INTRODUCTION

The process of reperfusion following ischemia can sometimes exacerbate tissue damage beyond that caused by the initial ischemic insult [1]. Reperfusion injury may occur when blood flow is restored to the target vessel, particularly during more severe stages of ischemia [2]. In comparison, a cytokine storm is a life-threatening systemic inflammatory state characterized by elevated levels of circulating cytokines and hyperactive immune cells. It manifests as various forms of immune dysregulation, characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction, which can progress to multiorgan failure if not adequately treated. A cytokine storm can be triggered by various treatments, infections, malignancies, autoimmune diseases, and genetic abnormalities [3,4]. At times, reperfusion injury and cytokine storm may present with similar clinical features and can even exacerbate each other [4]. In this report, we describe our experience in treating a patient with multiorgan failure resulting from reperfusion injury due to a popliteal vessel injury, which was managed with plasmapheresis.

CASE REPORT

A 31-year-old man, who was intoxicated at the time, sustained a stab wound to his left knee and was transported to our level I trauma center. Upon arrival, he presented with stupor, hypothermia, and acidosis (pH, 6.772; lactic acid, 27 mmol/L). Computed tomography angiography revealed an injury to the left popliteal vessels. Surgical exploration confirmed transection of both the left popliteal artery and vein; however, his calf muscle and foot retained their coloration. Within 3 hours of the injury, we performed end-to-end anastomosis to revascularize both the artery and the vein. Despite the absence of calf swelling and the healthy appearance of the muscle, we performed a prophylactic fasciotomy on the anterolateral aspect to prevent compartment syndrome. From the initial hospital visit to the end of surgery, the patient received a total of 14 units of packed red blood cells and 11 units of fresh frozen plasma. Intraoperative systolic blood pressure was maintained above 80 mmHg. Immediately after surgery, the patient’s blood pressure and hemoglobin levels were stable; however, we noted elevated aspartate aminotransferase (AST) and alanine transaminase (ALT) levels (712 and 612 U/L, respectively) and prolonged prothrombin time (44.5%), necessitating additional transfusions of fresh frozen plasma.

On postoperative day 1, the patient’s hemoglobin levels remained stable, the acidosis was resolved (pH, 7.368), and the lactic acid level decreased to 2.3 mmol/L (Fig. 1). However, thrombocytopenia persisted with a platelet count of 68×10³/μL, and prothrombin time was still prolonged at 32.3%. The patient’s AST and ALT levels also increased further to 1,655 and 1,465 U/L, respectively. Although the calf muscle appeared healthy, we administered massive hydration and added hydrocortisone to manage potential reperfusion injury.

On postoperative day 2, the patient’s AST and ALT levels increased to 8,600 and 6,690 U/L, while his creatine phosphokinase and lactate dehydrogenase levels rose to 26,817 and 7,398 U/L, respectively. The interleukin 6 (IL-6) level measured 178 pg/mL, and ferritin reached 41,079 ng/mL. C-reactive protein was recorded at 3.55 mg/dL, and the D-dimer level exceeded 20 μg/mL fibrinogen equivalent units. Clinically, we initially considered reperfusion injury, and despite the low quantitative value of IL-6, we chose to implement treatments that could also be effective against cytokine storm. Consequently, we opted for plasmapheresis, a therapy that addresses both reperfusion injury and cytokine storm, in response to the patient’s rapidly deteriorating condition.

After two cycles of plasmapheresis over 2 days, the patient’s AST and ALT levels decreased to 243 and 676 U/L, respectively (Fig. 2); creatine phosphokinase and lactate dehydrogenase decreased to 882 and 272 U/L, respectively; IL-6 decreased to 16.4 pg/mL; and ferritin decreased to 981 ng/mL (Fig. 3). The patient developed pulmonary edema following plasmapheresis, but this condition resolved within a few days. Notably, thrombocytopenia and disseminated intravascular coagulation also improved, permitting discharge without further complications.

