Elimination of drugs by the new polyamide hemofilter FH77H during various in vitro conditions.

BACKGROUND/AIMS: Multiple organ failure alters the dosage of drugs during hemofiltration. To separate factors, we utilized in vitro hemofiltration to investigate different blood flows, protein concentrations and intracellular drug partition with the FH77H polyamide membrane. METHODS: One liter of warm heparinized fresh human blood was hemofiltrated in two series: (1) with digoxin, netilmycin, phenobarbital, ceftriaxone and teicoplanin, and (2) with amikacin, theophylline, ceftazidim, phenytoin and vancomycin and, in addition, with cell-free fresh frozen plasma. RESULTS: The increased volumes of distribution of aminoglycosides and theophylline were a combined result of partition into cells and adsorption into the filter membrane. The deviations of drug sieving from predicted values were due to different affinities of the drugs on whole blood binding sites. CONCLUSION: The in vitro composition of drugs and blood improved the detection of factors that influence drug elimination during hemofiltration. The FH77H polyamide hemofilter facilitates more precise predictions of drug dosages by low adsorption rates to the membrane.

[Hemodynamic-kinetic controlled extracorporeal circulation in heart surgery]. / Hämodynamisch-kinetikgesteuerte extrakorporale Zirkulation in der Herzchirurgie.

Mimicking the physiological characteristics of the circulatory system, pulsatile bloodflow has also been introduced into extracorporeal perfusion to avoid known postoperative complications. In a mathematical consideration of the situation bloodflow is seen as a function of time F(t) for approximately constant vessel diameter over a given time. The kinetic energy of a column of blood produced by the heart-lung machine is transmitted directly to the arterial circulation via the aorta. The nature of the energy release can give rise to both positive (organ perfusion) and negative (damage to endothelium) effects. This study investigates how this energy release can be optimised, using the following experimental approach. A Doppler flow-measuring probe is placed on the ascending aorta to monitor the extracorporeal circulation. At the same time, the blood pressure is measured and converted to a pressure-flow curve via an A/D converter. On the basis of the parameters thus obtained, the energy released by the heart-lung machine is calculated. By regulating the functional parameters of a new generation of heart-lung machines, the bloodflow can then be adapted to the physiological requirements. Within the pulse period (cycle) a 20% rise phase ending in a slightly increasing plateau is established. The energy increase within a cycle should not exceed 150 joules. To optimize the mode of functioning of the heart-lung machine, we introduced the "energy-equivalent pressure" (EEP). Adaptation of the EEP to the physiological conditions required a basic flow of 60% at a pulse rate of 60/min and a pulse duration of 35% within the pulsatile flow interval.

Pharmacokinetics of ceftriaxone in patients undergoing continuous veno-venous hemofiltration.

Continuous hemofiltration is used widely in the management of patients with acute renal failure, but administration guidelines for many drugs have yet to be established. In this study, the pharmacokinetics of ceftriaxone were compared in patients with normal renal function (n = 9), mild renal insufficiency (n = 5), and acute renal failure receiving continuous veno-venous hemofiltration (n = 6). Pharmacokinetic parameters were determined under steady state conditions. Patients with mild renal insufficiency had a significantly lower renal clearance and longer half-life of ceftriaxone; however, drug recovery in the ultrafiltrate with continuous veno-venous hemofiltration was similar to that in the urine of patients with normal renal function. Pharmacokinetic parameters for renal, nonrenal, and systemic clearance and for volume of distribution and half-life were also similar between patients receiving continuous veno-venous hemofiltration and those with normal renal function. The sieving coefficient (S) of ceftriaxone (0.69) significantly exceeded the expected free fraction in plasma, confirming previous reports that protein binding does not limit the sieving of this compound. The results suggest that a reduction in the usual daily dose of ceftriaxone is not required in patients with acute renal failure receiving continuous veno-venous hemofiltration.

Drug administration in critically ill patients with acute renal failure.

