Separator fluid volume requirements in multi-infusion settings

INTRODUCTION. Intravenous (IV) therapy is a widely used method for the administration of medication in hospitals worldwide. ICU and surgical patients in particular often require multiple IV catheters due to incompatibility of certain drugs and the high complexity of medical therapy. This increases discomfort by painful invasive procedures, the risk of infections and costs of medication and disposable considerably. When different drugs are administered through the same lumen, it is common ICU practice to flush with a neutral fluid between the administration of two incompatible drugs in order to optimally use infusion lumens. An important constraint for delivering multiple incompatible drugs is the volume of separator fluid that is sufficient to safely separate them. OBJECTIVES. In this pilot study we investigated whether the choice of separator fluid, solvent, or administration rate affects the separator volume required in a typical ICU infusion setting. METHODS. A standard ICU IV line (2m, 2ml, 1mm internal diameter) was filled with methylene blue (40 mg/l) solution and flushed using an infusion pump with separator fluid. Independent variables were solvent for methylene blue (NaCl 0.9% vs. glucose 5%), separator fluid (NaCl 0.9% vs. glucose 5%), and administration rate (50, 100, or 200 ml/h). Samples were collected using a fraction collector until <2% of the original drug concentration remained and were analyzed using spectrophotometry. RESULTS. We did not find a significant effect of administration rate on separator fluid volume. However, NaCl/G5% (solvent/separator fluid) required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). Also, G5%/G5% required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). The significant decrease in required flushing volume might be due to differences in the viscosity of the solutions. However, mean differences were small and were most likely caused by human interactions with the fluid collection setup. The average required flushing volume is 3.7 ml. CONCLUSIONS. The choice of separator fluid, solvent or administration rate had no impact on the required flushing volume in the experiment. Future research should take IV line length, diameter, volume and also drug solution volumes into account in order to provide a full account of variables affecting the required separator fluid volume

197 Influence of inhalation mode on aerosol lung deposition in patients with cystic fibrosis PART 1: Pharmacokinetic data as representative of lung deposition

Objectives: To investigate the impact of two different inhalation flow maneuvers (TIM = slow and deep inhalation and TBM = normal tidal breathing) on aerosol lung deposition in patients with CF using pharmacokinetic parameters as a representation of lung deposition. Methods: Randomized, open-label, cross-over study. The study group consisted of 18 adult patients with a confirmed diagnosis of CF (genetic analysis). Each patient inhaled a tobramycin solution twice during separate study visits: once in TIM and the other time in TBM mode. Blood samples were collected in order to model tobramycin pharmacokinetics. Outcome measurements: Relative bioavailability (Frel) of tobramycin is defined as the ratio of AUCTIM to AUCTBM, in which the AUC represents the plasma concentration area under the curves. A ratio greater than 1 indicates higher lung deposition for TIM compared to TBM. Individual pharmacokinetic parameters were calculated and assimilated with patient tobramycin serum values using a computerized CF-based Bayesian population model (MW-Pharm, Mediware). Results: Frel was 1 or greater for all patients (mean = 1.55, sd = 0.39, 95%CI = 1.37-1.73). In addition, mean Frel was significant higher than the value of 1 (mean difference = 0.55,

Effect of nebulized colistin sulphate and colistin sulphomethate on lung function in patients with cystic fibrosis:A pilot study

Background: Pulmonary administration of colistin is one of the antimicrobial treatments used in Cystic Fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. Dry powder inhalation of colistin may be an attractive alternative to nebulization of colistin. However, nebulized colistin can cause bronchoconstriction in CF patients. Therefore, in the progress of developing a dry powder formula, the choice of the inhaler and its contents should be guided by optimal efficacy and the least possible side effects. To investigate the side effects, a study was initiated to compare the tolerability of colistin sulphate to colistin sulphomethate per nebulization in CF-patients. Methods: Nine CF-patients chronically infected with P. aeruginosa participated in a double blind, randomized cross over study. On two visits to the outpatient clinic, patients were submitted to either nebulized colistin sulphate or colistin sulphomethate solution. Lung function tests were performed immediately before and 15 and 30 min after nebulization. Results: Nebulization of colistin sulphate caused a significant larger mean decrease in lung function compared to nebulized colistin sulphomethate. A significant decrease in mean changes (SD) in FEV1 at 30 min and FVC at 15 and 30 min after nebulization compared to baseline of -7.3% (8.6%), -5.7% (7.3%) and -8.4% (7.5%) respectively was seen after colistin sulphate nebulization compared to colistin sulphomethate (

41 Pharmacokinetics of nasally administered tobramycin, colistin sulphomethate sodium and a combination of tobramycin and colistin sulphomethate sodium

The paranasal sinuses can constitute a niche for bacteria which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. Objectives: Investigation of the pharmacokinetics (PK) of nasally administered tobramycin (T), colistin sulphomethate sodium (CSS) and a combination of both drugs using systemic absorption, expressed as % absorbed, as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. Methods: Ten adult CF patients performed three different nasal irrigations: 300 mg of T, 2 million IU of CSS and 300 mg of T combined with 2 million IU of CSS. Serum concentrations T and CSS were analysed using a validated assay. Individual PK parameters were calculated and assimilated with T and colistin serum values using a computerized CF-based population model. Maximum serum level (Cmax), trough serum level (Ctrough ) and bioavailability (F) were calculated. T Cmax >30 mg/L and Ctrough >0.5 mg/L were considered to be toxic. For colistin toxic levels are not known. Tolerability was measured using a Visual Analog Scale (VAS). Results: Following the T and the combined irrigation only 2 patients had detectable tobramycin serum levels with a Cma

