As aminoglycosides show concentration-dependent killing, once-daily aminoglycoside (ODA) regimens have been instituted. Data on experience with ODA regimens in critically ill patients are limited.
1) ...To evaluate the ODA-program in critically ill patients; 2) to describe the pharmacokinetics of aminoglycosides (gentamicin and tobramycin); and 3) to assess the incidence of nephrotoxicity associated with an ODA regimen in this specific of group patients.
A prospective, descriptive study.
Eighteen-bed surgical and 12-bed medical intensive care unit in a referral centre.
Eighty-nine critically ill patients with a suspected or confirmed infection for which gentamicin or tobramycin was indicated and a creatinine clearance > 30 ml/min were monitored. One hundred and nine pharmacokinetic profiles were gathered.
A first dose of 7 mg/kg/24 h of gentamicin or tobramycin was given to every patient independent of renal function. Subsequent doses were chosen on the basis of the pharmacokinetic results of the first dose.
Serum samples were collected 1 h and 6 h after start of the aminoglycoside infusion. All samples were assayed by using immunofluorescence. Pharmacokinetic parameters were estimated using a one-compartment model.
The volume of distribution of aminoglycosides was significantly higher in critical ill patients with septic shock than in those without. Consequently, the maximum concentration reached was significantly lower in patients with septic shock. In P. aeruginosa infections the mean (SD) estimated Cmax/MIC ratio was 10.3 (3.3). In n = 17 (49%) of the patients treated > 24 h ( n = 35), a dose adjustment or lengthening of interval was necessary. The recommended dosing interval based on the Hartford Hospital nomogram and one-serum concentration at 6 h was correct in only 62% of all cases. Signs of renal impairment occurred in n = 12 (14%) of the patients; in all survivors renal function recovered completely and no haemofiltration was needed.
An ODA-regimen of 7 mg/kg produced Cmax/MIC ratios > 10 in the majority of critically ill patients in our population. Septic shock and renal dysfunction caused an aberrant pharmacokinetic profile of aminoglycosides in these patients. Therefore, individual therapeutic drug monitoring is warranted. Signs of renal impairment were common in the presence of shock, but appeared to be reversible.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ceftazidime demonstrates time-dependent killing, which is maximal at 4 × or 5 × MIC for the organism, consequently continuous infusion (CI) has been proposed to ensure adequate ceftazidime ...concentrations for the entire course of therapy. Severe intra-abdominal infections (IAIs) require surgical or percutaneous drainage for management, and ceftazidime is frequently prescribed. Cardiovascular or metabolic changes and renal or liver dysfunction may alter drug pharmacokinetics during severe IAIs, and no data exist on concentrations of ceftazidime reached in the peritoneal fluid. The objectives here were to determine the pharmacokinetics of ceftazidime during continuous and intermittent administration in patients with severe IAIs, and to measure the concentrations of ceftazidime in the peritoneal exudate. Eighteen surgical patients with severe IAI and a creatinine clearance of >30 mL/min were studied. A non-randomized pilot study of six patients treated with CI alone was followed by a prospective, randomized comparative study of 12 patients. Pilot study patients received ceftazidime 1 g iv followed by a 4.5 g CI over 24 h. Randomized patients received either ceftazidime continuously as above or 1.5 g tds. Samples for pharmacokinetic analyses were collected on days 2 and 4. Ceftazidime concentrations were determined by high-performance liquid chromatography. CI resulted in a mean serum concentration >40 mg/L and a T> 4 × MIC for most pathogens encountered in severe IAIs for >90% of the course of therapy in both serum and peritoneal exudate. Eight-hourly administration resulted in T> 4 × MIC for most pathogens encountered in severe IAIs for >90% of the dosing interval, but in peritoneal exudate for only 44% of the dosing interval. During CI, AUCs in the peritoneal exudate were c. 60% of the concomitant serum AUCs. In critically ill surgical patients with severe IAIs, CI of ceftazidime resulted in more favourable concentrations in serum and peritoneal exudate than 8-hourly bolus infusion.
Background: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous ...infusion might have pharmacodynamic advantages. Objectives: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation. Methods: Fifteen patients undergoing liver transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000 mg iv four times daily). Samples were collected during the first 48 h after liver transplantation. Concentrations of CTX and DCTX were determined by HPLC. Results: During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest serum concentration was 5 mg/L in the CI group and levels were undetectable in the BI group. Target serum concentrations of ≥4 mg/L were reached for 100% of the dosing interval during CI and ∼60% during BI. Post-operatively, the mean concentration in serum after CI was 26 mg/L. The lowest serum concentration was 8 mg/L in the CI group and levels were undetectable after BI. The peroperative pharmacokinetics of CTX in this patient group were deranged and variable, mainly caused by an increased volume of distribution and decreased hepatic clearance. Metabolism was hampered, but DCTX area under the curve (AUC)/CTX AUC ratios varying between 0.7–0.9 were reached peroperatively. Post-operatively, DCTX AUC/CTX AUC ratios were higher (1.1–1.4). Unchanged CTX in bile was ∼0.1% of the administered dose, leading to concentrations >4 mg/L throughout the dosing interval for both regimens. Conclusion: Although an intermittent bolus infusion of CTX 1000 mg produces t > target concentration for 60% of the dosing interval during liver transplantation, serum concentrations may be insufficient during the reperfusion phase. Continuous infusion overcomes this. Post-operatively, CTX clearance is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.
