Keywords
Sepsis-associated coagulopathy, Pediatric septic shock, Coagulation profile, Clinical outcomes, Morbidity, PICU prognosis
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Pulivarthi C, Meshram RJ and Taksande A. A prospective observational study of sepsis-associated coagulopathy (SAC) in septic shock in the pediatric intensive care unit of tertiary care hospital in central rural India [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:67 (https://doi.org/10.12688/f1000research.141235.1)
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Study Protocol
A prospective observational study of sepsis-associated coagulopathy (SAC) in septic shock in the pediatric intensive care unit of tertiary care hospital in central rural India
[version 1; peer review: awaiting peer review]
PUBLISHED 15 Jan 2024
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Datta Meghe Institute of Higher Education and Research collection.
Abstract
Corresponding author:
Chaithanya Pulivarthi
Competing interests:
No competing interests were disclosed.
Grant information:
The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2024 Pulivarthi C et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Pulivarthi C, Meshram RJ and Taksande A. A prospective observational study of sepsis-associated coagulopathy (SAC) in septic shock in the pediatric intensive care unit of tertiary care hospital in central rural India [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:67 (https://doi.org/10.12688/f1000research.141235.1)
First published: 15 Jan 2024, 13:67 (https://doi.org/10.12688/f1000research.141235.1)
Latest published: 15 Jan 2024, 13:67 (https://doi.org/10.12688/f1000research.141235.1)
Introduction
Shock presents as an acute syndrome stemming from cardiovascular dysfunction and the circulatory system's incapacity to furnish adequate oxygen and nutrients, failing to meet the metabolic requirements of vital organs. The triad of fever, tachycardia, and tachypnea is common in benign infections among children.1 The suspicion of septic shock arises when these symptoms are accompanied by additional indicators such as altered mental state, prolonged capillary refill exceeding 2 seconds (indicative of cold shock), rapid capillary refill (indicative of warm shock), weakened or bounding peripheral pulses, or urinary output reduced to less than 1 ml/kg/hr. Hypotension, a sign of advanced septic shock, emerges relatively later in the progression.1,2
Septic shock often presents an array of coagulation irregularities, with the gravest form being disseminated intravascular coagulation (DIC). The genesis of DIC entails a complex interplay encompassing proinflammatory cytokines, factors that promote and inhibit coagulation, as well as dysfunction of the endothelium. While the exact prevalence of coagulation dysfunction associated with sepsis and DIC in children remains uncertain, approximations indicate rates of approximately 50 to 70% in the pediatric population and around 35% in adults.3–5
DIC signifies the breakdown of normal hemostatic mechanisms, potentially leading to organ dysfunction due to microthrombi-induced infarction, ultimately increasing mortality rates. Despite developing two validated diagnostic scoring systems for DIC in adults, a clear consensus needs to be provided in both adult and pediatric populations. Recognizing these challenges, a recent study in adults endeavored to formulate a simplified set of criteria to diagnose sepsis-associated coagulopathy (SAC), relying solely on platelet count and international normalized ratio (INR) values.3–5 The INR, initially devised to monitor vitamin-K antagonist therapy, is assessed in this study as a proxy measure for the extent of coagulopathy. The severity of SAC, as determined by this approach, independently predicted in-hospital mortality in the Pediatric Intensive Care Unit (PICU). To our knowledge, no analogous investigations have yet been conducted within the pediatric septic shock cohort.6
Protocol
Study design and setting
This research employs a prospective observational design, whereby consecutively selected children who satisfy the predetermined inclusion criteria will be observed and analyzed. This study will occur within the Pediatric Intensive Care Unit (PICU) Department of Pediatrics at Acharya Vinoba Bhave Rural Hospital. This facility is a tertiary care hospital boasting a capacity of 1525 beds and is situated in Sawangi (Meghe), Wardha, Maharashtra.
Sampling method and duration
A consecutive sampling approach will be employed to select patients over a 2-year study period.
Inclusion and exclusion criteria
Inclusion criteria: This study will encompass critically ill children between 1 month and 18 years admitted to the PICU due to sepsis accompanied by coagulopathy.
Exclusion criteria:
Data collection
The data collection process involves a comprehensive examination of patient information and clinical assessments, overseen by the corresponding author, Dr. Chaithanya Pulivarthi. To begin with, demographic data, including age, gender, weight, and vital signs (such as heart rate, peripheral pulses, saturation, and blood pressure, as determined through a general physical examination), will be meticulously documented using a predefined format upon admission to the Pediatric Intensive Care Unit (PICU). Furthermore, the initial diagnosis upon admission to the PICU will be recorded.
A thorough clinical examination will be conducted, accompanied by various laboratory investigations. These investigations will encompass a Complete Blood Count (CBC) using the Coulter method,7 Kidney Function Tests (KFT), Liver Function Tests (LFT), and C-reactive protein (CRP) measurements using dry chemistry,8 as well as blood culture analysis utilizing Bactec culture media.9 The results obtained from these tests will be diligently recorded within the predefined format.
