaminfreisetzungsreaktion in Probanden zu einem großen Teil validiert. So läßt sich eine durchschnittliche Histaminfreisetzungsreaktion als eine systemische anaphylaktoide Reaktion charakterisieren, mit klinischen Symptomen wie Tachykardie und leichte Hypertension, verstreuten Effloreszenzen, respiratorischen Symptomen im Bereich des Kehlkopfs und der Nasenschleimhautund durch pathologische Plasmahistaminspiegel (>1 ng/ml). Außerdem wurden die Histaminfreisetzungsreaktionen in kutane, systemische und lebensbedrohliche Reaktionen eingeteilt, wobei klinische und operationale Kriterien sowie Plasmahistaminspiegel für die Klassifikation verwendet wurden.

Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: Analysis of various components in cremophor El and development of a compound with reduced toxicity

Anaphylactoid reactions in man following administration of drugs solubilized with cremophor El® (polyethylenglycolglycerol riconoleate) are a considerable clinical problem. Since these reactions occur in dogs on first exposure and in pigs on second exposure, the ‘dog model’ was used in this communication to analyse components and chemical modifications of cremophor El and its components for their clinical effects, their hypotensive actions and their histamine-releasing capacity.Two series of experiments in 1978 and 1980 were performed in 144 adult mongrel dogs of both sexes. In these studies histamine release wasnot related to the effect of the solubilizing agents as tensides and was elicited by rather low doses (about 10–100 mg/kg i.v.). The effect of these substances on blood pressure and on blood histamine levels was connected with distinct chemical features: the most potent compounds were oxethylated and additionally esterified unsaturated or hydroxylated fatty acids.Several phases in hypotensive reactions were observed, including an immediate response, a delayed blood pressure response and a late response about 15–20 min after injection. Only the delayed response was associated with histamine release. The combination of cardiovascular effects and histamine release was fatal on some occasions indicating that histamine release can be dangerous.Compared to cremophor El, the tenside effect was equal, but the toxicity was reduced in oxethylated 12-hydroxystearic acid. It is recommended that this solubilizer should be used in further extended studies in animals and — if these are successful—in clinical trials.

Reliability and practicability of the fluorometric-fluoroenzymatic histamine determination in pathogenetic studies on peptic ulcer: Detection limits and problems with specificity

Histamine, among various “biologic-physiologic” abnormalities, is considered as a pathogenetic factor in chronic duodenal ulcer disease. The 10–30 per cent difference between its concentration in gastric and duodenal mucosa of patients compared to healthy controls, however, has to be demonstrated to be specific for the disease. It has to be shown to be neither a methodological artefact nor a common effect, concomitant factor or consequence. This study, after a series of pathogenetic trials examines systematic errors (biases) in the fluorometric-fluoroenzymatic histamine assay under the conditions of field studies including tests on specificity over a time period of 10 years. It concentrates on sensitivity (detection limits) and specificity of a standard technique described herein.A modified Shore procedure for large scale assays in human biopsies was developed including reference luminescence values for all reagents, cleaning material and glassware, reduction of OPD concentration to 0.05%, purification ofn-heptan, omission of centrifugation steps in the extraction procedure and use of 2 ml 1M HClO4 in the homogenization step to prevent losses of histamine due to adherence to the mechanical homogenizer. This assay was sensitive enough to measure histamine without difficulty in any biopsy taken. The detection limit was 3 ng/biopsy, but the smallest quantities of the amine ever obtained were 10.6 and 18.3 ng/biopsy (depending on both histamine content and biopsy weight).A series of problems had to be solved both in achieving and demonstrating specificity. It had to be defined not only for the assay in general, but also for assessing the difference in histamine content between ulcer patients and healthy controls. Exogenous more than endogenous fluorescing material interfering with the determination had to be excluded. A series of pitfalls were detected which had to be overcome in demonstrating the specificity of the assay by physicochemical and enzymatic tests. The specificity of the identification tests was more often impaired than the histmine assay itself. Fluorescing material interfering with the assay occurred in the homogenization, extraction and condensation steps, was found in water, OPD, the organic solvents, the cleaning material and in all kinds of plastic vessels. Plasticizers were shown by physicochemical characteristics including fluorescence spectra to be most likely responsible for this interfering material. Rules were developed to exclude such hazards in specificity in longterm pathobiochemical studies.

