Comparison of methods for intravenous infusion of fat emulsion during extracorporeal membrane oxygenation

STUDY OBJECTIVES: To characterize the effects of infusing fat emulsion during neonatal extracorporeal membrane oxygenation (ECMO) by comparing results from patients receiving fat emulsion through the ECMO circuit with those receiving fat emulsion through separate intravenous access. A second goal was to identify the optimal route for administration. DESIGN: Prospective, randomized, open-label trial. SETTING: Neonatal intensive care unit in a 106-bed quaternary care pediatric hospital. SUBJECTS: Nine neonates receiving ECMO who required intravenous nutrition. Intervention. Patients received 1-3 g/kg/day of fat emulsion into either the ecmo circuit or separate intravenous access. MEASUREMENTS AND MAIN RESULTS: The ECMO circuit and samples of blood were evaluated hourly for phase separation, layering out of the emulsion from blood, agglutination, and blood clots. After completion, the oxygenators were dissected and examined. Data were compared with an unpaired t test. The characteristics of the groups were similar, except for a higher mean weight in the ECMO circuit group (3.6 +/- 0.3 kg vs 2.8 +/- 0.4 kg, p=0.03). The mean +/- SD triglyceride level during the study was 87 +/- 79 mg/dl, with no significant difference between the two groups. Two patients in each group had elevated triglyceride levels. No cases of phase separation occurred. In the five patients who received fat emulsion into the ECMO circuit, three had layering out of the emulsion and agglutination, and all developed clots in the circuit despite adequate anticoagulation. Of the four patients in the intravenous-access group, one had layering and agglutination, and two had blood clots. CONCLUSIONS: Although both methods were associated with layering out, agglutination, and clot formation, these effects occurred more frequently with administration into the ECMO circuit, particularly in areas of stasis. This may result in disruption of normal ECMO blood flow and impaired delivery of calories. Fat emulsion should therefore be administered through separate intravenous access during ECMO whenever possible.     

Pharmacokinetics of Sulfamethoxazole and Trimethoprim During Venovenous Extracorporeal Membrane Oxygenation: A Case Report

Extracorporeal membrane oxygenation (ECMO) therapy could affect drug concentrations via adsorption onto the oxygenator and/or associated circuit. We describe a case of a 33-year-old man with severe respiratory failure due to Pneumocystis jirovecii infection on a background of recently diagnosed human immunodeficiency virus infection. He required venovenous ECMO therapy for refractory respiratory failure. Intravenous sulfamethoxazole-trimethoprim (100 and 20 mg/kg/day) was administered in a dosing regimen every 6 hours. Pre-oxygenator, post-oxygenator, and arterial blood samples were collected after antibiotic administration and were analyzed for total sulfamethoxazole and trimethoprim concentrations. The peak sulfamethoxazole and trimethoprim concentrations were 122 mg/L and 5.3 mg/L, respectively. The volume of distribution for sulfamethoxazole was 0.37 and 2.30 L/kg for trimethoprim. The clearance for sulfamethoxazole was 0.35 ml/minute/kg and for trimethoprim was 1.64 ml/minute/kg. The pharmacokinetics of sulfamethoxazole and trimethoprim appear not to be affected by ECMO therapy, and dosing adjustment may not be required.     

丙泊酚长链脂肪乳和中／长链脂肪乳注射液对肝脏能量代谢的影响

目的：观察丙泊酚长链脂肪乳注射液（LCT ）和丙泊酚中／长链脂肪乳注射液（MCT／LCT ）短时间恒速输注对肝脏能量代谢的影响。方法选择年龄为18～50岁,术前 ASA分级Ⅰ～Ⅱ级的20例择期手术病人,随机分为2组,每组10例,分别行丙泊酚长链脂肪乳注射液4 mg · kg-1· h-1维持麻醉（L组）、丙泊酚中／长链脂肪乳注射液4 mg · kg-1· h-1维持麻醉（M组）。在气管插管后（T1）、维持输注丙泊酚麻醉2 h后（T 2）,各取静脉血检测乙酰乙酸、β-羟丁酸值,计算血酮体比率（乙酰乙酸／β-羟丁酸）。结果 T1、T2时点两组乙酰乙酸、β-羟丁酸和血酮体比率之间比较,差异均无统计学意义（P＞0．05）。结论丙泊酚长链脂肪乳注射液和丙泊酚中／长链脂肪乳注射液短时间持续输注对肝脏能量代谢没有明显的影响。     

Stability and sorption of FK 506 in 5% dextrose injection and 0.9% sodium chloride injection in glass, polyvinyl chloride, and polyolefin containers.

