Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation.

BACKGROUND: The objective of this systematic review and meta-analysis was to assess the relationship between the chloride content of intravenous resuscitation fluids and patient outcomes in the perioperative or intensive care setting. METHODS: Systematic searches were performed of PubMed/MEDLINE, Embase and Cochrane Library (CENTRAL) databases in accordance with PRISMA guidelines. Randomized clinical trials, controlled clinical trials and observational studies were included if they compared outcomes in acutely ill or surgical patients receiving either high-chloride (ion concentration greater than 111 mmol/l up to and including 154 mmol/l) or lower-chloride (concentration 111 mmol/l or less) crystalloids for resuscitation. Endpoints examined were mortality, measures of kidney function, serum chloride, hyperchloraemia/metabolic acidosis, blood transfusion volume, mechanical ventilation time, and length of hospital and intensive care unit stay. Risk ratios (RRs), mean differences (MDs) or standardized mean differences (SMDs) and confidence intervals were calculated using fixed-effect modelling. RESULTS: The search identified 21 studies involving 6253 patients. High-chloride fluids did not affect mortality but were associated with a significantly higher risk of acute kidney injury (RR 1.64, 95 per cent c.i. 1.27 to 2.13; P < 0.001) and hyperchloraemia/metabolic acidosis (RR 2.87, 1.95 to 4.21; P < 0.001). High-chloride fluids were also associated with greater serum chloride (MD 3.70 (95 per cent c.i. 3.36 to 4.04) mmol/l; P < 0.001), blood transfusion volume (SMD 0.35, 0.07 to 0.63; P = 0.014) and mechanical ventilation time (SMD 0.15, 0.08 to 0.23; P < 0.001). Sensitivity analyses excluding heavily weighted studies resulted in non-statistically significant effects for acute kidney injury and mechanical ventilation time. CONCLUSION: A weak but significant association between higher chloride content fluids and unfavourable outcomes was found, but mortality was unaffected by chloride content.

Choice of fluid in acute illness: what should be given? An international consensus.

Fluid management during critical illness is a dynamic process that may be conceptualized as occurring in four phases: rescue, optimization, stabilization, and de-escalation (mobilization). The selection and administration of resuscitation fluids is one component of this complex physiological sequence directed at restoring depleted intravascular volume. Presently, the selection of i.v. fluid is usually dictated more by local practice patterns than by evidence. The debate on fluid choice has primarily focused on evaluating outcome differences between 'crystalloids vs colloids'. More recently, however, there is interest in examining outcome differences based on the chloride content of crystalloid solutions. New insights into the conventional Starling model of microvascular fluid exchange may explain that the efficacy of colloids in restoring and maintaining depleted intravascular volume is only moderately better than crystalloids. A number of investigator-initiated, high-quality, randomized controlled trials have demonstrated that modest improvements in short-term physiological endpoints with colloids have not translated into better patient-centred outcomes. In addition, there is substantial evidence that certain types of fluids may independently worsen patient-centred outcomes. These include hydroxyethyl starch and albumin solutions in selected patient populations. There is no evidence to support the use of other colloids. The use of balanced salt solutions in preference to 0.9% saline is supported by the absence of harm in large observational studies. However, there is no compelling randomized trial-based evidence demonstrating improved clinical outcomes with the use of balanced salt solutions compared with 0.9% saline at this time.

Modulation of fluorouracil antitumor activity by folic acid in a murine model system.

The biochemical basis for modulation of fluorouracil (FU) activity by leucovorin is elevation of the metabolite methylenetetrahydrofolate, which stabilizes the inhibitory ternary complex formed between thymidylate synthase and the active metabolite of FU, 5-fluorodeoxyuridylate. Folic acid, because it can also potentially be metabolized to methylenetetrahydrofolate, was evaluated for its ability to potentiate FU antitumor activity in a dietary folic acid restricted murine model. The plasma pharmacokinetics and tissue distribution of folic acid and all stable metabolites thereof were determined in the model to establish administration schedules. FU was administered to mice implanted subcutaneously with a mammary adenocarcinoma 4 hr after folic acid administration, when the metabolites, methylenetetrahydrofolate and tetrahydrofolate, were elevated maximally in both plasma and tumor tissue. While FU alone suppressed growth 25%, folic acid in combination with FU increased growth suppression to over 70%. These results indicate that folic acid is a potent modulator of FU activity and could be considered as an alternative to leucovorin in the clinical setting.

