On the relative safety of parenteral iron formulations.

BACKGROUND: Intravenous iron is usually required to optimize the correction of anaemia in persons with advanced chronic kidney disease and end-stage renal disease. Randomized clinical trials may have insufficient power to detect differences in the safety profiles of specific formulations. METHODS: We obtained data from the US Food and Drug Administration on reported adverse drug events (ADEs) related to the provision of three formulations of intravenous iron during 1998-2000. We estimated the relative risks [odds ratios (OR)] of ADEs associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran using 2 x 2 tables. RESULTS: The total number of reported parenteral iron-related ADEs was 1981 among approximately 21,060,000 doses administered, yielding a rate of 9.4 x 10(-5), or approximately 94 per million. Total major ADEs were significantly increased among recipients of higher molecular weight iron dextran (OR 5.5, 95% CI 4.9-6.0) and sodium ferric gluconate complex (OR 6.2, 95% CI 5.4-7.2) compared with recipients of lower molecular weight iron dextran. We observed significantly higher rates of life-threatening ADEs, including death, anaphylactoid reaction, cardiac arrest and respiratory depression among users of higher molecular weight compared with lower molecular weight iron dextran. There was insufficient power to detect differences in life-threatening ADEs when comparing lower molecular weight iron dextran with sodium ferric gluconate complex. CONCLUSIONS: Parenteral iron-related ADEs are rare. Using observational data, overall and most specific ADE rates were significantly higher among recipients of higher molecular weight iron dextran and sodium ferric gluconate complex than among recipients of lower molecular weight iron dextran. These data may help to guide clinical practice, as head-to-head clinical trials comparing different formulations of intravenous iron have not been conducted.     

Update on adverse drug events associated with parenteral iron.

BACKGROUND: We previously compared the safety profile of three formulations of intravenous iron used during 1998-2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran. Since that time, iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. METHODS: We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous iron during 2001-2003, including higher and lower molecular weight iron dextran, sodium ferric gluconate complex and iron sucrose. We estimated the odds of intravenous iron-related ADEs using 2 x 2 tables and the chi(2) test. RESULTS: The total number of reported parenteral iron-related ADEs was 1141 among approximately 30,063,800 doses administered, yielding a rate of 3.8 x 10(-5), or roughly 38 per million. Eleven individuals died in association with the ADE. Relative to lower molecular weight iron dextran, total and life-threatening ADEs were significantly more frequent among recipients of higher molecular weight iron dextran and significantly less frequent among recipients of sodium ferric gluconate complex and iron sucrose. The absolute rates of life-threatening ADEs were 0.6, 0.9, 3.3 and 11.3 per million for iron sucrose, sodium ferric gluconate complex, lower molecular weight iron dextran and higher molecular weight iron dextran, respectively. Based on differences in the average wholesale price of iron sucrose and lower molecular weight iron dextran in the US, the cost to prevent one life-threatening ADE related to the use of lower molecular weight iron dextran was estimated to be 5.0-7.8 million dollars. The cost to prevent one lower molecular weight iron dextran-related death was estimated to be 33 million dollars. CONCLUSIONS: The frequency of intravenous iron-related ADEs reported to the FDA has decreased, and overall, the rates are extremely low. This is the fourth report suggesting increased risks associated with the provision of higher molecular weight iron dextran. Life-threatening and other ADEs appear to be lower with the use of non-dextran iron formulations, although the cost per ADE prevented is extremely high.     