Ethics statement

Written informed consent for publication of the research details was obtained from the patient.

DISCUSSION

Organ ischemia can have catastrophic consequences, such as myocardial infarction and cerebral infarction, which result in permanent tissue damage. Paradoxically, the process of reperfusion following ischemia can cause more harm than the initial ischemic tissue damage [1]. Reperfusion injury may occur when the target blood vessel is revascularized, particularly during more severe stages of ischemia [2]. The hallmark feature of reperfusion injury is severe limb swelling accompanied by a dramatic increase in compartment pressure, known as compartment syndrome. Patients experience intense pain in the affected limb, particularly during passive muscle stretching, and may also exhibit hyperesthesia [2,5,6]. For patients with compartment syndrome, surgical fasciotomy is essential to prevent permanent damage to neurologic and soft-tissue structures. Notably, however, compartment syndrome is not necessarily a prerequisite for reperfusion injury and may not occur in every case [2]. The rapid production of various reactive oxygen species (ROS) during reperfusion leads to mitochondrial damage and electrolyte imbalances. Reperfusion injury can also trigger a complex inflammatory immune response, even in the absence of a specific pathogenic trigger. These reactions contribute to cell and tissue damage. When reactive mediators enter the systemic circulation following vascular revascularization, they can cause systemic inflammation and multiple organ failure [1,7].

Cytokine storm is a life-threatening systemic inflammatory state characterized by elevated circulating cytokine levels and hyperactive immune cells. It includes a range of immune dysregulation disorders that present constitutional symptoms, systemic inflammation, and multiorgan dysfunction. Without proper treatment, this dysfunction can progress to multiorgan failure [3,4,8]. Patients with cytokine storm typically exhibit symptoms such as fever (which may be high grade in severe cases), fatigue, loss of appetite, headache, skin rash, diarrhea, joint pain, muscle pain, and neuropsychiatric manifestations [3,9]. Laboratory tests often indicate nonspecific inflammatory markers like elevated C-reactive protein, ferritin, and D-dimer levels, along with increased proinflammatory cytokines including tumor necrosis factor α, interferon γ, and IL-1. Among these, IL-6 serves as a leading marker [3,8,9]. However, these mediators do not interact with signaling pathways in a straightforward or consistent manner. Their quantitative values do not reliably reflect clinical features or prognosis. Furthermore, most parameters, including IL-6, are not measurable in all healthcare facilities [4,8].

As described, both reperfusion injury and cytokine storm can precipitate systemic inflammation and multiorgan failure, requiring supportive care to preserve critical organ function. However, the treatment strategies for these conditions differ in their focus. The primary goal when managing cytokine storm is to eradicate inflammatory mediators and triggers that inappropriately activate the immune system [3,9]. In contrast, the therapeutic approach for reperfusion injury centers on reducing the duration of hypoperfusion and eliminating ROS [7].

Plasmapheresis is an extracorporeal treatment that facilitates the selective collection of blood components and the removal of pathogenic materials such as immunoglobulins, immune complexes, and inflammatory mediators from the plasma. This process involves separating the corpuscular components of the blood from the plasma through centrifugation or filtration. The separated plasma is then completely discarded and replaced with an equal volume of replacement solution. Plasmapheresis has been employed in the treatment of autoimmune diseases and certain poisonings—pathological conditions in which rapid removal of toxins from the plasma is necessary [10].

Prompted by the recent surge in COVID-19 cases, several studies have demonstrated the effectiveness of plasmapheresis in removing cytokines during a cytokine storm [11,12]. Plasmapheresis has been found to significantly reduce inflammatory mediators, improve hepatic function, and potentially alleviate oxidative stress induced by ROS [12–14]. While reperfusion injury and cytokine storm exhibit similar clinical features and primarily require supportive care to prevent organ dysfunction, specific treatment becomes necessary in cases of severe progression.