The effects of the diluent, the storage container, light, and infusion through various types of tubing on the stability and sorption of FK 506 were studied. Solutions of FK 506 in 0.9% sodium chloride injection or 5% dextrose injection were stored at room temperature (24 +/- 2 degrees C) in glass i.v. bottles, polyvinyl chloride (PVC) minibags, and polyolefin containers. FK 506 solution in 0.9% sodium chloride injection was stored in plastic syringes at room temperature and either exposed to normal room light or stored in the dark. FK 506 solution in 5% dextrose injection was placed in plastic syringes and infused through PVC anesthesia extension tubing, PVC i.v. administration set tubing, and fat emulsion tubing over a two-hour period. The infused samples and samples collected from the containers and syringes at intervals up to 48 hours were analyzed for FK 506 concentration by high-performance liquid chromatography. FK 506 concentrations remained greater than 90% of initial concentration for admixtures in 5% dextrose injection stored in glass bottles for 48 hours and for admixtures in 5% dextrose injection or 0.9% sodium chloride injection stored in polyolefin containers for 48 hours. No change in concentration was measured for admixtures in 0.9% sodium chloride injection stored in plastic syringes, and exposure to light did not affect the stability of FK 506 solution. No substantial change in concentration occurred in FK 506 solution in 5% dextrose injection infused through PVC anesthesia extension tubing, PVC i.v. administration set tubing, or fat emulsion tubing. FK 506 admixtures prepared with 5% dextrose injection or 0.9% sodium chloride injection should be stored in polyolefin containers. If polyolefin containers are not available, solutions should be prepared with 5% dextrose injection and stored in glass bottles.     

Vancomycin Pharmacokinetics in Neonates Receiving Extracorporeal Membrane Oxygenation

Vancomycin is administered as both prophylaxis and treatment in neonates receiving extracorporeal membrane oxygenation (ECMO), typically after surgery. An open-label, retrospective study was conducted to determine dosing strategies in all neonates who received vancomycin during ECMO and compare pharmacokinetic values with those of matched controls not receiving ECMO. Fifteen neonates receiving ECMO were given vancomycin infused into the circuit, with dosages based on weight and gestational age. Blood for serum concentrations was drawn around the third dose, for trough concentrations immediately before the dose, and for peak concentrations 1 hour after infusion. Samples were analyzed by fluorescence polarization immunoassay. The most frequent regimen for both groups (8 ECMO, 13 controls) was 10 mg/kg every 8 hours. It produced peak and trough concentrations of 27.5 ± 4.3 and 13.7 ± 2.7 μg/ml, and 23.0 ± 5.4 and 13.2 ± 4.5 μg/ml, respectively. Pharmacokinetic analysis using a one-compartment model revealed volume of distribution of 0.45 ± 0.18 L/kg, half-life of 8.29 ± 2.23 hours, and total body clearance of 0.65 ± 0.28 ml/min/kg in ECMO recipients. Volume of distribution and clearance were not significantly different in controls (0.39 ± 0.12 L/kg, 0.79 ± 0.41 ml/min/kg), but half-life was shorter (6.53 ± 2.05 hrs, p = 0.02). Based on long volume of distribution in neonates receiving ECMO, we recommend that empiric vancomycin regimens incorporate a longer dosing interval than the 6–8 hours commonly recommended for term infants. The effects of severity of illness on drug elimination require additional study.     

1例输液港植入术后囊袋切口脂肪液化并血栓形成的护理

目的 探讨股静脉输液港植入术后囊袋切口脂肪液化及下肢静脉血栓形成的护理效果.方法 对1例因股静脉置入输液港后发生囊袋切口脂肪液化并血栓形成的肺癌患者,通过正确进行伤口评估、囊袋切口运用了湿性愈合及减痛换药的护理;同时动态观察右下肢静脉血栓及时进行下腔静脉滤网置入术的处理.结果 患者输液港囊袋伤口愈合良好,输液港拔出后未发生血栓脱落.结论 正确进行伤口评估,湿性愈合及减痛换药理论,使用适宜的敷料,进行有效的伤口护理,可减轻患者的痛苦,促进伤口愈合,有效防止并发症.     