Adverse events in chronic hemodialysis patients receiving intravenous iron dextran--a comparison of two products

BACKGROUND: Parenteral iron therapy is required in a majority of chronic dialysis patients who are receiving recombinant human erythropoietin (r-HuEPO) in order to provide adequate iron for erythropoiesis. At this time, there are only two formulations of parenteral iron dextran available for clinical use in the USA. These two preparations of iron dextran have different physical and chemical characteristics that might affect the adverse events experienced by dialysis patients receiving iron dextran. METHODS: We performed a retrospective analysis of all 665 courses of parenteral iron dextran which were administered in our hemodialysis unit from June 1992 through July 1997. An adverse event (AE) was defined as any event which led to interruption of the prescribed course of iron therapy or precluded subsequent administration of parenteral iron in the presence of documented iron deficiency. Database elements included patient age, gender, cause of renal failure, and prior history of drug allergy. The average hemoglobin value and serum iron parameters (iron, total iron binding capacity (TIBC), percent saturation of TIBC, and ferritin) were recorded both pre- and post-iron administration, when available. A course of parenteral iron dextran consisted of a 25-mg test dose, followed by four or five doses of 300 mg each. Iron dextran was infused into the venous limb of the hemodialysis blood circuit over the last 30-60 min of a dialysis treatment. The two forms of iron dextran were designated as Iron A (molecular weight = 165,000) and Iron B (molecular weight = 267,000). RESULTS: Fifty-seven percent of our patients were male, 92% were of white race, and diabetes was the most common cause of renal failure (34%). Sixty-four percent of the patients were 60 years of age or older, and 39% had a history of allergy to one or more drugs. We observed 33 AEs during the administration of parenteral iron dextran, and these AEs occurred in 21 courses of parenteral iron dextran administration. Eighteen of the AEs were gastrointestinal in nature; 7 AEs were cutaneous in nature, 6 AEs had systemic manifestations, while only 2 AEs caused respiratory problems. Two of the AEs were felt to be anaphylactoid in nature. Female gender (p = 0.06) and iron dextran product (p = 0.02) were identified as potential risk factors for the development of an AE. There were 468 courses of Iron A administered, 10 of these courses were complicated by 15 AEs (one or more AE per course). One hundred and ninety-seven courses of Iron B were administered and 11 (5.6%) courses were complicated by the development of 18 AEs (9.1 AEs per 100 courses). Serum iron rose by 22 microg/dl and TIBC saturation increased by 14% after the administration of parenteral iron. The average serum ferritin level rose by 430 microg/l and hemoglobin values rose by an average of 0.8 g/dl. There were no significant differences in the changes of iron parameters or hemoglobin levels between the two iron dextran preparations. CONCLUSIONS: The administration of parenteral iron dextran to chronic hemodialysis patients has a relatively high degree of safety. Both iron products were equally efficacious in increasing serum iron parameters and hemoglobin levels. Even when corrected for other factors, there was a significant difference in the observed AEs between the two formulations of parenteral iron dextran. Our observations, if true, may have important implications for the management of anemia in chronic hemodialysis patients. If a significant number of AEs prohibit the administration of a specific iron dextran product to a large number of chronic hemodialysis patients, then anemia management may become suboptimal. In the future, newer iron products may provide even safer alternatives for the administration of parenteral iron to chronic hemodialysis patients.     

Safety of total dose iron dextran infusion in geriatric patients with chronic kidney disease and iron deficiency anemia

There are limited data on total dose infusion (TDI) using iron dextran in geriatric chronic kidney disease (CKD) patients with iron-deficiency anemia (IDA). Our goal was to evaluate the safety of TDI in this setting. We conducted a retrospective chart review spanning a 5 year period (2002–2007), including all patients with CKD and IDA who were treated with iron dextran TDI. Patient demographics were noted, and laboratory values for creatinine, hemoglobin and iron stores were recorded pre- and post-dose. TDI diluted in normal saline was administered intravenously over 4-6 hours after an initial test dose. One hundred fifty-three patients received a total of 250 doses of TDI (mean?±?SD?=?971?±?175?mg); age was 69?±?12 years and creatinine 3.3?±?1.9?mg/dL. All stages of CKD were represented (stage 4 commonest). Hemoglobin and iron stores improved post-TDI (P?P?=?0.1433 by Fishers Exact Test). Iron dextran TDI is relatively safe and effective in correcting IDA in geriatric CKD patients. Fewer AEs were noted with the LMW compared to the HMW product. LMW iron dextran given as TDI can save both cost and time, helping to alleviate issues of non-compliance and patient scheduling.     

