Jiri Zahora

Tolerability and Outcomes of Kinetically Guided Therapy With Gentamicin in Critically Ill Neonates During the First Week of Life: An Open-Label, Prospective Study

BACKGROUND Aminoglycosides are bactericidal antibiotics used worldwide for the treatment of serious infections in critically ill patients, including neonates. Critically ill neonates constitute a unique challenge in dosing owing to the pathologic alterations that accompany severe illness and the rapidly changing conditions of these patients. OBJECTIVES The main objective of this study was to analyze the kinetically guided dosage adjustment of gentamicin in neonates critically ill during the first week of life based on plasma concentrations after the first dose and to identify the impact of covariates (eg, fluid intake, body fluid retention) with respect to gestational age (GA). Tolerability of therapy was also assessed. METHODS This 10-day, open-label, prospective study included neonates critically ill during the first week of life admitted to the neonatal intensive care unit of a childrens hospital between January 2006 and July 2009. Hearing and renal assessments were conducted over a 24-month follow-up period. The patients were treated with gentamicin for suspected sepsis, proven sepsis, or pneumonia as an early sign of sepsis. The first and second doses of gentamicin 4 mg/kg were adjusted according to birth weight and GA: group 1 (GA < 34 weeks), 48-hour interdose intervals; group 2 (GA 34-38 weeks), 36 hours; and group 3 (GA > 38 weeks), 24 or 48 hours. Individual pharmacokinetic parameters were estimated after the first dose (given in 30-minute intravenous infusions) using 4 concentrations. Individual pharmacokinetic parameters were estimated by fitting the parameters of a 2-compartment model into 4 concentrations. The last 2 blood samples were taken 30 minutes before the fourth infusion (C(trough,3)) and 1 hour after its start (C(max,4)). Dosing was individualized to reach target ranges for the C(trough,3) (0.5-2.0 mg/L) and C(max,4) (6-10 mg/L) values. If needed, initial dosing was changed after the second dose by adjusting (reducing or increasing) the third and subsequent doses, or by adjusting (prolonging or shortening) the interdose intervals. C(trough,3) and C(max,4) were assessed to determine differences between predicted and assayed values. Fluid retention was registered as the difference between fluid intake and urine output at different intervals related to the first dose per kilogram of birth weight, and from the start of the first infusion (0 hour) to the day of the fourth infusion. The C(max)/minimum inhibitory concentration (MIC) ratio was determined for assessment of optimal response. Tolerability was evaluated during the 24-month follow-up period using renal sonography to screen for nephrocalcinosis and transient evoked otoacoustic emission recordings to evaluate hearing abnormalities. RESULTS A total of 84 neonates (all white; 53 males, 31 females; birth weight range, 0.8-4.56 kg; GA range, 24-42 weeks) were enrolled in 3 groups: group 1, GA < 34 weeks, n = 27; group 2, GA 34-38 weeks, n = 22; and group 3, GA > 38 weeks, n = 35. The C(max) value detected 1 hour after the start of the first infusion (C(max,1)) reached the target range of 6-10 mg/L in 66 of the 84 neonates (79%). After the initial dose, C(max,1) was variable (%CV, 29%); the failure rate to reach 6 mg/L was 13%. V(d) decreased with GA (r = -0.30, P < 0.01) and achieved mean (SD) rates of 0.51 (0.10), 0.48 (0.13), and 0.40 (0.15) L/kg in groups 1, 2, and 3, respectively. Neither C(max) nor V(d) was correlated with fluid intake relative to the first infusion. Mean gentamicin clearance measured after dose 1 (0.47 [0.23], 0.66 [0.26], and 0.76 [0.32] mL/min/kg) increased with GA (r = 0.45, P < 0.001). The interdose interval was prolonged after the second and subsequent infusions in 8 of 84 neonates (10%) or by decreasing the third dose and subsequent doses in 51 neonates (61%). The target C(max,4) and C(trough,3) values occurred in 63% (22 of 35) and 83% (29 of 35) of full-term patients (GA >38 weeks), respectively. In preterm neonates, the target range for C(max,4) was reached in 11 of 27 patients (41%) in group 1 and 11 of 22 patients (50%) in group 2; for C(trough,3), the target range was reached in 25 patients (93%) in group 1 and in 16 (73%) in group 2. C(trough,3) >2 mg/L was detected in 1 full-term neonate, and gentamicin was withdrawn. Suspected fluid retention within the time period of 0 hour to the day of the fourth infusion was well correlated with actual body weight (r = 0.58, P < 0.001), but it was negatively correlated with C(max,4) (r = -0.25, P = 0.02). Thirteen of the 84 neonates (15%) had confirmed sepsis. C(max)/MIC was >12 except for 2 resistant staphylococcal infections (C(max)/MIC = 0.4); amikacin and vancomycin were substituted for gentamicin in these cases. Clinical signs and laboratory data indicative of suspected sepsis disappeared in 5 to 10 days in 68 of 71 neonates. In 1 neonate, gentamicin was withdrawn after dose 4 because of a high C(trough,3) value. In the 3 remaining neonates, C-reactive protein was decreased >10 days without changing therapy. Two neonates died, 1 of severe hypoxic-ischemic encephalopathy as a consequence of perinatal asphyxia and another of stage IV intraventricular hemorrhage. Transient renal dysfunction attributable to gentamicin was detected in 1 case. No signs of late toxicity (nephrocalcinosis) were found during the second year of follow-up. Two neonates were diagnosed with unilateral hearing loss, a secondary phenomenon of hypoxic-ischemic encephalopathy thought to be related to the severe perinatal asphyxia. CONCLUSIONS The initial dose of gentamicin 4 mg/kg for these critically ill premature and mature neonates with sepsis during the first week of life was high enough to reach bactericidal C(max,1) within 6-10 mg/L. C(max,1) <6 mg/L occurred in 13% of neonates. The interdose interval modified according to the recommendation resulted in C(trough) values within the target range of 0.5-2.0 mg/L in all but 2 neonates. The kinetically guided maintenance dosing of gentamicin based on plasma concentrations after the first dose should be optimized, taking into account actual body weight. (EudraCT number: 2005-002723-13).

