[Pharmacokinetics in newborns and infants]. / Pharmakokinetik bei Neugeborenen und Säuglingen.

Physiologic changes influence the pharmacokinetics of drugs relevant to anesthesia in neonates and infants. The neonatal phase is the phase of life with the most rapid and dramatic changes of organ-functions responsible for pharmacokinetics of most anesthetics. Changes in body composition and the content of plasma proteins influence volume of distribution, the drug distribution to different compartments and the amount of free fraction in plasma. Due to the immaturity of hepatic microsomal enzyme systems there is a decreased metabolism particular of agents which undergo low hepatic extraction like Diazepam, Morphine or some local anesthetics. In the first year of life capacity of the enzymatic systems increases and also clearance increases. Until puberty the clearance of some drugs is greater than the adult level. There are also pharmacodynamic changes like modified sensitivity to some drugs like volatile anesthetics or neuromuscular blocking agents. In summary neonates and infants are a highly heterogenous group with large interindividual differences. Therefore the dosage of anesthetic agents must be individualized to achieve optimal pharmacodynamic effects without toxicity in this age group.

[Postoperative cognition disorders in elderly patients. The results of the "International Study of Postoperative Cognitive Dysfunction" ISPOCD 1)]. / Postoperative Störungen der kognitiven Leistungsfähigkeit bei älteren Patienten. Die Ergebnisse der "International Study of Postoperative Cognitive Dysfunction" (ISPOCD 1).

OBJECTIVE: Cognitive dysfunction is a known problem after operations and may be especially relevant in the elderly. The aim of this international multicentre study was to investigate short- and long-term cognitive dysfunction in elderly patients and to elucidate the relevance of hypoxaemia and hypotension as causative factors. METHODS: 1218 patients aged 60 years and older and scheduled for major non-cardiac surgery under general anaesthesia were investigated. Oxygen saturation was measured by continuous pulse oximetry before surgery and throughout the day of and the first 3 nights after surgery. Blood pressure was recorded every 3 minutes during the operation and every 15-30 min for the rest of that day and night. Cognitive testing was performed before and 1 week and 3 months after the operation. Cognitive dysfunction was identified with neuropsychological tests compared with controls recruited from the UK (n = 176) and the same countries as study centres (n = 145). RESULTS: Postoperative cognitive dysfunction was present in 25.8% of patients 1 week after surgery and in 9.9% 3 months after surgery, compared with 3.4% and 2.8%, respectively, of the UK controls. Increasing age and duration of anaesthesia, little education, a second operation, postoperative infections, and respiratory complications were the risk factors for early postoperative cognitive dysfunction, but only age was a risk factor for long-term postoperative cognitive dysfunction. Hypoxaemia and hypotension were not significant risk factors at any time. CONCLUSION: With this investigation long-term cognitive dysfunction could be proven definitively for elderly patients after major operations under general anaesthesia. No factors with prophylactic or therapeutic influence were detectable so that aetiology and pathophysiology of POCD could not be further determined.

Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction.

BACKGROUND: Long-term postoperative cognitive dysfunction may occur in the elderly. Age may be a risk factor and hypoxaemia and arterial hypotension causative factors. We investigated these hypotheses in an international multicentre study. METHODS: 1218 patients aged at least 60 years completed neuropsychological tests before and 1 week and 3 months after major non-cardiac surgery. We measured oxygen saturation by continuous pulse oximetry before surgery and throughout the day of and the first 3 nights after surgery. We recorded blood pressure every 3 min by oscillometry during the operation and every 15-30 min for the rest of that day and night. We identified postoperative cognitive dysfunction with neuropsychological tests compared with controls recruited from the UK (n=176) and the same countries as study centres (n=145). FINDINGS: Postoperative cognitive dysfunction was present in 266 (25.8% [95% CI 23.1-28.5]) of patients 1 week after surgery and in 94 (9.9% [8.1-12.0]) 3 months after surgery, compared with 3.4% and 2.8%, respectively, of UK controls (p<0.0001 and p=0.0037, respectively). Increasing age and duration of anaesthesia, little education, a second operation, postoperative infections, and respiratory complications were risk factors for early postoperative cognitive dysfunction, but only age was a risk factor for late postoperative cognitive dysfunction. Hypoxaemia and hypotension were not significant risk factors at any time. INTERPRETATION: Our findings have implications for studies of the causes of cognitive decline and, in clinical practice, for the information given to patients before surgery.

