The Danish national haemoglobinopathy screening programme: Report from 16 years of screening in a low-prevalence, non-endemic region.

The Danish national haemoglobinopathy screening programme seeks to determine parental haemoglobinopathy carrier state antenatally. In this retrospective register-based study, we evaluated the 16-year trajectory of this programme, utilising the Danish Red Blood Cell Centre's laboratory database, covering approximately 77% of the Danish population. During the study period, we observed a substantial increase in annual diagnostic examinations performed, from 389 in 2007 to 3030 in 2022. Women constituted 88% of these cases, aligning with the emphasis of the screening programme. Of these, 54% of women of reproductive age (15-40 years) and 10% of women >40 years were specified as pregnant. During our study period, 61 children were born with a severe haemoglobinopathy, out of which 23 children were born from mothers not residing in Denmark during their first trimester thus not included in the screening programme. Prenatal invasive testing was performed for 60 fetuses, identifying 12 with homozygous or compound heterozygous haemoglobinopathy. The Danish haemoglobinopathy screening programme has provided screening, information and reproductive choices for numerous families. During the study period, screening for haemoglobinopathies has been steadily increasing and is expected to continue to increase. Awareness of and adherence to the screening programme is subject of further investigation and optimisation.

Iron supplements in pregnant women with normal iron status: A systematic review and meta-analysis.

INTRODUCTION: Effects of daily iron supplementation in iron replete pregnancy are unclear. This systematic review aimed to assess benefits and harms of oral iron supplements in pregnant women without anemia and iron deficiency. MATERIAL AND METHODS: We predefined and registered a protocol in PROSPERO (CRD42020186210) and performed the review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We searched for randomized clinical trials (RCTs) and observational studies comparing daily oral iron supplementation with no iron supplements in non-anemic iron replete pregnant women. Searches were conducted in MEDLINE (by PubMed), EMBASE (by OVID), Cochrane Library, and ClinicalTrials.gov from inception to September 2022 without language restrictions. Two authors independently screened records, extracted data, and assessed risk of bias using the revised Cochrane risk of bias tool (RoB2). One author read full-texts, assessed certainty of evidence by GRADE and conducted meta-analyses using a random-effects model. Primary outcomes included iron deficiency anemia, iron deficiency, hemoglobin >130 g/L, elevated iron status, small for gestational age newborns, low birthweight newborns, preterm birth, and congenital anomalies. RESULTS: Eight RCTs (2822 women) but no observational studies were eligible for inclusion. Daily oral iron supplementation in pregnancy probably reduces iron deficiency anemia at term (risk ratio [RR]: 0.51, 95% confidence interval [CI]: 0.38-0.70; 4 RCTs, 1670 women; I2 = 13%; moderate-certainty evidence) and the incidence of low birthweight babies (RR: 0.30, 95% CI: 0.13-0.68; 2 RCTs, 361 infants; I2 = 0%; moderate-certainty evidence). In addition, it may reduce iron deficiency at term (RR: 0.74, 95% CI: 0.60-0.92; 4 RCTs, 1663 women; I2 = 58%; low-certainty evidence) and the incidence of small for gestational age babies (RR: 0.39, 95% CI: 0.17-0.86; 1 RCT, 213 infants; I2 not estimable; low-certainty evidence). CONCLUSIONS: Daily iron supplementation in iron replete non-anemic pregnant women probably reduces the risk of maternal iron deficiency anemia at term and low birthweight.

Intravenous ferric derisomaltose versus oral iron for persistent iron deficient pregnant women: a randomised controlled trial.

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 (ferritin < 30 µg/L). METHODS: 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 non-anaemic (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 follow-up, 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. CLINICAL TRIAL REGISTRATION: European Clinical Trials Database: EudraCT no.: 2017-000776-29 (3 May 2017); ClinicalTrials.gov: NCT03188445 (13 June 2017). The trial protocol has been published: https://dx.doi.org/10.1186%2Fs13063-020-04637-z .

Maternal first trimester iron status and its association with obstetric and perinatal outcomes.