WS14.5 Influence of breathing pattern on pulmonary aerosol deposition in patients with cystic fibrosis (CF): a pharmacokinetic approach

The therapeutic effect of inhaled antibiotics on lung infection in CF patients is dependent on the aerosol deposition achieved in the lungs. Objectives: To evaluate the influence of two breathing patterns on pulmonary aerosol deposition using pharmacokinetic parameters as surrogate for deposition. Methods: In a randomized, open-label, crossover study pulmonary deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. According to their lung function, patients were categorized in subgroup 1, 2 or 3 corresponding to FEV1 predicted ≤59%, 60-79% or ≥80%. Blood samples were collected in order to model tobramycin pharmacokinetics. Results: Mean Cmax and AUC0-24hr were significantly increased for TIM compared to TBM. Inhalation in TIM also resulted in higher mean Cmax and AUC0-24hr for each subgroup. Mean bioavailability of TIM relative to TBM breathing pattern (Frel) was 1.53±0.41 and mean Frel in each subgroup was also significantly higher than 1. Subgroup category did not affect the results. Conclusion: Slow and deep inhalation of aerosolized tobramycin with the I-neb nebulizer resulted in an estimated 53% higher lung deposition compared to tidal breathing. This result was independent from lung function category, which suggests that regardless the disease state, slow and deep inhalation always results in higher pulmonary aerosol deposition compared to tidal breathing

71 Pharmacokinetics of nasal administered tobramycin in patients with cystic fibrosis

Recent studies showed that the paranasal sinuses can constitute a niche for bacteria. To date no effective treatment for these bacteria is available. Off label administration of nasal antibiotics may be an option. However, first safety of this treatment has to be established. Objectives: With this pilot study in two patients the pharmacokinetic parameters of nasal administered tobramycin were investigated. Methods: In two hospitalised CF-patients, treated with intravenous tobramycin, after a wash-out period, 320 mg of tobramycin, dissolved in 200 ml isotonic saline, was administered to the nose using nasal lavage. Eleven venous blood samples were collected and with a Liquid Chromatography Tandem Mass Spectometer (LCMSMS) method, serum tobramycin concentrations were determined. Tobramycin pharmacokinetic parameters were calculated using the MW\Pharm software package. Systemic absorption was calculated by dividing AUC after nasal administration by AUC after intravenous administration corrected for the administered dose. Results: In patient 1, a female of 32 years old, the maximum concentration (Cmax) of tobramycin was 0.027 mg/L. This Cmax was reached 30 minutes after the nasal lavage with tobramycin (tmax). In total 0.20% (0.62 mg) of the tobramycin was systemically absorbed. In patient 2, a male of 36 years old, the Cmax was 0.029 mg/L. The tmax was 45 minutes and in total 0.16% (0.51 mg) of tobramycin was absorbed. Conclusion: Nasal lavage with 320 mg tobramycin did not result in toxic serum levels. The results of two patients showed a fast absorption of tobramycin and a slow elimination. Approximately 0.20% of the tobramycin was absorbed by the sinonasal mucosa

Efficacy and pharmacokinetics of intravenous paracetamol in the critically ill patient

Introduction: Paracetamol (PCM) is a drug with analgesic and antipyretic properties. Despite its frequent use, little is known about its efficacy and pharmacokinetics (PK) when intravenously administered in the critically ill patient. A previous study suggests that therapeutic concentrations are not always reached [1]. The primary aim of this open-label, multiple-dose study was to evaluate intravenous PCM therapy in critically ill, secondary aim was to study the PK of intravenous PCM. Methods: Ventilated patients needing PCM treatment according to our ICU protocol (1 g PCM intravenously four times daily) were eligible for inclusion. Excluded were those with severe liver failure and those treated with PCM on the time of admission to the ICU. Blood samples were collected at 0, 30, 60, 180 and 300 minutes after the first and, if possible, the fifth and 21st doses. A computerized model was used to estimate population PK. Results: Nineteen patients were included of which 13 were male, with a mean APACHE IV score of 94.8. No antipyretic effect could be measured in any of the patients. PK parameters have been calculated for all patients after the first PCM dose. The half-life was 2.2 hours, the volume of distribution was 1.03 l/kg, and the clearance was 0.33 l/kg/hour. Data from 15 patients could be analysed after the fifth dose and from five patients after the 21st dose. The PK of intravenous PCM in our population show a biphasic profile (Figure 1). One hour after the dose, the mean serum concentration level was below the therapeutic level. In 18 out of 19 patients serum concentration dropped below 5 mg/ml before the next dose, resulting in a lack of build-up of a suitable therapeutic level of PCM after multiple dosages. Conclusions: The recommended dose of 1 g intravenous PCM four times daily is not sufficient to achieve a therapeutic effect in critically ill patients. This can be explained by the low serum levels reached. These results warrant the development of an adequate dosing scheme for intravenous PCM followed by a large clinical trial studying the effects and safety of this regimen in critically ill patients

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis:A randomised comparison

AbstractBackgroundCircadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity.AimTo investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission.MethodsChildren (age 5–18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin.ResultsEighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%).ConclusionsRenal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245)