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Tuesday, July 28, 2026

Typhlitis (Neutropenic Enterocolitis): A Multidisciplinary Approach- Juniper Publishers

Reviews and Research- Juniper Publishers

Abstract

Typhlitis, or neutropenic enterocolitis, is a life-threatening gastrointestinal complication that predominantly affects immunocompromised patients, particularly those undergoing intensive chemotherapy for hematologic malignancies. The pathophysiology of typhlitis is characterized by mucosal injury, bacterial translocation, and systemic inflammatory response, often resulting in sepsis and multi-organ failure if not promptly managed. Early diagnosis relies on clinical suspicion supported by imaging modalities such as computed tomography (CT) to identify hallmark features including bowel wall thickening and pneumatosis intestinalis. Management primarily involves aggressive supportive care, including bowel rest, fluid resuscitation, and broad-spectrum antibiotics targeting gram-negative bacilli, gram-positive cocci, and anaerobes. Surgical intervention is reserved for patients with complications such as bowel perforation, necrosis, or uncontrolled hemorrhage, with right hemicolectomy and ileostomy being the preferred procedures in severe cases. Despite advances in antimicrobial therapy and critical care, the prognosis remains guarded, particularly in patients with profound and prolonged neutropenia. Long-term management focuses on recurrence prevention through prophylactic antibiotics, gut microbiome modulation, and personalized oncologic treatment strategies to minimize further mucosal injury. Emerging research on microbiome-targeted therapies holds promise for reducing gastrointestinal complications in neutropenic patients. A multidisciplinary approach is essential for optimizing outcomes and improving survival in affected individuals.

Keywords:Typhlitis; Neutropenic enterocolitis; Chemotherapy; Immunosuppression; Bacterial translocation; Surgical management; Gut microbiome; Multidisciplinary approach

Keywords:ALL: Acute Lymphocytic Leukemia; ANC: Absolute Neutrophil Count; CT: Computed Tomography; FMT: Fecal Microbiota Transplantation; GS: General Surgery; NPO: Nothing by Mouth; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; PTE: Pulmonary Thromboembolism

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Introduction

Typhlitis, also known as neutropenic enterocolitis, is a life-threatening inflammatory and infectious process that primarily affects the cecum and proximal colon in immunocompromised patients. It is most commonly observed in individuals with profound neutropenia, particularly those undergoing intensive chemotherapy for hematologic malignancies. The condition is characterized by transmural inflammation, often complicated by bacterial translocation, ischemia, and, in severe cases, perforation, leading to significant morbidity and mortality [1]. The relevance of typhlitis is particularly pronounced in oncology, hematology, and post-transplant settings, where aggressive immunosuppressive therapies predispose patients to gastrointestinal complications [2]. It is frequently reported in patients with acute leukemia, lymphoma, and those receiving bone marrow transplantation, as these populations experience prolonged and severe neutropenia. The increasing use of high-dose chemotherapy and novel immunotherapies has also increased awareness of this condition in recent years [2]. Epidemiologically, typhlitis has been reported in approximately 5-10% of patients receiving intensive chemotherapy, with the highest incidence observed in those with acute myeloid leukemia (AML) and recipients of hematopoietic stem cell transplants [3]. The mortality rate varies widely, ranging from 20% to 50%, depending on the severity at presentation and the presence of complications such as perforation, sepsis, or multiorgan failure. Rapid recognition and intervention are critical, as delays in diagnosis or inadequate management can lead to catastrophic outcomes. A multidisciplinary approach is essential to optimize treatment and improve survival rates. Given the highrisk nature and potential fatality of typhlitis, a comprehensive understanding of its pathophysiology, early diagnostic markers, and evidence-based treatment strategies is imperative for improving patient outcomes [4]. This review explores the current insights into the diagnosis, management, and prevention of typhlitis, emphasizing the need for multidisciplinary collaboration in high-risk populations.

Pathophysiology

Typhlitis is a potentially life-threatening condition that primarily affects people with lowered immune systems and individuals undergoing cancer chemotherapy [1-6]. The condition is characterized by inflammation of the cecum and potentially other parts of the intestinal tract, resulting from a complex interplay involving neutropenia, mucosal injury, and bacterial translocation.

Role of Neutropenia in Susceptibility to Bacterial Translocation

Neutropenia is marked by a drastic reduction in the number of neutrophils, a type of white blood cell vital for the body’s innate immune response [6]. This condition significantly distorts the immune defense mechanism, increasing infection susceptibility [6]. The gastrointestinal tract (GIT), which harbors a diverse band of commensal and pathogenic bacteria, becomes a potential source of systemic infection [6,7]. In a healthy immune system, neutrophils contain and regulate the gut microbiota effectively. However, during neutropenia, this containment is disrupted, facilitating the translocation of bacteria across the intestinal mucosa into the bloodstream with evidence of low neutrophil counts < 500 cell/microliter, elevated C-reactive (CRP), and erythrocyte sedimentation rate (ESR) [6-9]. The gut microbiota is not just localized; it interacts with various body systems, including the skin, oral cavity, lungs, vagina, and even the brain [6-8]. It effectively enhances the production of key immune components such as immunoglobulin A (IgA), antimicrobial peptides (AMPs), and several innate and adaptive immune cells, which are essential for maintaining gut health and overall immunity [6, pg2].

Mucosal Injury Due to Chemotherapy and Gut Microbiota Alterations

Chemotherapy often induces mucositis, which damages the intestinal epithelium and contributes to diminished secretion of digestive fluids [7,8]. This damage leads to a decreased population of good gut microbiota, compromising the gut’s barrier function and increasing the actions of inflammatory mediators such as cytokines and chemokines [7]. Wei, Wen, & Xian expanded that “Specific toll-like receptors (TLRs) located on immune cells identify the cell wall components of bacteria, including peptidoglycan, which is recognized by TLR-2, lipopolysaccharides (LPS) detected by TLR-4, flagellin by TLR-5, and unmethylated DNA (CpG DNA) through TLR-9” [7]. The injury caused by mucositis is progressive by dysbiosis, which occurs due to an imbalance in gut microbiota, negatively enhancing chronic inflammation and weakening mucosal integrity [7,8]. The altered composition of microbiota, combined with a diminished ability for epithelial regeneration, creates a permissive environment for bacterial invasion [7,8]. This invasion not only “disrupts immunological homeostasis but can also have profound impacts on mental health, linking gut and brain function through the brain-gut axis” [6-8] (Figure 1).

Bacterial Invasion and Ischemic Damage

Bacterial translocation [BT] triggers an inflammatory process that can lead to ischemic damage within the intestinal wall [7]. This ischemic process, on the other hand, arises due to impaired blood flow, exacerbating tissue necrosis and disrupting the gut’s morphological structure and function [7-8,10]. In the bloodstream, BT can trigger sepsis-a life-threatening systemic inflammatory cascade that can further compromise organ function [8,10]. Also, the proliferation exacerbations caused by bacterial invasion lead to intestinal perforation, where holes are formed in the intestinal wall, significantly increasing the risk of life-threatening complications, such as peritonitis and organ failure/s [10,11]. The mortality risk associated with typhlitis is substantial, underscoring the importance of early recognition, aggressive management, and preventive strategies in immunocompromised patients [11].

Clinical manifestations

The most common symptoms seen in neutropenic enterocolitis (NE) include fever and abdominal pain (often RLQ, but can be diffuse), in addition to nausea, vomiting, diarrhea, peritonitis, and abdominal distention [12,13]. Bowel wall thickening on imaging can help narrow the differential [14]. Though not as common, patients may also exhibit a palpable boggy cecum, melena, or hematochezia [13,15]. Abdominal compartment syndrome has also been reported in the setting of ascites [16]. Without symptomatic resolution and early diagnosis, progressive decline in the form of life-threatening complications, including sepsis, acute respiratory distress syndrome (ARDS), intraabdominal abscesses, pneumatosis intestinalis, bowel necrosis, perforation, hemorrhage, and multi-organ failure, can occur [12,17]. At-risk immunocompromised populations include those undergoing organ transplantation, those receiving chemotherapy treatment for hematological malignancies or solid tumors, and immunosuppressive conditions such as AIDS [18]. For those receiving chemotherapy, symptoms can occur anywhere between ten days to two weeks after treatment [13,15].

