Search

A high prevalence of iron deficiency exists in athlete populations. Various mechanisms, including increased losses through sweat, haemolysis, haematuria, and gastrointestinal micro-ischemia; inadequate dietary intake; and transient exercise-induced increases in the regulatory hormone, hepcidin, contribute to the increased prevalence in athletes. Indeed, hepcidin has been shown to peak around 3-6 hours post-exercise, limiting iron absorption form the gut. As the practitioner's ability to control losses is limited, the key to treatment of iron deficiency in athletes is optimal timing of dietary and oral iron supplementation around these periods of reduced gut absorption. While timing and dosing schedule strategies might be sufficient to treat iron deficiency non anaemia, the significant lag to impact iron status is relatively long. Therefore, in iron deficiency anaemia, the use of parenteral iron has the benefit of rapid repletion of iron stores and normalisation of haemoglobin status, while bypassing the action of hepcidin at the gut. Furthermore, newer intravenous formulations can be administered as a single total dose over 15-60 min and have a similar safety profile to oral treatment. This review discusses the existing evidence for parenteral iron use in athletes and the unique context for consideration when choosing the parenteral route in this population.

Purpose To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14-21 weeks pregnant with persistent iron deficiency (ferritinMethods In a single-centre, open-label, randomised controlled trial at a Danish hospital, women with persistent iron deficiency after routine oral iron treatment were allocated to receive 1000 mg IV iron (single-dose) or 100 mg elemental oral iron daily. Outcomes were assessed during an 18-week follow-up period. The primary endpoint was the proportion of nonanaemic (haemoglobin [Hb] >= 11 g/dL) women throughout follow-up. Other outcomes included changes in haematological parameters, patient-reported fatigue, and quality of life (QoL). Safety was assessed by recording adverse events.Results From July 2017 to February 2020, 100 women were randomised to IV iron and 101 to oral iron. Throughout followup, 91% of women were non-anaemic in the IV iron group compared with 73% in the oral iron group (18% difference [95% confidence interval 0.10-0.25]; p < 0.001). The mean Hb increase was significantly greater with IV iron versus oral iron at Weeks 6 (0.4 versus - 0.2 g/dL; p < 0.001), 12 (0.5 versus 0.1 g/dL; p < 0.001), and 18 (0.8 versus 0.5 g/dL; p= 0.01). Improvements in fatigue and QoL were greater with IV iron versus oral iron at Weeks 3 and 6. The incidence of treatment-related adverse events was comparable between treatment groups.Conclusion IV iron was superior in preventing anaemia compared with oral iron in pregnant women with persistent iron deficiency; biochemical superiority was accompanied by improved fatigue and QoL.

This study aimed to investigate the factors that are independently associated with hepcidin-25 and its relationship with doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron in stable maintenance hemodialysis patients (smHD) stratified by ESAs administration. In 103 adult smHD (ESAs therapy (N = 64) and ESAs-free (N = 39)), median values of biologically active hepcidin-25 (chemiluminescent direct ELISA assay) and ferritin levels were significantly higher whereas red blood cell count, hemoglobin, and hematocrit values were lower in ESAs therapy compared to ESAs-free group (P <.001, for all). Our results suggest that ESAs-independent smHD exhibit supposedly normal hepcidin-25 levels and preserved iron homeostasis, with a lower degree of anemia. The results of our multivariable model indicate that hepcidin-25 levels are independently and positively associated with iron stores and inflammation, and inversely with active erythropoiesis, regardless of ESAs administration. Maintenance ESAs and the intravenous iron dose were not related to hepcidin-25 levels.