Attitude towards clinical trials: Results of a survey of persons interested in research

AbstractObjective and design:Patient recruitment is a major problem in clinical trials. In a survey, the attitude of a public sample towards clinical trials was assessed. Subjects:In a survey 225 visitors to the Heinrich-Heine University were interviewed with respect to their attitude towards clinical trials. Methods:Visitors were interviewed with regard to sociodemographic variables, disease status, knowledge about and experience of trials and attitude towards clinical trials. Three scenarios for clinical trials were presented (dental trial, surgical trial, pharmaceutical trial). Results:In general, a positive attitude was found. Clinical trials were judged important by 89.5% of the survey participants; however, only 25% would take part in clinical trials. The likelihood of potential participation was lower in the surgical trial than in the dental or pharmaceutical trial scenarios. The willingness to participate was significantly higher in persons, who considered trials to be important, with general knowledge about clinical trials and with previous trial participation. Conclusions:The willingness to participate in a clinical trial is still low in the public. More information and involvement in clinical trials may improve the general attitude.

Histamine and stress ulcer: new components in organizing a sequential trial on cimetidine prophylaxis in seriously ill patients and definition of a special group at risk (severe polytrauma)

ZusammenfassungBei Patienten der chirurgischen Wach- und Intensivstation wurde eine kontrollierte klinische Studie über den Wert von Cimetidin zur Streßulcusprophylaxe durchgeführt. Die übliche Organisation und Darstellung einer kontrollierten Studie mußte wegen erheblicher theoretischer, ethischer und praktischer Schwierigkeiten bei Planung und Durchführung geändert werden:(1)Zuerst wurde die Untersuchung bei Patienten der Wach- und Intensivstation als randomisierte Doppelblindstudie mit fixem Stichprobenumfang geplant. Ausgeführt wurde eine einfach-blinde Sequentialstudie ausschließlich bei Patienten mit schwerem Polytrauma. Kurz vor Erreichen der vorgegebenen Signifikanzgrenzen wurde sie aus ethischen Gründen abgebrochen und nach Beratung mit einem externen Gutachter mit Hilfe des exakten Testes nach Fisher analysiert (p<0,025).(2)Die notwendigen Informationen über die Studie konnten nicht in einem einzigen Bericht zusammengepreßt werden. Als einer der Teile enthält diese Mitteilung Plan, Klinisches Material, Methoden und Statistik der Studie. Abschnitte über „Theoretische und ethische Aspekte“ und über „Historische Entwicklung der Studie“ wurden eingefügt. Zahlreiche Entscheidungen wurden bereits in Material und Methodik erläutert, um die enorme Komplexität des Entscheidungsprozesses bei klinischen Studien im Gegensatz zu der bei Tierexperimenten hervorzuheben.(3)Um Schlüsse von der Stichprobe auf die Zielpopulation zu erleichtern und Risikogruppen für Streßulkusentstehung zu definieren, wurden alle 6,634 Patienten der Klinik während der Dauer der Studie prospektiv auf klinisch-manifeste Streßläsionen untersucht. Als eines der wichtigsten Merkmale wurde weiterhin die Letalitätsrate für die Gesamtgruppe und für Untergruppen der Traumapatienten in unserer Klinik ermittelt. Streßulcera traten nur bei Patienten der Wachund Intensivstation auf, vor allem bei Patienten mit schwerem Polytrauma und postoperativen Komplikationen. Cimetidin verhütete sie äußerst wirksam beim schwer Polytraumatisierten. Es ist aber unnötig, das Arzneimittel über die Wach- und Intensivstation auszustreuen wie aus einem Füllhorn des Glücks.SummaryIn patients in a surgical intensive care unit a controlled clinical trial was performed concerned with the pathophysiological functions of histamine in stress ulcer disease and with the influence of cimetidine prophylaxis on this complication. The commonly used organization of a controlled clinical trial was enforced to be changed by considerable theoretical, ethical and practical difficulties in designing and conducting the study:(1)Initially the trial was planned as randomized double-blind using a fixed sample size of patients obtained from the intensive care unit. It was executed as a sequential single-blind study only in patients with severe polytrauma. For ethical reasons it was stopped before the bounderies were reached and was analysed according to the advice of an external referee using Fishers exact test (p<0.025).(2)The necessary informations about the trial could not be compressed to one single report. As one of several parts this article mainly deals with Design, Clinical materials, Methods and Statistics of the whole investigation. Distinctive sections on Theoretical and Ethical issues and on Historical development of the study were included. Numerous decisions were explained already in Materials and Methods to emphasize the enormous complexity of the decision process in clinical trials in contrast to that in most of the animal experiments.(3)In order to facilitate conclusions from our sample to the target population and to define subgroups of patients with a high risk for stress ulceration all 6,634 patients hospitalized in the Surgery Clinic during the time of the study were prospectively investigated for clinically manifest stress ulceration. Furthermore as one of the most important attributes the lethality rate was calculated for the whole group and various subgroups of trauma patients in our hospital. As a surprising and remarkable result of the study clinically manifest stress ulcers occurred exclusively in our patients in the intensive care unit and among them mainly in those with severy polytrauma and postoperative complications. Cimetidine was highly effective in preventing stress ulceration in severe polytrauma patients. But it seems absolutely unnecessary to distribute this drug in all patients of a surgical intensive care unit like from a cornucopia of happiness.