In the present case, we initially suspected reperfusion injury, which is comparatively common, and treated it conservatively. However, the patient’s condition continued to deteriorate. The absence of typical clinical signs and findings usually associated with reperfusion injury and cytokine storm made differential diagnosis challenging. Nevertheless, we considered plasmapheresis as a treatment option for both conditions. Following plasmapheresis, the patient’s condition improved rapidly. In cases of suspected reperfusion injury with very severe symptoms in trauma patients, plasmapheresis may be considered a viable treatment option, even when typical clinical features are not present.

ARTICLE INFORMATION

Author contributions

Conceptualization: all authors; Methodology: SHC; Project administration: SHC; Visualization: SHC; Writing–original draft: SHC; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for this study.

Data availability

Data sharing is not applicable as no new data were created or analyzed in this study.

Fig. 1.

Changes in acidosis and lactic acid. POD, postoperative day.

Fig. 2.

Changes in liver function tests pre- and post-plasmapheresis. POD, postoperative day; AST, aspartate aminotransferase; ALT, alanine transaminase.

Fig. 3.

Changes in creatine phosphokinase (CPK), lactate dehydrogenase (LDH), ferritin, and interleukin 6 (IL-6) pre- and post-plasmapheresis. POD, postoperative day.

REFERENCES

• 1. Zhang M, Liu Q, Meng H, et al. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024;9:12. ArticlePubMedPMCPDF
• 2. Olinic DM, Stanek A, Tataru DA, Homorodean C, Olinic M. Acute limb ischemia: an update on diagnosis and management. J Clin Med 2019;8:1215. ArticlePubMedPMC
• 3. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383:2255–73. ArticlePubMedPMC
• 4. Jarczak D, Nierhaus A. Cytokine storm: definition, causes, and implications. Int J Mol Sci 2022;23:11740. ArticlePubMedPMC
• 5. McNally MM, Univers J. Acute limb ischemia. Surg Clin North Am 2018;98:1081–96. ArticlePubMed
• 6. Tiwari A, Haq AI, Myint F, Hamilton G. Acute compartment syndromes. Br J Surg 2002;89:397–412. ArticlePubMedPDF
• 7. Naito H, Nojima T, Fujisaki N, et al. Therapeutic strategies for ischemia reperfusion injury in emergency medicine. Acute Med Surg 2020;7:e501. ArticlePubMedPMCPDF
• 8. Binkowska AM, Michalak G, Pilip S, Kopacz M, Slotwinski R. The diagnostic value of early cytokine response in patients after major trauma: preliminary report. Cent Eur J Immunol 2018;43:33–41. ArticlePubMedPMC
• 9. Karki R, Kanneganti TD. The ‘cytokine storm’: molecular mechanisms and therapeutic prospects. Trends Immunol 2021;42:681–705. ArticlePubMedPMC
• 10. Altobelli C, Anastasio P, Cerrone A, et al. Therapeutic plasmapheresis: a revision of literature. Kidney Blood Press Res 2023;48:66–78. ArticlePubMedPMCPDF
• 11. Fernandez J, Gratacos-Gines J, Olivas P, et al. Plasma exchange: an effective rescue therapy in critically ill patients with coronavirus disease 2019 infection. Crit Care Med 2020;48:e1350–5. ArticlePubMedPMC
• 12. Hashemian SM, Shafigh N, Afzal G, et al. Plasmapheresis reduces cytokine and immune cell levels in COVID-19 patients with acute respiratory distress syndrome (ARDS). Pulmonology 2021;27:486–92. ArticlePubMedPMC
• 13. Tonev D, Momchilova A. Oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in multiple sclerosis: focus on certain exogenous and endogenous Nrf2 activators and therapeutic plasma exchange modulation. Int J Mol Sci 2023;24:17223. ArticlePubMedPMC
• 14. Tonev DG, Momchilova AB. Therapeutic plasma exchange in certain immune-mediated neurological disorders: focus on a novel nanomembrane-based technology. Biomedicines 2023;11:328. ArticlePubMedPMC

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References

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