PURPOSE: To assess the following in singleton pregnant women: (1) associations between first trimester iron deficiency and obstetric and perinatal outcomes, (2) overall first trimester iron status and (3) post-treatment iron status after intensified iron supplementation. METHODS: A prospective cohort study was conducted with linkage of first trimester hemoglobin and plasma ferritin with obstetric and perinatal data from a hospital database. Blood sample data were obtained from a Danish University Hospital. The cohort was divided into groups according to ferritin and hemoglobin: (1) iron-deficient anemic (ferritin < 30 ng/mL and Hb < 110 g/L), (2) iron-deficient non-anemic (ferritin < 30 ng/mL and Hb ≥ 110 g/L), and (3) iron-replete non-anemic (ferritin 30-200 ng/mL and Hb ≥ 110 g/L). Obstetric and perinatal outcomes in each iron-deficient group were compared to the iron-replete non-anemic group using multivariable logistic regression. The effect of 4 weeks intensified iron supplementation on hemoglobin and ferritin was assessed by groupwise comparisons. RESULTS: The cohort comprised 5763 singleton pregnant women, of which 14.2% had non-anemic iron deficiency, and 1.2% had iron-deficiency anemia. Compared to iron-replete non-anemic women, iron-deficient anemic women had a higher risk of gestational diabetes (aOR 3.8, 95% CI 1.4-9.0), and iron-deficient non-anemic women had a higher risk of stillbirth (aOR 4.0, 95% CI 1.0-14.3). In group 1 and 2, 81.5% and 67.7% remained iron-deficient after intensified iron supplementation. CONCLUSION: Iron-deficiency anemia was associated with gestational diabetes, and non-anemic iron deficiency with stillbirth, although risk estimates were imprecise due to few events. Iron deficiency was present in 15.4% and often persisted despite 4 weeks intensified iron supplementation.

Iron concentration in breast milk normalised within one week of a single high-dose infusion of iron isomaltoside in randomised controlled trial.

AIM: We compared the iron concentration in breast milk after a single high dose of intravenous iron isomaltoside or daily oral iron for postpartum haemorrhage. METHODS: In this randomised controlled trial, the women were allocated a single dose of intravenous 1200 mg iron isomaltoside or oral iron at a mean daily dose of 70.5 mg. We included 65 women with sufficient breast milk three days after inclusion - 30 from the intravenous iron group and 35 from the oral iron group - and collected breast milk and maternal blood samples three days and one week after allocation. RESULTS: The mean (±SD) iron concentration in breast milk in the intravenous and oral groups was 0.72 ± 0.27 and 0.40 ± 0.18 mg/L at three days (p < 0.001) and 0.47 ± 0.17 and 0.44 ± 0.25 mg/L after one week (p = 0.64). Baseline samples were not available that soon after birth. CONCLUSION: A single high dose of intravenous iron isomaltoside for postpartum haemorrhage led to a transient increase in the iron concentration in breast milk three days after treatment compared with oral iron. The difference disappeared one week after treatment, and mean iron concentrations were within the normal range in all samples.

Less Is More? Impact of Single Venous Anastomosis on the Intrinsic Transit Time of Free Flaps.

Background The number of venous anastomoses advisable for a free flap continues to be controversial. Intrinsic transit time (ITT) is the time it takes dye during indocyanine green (ICG) microangiography to travel from the arterial to the venous anastomosis. ITT provides information on blood flow velocity and can predict postoperative circulatory complications. This study investigated the effect of the number of venous anastomoses on ITT. Methods The study enrolled 126 patients who had undergone microsurgical reconstruction and intraoperative ICG microangiography. Selection was limited to free gracilis and anterolateral thigh flaps as flaps with a single venous system. The retrospective assessment included reconstruction characteristics of the flaps, clinical outcome, ITT, and the number of venous anastomoses. Results The two groups were homogenous in terms of reconstruction characteristics. The single-venous anastomosis group (n = 75) had a reduced ITT (23.6 ± 11.7 vs. 43.8 ± 23.7 seconds; p < 0.001) compared with the double-anastomosis group (n = 51). A shorter ITT resulted in a significant reduction in the risk of reexploration for anastomotic thrombosis (OR 0.96; p = 0.024). Despite this, a higher reexploration rate tended to occur in the single-venous anastomosis group (9.3 vs. 7.8%; p = 1.0). Conclusion The results highlight the effect of shortening the ITT (thromboprotective blood flow acceleration) by using only one venous anastomosis. However, if the ITT is already at a low enough level with two veins, restriction to one vein does not appear to result in a reduced reexploration rate. For these flaps, the advantages of double-venous anastomosis prevail in terms of a backup drainage.

