The kinetics of metamizol and its metabolites in critical-care patients with acute renal dysfunction.

We have studied the clearance of monomethylaminoantipyrine (MMAAP), the pharmacologically active form of metamizol, in 46 patients in surgical intensive care with different degrees of renal dysfunction. In 23 patients without any renal impairment, mean clearance was 2.8 ml.min-1 x kg-1. Twenty-one patients with acute renal impairment had a significantly reduced clearance of MMAAP (0.83 ml.min-1 x kg-1). There was also reduced clearance in four patients with septic shock (1.0 ml.min-1 x kg-1). Kinetics of the metabolites of MMAAP (N-formylaminoantipyrine (FAAP), aminoantipyrine (AAP), and its secondary product N-acetylaminoantipyrine (AcAAP)) were calculated. FAAP and AcAAP showed delayed invasion, which can be explained by reduced hepatic metabolic activity. The product of N-demethylation, AAP, was not significantly altered. The delayed elimination of monomethylaminoantipyrine can be explained by reduced hepatic function in parallel with acute renal failure due to disturbed cardiovascular function caused by septic shock. This may also lead to disturbed hepatic macro- and microperfusion associated with altered oxygen supply and oxygen consumption.

Acute endocrine failure after brain death?

After brain death, 32 potential organ donors were studied to determine serum and plasma concentrations of hypothalamic-pituitary hormones, thyroid hormones, and cortisol over a period of up to 80 hr. Diagnosis of brain death was established either on the basis of clinical criteria (n = 16) or by angiography (n = 16). While 78% of the organ donors developed diabetes insipidus, none of the circulating hormones of the anterior pituitary gland showed a progressive decline in concentration according to their plasma half-lives. With the exception of arginine vasopressin (AVP), no hormone concentration was found to be subnormal due to the onset of brain death. The subnormal free triiodothyronine (FT3) values in 62% of cases (median FT3 of 2.2 pmol/L within the first 24 hr) and the cortisol concentration of 6.9 micrograms/dl correlate with the frequency of similar findings in patients with severe head injuries. While the adrenocorticotropic hormone (ACTH) concentrations of 10-53 pg/ml remained constant during the study period, thyroid-stimulating hormone (TSH) and human growth hormone (hGH) concentrations showed a 12- and 35-fold increase from baseline values after 30-40 hr. These results suggest that, despite the now generally accepted criteria of brain death, there is still some residual function, and thus also perfusion of the hypothalamic-pituitary neuroendocrine system. This residual function appears to be sufficient to maintain hormonal plasma levels at least in the low reference range in most donors. Hormonal depletion in organ donors subsequent to brain death, as suggested repeatedly in the literature, could not be confirmed. The analysis of serum or plasma concentration patterns of a number of hormonal parameters following brain death does not support the rationale for a routine replacement therapy of total triiodothyronine (TT3) or cortisol to maintain endocrine homeostasis prior to organ harvest. However, dexamethasone therapy may be followed by suppression of the adrenal cortex of the organ donor. In these cases, cortisol substitution may be indicated.

Hemodynamic responses to noxious stimuli in brain-dead organ donors.

The case report presents evidence for the spinal origin of the marked hypertensive responses to noxious stimuli that may occur in organ donors who fulfill the commonly accepted criteria of brain death. Cardiovascular spinal reflex activity does not invalidate these criteria. For the first time, the catecholamine plasma concentrations have been determined during spinal pressor reflex activity. Circulating epinephrine increased more markedly than norepinephrine in both cases, rising to 4.7 and 44 times the baseline concentration respectively. The relation between plasma norepinephrine and epinephrine suggests involvement of the adrenal medulla in the reflex arc. The literature on spinal hemodynamic reflexes is reviewed.

Measurement of plasma catecholamines by high-performance liquid chromatography with electrochemical detection in intensive care patients after dobutamine infusion.

