Incidence and clinical importance of perioperative histamine release: randomised study of volume loading and antihistamines after induction of anaesthesia

In 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 Polygeline (Haemaccel) in its now outdated formulation [40] was chosen as a clinical histamine releaser.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.

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

To demonstrate the efficacy of a premedication with H1- + H2-receptor antagonists against histamine-release responses in anaesthesia and surgery 3 randomized controlled trials were conducted in patients, volunteers and experimental animals (dogs). Cutaneous anaphylactoid reactions following infusion of polygeline (Haemaccel) in orthopedic patients were successfully abolished by premedication with 0.1 mg/kg dimethpyrindene (Fenistil) and 5 mg/kg cimetidine (Tagamet). Chlorpheniramine (Piriton) was also useful, but dimethpyrindene was more effective in the doses recommended and used. Side-effects of the premedication were not observed when the 2 drugs were slowly administered (2 min each). Systemic anaphylactoid reactions following infusion of polygeline were completely prevented in volunteers by the same premedication (0.1 mg/kg dimethpyrindene and 10 mg/kg cimetidine). Life-threatening reactions could not be tested in human subjects, but were elicited in experimental animals (dogs). In this species which resembles man in its sensitivity against histamine, in plasma histamine levels and in response to polygeline life-threatening reactions were prevented or in especially severe cases diminished to such an extent by the premedication with H1- + H2-blockers that this premedication was finally judged to be very effective against histamine-release responses of any grade of severity. To confirm this clinically very important hypothesis more clinical trials in patients at risk for anaphylactoid reactions to drugs are urgently needed.

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Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H1- plus H2-receptor antagonists: Synopsis of three randomized controlled trials

Histamine Release in Anaesthesia and Surgery: A New Method to Evaluate its Clinical Significance with Several Types of Causal Relationship

At first glance, it seems somewhat surprising to write a separate chapter on the very clinical subject of histamine in anaesthesia and surgery in a Handbook of Experimental Pharmacology. However, the story of histamine in anaesthesia and surgery can be traced back to the first 10–20 years after its discovery in nature 1910 by Ackermann and by Barger and Dale (for details see Kusche and Parkin 1986). The influence of anaesthesia on histamine actions in isolated tissues and in the whole organism was thoroughly investigated by H. Dale and others in a series of studies (for details see Feldberg and Schilf 1930). In addition, changes in the histamine content of tissues and body fluids were supposed to occur in wound shock, burns and various kinds of intestinal obstruction (ileus) according to the early reports of leading academic surgeons such as Wangensteen, Whipple, Dragstedt and others (for details see Feldberg and Schilf 1930; Guggenheim 1951).

Histamine in Anaesthesia and Surgery: Causality Analysis

Adverse reactions (pseudoallergic = anaphylactoid (severe) and allergoid (slight)) to polygeline (Haemaccel) are caused by histamine release. The mechanism by which other polypeptides produce these reactions is unfortunately hitherto unknown. "Purification" of Haemaccel led to a drug which was free from anaphylactoid reactions in a controlled clinical trial. Clinically insignificant allergoid reactions to polygeline (restricted to the skin) could be prevented by premedication with H1 + H2-receptor antagonists.

W. Lorenz

Papers

Incidence and mechanisms of adverse reactions to polypeptides in man and dog.

Definition of histamine release in human subjects and experimental animals using plasma histamine determinations in the whole individual

Histamine H1 and H2 receptor blockade as a supplementary premedication principle in elective surgery