Evaluation of multi-professional obstetric skills training for postpartum hemorrhage.

OBJECTIVE: To evaluate the effect of multi-professional obstetric skills training on the incidence of postpartum hemorrhage (PPH) indicated by red blood cell (RBC) transfusion and time delay in surgical interventions before, during, and after implementation of the training. DESIGN: A database audit. SETTING: University hospital, Rigshospitalet, Copenhagen, Denmark. POPULATION: Women receiving red blood cell (RBC) transfusion up to seven days postpartum before (2003), during (2005), and after (2007) the introduction of training. METHODS: Linkage of the Danish Medical Birth Registry and the local transfusion database, followed by audit of medical records. We identified 148 women with RBC transfusion for PPH in 10 461 deliveries and assessed the cause of PPH, surgical interventions and transfusion data. MAIN OUTCOME MEASURES: RBC transfusion. Delay to surgical intervention. RESULTS: RBC transfusion rates for PPH were 1.5% (2003), 1.6% (2005), and 1.2% (2007) (not statistically significant). The transfusion rates did not change after vaginal delivery but decreased after cesarean section [2.4, 2.1 and 0.7% (p<0.01)]. Transfusion requirements and pre-transfusion hemoglobin values did not change. The median time from delivery to manual removal of the placenta increased non-significantly (64, 70 and 75 minutes). The median time from decision to manual removal of the placenta remained unchanged (30 minutes). CONCLUSION: There was no effect of multi-professional obstetric skills training on the rate of RBC transfusion for PPH. The unchanged long delay in handling a retained placenta indicates a need for multi-disciplinary training in collaboration with staff from anesthesiology and the operation theater.

The intrinsic transit time of free microvascular flaps: clinical and prognostic implications.

BACKGROUND: Microscope-integrated indocyanine green near-infrared videoangiography (ICGA) is a new method for the intraoperative assessment of vascular flow through microvascular anastomoses. The intrinsic transit time (ITT) describes the time period from the dye appears at the arterial anastomosis (t(1)) till it reaches the suture line of the venous anastomosis (t(2)). As the transit time reflects blood flow velocity within the flap, prolonged ITT might correlate with low blood flow and a higher rate of postoperative thrombosis. We performed a clinical trial evaluating the association between intraoperative free flap transit time and early anastomotic complications in elective microsurgery. METHODS: One hundred consecutive patients undergoing elective microsurgical procedures underwent intraoperative ICG angiography (ICGA). In patients with anastomotic patency, angiograms were retrospectively reviewed and the intrinsic transit time was calculated. Postoperative outcome was registered and compared with the ITT. End points included early reexploration surgery and flap loss within the first 24 hours after surgery. RESULTS: Fourteen patients were excluded from the study due to technical anastomotic failure. The overall flap failure rate was 6% (5/86); the incidence of early re-exploration surgery was 10% (9/86). With a median of 31 seconds patients with an uneventful postoperative course showed significantly shorter ITTs than patients with flap loss or early postoperative reexploration (median: >120 seconds). An optimal cut-off value of ITT > 50 seconds was determined to be strongestly associated with a significantly increased risk of at least one positive end point. CONCLUSIONS: This study demonstrates a significant predictive value of the intrinsic flap transit time for the development of flap compromise and early re-exploration surgery.

Sensitivity and specificity of ICG angiography in free flap reexploration.