低分子右旋糖酐铁和蔗糖铁对慢性肾衰竭大鼠氧化应激的影响

目的 评价小剂量反复多次低分子右旋糖酐铁和蔗糖铁静脉用药后对慢性肾衰竭大鼠氧化应激的影响。 方法 以5/6肾大部切除术建立慢性肾衰竭大鼠模型。右肾切除术后第4周,将实验大鼠分为4组：低分子右旋糖酐铁（糖酐铁）组、蔗糖铁组、对照组、假手术组。观察6周,检测各组大鼠体内氧化应激、铁代谢等指标。 结果 糖酐铁组和蔗糖铁组大鼠血红蛋白明显高于对照组（P < 0.05）,而两铁剂组间差异无统计学意义。对照组大鼠的血清铁、血清铁蛋白、转铁蛋白饱和度显著低于假手术组（P < 0.05）;两铁剂组大鼠上述指标均显著高于对照组（P < 0.05）,而两铁剂组间差异无统计学意义。糖酐铁组和蔗糖铁组血浆晚期氧化蛋白产物（AOPP）显著高于对照组[（127.84±21.19） μmol/L、（134.21±29.38） μmol/L比 （81.83±19.93） μmol/L,P < 0.05],而两铁剂组间差异无统计学意义。两铁剂组大鼠血浆丙二醛（MDA）高于对照组,而蔗糖铁组高于糖酐铁组[（6.06±0.73） nmol/L比（4.99±0.80） nmol/L, P < 0.05]。糖酐铁组、蔗糖铁组和对照组大鼠血清超氧化物歧化酶（SOD）和总抗氧化能力（TAOC）差异无统计学意义。模型组大鼠血浆谷胱甘肽过氧化物酶（GSH-Px）水平显著低于假手术组（P < 0.05）,而蔗糖铁组显著低于糖酐铁组和对照组[（2123.11±74.78） nmol&#8226;ml-1&#8226;min-1比（2352.84±163.90） nmol&#8226;ml-1&#8226;min-1、（2310.23±125.99） nmol&#8226;ml-1&#8226;min-1,P < 0.05]。 结论 静脉补铁可部分纠正5/6肾大部切除肾衰竭大鼠的贫血,改善铁代谢指标。反复静脉小剂量补铁对慢性肾衰竭大鼠氧化应激状态有不良影响,而低分子右旋糖酐铁的不良影响低于蔗糖铁。     

Effect of an intravenous iron dextran regimen on iron stores, hemoglobin, and erythropoietin requirements in hemodialysis patients

Iron deficiency is a common cause of delayed or diminished response to erythropoietin (EPO) in hemodialysis patients. Although oral iron is often prescribed to replete iron stores, this approach to iron supplementation may not be adequate with chronic EPO therapy. Intravenous (IV) iron dextran may be an effective alternative approach to replete iron stores and may facilitate more cost-effective use of EPO. The purpose of this study was to evaluate an IV iron dextran regimen that consisted of a loading dose phase followed by monthly maintenance doses of iron dextran. The effect of this regimen on iron stores, hemoglobin, and EPO doses was evaluated. This was an open prospective study in adult hemodialysis patients who were iron deficient as defined by a serum ferritin less than 100 ng/mL or transferrin saturation (TSAT) of less than 20%. Patients were loaded with 1 g iron dextran in five divided doses and then received monthly maintenance doses of 100 mg for the 4-month study period. Values of serum ferritin, TSAT, hemoglobin, and EPO dose were followed for the 4-month study period. Thirty hemodialysis patients receiving EPO were identified as being iron deficient and were enrolled in the study. The mean serum ferritin increased significantly from 49 ng/mL at baseline to 225 ng/mL at the end of the study period (P < 0.0001). Mean TSAT also increased significantly from 27% to 33% (P = 0.002). Values for hemoglobin did not change significantly during the study period; however, there was a significant reduction in EPO dose from a mean baseline dose of 112 U/kg/wk to 88 U/kg/wk at the end of the study period (P = 0.009). Seventeen patients experienced an increase in hemoglobin or a decrease in EPO dose. Economic analysis showed that approximately $580 (Cdn) per patient per year could be saved by use of IV iron dextran. The administration of the IV iron dextran regimen in the iron-deficient hemodialysis population was effective at repleting and maintaining iron stores and reducing EPO use.     