Purpose To evaluate the efficacy and safety for mother and child of using intravenous iron isomaltoside (IV-IIM) during pregnancy. Methods Using an appointment register, we retrospectively identified all pregnant women who received a single dose of 1000 or 1500 mg IV-IIM in the maternity ward of Falu Hospital and subsequently gave birth between August 6, 2013 and July 31, 2018. Women who received IV-IIM (case group) were individually matched with pregnant women who did not receive IV-IIM (control group) by delivery date, maternal age (± 2 years), and parity. Adverse drug reactions (ADRs), demographic characteristics, hemoglobin and s-ferritin counts, pregnancy and delivery complications, and infant data (APGAR score, pH at umbilical artery, birthweight, birth length, intrauterine growth restriction and neonatal ward admission). Data were obtained from electronic patient charts. SPSS was used for descriptive statistics. Results During the 5-year period, 213 women each received a single administration of IV-IIM. Ten (4.7%) ADRs occurred during IV-IIM administration. All ADRs were mild hypersensitivity reactions, abated spontaneously within a few minutes, and did not recur on rechallenge. No association between IIM dose and ADR frequency was noted. Maternal and fetal outcomes, including hemoglobin counts at delivery and postpartum, were similar in the case and control groups. Conclusion These results support the convenience, safety, and efficacy of a single high-dose (up to 1500 mg) infusion of IV-IIM for iron deficiency or iron deficiency anemia during pregnancy.

Aims: Iron deficiency is common in patients with chronic kidney disease (CKD). Appropriate iron substitution is critical and intravenous iron is an established therapy for these patients. The objective of this study was to assess treatment routine, effectiveness, and safety of iron isomaltoside (Monofer (R), Pharmacosmos A/S, Holbaek, Denmark) in CKD patients in clinical practice. Materials and methods: This was a prospective observational study conducted in predialysis CKD patients treated with iron isomaltoside according to the product label and to routine clinical care. Results: The study included 108 patients with predialysis CKD: 22 were in stage 2 - 3, 41 in stage 4, and 45 in stage 5. The mean (standard deviation) age was 67 (15) years, and 55% of patients were male. The majority of patients (65%) received one iron isomaltoside treatment In patients with a baseline Hb < 10 g/dL, the mean dose of iron isomaltoside in the study was lower than the estimated total iron requirement (567 mg versus 921 mg). A treatment response of Hb >= 1 g/dL was achieved in 16/28 (57%) of patients, and the mean post-treatment Hb level was 10.5 g/dL. The probability of retreatment did not correlate with dose, but no dose administered was > 1,000 mg. There were no serious adverse drug reactions. One nonserious adverse drug reaction - injection site discoloration - was reported, and the patient had an uneventful recovery. Conclusion: Iron isomaltoside shows a good effectiveness and safety profile in predialysis CKD patients. However, some patients did not receive adequate iron doses to allow for optimal correction of their iron deficiency anemia.

Despite high prevalence of iron deficiency anemia (IDA) in patients with acute or chronic gastrointestinal bleeding (GIB), IDA and iron deficiency (ID) are frequently untreated. Reasons may be misconceptions about the impact and diagnosis of IDA and the efficacy of new treatments. Addressing these misconceptions, this article summarizes current evidence for better understanding and management of GIB-associated IDA. Despite only few controlled studies evaluated the efficacy of iron treatment in patients with GIB, there is consistent evidence suggesting that: (a) IDA should be diligently investigated, (b) effective treatment of ID/IDA improves outcomes such as health-related quality of life and can avoid severe cardiovascular consequences, and (c) intravenous iron should be considered as well-tolerated treatment in this setting. Overall, the misconceptions and practices outlined in this article should be replaced with strategies that are more in line with current guidelines and best practice in GIB and other underlying conditions of ID/IDA. (C) 2017 The Authors. Published by Elsevier Espana, S.L.U.