A procedure for the determination of plasma catecholamine concentrations in critical care patients after dobutamine infusion is presented. A modified chromatographic system is required with an additional washing procedure to achieve maximum sensitivity and stable chromatographic conditions. The influence of storage time on the catecholamine concentrations of plasma samples is reported in detail. A time-dependent decrease in catecholamine concentrations of up to 12 and 39% was found within two and ten months, respectively.

Elevated serum diiodotyrosine (DIT) in severe infections and sepsis: DIT, a possible new marker of leukocyte activity.

Ether link cleavage (ELC) of T4 yielding diiodotyrosine (DIT) has recently been shown in vitro to be the major pathway of T4 metabolism in phagocytosing leukocytes. To evaluate this pathway in vivo and the possible clinical relevance of DIT measurements in diseases with increased leukocyte activity, radioimmunological studies on serum levels of DIT and other thyroid parameters were performed in 125 critically ill patients classified into 3 groups with bacterial infections according to the severity of infection and 1 group without infections. While the pattern of iodothyronine and TSH levels typical for severe nonthyroidal disorders, i.e. decreased total T3 and elevated rT3, normal or decreased total T4 and TSH, and normal free T4, was found in all four groups of intensive care patients studied, elevated serum DIT was observed only in those patients whose clinical course was complicated by severe bacterial infections. Serial measurements revealed a close temporal connection between the infection phase and increased DIT levels. Median values and 16th to 84th percentile ranges (in parentheses) of serum DIT (normal range, 0.02-0.55 nmol/L) were as follows: sepsis, 1.38 (0.32-5.14); severe nonsystemic infections such as peritonitis and abscesses, 3.84 (0.24-17.2); moderate infections such as pneumonia and tracheobronchitis, 0.44 (0.18-1.16); and critical illness without infections, 0.14 (0.08-0.30) nmol/L. These elevations of circulating DIT could neither be correlated with changes in renal function nor attributed to drug effects. The results of the present study do not allow any definitive conclusions to be made about the mechanisms underlying the phenomenon of increased serum DIT levels in infections. Apart from this open question, DIT appears to be a relatively specific serum parameter for the presence and course of severe bacterial inflammations. Its measurement could provide useful clinical information, particularly for monitoring the time course of deep-seated infections.

Different modulation of the perioperative stress hormone response under neurolept-anaesthesia or enflurane for cholecystectomy.

Two groups of 13 patients, randomly allocated to receive either enflurane or neurolept anaesthesia for cholecystectomy, were compared in their cardiovascular and neuroendocrine response to surgery and in the postoperative period. There were no significant differences in blood pressure or heart rate. Catecholamine values were higher under neurolept anaesthesia towards the end of surgery and postoperatively. Median values for adrenaline during suture of peritoneum were 342 pg/ml and 88 pg/ml, respectively, P less than 0.05. In contrast, ACTH and cortisol rose to higher levels in enflurane treated patients. At the end of surgery median ACTH values were 75 pg/ml in NLA patients and 322 pg/ml in enflurane patients (P less than 0.01). Vasopressin increments during surgery were similar under both regimens, while prolactin was higher following induction of neurolept anaesthesia. It is discussed whether the differences in stress hormone secretion patterns under either form of anaesthesia reflect different stress protective properties or direct pharmacological effects of certain anaesthetics. We conclude that the hormonal stress response to surgery is critically dependent on the type of anaesthesia and may be discordant in different hormonal systems.

[Psychopharmacologic aspects in intensive care medicine]. / Psychopharmakologische Aspekte in der Intensivmedizin.

The realization that many intensive care patients develop psychoreactive problems ranging from confusion to depression to frank mutism led us to include Dehydrobenzperidol (DHB) in our analgesia and sedation scheme. The early prophylactic administration of this drug was found to be particularly effective in the prevention of delirium following an alcohol and/or drug overdose.

[Central anticholinergic syndrome in intensive care patients]. / Das zentrale anticholinerge Syndrom (ZAS) bei Intensivpatienten.

