PHARMACOKINETICS OF INTRAVENOUS CAFFEINE IN CRITICALLY ILL PATIENTS

The pharmacokinetics of intravenous caffeine used to measure liver function were evaluated in 20 critically ill patients. Each patient received a single dose of 3.0 mg/kg of caffeine benzoate as a 30-min i.v. infusion. Caffeine serum concentrations were analysed by an enzyme-multiplied immunoassay technique (EMIT). Caffeine pharmacokinetics fitted an open one-compartment model. The mean value for the half-life (t1/2) was 9.46 +/- 4.32 h, the volume of distribution was 0.55 +/- 0.13 l/kg, and the plasma clearance (Cl) was 0.85 +/- 0.44 ml/min/kg. The pharmacokinetics parameters of caffeine in critically ill patients compared with normal volunteers were characterized by a reduction in plasma clearance and prolongation in plasma half-life, whereas the volume of distribution remained unchanged.     

CLINICAL PHARMACOKINETICS OF INTRAVENOUS FLECAINIDE IN CRITICALLY ILL PATIENTS

Plasma flecainide (FLC) levels versus time were measured in a group of 10 acute myocardial infarction (AMI) patients at our Intensive Care Unit. These patients were treated with single doses of 150 mg FLC as a 30-min intravenous infusion. Mean FLC plasma concentration values at 0, 1, 2, 4, and 8 h following administration were 562 +/- 271, 342 +/- 129, 270 +/- 90m, 240 +/- 80 and 210 +/- 60 ng/ml, respectively. Flecainide pharmacokinetics fitted an open two-compartment model, with a rapid distribution phase and a slow elimination phase. Mean values for the terminal plasma half-life (t1/2 beta) was 22.0 +/- 9.7 h and the volume of distribution (V beta) was 7.99 +/- 3.02 1/kg. FLC is different to other i.v. antiarrhythmics in having a prolonged plasma half-life which is a decided advantage. In contrast to lidocaine, FLC has a pharmacokinetic profile that enables it to be used for treating ventricular arrhythmia without constant-rate i.v. infusion and without the need for complicated loading dosages in order to avoid a 'pharmacokinetic dip' over the first hour of treatment.     

MICROBIAL CONTAMINATION AND GROWTH IN TOTAL PARENTERAL NUTRITION SOLUTIONS

TPN bags (196) and giving sets were subjected to microbiological examination following administration within a busy nutrition ward. Of these, five (2.6%) were found to be contaminated with coagulase-negative Gram-positive cocci. In all but one instance the contamination was restricted to the terminal ends of the giving sets rather than to the nutrition bag itself. Isolation of micro-organisms from the ward environment suggested that the contamination had arisen extrinsically during the setting up of the infusions. Isolates from the contaminated products, together with type species of Escherichia coli and Candida albicans, were examined with respect to their growth requirements and used to challenge four TPN formulations. Growth and survival of the organisms was monitored for up to 21 days. In all instances significant numbers of organisms were recovered after 72 h. Significant growth of the Staphylococcal isolate and C. albicans occurred over the initial 48-72 h incubation, this appeared to be greater in extent for the lipid-containing formulations. The temperature of storage of the formulation was the major determining factor for microbial growth and survival. No survivors were recovered, however, from any formulation after 21 days.     

FURTHER STUDIES ON THE GROWTH OF MICRO-ORGANISMS IN TOTAL PARENTERAL NUTRITION SOLUTIONS

The growth of vegetative bacteria in mixtures containing amino acids, dextrose, inorganic salts and vitamins was examined. Escherichia coli and Klebsiella pneumoniae grew rapidly in Aminoplex 14, Vamin-glucose and Aminofusin L600 with 10% w/v dextrose. Growth of E. coli was slower in Synthamin 14 with 10% w/v dextrose. K. pneumoniae was unable to grow in this solution unless vitamins were added. Higher concentrations of dextrose inhibited growth in Synthamin 14, but had little influence on the growth of E. coli or K. pneumoniae in the presence of Vamin-glucose, Aminoplex 14 or Aminofusin L600. Pseudo-monas aeruginosa grew slowly in solutions containing amino acid combinations other than Synthamin 14. Staphylococcus epidermidis was unable to grow in any solutions except those containing Aminofusin L600 where growth was shown to occur only after a long lag phase. Vitamin supplements had little influence on growth rates. No organism was able to grow in any solution stored at 4^oC. Results indicate that, to prevent growth of micro-organisms, Total Parenteral Nutrition regimes mixed in 3-1 containers should be stored under refrigeration conditions unless used immediately.     