Diagnostic Approach

Laboratory Findings

Laboratory findings in typhlitis are crucial for diagnosing and managing the condition, often revealing signs of infection and inflammation. A key feature is neutropenia, typically observed in patients with chemotherapy or hematologic malignancies, where neutrophil counts are significantly low, sometimes below 500 cells/μL. Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are common, indicating systemic inflammation. In some cases, pancytopenia is seen, where reductions occur across all blood cell types, including red blood cells and platelets, especially in patients with severe bone marrow suppression. Additionally, lactate dehydrogenase (LDH) levels may rise due to tissue damage, and electrolyte imbalances such as hyponatremia and hypokalemia may occur due to gastrointestinal losses [19-23]. Procalcitonin (PCT) levels have been extensively studied as a biomarker for bacterial infections and sepsis, particularly in the context of febrile neutropenia and other severe infections. However, the specific relationship between PCT levels and typhlitis (neutropenic enterocolitis) remains less welldocumented in the literature [24]. While there is no direct evidence linking procalcitonin levels specifically to typhlitis, the elevated PCT levels observed in severe bacterial infections and sepsis suggest that it could serve as a valuable marker in the diagnosis and management of typhlitis in neutropenic patients [24]. The presence of these lab findings, combined with clinical symptoms like abdominal pain and fever and imaging showing bowel wall thickening, aids in diagnosing typhlitis. CRP levels, in particular, can be valuable for monitoring the severity of inflammation. The severity and duration of neutropenia directly correlate with the symptoms and outcomes of typhlitis, as neutrophil recovery is essential for resolution [21-24]. Differentiating typhlitis from other conditions is important, and stool studies are essential to rule out infections like Clostridioides difficile (C. difficile). Key tests for C. difficile include Nucleic Acid Amplification Tests (NAAT), Glutamate Dehydrogenase (GDH) Antigen Test, and Toxin A and B Enzyme Immunoassay (EIA). Additionally, routine stool cultures and NAATs are necessary for detecting other enteric pathogens such as Salmonella, Shigella, and Campylobacter [25]. Blood cultures are also vital in diagnosing and treating typhlitis, as neutropenic patients are at a high risk of bacteremia. Blood cultures should be collected before initiating antibiotics to ensure accurate pathogen identification, allowing for more targeted antimicrobial therapy, improving patient outcomes, and reducing complications [25].

Imaging Modalities

Imaging studies play a crucial role in diagnosing and managing typhlitis, with several modalities available depending on clinical circumstances and institutional capabilities. Computed tomography (CT) of the abdomen and pelvis with intravenous contrast is the gold standard for diagnosing typhlitis [12,17,26]. CT imaging typically reveals characteristic findings such as circumferential bowel wall thickening of the cecum and ascending colon, often exceeding 5 mm. The thickening may be asymmetric and can involve other colon or small intestine segments in more severe cases [26]. CT can also identify pneumatosis intestinalis, which appears as gas within the bowel wall, indicating advanced disease with mucosal disruption. In cases where perforation has occurred, CT can detect pneumoperitoneum (free air in the peritoneal cavity), an ominous sign that typically necessitates urgent surgical intervention. Additional findings may include pericecal fat stranding, cecal distention, and pericolonic fluid collections or abscesses, all of which help assess the disease’s extent and severity [26,27].

While CT remains the primary imaging tool, ultrasonography provides a valuable alternative, particularly in pediatric populations, pregnant patients, or settings where CT may not be readily available. Ultrasound findings in typhlitis include cecal wall thickening (typically appearing as a hypoechoic rim surrounding the cecum), decreased peristalsis, and increased echogenicity of pericecal fat. The non-invasive nature and absence of radiation exposure make ultrasound an attractive option for initial evaluation and follow-up studies. However, its accuracy is operator-dependent and may be limited by patient factors such as obesity or excessive bowel gas [27,28]. Magnetic resonance imaging (MRI) represents another alternative imaging modality that may be considered in select cases. MRI offers excellent soft tissue contrast without radiation exposure, making it suitable for patients who require repeated imaging studies. With high sensitivity, it can detect bowel wall thickening, mucosal enhancement, and pericolonic inflammation. However, the longer acquisition times, higher cost, and limited availability compared to CT or ultrasound restrict its routine use in the acute setting. Nevertheless, MRI may be particularly valuable in patients with renal insufficiency who cannot receive iodinated contrast agents for CT studies [27-31]. The choice of imaging modality should be tailored to the individual patient’s clinical situation, considering factors such as disease severity, comorbidities, and local resources. Regardless of the modality, prompt imaging is essential for early diagnosis and appropriate management of typhlitis.

Differential Diagnosis

The most common symptoms of Neutropenic enterocolitis (NE) are abdominal pain, diarrhea, and fever [32]. Nausea, vomiting, and abdominal distension are also common symptoms. Abdominal pain can be localized in the lower right quadrant or can be more diffuse. Tenderness on palpation can be found at the RLQ [33]. Typhlitis frequently mimics appendicitis on presentation, and the main difference is that appendicitis has leukocytosis and Typhlitis has neutropenia [34,35]. When comparing NE with Clostridioides difficile (C. difficile), colitis is a cause of diarrhea in hospitalized patients and using antibiotics like cephalosporins, Clyndamycin, and penicillin, among others. C. Difficile is one of the most common causes of nosocomial infections. C. difficile infection is usually suspected when hospitalized patients develop diarrhea, abdominal pain, and fever, but patients can develop dehydration, loss of appetite, and nausea as well [36].

Cytomegalovirus (CMV) is a member of the herpesvirus family and forms latent infection after the resolution of the primary infection. After the primary CMV infection, CMV remains in host cells, and CMV replication is controlled by the immune system in immunocompetent patients [37]. Immunodeficiency is the leading risk factor for invasive CMV diseases. Invasive CMV mostly affects the gastrointestinal tract in immunocompromised patients. Clinical manifestation of CMV colitis in immunocompromised patients varies and depends on the site of involvement, which could cause odynophagia, abdominal pain, hematochezia, and fever [38,39]. Inflammatory bowel disease (IBD), which comprises Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, systemic, autoimmune disease. Both may present with abdominal pain, diarrhea, rectal bleeding, or muscle spasms in the region of the pelvis and weight loss [40]. Ischemic colitis (IC), characterized by insufficient blood supply and oxygen delivery to the colon, is the most common form of bowel ischemia [41]. The severity of IC depends on the degree of parietal involvement, ranging from superficial mucosa inflammation to full-thickness transmural necrosis, a life-threatening condition that requires surgery [42]. Because of the overlapping symptoms of NE with many abdominal pathologies, this is an entity that should be considered in any differential for a patient with febrile RLQ pain, not just those with obvious immunosuppression.

Management Strategies: Internal Medicine and Surgery Perspectives

Supportive Care

The cornerstone of managing typhlitis begins with aggressive supportive care measures implemented immediately upon diagnosis. Bowel rest is essential to minimize intestinal peristalsis and reduce the risk of perforation in the compromised bowel wall. This typically involves establishing nothing-by-mouth (NPO) status until clinical improvement is observed. In patients presenting significant abdominal distention or radiographic evidence of ileus, nasogastric tube placement for intestinal decompression becomes necessary to relieve pressure on the affected bowel segments and reduce the risk of aspiration [43]. Fluid resuscitation represents another critical component of supportive care, as many patients present with significant volume depletion due to decreased oral intake, diarrhea, and third-spacing into the bowel wall and peritoneal cavity. Careful attention to fluid balance with isotonic crystalloid solutions helps maintain adequate tissue perfusion while preventing fluid overload. Concurrent with volume resuscitation, vigilant monitoring and correction of electrolyte abnormalities, particularly hypokalemia and hypomagnesemia which may result from gastrointestinal losses, is essential for preventing cardiac arrhythmias and optimizing intestinal function [44]. Pain management warrants special consideration in patients with typhlitis. Opioid analgesics are generally preferred for their efficacy and relatively favorable safety profile in this context. Importantly, non-steroidal anti-inflammatory drugs (NSAIDs) should be strictly avoided due to their association with increased risk of gastrointestinal mucosal damage and bleeding, which could exacerbate the already compromised intestinal mucosa in neutropenic patients. Additionally, NSAIDs may mask fever, an important clinical indicator of treatment response or disease progression. The administration of opioids should be balanced against their potential to exacerbate ileus, with careful titration and adjunctive measures such as stool softeners employed when necessary [45].