Patients with acute renal failure are commonly treated by continuous renal replacement therapies. To understand drug disposition in multiple organ failure patients, the pharmacokinetics of 18 drugs were evaluated in 243 patients. Continuous hemofiltration served as a model for constant elimination rates. In addition, the elimination of drugs was investigated during extracorporeal lung support. The dosage of 11 of 15 drugs had to be reduced as a result of these kinetic studies. Wide variability in volumes of distribution, clearances, and the extrarenal fractions of elimination were detected. There was a close correlation of the latter with Acute Physiology and Chronic Health Evaluation II scores of illness severity. A new algorithm was developed for primary estimates of drug dosage during hemofiltration and other organ support systems. Two in vitro studies confirmed the clinical results on drug sieving and provided important information on adsorption to membranes. A clinical validation study of the algorithm improved drug dosage. A simplified therapeutic drug monitoring approach is given.

[Anesthesia with propofol during an exacerbated course of acute intermittent porphyria]. / Anästhesie mit Propofol bei einem exazerbierten Verlauf der akuten intermittierenden Porphyrie.

In the eighth week of pregnancy the medical indication for induced abortion was established due to an exacerbating acute intermittent porphyria with life-threatening neurological symptoms. delta-aminolaevulinic acid and porphobilinogen were excessively increased in urine prior to the operation. Anaesthesia was induced with a bolus of propofol, alfentanil and droperidol, maintained by 67% of nitrous oxide and small bolus injections of the three drugs. The patient regained consciousness immediately after the operation, and reached full orientation and cooperativeness within five minutes. The postoperative period remained uneventful and the neurological and psychological symptoms returned to the pre-exacerbation status. Chorion gonadotropins and porphyria markers decreased within the next four weeks accompanied by a simultaneously progressing clinical improvement. The use of propofol and the other drugs appears justified even in exacerbated porphyria.

Pharmacokinetics and dosage adjustment of antibiotics during continuous extracorporeal lung assistance and hemofiltration.

Fifty-eight patients undergoing continuous volume-controlled hemofiltration (CVHF) and extracorporeal lung assistance (ECLA) received drug therapy determined by use of a new predictive algorithm in a validation study. Amikacin, netilmicin, tobramycin, ceftriaxone, vancomycin, and teicoplanin doses were given as predicted from clinical parameters. Corrections were necessary in 15 cases (e.g., CVHF 68% and ECLA 82% precision). There were no statistical differences between predicted and monitored drug doses. The correlation coefficient gave r2 = 0.921. Preliminary results from not yet analyzed drugs (ceftriaxone, teicoplanin) fit well into the curve. Because of rapid intraindividual changes, toxic drugs should continue to be monitored.

Evaluation and first validation study on a simplified drug dosage algorithm for multiple organ failure patients.

As reported previously, drug concentrations during continuous hemofiltration (HF) and extracorporeal lung assist (ELA) follow certain rules, which can be expressed by a simplified algorithm for dosage adjustment: Drug sieving (S, fu) depends on the protein free fraction with small limitations, while the extrarenal elimination rate is not a constant but correlates inversely with the clinical state, r = -0.34, p = 0.00067, n = 96. Up to now, more than 218 cases of drug dosage adjustments have been performed, following the described regimen: The expected concentration is obtained in 79-84% already from the first estimation for drugs such as aminoglycosides, vancomycin, teicoplanin, beta-lactam antibiotics, heart glycosides, and theophylline. Skilled therapeutic drug monitoring (TDM) with elaborated pharmacokinetic programs fails to improve these results significantly. Nevertheless, sporadic TDM is essential in these patients according to their rapidly changing clinical states.

[Drugs in the intensive care unit--need for dosage adjustment in organ failure]. / Arzneimittel auf der Intensivstation--Notwendigkeit der Dosisanpassung bei Organversagen.

Drug dosage in intensive care patients is a common problem that cannot be sufficiently solved in practice. To obtain an idea as to the variance of multiorgan failure during treatment, the pharmacokinetics of 17 drugs were evaluated in 96 patients. Continuous hemofiltration served as a model for constant elimination rates. In addition, the elimination of drugs was investigated during extracorporeal lung support. For 11 of 15 drugs on which kinetic studies had been completed, dose reductions had to be performed. Furthermore, widespread variance in their volume of distribution and their clearance and in the extrarenal fraction of elimination were detected. The latter showed a close correlation to clinical scores of illness. This led us to develop a new algorithm for primary estimations of drug dosage during hemofiltration. In a preliminary validation study, the algorithm seemed to show an improvement in the drug dosage in these populations. Nevertheless, a more simplified means of monitoring therapeutic drugs should be continued, especially for toxic agents.