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Oct 24, 2024

Investigating the effect of synbiotic supplementation on inflammatory indices in critically ill septic children: a protocol study for randomized control trial | Trials | Full Text

Trials volume 25, Article number: 712 (2024) Cite this article Metrics details Sepsis, a severe inflammatory response to infection, is a global health priority due to its high mortality and long-term

Trials volume 25, Article number: 712 (2024) Cite this article

Metrics details

Sepsis, a severe inflammatory response to infection, is a global health priority due to its high mortality and long-term disability rates. Its pathophysiology involves both inflammation and immune suppression. Managing sepsis requires significant healthcare resources and expenditure, with sepsis being a leading cause of hospital costs. Gut microbiotas play a crucial role in sepsis, and probiotics show promise in managing it by restoring microbial balance. Despite advances, targeted therapies for sepsis remain elusive, necessitating innovative approaches such as probiotic therapy.

Fifty-four eligible patients with sepsis will be randomly assigned to either the synbiotic or placebo group. The synbiotic supplement, KidiLact, comprises ten probiotic strains and prebiotic fructooligosaccharides. Participants will receive two sachets daily for 7 days, mixed with sterile water and administered orally or via gavage. Inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) will be evaluated. Anthropometric measurements, nutritional assessment, biochemical analysis, and clinical evaluation will be conducted to assess treatment outcomes. Statistical analysis will be performed to compare results between the two groups, employing SPSS version 19 with a significance level of P < .05.

This randomized clinical trial aims to evaluate synbiotic supplementation effects on inflammatory markers and clinical outcomes in pediatric sepsis patients in the pediatric intensive care unit (PICU). Probiotics have shown promise in reducing proinflammatory cytokines like IL-6, TNF-α, and CRP, which are vital in the inflammatory response. Synbiotics can enhance gut integrity, preventing pathogen translocation and reducing inflammation. If our expectations regarding the effects of probiotics are correct, we can use them as a cost-effective supplement to improve the condition of pediatric sepsis in hospitals.

IRCT,IRCT20230523058266N1 Registered 30 October 2023, https://irct.behdasht.gov.ir/trial/71397.

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Sepsis represents a systemic inflammatory response syndrome, characterized by life-threatening organ dysfunction triggered by confirmed or presumed infection [1, 2]. Designated as a medical emergency by the World Health Organization (WHO), sepsis prevention, identification, and treatment are recognized as critical global health priorities. While bacteria have historically been considered the primary causative agents, sepsis can also arise from viruses, fungi, and parasites [2]. Recent investigations have revealed a more nuanced understanding, highlighting those patients with sepsis experience both prolonged inflammation and immune suppression, hindering their recovery [3].

The management of sepsis demands substantial healthcare resources and entails considerable financial expenditure [2]. It is notable that many nations have identified sepsis as one of the most economically burdensome hospital conditions [1]. Epidemiological data underscore the persistent challenge of sepsis worldwide, particularly its significant morbidity and mortality among children [4,5,6,7,8]. Alarmingly, sepsis claims over one million lives annually globally among pediatric and infant populations. The prevalence of sepsis in PICUs (Pediatric Intensive Care Units) in Iran is reported to be 10–15% [9].

Hospitalization costs associated with sepsis have escalated dramatically over the past decade, totaling an estimated one billion dollars [10]. Regrettably, sepsis accounts for more than one third of fatalities in PICUs. The prevalence of sepsis in children is rising, fueled by factors such as chronic illnesses, the emergence of multidrug-resistant organisms (MDR), opportunistic infections, and intensified surveillance efforts [11].

Systemic syndromes like sepsis disrupt the gut environment, favoring pathogens over beneficial bacteria. The gut plays a pivotal role in the inflammatory cascade underlying sepsis. Disruption of intestinal epithelial homeostasis during sepsis leads to increased proinflammatory cytokine secretion, compromised barriers, and apoptosis, culminating in multi-organ failure [12]. Understanding the profound impact of gut microbiota on health and disease, alongside advances in sepsis pathophysiology, is crucial.