Antibiotic Therapy

Prompt initiation of empirical broad-spectrum antibiotic therapy is imperative in managing typhlitis given its potentially rapid progression and the immunocompromised state of affected patients. The selection of antimicrobial agents should provide comprehensive coverage against gram-negative bacilli (including Pseudomonas aeruginosa), gram-positive cocci, and anaerobic organisms, which commonly constitute the polymicrobial intestinal flora that may translocate across the damaged intestinal barrier [46]. Monotherapy options with excellent broad-spectrum coverage include piperacillintazobactam, meropenem, or imipenem-cilastatin. These betalactam antibiotics with beta-lactamase inhibitors or carbapenems provide robust activity against the typical pathogens encountered in typhlitis and are often preferred as first-line agents due to their excellent tissue penetration and proven efficacy in neutropenic infections. Alternatively, combination therapy with cefepime plus metronidazole offers comparable coverage, with cefepime targeting gram-negative and gram-positive aerobes while metronidazole provides dedicated anaerobic coverage [47]. For patients with prolonged neutropenia (typically exceeding 7-10 days), persistent fever despite appropriate antibacterial therapy, or those receiving intensive chemotherapy regimens associated with severe mucosal damage, consideration should be given to adding antifungal coverage. Candida species, particularly Candida albicans, may contribute to the pathogenesis of typhlitis in these high-risk individuals. Echinocandins (e.g., caspofungin) or lipid formulations of amphotericin B are typically recommended in this scenario due to their broad antifungal spectrum and favorable safety profile [48]. Antibiotic therapy should be continued until neutrophil recovery (absolute neutrophil count >500 cells/μL) and resolution of clinical symptoms, including defervescence, abdominal pain improvement, and normalization of gastrointestinal function. This typically requires a minimum of 10-14 days of treatment, though the duration may be extended based on clinical response and the presence of complications [49- 50].

Surgical Considerations (GS focus)

Typhlitis, also known as neutropenic enterocolitis, can be challenging to diagnose and to treat for most physicians, since there is a high mortality seen in these patients, and there are controversial opinions on its form of treatment. Initially, established management of the disease is recommended to follow a thorough electrolyte follow-up, bowel rest with nasogastric suction, total parenteral infusion, and blood transfusions depending on the patient’s hemodynamic status. Surgical intervention is only given in extreme cases, such as the patient presenting with signs and/or symptoms of necrosis, perforation, and persistent bleeding.The mortality rate has been reported to range from 50% to 100% in patients that have not been treated and require surgical intervention. Physicians don’t typically select abdominal surgery as their first choice to treat this disease because of exhaustive complications in patients with neutropenia [51-53]. Patients who happen to experience severe systemic symptoms, such as sepsis, or as well with those who evidently have signs of perforation, obstruction, massive bleeding, or abscess formation, require surgery effective immediately. All the necrotic tissue must be removed, typically through right hemicolectomy, ileostomy, and mucous fistula. In patients who carry a less severe case, a divided ileostomy may also be implemented. If this necrotic area is not excised, particularly in patients who are severely immunocompromised, it can be fatal. With prompt identification, typhlitis and its underlying causes risk of complications can be minimized with early preventive measures in a timely manner [52- 55]. The most common diagnosis prompting surgical consultation in neutropenic patients is neutropenic enterocolitis, followed by small bowel obstruction, Clostridium difficile infection, diverticulitis, appendicitis, cholecystitis, pseudo-obstruction, splenic rupture, and an unclear diagnosis. Neutropenic enterocolitis is a common complication of cytotoxic chemotherapy, and most of the patients with this specific pathology must be further evaluated for possible malignancies. There are certain diseases linked that predispose to have neutropenic enterocolitis, such as ALL (acute lymphocytic leukemia), being ranked as the highest risk. Patients mostly get treated with a right hemicolectomy, and although there have been reports of successful recovery, still surgery is not the first approach to treatment [53-56].

Although most patients get treated successfully with conservative management, those who had clinical signs of bowel perforation and/or peritonitis were submitted to surgery. Some of the other indications to surgery were the inability to diagnose bowel perforation, other pathologies such as appendicitis, and patients who were hemodynamically unstable (mostly due to life threatening hemorrhage). Most studies suggest a right hemicolectomy with a defunctioning ileostomy indication in the area where necrosis of the colon has occurred, in comparison to primary anastomosis which had a higher rate of complications in neutropenic patients. Another procedure that could be implemented in pancolonic disease is defunctioning ileostomy, but carries a heavier risk of prolonged postoperative sepsis in patients with poor neutrophil counts [54-59]. Clinical signs such as abdominal pain and fever in patients with typhlitis can serve as very important health indicators for physicians to suspect this pathology. Diagnosing this disease as early as possible and giving the right treatment can be lifesaving and enhance the prognosis. However, supportive care still remains the primary form of treatment and surgery must be needed to survive in minimal cases [59].

Prognosis and Long-Term Management

Typhlitis, or neutropenic enterocolitis, is a severe and potentially life-threatening complication observed in immunocompromised patients, particularly those undergoing chemotherapy for hematologic malignancies. The prognosis of typhlitis is influenced by several key factors, including the severity of neutropenia, the timeliness of intervention, and the patient’s response to therapy. Severe neutropenia, particularly an absolute neutrophil count (ANC) of less than 500 cells/μL, is associated with an increased risk of bacterial translocation, sepsis, and mortality (Gorschlüter et al., 2005). Early recognition and aggressive management with broad-spectrum antibiotics, bowel rest, and supportive care are essential to improving outcomes. Delayed intervention has been correlated with increased morbidity and higher rates of surgical intervention due to complications such as bowel perforation or necrosis (Rodríguez-Villar et al., 2021). The response to initial therapy, including clinical improvement and resolution of neutropenia, plays a crucial role in determining patient outcomes. Poor response or persistent symptoms despite appropriate treatment is indicative of a worse prognosis and often necessitates escalation of care [60].

The risk of recurrence of typhlitis is a major concern, particularly in patients undergoing multiple cycles of chemotherapy. Recurrent episodes have been reported in patients with continued myelosuppression and mucosal injury due to repeated cytotoxic exposure. The incidence of recurrence can be as high as 20-30% in high-risk populations, necessitating tailored preventive strategies (Rodríguez-Villar et al., 2021). Prophylactic antibiotics, particularly fluoroquinolones, have been explored as a potential preventive measure in patients with prolonged neutropenia or a history of typhlitis. While some studies suggest that prophylaxis reduces the incidence of febrile neutropenia and bacterial infections, concerns regarding antimicrobial resistance and microbiome dysbiosis warrant cautious use (Freifeld et al., 2011). Future research is needed to determine optimal patient selection criteria for prophylactic antibiotic therapy [61].

The gut microbiome has emerged as a crucial factor in the pathophysiology and prevention of typhlitis. Chemotherapyinduced mucosal injury, coupled with the broad-spectrum antibiotic use often required in neutropenic patients, can lead to significant alterations in gut microbiota composition. This dysbiosis has been linked to an increased risk of gastrointestinal infections and inflammation, contributing to the development of enterocolitis (Taur et al., 2014). Strategies to modulate the gut microbiome, including probiotic supplementation, prebiotic use, and fecal microbiota transplantation (FMT), are being investigated as potential interventions to restore intestinal homeostasis. Preliminary data suggest that preserving a diverse and healthy microbiota may reduce the incidence of gastrointestinal complications in neutropenic patients, but large-scale clinical trials are needed to confirm these findings and establish standardized protocols for microbiome-targeted therapies [62]. In conclusion, the prognosis of typhlitis is dependent on early recognition, timely intervention, and the severity of neutropenia. Recurrent episodes are a significant concern, particularly in patients undergoing multiple chemotherapy cycles, highlighting the need for effective preventive strategies. While prophylactic antibiotics may be beneficial in select high-risk patients, concerns about antimicrobial resistance must be carefully considered. Emerging evidence on gut microbiome modulation presents a promising avenue for reducing typhlitis risk, though further research is required to integrate these strategies into clinical practice. A multidisciplinary approach involving oncologists, infectious disease specialists, and gastroenterologists is essential for optimizing long-term management and improving patient outcomes [63].