[Pharmacokinetics from the viewpoint of the clinical anesthetist]. / Pharmakokinetik aus der Sicht des klinisch tätigen Anästhesisten.

Pharmacokinetics describes the time-depend course of plasma concentration of a drug. Pharmacodynamics describes the pharmacological effect of the substance. Both together form the pharmacological model used in clinical practice. The global descriptors total clearance Cltot, volume of distribution Vd, and half-life t1/2 allow for a first good approximation of drug delivery and a characterisation of drugs. Unwanted side-effects such as inadequate anaesthesia or prolonged recovery periods may be explained. The main clinical use of pharmacokinetics is to sustain dosing schemes based on scientific data. It also may be helpful in creating new administration schemes especially for continuous infusion of intravenous hypnotics or analgetics. New developments such as Target-Controlled Infusion (TCI) are based on pharmacokinetic data and computations and may be an improvement for the clinically working anaesthetist.

[Antagonists in anesthesia]. / Antagonisten in der Anästhesie.

In modern anaesthesia various antagonists are used. They provide efficient tools to facilitate better control of pharmacological effects and side effects of drugs routinely used in anaesthesia. Naloxone is a competitive antagonist of opioids without any intrinsic activity. It counteracts respiratory depression, pruritus, sedation and analgesia caused by opioids. It is fast-acting with a duration of action of 45 to 90 min. Several investigators have reported severe side effects of naloxone including hypertension, tachyarrhythmias, left heart failure and cardiac arrest, and hence the use of naloxone must be carefully considered in every single patient. Flumazenil is a competitive antagonist of benzodiazepines. It is a remarkably safe drug and very effective to terminate all benzodiazepine effects in anaesthesia and intensive-care patients. Serious complications caused by flumazenil have been reported in patients receiving benzodiazepines in the treatment of seizure disorders and in patients with mixed intoxications. Neostigmine is one of several antagonists of neuromuscular blocking agents. Its side effects include bradycardia, increased bronchial secretions and increased peristalsis. Indication depends on the results of neuromuscular monitoring. Physostigmine is an unspecific antagonist of the central anticholinergic syndrome, an acute psychosis that may be caused by numerous drugs used in anaesthesia. Generally, antagonists should be carefully titrated. In emergency medicine the use of these antagonists is not recommended; the primary goal is to restore vital functions.

The safe use of anaesthetics and muscle relaxants in older surgical patients.

Age greater than or equal to 75 years is not a special risk for adverse outcomes after general anaesthesia on its own but an indicator of risk. Biological or physiological age expressed by preoperative health status is much more important than chronological age. The type of anaesthesia seems to play no, or only a minor role. It is, however, most important to reduce the dosage considerably. As a rule of thumb, the dosage should be reduced by 10 to 15% for every decade over the age of 40. In addition, patients must be monitored extensively intra- and postoperatively, ideally in an intensive care setting. The controversy concerning regional versus general anaesthesia should be studied further. Regional anaesthesia techniques like high spinal or epidural anaesthesia that are haemodynamically effective do not reduce morbidity and mortality postoperatively but have the risk of profound hypertension. Peripheral blockades and spinal or epidural anaesthesia without additional sedation may, however, be associated with a reduced incidence of complications. The reduced reserves of geriatric patients demand for experienced anaesthetists and surgeons as well as intense intra- and postoperative monitoring. To secure a short recovery period, we recommend administration of short-acting drugs like propofol, midazolam, alfentanil, vecuronium, atracurium or isoflurane in appropriately reduced dosages.

[The cardiotoxicity of bupivacaine during pacemaker stimulation is dependent on the stimulation frequency. Results of an experimental study]. / Die Kardiotoxizität von Bupivacain unter Schrittmacher-stimulation ist abhängig von der Stimulationsfrequenz. Ergebnisse einer experimentellen untersuchung.

