Role Of Intravenous Iron Over Nonsurgical Transfusions In Major Burns

Summary

Anemia is a frequent condition in burn patients due to a mixture of blood loss and chronic inflammation. Transfusions increase the probability of serious infections and reduce overall survival, especially when unrelated to perioperative blood loss. Once the surgical phase in burn patients is completed, the role of parenteral iron administration in the reduction of subsequent transfusions is not well established. Burn patients subjected to at least two surgeries and presenting progressive anemia after concluding the surgical phase, without major symptoms, were selected (n=12). Those patients with confirmed iron deficiency were treated with intravenous (i.v.) ferric carboxymaltose (n=8). Subsequently, these patients were compared with a group of 18 control patients selected from our historical database (n=1375), matching controls by age (±5 years), sex, and TBSA burn (±6%). The objective was to verify if i.v. iron administration reduced the need for blood transfusions after the surgical phase. The analysis concluded that none of the cases treated required transfusions compared to 44% of the controls. There were no side effects related to the i.v. iron infusion. This result suggests that i.v. iron supplementation with ferric carboxymaltose could be an alternative in anemic patients without major symptoms once the surgical phase is completed. Iron deficiency should be assessed and i.v. supplementation must be administered if required in burn patients showing progressive anemia.

Introduction

Anemia is frequent in burn patients with total body surface area (TBSA) involvement greater than 10%.¹ Anemia in patients with major burns is considered a combination of anemia due to blood loss, mainly due to surgery and procedures such as dressing changes and phlebotomies, and the anemia characteristic of critical patients.² Anemia in critical patients presents a profile of inflammation anemia. Among its main characteristics is an increase in hepcidin production, therefore causing a decrease of oral iron absorption in the duodenum, as well as sequestration or immobilization of iron in the endothelial reticulum’s macrophages.^3,4 Both mechanisms of anemia, due to blood loss and inflammatory status, suggest that iron deficiency in these patients could be corrected with i.v. iron supplementation.

Seventy-five percent of major burn patients (TBSA >20%) receive transfusions of blood products (packed red blood cells).⁵ Recently, it has been shown that 50% of transfusions in burn patients are not perioperative, with etiology attributed to the anemia of the critical patient. Seventeen percent of the whole transfusions in these patients occur in the postoperative period, after their last surgery.⁶ The deleterious effects of transfusions are widely known and confirmed in burn patients. The transfusion of blood products is one of the predictive factors in reducing survival rates in these patients. An infection risk of 13% has been estimated for each transfused red blood cell concentrate, with non-perioperative transfusions having the greatest influence on survival, thus suggesting a greater emphasis on strategies aimed at minimizing this procedure.⁵ In major burn patients the last blood transfusion takes place at 29 days on average, often after the end of the excision and grafting phase.²

The observation of progressive anemia in some patients in our unit, once the surgical treatment phase was completed, led us to study their iron metabolism. Considering the limited and delayed efficacy of oral iron treatment in burn patients, the resulting iron deficiency was treated with i.v. iron infusion. Subsequently, the requirements of new transfusions in patients treated with i.v. ferric carboxymaltose were analyzed and compared with a group of historical controls, to clarify whether i.v. iron supplementation in patients with iron deficiency reduced the need for transfusions after the surgical treatment phase in major burns.

Materials and methods

This study was conducted at the Virgen del Rocío University Hospital in Seville, Spain, a public university hospital with 2,000 beds. The Burn Unit at this hospital is the regional reference institution for a population of over 10.5 million. Between February and December 2016, a study of iron metabolism was performed in every burn patient undergoing at least two surgical interventions (excluding the initial escharotomy) and showing progressive anemia 48 hours after the last surgical procedure, excluding those with major symptoms of anemia.Anemia was defined as hemoglobin levels ≤9.5 g/dL and no active bleeding.

As serum ferritin was frequently elevated due to inflammation, measurement of serum soluble transferrin receptors (STfR) was later performed. When iron deficiency was suspected (Hb <10g/dL, transferrin saturation <20%) an adjusted dose of i.v. ferric carboxymaltose (FCM) was administered according to SmPC (Hb level and body weight).

The variables collected were: age, sex, TBSA burn, deep dermal burn injury percentage, the need for emergency escharotomy on admission, number of surgical procedures performed, length of hospital stay, red blood cell concentrates transfused in the surgical or perioperative phase (from hospitalization to 48 hours after last surgery performed), packed red blood cells transfused after the surgical phase (48 hours after the last surgery and later on), and total packed red blood cells (PRBC) transfused. Hemoglobin values before i.v. FCM infusion in the case group were also recorded.

Hemoglobin values in the patients in the control group were recorded on the fifth postoperative day (median day of hemoglobin records in the case group of patients). A search for controls was carried out for the 8 patients treated with carboxymaltose, considered as cases. Those controls were selected from the unit database comprising patients registered between January 2008 and December 2015 (n=1375). Controls were matched by age (±5 years), sex and TBSA burn (±6%). Given the small size of the case group and the larger number of available controls, up to a maximum of 3 was established for each treated patient.

Once the controls were selected, the medical records of each patient were reviewed. Usually controls had received oral iron supplements from admission during their hospital stay at the Burn Unit, a common non-protocolized practice for burns patients until 2014. The number of transfusions performed after last surgery in case and control groups were compared. Informed consent was obtained from all patients. From the control group, informed consent for the use of their data was obtained at hospitalization protocol.