Microscope-integrated indocyanine green near-infrared videoangiography (ICGA) is a new imaging technique to assess vascular flow through diminutive vessels used in microvascular surgery. The purpose of this investigation was to evaluate the diagnostic accuracy of ICGA in detecting microvascular thrombosis in reexploration surgery. Patients undergoing emergent reexploration surgery after free tissue transfer were enrolled in this clinical study. After the patients had been returned to the operating room the pedicle vessels were exposed and a microangiography was performed. Independent of the result, the anastomoses were opened and surgically explored. Sensitivity and specificity was calculated, using the result of exploration surgery as a reference standard. Of 200 free flaps 20 (10%) underwent reexploration surgery. The most common surgical finding was microvascular thrombosis (55%). In one case vascular compromise was due to confusion of artery and vein with anastomosis of two veins. In 40% of patients an intact vascular pedicle was found. The sensitivity and specificity of ICGA to detect microvascular thrombosis was 100% and 86%, respectively. ICGA provides an excellent diagnostic accuracy for detecting microvascular thrombosis in reexploration surgery. Routine implementation of this technique may expedite a correct diagnosis and facilitate the surgical approach by preventing unnecessary surgical manipulation of intact anastomoses.

Association between blood loss at delivery and fatigue in the puerperium: a prospective longitudinal study.

Objective: The objective was to investigate the association between blood loss at delivery and physical and mental fatigue during the first 12 weeks postpartum. We also investigated the association between hemoglobin and postpartum fatigue.Methods: We performed a single center prospective longitudinal study of healthy women with a singleton delivery. Women completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale at 3 and 7 d, 3, 8 and 12 weeks postpartum. The hemoglobin level was measured at inclusion (baseline).Results: A total of 196 women with blood loss at delivery ranging from 100 to 2800 mL were included in the study. At 12 weeks follow-up the response rate was 92% (n = 181). We found a significant association between blood loss and scores of physical and mental fatigue within the first week postpartum. When adjusted for bleeding, hemoglobin measured at inclusion was not associated with fatigue at any given time point.Conclusions: The amount of measured blood loss was significantly associated with increased physical and mental fatigue in the first week postpartum. When adjusted for bleeding, baseline hemoglobin was no longer associated with physical and mental fatigue.

Intravenous iron isomaltoside versus oral iron supplementation for treatment of iron deficiency in pregnancy: protocol for a randomised, comparative, open-label trial.

BACKGROUND: Iron deficiency is common in pregnancy. If left untreated, iron deficiency can lead to iron deficiency anaemia, which is a condition related to maternal and neonatal morbidity. The prevalence of iron deficiency increases through the trimesters, which means that women with iron deficiency in the beginning of pregnancy also have a great risk of developing iron deficiency anaemia during pregnancy. Standard treatment is oral iron in individualised intensified doses based on screening values in 1st trimester. Maternal symptoms of iron deficiency and iron deficiency anaemia include fatigue, reduced physical performance, and restless legs syndrome (RLS). Severe anaemia may cause dizziness, dyspnea, palpitation, orthostatism, and syncope, and it decreases the woman's ability to cope with blood loss during delivery. The anaemia may also compromise contractility in the uterine musculature increasing the risk for prolonged labour, caesarean section, and postpartum haemorrhage. Foetal iron deficiency may cause low birthweight and adversely affect foetal and early childhood brain development with long-term deficits. METHODS: In this randomised comparative, open-label, single-centre, phase IV trial, 200 pregnant women between 14 and 21 weeks of gestation who have iron deficiency after 4 weeks of standard treatment will be randomised 1:1 to either a single 1000 mg dose of intravenously administered ferric derisomaltose/iron isomaltoside 1000 or a fixed dose of 100 mg oral ferrous fumarate containing 60 mg ascorbic acid. The primary endpoint is to prevent iron deficiency anaemia defined by a low level of haemoglobin throughout the trial. Other endpoints include other haematological indices of iron deficiency and anaemia, clinical outcomes by questionnaires, and collection of adverse events. Explorative endpoints by medical record follow-up include complications up to 7 days after delivery. DISCUSSION: This trial will provide evidence on how to prevent iron deficiency anaemia. The trial population represents a clinical reality where pregnant women often have sustained iron deficiency despite an increased oral iron dose. Thus, this evidence can be used to consider the optimal 2nd line of treatment in iron-deficient pregnant women. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database 2017-000776-29. Registered on 3 May 2017. ClinicalTrials.gov NCT03188445 . Registered on 15 June 2017.