Assay and identification of histamine in human gastric aspirate by a fluorometric-fluoroenzymatic technique. Its application in patients with chronic duodenal ulcer

Histamine assays can be unreliable in individual subjects or samples even though the particular method is in general working very well. Therefore the specificity and accuracy of histamine determination in the gastric aspirate of individual duodenal ulcer patients was thoroughly examined and shown to be satisfactory.Pitfalls of the fluorometric assay were investigated. A native (non-histamine) fluorescence in gastric aspirate which occurs before the addition of OPT was not removed by the original Shore procedure. In the combined assay (Dowex 50+ butanol extraction) this fluorescence no longer interferes with the assay.For the identification of histamine in a single gastric aspirate of an individual duodenal ulcer patient, the reversed blank (3M HCl added to the reaction mixture before OPT instead after OPT), excitation and fluorescence spectra, the heating test with spectra recorded and the HMT test were found to be reliable. The formaldehyde test and the heating test without recording the spectra were useless since they gave false negative results. Since the HMT test was regarded as a reference method it was thoroughly investigated both by theoretical considerations (enzyme kinetics) and by a series of measurements in a single patient as well as in a group of nine subjects.Samples from the period of peak acid output in response to pentagastrin showed an average histamine concentration of about 8 ng/ml and a histamine output of 1.5 μg/30 min.

8. Symptomloses und kompliziertes Ulcus pepticum als extreme Erscheinungsform der Ulcuskrankheit: Konsequenzen für die Wahl zwischen konservativer und chirurgischer Therapie

Asymptomatic recurrent ulcers following drugs and surgical therapy are true failures of treatment (Visick IV). Several types of bias at present do not allow any conclusion whether medical treatment and maintenance increase the rate of ulcer complications. The mechanisms of action for medical treatment with cimetidine and operative treatment with SPV are similar, but not identical. Bad compliance and incomplete vagotomies mainly account for success of mutual exchange between the two types of therapy. Using a decision tree with mortality as outcome recommendations are developed for a step-wise therapeutic concept in peptic ulcer patients.SummaryAsymptomatic recurrent ulcers following drugs and surgical therapy are true failures of treatment (Visick IV). Several types of bias at present do not allow any conclusion whether medical treatment and maintenance increase the rate of ulcer complications. The mechanisms of action for medical treatment with cimetidine and operative treatment with SPV are similar, but not identical. Bad compliance and incomplete vagotomies mainly account for success of mutual exchange between the two types of therapy. Using a decision tree with mortality as outcome recommendations are developed for a step-wise therapeutic concept in peptic ulcer patients.ZusammenfassungSymptomlose Rezidivgeschwüre nach medikamentöser und operativer Behandlung sind echte Therapieversager (Visick IV). Verschiedene Möglichkeiten von Bias lassen gegenwärtig nicht entscheiden, ob eine medikamentbse Therapie und Prophylaxe (maintenance) zu einer erhbhten Komplikationsrate führt. Die Wirkungsmechanismen der konservativen Therapie mit Cimetidin und der operativen mit SPV sind ähnlich, aber nicht identisch. Schlechte Arzneimitteleinnahme (compliance) und inkomplette Vagotomien begründen hauptsachlich den Erfolg beim gegenseitigen Wechsel zwischen beiden Behandlungsformen. Mit einem Entscheidungsbaum (Prognosekriterium Letalität) werden Empfehlungen für ein stufenweises therapeutisches Konzept beim Ulcuskranken entwickelt.

Thyroid function after surgery for autonomous and non-autonomous nodular endemic goitre--effect of iodide-substitution.

