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Abstract

Background:

Reperfusion injury, characterized by oxidative stress and inflammation, poses a significant challenge in cardiac surgery with cardiopulmonary bypass (CPB). Deferoxamine, an iron-chelating compound, has shown promise in mitigating reperfusion injury by inhibiting iron-dependent lipid peroxidation and reactive oxygen species (ROS) production.

Objectives:

The objective of our study was to analyze and evaluate both the efficacy and safety of a new and promising intervention, that is, deferoxamine for ischemia-reperfusion injury (I/R).

Design:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines are used to perform the study.

Data sources and methods:

We conducted a systematic review following PRISMA guidelines to assess the efficacy and safety of deferoxamine in reducing I/R injury following CPB. A comprehensive search of electronic databases, namely, PubMed, Scopus, and Embase, yielded relevant studies published until August 18, 2023. Included studies evaluated ROS production, lipid peroxidation, cardiac performance, and morbidity outcomes.

Results:

(a) ROS production: Multiple studies demonstrated a statistically significant decrease in ROS production in patients treated with deferoxamine, highlighting its potential to reduce oxidative stress. (b) Lipid peroxidation: Deferoxamine was associated with decreased lipid peroxidation levels, indicating its ability to protect cardiac tissue from oxidative damage during CPB. (c) Cardiac performance: Some studies reported improvements in left ventricular ejection fraction and wall motion score index with deferoxamine.

Conclusion:

Our review shows that deferoxamine is an efficacious and safe drug that can be used to prevent myocardial I/R injury following CPB. It also highlights the need for trials on a larger scale to develop potential strategies and guidelines on the use of deferoxamine for I/R injury.

Keywords

cardiac performance cardiopulmonary bypass (CPB)deferoxamine lipid peroxidation myocardial infarction oxidative stress reperfusion injury

Introduction

When blood flow is restricted to any tissue in the body, it can result in ischemia, which triggers a series of chemical reactions leading to cellular dysfunction and necrosis. Many studies suggest that this is primarily caused by the depletion of cellular energy and the buildup of toxic metabolites. Therefore, the immediate and essential step to rescue tissue from ischemia is tissue reperfusion. However, paradoxically, reperfusion can worsen tissue damage, a phenomenon known as reperfusion injury.¹

Cardiopulmonary bypass (CPB) is a method of extracorporeal circulation designed to provide circulatory and respiratory assistance while also maintaining temperature control to enable cardiac and major vascular surgeries.² It can be employed in any procedure in which the heart and lungs need to be stopped temporarily and their function replaced artificially.³

So, during cardiac surgery with CPB, the heart is isolated from the circulation, which inevitably induces myocardial ischemia.⁴ However, when blood flow is restored to the ischemic area, it leads to the production of reactive oxygen species (ROS), which further generate rapid and severe damage to the myocardium resulting in myocardial reperfusion injury.⁵ Clinically speaking, ischemia-reperfusion injury (I/R injury) on the myocardium following any cardiac surgery can give rise to conditions like arrhythmias, myocardial stunning, perioperative myocardial infarction (MI), and reduced cardiac output.⁶

ROS play a significant role in reperfusion injury, including superoxide anion radical, hydrogen peroxide, and hydroxyl radical. The hydroxyl radical is generated through the Haber–Weiss reaction, which involves the interaction between the superoxide anion radical and hydrogen peroxide.⁷

{}^{•}{O_{2}^{-}} + H_{2} O_{2} \to O 2 + O H^{-} + O H^{•}

Normally, the Haber–Weiss reaction occurs at a low rate and is not physiologically significant. However, in the presence of transition metals like iron (Fe+++ and Cu++) and copper, which act as catalysts, the reaction accelerates. This process can be represented as a two-step chemical reaction. In the first step, ferric iron is reduced to ferrous iron by reacting with the superoxide anion. In the second step, the formed ferrous iron is re-oxidized by hydrogen peroxide, resulting in the formation of the hydroxyl radical. This two-step reaction is also known as the superoxide-driven Fenton reaction.⁸