Intravenous iron preparations and ascorbic acid: effects on chelatable and bioavailable iron

BACKGROUND: There is growing interest to use ascorbic acid as adjuvant therapy for patients with recombinant human erythropoietin-hyporesponsiveness (rHuEpo). Several clinical studies showed the beneficial effect of ascorbic acid treatment on hematologic parameters in rHuEpo-treated hemodialysis patients with elevated or even normal iron stores. However, whether ascorbic acid directly affects stability and cellular metabolism of intravenous iron preparations (IVI) is not well understood. METHODS: The preparations for testing were iron sucrose (Venofer), ferric gluconate (Ferrlecit), and iron dextran (INFeD). HepG2-cells were used to investigate effects of ascorbic acid on iron bioavailability for the intracellular labile iron pool (LIP) from IVI by using the fluorescent calcein-assay, and cellular ferritin content was measured by enzyme-linked immunosorbent assay (ELISA). Transferrin-chelatable iron was assessed by fluorescent-apotransferrin, and cell toxicity was assayed by neutral red cytotoxicity test. RESULTS: The effects of vitamin C on different preparations do not reflect their known chemical stability (i.e., iron dextran >iron sucrose >ferric gluconate). Effects of ascorbic acid on the increase of the intracellular LIP, as well as on increasing mobilization to transferrin in serum, were limited to iron sucrose. Ascorbic acid did not increase cell toxicity and the amount of low molecular weight iron in serum. CONCLUSION: We conclude that corrected ascorbic acid levels in hemodialysis (HD) patients could increase the amount of bioavailable iron from iron sucrose, but not from other classes of IVI. Vitamin C administration could therefore result in a lower need of iron sucrose to correct anemia.     

Impact of iron dextran on polymorphonuclear cell function among hemodialysis patients

BACKGROUND: Polymorphonuclear cell (PMN) dysfunction and the increased use of parenteral iron may be important contributory factors to bacterial infections among patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD). We compared the in vitro impact of a commonly used parenteral iron preparation, iron dextran, on PMN function and viability between a group of HD patients with normal iron indices and healthy subjects. METHODS: Eleven patients with ESRD on HD and 10 healthy subjects were studied. PMN harvested from heparinized blood were incubated with iron dextran (0 - 20 mM) in culture medium (RPMI) for 24 hours at 37 degrees C with 5% CO2 following which function and viability were assessed by flow cytometry using appropriate fluorescent labels. RESULTS: Unstimulated, S. aureus and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated hydrogen peroxide (H2O2) production was significantly higher in PMN unexposed to iron dextran from HD patients compared to those from healthy subjects. Iron dextran had no impact on unstimulated PMN H2O2 production in either group. In the healthy group, the only significant change occurred with 4-beta-phorbol 12-beta-myristate 13-alpha-acetate (PMA) stimulation, where cells exposed to 0.2 and 2.0 mM iron dextran produced less H2O2 relative to PMN unexposed to iron dextran (p < 0.05). In the HD group, all concentrations of iron dextran significantly attenuated H2O2 production stimulated by S. aureus, fMLP and PMA compared to PMN unexposed to iron dextran. Although PMN phagocytosis decreased with exposure to increasing concentration of iron dextran in both healthy subjects and HD patients, these changes did not achieve statistical significance. No significant changes in PMN viability or apoptosis were seen in either group after exposure to iron dextran. CONCLUSIONS: These results indicate that iron dextran, a standard parenteral iron preparation, attenuates PMN function in HD patients with normal iron indices at clinically relevant concentrations. Further studies are required to evaluate and compare the impact of newer preparations of parenteral iron, such as iron sucrose and ferric gluconate, on PMN function.     

