Histamine metabolism after adverse reactions due to d-tubocurarine administration.

We investigated histamine release in five female patients, submitted for gynaecological surgery, after intravenous administration of the neuromuscular blocking agent d-tubocurarine. In these patients, we measured the plasma levels of histamine and its metabolites, N tau-methylhistamine and N tau-methylimidazoleacetic acid, making use of mass fragmentographic methods. The newly developed determination of plasma N tau-methylimidazoleacetic acid had a within-day coefficient of variation of 2.7% (n = 10). Normal values of N tau-methylimidazoleacetic acid in plasma ranged from 41.3-75.6 nmol/l (n = 13). All five patients developed anaphylactoid reactions: two patients showed severe systemic reactions, one patient a minor systemic reaction and two had skin reactions only. Plasma histamine and N tau-methylhistamine levels appeared to be the most reliable biochemical parameters for confirming both the occurrence and severity of an anaphylactoid reaction. In comparison with plasma histamine, the determination of plasma N tau-methylhistamine is less hampered by artefacts caused by blood collection and plasma preparation. Together with the fact that the increase in plasma N tau-methylhistamine levels after anaphylactoid reactions lasts much longer than the increase in plasma histamine levels, this leads to the conclusion that the determination of plasma N tau-methylhistamine is a useful retrospective parameter for histamine release in this type of pathological state. The plasma N tau-methylimidazoleacetic acid levels fluctuated considerably, showing only a significant increase after administration of d-tubocurarine in the two patients who had severe anaphylactoid reactions. This parameter is, therefore, less useful in such studies.

The effect of oropharyngeal decontamination using topical nonabsorbable antibiotics on the incidence of nosocomial respiratory tract infections in multiple trauma patients.

The incidence of respiratory tract infections was determined in 59 multiple trauma patients requiring prolonged intensive care (greater than 5 days) and receiving no antibiotic prophylaxis. Early pneumonia (less than 48 hr) with S. aureus, S. pneumoniae, and/or H. influenzae was found in 44% of patients. Secondary colonization of the oropharynx and respiratory tract with ICU-associated Gram-negative bacilli followed by pneumonia occurred in 12 patients (20%). The overall incidence of respiratory tract infections was 59%. In a prospective open trial three prophylactic antibiotic regimens were compared: 17 patients were treated with intestinal decontamination using nonabsorbable antibiotics (polymyxin E 400 mg, tobramycin 320 mg, amphotericin B 2,000 mg/day). No difference in infection rate was found. Twenty-five patients were treated with intestinal and oropharyngeal decontamination using an ointment containing 2% of the same antibiotics. Secondary colonization and infection of the respiratory tract with Gram-negative bacilli was significantly reduced (p less than 0.001). The incidence of early (Gram-positive) infections, however, was unchanged. Another group of 63 patients was treated with systemic antibiotic prophylaxis during the first days in combination with oropharyngeal and intestinal decontamination. The incidence of early pneumonia was significantly reduced (p less than 0.001). Five patients (8%) developed an infection. Superinfections were not observed.

Nosocomial gram-negative pneumonia in critically ill patients. A 3-year experience with a novel therapeutic regimen.

The efficacy of selective decontamination of the oral cavity and GI-tract in the treatment of established gram-negative pneumonia in critically ill patients was evaluated in a prospective open trial. 25 patients with pneumonia caused by Enterobacteriaceae or Pseudomonadaceae were studied. All patients were mechanically ventilated (range 2-60 days). Non-absorbable antibiotics (polymyxin E 100 mg, tobramycin 80 mg, amphotericin B 500 mg) were administered through the nasogastric tube four times a day. The oral cavity was decontaminated with an ointment containing 2% of the same antibiotics, applied to the buccal mucosa four times a day. For systemic therapy a combination of tobramycin (3-6 mg X kg-1) with either cefotaxim (50-100 mg X kg-1) or ceftazidime (100 mg X kg-1) was given both intravenously and by aerosol (50% IV dose/5 ml saline) four times a day. Eradication of pathogens from the respiratory tract was achieved in 24 patients within 9 days (median 5 days). The cure rate was 96%. Two patients had a relapse. Neither recolonization with resistant organisms nor supra-infections were found for the remaining period of mechanical ventilation (up to 60 days), also after systemic/aerosol therapy had been discontinued. Only 3 patients died (12%).

Operative risk in old age--an anesthesiological survey of octogenarians.

The anesthesiological records of 138 patients (158 operations), aged 80 years and older, were analysed retrospectively. Ninety-nine patients had received general anesthesia for 115 procedures. Complications and hemodynamic disturbances in this group were studied. Serious hemodynamic changes occurred 31 times in 24 patients. They were readily corrected and did not seem to have had any influence upon the mortality. The anesthesiological risk in our patients was negligible. The mortality in this survey is comparable to that of other series.

Ataranalgesia. A review.

A review is given of the pharmacodynamic effects of Ketamine and the commonly used Benzodiazepines especially regarding the clinical application of the substances in combination as socalled ataranalgesia. The literature as well as own experimental results show the advantages of ataranalgetic combinations for induction and maintenance of general anesthesia. Special comment is given for new results about the reversal of hypnotic action by means of 4-aminopyridine.

[Rohypnol poisoning as a cause of postanesthetic coma and the success of 4-aminopyridine therapy]. / Rohypnol-Intoxikation als Ursache eines postanaesthetischen Komas und Behandlungserfolg mit 4-Aminopyridin.