Chemical reaction:

\begin{matrix} {}^{•}{O_{2}^{-}} + F e^{3 +} \to F e^{2 +} + O_{2} \\ F e^{2 +} + H_{2} O_{2} \to F e^{3 +} + O H^{-} + O H^{•} \end{matrix}

Transition metals also act as catalysts for the oxidative degradation of lipids in cellular membranes through the generation of hydroxyl radicals ( ${OH}^{•}$ ). This process results in the production of alkoxy and peroxy radicals, which, in turn, lead to an elevation in membrane fluidity and a breakdown of membrane integrity.⁹ Besides reperfusion, prolonged hypothermia has also been found to induce iron-mediated lipid peroxidation, which leads to irreversible mechanical and electrical damage to the heart.¹⁰

In this situation, deferoxamine plays a crucial role because the injury is aggravated by the presence of iron. Deferoxamine is a highly specific iron-chelating compound that can slow down the reaction and prevent additional damage to the ischemic tissue. It effectively inhibits iron ion-dependent lipid peroxidation and the formation of highly ROS when oxygen and hydrogen peroxide are present in the presence of iron ions.¹¹ Furthermore, studies have demonstrated that the addition of deferoxamine during CPB surgery helps to maintain endothelium-dependent relaxation of coronary arteries,¹² decreases the severity of lung injury following surgery,¹³ attenuates cardiac stunning,¹⁴ and minimizes the incidence of arrhythmia.¹⁵ But most of these studies have been conducted in animals; thus, sufficient human based evidence is lacking. The aim of our study is to find out the efficacy and establish the research-based evidence on the benefit of deferoxamine to prevent reperfusion injury following CPB.

Methods

This systematic review is reported in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, as presented in Figure 1.¹⁶ The first step of our study begins with developing the research question. Our question was whether deferoxamine is effective and safe in reducing I/R injury following CPB.

Figure 1.

PRISMA flow diagram depicting the flow of information through the different phases of a systematic review.

Study inclusion and exclusion criteria

All original studies published until August 18, 2023, accessing the safety and/or efficacy of deferoxamine given before CPB, irrespective of dosing and sample size were eligible to be included in our study. Any studies of the following nature were considered to be excluded: in vitro or animal studies, case reports, case series with less than 10 cases, abstracts, meta-analyses, and reviews.

Search strategy and study selection

On August 18, 2023, three reviewers (SS, BB, and NS) individually conducted a systematic search for articles, published up to the present date, in three electronic databases (Scopus, Embase, and PubMed) using keywords (“Cardiopulmonary bypass” OR “CPB”) AND “Deferoxamine,” and “Myocardial reperfusion injury” AND “Deferoxamine.” The reference section of retrieved articles was checked to find any potential studies that might have been missed in the database search. All the studies obtained were imported to Mendeley Library. Duplicates were checked and removed using both the in-built Mendeley tool and manual methods. Following this, authors (SS, BB, and NS) screened the articles through title and abstract. Potential articles based on inclusion–exclusion criteria were retrieved for full-text content. Any discrepancies were resolved through discussion with a fourth reviewer (AL).

Data extraction and risk of bias assessment

Two reviewers (PP and BC) individually extracted data, and any discrepancies were resolved through discussion with other team members. The following data were extracted: Author, date of publication, study design, study site, sample size, female population, mean age, dose of drug, and evaluated parameters and presented in Table 1. The risk of bias was assessed using Cochrane’s RoB 2 tool¹⁷ and presented in Figure 2.

Table 1.

Characteristics of included studies.