Assessment of the patency of microvascular anastomoses using microscope-integrated near-infrared angiography: a preliminary study.

BACKGROUND: : Technical problems at the site of the anastomosis compromise an underappreciated proportion of microsurgical free tissue transfers. Intraoperative identification of technical errors may be able to prevent reexploration surgery and early flap failure. We report the first human study on a new microscope-integrated fluorescence angiography technique, which allows for intraoperative imaging of the anastomotic site. METHODS: : Fifty consecutive patients undergoing reconstructive microsurgical procedures were enrolled in the study. Intraoperative near infrared indocyanine green videoangiography (ICGA) was performed on all microsurgical anastomoses, after they had been assessed by the operating surgeon by conventional clinical patency tests. Anastomoses deemed to be occluded by the ICG-angiography were intraoperatively revised, and the result of revision was compared with angiographic findings. RESULTS: : In 11/50 (22%) of patients, where the surgeon had classified the anastomoses as patent, microangiography identified a total luminal occlusion (six) and/or significant alterations in blood flow (five), potentially predisposing toward postoperative flap failure. Intraoperative revision confirmed angiographic findings in 100% of cases, and was always associated with flap survival. The decision not to revise despite anastomotic occlusion by the intraoperative angiogram was always followed by flap loss or early reexploration. A delayed return of venous blood from the flap predisposed toward postoperative flap failure. CONCLUSIONS: : Hand-sewn anastomoses are subject to technical errors, and conventional patency tests have a low sensitivity for revealing anastomotic failure. Microscope integrated microangiography is an excellent method for identifying significant anastomotic problems, which would have otherwise gone unnoticed. The potential impact on early flap failure and reexploration surgery is considerable. (c) 2009 Wiley-Liss, Inc. Microsurgery 2009.

Intravenous iron isomaltoside treatment of women suffering from severe fatigue after postpartum hemorrhage.

Background and objectives: To explore if intravenous iron isomaltoside (Monofer®) leads to a better relief of fatigue than current treatment practice with oral iron in women suffering from severe fatigue after postpartum hemorrhage. Materials and methods: This is a subanalysis of a single-center, open-label, randomized controlled trial conducted in women suffering from postpartum hemorrhage. Participants were randomized 1:1 to 1200 mg iron isomaltoside or current treatment practice with oral iron. We measured fatigue by the Multidimensional Fatigue Inventory (MFI) and Edinburgh Postnatal Depression Scale, and determined hematological parameters. The subanalysis includes all participants with a high fatigue score (MFI physical fatigue score >15) at inclusion. The primary endpoint was aggregated change in physical fatigue score from inclusion to 12 weeks postpartum with a predefined minimum clinically relevant difference of 1.8. The trial is registered at ClinicalTrials.gov (identifier: NCT01895218). Results: A total of 85 women had a high fatigue score at inclusion. The aggregated change in physical fatigue score was -2.3 (confidence interval 95%: -3.3; -1.3) (p < .0001) in favor of iron isomaltoside. Significant differences in other fatigue and depression scores and hematological parameters were observed and all in favor of iron isomaltoside. There were no differences in side effects between the groups. Conclusions: In women suffering from severe fatigue after postpartum hemorrhage, a single dose of iron isomaltoside is associated with a statistically significant and clinically relevant reduction in aggregated physical fatigue within 12 weeks after delivery, when compared to current treatment practice with oral iron and with a similar safety profile.

Impairment of the Developing Human Brain in Iron Deficiency: Correlations to Findings in Experimental Animals and Prospects for Early Intervention Therapy.