To determine whether adoption of radiofrequency (RF) ablation in patients with symptomatic benign thyroid nodules (SBTNs) in a Dutch regional thyroid network resulted in clinical success and ...improvement in health-related and thyroid-related quality of life (QoL).
The eligibility criteria for RF ablation were as follows: (a) nodule size between 2.0 and 5.0 cm, (b) solid component >20%; (c) benign cytology in 2 separate cytological assessments, and (d) symptoms unequivocally related to mechanical compression. The primary end point of this study was volume reduction 1 year after ablation. The secondary outcomes were health-related and thyroid-related QoL, measured using the short form health survey questionnaire (SF-36) and thyroid-specific patient-reported outcome questionnaire (ThyPRO-39), respectively, as well as adverse event rates.
A total of 72 SBTNs in 67 patients were included. Median age was 50.0 (interquartile range, 41.0-56.0) years, and 91.0% were women. The median volume reduction at 6 weeks, 6 months, 1 year, 2 years, and 3 years was 51.0%, 63.9%, 65.2%, 81.3%, and 90.3%, respectively. The patients showed a significant improvement on the SF-36 physical component scale and ThyPRO-39 overall QoL-impact scale. An absolute improvement was seen in goiter and cosmetic complaints, determined using ThyPRO-39. The overall adverse event rate was 9.0%, of which 4.5% were considered major.
RF ablation is an effective treatment option for SBTNs, with a significant volume reduction and improvement in health-related and thyroid-related QoL.
(1) To determine the pharmacokinetics of sequential intravenous and enteral fluconazole in the serum of surgical intensive care unit (ICU) patients with deep mycoses. (2) To determine the ...concentrations of fluconazole reached at the site of infection. (3) To determine if enteral administration of fluconazole, which has an important pharmaco-economic advantage, is justified in this specific patient group.
Descriptive, sequential study as a part of a therapeutic drug monitoring programme.
Eighteen-bed surgical ICU in a referral centre.
Fourteen critically ill surgical patients with recent gastro-intestinal (GI) surgery and deep mycosis caused by a fluconazole-susceptible fungus and a calculated creatinine clearance of more than 40 ml/min.
Fluconazole dosage regimen: 400 mg i. v. every 24 h with an extra dose of 400 mg i.v. after 12 h on day 1. If the clinical condition allowed enteral administration on day 4, the content of two capsules of 200 mg was given via the feeding tube with concomitant enteral feeds.
Serum, exudate from the site of infection and urine samples collected at assumed steady state ( after > or = 5 doses). Fluconazole concentrations were determined by high-performance liquid chromatography (HPLC). The mean area under the concentration curve (AUC0-24 h) in serum after enteral administration did not significantly differ from the AUC0-24 h during intravenous treatment. The elimination half-life was longer compared to healthy volunteers. The mean (95% CI) estimated bioavailability was 124 (90-158)%. The mean (95% CI) area under the concentration time curves (AUCs) achieved in the exudate from the site of infection were 67 (55-79)% of the AUCs reached in serum for both regimens.
In critically ill patients with recent GI surgery and/or peritonitis the bioavailability of enteral fluconazole was adequate. The concentrations of fluconazole reached in exudate were lower than those in serum for both regimens, but adequate to treat most cases of deep mycoses in this specific patient group.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A football player was diagnosed with myositis ossificans of his right adductor longus muscle after an acute injury. Conservative treatment failed and 1 year after the initial trauma the patient ...underwent surgical excision of a large ossification. Seven months postoperatively, the patient was fully recovered and returned to his preinjury activity levels. We present our approach to this case and discuss our considerations, referring to background information about this rare disease.
We tested the effects of continuous infusion of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on cardiovascular performance and pulmonary gas exchange in ...patients with hyperdynamic septic shock.
Prospective clinical study.
ICU of a university hospital.
Eleven critically ill patients with severe refractory septic shock.
Standard hemodynamic measurements were made and blood samples taken before, during, and after 12 h of continuous infusion of 1 mg/kg/h of L-NAME.