Conclusion

Typhlitis remains a critical and potentially fatal complication in immunocompromised patients, particularly those undergoing cytotoxic chemotherapy. Despite advances in supportive care and antimicrobial therapy, the condition continues to pose significant management challenges due to its rapid progression, high morbidity, and risk of recurrence. Early recognition through clinical suspicion and imaging is paramount in initiating timely interventions and reducing mortality. While most cases can be managed conservatively with bowel rest, broad-spectrum antibiotics, and fluid resuscitation, a subset of patients with severe complications such as bowel perforation, necrosis, or persistent sepsis requires surgical intervention. Right hemicolectomy with ileostomy remains the procedure of choice in such cases, though surgery is associated with increased perioperative risks in neutropenic individuals. Long-term management strategies emphasize recurrence prevention, including judicious use of prophylactic antibiotics and emerging microbiome-targeted therapies aimed at preserving intestinal integrity. Future research should focus on refining risk stratification models, optimizing prophylactic strategies, and exploring innovative microbiomemodulating interventions. Given the complexity of typhlitis, a multidisciplinary approach is crucial in improving patient outcomes and survival rates.

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Thursday, July 23, 2026

Therapeutic and Prognostic Factors of Upper Gastrointestinal Bleeding in the Intensive Care Unit in a Sub-Saharan African Country- Juniper Publishers

Anesthesia & Intensive Care Medicine- Juniper Publishers

Abstract

Background: The aim of our study was to determine the therapeutic and prognostic factors of upper gastrointestinal bleeding (UGB) in the ICU.

Patients and Methods: This was a retrospective descriptive study of records of patients admitted to the ICU from January 2012 to April 2017. Records of patients admitted to UGB in two intensive care units were included. The sampling was consecutive and non-exhaustive. Data were coded and analyzed using SPSS software.

Results: The sample size was 30 cases. The mean age was 55.3 ± 19.1 years. The sex-ratio was 2.3. Nineteen patients were seen more than 72 hours after the onset of bleeding (63.4%). The most frequent mode of revelation was hematemesis (50.7%). Endoscopy was performed in seven patients (23.3%). The management, in addition to resuscitation measures, consisted of parenteral administration of omeprazole. Haemostatic treatment was performed in one patient (3.4%). The mortality rate was 50%.

Conclusion: Upper gastrointestinal bleeding is an important cause of mortality in the ICU.

Keywords: Upper Gastrointestinal Bleeding; Management; Outcome; ICU

Introduction

Upper gastrointestinal bleeding (UGB) is one of the important medical emergencies worldwide, accounting for high morbidity and mortality [1-4]. It requires careful management regardless of the abundance of bleeding and the mode of revelation. Its management should be rapid and appropriate, often requiring endoscopic haemostasis. It remains, despite major advances in technology, a real vital threat. The prevalence of digestive haemorrhage varies from one country to another. UGB is defined as bleeding within the lumen of the gastrointestinal tract from any location between the upper oesophagus to the duodenum at the ligament of Treitz [5].

Critical care physicians are involved in the treatment of patients with gastrointestinal bleeding in several ways. First, patients outside the ICU suffering from gastro-intestinal tract bleeding with hypovolemic shock may need ICU treatment. Secondly, patients can develop gastrointestinal bleeding as a complication during their treatment in intensive care [6]. The global mortality ranges from 5% to 30%. According to French studies, the annual incidence of UGB is roughly estimated at about 100 to 150 episodes per 100,000 inhabitants [7]. The in-hospital mortality appeared to be around 10% in United Kingdom. In countries with limited resources and no endoscopic haemostasis, mortality from digestive haemorrhages is around 30%-40%. The aim of our study was to determine the therapeutic and prognostic factors of UGB in ICU in a low-income country.

Patients and Methods

This was a descriptive, retrospective study. It included records of patients admitted to two intensive care units from January 1st, 2012, to April 30th, 2017. It included the complete records of patients admitted to the intensive care unit for acute upper gastrointestinal bleeding in the intensive care units of the Yaoundé Central Hospital and the Yaoundé University Teaching Hospital. Data collection began after approval by the National Ethics Committee. Information was collected using a pre-established data sheet. The variables studied were socio-demographic data (age, sex), clinical data (pathological history, haemodynamic parameters, mode of bleeding, admission time, initial assessment of the bleeding, biological examinations, and endoscopic findings), therapeutic data (resuscitation measures, specific treatment) and prognostic data (prognostic scores, complications, evolution, death). Patients were stratified based on prognostic scores.

These were the Advanced Trauma Life Support Classification of the American College of Surgeons (ATLAS) and the preendoscopic Rockall score. Resuscitative measures consisted of IV fluids, oxygen therapy, intubation and mechanical ventilation and blood transfusion. Data collected was entered using CSPRO 6.3 software and analyzed using SPSS 21 software. Quantitative data was expressed as means, standard deviations for those following a nominal distribution and median and interquartile range for those with a non-nominal distribution. Categorical data were represented as numbers and percentages. The search for associations between qualitative variables was carried out using the Chi-square test or Fisher’s exact test. Medical confidentiality was respected. All information obtained was treated with utmost confidentiality.

Results

During the study period, fifty-five (55) cases of gastrointestinal bleeding were identified. A total of 32 cases with complete medical files were found from which two cases of lower gastrointestinal bleeding were excluded. This left us with a sample size of 30 patients. From 2012 to 2017, 3159 patients were admitted to the 2 intensive care units. The prevalence of upper gastrointestinal bleeding was 1.74%. The male gender was predominant, with a sex ratio of 2.3:1. The mean age was 55.3 ± 19.1 years, with extremes ranging from 16 to 82 years. The mean haemoglobin level on admission was 6.6 ± 1.9g/dl with extremes from 3.50 to 12.5g/dl. Nineteen patients were admitted to the intensive care unit more than 72 hours after the onset of bleeding (63.4%). The pre-endoscopic Rockall score was greater than 0 in 29 patients (96.7%).

UGB: Upper gastrointestinal bleeding.

HIV: Human Immunodeficiency Virus.

The ATLAS classification on arrival was greater than 1 in 28 patients (93.7%). Endoscopy was performed in seven patients (23.4%). It was performed more than 72 hours after the onset of bleeding. Forrest III ulcerative lesions were the most common (n=3, 42.8%). The management of UGB combined resuscitation and specific measures. IV fluids were administered to all patients. Oxygen was administered in 13 patients (43.3%). Three patients were intubated and put on mechanical ventilation (10%). A total of 26 patients (87.7%) received blood transfusions. Packed red blood cells were the most frequently administered blood product (n=14, 53.8%). Endoscopic haemostatic treatment was performed in one patient with an active Forrest Ib bleed (14.3%). It consisted of an adrenaline injection diluted at 1:10,000. All patients received parenteral omeprazole. Tranexamic acid was administered in seven patients (23.4%). The average length of hospital stay was 5.6 ± 4.9 days, with extremes ranging from 1 to 21 days. The death rate was 50% (Table 1-3).