FACTORS INFLUENCING THE STABILITY OF ASCORBIC ACID IN TOTAL PARENTERAL NUTRITION INFUSIONS

Ascorbic acid stability in TPN infusions in 3-litre plastic bags was examined. Vitamin C was found to degrade slowly in mixtures which do not contain trace elements. In the presence of copper, degradation proceeds rapidly until dissolved oxygen is depleted. Reducing the copper concentration had only a minor influence on degradation rate. However, this copper-catalyzed reaction was prevented if cysteine was present in the TPN regimen. The amount of ascorbic acid degraded depended on the dissolved oxygen content of the infusion, the amount of residual air in the bag after filling and the permeability of the plastic to oxygen. In the absence of copper, 20–30 mg ascorbic acid was broken down within 24 h at ambient temperatures, but if copper was present, 150–200 mg was degraded within 2–4 h. The contribution of dehydroascorbic acid to the amount of vitamin C delivered to the patient was negligible. It is concluded that either vitamin C and trace element injections containing copper should not be added to the same bag, or an adequate coverage of ascorbic acid must be included to allow for losses by oxidation before and during administration.     

GROWTH OF MICROORGANISMS IN TOTAL PARENTERAL NUTRITION MIXTURES AND RELATED CLINICAL OBSERVATIONS

The effect of lipid addition to TPN (Total Parenteral Nutrition) solutions on microbial growth was investigated. Staphylococcus epidermidis , which failed to grow or grew poorly in the absence of lipid, reached > 10⁴ cfu/ml (colony forming units per ml), from an initial inoculum of approximately 50 cfu/ml after 24 h when lipid was added. Candida albicans grew more slowly in the presence of lipid, but nevertheless reached 10⁴ cfu/ml after 40 h incubation. Klebsiella aerogenes grew readily in all solutions, whereas Escherichia coli failed to grow in any solution. Growth of S. epidermidis and K. aerogenes was improved when the inoculum consisted of starved cells; however, growth of starved cells of C. albicans lagged behind that of unstarved cells. The ability of S. epidermidis to grow in lipid-containing TPN mixtures is particularly important, since this organism is frequently associated with sepsis.
In an infant surgical unit, where TPN is under the care of a nutrition team, samples of TPN fluids and giving sets were examined for microbiological contamination at the end of the 24 h administration period. Contamination was found in eight of the 98 systems examined from eight patients. The organisms were identified as coagulase-negative staphylococci and diphtheroids.     

重度颅脑损伤后病人肠内外营养的比较

目的探讨重度颅脑损伤病人肠内外营养结合的临床应用意义及合理性。方法危重颅脑损伤病人56例,随机分为2组,观察组29例,行肠内营养（EN）和肠外营养（PN）结合支持14 d;对照组27例,行全肠外营养（TPN）支持14 d。于治疗1、7、14 d检测并比较两组血清总蛋白、清蛋白、血红蛋白、淋巴细胞计数及并发症发生率。结果治疗14 d时观察组血清总蛋白、清蛋白、血糖、血红蛋白及外周血淋巴细胞总数均高于对照组,差异有显著性（t=5.068~87.655,P〈0.05）。观察组并发症发生率低于对照组（P=0.04）。结论重度颅脑损伤EN和PN结合应用,可以明显改善病人的营养状况,提高重度颅脑损伤病人治愈率、生存率。     