Author, date	Study design	Study site	Sample size		Female population		Mean Age		Dose or regimen of deferoxamine	Evaluated parameters
Author, date	Study design	Study site	Case	Control	Case	Control	Case	Control	Dose or regimen of deferoxamine	Evaluated parameters
Menasché et al., 1988	Prospective study	France	12	12	7	7	60.8 ± 5.0	56.3 ± 4.8	Deferoxamine was given both intravenously (30 mg/kg of body weight, starting 30 min before and ending 30 min after bypass) and as an additive to the cardioplegic solution (250 mg/l)	Superoxide production (nmol/10⁶ PMN/min)
Menasché et al., 1990	Prospective study	France	10	10	1	1	59 ± 4	61 ± 3	Intravenous infusion of deferoxamine at the dose of 30 mg/kg body weight was started 30 min before the onset of CPB and extended over the ensuing 4 hAdditionally, the drug at a dose of 250 mg/l was added to each infusion of cardioplegic solution and to that of the reperfusion solution	LDL-TBARS (μmol/mmol LDL-phospholipids)
Drossos et al., 1995	Prospective study	Greece	7	7	N/A	N/A	62	59.1	1000 mg/l added to the cardioplegic solution	Superoxide radical production (nmol/min/gram)TBARS (nmol/min/gram)
Paraskevaidis et al., 2005	Prospective study	Greece	25	20	0	0	60.8 ± 8.6	62.2 ± 6.4	4 g of deferoxamine dissolved in 250 ml of dextrose infused continuously at a rate of 31.2 ml/h for 8 h immediately following induction of anesthesia	TBARS, transesophageal echocardiography—WMSI, EF

CPB, cardiopulmonary bypass; EF, ejection fraction; LDL, low-density lipoprotein; PMN, polymorphonuclear neutrophil; TBARS, thiobarbituric acid reactive substances; WMSI, wall motion score index.

Figure 2.

Risk of bias of individual studies assessed by using Cochrane RoB 2 tool.

Outcome measures

Our objective was to assess the efficacy and safety of deferoxamine in preventing reperfusion injury after CPB for any heart disease. The outcomes for efficacy were assessed using ROS production, rate of lipid peroxidation, and post-treatment cardiac performance. Wall motion score index (WMSI) was used to access post-treatment cardiac performance. Transthoracic echocardiographic assessment of WMSI is a simple method for semi-quantifying left ventricular ejection fraction (LVEF) and thus assessing segmental left ventricular (LV) function.¹⁸

To assess safety, any events of postoperative MI and hospital stay were considered. The inflammatory mediators released during CPB are found to have negative effect on myocardial functioning.¹⁹ A study in 2019 has also used length of stay in ICU and hospital along with postoperative complication including MI as predictor of morbidity following CPB.²⁰

Results

Endpoint assessment

The studies included evaluated the outcome in terms of superoxide generation, thiobarbituric acid reactive substances (TBARS) level, cardiac performance, and morbidity. We reported morbidity based on any event of new-onset MI and duration of hospital stay.

ROS production

Menasché et al.²¹ tested the ROS generation through N-formylmethionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA) stimulation of polymorphonuclear neutrophil (PMN) collected before and after the bypass surgery. On FMLP stimulation, the pre-CPB superoxide production was 4.1 ± 0.4 nmol/10⁶ PMN/min in the control group and 3.4 ± 0.3 nmol/10⁶ PMN/min in the treatment group. There was a statistically significant (p < 0.05) decrease in post-CPB superoxide production in the treatment group (1.9 ± 0.3 nmol/10⁶ PMN/min) as compared with the control group (3.7 ± 0.2 nmol/10⁶ PMN/min). The between-group study of superoxide production is found to be more pronounced with FMLP than with PMA stimulation. In the same study, pre-CPB level of superoxide production on PMA stimulation was 11.1 ± 2.0 nmol/10⁶ PMN/min and 6.9 ± 1.5 nmol/10⁶ PMN/min in the control and treatment groups, respectively. On post-CPB evaluation, the value was 12.6 ± 2.5 nmol/10⁶ PMN/min in the control and 7.1 ± 0.9 nmol/10⁶ PMN/min in the treatment group.²¹ Likewise, according to Drossos et al.,²² there was a significant difference (p < 0.001) in the mean value of superoxide radical production between the two groups as it was 59.8 ± 17.0 nmol/min/g for the control group and 21.3 ± 8.1 nmol/min/g for treatment group in post-CPB assessment.²²