Controversies in iron management

BACKGROUND: Iron therapy is required in hemodialysis patients receiving erythropoietic stimulators in order to achieve the target hemoglobin in the most efficient way. While oral iron has been disappointing in this regard, parenteral iron has been widely used, despite a significant incidence of severe side effects when iron dextran is used. The recent availability of a more effective form of oral iron (heme-iron), and safer forms of parenteral iron (iron sucrose and iron gluconate) has made iron management in this population simpler. Many questions remain, however, about the use, efficacy, and safety of these compounds in hemodialysis patients. METHODS: Current literature was reviewed and combined with the authors' clinical experience to address a number of current questions regarding the use of iron in hemodialysis patients. RESULTS: Although oral non-heme iron is infrequently sufficient to maintain iron stores in hemodialysis patients, recent studies suggest that heme-iron may be more useful in this regard. Heme-iron is absorbed to a greater extent than non-heme iron, and is better tolerated. Small studies have shown that when heme-iron is administered, less parenteral iron and lower doses of erythropoietin (EPO) are needed to maintain target hemoglobin. Current evidence suggests that both iron sucrose and iron gluconate are safer than iron dextran, and the latter should only be used in extraordinary circumstances. While in vitro studies have demonstrated some differences in the effects of iron sucrose and iron gluconate on cellular toxicity, the clinical importance of these has not been determined. Both compounds can be used safely for repletion and maintenance therapy, and doses of up to 300 mg of either are generally well tolerated when such higher doses are needed, as in peritoneal dialysis (PD) patients or chronic kidney disease (CKD) patients not on dialysis. CONCLUSION: A number of questions remain regarding the appropriate use, efficacy, and potential toxicity of iron therapy in dialysis patients. Further prospective research should address the myriad questions raised in this review.     

Prevention of iron deficiency in preterm neonates during infancy

The preterm infant inevitably develops iron deficiency unless supplementary iron is given. Oral iron supplementation is preferred in ideal social circumstances but, where compliance with such therapy is uncertain, intramuscular iron dextran may be a more effective treatment. A study was conducted to compare the effectiveness of two methods of preventing iron deficiency of prematurity. One group of healthy premature infants was given oral iron 2 mg/kg/d until the age of 6 months. The second similar group was given 100 mg as intramuscular iron dextran (Imferon; Fisons) between the ages of 6 and 8 weeks. Both kinds of supplementary iron appeared to have benefited the majority of infants in this trial.     

Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients.

BACKGROUND: Reliable information on the incidence of severe reactions to iron dextran is limited. Administration of agents of resuscitation in acute anaphylaxis may serve as a marker to quantify life-threatening adverse drug reactions. METHODS: To determine the incidence of the most serious reactions to intravenous (i.v.) iron dextran, we searched the Gambro Healthcare US medical database for evidence of same-day administration of both i.v. iron dextran and parenteral adrenaline, corticosteroids or antihistamines. We confirmed each case as an iron dextran sensitivity reaction by direct inquiry. We also determined the total reported number of suspected adverse iron dextran reactions. RESULTS: During the 16 month study period, we determined that 1,066,099 doses of i.v. iron dextran were given to 48,509 patients, including 20,213 patients who had not previously received iron dextran (iron dextran na?ve). We identified seven patients who experienced reactions requiring resuscitative agents, all in response to a test dose (five patients) or first therapeutic dose (two patients), and therefore all in the iron-na?ve (incident) group. Thus, we found the incidence of iron dextran reactions requiring resuscitative agents to be 0.035% (7 out of 20,213). No reaction was fatal. In a combined group of incident and prevalent patients, we found 337 total reports of suspected adverse reactions to iron dextran, without regard to severity of reaction, yielding an overall per patient adverse drug event (ADE) rate of 0.69% (337 out of 48,509) and per exposure rate of 0.03% (337 out of 1,066,099). CONCLUSIONS: The incidence of reactions to iron dextran requiring resuscitative medications, per exposure or per patient, is approximately 0.035%. Reactions of this severity occur after either the test dose or first dose of iron dextran.     