SummaryThe aim of this study was to evaluate the influence of postoperative iodide-substitution on the function of thyroid remnants of different quality and quantity in order to define the appropriate prophylaxis (iodide or thyroid hormone) to prevent recurrent goitre.In a prospective, randomized clinical trial, the following patients were examined:group I: simple, non-autonomous nodular goitre, bilateral thyroidectomy (n=40);group II: simple, non-autonomous nodular goitre, “selective” (unilateral) thyroidectomy (n=40);group III: autonomous nodular goitre, bilateral thyroidectomy (n=40);group IV: autonomous nodular goitre, “selective” (unilateral) thyroidectomy (n=35). The following parameters were measured 6 and 12 weeks postoperatively. Serum-total-T4, -T3,-TSH, TRH-test, 99mTc-Thyroid-Uptake (TcTU). Six weeks postoperatively the 4 groups were separately randomized into controls and treatment groups, who received 200 µg iodide/day orally. Six weeks postoperatively, patients in group I had lower T4 levels and both basal and stimulated TSH were higher than in the other groups, however no significant differences were observed in T3, T4/T3 ratio and TcTU.Twelve weeks postoperatively patients from groups I, II and III, who had been treated with iodide, had lower T3 and TcTU values but higher T4 and T4/T3 than the appropriate controls. Basal and stimulated TSH showed no differences between controls and iodide-treated patients in these groups. In group IV, T4and T3 showed a tendency to elevation (n.s.), and basal and stimulated TSH as well as TcTU were lower in patients with iodide.Iodide-substitution (200 µg/day) has no major influence on the pituitary-thyroid axis, except after “selective” surgery for autonomous nodular goitre (group IV). Generally, iodide treatment abolishes the symptoms of iodine-deficiency, improving the autoregulatory capacity of the thyroid remnant. It could replace thyroid hormone as a prophylaxis against recurrent goitre in the majority of patients after “selective” thyroid surgery.

4. Grundlagen chirurgischer Indikationen: Hilfen zur Entscheidungsfindung

SummarySeveral types of clinical studies provide important decision aids for surgical indications. They include quantitative data on outcomes and utility analysis, graphic illustration of the various possibilities for decisions by decision trees, controlled clinical trials with data used in decision trees and - if these trials fail for several reasons -carefully conducted and documented prospective and retrospective trials. Items for defining the term “surgical indication” were illustrated by constructing a decision tree for treatment of chronic duodenal ulcer.ZusammenfassungAus dem Gebiet der klinischen Studien können für chirurgische Indikationen Entscheidungshilfen angeboten werden. Es sind dies Quantifizierung von Prognose und Nutzen durch Risikoabschätzung, graphische Darstellung von Entscheidungsmöglichkeiten durch Entscheidungsbäume, kontrollierte klinische Studien zur Erstellung der Entscheidungsbäume, und falls sie nicht qualifiziert oder nicht vorhanden sind, auch sorgfältige prospektive und retrospektive Studien. Am Beispiel der Indikation zum operativen Eingriff beim chronischen Ulcus duodeni werden die Kennzeichen des Stellens der Operationsindikation erläutert: Ein Erkenntisprozeß und Sich-Entscheiden zur Operation, unter Bedingungen der Unsicherheit, zu einem momentanen Zeitpunkt nur mit einer Arbeitsdiagnose, mit dem Ziel des größtmöglichen Nutzens für den Patienten, unter Beachtung der Folgen der Folgen, und dies, bitte, möglichst schnell.

Acute acalculous cholecystitis in severely traumatized patients: a prospective sonographic study

SummaryAcute acalculous cholecystitis is a well known complication in severely traumatized patients. Existing data originate from retrospective analyses and episodic case reports. In a prospective ultrasonographic study 25 polytraumatized patients admitted to our intensive care unit between January 1, 1989, and December 31, 1989, were examined in daily intervals for this condition. Trauma scoring was performed according to the injury severity score (ISS) and polytrauma score (PTS). “Stress cholecystitis” was defined as a combination of hydrops of the gallbladder, an increased mural thickness (>3.5 mm), and the demonstration of “sludge.” We were able to demonstrate this diagnostic triad in four out of 25 patients (=16%). As a consequence early elective cholecystectomy was done in one patient. The remaining patients were treated conservatively. The incidence of stress cholecystitis in severely traumatized patients is probably higher than figures so far published suggest. Ultrasonography is a reliable method of early detection and follow-up for this complication.