Discussion

The main limitation of our study was the sample size, owing to the retrospective nature of the study. Some records were not found, highlighting the difficulties of archiving in our context. Another limitation was the type of study: data was collected in two different ICU wards to increase our chances of getting cases of UGB. As a result, there is bound to be a selection bias due to the divergent practices that two different ICU wards may have. The prevalence of UGB in the ICU was 1.74%. This was like findings in literature. Cook et al. in England in 1995 found a prevalence of less than 2% [8]. The incidence of upper GI haemorrhage is estimated at 143 cases per 100,000 inhabitants in France and 150 cases per 100,000 inhabitants in the USA. In Africa, several studies have reported a hospital prevalence ranging from 2 to 17.7% [9]. Our series was predominantly male with a sex-ratio of 2.3. The mean age was 55.3 ± 19.1 years. This is consistent with data from several series studied [10-11]. Our older population is because the patients referred to the ICU were mostly high-risk, elderly patients with comorbidities. The most frequent modes of revelation of UGB were haematemesis (50.7%) and melaena (29.7%). Bleeding from the gastrointestinal tract may present in five ways:

1) Haematemesis

2) Melaena

3) Haematochezia

4) Occult gastrointestinal bleeding,

5) Features of blood loss

Or anemia such as light headedness, syncope, angina, or dyspnoea. UGB typically presents with symptoms of melaena (black, malodorous feces caused by altered haemoglobin), or haematemesis (coffee-ground appearing blood-stained vomitus, caused by blood interaction with gastric acid [12]. The management of UGB combined resuscitation and specific measures. The cornerstone of the treatment of UGIB in intensive care patients is good clinical care: restore circulation, oxygenation, and haemoglobin levels. In addition, clotting disorders should be treated to enhance clot formation and haemostasis. Usually, these measures are sufficient to stop bleeding. When bleeding persists, the next step is to obtain an endoscopic examination with or without endoscopic treatment. Rapid assessment, resuscitation and correction of coagulopathy should be undertaken, and investigation or definitive management urgently arranged. For UGB, endoscopy remains the cornerstone of investigation and treatment. Initial management of haemorrhage is common to any source and involves standard resuscitative measures.

Assessment of the patient’s airway and respiratory system is performed initially, with attention made to ensure adequacy of ventilation. The patient’s heart rate and blood pressure are recorded and wide bore peripheral venous access obtained (at least two 16 or 18- gauge intravenous cannulas) [13-14]. In all cases, patients who are in a state of hypovolemic shock need appropriate shock treatment with fluids, blood- and plasma transfusions and if needed, vasopressors. Blood loss was estimated to be greater than 500ml in 28 patients (93.7%). It was class 1 ATLS. The ATLS guidelines on haemorrhage severity and class of hypovolaemic (haemorrhagic) shock are useful tools in the estimation of blood loss in patients with significant gastrointestinal bleeding. A prompt fluid bolus of 500 ml of crystalloids is recommended for initial volume replacement. It may be prudent to adopt a policy of ‘permissive hypotension’ (maintaining blood pressure at a level required to maintain tissue perfusion and cognition) until definitive control of the source of bleeding can be established.

Blood transfusion was performed in 26 patients (87.7%). The most used blood product was packed red blood cells. Whole blood was used in 38.5% of cases. Transfusion management was in accordance with the international consensus [15]. However, there is still a high use of whole blood. This may be due to the unavailability of other labile blood products in our setting. Hospitals have a transfusion policy where, for stable patients, packed red blood cell transfusion is recommended below a threshold (typically Hb ≤ 7g/dl. When used, NICE guidelines recommend a transfusion target of Hb 8.0 g/dL in patients with cardiovascular disease and 7.0 g/dL in those without [16].

Studies have quantified massive (or major) gastrointestinal haemorrhage as requiring transfusion of at least four units of packed red blood cells. The NHS transfusion service defines it as loss of one blood volume in 24 hours (70 ml/kg), 50% of total blood volume within 3 hours, or blood loss more than 150 ml/minute. A clinical aid includes systolic blood pressure less than 90 mmHg or heart rate more than 110 beats per minute. Omeprazole administration protocols were disparate, depending on the practitioner. The recommended protocols were 80mg bolus and then 40mg/12 hours (73.3%), and 8mg/hr. with an electric syringe pump for 72 hours in one patient (3.3%). Most guidelines agree that following an endoscopic diagnosis of ulcerative disease with high-risk features, high dose proton pump inhibitor is recommended.

The European Society of Gastrointestinal Endoscopy (ESGE) recommends intravenous high dose proton pump inhibitor (omeprazole 80 mg) be given as a bolus on presentation followed by continuous infusion (omeprazole 8 mg/hr.) for all patients requiring admission. Tranexamic acid was used in 7 patients (23.3%). This drug is not recommended for the intensive care management of upper GIB. Tranexamic acid has traditionally been given to patients presenting with gastrointestinal haemorrhage. However, the landmark HALT-IT trial found no difference between tranexamic acid infusion and placebo for mortality, blood transfusion and re-bleeding. With only a very small increase in venous thromboembolism, most guidelines no longer recommend tranexamic acid for GI bleeding [17]. Approximately one in four patients benefited from endoscopy. The time to perform endoscopy was > 72 hours.

This was due to the low level of technical facilities in these two hospitals and the high cost of endoscopy in our setting. This was different from the international recommendations for the management of upper GIB which suggest that endoscopy should be performed within 24 hours of the clinical manifestations of the haemorrhage in a stable patient. Patients who are haemodynamically unstable and with evidence of active bleeding should undergo immediate endoscopy after initial resuscitative measures. All patients requiring admission should receive endoscopy within 24 hours. Even after a period of stabilization, if the patient further deteriorates, immediate repeat intervention is necessary. Ulcerative lesion was the main endoscopic lesion found. This is consistent with the study by Ankouane et al, which found a peptic ulcer lesion in 38% of patients. Bagny et al. in Togo reported an ulcer lesion in 26% of cases. This high prevalence of ulcerative lesions was explained by the fact that the patients were elderly subjects with comorbidities.

Peptic ulcer disease is the most common cause for upper GI bleeding and accounts for approximately 31% to 67% of presentations. Benign peptic ulcers are best assessed endoscopically where they are typically described as having smooth, rounded edges. The Forrest classification categorises ulcers into three classes, which helps guide management and stratifies risk in patients at high risk of re-bleeding and mortality. Any ulcer other than a 2c or 3 is considered high risk. Only one patient received perendoscopic haemostatic treatment. This result could be explained by the non-availability of an endoscopy unit in these two hospitals. This highlights the lack of infrastructure for the management of UGB. The death rate was 50%. This was due to the severity of the patients admitted to the intensive care unit. The pre-endoscopic Rockall score was greater than 0 in 29 patients (96.7%), indicating a high risk of mortality. The in-hospital mortality appeared to be around 10% in United Kingdom. In countries with limited resources and no endoscopic haemostasis, mortality from digestive haemorrhages is around 30% - 40%. Mortality related to UGB was 36.6% in Brazzaville.

It remains high between 17 and 40% in other African countries [18-19]. On the other hand, in the centres that perform endoscopic haemostasis, mortality is low [20-22]. It was of 3% in Gabon in 2018, around 5% in France. The severity of bleeding is assessed by four main clinical factors and the haematocrit. The clinical factors are tachycardia greater than 110 beats per minute, systolic hypotension less than 80mmHg, tachypnoea greater than 20 cycles and the presence of skin mottling. Several scoring systems rate the severity of illness and their prognostication of patients who present with bleeding outside the ICU. A recent study showed that the AIMS65 and Glasgow- Blatchford scores performed better than the pre-endoscopic Rockall score and pre-endoscopi. Baylor score. There is an association between endoscopy performed more than 24 hours after admission and increased risk of mortality. In multivariate analysis, the risk factors for mortality were age between 30 and 60 years old, male sex and late hospitalization. The high mortality rate in our series is probably related to the lack of endoscopic haemostasis.

Conclusion

The prevalence of UGB in the ICU is low. Males predominate. The management was based on emergency measures and specific treatment. Mortality is high. The reduction of the mortality rate in ICU requires considering the identified risk factors and the acquisition of endoscopic haemostasis equipment.