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In early embryonic life, iron is already needed for proper development of the brain with the proliferation, migration, and differentiation of neuro-progenitor cells. This is underpinned by the widespread expression of transferrin receptors in the developing brain, which, in later life, is restricted to cells of the blood-brain and blood-cerebrospinal fluid barriers and neuronal cells, hence ensuring a sustained iron supply to the brain, even in the fully developed brain. In embryonic human life, iron deficiency is thought to result in a lower brain weight, with the impaired formation of myelin. Studies of fully developed infants that have experienced iron deficiency during development reveal the chronic and irreversible impairment of cognitive, memory, and motor skills, indicating widespread effects on the human brain. This review highlights the major findings of recent decades on the effects of gestational and lactational iron deficiency on the developing human brain. The findings are correlated to findings of experimental animals ranging from rodents to domestic pigs and non-human primates. The results point towards significant effects of iron deficiency on the developing brain. Evidence would be stronger with more studies addressing the human brain in real-time and the development of blood biomarkers of cerebral disturbance in iron deficiency. Cerebral iron deficiency is expected to be curable with iron substitution therapy, as the brain, privileged by the cerebral vascular transferrin receptor expression, is expected to facilitate iron extraction from the circulation and enable transport further into the brain.

Effects of statins on renal sodium and water handling: acute and short-term effects of atorvastatin on renal haemodynamics, tubular function, vasoactive hormones, blood pressure and pulse rate in healthy, normocholesterolemic humans.

BACKGROUND: Statins have a beneficial effect on cardiovascular morbidity and mortality due to a reduction in plasma cholesterol. However, statins seem to have effects beyond the lowering of plasma cholesterol. We hypothesize that these effects are caused by an effect on renal function. METHODS: We measured the effects of atorvastatin (AS) on renal function in two randomized, placebo-controlled, double-blinded and crossover studies in healthy man. In an acute trial (Study 1), 19 subjects received either 80 mg AS as a single dose or placebo. In a short-term trial (Study 2), 20 subjects received either 80 mg AS or placebo daily for 4 weeks. In both studies glomerular filtration rate (GFR), renal plasma flow (RPF), plasma concentrations of angiotensin II (Ang II), renin (PRC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), aldosterone (Aldo), vasopressin (AVP) and blood pressure (BP) were determined. RESULTS: In Study 1 AS decreased fractional excretion of sodium (FE(Na)) significantly (P = 0.035), but very modestly, and reduced diastolic BP (P = 0.024). Apart from this, we found no significant differences in GFR, RPF, tubular function and vasoactive hormones in either Study 1 or 2. CONCLUSIONS: An acute dose of AS decreased FE(Na) and DBP in healthy humans. The reduction in fractional urinary sodium excretion was very modest and transitory, and most likely secondary to the fall in diastolic blood pressure (DBP). However, renal haemodynamics, tubular function, vasoactive hormones and blood pressure were unchanged during short-term statin treatment in healthy man.

Intravenous iron treatment in the puerperium.

Iron deficiency and anaemia in the puerperium are associated with several important clinical consequences, most prominently physical fatigue. Current treatment practice with oral iron supplementation is associated with gastrointestinal side-effects and subsequent poor compliance. Red blood cell transfusion is also widely used to treat severe postpartum anaemia, though accumulating evidence questions its risk-benefit ratio. Intravenous iron has in previous studies been associated with fast improvement of haemoglobin and iron biochemical markers in the treatment of postpartum anaemia, but there is a lack of studies on patient reported outcomes.
 The thesis is based on three studies of intravenous iron (Monofer, iron isomaltoside) as an alternative to current treatment practice in postpartum iron deficiency and anaemia.
The first study is a randomised controlled trial comparing a high single-dose iron infusion with oral iron in women after postpartum haemorrhage without severe anaemia. The primary outcome was the aggregated change in physical fatigue within 12 weeks postpartum. We found a difference that was statistically significant, but less than the consensus-based and predefined minimal clinically relevant level. Across visits, particularly in the first weeks postpartum, we found statistically significant differences in fatigue and depression scores, all in favour of intravenous iron. We confirmed previous findings of a fast haematopoietic response and prompt replenishment of iron stores that persisted throughout the 12 weeks of follow-up. 
The second study, a randomised controlled pilot study, tested feasibility and exploratory outcomes of a high single-dose iron infusion compared with red blood cell transfusion for the treatment of severe postpartum anaemia. We found that randomisation could be feasible with some adjustments for a future study design. The difference in biochemical markers was larger than the patient-reported outcomes in the first week. A larger trial is needed to determine whether a high single-dose iron infusion is non-inferior to red blood cell transfusion in severe postpartum anaemia. 
The third study compared iron concentration in breast milk in a randomised sample of women receiving high single-dose iron infusion or oral iron. A high single-dose iron infusion lead to a transient increase in the iron concentration in breast milk, which remained within the normal range. 
In conclusion, iron isomaltoside seems to be associated with improved patient-reported outcomes compared to oral iron treatment, and in severe postpartum anaemia intravenous iron seems promising as an alternative to red blood cell transfusion.