Preclinical studies suggest that a diverse and balanced gut microbiota can enhance host immunity against enteric and systemic pathogens. Conversely, an imbalance in this microbiota may increase susceptibility to sepsis [13, 14]. Despite advances in understanding pathophysiological mechanisms, targeted therapies to modulate the dysregulated host response have not succeeded. Presently, physicians can only offer supportive care and antibiotics, emphasizing the necessity for innovative strategies [15]. Probiotics, nonpathogenic bacteria inhabiting the intestine, offer numerous benefits to the host [12].

Recent randomized controlled trials have highlighted the potential of probiotics in both pediatric and adult populations within intensive care units (ICUs). Leveraging probiotics as a potential treatment for severe infections and septic shock holds promise as a cost-effective preventative strategy, particularly in the context of escalating antimicrobial resistance [12]. Recognizing the severity of sepsis, particularly in pediatric patients, given its high complication and mortality rates, this study aims to investigate the potential impact of probiotics on the management of sepsis in children hospitalized in the PICU.

This study aims to investigate whether a synbiotic supplement can reduce inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) in children with sepsis admitted to the PICU.

Additionally, the study aims to assess whether the administration of a synbiotic supplement can decrease the length of hospitalization in the PICU, the duration of ventilator support, the duration of antibiotic treatment, and the mortality rate.

The primary hypothesis of the research is that the synbiotic supplement will have a mitigating effect on inflammatory markers. Secondary hypotheses include the reduction of hospitalization duration in the PICU, duration of ventilator support, duration of antibiotic therapy, and mortality rate compared to placebo.

This triple-blind, randomized controlled trial will be conducted at Akbar Children’s Hospital in Mashhad, Iran. A total of fifty-four pediatric patients aged 1 month to 10 years with sepsis will be recruited from the PICU. The study protocol has received approval from the Ethical Committee of Mashhad University of Medical Sciences (IR.MUMS.MEDICAL.REC.1402.352) and has been registered in the Iranian Registry of Clinical Trials (IRCT20230523058266N1). Participants will provide informed consent, signed by their legal guardians, prior to enrollment.

Sample size calculation was based on data from Angurana et al. wherein the anticipated reduction in the inflammatory marker interleukin-6 in the synbiotic supplement group was compared to the placebo group after 7 days of intervention and at the study’s conclusion. Using the formula for calculating sample size for comparing two proportions with 80% power, a sample size of twenty-five individuals was determined for each group. Accounting for a dropout rate of up to 5%, 27 individuals will be assessed in each group [16].

All participants will be briefed on the study’s objectives and design.

Inclusion criteria

Exclusion criteria

Patients hospitalized in the PICU diagnosed with sepsis with an anticipated hospital stay of more than 4 days in the PICU

Immunodeficiency or malignancy

Age ranging from 1 month to 10 years

Prior receipt of steroid therapy or immunotherapy

Parental or legal guardian with parental consent for participation in the study

Congenital abnormalities incompatible with life

Previous gastrointestinal surgery within the last month

Diagnosis of ulcerative colitis

Presence of short bowel syndrome

Patient discharge or transfer to other hospital departments

Taking synbiotic supplement in the last 1 month

Following eligibility assessment and obtaining an informed consent form from the patient’s parents or legal guardian, fifty-four patients with sepsis hospitalized in the PICU will be randomly assigned to either the synbiotic group or the placebo group. Participant flow diagram according to the Consolidated Standards of Reporting Trials (CONSORT) presented in Fig. 1.

Participant flow diagram according to the Consolidated Standards of Reporting Trials (CONSORT)

Sepsis diagnosis will be established based on the presence of infection, supported by clinical or microbiological evidence, along with the manifestation of at least two of the four systemic inflammatory response criteria (SIRS), as will be confirmed by a pediatrician. The SIRS criteria include (1) body temperature (rectal) exceeding 38 °C or falling below 36 °C, (2) heart rate surpassing 90 beats per minute, (3) respiratory rate exceeding 20 breaths per minute or partial pressure of carbon dioxide less than 4.3 kPa, and (4) neutrophil count exceeding 12,000/mm3 or neutropenia less than 4000/mm3 with 10% or more immature neutrophils in peripheral blood.