Effects of antisense-based folypoly-gamma-glutamate synthetase down-regulation on reduced folates and cellular proliferation in CCRF-CEM cells.

The effect of down-regulation of folylpoly-gamma-glutamate synthetase (FPGS) activity on intracellular reduced folate accumulation and cellular proliferation was examined, using an inducible antisense expression system in the human T-lymphoblastic leukemia cell line CCRF-CEM. FPGS catalyzes the addition of gamma-glutamyl residues to natural folates and classical antifolates, which results in their enhanced cellular retention and increased cytotoxicity. As such, this enzyme has become a focus as a potential anticancer drug target. However, direct evidence to support this concept has been elusive. Hence, a study was undertaken using an antisense-based expression system to down-regulate FPGS activity. This inducible expression system was used to demonstrate that lower FPGS activity can lead to substantially lower intracellular folate content, which coincides with suppression of thymidylate synthesis and inhibition of cellular proliferation.

Impact of schedule on leucovorin potentiation of fluorouracil antitumor activity in dietary folic acid deplete mice.

A dietary folic acid depleted mouse model was established and used to evaluate the relationship between elevation of reduced folates after leucovorin (LV) administration and potentiation of fluorouracil (FU) response of an implanted tumor. C3H mouse mammary adenocarcinomas from mice maintained on a folic acid deplete diet had modestly decreased methylenetetrahydrofolate and tetrahydrofolate levels, and were somewhat less responsive to FU alone compared with replete animals. LV administration resulted in a substantial increase in tumor folate by 1 hr that returned to near basal levels by 12 hr. Reduced folates were elevated to a lesser extent in animals on a standard diet. Tumor growth was suppressed approximately 80% when FU was administered to depleted animals 1 hr after LV administration, compared with approximately 50% suppression in control mice. LV administered 12 hr before FU resulted in tumor growth stimulation that was consistent with the pronounced growth stimulation when LV was administered without FU. These results show that dietary folic acid depletion can lead to a more responsive FU/LV model and that administration of LV at an improper time before FU not only can fail to potentiate but also can result in tumor growth stimulation.

Disposition of leucovorin and its metabolites in dietary folic acid-deplete mice - comparison between tumor, liver, and plasma.

PURPOSE: A comprehensive pharmacokinetic study of leucovorin (5-formyltetrahydrofolate, 5-HCO-FH4) and its metabolites was conducted in plasma, liver and implanted tumor tissue from mice maintained on a low folic acid diet. While it has been previously demonstrated that the antitumor activity of fluorouracil (FU) can be potentiated by 5-HCO-FH4, the optimum time for administration of FU after 5-HCO-FH4, to maximally elevate the active folate metabolite methylenetetrahydrofolate in tumor has not been established. Human plasma studies have defined the pharmacokinetics of circulating 5-HCO-FH4 and its metabolites, but comparison with human tumor accumulation has not been practicable because of sampling difficulties. As an alternative, a mouse model system, based on low dietary folic acid, was used to evaluate plasma, liver and implanted tumor reduced folates after administration of 5-HCO-FH4. METHODS: Plasma and tissue samples were collected from folate-deplete mice over a 12-h period after intraperitoneal administration of 90 mg/kg [R, S] 5-HCO-FH4. Reduced folates were evaluated using a ternary complex assay. RESULTS: The time at which maximal accumulation of parent compound and all metabolites, except 5-methyltetrahydrofolate (5-CH3FH4), occurred in tumor was the same as in plasma. Alternatively, peak liver accumulation was delayed relative to plasma for all folates except 5-CH3FH4. CONCLUSIONS: The results suggest that mouse plasma accumulation of reduced folates, with the exception of 5-CH3FH4, can predict tumor accumulation. Hence, evaluation of human plasma folate accumulation may potentially provide a means to improve the timing of the administration of FU relative to 5-HCO-FH4 to achieve a superior therapeutic outcome.