Uvod: Anemija je jedna od glavnih komplikacija koja se javlja u hroniĉnoj bolesti bubrega (CKD), terminalnoj bolesti bubrega (ESRD) i na dijalizi i nezavistan je prediktor morbiditeta i mortaliteta kod ovih bolesnika (10,11). Smanjena produkcija endogenog eritropoetina (Epo) i nedostatak gvoţĊa (Fe) dva su neodvojiva razloga usporavanja i prekida diferencijacije i maturacije eritrocita u kostnoj srţi i predstavljaju glavne razloge koji dovode do smanjene eritropoeze u bolesnika na dijalizi. Korekcija statusa feremije redovnom nadoknadom Fe od kljuĉne je vaţnosti u leĉenju anemijskog sindroma kod bolesnika sa CKD, ESRD i na dijalizi. Svakako opravdano, primena preparata Fe je u porastu, zajedno sa primenom rekombinantnog humanog eritropoetina (rHu Epo), (49), a preporuĉen ciljni hemoglobin (HGB) je korigovan sa 130 na 105-110 g/L, na osnovu utvrĊenog bezbedonosnog profila rHu Epo za bolesnike sa CKD (50-52). Aktuelni vodiĉi leĉenja anemije na hemodijalizi (K/DIGO) liberalizuju upotrebu Fe kod bolesnika sa CKD (53). Angiotenzin II direktno povećava proliferaciju eritroidnih progenitora u in vitro uslovima (41,42). Pokazana je veća potreba za koliĉinom rHuEpo kod bolesnika sa ACE genotipom II za postizanje adekvatne korekcije krvne slike, u odnosu na bolesnike sa DD genotipom na hroniĉnoj ambulatornoj peritonealnoj dijalizi (44). Kardiovaskularni status bolesnika na hemodijalizi je pod snaţnim uticajem stepena anemije i medijatora iz sistema renin-angiotenzin, koji se moduliraju pod uticajem polimorfizma konvertaze angiotenzina I (ACE) genotipa. Hipertrofija leve komore (HLK) veoma je ĉesta u CKD (do 40% bolesnika), a prema pojedinim istraţivanjima i do 75% bolesnika na dijalizi razvije HLK (158,173). U literaturi nema podataka o meĊudejstvu modaliteta supstitucije Fe (IV prema peroralnom), ACE genotipa i odgovora na terapiju rHu Epo kod bolesnika na hemodijalizi, što je od kliniĉkog interesa za modulaciju protokola terapije anemije..., Introduction: Anemia is one of the major complications which occurs in chronic kidney disease (CKD), end-stage renal disease (ESRD) and on dialysis and is an independent predictor of morbidity and mortality in these patients (10,11). Decreased production of endogenous erythropoietin (Epo) and iron deficiency (Fe) are the two inseparable reasons of slowdown and disruption of differentiation and maturation of red blood cells in the bone marrow and are the main reasons that lead to reduced erythropoiesis in dialysis patients. Correction of the feremia status with regular compensation of Fe is crucial in treating anemia syndrome in patients with CKD, ESRD and dialysis. Certainly justified, the use of Fe medicines is on the rise, along with the implementation of recombinant human erythropoietin (rHu Epo), (49), and the recommended target HGB is adjusted from 130 to 105-110 g / L, based on the established complex security profile rHu Epo in patients with CKD (50-52). The current guideline of the treatment of anemia in hemodialysis patients (K/DIGO) liberalizes the use of Fe in patients with CKD (53). Angiotensin II directly increases the proliferation of erythroid progenitors in in vitro conditions (41,42). A greater need is expressed for the amount of rHu Epo in patients with ACE genotype II to achieve adequate correction of the blood count, compared to patients with the DD genotype on chronic ambulatory peritoneal dialysis (44). The cardiovascular status of patients on hemodialysis is strongly influenced by the degree of anemia and mediators of the renin-angiotensin system, which can be modulated by the influence of angiotensin converting polymorphism I (ACE) genotype. Left ventricular hypertrophy (LVH) is very common in CKD (up to 40% of patients), and according to some studies up to 75% of patients on dialysis develop LVH (158,173). In the literature there is no data on interacting modalities of Fe substitution (IV towards peroral), ACE genotype and responses to rHu E