EFFECTS OF A NON-VASOCONSTRICTOR DOSE OF PHENYLEPHRINE ON PROSTAGLANDIN E2 AND RENIN RELEASE IN ANAESTHETIZED DOGS

Phenylephrine (1 μg/min) was infused into the renal artery of pentobarbitone anaesthetized dogs. Systemic blood pressure and renal blood flow were monitored. Arterial and renal venous blood samples were collected before and 10 min after the start of the infusion. Plasma prostaglandin E₂ concentration and plasma renin activity were measured by radioimmunoassay. This dose of phenylephrine did not affect systemic blood pressure and renal blood flow. However, both prostaglandin E₂ and renin secretion rates were increased by the infusion of phenylephrine. These results suggest that renal α-adrenoceptors participate in prostaglandin and renin release independent of the changes in systemic blood pressure and renal blood flow.     

A modified fluorescence polarization immunoassay method incorporating fat emulsion (FE-FPIA) to determine cyclosporin A concentrations in rat skin.

We have developed a simple, sensitive and reliable assay procedure for cyclosporin A (CyA), a modified fluorescence polarization immunoassay method incorporating fat emulsion (FE-FPIA), to determine the CyA content in rat skin. The conventional fluorescence polarization immunoassay (FPIA) method for CyA using a commercially available FPIA kit, TDX cyclosporine monoclonal whole blood, was modified. A fat emulsion for intravenous infusion, Intralipos, was incorporated for dissolving the CyA extracted from the skin tissue, and a mixture of MeOH/purified water was used as the sample pretreatment medium instead of the precipitation reagent in the conventional FPIA kit intended for whole blood samples. These modifications enabled us to produce a reliable and the sensitive assay of CyA in skin tissue. The reproducibility (coefficient of variation), detection limit, and assay time for FE-FPIA were below 2%, 25 ng/ml, and about 24 min/24 samples, respectively, and were comparable with those for the whole blood samples determined by the conventional FPIA. Pre-purification of samples required by the HPLC assay is not needed in the FE-FPIA method. The usefulness of the FE-FPIA method in evaluating the topical pharmacokinetics of CyA in skin is discussed.     

EXPOSURE OF BLOOD TO VAPORS OR GASES: A NOVEL MODEL WITH BENZENE AS EXEMPLAR

An artificial membrane oxygenator has been used to mimic the physiological interface between the blood and vapors or gases, to investigate the toxic effects on blood parameters. The parameter investigated has been the human erythrocyte membrane bound acetylcholinesterase (EMBAChE). The COBE artificial membrane lungs have been used. These artificial lungs are known to support normal pulmonary function during surgery. The artificial lungs were incorporated into a purpose-built circuit designed to mimic the physiological events on exposure of blood to solvent vapor in the lung. This technique allowed blood to circulate at a known rate with a steady flow and to be maintained at 37 C. This provided the means to oxygenate the blood and provide a controlled supply of solvent vapor to the blood. Blood samples over time were taken from the circuit. The EMBAChE was established for these samples. Benzene was used as an example of a toxic solvent vapor. It was found that a statistically significant rise in EMBAChE occurred over a period of 80 min under controlled, benzene in air, flow conditions when compared with the same flow conditions with air alone. The mean concentration of benzene delivered was calculated to be 60.7 ppm / min SEM of 2.7 with a total concentration of benzene approximating 4800 ppm 30% over the 80 min under the flow conditions used. This study shows that the artificial membrane lungs can be a useful tool to investigate the effect of toxic solvent vapors on blood and on human EMBAChE in particular.     

Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) may affect the pharmacokinetics of certain drugs. The objectives of this study were to determine (1) the pharmacokinetics of gentamicin in neonates on ECMO and compare them to reported values for a similar patient population not on ECMO, (2) if the pharmacokinetics of gentamicin differ between venous-venous and venous-arterial bypass, and (3) if the pharmacokinetics of gentamicin are affected by oxygenator surface area (0.6 m2 vs 0.8 m2 oxygenators). The medical records of 29 term neonates who received gentamicin while on ECMO were reviewed. Data collected included gentamicin dosage, peak and trough serum concentrations determined at steady state, duration of treatment, time on ECMO, daily weights, and pertinent laboratory values. An initial dosage of gentamicin 2.5 mg/kg every 18 hours is suggested for term neonates on ECMO. Dosage adjustments should be based on gentamicin serum concentrations, and modifications may also be required after ECMO.     

Intravenous Lipid Emulsion Given to Volunteers does not Affect Symptoms of Lidocaine Brain Toxicity

Intravenous lipid emulsion has been suggested as treatment for local anaesthetic toxicity, but the exact mechanism of action is still uncertain. Controlled studies on the effect of lipid emulsion on toxic doses of local anaesthetics have not been performed in man. In randomized, subject‐blinded and two‐phase cross‐over fashion, eight healthy volunteers were given a 1.5 ml/kg bolus of 20% Intralipid^® (200 mg/ml) or Ringer's acetate solution intravenously, followed by a rapid injection of lidocaine 1.0 mg/kg. Then, the same solution as in the bolus was infused at a rate of 0.25 ml/kg/min. for 30 min. Electroencephalography (EEG) was recorded, and 5 min. after lidocaine injection, the volunteers were asked to report subjective symptoms. Total and un‐entrapped lidocaine plasma concentrations were measured from venous blood samples. EEG band power changes (delta, alpha and beta) after the lidocaine bolus were similar during lipid and during Ringer infusion. There were no differences between infusions in the subjective symptoms of central nervous system toxicity. Lidocaine was only minimally entrapped in the plasma by lipid emulsion, but the mean un‐entrapped lidocaine area under concentration–time curve from 0 to 30 min. was clearly smaller during lipid than Ringer infusion (16.4 versus 21.3 mg × min/l, p = 0.044). Intravenous lipid emulsion did not influence subjective toxicity symptoms nor affect the EEG changes caused by lidocaine.     

帕珠沙星静脉滴注引发低血糖

1例89岁男性2型糖尿病和高血压患者，因肺部感染住院。患者于停用降血糖和降血压药物后，静脉滴注帕殊沙星0.3g，2次／d。在第3次静脉滴注1h后突然出冷汗，血糖自10mmol／L降至2．7mmol／L。立即停用帕殊沙星，静脉注射50％葡萄糖注射液60ml，静脉滴注10％葡萄糖注射液，并增加进食量。24h后血糖逐渐上升至5．6mmol／L。     

Simultaneous application of intravenous fat emulsion and charcoal hemoperfusion in quetiapine overdose case

The simultaneous application of intravenous fat emulsion and charcoal hemoperfusion in the case of severe quetiapine poisoning is described. The initial blood concentration of quetiapine was 5.9 µg/mL and rapid deterioration in the patient status was observed. When a lipid emulsion was infused a fast blood pressure recovery occurred which allows to perform extracorporeal clearance using charcoal hemoperfusion. At the end of the procedure the quetiapine concentration was decreased down to 1.5 µg//mL and fast recovery of the patient was observed.     

Artificial oxygen carriers based on perfluorodecalin-filled poly(n-butyl-cyanoacrylate) nanocapsules

Abstract

Poly(n-butyl-cyanoacrylate)-nanocapsules filled by perfluorodecalin (PFD) are proposed as potential oxygen carriers for blood substitute. The capsule dispersion is prepared via interfacial polymerisation from a PFD emulsion in water which in turn is generated by spontaneous phase separation. The resulting dispersion is capable of carrying approximately 10% of its own volume of gaseous oxygen, which is approximately half of the capacity of human blood. The volumes of the organic solvents and water are varied within a wide range, connected to a change of the capsule radius between 200 and 400?nm. The principal suitability of the capsule dispersion for intravenous application is proven in first physiological experiments. A total amount of 10?ml/kg body weight has been infused into rats, with the dispersion supernatant and a normal saline solution as controls. After the infusion of nanocapsules, the blood pressure as well as the heart rate remains constant on a normal level.     

Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates

Extracorporeal membrane oxygenation (ECMO) is a prolonged form of cardiopulmonary bypass used to support patients with life-threatening respiratory or cardiac failure. In neonates, ECMO is used for a variety of indications, including sepsis and pulmonary diseases such as meconium aspiration syndrome, persistent pulmonary hypertension or congenital diaphragmatic hernia. In recent years, ECMO has been increasingly used after surgery to correct congenital cardiac defects. Despite the need for numerous drugs to maintain the ECMO circuit and treat the patient's underlying illness, relatively little is known of the disposition of drugs in this patient population. To date, the largest number of pharmacokinetic studies have been conducted with gentamicin and vancomycin. Both drugs have been found to have an increased volume of distribution, probably as a result of the addition of a large exogenous blood volume for circuit priming. Elimination half-lives for both drugs are prolonged during ECMO, with several studies demonstrating a return to expected values after decannulation. The reason for this prolonged elimination is probably multifactorial, with a reduction in renal function as the primary determinant. This same pattern of an increased volume of distribution and prolonged elimination has been found for several other drugs, including tobramycin, bumetanide and ranitidine. Other factors that affect drug disposition during ECMO include loss of the drug from adhesion to the circuit components and loss in the circulating blood volume during changes in the equipment. The benzodiazepines and propofol are largely sequestered within the circuit. Serum concentrations of heparin, morphine, fentanyl, furosemide, phenytoin and phenobarbital are also reduced by these mechanisms. The addition of haemofiltration or dialysis in up to a quarter of ECMO patients further complicates the determination of population pharmacokinetic parameters. The literature published to date on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment; however, more research is needed to identify optimal administration strategies for this patient population.     

Total body,systemic and pulmonary clearance and fractional extraction of unlabelled and differently 3H-labelled noradrenaline in the anaesthetized rabbit

1. Rabbits were anaesthetized with urethane/chloralose and infused intravenously with trace amounts of 3H-2,5,6-, 3H-7,8- or 3H-7-(-)noradrenaline either without or with unlabelled (-)noradrenaline being simultaneously infused (0.2 micrograms kg-1 min-1). To obtain clearance values and extraction ratios for the pulmonary, systemic and total circulation, steady-state concentrations of infused noradrenaline were determined in mixed central venous (Cv) and arterial (Ca) plasma. Heart rate and blood pressure were recorded via the carotid artery, and the dye dilution method was used to determine the cardiac output of plasma. 2. The simultaneous infusion of unlabelled noradrenaline, which increased plasma levels of noradrenaline by a factor of 5, had no significant effect on either heart rate, blood pressure or cardiac output (when determined at steady state of the noradrenaline infusion). 3. The simultaneous infusion of unlabelled noradrenaline did not affect the clearance values of any of the three type of 3H-noradrenaline. Moreover, the clearances of the various types of 3H-noradrenaline were virtually identical and agreed with that of unlabelled noradrenaline. However, the clearance of labelled and unlabelled noradrenaline from arterial plasma was 1.15 times higher than that from central venous plasma. This factor corresponded to the ratio of Cv/Ca and pointed towards net removal of noradrenaline from the pulmonary circulation. 4. The fractional pulmonary extractions [1-(Ca/Cv)] of the three types of 3H-noradrenaline did not differ from each other and were not affected by the simultaneous infusion of unlabelled noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)     

CONVERSION OF ANGIOTENSIN I TO ANGIOTENSIN II IN SHEEP

1. The methodology for measurement of angiotensin I in whole blood is described. 2. Angiotensin I was measured in arterial and venous blood samples from sodium-loaded, sodium-replete and sodium-depleted sheep. Venous blood concentrations were higher than arterial angiotensin I concentrations. Arterial angiotensin I concentrations increased with increasing sodium deficiency. 3. Angiotensin II was infused into six sodium-replete sheep, the blood concentrations of angiotensin II measured and the metabolic clearance rates calculated. The average value was 121 ± 21 1/h. 4. Angiotensin I was then infused into these sheep and arterial and venous blood concentrations of angiotensins I and II determined. From this data and the metabolic clearance rate of angiotensin II, the degree of conversion of angiotensin I to II was calculated. The values varied in different sheep from 54 ± 2% to 105 ± 6% (n= 6).     