Randomization will be performed using dedicated randomization sites (Sealed Envelope), employing block randomization (blocks of 4 and 6). Synbiotic and placebo sachets will be indistinguishably packaged in containers with identical appearance, odor, and taste. Opaque packages will contain either synbiotic or placebo, each labeled with a random allocation number. The allocation of random numbers and preparation of packages will be conducted by an individual not involved in patient registration, data collection, entry, or analysis. Separate codes will be assigned to the packages, ensuring blinding of patients, researchers, evaluators, and analysts.

We do not anticipate any requirement for unblinding, but if required, the trial manager, data coordinator, implementation support facilitators, and care home managers will have access to group allocations, and any unblinding will be reported.

The KidiLact synbiotic supplement (Zist Takhmir Company, Tehran, Iran) comprises ten strains of probiotic bacteria (109CFU), including Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus reuteri, Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Streptococcus thermophiles, and prebiotic fructooligosaccharides.

Prior to study initiation, the content of the supplement and placebo underwent blinded laboratory examination to ensure accuracy.

Participants will receive two KidiLact sachets (Zist Takhmir Company, Tehran, Iran) daily administered by a nurse. It is essential to note that KidiLact sachets will be stored in the refrigerator to maintain the maximum potency of probiotic bacteria strains. Based on Angurana et al.’s 2018 study, the effective dosage of synbiotics is two sachets per day for 7 days, which demonstrated a reduction in inflammatory markers such as IL-6, TNF-alpha, ESR, and CRP. Consequently, the dosage for this study has been determined based on this research and calculated by a qualified pharmacologist consultant [16].

The control group will receive a placebo (Zist Takhmir Company, Tehran, Iran) containing maltodextrin and with a similar appearance.

The contents of the probiotic or placebo sachet will be mixed with 5 mL of sterile water in a plastic cup and administered to the patient via gavage if enteral nutrition is provided. For patients receiving oral nutrition, the mixture will be fed directly to the patient.

To prevent potential interactions with antibiotics, a minimum 8-h interval will be observed between the administration of the probiotic supplement and antibiotics.

Research team will ensure the correct implementation of the intervention by clinical supervision of the intervention process. The researcher will visit the patients daily to monitor their progress, review their tests, and assess their overall condition. Additionally, doctors and nurses will conduct daily visits to evaluate the patients’ test results and general health history. The experimental steering committee will convene biweekly to review the work process, monitoring, recording, and addressing any potential complications.

Body weight will be measured using a digital scale with an accuracy of 0.1 kg, while height will be measured with a tape measure. For individuals who can stand, height measurement will be taken with bare feet, whereas for those connected to ventilators, height will be measured while lying down. Body mass index will be calculated as body weight (kg) divided by the square of height (m2) [17].

Nutritional adequacy and changes in food intake will be recorded daily. The prescribed and delivered amounts of energy and protein will be monitored and the difference calculated and recorded.

Peripheral blood samples (2 mL) will be collected in plain vials from each patient by venipuncture within 12 h of sepsis diagnosis (baseline sample) and on the seventh day. Blood samples will be transported to the laboratory on ice, centrifuged for 20 min at 2500 rpm to separate serum, and stored at – 70 °C until analysis. Levels of inflammatory markers including CRP, ESR, TNF-α, and IL-6 will be quantitatively determined using enzyme-linked immunosorbent assay kits (Karmania Pars Gen, Iran) according to the manufacturer’s protocols.

Given the dynamic nature of patients’ conditions in the PICU and the potential impact of these fluctuations on our intervention’s outcomes, thorough clinical evaluation and follow-up are imperative. Thus, parameters such as the duration of PICU stay, mortality rate, duration of ventilator support, and length of antibiotic treatment until discharge will be initially assessed and subsequently re-evaluated via telephone.