Software For Practical Training In Medical Biophysics

Abstract. The course of medical biophysics at our medical faculty consists of three parts. The first one and the most extended one is medical biophysics, the second one is introduction to medical data processing and the last one is biostatistics. Mainly the conventional forms of teaching are used – lectures, seminars and practical training. At present we have six practical trainings: Audiometry, Principle of computed tomography, Noninvasive measurement of electrical heart activity and blood pressure, Magnitude measurement of microscopic objects, Mechanical properties of Nitinol and Diagnostic use of ultrasound. To increase efficiency of the teaching process we have decided to combine and to apply all three parts of our course in every practical training. The base of all practical trainings is some medical or biophysical problem. Students must learn how to work with measuring device, they must collect data and they must process them and prepare final report. So we have decided to make the best account of personal computers, of software for data acquisition and statistical data processing and of local area network (LAN). For some tasks we use commercial software, when it was necessary we have developed our own one. For all practical trainings we use personal computers connected to LAN. Computers are provided for measuring with either AC/DC converters and sensors (Mechanical properties of Nitinol, Noninvasive measurement of electrical heart activity) or they communicate with measuring unit (audiometer, digital camera, ultrasonograph, spectrometer). We use some commercial software as DP Soft by Olympus for image processing and remote controlling of digital camera, MS Excel for statistical data processing or MS Word for creating final reports. Software for remote controlling of audiometer and database of patients was customized to be consistent with our special demands. For measuring of mechanical properties of Nitinol we have developed software for data acquisition by means of LabVIEW (National Instruments). We have developed also a number of teaching programs for biophysics (Construction of electrical heart axes, Propagation and reflection of ultrasound waves through interfaces between tissues, Blood circulation, Model of multithermocouple probe in the temperature gradient, Principle of osmosis, …) and for biostatistics (Theoretical models of random quantities, STATPROMED – interactive hypertext textbook of biostatistics). For developing of this software we use Authorware (Macromedia). Resulting practical tasks are very complex. Besides of investigating and cognition of basic biophysical phenomena and principles the students have possibility to learn and to train new modern ways of data acquisition and data processing. They also obtain experiences with various types of software and their effective exploitation.

Technical Note Parasitic thermovoltage in the multithermocouple probe, its explanation and elimination

The parasitic thermovoltage can influence the temperature measurement during hyperthermia using the miniature multithermocouple probes with a common wire. It was noticed that, when a thermocouple junction is placed in a sharp thermal gradient, a parasitic thermovoltage is added to the voltage of all remaining thermocouples situated in the direction to the tip of the probe. This article gives the theoretical explanation, experimental verification, and practical elimination of this phenomenon.