Hepatic iron in the control of iron absorption in a rat liver transplantation model

Rat liver transplantation was utilized to study the effect of hepatic iron on the control of iron absorption. Six iron-loaded and six normal livers were transplanted into normal or iron-loaded animals. Iron absorption was measured pretransplant and 10 days posttransplant by total-body counting (59Fe). The animals were loaded with oral carbonyl iron to produce a predominantly parenchymal hepatic iron distribution and with parenteral iron dextran to produce a predominantly reticuloendothelial iron distribution. The carbonyl iron-loaded livers contained 175 +/- 6.6, the iron dextran livers 180 +/- 41, and the normal livers 6.6 +/- 2.8 mumol FE/g dry wt. Iron absorption was unchanged by the insertion of normal livers into normal animals. The transplantation of carbonyl iron-loaded livers into normal animals caused a marked decrease in iron absorption posttransplant from 7.2 +/- 0.9% to 0.3 +/- 0.4% (P less than .001) posttransplant. Neither the transplantation of iron dextran-loaded livers into normal animals nor the transplantation of normal livers into iron-loaded animals significantly altered iron absorption at 10 days posttransplant. These results are consistent with the hypothesis that hepatocyte iron stores are a major determining factor controlling iron absorption.     

Labile iron in parenteral iron formulations: a quantitative and comparative study.

BACKGROUND: Evidence of iron-mediated oxidative stress, neutrophil dysfunction and enhanced bacterial growth after intravenous (IV) iron administration has been ascribed to a labile or bioactive iron fraction present in all IV iron agents. METHODS: To quantify and compare the size of the labile fraction in several classes of IV iron agents, we examined iron donation to transferrin (Tf) in vitro. We added dilutions of ferric gluconate, iron sucrose and each of two iron dextran preparations to serum in vitro, passed the resulting samples through alumina columns to remove iron agent and free organic iron, and measured Tf-bound iron in the resulting eluates. Comparing results to serum samples without added iron, we calculated delta Tf-bound iron for each agent at each concentration. Finally, we compared delta Tf-bound iron to the concentration of added agent and calculated the percent iron donation to Tf. RESULTS: We found that Tf-bound iron increased with added iron concentration for each agent: delta Tf-bound iron was directly related to the concentration and type of iron agent (P<0.001). Mean percent iron donation to Tf ranged from 2.5 to 5.8% with the following progression: iron dextran-Dexferrum相似文献   

Iron availability and complex stability of iron hydroxyethyl starch and iron dextran a comparative in vitro study with liver cells and macrophages.

BACKGROUND: Intravenous iron (IVI) therapy is required in patients with end-stage renal disease (ESRD) under chronic haemodialysis (HD). In this in vitro study we investigated the availability and stability of iron hydroxyethyl starch (iron-Hes) compounds in THP-1 cells (macrophage phenotype) and liver cells (HepG2 cells) and compared it with the well-known iron dextran. METHODS: The uptake and release of these iron formulations by THP-1 cells (macrophage phenotype) and HepG2 cells were investigated with atomic absorption spectrometry (AAS). Ferritin was measured by ELISA. HepG2 cells were used to investigate effects of IVI on the intracellular labile iron pool (LIP), which was measured by using the fluorescent calcein assay. The amount of redox-active iron within the iron formulations was assayed using dichlorofluorescein as fluorescent probe. RESULTS: All iron preparations were taken up, stored in ferritin and released again by macrophages and HepG2-cells. This study shows that the availability and stability of iron-HES formulations in vitro are comparable with the well-known iron dextran compounds. CONCLUSIONS: Our results indicate that these new iron formulations have a good stability and availability in vitro and are comparable with the well-known iron dextran complexes.     

Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis

BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.     