Additionally, gastrointestinal (GI) symptoms (diarrhea, vomit, constipation, abdominal distension) and their duration will be meticulously documented by a professional nurse. Furthermore, we will evaluate and record the general functional capacity of individuals involved in the study. To collect data, names and coded characteristics are first recorded and archived on paper. This information is then entered electronically under secure conditions using a special code. Privacy is ensured, and the security of the data is meticulously checked.

Statistical analysis will be performed using SPSS version 19 (SPSS Inc.). A significance level of P < .05 will be considered. Continuous variables will be reported as mean ± SD, while categorical variables will be presented as frequency (%). Normality of variables will be assessed using Kolmogorov–Smirnov test, and the chi-squared test will be used to compare background qualitative characteristics between groups. Independent sample t-test will compare mean values between groups at baseline and end of the study, with paired t-test used to compare pre-treatment and post-treatment values. Analysis of covariance will be employed to adjust for baseline differences and covariates. Trial procedure flow chart presented in Fig. 2.

Trial procedure flow chart

In this current randomized clinical trial, our objective is to assess the effects of synbiotic supplementation on inflammatory markers and clinical outcomes in pediatric patients with sepsis hospitalized in the PICU.

Numerous experimental studies have demonstrated the immunomodulatory effects of probiotics, including downregulation of proinflammatory cytokines and upregulation of anti-inflammatory cytokines [16]. Angurana et al. conducted a randomized clinical trial investigating the impact of probiotics on cytokine levels in critically ill children with severe sepsis, revealing a significant decrease in IL-6, TNF-alpha, and CRP levels following probiotic administration [16]. Similarly, recent studies have reported significant reductions in CRP and IL-6 levels in critically ill patients receiving probiotics [18,19,20,21].

Inflammation is a complex and dynamic protective response triggered by various stimuli such as cell injury, microbial infections, trauma, or exposure to toxins within vascularized tissues. Upon encountering the causative agent, the body initiates processes aimed at diluting, destroying, or isolating it, thereby initiating a sequential cascade of molecular events that leads to tissue repair, healing, and regeneration. Pro-inflammatory cytokines, a collective term for immunoregulatory cytokines that promote inflammation, play a crucial role in orchestrating early responses. Notable examples include interleukin-1 alpha, interleukin-1 beta, IL-6, and TNF-α. CRP stands out as the most utilized nonspecific prognostic inflammatory biomarker. Following the onset of inflammation, CRP levels exhibit a dramatic surge within 6 h, with the final increase sometimes reaching up to 60-fold higher than baseline levels [22].

CRP emerges as a widely used nonspecific prognostic inflammatory biomarker. Within 6 h of inflammation onset, CRP levels experience a remarkable surge, often escalating up to 60-fold higher than baseline levels [22]. Produced by the liver and endothelial cells, CRP serves as an acute phase reactant, offering sensitivity in detecting SIRS and serving as a valuable indicator of the extent of an inflammatory process. When combined with another inflammatory cytokine, IL-6, CRP demonstrates a positive correlation with illness severity. This combination can effectively predict subsequent organ dysfunction and mortality [16]. IL-6, a 21-kDa glycoprotein synthesized by various cell types such as lymphocytes, fibroblasts, and monocytes, induces acute phase protein production in the liver. Clinical studies underscore IL-6 as a reliable indicator of cytokine cascade activation, and it serves as a predictor for subsequent organ dysfunction and mortality [21].

Nosocomial infections pose a prevalent challenge among patients hospitalized in the ICU, significantly exacerbating morbidity and mortality rates that are already heightened due to the critical nature of their illnesses. Furthermore, patients suffering from multiple traumas requiring mechanical ventilation, particularly those with chest trauma, face an elevated risk of infection. These infections are strongly associated with compromised immune function and dysfunction of the gut barrier, perpetuating a sustained systemic inflammatory response. In certain instances, these infections can culminate in multiple organ and system dysfunction, leading to mortality [18]. While the exact pathogenesis of sepsis and multiple organ failure remains elusive, there is a prevailing belief that the gut functions as a central player in these conditions. Although the precise mechanism is not fully elucidated in humans, evidence suggests alterations in GI microflora linked with acute illness, gut ischemia, immunosuppression, broad-spectrum antibiotic use, and stress induced by nutrient deprivation [19].