In a 20 year old female nurse prolonged recovery (4 hours) unexpectedly followed to Rohypnol intoxication, the oral intake of which was realised only in the later period of postanaesthetic coma. Naloxone and physostigmine failed to achieve improvement but 4-aminopyridine was immediately successful.

Epidemiology of adverse reactions in anaesthesia in Germany and the Netherlands.

We consider 292 anaphylactoid reactions from the own material (1964-1980) out of two different Departments of anesthesiology to attempt to review the continental epidemiology of this life-threatening adverse drug reaction. We conclude the following: The specialty of this type of adverse reaction is likely to prove a special separating name i.e. "anaphylactoid reaction". The overall frequency can be estimated for 1 : 400-600 in anesthesiology, a preponderance of females may be possible. There is no predictability of the reaction, not even by sophisticated history. But it is possible to avoid the development of severe shock by early diagnosis and immediate full causative therapy. With growing experience in diagnosis and therapy the mortality of anaphylactoid reaction should be irrelevant in the near future.

Pharmacodynamics and reversal of benzodiazepine-ketamine ataranalgesia.

We describe the combined use of ketamine with benzodiazepines, which produces a state of ataranalgesia. From our investigation of the combination of ketamine with three such drugs--diazepam, flunitrazepam and midazolam--we conclude that the ketamine-midazolam sequence is the best combination in terms of preservation of physiological homeostasis and recovery time. In addition, we describe the reversal of ketamine-diazepam ataranalgesia by the new cholinergic agonist, 4-aminopyridine.

[Cardiocirculatory and respiratory effects of the combination of midazolam and ketamine]. / Kardiozirkulatorische und respiratorische Wirkung der Kombination von Midazolam und Ketamin.

This study summarizes our results with various ataralgesic combinations and their effects on circulation and respiration. Together with the new water-soluble 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine midazolam, Ro 21-3981, Dormicum), 7-chloro-1,3-dihydro-1-methyl-5-phenyl-(2H)1,4-benzodiazepin-2-one (diazepam) and 5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one (flunitrazepam) are also considered, for the purpose of comparison. Pharmacokinetic studies confirm the clearly shorter duration of action of midazolam. The poor respiratory depressant action of the benzodiazepines can be easily and rapidly increased by premedication, ataralgesic combinations and substances for the prolongation of anaesthesia. Adequate spontaneous respiration is possible only in exceptional cases. The threshold doses for 100% suppression of cardiac stimulation due to 2-(o-chlorophenyl)-2-methylaminocyclohexanone (ketamine) were determined for all three benzodiazepines. These doses are also valid for hypertension. The effect of intubation is not suppressed by the ataralgesic combination alone, whereas it does suppress the increase in pressure in the pulmonary circulation which is synchronous with the systemic blood pressure. The rise in intracranial pressure following ketamine alone is also prevented by premedication with benzodiazepines, which on the other hand offer no protection against certain other effects (hypoxia, hypercapnia, intubation), The same is true for increases in intraocular pressure. According to the results of investigations carried out, the new benzodiazepine midazolam justifies our hope for a substance with a similar basic effect, but with a clearly improved pharmacokinetic profile.

Antagonism of ketamine-diazepam anaesthesia by 4-aminopyridine in human volunteers.

Five healthy human volunteers were anaesthetized on two separate occasions, 1 week apart, using a standard diazepam-ketamine induction followed by an infusion of ketamine for 1 h. Ten minutes after stopping the infusion, either 4-aminopyridine 0.3 mg kg--1 in saline or the same volume of saline alone was administered i.v. It was concluded that 4-aminopyridine enhanced dramatically the rate of recovery of the subjects to full consciousness and normal motor co-ordination when compared with the saline controls.

Antagonism of the cardiovascular effects of ketamine by diazepam in volunteers.

In healthy volunteers pretreated with atropine (0.5 mg), ketamine given as a bolus i.v. injection (2 mg/kg) followed by an infusion of ketamine (1 mg/kg/hr) for one hour, caused a significant rise in blood pressure and heart rate. This cardiovascular stimulation was rapidly counteracted by diazepam (0.2 mg/kg i.v.) given when the response to ketamine was already maximal.

Effects of the analeptic drug, 4-aminopyridine, upon post-operative respiratory depression in patients. A preliminary study.

The analeptic agent, 4-aminopyridine, was given to patients who had undergone elective ear, nose and throat surgery and showed severe central respiratory depression due to intra-operative fentanyl administration. The respiratory depression due to fentanyl was found to be partially antagonised by 4-aminopyridine. In view of these preliminary findings it is suggested that the drug might find a use in combatting postoperative fentanyl-induced respiratory depression.

[Risk of general anaesthesia (author's transl)]. / Das Risiko der Allgemeinanästhesie.

95 506 patients who received general anesthesia during the period of 1964--1977 were studied. The account of all actual or possible life threatening complications during the anesthesia is given: oedema of the glottis, air embolism, accidental injection of the wrong drug, respiratory insufficiency, hypoxia, pulmonary oedema, airway occlusion by the cuff, vomiting and aspiration, anaphylactoid reaction, death within 24 hours, death on the table. Deaths not attributable to anaesthesia are listed separately. We have found that in one of every 139 anaesthetics given there was a life threatening complication to the patient. In every 197th anaesthetic there was a clear connection with the anaesthetic technique used. In contrast with the great number of near fatal complications the rate of irreversible damage or mortality connected with general anaesthesia was low.