The cardiotoxic effects of bupivacaine are related to the temporal dispersion of effective refractory periods in different parts of the cardiac conduction system. This effect facilitates the occurrence of re-entry arrhythmias under burst stimulation [4, 8]. In this study physiological increments in heart rate were simulated by cardiac pacing, and the electrophysiological and haemodynamic effects under the influence of cardiotoxic concentrations of bupivacaine were measured. METHODS. After institutional approval we generated cardiotoxic arterial plasma concentrations of bupivacaine (6.9 +/- 1.6 micrograms/ml) in pigs (n = 8; 15-22 kg) by i.v. injection of 4 mg bupivacaine/kg, followed by a constant rate infusion of 0.2 mg/kg per min [8]. The pigs were anaesthetized with midazolam, fentanyl and pancuronium and normoventilated with a FiO2 of 0.4. Internal right atrial and right ventricular pacing was performed with increasing frequencies of 20, 40, 60, 80 and 100 stimulations/min above individual spontaneous heart rates (AL) before (control) and after the administration of bupivacaine. ECG, MAP, LVSP, dp/dtmax and stimulation thresholds were recorded. Student's t-test, and the U-test of Wilcoxon, Mann and Whitney were used for statistical testing with a significance level of 0.05. RESULTS. By inducing a frequency-dependent increase in stimulation threshold, bupivacaine prevented regular atrial pacing with frequencies higher than AL + 60. Ventricular pacing with a frequency of AL+40 induced a lethal arrhythmia in 1 animal. In the remaining 7 pigs ventricular pacing showed a frequency-dependent increase in stimulation thresholds (Fig. 1) and stimulus-QRS intervals (Fig. 5). MAP (Fig. 2), LVSP (Fig. 3) and cardiac inotropy (Fig. 4) showed frequency-dependent decreases under ventricular pacing. CONCLUSIONS. The toxic effects of bupivacaine on pacing thresholds, av conduction, intraventricular conduction, cardiac inotropy, and blood pressure are modulated by the stimulation frequency of a cardiac pacemaker. The cardiotoxic effects of bupivacaine seem to be use dependent. Even minor increments in heart rate can induce malignant arrhythmias. Cardiac pacing can be difficult in the presence of toxic bupivacaine concentrations, and high-frequency pacing should be avoided. It has to be verified whether higher heart rates generated by the physiological pacemakers of the heart do also increase the cardio-circulatory toxicity of bupivacaine. If that holds true, drugs that can induce tachycardias should be avoided in the treatment of bupivacaine toxicity.

Benzodiazepine antagonists. An update of their role in the emergency care of overdose patients.

The benzodiazepine antagonist flumazenil is a very valuable tool in the diagnosis and treatment of intoxications in which benzodiazepines are involved. In case of a positive response, patients will regain consciousness immediately, thus verifying the diagnosis and making a brief history possible to identify other drugs that might be involved. Moreover, invasive diagnostic and therapeutic procedures like gastric lavage, lumbar puncture, mechanical ventilation, etc., may then be unnecessary. In cases of pure benzodiazepine overdose a single injection of flumazenil 0.2mg should be given, followed by individually titrated increments of 0.1 mg/min until the patient is awake and responsive. In these cases a total dose of 2mg is usually sufficient. Higher doses of flumazenil may be necessary in cases of combined drug overdose. Because of its high therapeutic index, the administration of flumazenil is usually not accompanied by serious adverse effects. Benzodiazepine withdrawal syndromes characterised by transient anxiety and depression can occur, but the incidence is low. Increases of blood pressure and heart rate due to a release of catecholamines are possible, which might endanger patients with cardiovascular diseases. In severe cases, seizures have been observed which usually respond well to small doses of benzodiazepine agonists. In all cases of successful treatment it should be remembered that the effect of flumazenil deteriorates after 1 to 2h, which usually leads at first to resedation. In these patients additional bolus injections or a continuous infusion (0.1 to 0.5 mg/h) may be necessary. The effectiveness of flumazenil in cases of alcohol (ethanol) poisoning is questionable and should be further investigated.