Lipid peroxidation

Low-density lipoprotein (LDL) susceptible to lipid peroxidation was measured by Menasché et al.,²³ which shows TBARS concentrations of 15.2 ± 10.5 µmol/mmol LDL-phospholipids and 14.6 ± 5.9 µmol/mmol LDL-phospholipids in control and treatment group, respectively, on pre-CPB assessment of right atrium. On post-CPB evaluation, this value was 45.7 ± 17.2 µmol/mmol LDL-phospholipids and 6.9 ± 2.9 µmol/mmol LDL-phospholipids in the control and treatment groups, respectively. Likewise, in the left atrium, TBARS level was 16.4 ± 8.4 µmol/mmol and 11.2 ± 6.3 µmol/mmol LDL-phospholipids pre-CPB in the control and treatment groups, which on post-CPB measurement was 62.7 ± 20.5 µmol/mmol LDL-phospholipids in the control group and 10.3 ± 3.9 µmol/mmol LDL-phospholipids in the treatment group.²³ According to findings from Paraskevaidis et al.,²⁴ TBARS was 2.1 ± 0.7 nmol/ml in the control group, which increased to 4.8 ± 1.1 nmol/ml after CPB. But, in treated patients, it was 2.6 ± 0.6 nmol/ml, which remained at 2.4 ± 0.9 nmol/ml on post-CPB evaluation.²⁴ Drossos et al.²² reported a TBARS concentration of 80 ± 23.4 nmol/min/g in the control group and 38.7 ± 23.8 nmol/min/g in the treated group (p < 0.01).

Cardiac performance

Menasché et al.,²¹ reported that 2 out of 12 control and 1 out of 12 treatment cases have cardiac index less than 2 l/min/m². Also, one of the controls and two from the treatment group required inotropic support due to hemodynamic instability.²¹ Menasché et al.,²³ however, found no significant difference in cardiac index and LV stroke work index measured between control and treatment groups in 6, 12, and 24 h postoperatively. In the study done by Paraskevaidis et al.,²⁴ ejection fraction (EF) increased by 8.8 ± 8.4% in the treatment group and by 1.3 ± 6.7% in the control group, which was statistically significant (p < 0.05). WMSI was the same in both the groups before CPB, that is, 2.4 ± 0.2. After CPB, WMSI decreased significantly to 1.7 ± 0.3 in the treatment group, whereas it was 2.2 ± 0.3 in the control group. Change in cardiac output before and after CPB was not statistically significant and was 0.5 ± 0.3 l/min in the control group and 0.8 ± 0.3 in the treatment group.²⁴

Morbidity

There were no events of perioperative and postoperative MI in either of the groups.^23,24 Also, the duration of ICU stay was 30.9 ± 18.4 h in the control group and 22.0 ± 2.5 h in the treatment group. The mean duration of hospital stay was 7.6 and 6.7 days, respectively, for control and treatment cases. These findings were not found statistically significant.²⁴

Discussion

Many organs, including the heart, brain, kidney, liver, and lung, are susceptible to I/R injury. I/R injury occurs through a series of oxidative stress leading to inflammation, mitochondrial dysfunction, and calcium overload ultimately resulting in microvascular dysfunction and the activation of cell death pathways.²⁵ During cardiac surgery with CPB, the heart is isolated from the circulation, inevitably inducing myocardial ischemia.⁴ Paradoxically, reperfusion to the ischemic area leads to the production of ROS, which further worsens myocardial tissue damage, resulting in myocardial reperfusion injury.⁵ Thus, many antioxidants like vitamin C, vitamin E, beta-carotene, and N-acetyl cysteine have been tried to overcome reperfusion injury.^26,27