毛细管气相色谱法测定鱼油脂肪乳注射液中DHA和EPA的含量

目的采用毛细管气相色谱法对鱼油脂肪注射液的DHA和EPA含量进行测量的效果进行研究分析。方法抽取同一批次的鱼油脂肪注射液,采用毛细管气象色谱法对DHA和EPA的含量进行测定,载气选择氦气,流速控制在0.5mL/min,柱温进行程序升温,采用FID检测器,分流比为5：1,进样口温度控制在300℃,进样量为1μL。结果经过仔细研究后笔者发现,被检测的鱼油脂肪注射液中DHA甲酯的浓度在0.216～0.712g/L,EPA甲酯的浓度在0.224～0.768g/L的现象关系非常明显,两种成分的回收率均在99%以上,RSD水平均在0.50%以上。结论采用毛细管气象色谱法对鱼油脂肪注射液的DHA和EPA含量进行测量主要具有操作简单、方便快捷、准确度高、重现性好等特点,可作为今后对该药物的成分含量进行测定的常规方法。     

Effect of primary fluids and dilutional volumes on the delivery of cefazolin sodium by a membrane infusion device

The influence of primary fluids and dilutional volumes on the accuracy of in vitro delivery of cefazolin sodium by gravity flow through a new controlled-release membrane infusion device was studied. For primary fluid studies, cefazolin 1 g (as the sodium salt) in 10 mL of sterile water for injection was injected into the drug chamber, which is separated by a membrane from the fluid chamber; the entire dose passes into the fluid chamber over a set time. The inlet port of the fluid chamber was connected to the 1-L primary fluid bag, and the outlet port was connected to an administration set. The primary fluids included 0.9% sodium chloride injection; 5% dextrose injection; 10% dextrose injection; 5% dextrose and 0.45% sodium chloride injection; 5% dextrose, 0.45% sodium chloride, and potassium chloride 20 meq/L injection; and 2.2% amino acids with electrolytes in 25% dextrose injection. For dilutional volume studies, cefazolin sodium 1 g diluted in 5, 10, and 15 mL of sterile water for injection was infused with 0.9% sodium chloride injection. The flow rate was set at 1 mL/min. Serial samples were collected in triplicate every five minutes over a 90-minute period and analyzed by high-performance liquid chromatography. The time needed to deliver more than 95% of the cefazolin doses ranged from 35 to 50 minutes using various primary fluids and from 35 to 55 minutes using various dilutional volumes. The manufacturer recommends that a cefazolin dose be delivered completely within 30-60 minutes. The solutes in the primary fluids and the volume injected did not appear to affect the delivery of cefazolin by a controlled-release membrane device.     

Alteration of therapeutic efficacy of lipid microspheres incorporating prostaglandin E1 by mixing with aqueous solution

To clarify whether the therapeutic efficacy of lipid microspheres incorporating prostaglandin E(1) (lipo-PGE(1)) is altered when mixed and coinfused with clinical solutions, the original lipo-PGE(1) solution (20 microg/mL) was mixed with three clinical infusion solutions: 0.9% sodium chloride solution, Hartmann's solution, and fat emulsion for parenteral nutrition. These diluted lipo-PGE(1) (2 microg/mL) solutions were administered to rats, and their hemodynamic and antiplatelet effects were examined. Peripheral blood flow was increased by 76 +/- 4% from the control level when the lipo-PGE(1) solution diluted with the fat emulsion was administered, while it was increased by 43 +/- 6% and 36 +/- 7%, respectively, when the lipo-PGE(1) solutions diluted with 0.9% sodium chloride and Hartmann's solution were administered. As for the antiplatelet effects of the lipo-PGE(1) solutions, the progression of digit gangrene in thromboangiitis obliterans (TAO) rats was significantly suppressed by the administration of lipo-PGE(1) solution diluted with the fat emulsion, but it was not suppressed by lipo-PGE(1) solution diluted with 0.9% sodium chloride. These findings indicate that the therapeutic efficacy of lipo-PGE(1) is decreased when it is mixed with an aqueous solution such as 0.9% sodium chloride.