Evidence suggests that synbiotics can effectively reduce intestinal permeability by enhancing the tight junctions between the cells in the outer layer of the intestine. This tightening reduces the likelihood of pathogen translocation from the intestine into the bloodstream [18]. In the ICU setting, a massive portion of patients experience a loss of their total Lactobacillus flora. However, this loss can be effectively compensated for by administering a specific synbiotic preparation. Recent research has highlighted the presence of various microorganisms, such as lactobacilli and bifidobacteria, which occupy critical receptors on intestinal epithelial cells. This occupation prevents colonizing pathogens from establishing a niche for persistence and proliferation. Therefore, an alternative approach to addressing changes in gut commensal flora involves preserving or reestablishing normal gut flora with probiotics and prebiotics [19]. The ability of probiotics to adhere to intestinal cells is crucial for modifying the host mucosal and systemic immune systems. Additionally, certain lactobacilli produce antimicrobial substances, including bacteriocins, which directly inhibit the growth of potential pathogens. It is through these mechanisms that probiotics are believed to exert their beneficial effects on the host [20]. Furthermore, probiotics may reduce the adherence and translocation of enteric pathogens or directly affect the gut-associated lymphoid tissue. In vitro studies have confirmed that certain bacterium types can reduce cytokine production from colonic epithelial cell monolayers following exposure to enteric pathogens [20].

The mechanism by which prebiotics decrease inflammation may be attributed to their ability to prevent the colonization of pathogenic bacteria and the overgrowth of opportunistic pathogens [23]. Additionally, prebiotics have been shown to improve intestinal motility and intestinal permeability, thereby enhancing the integrity of the epithelial surface of the intestines. The combined action of restraining pathogens and inhibiting their adherence to the epithelial surface may also contribute to enhancing the patient’s resistance to endogenous infections [24, 25]. Prebiotics protect against inflammation by potentially increasing the barrier function to prevent pathogenic bacteria and toxins from migrating across the intestinal mucosa, thus promoting competitive exclusion of potential pathogens. Furthermore, prebiotics may modify the host’s response to bacterial toxins and enhance their immune responses [26]. This effect aligns with the ability of prebiotic oligosaccharides, designed to function as receptor analogs, thereby preventing pathogens from adhering to the epithelial surface of the digestive tract [27].

On the other hand, we hypothesized that probiotic supplementation could lead to a reduction in the duration of hospitalization in the PICU, the length of ventilator connection, and the mortality rate.

In a study by Angorana et al., it was demonstrated that the group receiving the probiotic supplement experienced a decrease in the duration of hospitalization compared to the placebo group [16]. Similarly, Mahmoodpoor et al. reported a significant reduction in both ICU and hospital stay durations with probiotic administration, along with a nonsignificant decrease in mechanical ventilation duration [28]. Kotzampassi et al. found that probiotic supplementation was linked to a shorter duration of mechanical ventilation and a decrease in the mortality rate [19]. Additionally, Tan et al. and Gou et al. observed reductions in hospital and PICU stay durations among individuals receiving probiotics [29, 30]. Moreover, Wang et al. demonstrated a reduction in mortality rates in individuals receiving probiotic supplements [6].

Probiotic administration may reduce ICU and hospital stay durations by potentially preventing gastric and oropharyngeal colonization and decreasing the presence of MDR [28]. Furthermore, synbiotics can enhance barriers against migrating bacteria and their products across the mucosa, competitively exclude potential pathogens, modify host responses to microbial products, augment IgA mucosal responses, and upregulate immune responses. These mechanisms collectively contribute to reducing inflammation and infection, thereby decreasing ICU and hospital stay durations [31].

Considering the outcomes of similar studies and the mechanisms mentioned above, we have also decided to undertake this study.

