Despite recent advances in ALI management, it is still a challenging issue associated with high mortality. The in-hospital mortality rate in our institution was 28.1% in the past 3 years (2015–2018). This number was larger than other studies, which is likely due to the late presentation of patients in our cohort. Clason et al. reported that the 30-days mortality rate among ALI patients was around 26%.6 Baril et al. showed that the in-hospital mortality for ALI declines from 12.1% in 1998 to 9.0% in 2009 (P < .001) in the United States Medicare population.5 Endovascular therapy for the treatment of ALI is increasingly used and contributes to mortality reduction in the Medicare population. In our institution, the percentage of patients undergoing endovascular therapy and surgical embolectomy was only 0% and 21.3%, respectively. The remainder of the patients was only managed by anticoagulation without primary reperfusion during hospitalization. The choice of therapeutic modalities was not associated with mortality in our patients. A meta-analysis demonstrated no significant difference in short-term and 12-months mortality, limb amputation, and recurrent ischemia in endovascular or surgical approach in ALI.7
There were differences in the subjects' baseline characteristics regarding history of cardiac operation, aortic lesion, and ischemic sign on ECG between survivor and non survivor groups (P-value: 0.006, < 0.001, and 0.037 respectively). These findings describe the degree of atherosclerotic burden and vascular damage in a patient's body. Patients who presented with any of these history have higher mortality risk. According to several studies, cardiopulmonary complications account for the majority cause of death. Approximately 15 to 20 percent of patients die within one year of presentation of their limb ischemia, usually from the medical illnesses that predispose them to acute limb ischemia.1,8,9
Most of the studies reported the risk factors associated with 30-days and 1-year mortality. The data on factors that contribute to in-hospital mortality is currently lacking. This study showed that in-hospital development of cardiac arrhythmias and acute renal failure were associated with mortality. Previously, 30-days mortality and amputation were attributed to several factors, including increasing age, level of occlusion, recent myocardial infarction, pre-existing peripheral arterial disease, and cardiopulmonary functional class.6 United States Medicare registries indicate that patients with advanced age, chronic renal failure, dementia, cancer, and atrial fibrillation have higher 30-days mortality.5 In our registry, all of these factors did not contribute to in-hospital mortality.
History of recent cardiac operation is one of the factors contributing to in-hospital mortality. In this registry, 30 from 160 patients had ALI after CABG or valve surgery. Most of these patients have a history of IABP insertion prior to or after the procedure. Approximately 32.6% of patients with ALI who underwent IABP insertion died in-hospital. Allen et al. found that IABP insertion to cardiac surgery patients is a strong risk factor for acute leg ischemia. Morbidity and mortality of ALI after cardiac surgery were 92% and 46%, respectively.10 Folkert et al. showed that IABP insertion leads to a five-fold increase in ALI.11 It is interesting to note that vascular complications, including acute limb ischemia remains a significant risk associated with IABP, occurring in 6–25% of cases. IABP insertion could cause leg ischemia from several mechanisms, insertion to femoral branches rather than the common femoral artery could cause limb ischemia, improper insertion/needle puncture, which is too low is the most common cause of ischemic complication during IABP.12,13
Lethality in ALI is attributed to the reperfusion injury. After occlusion and tissue ischemia, blood flow restoration may paradoxically exacerbate prior ischemic injury by an overt inflammatory response that promotes local tissue destruction and remote organ dysfunction.14,15 Reperfusion to severely ischemic muscles may induce the release of toxic metabolites such as potassium, free radicals, and myoglobin, culminating in a life-threatening systemic complications including renal, cardiac and pulmonary failure.16,17 Reperfusion to rhabdomyolytic muscle induces the release of myoglobin, causing acute tubular necrosis. Reperfusion also induces overflow of intracellular potassium and hydrogen ions due to the destroyed potassium-sodium pump causing metabolic acidosis and cardiac arrhythmia.16 Acute renal injury and life-threatening arrhythmia are amongst the fatal ALI complications. In our registry, acute renal injury and fatal arrhythmia contributed significantly to in-hospital mortality.
Vitamin E has been known for its antioxidant effect and reducing ischemic reperfusion injury. Vitamin E can inactivate reactive oxygen species (ROS), where its production increased after reperfusion occurred. Reperfusion will increase ROS release, infiltration of inflammatory cells and humoral mediators which further potentiates cellular damage.22 Initiation and propagation of ischemic-reperfusion injury depend upon transcription factor activation, which is responsible for the induction of inflammatory genes required for rapid production of some proteins such as cytokine, adhesion molecules, complement factors, and NO synthase.23,24 Vitamin E also affects the regulator of signal transduction and modification of NF-κB as predominant transcription factor activation during reperfusion.25 A vitamin E pre-treatment in a model of ischemic-reperfusion of lower limb muscle of patients undergoing aortic cross-clamp during surgical repair of abdominal aortic aneurysm was shown to prevent the accumulation of neutrophils within ischemic and reperfused muscle by reducing expression of endothelial adhesion proteins such as E-selectin and ICAM-1.26 In patients undergoing aortic aneurysm resection, vitamin E administration was associated with reduced oxidative skeletal muscle damage secondary to ischemia-reperfusion injury.27
In our institution, we administered 200 mg of Vitamin E per day in patients with ALI to reduce ischemia-reperfusion injury; however, we cannot provide it for all patients due to insurance reimbursement cap. Surprisingly, our study showed that a no vitamin E treatment in the acute phase of ALI causes a six-fold increased risk for in-hospital mortality. Arato et al. demonstrate that 200 mg vitamin E administration in patients undergoing lower limb vascular surgery, starting from preoperative day until seven days post-operative reduced the level of oxidative stress (lipid peroxidation, antioxidant enzymes) generated after ischemia-reperfusion insult. Vitamin E administration could also reduce white blood cell activation (MPO activation, free-radicals production, expression of adhesion molecules), reverse prooxidant-antioxidant balance and the consecutive local inflammatory process during early reperfusion compare to placebo.28 To the best of the authors' knowledge, this is the first study to demonstrate the benefit of Vitamin E supplementation in ALI patients. Further randomized controlled trials should be performed to generate more concrete evidence.
In-hospital morbidity of ALI found in our hospital mainly consists of sepsis, arrhythmia (tachy/bradyarrythmia), bleeding (gastrointestinal and cerebral), acute renal injury, and their proportion was significantly higher in non-survivor group. Primary amputation rate during hospitalization is about 20%. We also observed that the number of bleeding correlates with the number sepsis in both survivor and non-survivor groups of in-hospital mortality analysis. Sepsis is one of the most common causes of disseminated intravascular coagulation, which would most likely give way to major bleeding requiring blood transfusion. This explains why bleeding was an independent predictor of mortality in the multivariate analysis for in-hospital and 30-days mortality.29,30
Limitation
The registry was single-center, and the data was collected from a National Referral Hospital. There is a potential for selection bias which may explain the high mortality. The data were collected both prospective and retrospectively from medical records. Some of them have incomplete data or were lost to follow up. The treatments were based on physician discretion; nevertheless, it reflects real-world practice.