Intensive care patients develop altered patterns of behaviour for a variety of reasons. However, the drug therapy instituted to ameliorate these psychoreactive problems may give rise to complications such as the central anticholinergic syndrome. Cholinergic receptors are scattered at random throughout the central nervous system. The depression of cholinergic transmission is not only secondary to the administration of drugs but is also due to abnormalities affecting other transmitter systems. To date, no definitive criteria have been established for the diagnosis of the central anticholinergic syndrome. The diagnosis is made by exclusion and by the administration of physostigmine either as an i.v. bolus of 0.03 mg/kg or as an infusion at the rate of 1-2 mg/h.

[How is the use of low molecular weight heparin in regional anesthesia evaluated?]. / Wie ist der Einsatz von NMH bei Regionalanästhesien zu beurteilen?

It is difficult to predict the risk of bleeding in regional techniques under concomitant LMH administration, as each LMH preparation has a particular mode of action and different pharmacological properties. Although complications due to bleeding, that occurs during the execution of a regional technique, are extremely rare, epidural anaesthesia with or without a catheter should be avoided during LMH administration. Where strongly indicated, a spinal anaesthetic can be performed by an experienced colleague. Epidural anaesthesia should not be carried out until at least 12 hours after the last dose of LMH.

Comparison of efficacy and safety of teicoplanin in gram-positive infections: a multicentre study.

A multicentre open trial included 219 hospitalized patients suffering from various Gram-positive infections. Previous antimicrobial therapy had been carried out in 37% of patients. The initial teicoplanin dose was 400 mg for 77.6% and 800 mg for 12.6% of the patients, 9.8% received other initial doses. The dose on subsequent days was 200 mg or less for 63% of patients and 400 mg for the remaining 27%. The mean duration of treatment was 11 days. Concomitant antibiotic treatment was given in 35% of cases. The overall clinical success rate was 86.9%. Therapy failure or recurrence of infection was seen in 5% and 2%, respectively. Elimination of pathogens was seen in 85.1% of all evaluable cases. Adverse drug reactions were observed in 14 patients. From these results, we conclude that teicoplanin is safe and effective in the therapy of many different infections caused by Gram-positive bacteria.

Patterns of endocrine secretion during sepsis.

In septic patients the clinical course of the disease is characterized by high DIT and rT3 serum concentrations as well as a low T3-syndrome. While rT3 is elevated in almost all critically ill patients, the increase in DIT is indicative of severe infection. Prolactin levels are regularly elevated in sepsis although to variable degrees. Catecholamines and vasopressin should be regarded as acute responders. The pattern of cortisol secretion is uncertain. In most situations the secretion appears to be elevated; the circadian rhythm is disturbed.

[Patient-adapted, ion selective analysis--characteristics of a new instrument]. / Patientennahe, ionenselektive Analytik--Charakterisierung eines neuen Gerätes.

We report on a newly developed instrument with ion-selective electrodes (IONOMETER EF) for the measurement of sodium, potassium and calcium. The measurements in whole blood and plasma from intensive care patients were compared with flame photometry. We assessed the precision and accuracy of these measurements. The precision of the analysis is excellent: K+ 4.69 +/- 0.03 mmol/l; Na+ 139.2 +/- 0.27 mmol/l; Ca++: 1.23 +/- 0.03 mmol/l. When assessing the accuracy, the characteristics of the ionselective device have to be considered, as well as differences in solvent volumes, when compared with flame photometry. The correlation coefficient of potentiometric analyses of whole blood and plasma is r = 0.99. It seems to be appropriate to define new normal ranges for ionselective electrode systems.

Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

Monitoring of pentobarbital plasma levels in critical care patients suffering from increased intracranial pressure.

Pentobarbital plasma levels were determined in 16 critical care patients receiving a dose of approximately 30 mg/kg/day and suffering from severe head injury. In 10 patients monitored more than six times, a continuous decrease in plasma concentrations, caused by a mean increase in pentobarbital total plasma clearance from 0.81 to 1.06 ml/min/kg, was found. This effect might be due to autoinduction of hepatic drug-metabolizing enzymes. As clearance values showed marked inter- and intraindividual variability, it is necessary to monitor pentobarbital plasma levels frequently to adapt the dosage to the changes in clearance. Infrequent determinations are of little clinical value, as the necessary changes in pentobarbital dosage will not be predicted precisely enough.