Continuous variables have been expressed as median (interquartile range) and the Mann-Whitney U test was used to compare the two study groups. Qualitative variables were expressed as absolute and relative frequencies. The Chi-square test or Fisher’s exact test was used when necessary in group comparisons. For the statistical analysis, the SPSS 23.0 package was used. Values of p <0.05 were considered statistically significant.

Results

Twenty-three patients underwent surgery at least twice during the study period (Table I). Twelve of these patients presented progressive anemia once the surgery phase had finished and were initially selected for the study group. Four of them were excluded from the study, two patients due to extremely high levels of ferritin or active severe sepsis and the other two because of a rapidly progressive anemia requiring blood transfusion (hemoglobin <8 g/dL). Finally, iron metabolism tests in the other 8 patients suggested iron deficiency and they were considered for i.v. iron replacement with ferric carboxymaltose (Hb <10 g/dL, transferrin saturation <20%) (Table II).

Table I. Group where iron deficiency was evaluated (n=12 patients) versus group where iron deficiency was not evaluated (n=11 patients).

Table II. Iron metabolism in evaluated patients (n=12).

No transfusions were needed in these patients after i.v. iron administration, since hemoglobin values remained stable or not progressing until our unit transfusion thresholds (hemoglobin <8 g/dL, symptomatic patients). Post parenteral FCM, hemoglobin measurements were performed following clinical criteria, with the average measurement completed in 4.5 days (range: 3 to 6 days).

Eighteen controls were selected from our historical database (n=1375), matching controls by age (±5 years), sex and TBSA burn (±6%). Once case and control groups were established, no significant differences were found between patients in both groups regarding gender, the need for escharotomies, and the presence of inhalation associated with burn injury. Additionally, no significant differences were found regarding age, TBSA burn, deep burn areas, number of surgical procedures (excluding emergency escharotomy) or length of hospital stay. Moreover, no significant differences between groups were observed regarding hemoglobin values after the last surgical procedure (in an average range of 4 days). As for transfusions, no significant differences were detected between cases and controls regarding the number of PRBC transfused perioperatively (Table III).

Table III. Comparison of case and control groups.

However, important differences were found in the number of PRBC in the postsurgical phase (from 48 h after the last surgery). One out of every four patients in the control group (25%) was transfused at least two PRBC, while no transfusions were needed after i.v. ferric carboxymaltose administration in the case group (p=0.03).

When transfusions are considered a dichotomous variable, 44% of the patients in the control group received transfusions 48 hours after their last surgery (p=0.03), compared to 0% in the case group.

Regarding oral iron administration and its relationship with post-surgical PRBC transfusions in the control group, notable differences were also recorded, since none of the case patients received oral iron, as compared to 72% of the controls (n=13, p=0.02). Bivariate analysis showed no significant differences between the controls that received oral iron and required postoperative transfusion, compared to those receiving oral iron and no postsurgical transfusions (64 vs. 38%, p=0.6).

There were no treatment-related side effects after i.v. FCM infusion.

Discussion

Our results corroborate the relevance of anemia in critical burn patients, underlining the role played by iron deficiency. This deficit may be explained by two factors: the continuous blood losses through surgeries and treatments, and the patient’s inability to replenish iron deposits at an adequate rate. The last factor can be explained by decreased iron absorption in the duodenum due to high production of hepcidin for the underlying inflammation in a critical burn patient. ^7,8 In our study, oral iron supplementation has shown to be insufficient in the repletion of iron deposits and in reducing the need for blood transfusions, as described in published studies concerning other medical pathologies.⁹

The lack of progression of anemia after i.v. iron administration suggests that an iron deficiency correction is necessary to avoid transfusions once the surgical phase is over. This lack of progression of anemia appeared early, as seen in our results, even though hemoglobin increases associated with i.v. iron treatment have shown maximum effects 4 weeks after administration.¹⁰

The reduction in transfusions is low but, considering that non-perioperative transfusions are related to increased mortality in burn patients, their clinical relevance is high.⁵

The absence of serious adverse effects and the lack of association to infections of i.v. iron administration in critical patients support its use in iron deficiency anemia. ¹¹ Although a recent meta-analysis has not detected clear differences in the reduction of transfusions in critical patients treated with carboxymaltose,¹² the heterogeneity of the studies analyzed as well as the low doses used in them may question such results.³

In our study, a single dose of ferric carboxymaltose reduced the transfusions needed during the non-surgical phase in critical burn patients. However, larger series may be needed to confirm this outcome. This effect has been proven in the postoperative phase in patients with various major elective surgeries.¹³

Limitations to our study include a small sample size and the retrospective nature of the control group. Additionally, it is important to remark that hemoglobin levels after i.v. iron administration were not measured homogeneously on the same day to validate them as controls, as they were performed in the context of the usual clinical monitoring of patient process and were not part of a study protocol. However, hemoglobin levels of those treated with i.v. iron were similar to hemoglobin levels in control patients at discharge, which showed that the higher transfusion needs of the latter were not due to post-transfusion hemoglobin target elevation.

Conclusion

Given the usual need for several surgical procedures during the surgical phase treatment in critical burn patients, the results of this study may open a window of opportunities to the analysis of the role of i.v. iron in this phase. Recently, a correlation has been published between blood hepcidin levels and response to i.v. iron administration, which could help in the selection of i.v. supplementation subsidiary patients.¹⁴

Therefore, our results suggest that i.v. ferric carboxymaltose reduced the need for transfusions once the surgical phase was completed. Iron deficiency should be assessed and i.v. supplementation must be administered if required in burn patients showing progressive anemia. Due to the small sample size further studies are needed to confirm our results, in what we consider a pilot approachment to i.v. iron supplementation.