CLINICAL EVALUATION OF THEOPHYLLINE BINDING TO PLASMA PROTEIN IN BRONCHIAL ASTHMATIC PATIENTS

Theophylline binding to plasma protein was studied with seven bronchial asthmatic inpatients. The extent of protein binding was monitored using an ultrafiltration device, EMIT® FreeLevel_TM System 1, whose performance is pH independent between 7·5 and 8·5 and concentration independent between 2 and 10 mcg/ml. When protein-free theophylline solutions are used a linear pH dependency was observed between 7·0 and 8.3. With theophylline-spiked human plasma using the same samples, the binding was found to be concentration-independent in the range 5 to 40 mcg/ml. The intra- and inter-individual variations in theophylline binding to plasma proteins were relatively large. A calculation procedure for predicting free fractions at normal physiological plasma pH, 7.4, using the observed free fraction at a given plasma pH is proposed. A good correlation was obtained between plasma and salivary theophylline concentrations. Salivary levels alone, however, are unreliable for monitoring theophylline therapy.     

STORAGE OF MIXTURES FOR TOTAL PARENTERAL NUTRITION III. STABILITY OF VITAMINS IN TPN MIXTURES

TPN mixtures should contain all nutritional element necessary in the nutritional therapy—including unstable vitamins. In this study the stability of ascorbic acid and folic acid was investigated in a TPN mixture containing 12 vitamins by HPLC and microbiological assays. The degradation of both vitamins proceeded by first order kinetics. Half-lives for ascorbic acid were 1.1 h, 2.9 h, and 8.9 h when stored at 24° by daylight, 24° protected from light, and 4° protected by light, respectively. Under similar conditions half-lives for folic acid were 2.7 h, 5.4 h, and 24 h. The degradation rates found make pre-addition of these two vitamins to TPN mixtures questionable, storage for longer periods is inappropriate. For TPN patients receiving additional fluid intravenously it was found that addition of multivitamins to isotonic NaCl-solution was advisable. For other TPN patients alternative ways of vitamin administration might be preferable. When testing the stability of vitamins in TPN mixtures it was found that the brand of multivitamin preparation used was of importance. It should be stressed that data on the stability of vitamins derived from studies on the addition of a single vitamin cannot be extrapolated to multivitamin preparations because of possible mutual vitamin interactions.     

肠内营养支持对危重病人营养状态及内毒素水平影响

目的探讨肠内营养（EN）支持对危重病人营养状态及内毒素水平影响。方法选择64例不能经口进食的危重病人,分为完全肠外营养（TPN）组及TPN＋EN组,TPN组采用完全静脉营养支持,TPN＋EN组在病人营养支持全程或部分时间采用EN营养支持,比较两组病人营养支持前后营养状态、血清内毒素及炎性递质的水平。结果治疗1周后,TPN＋EN组病人血清前血清清蛋白、前清蛋白水平高于TPN组（t=2．92、3．58,P〈0．05）,血清内毒素、白介素6及肿瘤坏死因子a水平低于TPN组（t=3．54～7．36,P〈0．05）。结论EN支持能够改善危重病人的营养状态,减少病人体内细菌内毒素的生成及炎性损伤。     

SURGICAL NUTRITIONAL TEAM AND ITS IMPACT ON TOTAL PARENTERAL NUTRITION IN THE NATIONAL UNIVERSITY HOSPITAL,SINGAPORE

The Surgical Nutrition Advisory Team (SNAT) of our hospital, formed in October 1992, decided to study the impact of such a team on the six months before and after its formation on catheter care and nutritional support in total parenteral nutrition. Our study showed that with a dedicated nutritional team, catheter sepsis was reduced from 35.1% to 15.4%. The median lifespan of central catheters was increased from 7 to 11 days. Mechanical complications were reduced from 11% to zero. Better patient selection resulted in more severely malnourished patients receiving preoperative nutrition and fewer postoperative patients being started on total parenteral nutrition. Better monitoring of nutritional requirements, electrolyte and metabolite levels and consequently faster correction of abnormal blood levels, were also obtained.     