[The blood level and a pharmacokinetic model of prilocaine during a continuous brachial plexus blockade]. / Blutspiegel und pharmakokinetisches Modell von Prilocain bei der kontinuierlichen Plexus-Brachialis-Blockade.

Continuous brachial plexus blockade achieved by repeated injections through an axillary catheter is used increasingly often for microsurgical procedures and for postoperative pain relief. Repetitive administration, especially of long-acting agents, can cause problems with local anesthetic toxicity. Based upon a pharmacokinetic analysis of prilocaine serum concentrations after single-dose axillary plexus blockade in 14 patients, a pharmacokinetic model was established from which to predict serum concentrations after successive doses. METHODS. Each of 14 patients (ASA I-II, age 42 +/- 20 years, height 171 +/- 10 cm, body weight 72 +/- 9 kg) undergoing minor hand surgery received a single dose of 600 mg (40 ml 1.5%) prilocaine for axillary plexus blockade. Serial samples were taken from the contralateral antecubital vein and serum local anesthetic concentrations were measured by gas chromatography. Least square, non-linear regression analysis was performed to fit a triexponential curve; standard formulas were applied to develop the corresponding open two-compartment model. Computer simulation was carried out to predict the accumulation of mean local anesthetic concentrations after repetitive dosages. The kinetic model was verified with another set of 5 patients receiving a repetitive dose of prilocaine. The initial dose was 400 mg (40 ml 1%), followed by insertion of a catheter which allowed repetition at 2 and 4 h. The repetition dose was 300 mg (20 ml 1.5%). RESULTS. Maximal prilocaine serum levels of 2.32 +/- 0.80 micrograms/ml were found after 34 +/- 13 min. Mean pharmacokinetic data of the open two-compartment model with first order absorption from extravascular sites were: t alpha 1/2 = 10 min; t beta 1/2 = 139 min; V1 = 661; V dss = 254 1; Cltot = 2310 ml/min; tabs 1/2 = 35 min. The comparison of predicted and observed serum concentrations after continuous anesthesia was excellent. DISCUSSION. Pharmacokinetic data after axillary plexus blockade are comparable to those found after i.v. injection. Low serum levels were found throughout the 8 h of investigation and accumulation in serum was minimal following repetitive doses. There was no loss of action on repetition. Predicted values after pharmacokinetic modeling showed good agreement with actual measured values. Prilocaine may be a reasonable choice for repetitive use, as is appears to be toxicologically safe. Methemoglobinemia resulting from metabolites of prilocaine did not lead to complications in our study. It may, however, be a problem with repetitive dosages. Further investigations concerning this question would be useful.

[An infusion model for intraoperative peridural anesthesia by catheter using mepivacaine]. / Ein Infusionsmodell zur intraoperativen Katheterperiduralanästhesie mit Mepivacain.

With the introduction of repetitive or continuous catheter techniques in regional anaesthesia, potential systemic intoxication hazards have increased. Especially high dose techniques such as peridural anaesthesia or plexus brachialis blockade consecutively generate high blood levels. In this study, blood levels collected from 20 patients (36 +/- 19 y, 173 +/- 9 cm, 73 +/- 15 kg) after lumbar epidural anaesthesia with mepivacaine led to the development of a linear open one-compartment-model (VD,ss: 109 l, Cltot: 594 ml/min, t1/2abs: 13 min, t1/2 beta: 149 min). With that model, dosage strategies could be studied via computer simulation. A mepivacaine dosage regimen for lumbar epidural anaesthesia, consisting of 250 mg as an initial bolus dose and an infusion rate of 150 mg/h after 15 min, cumulated to maximum concentrations of 2.5-3.5 micrograms/ml after 150 min. Such an infusion regimen may lead to concentrations of more than 4 micrograms/ml if applied for longer than 4 h. The pharmacokinetic computer simulation proved to be precise and could be compared to the measured blood levels of mepivacaine.

[The recovery period following total intravenous anesthesia using propofol and alfentanil versus inhalation anesthesia using nitrous oxide and enflurane at 1.3 MAC]. / Untersuchungen zur Aufwachphase nach totaler intravenöser Anästhesie mit Propofol und Alfentanil versus Inhalationsnarkose mit Stickoxidul und Enfluran bei 1.3 MAC.