Â

BackgroundIntravenous iron use in hemodialysis patients has greatly increased over the last decade, despite limited studies on the safety of iron.MethodsWe studied the association of receipt of intravenous iron with hospitalizations in an incident cohort of hemodialysis patients. We examined 9544 patients from Dialysis Clinic, Inc. (DCI). We ascertained intravenous iron use from DCI electronic medical record and USRDS data files, and hospitalizations through Medicare claims. We examined the association between iron exposure accumulated over 1-, 3- or 6-month time windows and incident hospitalizations in the follow-up period using marginal structural models accounting for time-dependent confounders. We performed sensitivity analyses including recurrent events models for multiple hospitalizations and models for combined outcome of hospitalization and death.ResultsThere were 22 347 hospitalizations during a median follow-up of 23 months. Higher cumulative dose of intravenous iron was not associated with all-cause, cardiovascular or infectious hospitalizations [HR 0.97 (95% CI: 0.77-1.22) for all-cause hospitalizations comparing >2100 mg versus 0-900 mg of iron over 6 months]. Findings were similar in models examining the risk of hospitalizations in 1- and 3-month windows [HR 0.88 (95% CI: 0.79-0.99) and HR 0.88 (95% CI: 0.74-1.03), respectively] or the risk of combined outcome of hospitalization and death in the 6-month window [HR 0.98 (95% CI: 0.78-1.23)].ConclusionsHigher cumulative dose of intravenous iron may not be associated with increased risk of hospitalizations in hemodialysis patients. While clinical trials are needed, employing higher iron doses to reduce erythropoiesis-stimulating agents does not appear to increase morbidity in routine clinical care.

This randomized trial evaluated ferric carboxymaltose without erythropoiesis-stimulating agents (ESA) for correction of anemia in cancer patients with functional iron deficiency. Patients on treatment for indolent lymphoid malignancies, who had anemia [hemoglobin (Hb) 8.5-10.5 g/dL] and functional iron deficiency [transferrin saturation (TSAT) <= 20 %, ferritin >30 ng/mL (women) or >40 ng/mL (men)], were randomized to ferric carboxymaltose (1,000 mg iron) or control. Primary end point was the mean change in Hb from baseline to weeks 4, 6 and 8 without transfusions or ESA. Difficulties with patient recruitment led to premature termination of the study. Seventeen patients (8 ferric carboxymaltose and 9 control) were included in the analysis. In the ferric carboxymaltose arm, mean Hb increase was significantly higher versus control at week 8 (p = 0.021). All ferric carboxymaltose- treated patients achieved an Hb increase >1 g/dL (control 6/9; p = 0.087), and mean TSAT was >20 % from week 2 onwards. No treatment-related adverse events were reported. In conclusion, ferric carboxymaltose without ESA effectively increased Hb and iron status in this small patient population.

Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48 m in the immediate intervention group and decreased a mean 11.45±49.46 m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46 g/dL in the immediate intervention group and declined a mean 0.39±0.85 g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.

Background: Treatment with parenteral iron causes oxidative stress, inflammation and endothelial dysfunction. Ferric carboxymaltose (FCM) is a new preparation of non-dextran iron which, due to its pharmacokinetics and stability, may induce less toxicity than other iron molecules. The aim of this study was to analyse the effect of FCM on inflammation and adhesion molecules in chronic kidney disease (CKD). Methods: Forty-seven patients with predialysis CKD and irondeficiency anaemia received a single dose of FCM (15mg/kg, maximum dose 1 gram). At baseline and after 60 minutes (acute effect) and after 3 weeks and 3 months (sub-acute effect), we determined inflammatory markers: C-reactive protein (CRP), interleukin-6 (IL-6) and endothelial dysfunction: intercellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM). Results: Treatment with FCM was associated with a significant increase in haemoglobin levels: 10 (0.7) vs. 11.4 (1.3)g/dl, p<.0001. CRP, IL- 6, ICAM and VCAM levels did not correlate with baseline haemoglobin or ferritin levels and there was no relationship between changes in these markers and those of haemoglobin after administration of FCM. No significant, acute or subacute changes occurred in any of the inflammatory or endothelial markers studied. Statin therapy was associated with lower VCAM concentrations. Conclusions: Treatment with high doses of FCM in patients with predialysis CKD has no proinflammatory effect and does not alter levels of adhesion molecules ICAM and VCAM in this population. © 2013 Revista Nefrología. Órgano Oficial de la Sociedad Española de Nefrología.