Continuous infusion of L-NAME increased mean arterial pressure (MAP) from 65±3 (SEM) to 93±4 mm Hg and systemic vascular resistance (SVR) from 962±121 to 1,563±173 dyne ·s· cm–5/m2. Parallel to this, cardiac index (CI) decreased from 4.8±0.4 to 3.9±0.4 L/min/m2 and myocardial stroke volume (SV) was reduced from 43±3 to 34±3 mL/m2. Left ventricular stroke work was increased in the first hour of L-NAME infusion from 31 ±3 to 43±4 g· m/m2 (all p<0.01 compared with baseline). Heart rate, cardiac filling pressures, and right ventricular stroke work did not change significantly (p>0.05). L-NAME increased the ratio of arterial Po2 to the fraction of inspired O2 from 167±23 to 212±27 mm Hg (p<0.05). Venous admixture (QVA/QT) was reduced from 19.4±2.6% to 14.2±2.1% (p<0.05) and oxygen extraction ratio increased from 21.1±2.4% to 25.3±2.7% (p<0.05). Oxygen delivery (Do2) was reduced following L-NAME, whereas oxygen uptake and arterial lactate and pH were unchanged.
Prolonged inhibition of NO synthesis with L-NAME can restore MAP and SVR in patients with severe septic shock. Myocardial SV and CI decrease, probably as a result of increased afterload, since heart rate and stroke work were not reduced. L-NAME can improve pulmonary gas exchange with a concomitant reduction in QVA/QT. L-NAME did not promote anaerobe metabolism despite a reduction in Do2.
The purpose of this study was to assess and compare the humidification, heating, and resistance properties of three commercially available heat-moisture exchangers (HMEs). To mimic clinical ...conditions, a previously validated, new, realistic experimental set-up and measurement protocol was used.
Prospective, comparative experimental study.
Surgical Intensive Care Unit, University Hospital of Rotterdam.
An experimental set-up consisting of a patient model, measurement systems, and ventilator and three different HME types.
The air flow, pressure in the ventilation circuit, pressure difference over the HME, and partial water vapour pressure and temperature at each side of the HMEs were measured. Measurements were repeated every 30 min during the first 2 h and every hour up to 24 h for each HME at six different ventilator settings. The mean inspiratory and maximum expiratory resistance, flow-weighted mean absolute humidity and temperature outputs, and humidification and heating efficiencies of HMEs were calculated.
The Dar Hygroster had the highest humidity output, temperature output, humidification efficiency, and heating efficiency values throughout the study (32.8 +/- 21. mg/l, 32.2 +/- 0.8 degrees C, 86.3 +/- 2.3%, and 0.9 +/- 0.01%, respectively) in comparison to the Humid-Vent Filter (25.3 +/- 3.2 mg/l, 31.9 +/- 0.8 degrees C, 72.2 +/- 5.3%, 0.9 +/- 0.02%, respectively) and the Pall Ultipor BB100 breathing circuit filter (23.4 +/- 3 mg/l, 28.3 +/- 0.7 degrees C, 68.8 +/- 5.9%, 0.8 +/- 0.02%, respectively). The inspiratory and expiratory resistance of the HMEs remained below clinically acceptable maximum values (2.60 +/- 0.04 and 2.45 +/- 0.05 cmH2O/l per s, respectively).
The Dar Hygroster filter was found to have the highest humidity and temperature output of all three HMEs, the Humid-Vent filter had a satisfactory humidity output only at low tidal volume flow rate and minute volume settings, whereas the Pall Ultipore BB 100 never achieved a sufficient humidity and temperature output.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Few data are available on the pharmacokinetics of multiple enteral dosing of ciprofloxacin in critically ill intensive care patients and none for those with severe gram-negative intra-abdominal ...infections (GNIAI).
To determine the bioavailability of enteral ciprofloxacin in tube-fed intensive care patients with severe GNIAI.
A randomized crossover study.
University-based medical center.
5 critically ill intensive care patients with GNIAI and an estimated creatinine clearance > 25 ml/ min who received continuous tube feeding.
Multiple doses of enteral 750 mg b.i.d. versus 400 mg b.i.d.i.v. ciprofloxacin.
The calculated 12-h area under the serum concentration versus time curve after 750 mg b.i.d. enteral dosing was equivalent to that after 400 mg b.i.d.i.v. The mean bioavailability of enteral dosing was 53.1% 95% confidence interval (CI) 43.5-62.8. In seven additional patients, the mean serum steady-state concentration at 2 h after enteral administration was 3.9 microg/ml (95% CI 1.9-5.9), not significantly different from that found in the crossover study (p = 0.4).
In tube-fed intensive care patients with severe GNIAI, the bioavailability of enteral ciprofloxacin is adequate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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