精氨酸强化低热量营养支持在上消化道肿瘤术后的应用

目的比较精氨酸强化低热量高支链氨基酸静脉营养支持与传统静脉高营养对食管癌、贲门癌、胃癌患者术后化疗中的作用。方法对上消化道癌术后患者分别采用精氨酸强化高支链氨基酸低热量营养支持和传统静脉高营养支持,观察相应监测指标的变化并进行比较。结果研究组在淋巴细胞记数外,其余变化均相近,无统计学意义。在主观营养评估(SGA)和生活质量评分(KPS)上,研究组要明显高于对照组,且存在统计学差异。结论精氨酸强化低热量高支链氨基酸静脉营养支持能够有效预防和减少静脉营养的常见并发症,并对上消化道肿瘤术后辅助化疗具有积极意义,值得推广。     

EFFECT OF ELECTROLYTES IN THE PRESENCE OF SOME TRACE ELEMENTS ON THE STABILITY OF ALL-IN-ONE EMULSION MIXTURES FOR TOTAL PARENTERAL NUTRITION

In a previous study (1) we showed that the ‘all-in-one’ emulsion mixtures investigated for total parenteral nutrition are stable for 1 month when kept in ethylene vinyl acetate polymer (EVA) bags and refrigerated at 4°. Analogous experiments were performed with the addition of two different solutions of trace-elements: one was prepared in the pharmacy while the other was commercially obtained (Addamel®, Kabi Vitrum). A Coulter counter TA II with a 30 μm orifice was used for globule size measurements. Particles with diameters ranging from 0.6 up to 16 μm were measured. No significant changes in particle size were noticed during storage and the routine addition of trace elements to the ‘all-in-one’ mixtures was thus possible. These emulsions can be stored without stability problems for at least 8 days.     

添加短链脂肪酸的TPN对术后化疗大鼠结肠粘膜细胞增殖作用的研究

目的探讨添加短链脂肪酸(SCFAs)的全肠外营养(TPN)对术后化疗大鼠结肠粘膜细胞增殖作用的影响。方法30只SD大鼠在无渣饮食2d后建立TPN和结肠吻合模型。术后随机分为TPN对照组(对照组)、化疗+TPN组(化疗组)、化疗+TPN+SCFAs组(SCFAs组),每组10只。进行实验5 d,术后第6 d留取标本采用流式细胞术分析结肠粘膜细胞周期,观察其增殖情况。结果化疗组结肠粘膜细胞增殖期百分比(6.23±2.75)%显著低于对照组[(9.81±2.78)%,P=0.014]和SCFAs组[(11.57±3.54)%,P=0.001];化疗组结肠粘膜细胞的增殖指数(11.87±2.61)%显著低于其他2组[(20.25±7.22)%,P=0.002;(19.70±5.12)%,P=0.003]。结论添加SCFAs的TPN能促进术后化疗大鼠结肠粘膜细胞的增殖。     

INTRINSIC AND EXTRINSIC MICROBIAL CONTAMINATION OF HOME TOTAL PARENTERAL NUTRITION MANUFACTURED IN EVA-INFUSION BAGS (THE I.V. BAG®)

Microbial contamination of total parenteral nutrition including fat emulsions in 1-3 litres plastic infusion bags (the i.v. bag) was studied during production in the pharmacy and administration both at home and in the hospital. Production contamination was investigated by dispensing test bags containing growth medium mixed with dextrose-salt solution. In this highly sensitive system, contamination was detected in less than 4% of cases. In-use contamination was estimated at the end of the infusion. The average contamination rate (+/- growth) in the five patients studied was 6.7% accompanied by considerable variation. Identification of the contaminants revealed that 85% of the contaminated bags contained staphylococci, indicating skin contamination. An investigation on the effect of the procedure used for attaching the infusion set on the contamination rate, was carried out with bags that contained sterile growth medium. This showed no contamination in 14 cases indicating the catheter as the most plausible source of contamination. It is concluded that both production in the community pharmacy and administration in the home are not associated with a higher microbial contamination than in central hospitals. It is, however, recommended that the microbial quality of the production process and the administration procedure are regularly monitored.