Patients with chronic kidney disease (CKD), especially those requiring maintenance hemodialysis treatments, may lose up to 3 g of iron each year because of frequent blood losses. Higher doses of erythropoiesis-stimulating agents (ESAs) may worsen iron depletion and lead to an increased platelet count (thrombocytosis), ESA hyporesponsiveness, and hemoglobin variability. Hence, ESA therapy requires concurrent iron supplementation. Traditional iron markers such as serum ferritin and transferrin saturation ratio (TSAT) (ie, serum iron divided by total iron-binding capacity [TIBC]), may be confounded by non-iron-related conditions. Whereas serum ferritin <200 ng/mL suggests iron deficiency in CKD patients, ferritin levels between 200 and 1,200 ng/mL may be related to inflammation, latent infections, malignancies, or liver disease. Protein-energy wasting may lower TIBC, leading to a TSAT within the normal range, even when iron deficiency is present. Iron and anemia indices have different mortality predictabilities, in that high serum ferritin but low iron, TIBC, and TSAT levels are associated with increased mortality, whereas hemoglobin exhibits a U-shaped risk for death. The increased mortality associated with targeting hemoglobin above 13 g/dL may result from iron depletion-associated thrombocytosis. Intravenous (IV) iron administration may not only decrease hemoglobin variability and ESA hyporesponsiveness, it may also reduce the greater mortality associated with the much higher ESA doses that have been used in some patients when targeting higher hemoglobin levels.

The aim of this thesis was to determine the relevant dose of arbepoetin-alfa (DA) in patients with lymphoproliferative diseases (LPD) and chemotherapy induced anemia (CIA), to study the clinical impact of intravenous (IV) iron supplementation combined with epoetin beta treatment, to identify factors that might predict hemoglobin (Hb) response to treatment with epoetins and to investigate safety of DA. A dose-finding phase II study was able to assess a reasonable DA dose of 2.25 μg/kg once weekly for the treatment of CIA in patients with LPD. Dose-response trends were observed for the different dose cohorts although not statistically significant for any of the endpoints. However a significantly higher proportion of patients achieved Hb response (increase ≥2 g/dL) in the combined DA groups than in placebo (P<0.001). A larger pivotal phase II trial was performed in a similar setting o confirm that the dose 2.25μg/kg once weekly was appropriate and safe. The proportion of patients achieving Hb response was significantly higher in the DA group (60%) than in the placebo group (18%) (P<0,001) and resulted in higher mean changes in Hb than placebo from baseline, 2.66 g/dl versus 0.69 /dl. Also a significantly lower proportion of patients in the DA group (31%) received RBC tranfusions than in the placebo group (48%). The short-term safety of DA with the tested dose was confirmed. The efficacy of DA was consistent for all end points independent of malignancy type or baseline endogenous erythropoietin serum levels. The correction of moderate anemia in truly iron repleted patients with clinically stable LPD not receiving hemotherapy or RBC transfusions with epoetin beta treatment, with or without IV iron treatment was studied in an open label randomized trial. Also the impact on iron kinetics was assessed. The mean change in Hb concentration from baseline to end of treatment (EOT ) was 2.91 versus 1.50 g/dL respectively (P<0.0001). There was a significant (P<0.0001) difference

This randomized study assessed if intravenous iron improves hemoglobin (Hb) response and permits decreased epoetin dose in anemic (Hb 9-11 g/dl), transfusion-independent patients with stainable iron in the bone marrow and lymphoproliferative malignancies not receiving chemotherapy. Patients (n=67) were randomized to subcutaneous epoetin beta 30 000 IU once weekly for 16 weeks with or without concomitant intravenous iron supplementation. There was a significantly (P<0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase >or=2 g/dl was significantly higher in the iron group (93%) than in the no-iron group (53%) (per-protocol population; P=0.001). Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference. The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (P=0.029) and after 15 weeks approximately 10 000 IU (>25%) lower in the iron group, as was the total epoetin dose (P=0.051). In conclusion, the Hb increase and response rate were significantly greater with the addition of intravenous iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.