D-glucaric acid excretion in critical care patients--comparison with 6 beta-hydroxycortisol excretion and serum gamma-glutamyltranspeptidase activity and relation to multiple drug therapy.

The incidence of increased drug metabolism activity as a consequence of multiple drug therapy at a surgical intensive care ward has been studied non-invasively by determinations of daily urinary D-glucaric acid (GA) excretion rates. Among 165 randomly selected patients, GA excretion was stimulated in 76 cases (= 46%). Exploratory data analysis showed that increases in GA excretion are primarily due to administration of barbiturates (pentobarbitone, Nembutal), miconazole (Daktar) and, to a lesser extent, neuroleptics. Surprisingly, the large number of simultaneously administered additional drugs failed to increase GA excretion. Urinary 6 beta-hydroxycortisol (6 beta-OHF) and 17-hydroxycorticosteroid (17-OHCS) excretion rates were correlated in 34 patients with GA excretion; patients not receiving known enzyme inducers showed low GA values but high 6 beta-OHF and 17-OHCS values, however, with a ratio of 6 beta-OHF/17-OHCS in the normal range. Patients receiving high dose pentobarbitone treatment failed to exhibit significantly increased 6 beta-OHF and 17-OHCS or 6 beta-OHF/17-OHCS values. Miconazole treatment resulted in a significantly increased ratio of 6 beta-OHF/17-OHCS. gamma-Glutamyltranspeptidase activity in serum showed no correlation with GA excretion (n = 91).

[Bupivacaine 0.5% CO2 in spinal anesthesia]. / Bupivacain 0.5% CO2 in der Spinalanästhesie.

The clinical usage of 0.5% bupivacaine-CO2 for spinal anaesthesia was tested in 45 patients. The use of bupivacaine CO2 is safe, segmental dificits were not observed. Compared to bupivacaine-HCl the latency period is shorter (7.7 min), whereas the duration of maximal analgesic spread (105 +/- 31 min) is identical. 93% of the patients had a complete motor blockade. The solubility of bupivacaine-CO2 in CSF (1.75 mg ml-1) is more than double the solubility of bupivacaine-HCl (0.8 mg ml-1), thus lowering the risk of precipitation.

The effect of dopamine on muscle PO2 in healthy volunteers and intensive care patients.

The effect of systemic dopamine administration (2-10 micrograms kg-1 min-1) on the Po2 distribution (histograms) and the mean Po2 in the m. vastus lateralis of m. quadriceps femoris in nine healthy volunteers and seven critically ill patients has been studied with a newly developed bedside measuring procedure. Dopamine initially raised mean muscular Po2 in both groups. In the volunteers, mean muscular Po2 thereafter decreased gradually but still remained slightly elevated after 30 min of dopamine infusion. This increase in muscle oxygenation could be abolished by the administration of a dopamine antagonist (metoclopramide). In the patients, the initial dopamine-induced increase of Po2 was significantly slower and reached a plateau within 30 min. The results are discussed with special attention given to the data available on the action of dopamine on given peripheral circulation.

Comparison of midazolam, diazepam and placebo i.m. as premedication for regional anaesthesia. A randomized double-blind study.

In a randomized double-blind study, midazolam 0.1 mg kg-1 i.m. was compared with diazepam 0.2 mg kg-1 and placebo as premedication for patients undergoing urological interventions under spinal anaesthesia. The sedative and anxiolytic effects of midazolam were evident 5-10 min after administration, and were maximum between 30 and 90 min. After this, rapid recovery was observed. More than 90% of the patients receiving midazolam were totally or partially amnesic for the procedures in the induction room and the operation theatre. Amnesia was not seen in the patients receiving diazepam or placebo and, in contrast to midazolam, diazepam had almost no sleep-inducing effect. In a few patients, the depth of sleep achieved with midazolam 0.1 mg kg-1 was such that co-operation was impaired.