Within 24 hours of admission to the PICU, the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score will be calculated to assess the severity of organ dysfunction and guide treatment decisions. Dr. Chaithanya Pulivarthi will oversee the assessment of the PELOD-2 score, utilizing PELOD-2 charts.10
Critical outcome variables will also be meticulously documented. These variables encompass crucial details such as the length of ICU stay, the number of days requiring mechanical ventilation, specifics regarding inotropic usage, occurrences of Acute Kidney Injury (AKI), the need for renal replacement therapy, and the ultimate patient outcome, which may either be discharge or mortality.
To facilitate data analysis and interpretation, the outcome variables will be categorized into three groups based on coagulation profile perturbations: Normal Sepsis Associated Coagulopathy (SAC), Non-severe SAC, and Severe SAC. This systematic approach to data collection ensures a comprehensive and well-organized evaluation of each patient's condition and response to treatment within the PICU setting.
Collection of demographic information and clinical data
Demographic data will be meticulously collected for patients diagnosed with sepsis in the Pediatric Intensive Care Unit (PICU). This information will encompass critical aspects such as age and gender. Additionally, a comprehensive clinical assessment will be conducted on all cases under study, involving the measurement of heart rate, respiratory rate, blood pressure, and saturation levels. Thorough clinical examinations will also encompass system-specific evaluations, including cardiovascular and respiratory auscultation.
A comprehensive set of laboratory parameters will be assessed for all study participants. This includes key metrics such as total leukocyte count, platelet count, C-reactive protein levels, and coagulation markers like Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR), and blood cultures. Every case within the study will undergo these laboratory investigations.
Sepsis definition and criteria
A stringent definition and set of criteria for sepsis have been meticulously outlined and established. These criteria will serve as the guiding framework for patient selection and evaluation. Patients will be meticulously assessed against these criteria to ensure their accurate classification.
Data collection and analysis
Comprehensive information pertinent to each patient, including causative factors, disease progression, administered treatments, and relevant clinical courses, will be systematically collected. Subsequently, this data will be subjected to rigorous analysis.
Outcome parameter definition
Precise parameters that define the outcomes of interest have been established for this study. These parameters will guide the assessment of patient outcomes, aiding in identifying trends and patterns.
Evaluation of coagulopathy
As stipulated by the inclusion criteria, all critically ill patients admitted to the PICU exhibiting clinical and laboratory indicators indicative of septic shock will undergo a thorough evaluation for signs of coagulopathy. Coagulation parameters such as PT, APTT, and INR will be scrutinized. These patients will then be categorized into three groups: those without Sepsis Associated Coagulopathy (SAC), those with non-severe SAC, and those with severe SAC.
Followup and Correlation
The patient will undergo daily follow-up assessments, including the acquisition of updated coagulation profile reports (PT, APTT, INR), which will continue until conclusive outcomes are determined. All laboratory data gathered, encompassing coagulation parameters and other pertinent metrics, will be rigorously correlated, and subjected to in-depth analysis.
Sample size calculation
The sample size determination process resulted in a calculated value of 129, leading us to include 130 patients in our study. The calculation took into account various parameters: a population size factor of 0.90 for finite population correction, a hypothesized percentage frequency of the outcome factor in the population set at 0.70, confidence limits of 0.3% out of 100, a design effect of 0.10 (applicable for cluster surveys), and a confidence level of 95%. Consequently, the required sample size was determined to be 139.
Data analysis
We will utilize SPSS version 25 for statistical exploration. Descriptive statistics will be computed, presenting mean, median, and standard deviation for demographic, clinical, and laboratory variables. Sepsis Associated Coagulopathy (SAC) incidence will be calculated as a percentage. Univariate analysis will involve tests like chi-square, t-tests, ANOVA, or non-parametric alternatives using SPSS's “Compare Means” or “Frequencies” functions. Multivariate analysis will employ the “Logistic Regression” function to pinpoint independent risk factors for SAC. Through ANOVA or non-parametric tests, outcomes will be compared across SAC severity categories via SPSS's “Compare Means” function. Correlations between laboratory parameters and clinical outcomes will be determined using the “Correlations” function. SPSS's “Survival Analysis” function will facilitate Kaplan-Meier curves and Cox proportional hazards regression if relevant. SPSS's tools for generating tables, graphs, and charts will aid reporting and visualization. Data manipulation tasks, including variable creation and recording, will be simplified using SPSS. Sensitivity analysis will involve exploring diverse scenarios and adjusting assumptions. Collaboration with a skilled statistician will ensure rigor in the analysis process.
Patient enrollment and informed consent
Upon admission to the PICU, patients meeting the inclusion criteria will be promptly enrolled in the study following the acquisition of inform and written consent from the legal guardian of the patients.
Ethical considerations
The Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) has approved the study protocol on 27/06/2022. Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study's objectives. Reference Number: DMIHER (DU)/IEC/2022/1080.