n/a, Background and aims: Hypophosphatemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside (IIM). Both intravenous iron preparations are used to treat iron deficiency of different causes and across medical disciplines. The objectives of this study were to determine frequency, severity, duration and risk factors of incident hypophosphatemia as well as to describe potential clinical complications of hypophosphatemia after treatment with FCM and IIM. Methods: A meta-analysis of prospective clinical trials reporting on hypophosphatemia after treatment with FCM or IIM was carried out after a systematic literature search. Case reports and case series of symptomatic hypophosphatemia after either iron preparation were also analyzed in a pooled analysis of symptoms and laboratory findings. In addition, two cohort studies, one in children, one in gastroenterology clinic patients were performed. Results: Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphatemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%; p<0.001), and significantly greater mean decreases in serum phosphate (0.40 versus 0.06 mmol/L; p<0.001). Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphatemia. In a cohort of gastroenterology clinic patients, the risk of developing hypophosphatemia was greater after FCM compared with IIM (45.5 % vs. 4 %). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after treatment with FCM (32.7%). A significant increase in the active form of the phosphate regulating hormone FGF-23 was observed after i.v. iron treatment in patients who developed hypophosphatemia. Hypophosphatemia occurred in 17.1% of children after the first FCM dose. Gender-specific differences were observable in phosphate dynamics, with girls being more prone to a decrease in p, Dr. med. univ. Benedikt Schäfer, Abweichender Titel laut Übersetzung der Verfasserin/des Verfassers, Dissertation Medical University of Innsbruck 2020

Introduction: Perioperative allogeneic red blood transfusions (ARBT) are associated with impaired short and long term outcomes. Consequently, perioperative ARBT should be avoided, yet preoperative anaemia increases this need. The study aimed to compare the efficacy of preoperative intravenous (IVI) and oral iron (OI) in reducing ARBT use in anaemic patients undergoing colorectal cancer (CRC) surgery. Methods: 116 anaemic patients with non-metastatic CRC adenocarcinoma were recruited preoperatively and randomised to receive either OI (ferrous sulphate) or IVI (ferric carboxymaltose). Perioperative changes in Haemoglobin (HB) and ARBT were recorded across groups. Parametric data was compared with 2 tailed T-test and non-parametric paired data with Wilcoxon Rank test, and Mann-Whitney U test. Nominal data was compared with 2-tailed Chi squared test. Results: There was no difference in demographic data between groups. HB levels at recruitment were comparable (OI 10.4g/dL 95%CI 10.1-10.7; IVI 10.2g/dL 95%CI 9.8-10.5, P=0.24), as was median treatment duration (OI 21 days IQR 15-33; IVI 21 days IQR 15-34, P=0.75). However, HB levels were higher on the day of Surgery in IVI (11.9g/dL 95%CI 11.5-12.3 vs OI 11g/dL 95%CI 10.6-11.4, P<0.01). Median preoperative HB change in patients not transfused preoperatively was higher in IVI (1.5g/dL IQR 0.9-2.6 vs OI 0.5g/dL IQR-0.1-1.3, P<0.01). There were fewer anaemic patients at surgery in the IVI group after treatment (75% vs 90%, P<0.05). OI patients received a mean 0.63u (95%CI 0.26-1) from recruitment to day 28 postoperatively vs mean 0.47u (95%CI 0.1-0.84) for IVI. Neither number of patients transfused (P=0.33) nor mean units transfused (P=0.54) differed over this period. When patients with heavy intraoperative losses (>1.5L) were excluded in subgroup analysis, a significant difference in mean units of blood transfused was seen up to 7 days post operatively (n= 108; OI 0.6u 95%CI 0.23-0.96; IVI 0.16u 95%CI 0.01-0.3, P< 0.05) and