Assessment of splanchnic perfusion by gastric tonometry in patients with acute hypovolemic burn shock.

OBJECTIVE: To compare the changes in pHi and intramucosal-arterial CO(2)-gap with invasive haemodynamic and global perfusion measurements during hypovolemic burn shock and to evaluate the sensitivity of these parameters as an early predictor of mortality in patients with extensive burns. DESIGN: Prospective, controlled, clinical study. SETTING: An eight-bed intensive burn care unit in a university-affiliated hospital. PATIENTS: Fifty severely burned patients with TBSA burned >25% BSA. METHODS: During the first 48h after burn, gastric intramucosal CO(2) was measured every 8h using automated air tonometry. pHi and intramucosal-arterial CO(2)-gap were calculated. Simultaneously invasive haemodynamic data were registered by the transpulmonary thermodilution technique, using the mean of triplicate injections. The intramucosal-arterial CO(2)-gradient and pHi were compared with haemodynamic and global perfusion data by regression analysis. Mean pHi and CO(2)-gap values at 8 and 24h after injury were compared between survivors and non-survivors to evaluate the prognostic significance of this parameter. RESULTS: Regression analyses revealed no or a negligible correlation between intramucosal and haemodynamic or perfusion data, even during the critical low flow-high resistance phase of resuscitation. Mean pHi and PCO(2)-gap at 8 and 24h did not differ significantly between survivors and non-survivors. CONCLUSION: Gastric tonometry is a poor indicator of splanchnic perfusion in patients with burn shock, even when all precautions are taken to prevent methodological errors. The intramucosal-arterial PCO(2)-gap and pHi do not distinguish survivors from non-survivors. Therefore, gastric tonometry does not seem to improve the ability to anticipate and avert regional anaerobic metabolism during burn shock and its routine use in these patients cannot be recommended.

Reproducibility of transpulmonary thermodilution measurements in patients with burn shock and hypothermia.

Thermal noise, including hypothermia and short-term variations in body temperature, has been reported to influence the accuracy and reproducibility of thermodilution measurements. This variation might theoretically limit the usefulness of this technique in patients with acute burns. We therefore sought to determine the reproducibility of hemodynamic parameters derived from arterial thermal dilution in patients with acute burns and hypothermia. This was a prospective, clinical study of 50 mechanically ventilated patients with burns involving more than 25% of the body surface area that were treated at an eight-bed intensive care burn unit in a university-affiliated hospital. A total of 750 arterial thermodilution measurements were analyzed using the COLD system. Triplicate measurements of the intrathoracic blood volume, cardiac output, total blood volume, and extravascular lung water were performed at regular intervals during the first 48 hours after the thermal injury. Reproducibility was assessed by the coefficient of variation of the triplicate measurements. The correlation of variation was less than 10% at all measurement times for cardiac output, intrathoracic blood volume, and total blood volume. For the extravascular lung water, the coefficient of variation ranged from 9.5% to 12.9%. A maximum of 12.9% was found at 48 hours after burn. No correlation was found between body core temperature and the reproducibility of intrathoracic blood volume index (r = 0.145), cardiac index (r = 0.217), or extravascular lung water index (r = 0.167). The parameters derived from arterial thermodilution show a clinically sufficient reproducibility in patients with acute burns associated with thermal instability.