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Monday, July 20, 2026

Randomized Controlled Trial on the ASSYST Treatment Intervention with Female Children Polytraumatized by Adverse Childhood Experiences, Neglect, and Maltreatment- Juniper Publishers

Pediatrics & Neonatology- Juniper Publishers

Abstract

The aim of this randomized controlled trial with an intention-to-treat analysis was to evaluate the effectiveness, efficacy, and safety of the Acute Stress Syndrome Stabilization Individual (ASSYST-I) treatment intervention in reducing posttraumatic stress disorder (PTSD) symptoms in female children polytraumatized by adverse childhood experiences, neglect, and maltreatment. A total of 40 female children met the inclusion criteria and participated in the study. Participants’ ages ranged from 8 to 17 years old (M =14.67 years). A two-arm randomized controlled trial (RCT) design was applied. PTSD symptoms were measured in three-time points for all participants in the study. Results showed that the intervention had a significant effect for time on PTSD symptoms (F (2,76) = 36.92 p <.000, η² = .493). A significant effect for group was also found (F (1, 38 = 32.7, p<.005, η² = .896) with a large effect, and a significant interaction between time and group, (F (2, 76) = 56.00, p <.000, η² = .600). Means comparison using t test between groups showed significant differences between the Treatment Group (TG) and the Control Group (CG) in the three-time points comparisons showing a large effect on Time 2 (Post-treatment assessment) which was maintained on Time 3 (Follow-up assessment). Results on the Reliable Change Index (RCI) and the Clinically Significant Change (CSC) Margin showed that the ASSYST-I treatment intervention exhibited reliable change on PTSD symptom reduction and clinically significant change, indicating that the treatment group participants are more likely to belong to the non-PTSD population after the intervention. Conversely, the control group participants are more likely to belong to the PTSD population. No adverse effects or events were reported by the participants during the treatment procedure administration or at follow-up. None of the participants showed clinically significant worsening/exacerbation of symptoms after treatment. Participants in the control group received the intervention treatment after the follow-up assessment, fulfilling our ethical criteria.

Keywords: Acute Stress Syndrome Stabilization; ASSYST; Posttraumatic stress disorder (PTSD), Female Children; Adverse Childhood Experiences; Neglect and Maltreatment

Introduction

Childhood abuse, neglect, and maltreatment, and especially polytraumatization, are known contributing factors to long-term insidious detrimental health defects. While definitions of abuse, neglect, and maltreatment vary and have evolved, the consensus in the scientific literature is that child maltreatment refers to acts of both commission (abuse) and omission or deprivation (neglect) that result in harm, potential harm, or threat of harm to a child and encompasses a variety of lived experiences [1]. These health defects in adults, such as diabetes, heart attack, obesity, cardiovascular and respiratory diseases, cancer, higher mortality rate, drug abuse, depression, anxiety, have been correlated with those who have lived adverse childhood experiences or ACEs, which include child abuse, neglect, and maltreatment, and are partially due to homeostatic changes to physiology and epigenetic processes during critical developmental periods [2-9].

Specifically, ages 3–5 have been associated with hippocampus development and exposure to abuse, neglect, and maltreatment may result in heightened vulnerability to later dissociation and posttraumatic stress disorder (PTSD), with ages 11–13 a key period affecting hippocampal development if exposed to abuse and neglect, age 10-11 affecting amygdala development, and ages 14-16 affecting prefrontal cortex development [10]. The neural processes affected in those who have experienced child abuse, neglect, and maltreatment are mainly in fronto-limbic networks including the medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, hippocampus, and amygdala, with neglect related to developmental changes in insula activation during risk processing and abuse related to developmental changes in fronto-parietal activation during cognitive control [11]. Studies also show that a smaller volume and altered activity patterns in the ventromedial region of the prefrontal cortex (vmPFC) have been observed in children with PTSD, suggesting the implication of frontal lobe circuitry in altered fear extinction features, affecting fear conditioning and learning, having important treatment implications [12].

The prevalence of child abuse, neglect, and maltreatment is alarming. On April 6, 2022, the United States Center for Disease Control and Prevention (CDC) reported that 1,750 children died of abuse and neglect in the year 2020 and that of the 74.2 million children in the US 10.6 million, or 1 out of 7, has experienced maltreatment in the previous year, which is likely underestimated due to lack of reporting [13]. Therefore, the need for prevention of child abuse, neglect, and maltreatment is crucial. In instances where prevention is not occurring, effective, efficient, and safe evidence-based PTSD treatment interventions for polytraumatized children is essential for the health, growth, and functioning of individuals, families, and communities.

AIP Theoretical Model

According to the Adaptive Information Processing (AIP) theoretical model memory networks of stored experiences are the basis of both human mental health and human pathology across the clinical spectrum. AIP disruptions due to high arousal states from adverse life experiences result in pathogenic memories that are inadequately processed and dysfunctionally stored in the brain. The information stored in these neurophysiological memory networks generates the present suffering, difficulties, and symptoms across the clinical spectrum [14,15].

PTSD and Intrusion Symptoms

According to the Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) posttraumatic stress disorder (PTSD) is a trauma- and stressor-related disorder occurring after exposure to one or more traumatic events (Criterion A). These Criterion A events include, but are not limited to, threatened or actual physical assault (e.g., childhood physical abuse, physical attack), threatened or actual sexual violence (e.g., forced sexual penetration, alcohol/drug-facilitated sexual penetration, abusive sexual contact, noncontact sexual abuse, sexual trafficking) (p. 274) [16].

PTSD Intrusion Symptoms associated with the traumatic event(s), beginning after the traumatic event occurred, are 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). 2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s). 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). 5. Marked physiological reactions to internal or external clues that symbolize or resemble an aspect of the traumatic event(s). “These intrusive memories often include sensory (e.g., sensing the intense heat that was perceived in a house fire), emotional (e.g., experiencing the fear of believing that one was about to be stabbed), or physiological (e.g., experiencing the shortness of breath that one suffered during a near-drowning) components.Some individuals with the disorder do not have intrusive memories of the event itself, but instead experience intense psychological distress or physiological reactivity when they are exposed to triggering events that resemble or symbolize an aspect of the traumatic event” (p. 271, 282-283) [16].

Acute Stress Syndrome Stabilization Individual Treatment Intervention

The Acute Stress Syndrome Stabilization (ASSYST) Individual treatment intervention was born during humanitarian fieldwork and is an AIP-informed, evidence-based, carefully field-tested, and user-friendly psychophysiological algorithmic approach, whose reference is the EMDR Protocol for Recent Critical Incidents and Ongoing Traumatic Stress (EMDR-PRECI) [17-25]. This treatment intervention is specifically designed to provide in-person or online support to clients who present Acute Stress Disorder (ASD) or Posttraumatic Stress Disorder (PTSD) intense psychological distress and/or physiological reactivity caused by the disorders’ intrusion symptoms associated with the memories of the adverse experience(s).

The objective of this treatment intervention is focused on the patient’s Autonomic Nervous System sympathetic branch hyperactivation regulation through the reduction or removal of the activation produced by the sensory, emotional, or physiological components of the pathogenic memories of the adverse experience(s) to achieve optimal levels of Autonomic Nervous System activation, stop the three major stress hormones [adrenaline (epinephrine), noradrenaline (norepinephrine), and cortisol] secretion, and reestablish the Prefrontal Cortex functions (e.g., processing of information); thus, facilitating the AIP-system and the subsequent adaptive processing of information [26].

Previous ASSYST Treatment Intervention Studies:

Seven previous studies on the ASSYST treatment interventions have proven their efficacy and safety with different populations: (I) General population in lockdown and with ongoing traumatic stress during the COVID-19 Pandemic. (II) TeleMental Health counseling to the general population after adverse experiences. (III) Mental Health Professionals working during the COVID-19 Pandemic with patients suffering from trauma-related disorders and stressors. (IV) General population with non-recent pathogenic memories. (V) Adult Syrian refugees living in Lebanon. (VI) Adult Females with Adverse Childhood Experiences. (VII) Public sector workers during the COVID-19 pandemic [27-33].

Reliable Change Index and Clinically Significant Change Margin

To know whether PTSD symptoms change does indeed indicate reliable and clinical significant change in this study, we used the Reliable Change Index (RCI) and the Clinically Significant Change (CSC) Margin. The RCI is used to determine if the magnitude of observed change over time on a given measure is beyond what should be attributed to measurement error. The CSC is used to determine if an observed end score on a measure of symptomatology indicates that respondent is more likely to belong to the non-disordered population than the disordered population. For the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL- 5), the more conservative value of the RCI is 18-points and ≤ 28 end score for the CSC margin [34].

Objective

The objective of this randomized controlled trial with intention-to-treat analysis was to evaluate the effectiveness, efficacy, and safety of the Acute Stress Syndrome Stabilization Individual (ASSYST-I) treatment intervention in reducing posttraumatic stress disorder (PTSD) symptoms in female children polytraumatized by adverse childhood experiences, neglect, and maltreatment.

