Modeling and closed-loop control of hypnosis by means of bispectral index (BIS) with isoflurane.

A model-based closed-loop control system is presented to regulate hypnosis with the volatile anesthetic isoflurane. Hypnosis is assessed by means of the bispectral index (BIS), a processed parameter derived from the electroencephalogram. Isoflurane is administered through a closed-circuit respiratory system. The model for control was identified on a population of 20 healthy volunteers. It consists of three parts: a model for the respiratory system, a pharmacokinetic model and a pharmacodynamic model to predict BIS at the effect compartment. A cascaded internal model controller is employed. The master controller compares the actual BIS and the reference value set by the anesthesiologist and provides expired isoflurane concentration references to the slave controller. The slave controller maneuvers the fresh gas anesthetic concentration entering the respiratory system. The controller is designed to adapt to different respiratory conditions. Anti-windup measures protect against performance degradation in the event of saturation of the input signal. Fault detection schemes in the controller cope with BIS and expired concentration measurement artifacts. The results of clinical studies on humans are presented.

Time pattern of allergic reactions to drugs.

Generalized, allergic reactions to drugs show time patterns different from those based on pharmacological concepts. We distinguish three types of reactions: acute reactions (reaction time (RT): 0-60 minutes), subacute reactions (RT: 1-24 hours) and reactions of the latent type (RT: 1 day to several weeks). In this study, allergic reactions in the strict sense are supplemented by reactions considered to be based on intolerance or idiosyncrasy to aspirin, pyrazolones, paracetamol, NSAIDs, quinidine, iodine-containing contrast media and some as yet not understood reactions to local anaesthetics. Out of a total of 23,935 drug monitoring patients with 32,317 hospitalizations in the clinical divisions of internal medicine at three Swiss hospitals during the 1974-1987 period, 951 patients with 1,040 probably or definitely drug-related events of the selected type were recorded. Ultimately, 287 patients with 310 adverse drug reactions (ADRs) fulfilled our selection criteria and were classified into six groups of syndromes (Table 1). (Of the reactions described as maculopapular rash, unspecified rash and special exanthema, only the 159 reactions from the 1985-1987 period out of a total of 889 reactions of this type observed during the whole study period were included in our secondary evaluation.) The total number of 310 reactions (100%) showed the following RT distribution: 36 (11.6%) were of the acute type, 13 (4.2%) of the latent type, 12 (3.9%) could be interpreted as two distinct possible types of reaction to different drugs, and for 3 (1.0%) reactions, the type of reaction was indeterminable. The majority of reactions, 246 (79.4%), were of the subacute type starting within 24 hours of the last drug exposure. Among the 36 reactions of the acute type, 7 events of acute severe dyspnoea were observed which seemed to be as life-threatening as anaphylactic or anaphylactoid shock. These hospital-epidemiological data are of interest for focusing basic research and developing further principles of drug safety.