Intravenous iron replacement for persistent iron deficiency anemia after Roux-en-Y gastric bypass

BackgroundIron deficiency is a major postoperative complication of Roux-en-Y gastric bypass surgery. Oral replacement can fail to correct the deficiency. Thus, recourse to parenteral iron administration might be necessary. Our objective was to evaluate the effectiveness and safety of a standardized 2 g intravenous iron dextran infusion in the treatment of iron deficiency after Roux-en-Y gastric bypass surgery. The setting was a university-affiliated community hospital in the United States.MethodsWe reviewed the medical records of 23 patients at our institution who had received 2 g of iron dextran intravenously for recalcitrant iron deficiency after Roux-en-Y gastric bypass surgery. We obtained the demographic data and the complete blood count and serum iron studies obtained before treatment and at outpatient visits after infusion.ResultsBefore treatment, all 23 patients were iron deficient (average ferritin 6 ng/mL) and anemic (average hemoglobin 9.4 g/dL). By 3 months, the average ferritin and hemoglobin had increased to 269 ng/mL and 12.3 g/dL, respectively. The hemoglobin levels remained stable throughout the follow-up period. The iron stores were adequately replaced in most patients. Four patients required a repeat infusion by 1 year, because the ferritin levels had decreased to <15 ng/mL. The probability of remaining in an iron replete state was 84.6% (95% confidence interval 78–91.2%). One patient required warm compresses for superficial phlebitis. No other significant adverse events were reported.ConclusionIntravenous administration of 2 g of iron dextran corrects the anemia and repletes the iron stores for ≥1 year in most patients. This therapy is safe, tolerable, efficient, and effective.     

Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans.

Use of recombinant human erythropoietin in patients with end-stage renal disease has highlighted iron deficiency as the major cause of resistant anemia. The current mainstay of intravenous (i.v.) iron replacement therapy, iron dextran, has been shown in prior studies to have a risk of serious life-threatening anaphylaxis of just under 1 per 100 patients exposed. The current study assessed the safety profile of an alternative i.v. iron, sodium ferric gluconate complex in sucrose (Ferrlecit), as compared with iron dextrans. Sodium ferric gluconate complex in sucrose, a unique chemical preparation, has been in use since 1959, principally in Europe, at a rate of approximately 2.7 million i.v. doses per year (1992 to 1996) in Germany and Italy alone. For iron dextran, usage in the United States was comparable--principally renal hemodialysis--and estimated from market sources at 3.0 million doses per year (1995). From 1976 to 1996, there were 74 allergic adverse events reported for sodium ferric gluconate complex in sucrose to the World Health Organization (WHO), German Health Bureau, and the manufacturer (all combined). For the years 1992 to 1996, sodium ferric gluconate complex in sucrose had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the United States in 1995. Case fatalities for sodium ferric gluconate complex in sucrose and iron dextran within these reports were then compared. For sodium ferric gluconate complex in sucrose, there were no reports of deaths over the entire period (1976 to 1996). However, for iron dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the United States between 1976 and 1996, yielding a case-fatality rate of 15.8%. These data show that sodium ferric gluconate complex in sucrose, when compared with iron dextrans in comparably sized patient usage populations with similar total rates of reporting of allergic events, has a significantly lower reported mortality rate (P < 0.001). Thus, the data justify usage of sodium ferric gluconate complex in sucrose as the safer iron replacement therapeutic agent.     

Chronic peritoneal dialysis in iron-deficient rats with solutions containing iron dextran

