ECMO as salvage therapy for neutropenic enterocolitis with refractory septic shock and abdominal compartment syndrome in a patient with acute lymphoblastic leukemiaMichal Frelich1,2, Filip Burša1,2,3*, Peter Sklienka,1,23 Jan Máca1,2,3, Iveta Laryšová4 and Jaroslav Štěrba51Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, Ostrava, Czech Republic2Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic3Institute of Physiology and Pathophysiology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic4Department of Pediatrics, Faculty of Medicine, University Hospital Ostrava, Ostrava University, Ostrava, Czech Republic.5Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic* 17.listopadu 1790, Ostrava, Czech Republic, filip.bursa@fno.cz, +420777806460Word count: 1117Number of tables: 0, number of figures: 1Running title: ECMO as salvage therapy in a patient with acute lymphoblastic leukemiaKeywords: neutropenic enterokolitis, ECMO, refractory septic shock, acute lymphoblastic leukemiaConflict of interest: noneTo the Editor:Infectious complications, including neutropenic enterocolitis (NE), are a serious consequence of immunosuppressive therapy for children with cancer. NE is characterised by a variety of non-specific symptoms, including fever, abdominal pain, diarrhoea and vomiting These symptoms typically manifest one to three weeks after chemotherapy. (1) Although this syndrome has been recognised for over 60 years, its pathophysiology remains unclear. The primary insults are immune deficiency and coagulation disturbances associated with the underlying malignancy, as well as damage to the intestinal mucosa caused by the administration of chemotherapy. This is followed by bacterial invasion of the intestine in neutropenic, immunosuppressed patients. The proliferating bacteria produce endotoxins that damage enterocytes further and cause microvascular thrombosis, leading to subsequent intestinal ischaemia. (2) In some patients, the translocation of bacteria into the bloodstream can lead to sepsis. (1,2)The patient (a 8-year-old girl) was diagnosed with acute lymphoblastic leukaemia (B-ALL, IKZF1del) in May 2023. She was treated according to the AEIOP BFM 2017 protocol, which resulted in the rapid clearance of blast cells and bone marrow MRD negativity after 33 days of treatment. (3) On D35, the patient developed diffuse abdominal pain, nausea and vomiting. A CT scan of the abdomen showed distension of the bowel and a small amount of fluid in the small pelvis. Blood tests revealed severe neutropenia and elevated inflammatory parameters (CRP 237 mg/L, PCT 2.83 ng/L and Il-6 18870 ng/L). Given her condition and medical history, the patient was admitted to the pediatric intensive care unit (PICU).According to the Nesher and Rolston criteria, the diagnosis of neutropenic enterocolitis as the primary clinical manifestation of her febrile neutropenia was made. (2) The patient’s general condition deteriorated rapidly, resulting in altered consciousness and respiratory failure, which required intubation and mechanical ventilation. Despite the early initiation of combined empirical antibiotic therapy (meropenem, metronidazole, amikacin, biseptol and amphotericin B), the patient developed refractory (catecholamine-resistant) septic shock within hours of admission to the PICU, requiring excessive doses of vasopressors (norepinephrine 2.5 µg/kg/min and epinephrine 0.05 µg/kg/min in combination with vasopressin at a dose of 0.11 IU/h). Repeated boluses of methylene blue only stabilised the circulation in the short term, after which the catecholamine dose had to be increased. Anuria necessitated continuous renal replacement therapy (CRRT), to which a CytoSorb cartridge was added.Although the 2020 Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children recommend venoarterial exracorporal membrane oxygenation (hereinafter referred to as va ECMO) as a rescue therapy in patients with refractory septic shock (with a low level of evidence and a weak recommendation), its use in children with cancer is still controversial.(4,5) However, as the prognosis of children with malignant disease has improved significantly over the last 20 years, ECMO may be a viable and ethically justifiable support for these critically ill patients. (5) Furthermore, in our patient, echocardiography revealed severe sepsis-induced myocardial dysfunction (SMD) with low cardiac output (1,7l/min), and thus a greater effect of va ECMO on haemodynamic stabilisation can be expected in this case compared to refractory vasoplegic shock.(6) Consistent with the above, the effect of ECMO was immediate in our patient, because within 2 hours of its initiation, it was possible to reduce the norepinephrine to half the original dose and to completely stop the continuous administration of epinephrine and vasopressin. In addition, the heart rate decreased (from 200 to 140/min) and spontaneous diuresis occurred at a rate of 0.5-1 ml/kg/hr. The administration of levosimendan led to progression of hypotension, so therapy was stopped and milrinone was started at a dose of 0.75 µq/kg/min.This case illustrates the need for measurement of cardiac output (CO) in children with septic shock, as 32-47 % of them have some degree of SMD. (7) Echocardiography should be performed especially in children who do not achieve a satisfactory mean arterial pressure despite adequate fluid resuscitation and increasing doses of vasopressors. The pathophysiology of SMD is still not fully understood, although it was first described by Parker in 1984. The myocardium is functionally and structurally damaged by endotoxin, inflammatory cytokines and mitochondrial dysfunction. NO production plays an important role in the pathophysiology of SMD, which, in addition to exacerbating mitochondrial dysfunction, leads to a reduced myofibril response to calcium and a downregulation of β-adrenergic receptors. In surviving patients, normalisation of CO is achieved within 7-10 days. (8) The contribution of four standard doses of anthracyclines to cardiac dysfunction during the induction phase of leukaemia treatment remains speculative.After 30 hours of uneventful ECMO run, the ECMO flow began to deteriorate. After ruling out all the usual causes (hypovolemia, cannula malposition, thrombosis in circuit), the patient’s intra-abdominal pressure (IAP) was measured and a diagnosis of abdominal compartment syndrome (ACS) was made with an IAP consistently above 22 mmHg, anuria, decrease in ECMO flow and circulatory instability. This was surprising, as ACS is a rare complication of NE that has only been described in adult patients. (9) Managing this condition in patients on ECMO is difficult because negative fluid balance, the basic therapeutic measure, is usually not tolerated. These patients are also usually deeply anaesthetised and paralysed. Desufflation colonoscopy with lavage did not decrease IAP. The patient was taken to the operating theatre, where a decompressive laparotomy and a VAC (Vacuum Assisted Closure) system were performed (Figure 1). A recent study has shown that decompressive laparotomy is an effective and safe treatment for paediatric ACS, even in patients receiving ECMO (10). The patient’s condition improved rapidly, and she was weaned from ECMO after nine days. The laparotomy was closed one week later.The further treatment course for her acute leukaemia was strictly individualised, balancing the biology of the leukaemia, MRD dynamics, and tolerance of treatment.Antineoplastic treatment was resumed 50 days after admission to the ICU with septic shock, with blinatumomab chosen as the initial treatment. Further treatment consisting of additional blinatumomab and high-dose methotrexate was well tolerated. However, obstructive ileus occurred during reinduction therapy, requiring open surgery and resection of the stenotic part of the small intestine. The patient has made a full recovery, however standard protocolar reinduction was not completed as planned and she uneventfully continues maintenance chemotherapy in a 1st CCR 24 months from her severe, life threatening complication.This case study illustrates the potential of ECMO support for selected patients with refractory septic shock and SMD, including children with cancer. It also highlights the importance of regularly measuring intra-abdominal pressure to enable the early diagnosis and management of ACS in children with severe NE. This condition can lead to critical reductions in ECMO blood flow and systemic hypoperfusion. The case also documents the need for meticulous supportive care measures, including the availability of advanced intensive care facilities, for children with cancer.Figure 1 Decompression laparotomy and VAC system in ECMO-supported patient