Recovery of motor and mental functions were investigated in two groups with 20 young patients each. One group received total intravenous anaesthesia (TIVA) with propofol and alfentanil for urological surgery and the other group received nitrous oxide-oxygen anaesthesia in combination with 1.3 MAC of enflurane for lumbar nucleotomy. The following parameters were investigated before and up to 100 minutes after extubation: simple and discriminating motor activities, vigilance and short and long term memory. --Simple and in discriminating motor actions show a significantly faster recovery was seen in the TIVA group during the first 20 minutes after extubation compared to the enflurane-treated patients. Speech-related functions were particularly inhibited in the inhalational anaesthesia group. After 30 to 40 minutes the propofol-alfentanil group was able to meet all requirements while patients with inhalational anaesthesia needed 80 minutes to reach the same level. Recovery of short and long-term memory was also significantly shorter in the TIVA group. This clearly indicates a faster return of mental and motor functions following total intravenous anaesthesia with propofol and alfentanil. However the large dosages of alfentanil may be a problem with regard to post-anaesthetic respiratory depression. Further studies with larger numbers of patients will be necessary to evaluate the potential side effects of continuous propofol/alfentanil infusion. Presently, safety demands require, at least a sixty-minute post anaesthesia monitoring for patients receiving this new anaesthesia method.

[The pharmacokinetics of lidocaine in resuscitation conditions. Results of experimental studies on swine]. / Pharmakokinetik von Lidocain unter Reanimationsbedingungen. Ergebnisse tierexperimenteller Untersuchungen am Schwein.

To re-evaluate dosage requirements for i.v. and endobronchial (e.b.) lidocaine therapy under the conditions of cardiac arrest, we investigated the pharmacokinetics of lidocaine after i.v. and e.b. administration in an animal cardiopulmonary resuscitation (CPR) model. METHODS. We induced cardiac arrest by ventricular fibrillation in 16 normoventilated pigs under i.v. anesthesia. Resuscitation started after 3 min with resumed ventilation and internal cardiac compressions. Simultaneously, 8 animals received 10 micrograms epinephrine/kg and 2 mg lidocaine/kg via peripheral i.v. injection and another 8 received 100 micrograms epinephrine/kg and 2 mg lidocaine/kg via e.b. instillation. During CPR and the 1st hour of restored spontaneous circulation the ECG, heart rate, and mean arterial pressure were continuously recorded. Plasma concentrations of lidocaine were measured by gas chromatography in venous blood, which was collected automatically at intervals of 30 s. RESULTS. All animals were resuscitated successfully after 3.7 +/- 1.6 min (i.v.) and 3.8 +/- 1.1 min (e.b., means +/- SD). With no differences during CPR, the hemodynamic situation of the e.b. medicated animals was characterized by higher arterial pressures from 10-15 min and higher heart rates from 10-60 min of restored spontaneous circulation. Median maximum concentrations of lidocaine after i.v. (3.2 range 1.3-9.6 micrograms/ml) and e.b. administration (3.1 range 1.1-8.6) were measured after 5.5 min (range i.v. = 4-10 min, e.b. = 3-7 min). Mean concentrations within a therapeutic range of 2-5 micrograms/ml were reached after 2-3 min and remained within these limits for 20-25 min after both routes of administration. Individual lidocaine concentrations below the therapeutic level of 2 micrograms/ml were measured in one experiment after i.v. application and in three experiments after e.b. administration. The individual time concentration profiles were mathematically approximated using an open two - compartment model with first-order absorption. The absorption half-life of e.b. lidocaine was 3.9 min, and mean bioavailability was 90%. Elimination pharmacokinetics of i.v. and e.b. lidocaine were nearly identical, with elimination half-lives of 25 min (e.b.) and 42 min (i.v.). Total body clearances were 401 ml/min (e.b.) and 362 ml/min (i.v.). CONCLUSION. An i.v. bolus of lidocaine during CPR should not exceed 2 mg/kg. During CPR without i.v. access the e.b. instillation of lidocaine can be recommended, but to ensure therapeutic concentrations a minimum dosage of 2 mg/kg is suggested.