BACKGROUND: We evaluated the effects of different concentrations of iron dextran administered through the intraperitoneal route, in iron-deficient rats, on hematocrit (Hct in percentage), serum iron (mg/dL), total iron binding capacity (TIBC in mg/dL), and the function and histology of the peritoneal membrane. METHODS: Seventy-two male Sprague-Dawley rats weighing 85 to 110 g were divided into two groups and seven subgroups. Group I consisted of rats on iron-deficient chow, and group II consisted of rats on normal chow. Both groups contained dialysis control subgroups (N = 12: IA, IID), dialyzed with Dianeal solution, and tissue control subgroups (N = 6: IE, IIN), in which rats were not dialyzed and catheters were not implanted. Study group I contained the following study subgroups (N = 12): (B) rats dialyzed with Dianeal solution containing 2 mg/L of iron dextran and (C) rats dialyzed with Dianeal solution containing 1 mg/L of iron dextran. Group IID was dialyzed with Dianeal solution containing 2 mg/dL of iron dextran. Study duration was 12 weeks with peritoneal equilibration tests (PETs) performed at baseline, 6 weeks, and 12 weeks. Prior to baseline, rats were placed on iron-deficient chow or normal chow for three weeks. Dialysis was performed with three 25 mL volume exchanges per day. Hematocrit (Hct), serum iron (Fe), and total iron binding capacity (TIBC) were determined for each study interval. After the final PET, the animals were sacrificed, and the peritoneal membrane was evaluated by gross inspection and light microscopy. RESULTS: Rats on an iron-deficient diet developed severe iron-deficiency anemia after three weeks of the diet (Hct 27; Fe 21 to 23; TIBC 799 to 806). After 12 weeks, the rats remained anemic in groups A (Hct 34 +/- 0.9; Fe 16 +/- 2; TIBC 998 +/- 27) and IE (Hct 38 +/- 2.7), whereas the rats corrected anemia in group B (Hct 45.8 +/- 1.8; Fe 115 +/- 15; TIBC 546 +/- 77). The results were not significantly different from those of group IID (Hct 47.1 +/- 1.6; Fe 94 +/- 19; TIBC 516 +/- 46). In group C, Hct (44.8 +/- 2.1) and Fe (94 +/- 19) did not differ significantly from group IID, but TIBC (734 +/- 76) remained significantly higher than that in the group IID. Peritoneal iron deposits were not detected. The morphometric analysis of the submesothelial space did not reveal any difference in thickness between dialysis groups. PETs were not significantly different among groups. CONCLUSIONS: Intraperitoneal iron dextran supplementation in concentrations of 2 mg/L of dialysis solution is nontoxic to the peritoneum and effective in correcting iron deficiency in rats maintained on an iron-deficient diet. Iron dextran in concentration of 1 mg/L of dialysis solution may be sufficient for correcting a lesser degree of iron deficiency.     

Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients

BACKGROUND: Iron dextran administration is associated with a high incidence of adverse reactions including anaphylaxis and death. Although dextran, rather than iron, is believed to be the cause of these reactions, it is not known whether iron dextran-sensitive patients can be safely administered another form of parenteral iron, sodium ferric gluconate in sucrose (SFGC). METHODS: In a 69 center, prospective, double-blind, controlled trial of safety and tolerability of SFGC, the rate of reactions to SFGC and placebo in 144 iron dextran-sensitive patients was compared with 2194 patients who were previously tolerant to iron dextran preparations. Serum tryptase levels, a marker of mast cell degranulation, also were measured. RESULTS: Among 143 iron dextran-sensitive patients exposed to SFGC, three (2.1%) were intolerant. All three had suspected allergic events to SFGC, including one patient with a serious reaction (0.7%). One dextran-sensitive patient (0.7%) had a suspected allergic reaction after placebo. In contrast, among 2194 iron dextran-tolerant patients, reactions to SFGC were significantly less common, with SFGC intolerance seen in seven patients (0.3%; P = 0.020), including five (0.2%) who had suspected allergic events (P = 0.010), but none who had serious events (0.0%; P = 0.061). Two iron dextran-tolerant patients (0.09%) had allergic-like reactions following placebo injections. Two of the three suspected allergic events in the iron dextran-sensitive group were confirmed as mast cell dependent by a 100% increase in serum tryptase, while there were no confirmed allergic events in the iron dextran-tolerant group. Long-term exposure to SFGC in iron dextran-sensitive patients resulted in intolerance in only one additional patient and no serious adverse events. CONCLUSIONS: Patients with a history of iron dextran sensitivity had approximately sevenfold higher rates of reaction to both placebo and SFGC compared to iron dextran tolerant patients. However, logistic regression analysis, performed to account for the higher reaction rate to placebo, suggests that this increased reactivity was not drug-specific nor immunologically mediated, but represented host idiosyncrasy. These results support the conclusions that reactions to SFGC can be attributed to pseudoallergy, and that SFGC is not a true allergen.