For a few decades, it has been known that diverse types of cell deaths during I/R injury include apoptosis, necrosis, and autophagy-associated cell deaths.²⁸ Lately, in 2012, ferroptosis, a nonapoptotic form of cell death, was described for the first time while studying an anticancer drug.²⁹ Accumulation of lethal amounts of iron-dependent lipid hydroperoxides is seen in ferroptosis.³⁰ Ferroptosis is characterized by lipid peroxidation, of which polyunsaturated fatty acids, a component of the cell membrane, are easily susceptible lipids to undergo peroxidation.³¹ Erastin, RSL 3, sulfasalazine, and sorafenib are a few chemicals and drugs that can cause ferroptosis, which can be prevented by iron chelators, antioxidants, and peroxidation inhibitors.³⁰ A study conducted by Baba et al. confirmed that ROS production and iron content increase during I/R injury,^32,33 and iron overload is a significant contributor to myocardial cell injury.³⁴ It is found that iron promotes lipid oxidation via the Fenton reaction.^8,35 Deferoxamine, an iron chelator, can exhibit a protective effect on myocardial ischemia-reperfusion by forming complexes with iron and inhibiting ferroptosis.^29,36 The protective effect of deferoxamine in I/R injury has been studied in organs like the brain and heart, mostly in animal models.^3,9,37,38 Besides, it is worth mentioning that hypothermia facilitates CPB and deferoxamine can prevent hypothermia-induced lipid peroxidation and cardiac damage as well.¹⁰

Our review shows that deferoxamine can cause a statistically significant decrease in ROS production and thus decrease myocardial oxidative stress. We also found that there is decreased lipid peroxidation of cardiac tissue after CPB, provided that deferoxamine was used. In terms of cardiac performance after CPB, the use of deferoxamine improved the LVEF more than in the control group and the WMSI decreased more in the deferoxamine group than in the control group. However, studies by Menasché et al. in 1988 and 1990 showed similar cardiac index between both the treatment and control groups.^21,23 There were no episodes of postoperative MI in either of the groups, and the mean duration of hospital stay was less in the treatment group compared to the control group, though it was not statistically significant.

There is no established consensus regarding the dosing and route of deferoxamine to be used to prevent reperfusion injury. We found that deferoxamine can be given either peripherally through IV infusion or can be mixed in a cardioplegic solution as well. In the study by Paraskevaidis et al.,²⁴ 4 g of deferoxamine was dissolved in 250 ml of dextrose solution and infused continuously for 8 h in the treatment group. Menasché et al. have used deferoxamine both peripherally via the IV route (30 mg/kg body weight) and mixed in cardioplegic solution at a concentration of 250 mg/l in both of their studies. In 1988, he had given deferoxamine peripherally even after the completion of bypass surgery, but in 1990, he had given the drug only before the surgery and not after the completion of the surgery.^21,23 However, Drossos et al.,²² in their study, used a different concentration, that is, 1000 mg/l deferoxamine added to the cardioplegic solution.²²

Different dosing of deferoxamine shows toxicities like hypotension, neurotoxicity, growth retardation, opportunistic infection, ophthalmic and renal complications, hearing loss, and headaches.^39,40 None of these side effects were observed in any of the included articles.

A major limitation of our study is the heterogeneity of the included studies in terms of dosing and outcome measurement. Some outcomes like EF and WMSI are subjected to interobserver variation. Additionally, we found a limited number of human-based studies, accounting only four articles to match our inclusion criteria. All of these are carried out in a limited number of patients and mostly from similar regions. Furthermore, the studies did not thoroughly assess the complications associated with deferoxamine. As a result, it is premature to draw firm conclusions about the effectiveness of deferoxamine in preventing or reducing I/R injury or about its side effects. Thus, extensive trials and cohort studies are recommended for a well-established outcome. The strength of this systematic review is that we explored the potential of iron chelators like deferoxamine to reduce I/R injury in human from the available resources.

Conclusion

Our systematic review shows that deferoxamine is an efficacious and safe drug that can be used to prevent myocardial I/R injury following CPB. It also highlights the need for trials on a larger scale to develop potential strategies and guidelines on the use of deferoxamine for I/R injury.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Aashish Lamichhane

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Unlocking the potential of deferoxamine: a systematic review on its efficacy and safety in alleviating myocardial ischemia-reperfusion injury in adult patients following cardiopulmonary bypass compared to standard care