Discussion
Sepsis presents a significant health challenge within the Pediatric Intensive Care Unit (PICU). The timeliness of treatment administered in the initial hours following the onset of sepsis can profoundly impact the patient’s outcome. The emergence of coagulopathy, which leads to unfavorable results, is a commonly observed phenomenon among patients affected by sepsis. While the overall mortality rate for patients afflicted by sepsis is declining, the incidence of sepsis and the subsequent deaths attributed to it are on an upward trajectory.11
Loberger JM et al.12 emphasized that a substantial portion of patients with positive blood cultures exhibited severe Sepsis-Associated Coagulopathy (SAC), and this disparity between the severe and non-severe groups was statistically significant. This implies a potential correlation between bacteremia and the development of SAC. This assertion is buttressed by various infectious manifestations, such as meningococcemia associated with purpura fulminans, one of the gravest indications of Disseminated Intravascular Coagulation (DIC). It should be noted that although most patients with Gram-negative bacteremia demonstrated severe SAC, the sample size remains insufficient to formulate definitive conclusions. The production of endotoxins by numerous Gram-negative bacteria is pivotal to the inception of DIC, being instrumental in initiating thrombin generation, a pivotal step in this process.
El-Nawawy AA et al.12 conducted a study focused on evaluating the impact of early hemostatic intervention on disseminated intravascular coagulopathy in patients contending with severe sepsis/septic shock. The investigation centered on patients admitted to the ICU prior to the clear manifestation of disseminated intravascular coagulopathy. Among the cohort of 80 patients included in this study, all of whom were at the subclinical stage of disseminated intravascular coagulopathy in conjunction with severe sepsis/septic shock, a random allocation was performed, dividing them into two distinct groups designated as group 1 and group 2. The outcomes revealed a noteworthy rise in mortality rates within group 2. Furthermore, the progression toward evident disseminated intravascular coagulopathy was significantly more frequent among patients in group 2 when contrasted with their counterparts in group 1 (45% versus 10%, respectively) (p<0.0001).
Lindell RB et al.13 pointed out that precise identification of children afflicted by severe sepsis and septic shock in the Virtual Pediatric Systems database requires specific diagnostic codes designed for these specific conditions. The accuracy of these codes and the depth of clinical detail provided by the database establish a solid foundation for conducting sophisticated epidemiological studies on pediatric severe sepsis and septic shock within this extensive multicenter repository.
Ren C et al.14 conducted an in-depth investigation into the potential predictive role of sepsis-associated coagulopathy (SAC) in relation to the clinical outcomes of critically ill patients contending with postoperative sepsis. Their research revealed that among the 175 patients enrolled in the study within the ICU setting, 41.1% (72 patients) exhibited the presence of SAC. Notably, the subset of patients affected by SAC demonstrated notably higher rates of in-hospital mortality in comparison to those without SAC (37.5% versus 11.7%; p<0.001). The results of both univariate and multivariate regression analyses substantiated a significant correlation between the existence of SAC and the heightened in-hospital mortality observed in sepsis patients specifically within surgical intensive care units, with a calculated hazard ratio (HR) of 3.75 and a 95% confidence interval (CI) ranging from 1.90 to 7.40 (p<0.001).
Weiss SL2 reported that among 6,925 screened patients, the prevalence of severe sepsis stood at 8.2% (95% confidence interval 7.6-8.9%). The primary sites of infection were the respiratory tract (40%) and the bloodstream (19%). Standard therapeutic measures encompassed mechanical ventilation (74% of patients), vasoactive drug infusions (55%), and corticosteroid administration (45%). The in-hospital mortality rate was recorded at 25% and exhibited no variance based on age or the distinction between developed and resource-constrained nations. At the juncture of sepsis detection, 67% of patients presented with multiple organ failure, with 30% subsequently experiencing the emergence or progression of multiple organ failure.
Loberger JM12 introduced a straightforward classification scheme for gauging the severity of SAC in PICU patients within 48 hours of admission, employing platelet counts and International Normalized Ratios (INRs). Crucial parameters, such as positive blood cultures and the duration of ventilator use, were incorporated into this framework to yield predictive insights. Interleukins are central to the immune system and play a pivotal role in a spectrum of immunological, inflammatory, and infectious conditions, including sepsis syndrome. The levels of interleukins are correlated with overall survival. They may wield direct or indirect influence over certain regulators of coagulation and fibrinolysis, potentially disrupting the delicate balance of hemostasis and thrombosis.13
The early detection and proactive resuscitation of neonatal septic shock by community physicians can serve as a lifesaving measure. Valerani E et al.14 concluded that SAC was associated with elevated 28-day mortality rates among sepsis patients. The administration of recombinant human soluble thrombomodulin (rhsTM) demonstrated a reduction in 28-day mortality, specifically among patients afflicted by SAC, as opposed to those lacking SAC.
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how to cite this article
Pulivarthi C, Meshram RJ and Taksande A. A prospective observational study of sepsis-associated coagulopathy (SAC) in septic shock in the pediatric intensive care unit of tertiary care hospital in central rural India [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:67 (https://doi.org/10.12688/f1000research.141235.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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