Method

Study design

To measure the effectiveness of the ASSYST-I on the dependent variable PTSD symptoms, this study with an intention-to-treat analysis used a two-arm randomized controlled trial (RCT) with a waitlist no-treatment control group design. PTSD symptoms were measured at three time points for all participants in the study: Time 1. Pre-treatment assessment; Time 2. Post-treatment assessment; and Time 3. Follow-up assessment. For ethical reasons, all participants in the control group received the intervention treatment after the follow-up assessment was competed.

Ethics and research quality

The research protocol was reviewed and approved by the EMDR Mexico International Research Ethics Review Board (also known in the United States of America as an Institutional Review Board) in compliance with the International Committee of Medical Journal Editors recommendations, the Guidelines for Good Clinical Practice of the European Medicines Agency (version 1 December 2016), and the Helsinki Declaration as revised in 2013. The research quality of this study was based on the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement and the Standard Protocol Items Recommendation for Interventional Trials (SPIRIT) 2013 checklist [35,36].

Participants

This study was conducted in Toluca City, Mexico, from May to July 2023, with the Mexican (Latina) female child population with pathogenic memories from adverse childhood experiences (ACEs), neglect, and maltreatment living in a center under the Mexican Government’s protection. Forty-seven potential participants were recruited. Inclusion criteria was: (a) being a female child, (b) having pathogenic memories from ACEs, neglect, and maltreatment causing current distress, (c) voluntarily participating in the study, (d) not receiving specialized trauma therapy, (e) not receiving drug therapy for PTSD symptoms, (f) having a PCL-5 total score of 33 points or more. Exclusion criteria was: (a) ongoing self-harm/suicidal or homicidal ideation, (b) diagnosis of schizophrenia, psychotic, or bipolar disorder, (c) diagnosis of a dissociative disorder, (d) organic mental disorder, (e) a current, active chemical dependency problem, (f) significant cognitive impairment (e.g., severe intellectual disability, dementia), (g) presence of uncontrolled symptoms due to a medical illness. Seven of the 47 potential participants were excluded due to having PCL-5 scores under 33 points (subclinical symptoms). These seven participants have been living in the center since they were very young and were not exposed to prolonged adverse experiences like the other participants. A total of 40 females children met the inclusion criteria and participated in the study. Participants’ ages ranged from 8 to 17 years old (M =14.67 years). Participation was voluntary with the participants’ and their legal guardians signed informed consent in accordance with the Mental Capacity Act 2005.

Instruments for Psychometric Evaluation

a) We used the Trauma Screen Checklist from the Child PTSD Symptom Scale for DSM-5 for trauma-exposed children and adolescents for the study participants to choose the traumatic events they have lived prior to being rescued by the Mexican Government. This list contains 15 frightening or stressful events that can happen to children and all of them fulfill DSM-5 PTSD Criterion A. Participants chose the event that bothered them the most to answer the PCL-5 during the three assessment times [37,38].

b) To measure PTSD symptom severity and treatment response, we used the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) provided by the National Center for PTSD (NCPTSD) with the time interval for symptoms to be the past week. The instrument was translated and back-translated to Spanish. It contains 20 items, including three new PTSD symptoms (compared with the PTSD Checklist for DSM-IV) [39,40]: blame, negative emotions, and reckless or self-destructive behavior. Respondents indicated how much they have been bothered by each PTSD symptom over the past week (rather than the past month), using a 5-point Likert scale ranging from 0=not at all, 1=a little bit, 2=moderately, 3=quite a bit, and 4=extremely. A total symptom score of zero to 80 can be obtained by summing the items. The sum of the scores yields a continuous measure of PTSD symptom severity for symptom clusters and the whole disorder. Psychometrics for the PCL-5, validated against the Clinician- Administered PTSD Scale-5 (CAPS-5) diagnosis, suggest that a score of 31-33 is optimal to determine probable PTSD diagnosis, and a score of 33 is recommended for use at present [38-40].

Procedure

Randomization, Allocation Concealment Mechanism, and Blinding Procedure

A computer-generated simple randomization with a 1:1 allocation ratio was used. Two independent assessors blind to treatment conditions conducted the randomization process to avoid allocation influence. The treatment random allocation sequence was concealed using sequentially numbered, opaque, sealed, and stapled envelopes who were open only after they were irreversibly assigned to the participants. The safekeeping of the envelopes and the assignment of participants to each arm of the trial (implementation of the random allocation sequence) was overseen by a person not involved in the research study and independent of the enrollment personnel. The treatment allocation of the participants was blinded for the research assistants who conducted the intake interview, initial assessment, and enrollment, and also for the independent assessors who conducted the followup assessments. Participants were instructed to not reveal their treatment allocation to the persons conducting the assessments. Twenty participants were allocated in the treatment group (TG) and twenty participants in the control group (CG). See Figure 1. Flow Diagram.

Enrollment, Assessments Times, Blind Data Collection, and Confidentiality of Data

Treatment group (TG) and control group (CG) participants completed the instruments in person and on an individual basis during distinct assessment moments. During Time 1, research assistants formally trained in all of the instruments’ administration, who were not blind to the study, but blind to the participant’s treatment allocation, conducted the intake interview, collected demographic data (e.g., name, age, gender, and contact information), assessed potential participants for eligibility based on the inclusion/exclusion criteria, obtained signed informed consent from the participants and their legal guardians, conducted the pre-treatment application of instruments, enrolled participants in the study, and randomly assigned each treatment group participant to one of the four clinicians formally trained in the ASSYST-I that participated in this study.

The research assistants also assisted the participants in identifying the pathogenic memory of their worst adverse experience from the Trauma Screen Checklist to be treated with the ASSYST-I. Each identified memory was written down by the research assistants on the Memory Record Sheets that were utilized by the clinicians during the ASSYST-I treatment intervention and utilized by participants during the three assessments times to ensure participants were focusing on the same memory when they received the treatment intervention, as well as the specific assessment time when they completed the assessment tools.

To obtain maximally interpretable PCL-5 scores, research assistants and independent assessors a) discussed with each participant the purpose of the instrument in detail, b) encouraged attentive and specific responding, c) invited participants to read each question carefully before responding and to select the correct answer, d) clarified their questions about some the symptoms, such as differentiating between intrusive memories and flashbacks, e) reworded conceptually complex symptoms (i.e., symptoms in the reexperiencing cluster) when necessary, f) reminded participants of the last-week symptom’s time frame, as well as, g) to only report symptoms related to the pathogenic memory of their worst adverse experience and not based on their everyday general distress.

During Time 2 (post-treatment assessment 7 days after treatment), and Time 3 (follow-up assessment 30 days after treatment), assessments were conducted for all participants by blind to treatment allocation independent assessors with formal training in administration of the instruments. The data safe keeper independent assessor received the participant’s assessment instruments that were answered during Times 1, 2, and 3. All data was collected, stored, and handled in full compliance with the EMDR Mexico International Research Ethics Review Board requirements to ensure confidentiality. Each study participant and their legal guardians gave their consent for access to their data, which was strictly required for study quality control. All procedures for handling, storing, destroying, and processing data were in compliance with the Data Protection Act 2018. All persons involved in this research project were subject to a signed professional confidentiality agreement.

Withdrawal from the Study and Missing Data

All research participants had the right to withdraw from the study without justification at any time and with assurances of no prejudicial result. If participants decided to withdraw from the study, they were no longer followed up in the research protocol. There were no withdrawals or missing data during this study.

Treatment

Clinicians and Treatment Fidelity

The ASSYST-I was provided in-person to individual participants by four licensed clinicians formally trained in this treatment intervention. Clinicians received on-going supervision and clinical feedback from the research project Clinical Director through daily group supervision and completing detailed session summary forms for each session with each participant that they were assigned that were designed specifically for the ASSYST-I treatment intervention to guide, elicit, monitor, and facilitate clinicians’ treatment adherence.