The planned involvement of a multidisciplinary team comprising nutritionists, pharmacologists, and pediatricians is anticipated to enhance the robustness and precision of the research. Additionally, the planned utilization of a synbiotic supplement containing various probiotic strains may potentially potentiate therapeutic effects and improve the overall quality of the research. Another strength of the study is its intention to evaluate multiple cytokines in children with sepsis, which will allow for a comprehensive understanding of the inflammatory response and the potential impact of synbiotic supplementation.

Anticipated limitations include the fact that the study will be conducted in a single center, which may limit the generalizability of the findings. Furthermore, the study protocol does not include investigation of GI colonization patterns in the two study groups. Additionally, since this is a protocol study, the focus will primarily be on short-term outcomes, and exploration of long-term or sustained effects of probiotics following completion of therapy is not planned at this stage.

Given the significant burden of sepsis and its complications, our study investigates whether synbiotic supplements can effectively reduce inflammation severity, complications, mortality, and length of hospitalization in children within the PICU. If successful, these supplements could serve as a cost-effective adjuvant therapy, potentially reducing inflammation and enhancing nutritional adequacy, which may lead to improved recovery and overall patient well-being. Our findings could pave the way for future research into the benefits of this relatively inexpensive intervention, specifically its role in minimizing complications and enhancing outcomes. Graphic abstract and Template of the schedule of enrolment, interventions, and assessments presented in Figs. 3 and 4.

Graphic abstract

Template of the schedule of enrolment, interventions, and assessments

Version 1, date recruitment: 6 December 2023; date completed recruitment: 5 July 2024.

The final trial dataset is at the disposal of the Mashhad University of Medical Sciences, and upon request, an e-mail should be given to the corresponding author, and after the decision of the research team, it will be provided to the individuals.

World Health Organization

Pediatric intensive care units

Interleukin-6

Tumor necrosis factor alpha

C-reactive protein

Erythrocyte sedimentation rate

Systemic inflammatory response criteria

Intensive care unit

Multidrug-resistant organisms

Gastrointestinal

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The personal information of the participants and study data are managed by the Mashhad University of Medical Sciences and stored in their secure database to ensure confidentiality. Researchers seeking access to this data must submit a request via email to the research team. Upon review and approval, the research team will grant access to the requested data.

Given the widespread use of synbiotic supplements among individuals visiting pediatric clinics and the growing interest in their use for children, we aimed to investigate the efficacy of these supplements in septic children hospitalized in the PICU. Our goal will be to obtain useful and effective results.

Mashhad University of Medical Sciences

Protocol sponsor: Mashhad University of Medical Sciences

Email: [email protected]

Telephone: 05138411538

Gholamreza Khademi and Fatemeh Roudi are equal corresponding authors.

Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Ali Chamani, Faezeh Mashhadi, Mohsen Nematy & Fatemeh Roudi

Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Gholamreza Khademi & Majid Sezavar

Department of Community Medicine and Public Health, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Maryam Emadzadeh

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Ali Chamani, Faezeh Mashhadi, and Fatemeh Roudi: developed the idea and the text and carried out the final revision. Maryam Emadzadeh: helped with the methodology and developed the statistical analyses. Gholamreza Khademi, Mohsen Nematy, and Majid Sezavar: assisted in the development and revision of the text. All authors approved the final manuscript and are responsible for all aspects of the work.

Correspondence to Gholamreza Khademi or Fatemeh Roudi.

Research Ethics Committees IR.MUMS.MEDICAL.REC.1402.352. Written, informed consent to participate will be obtained from all participants.

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Chamani, A., Mashhadi, F., Khademi, G. et al. Investigating the effect of synbiotic supplementation on inflammatory indices in critically ill septic children: a protocol study for randomized control trial. Trials 25, 712 (2024). https://doi.org/10.1186/s13063-024-08514-x

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Received: 31 July 2024

Accepted: 27 September 2024

Published: 24 October 2024

DOI: https://doi.org/10.1186/s13063-024-08514-x

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