Intravenous iron isomaltoside 1000 administered by high single-dose infusions or standard medical care for the treatment of fatigue in women after postpartum haemorrhage: study protocol for a randomised controlled trial.

BACKGROUND: Postpartum haemorrhage can lead to iron deficiency with and without anaemia, the clinical consequences of which include physical fatigue. Although oral iron is the standard treatment, it is often associated with gastrointestinal side effects and poor compliance. To date, no published randomised controlled studies have compared the clinical efficacy and safety of standard medical care with intravenous administration of iron supplementation after postpartum haemorrhage.The primary objective of this study is to compare the efficacy of an intravenous high single-dose of iron isomaltoside 1000 with standard medical care on physical fatigue in women with postpartum haemorrhage. METHODS/DESIGN: In a single centre, open-labelled, randomised trial, women with postpartum haemorrhage exceeding 700 mL will be allocated to either a single dose of 1,200 mg of iron isomaltoside 1000 or standard medical care. Healthy parturients with a singleton pregnancy will be included within 48 hours after delivery.Participants will complete structured questionnaires that focus on several dimensions of fatigue and mental health (Multidimensional Fatigue Inventory, Edinburgh Postnatal Depression Scale and the Postpartum Questionnaire), at inclusion and at follow-up visits after three days, one week, three weeks, eight weeks, and 12 weeks postpartum. The primary endpoint is the aggregated change in physical fatigue score within 12 weeks postpartum, as measured by a subscale of the Multidimensional Fatigue Inventory. The primary objective will be considered to have been met if an intravenous high single dose of iron isomaltoside 1000 is shown to be superior to standard medical care in women after postpartum haemorrhage regarding physical fatigue.For claiming superiority, we set the minimal clinically relevant difference between the mean scores at 1.8, and the assumed standard deviation at 4.2. Hence, 87 participants per treatment group are needed in order to demonstrate superiority; to provide an extra margin for missing data and dropouts, 200 women will be included. DISCUSSION: The study will provide evidence on relevant clinical outcomes beyond biochemical parameters for intravenous iron isomaltoside 1000 compared to standard medical care in women after postpartum haemorrhage. TRIAL REGISTRATION: This trial is registered with Clinicaltrials.gov (identifier: NCT01895218) on 26 June 2013.

Effect of crystalloid resuscitation and inhalation injury on extravascular lung water: clinical implications.

STUDY OBJECTIVE: Arterial thermal dilution with an integrated fiberoptic monitoring system (COLD Z-021; Pulsion Medical Systems; Munich, Germany) allows measurement of extravascular lung water (EVLW) and pulmonary permeability index (PPI). The aim of this study was to evaluate the widespread clinical assumption that early respiratory failure following burn and inhalation injury is due to interstitial fluid accumulation in the lung. DESIGN: Clinical, prospective study. SETTING: ICU of a university referral center of burn care. PATIENTS: Thirty-five severely burned adults (> 20% of body surface area). INTERVENTIONS: Resuscitation therapy was guided by the results of hemodynamic monitoring using the intrathoracic blood volume (ITBV) as a cardiac preload indicator. The resuscitation goals included a normalization of preload (ITBV > 850 mL/m(2)) and cardiac index (> 3.5 L/min/m(2)) within 24 h after ICU admission. Fluid loading was implemented to reach these goals. MEASUREMENTS AND RESULTS: One hundred forty lung water measurements were performed at 0 h, 12 h, 24 h, and 48 h after admission to the ICU. Significant elevation of EVLW and PPI was found in three measurements (2%) at 48 h after ICU admission, and was in one patient associated with inhalation injury. EVLW and PPI were not significantly different between patients with and without inhalation injury. No correlation was found between resuscitation volume and EVLW (r(2) = 0.02) or between the alveolar-arterial oxygen pressure difference and EVLW (r(2) = 0.017). Chest radiograph abnormalities were found in 2 of 22 patients with inhalation injury; these were not associated with increased values of EVLW. CONCLUSION: Early fluid accumulation in the lung in burned patients is very uncommon, even in the presence of inhalation injury. There is no evidence that thermal injury causes an increase in pulmonary capillary membrane permeability.