Treatment Description and Treatment Safety

An AIP & Symptom trajectory-based stepped care approach to adverse experiences was used during this study. This means a stepped progression of mental health care provided in an increasingly intensified manner based on the ongoing monitoring of the PTSD symptom trajectory during the study. The main objectives of this approach are a) to strategize treatment, b) to provide the treatment interventions according to the progression of the pathophysiology, and c) to improve symptom relief and clinical outcomes. After an adverse experience, the steps we follow are based on current evidence-based interventions. Step 1. Watchful waiting (monitoring of symptoms over time). Step 2. Psychoeducation, and support from families and close friends. Step 3. ASSYST for Individuals or Groups. Step 4. EMDR Integrative Group Treatment Protocol. Step 4. EMDR Protocol for Recent Critical Incidents and Ongoing Traumatic Stress. Step 5. Pharmacotherapy.

Participants’ treated memories were an average of 4.56 years old and received six in-person sessions, with an average length of 35-40 minutes per session. The ASSYST-I treatment intervention focused on the pathogenic memory produced by the worst adverse experience selected during T1. Pre-treatment assessment. To ensure the continuity and congruency of the intervention and measurement of its efficiency and efficacy, as mentioned above, during the intake interview after the memory was selected, the research assistants conducting the intake interview wrote down the specific memory on a Memory Record Sheet, which was used during each session of the ASSYST-I treatment procedure and was referenced to answer T1, T2, and T3 assessments.

At the beginning of the first treatment session, the participants were asked to run a mental movie of the specific previously selected memory, and then to choose the worst part. The treatment intervention was considered complete when the participant’s subjective levels of disturbance associated with the pathogenic memory decreased to zero or one (ecological/realistic). The ASSYST treatment intervention was provided to all the treatment group participants in an intensive treatment modality with two 60 minutes (max) sessions provided per day over three consecutive days.

Treatment safety was defined as the absence of adverse effects, events, or symptoms worsening. Therefore, participants were instructed by their clinicians to immediately report any adverse effects (e.g., dissociative symptoms [derealization/ depersonalization], fear, panic, freeze, shut down, collapse, fainting); events (e.g., suicidal ideation, suicide attempts, selfharm, homicidal ideation); or symptoms worsening during the entire study timeframe. A clinician working at the center on a regular basis was in charge of reporting to the research project Clinical Director any adverse effects, events, or worsening of symptoms during the study. No adverse effects or events were reported by the TG participants during the treatment procedure administration or at thirty-day follow-up. None of the participants in the TG showed clinically significant worsening/exacerbation of symptoms on the PCL-5 after treatment.

Examples of the Pathogenic Memories Treated with the ASSYST-I

Participants chose an average of five out of the fifteen traumatic events from the Trauma Screen Checklist. Examples of pathogenic memories treated during the ASSYST-I sessions were: a) Having been expelled from her house at age 8, being homeless, suffering continuous sexual rape including 10 men at the same time, and severe physical violence for years; b) having been burned on the genitals and legs with a lighter and on the back with a frying pan, and stabbed in the hand with a knife by the stepmother; c) attempted drowning in a water tank, hit with an electric cable, and burned by the stepmother; d) having been kidnapped, and for a whole year sexually abused, beaten, and her body used to test injected drugs; e) having been exploited by a sect; f) being tied to a chair and beaten by both parents.

Statistical Analysis

To analyze the effect of the ASSYST-I treatment on PTSD symptoms, analyses of variance (ANOVA) for three times repeated measurements (Time 1. Pre-treatment assessment; Time 2. Post-treatment assessment; and Time 3. Follow-up assessment), comparing Treatment group (TG) vs Control group (CG) was carried out. Eta squared (η²) is reported to show the effect sizes. Mean comparisons between and within groups using t test were conducted; Cohen´s d, is included to report the effect size.

Results

Effects on PTSD symptoms

Results showed that the intervention had a significant effect for time on PTSD symptoms (F (2,76) = 36.92 p <.000, η² = .493). A significant effect for group was also found (F (1, 38 = 32.7, p<.005, η² = .896) with a large effect, and a significant interaction between time and group, (F (2, 76) = 56.00, p <.000, η² = .600).

Mean comparisons between groups

Means comparison using t test between groups showed significant differences between the Treatment Group (TG) and the Control Group (CG) in the three time-point comparisons. For Time 1. Pre-treatment assessment (M = 55.70, SD = 10.50 vs M = 46.40, SD = 14.50), t (38) = 2.32, p<.05, d = .73, with a medium effect size. For Time 2. Post-treatment assessment. (M = 27.55, SD = 20.71 vs M = 52.00, SD = 15.74), t (38) = -4.20, p = .000, d = -1.72, with a large effect size and for Time 3. Follow-up assessment (M = 20.65, SD = 18.62 vs M = 48.95, SD = 15.46), t (38) = - 5. 22, p = .000, d = -1.65, also with a large effect size.

Mean comparisons within groups:

Intragroup means comparisons using t test for Treatment group (TG) showed significant differences between Time 1 Pretreatment assessment and Time 2. Post-treatment assessment, t (19) = 7.40, p=.000, d = .73, with a medium effect size. Comparisons between Time 2. Post-treatment assessment and Time 3 Follow-up assessment, t (19) = 2.17, p < .05, d =. 24 also showed significant differences, with a small effect size.

Intragroup means comparisons using t test for Control group (CG) showed significant differences both with a small effect size. between Time 1. Pre-treatment assessment and Time 2. Posttreatment assessment, t (19) = -2.56, p =.01, d = -.25 and between Time 2. Post-treatment assessment and Time 3. Follow-up assessment, t (19) = 3.70, p=.001, d = .13. See Table 1 and Figure 2.

*Statistically significant differences between groups with a large effect size.

Discussion

The aim of this randomized controlled trial with an intentionto- treat was to evaluate the effectiveness, efficacy, and safety of the Acute Stress Syndrome Stabilization Individual (ASSYST-I) treatment intervention in reducing posttraumatic stress disorder (PTSD) symptoms in female children polytraumatized by adverse childhood experiences, neglect, and maltreatment. A total of 40 females children met the inclusion criteria and participated in the study. Participants’ ages ranged from 8 to 17 years old (M =14.67 years). A two-arm randomized controlled trial (RCT) design was applied.

Result showed statistically significant differences between groups from the pre-treatment assessment with a lower score for PTSD symptoms for the Control group, the effect size of these differences by Time 1 was considered small according to Cohen´s calculator. However, significant differences with a large effect size were found for the Post-treatment and Follow-up assessment comparing the two groups. For the Post-treatment assessment scores had increased for the Control Group in contrast with the Treatment group, this statistically significant difference was confirmed with the large effect size obtained. These differences between groups were maintained by the follow up assessment and can be attributed to the treatment.

Regarding the Reliable Change Index (RCI), 18 out of 20 TG participants (90%) exhibited reliable change on symptom reduction with an average of 37.61 points of PTSD symptom reduction, 18-points being the more conservative value. This is indicative that the ASSYST-I treatment intervention reduced PTSD symptom severity beyond what is attributable to measurement error.

In reference to the Clinically Significant Change (CSC) margin, 14 out of 20 TG participants (70%) exhibit clinically significant change, indicating that these participants are more likely to belong to the non-PTSD population. Following our AIP & Symptom trajectory-based stepped care approach to adverse experiences, EMDR therapy was provided to the six participants that did not reach a CSC margin after the Time 3 Follow-up assessment.

Conclusion

The evidence of the detrimental mental and physical effects of ACEs, particularly child abuse, neglect, and maltreatment, has been well documented and researched, and the individual and societal negative outcomes are widely known. Prevention is the most effective and ideal approach to combating PTSD and PTSD symptoms in children and adolescents. For those who have experienced ACEs or various types of child maltreatment, vital to the health of children, and long-term health outcomes of adults is an effective and efficient (time and cost) PTSD treatment intervention that can be used with children to prevent undesirable long-term health outcomes. With the abundance of studies demonstrating the negative effects of ACEs and childhood maltreatment, there is a lack of studies with evidence for effective PTSD treatment in polytraumatized children, which is a devastating problem that does not know regional confinement, causing mental and physical health problems, at a neural and structural level, that requires high quality, evidence-based PTSD treatment interventions. This paper is intended to fill some of the gap in the lack of research and evidence for PTSD treatment interventions for polytraumatized children.