Hemodynamic Resuscitation and Monitoring in Early Sepsis

Study Overview
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Brief Summary
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Hemodynamic Resuscitation and Monitoring in Early Sepsis (HERMES Study) involves recording of patient's medical data related to that has been collected as part of his/her routine medical care in ICU. Presently there is no data from Indian ICUs on the way patients in early sepsis are resuscitated and monitored. There may exist a wide variation in clinical practice. The investigators would like to conduct an observational study in various levels of Indian ICUs, to prospectively collect data on adult patients admitted to ICU with early sepsis in a 60-day window period. Investigator would like to study the hemodynamic resuscitation and monitoring performed in these patients. In addition, Investigator would like to identify factors associated with improved outcomes and achieving the goals of the sepsis bundles in one, three and six hours. The objectives of the study is to capture the patient characteristics and hemodynamic resuscitation and monitoring practices in patients presenting with early sepsis and hypotension to Indian ICUs Investigator plan to recruit 50 -100 centers nationwide. Each center will be asked to collect data from at least 10 patients in a maximum time window of 60 days. A convenience sample of minimum 500 patients presenting to ICU with suspected sepsis and hypotension will be taken. Each Centre will guarantee the integrity of data collection and ensure timely completion of the case record forms. Each center will select a 60 day window period for patient recruitment. The start date may be anytime any time between 1st August to 15th October 2019. Therefore, the recruitment window period will end for a respective centre, anytime between 30th September and 14th December 2019, depending on the start date. All consecutive patients in the 60-day period will be screened and those eligible will be enrolled. This is an ISCCM(Indian Society of Critical Care Medicine) Research Committee funded study. The ISCCM will fund the Principal Investigator for all expenses related software development, website hosting, secretarial assistance and miscellaneous expenses related to the conduct of the study, data analysis and publication. No funding will be given to the investigators from the various participating centers for contributing data.

Detailed Description
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INTRODUCTION Septic shock is the most commonly occurring of all types of shock.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. The sepsis bundle has been central to the implementation of the Surviving Sepsis Campaign (SSC) from the first publication of its evidence-based guidelines in 2004 through subsequent editions. Developed separately from the guidelines publication by the SSC, the bundles have been the cornerstone of sepsis quality improvement since 2005. An updated version was published in 2016 Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock. There is compelling nature of the evidence in the literature which demonstrates an association between compliance with bundles and improved survival in patients with sepsis and septic shock. This has led to the adoption of the SSC measures by the National Quality Forum (NQF) and other departments. The important relationship between the bundles and survival was confirmed in a publication from this initiative. The Surviving Sepsis Campaign released an updated one-hour sepsis bundle, which combines recommendations listed in the three-hour and six-hour bundles. This includes 5 elements: 1. measuring lactate levels 2. obtaining blood cultures before administering antibiotics 3. administering broad-spectrum antibiotics 4. fluid resuscitation for hypotension or lactate level ≥ 4 mmol/L and 5. use of vasopressors for hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg. Presently there is no data from Indian ICUs on the way patients in early sepsis are resuscitated and monitored. There may exist a wide variation in clinical practice.The Investigator would like to conduct an observational study in various levels of Indian ICUs, to prospectively collect data on adult patients admitted to ICU with early sepsis in a 60-day window period. Investigator would like to study the hemodynamic resuscitation and monitoring performed in these patients. In addition, investigator would like to identify factors associated with improved outcomes and fulfilling the goals of the one hour SSC bundles within one, three and six hours in patients with sepsis and septic shock. OBJECTIVES To capture the patient characteristics and hemodynamic resuscitation and monitoring practices in patient presenting with early sepsis and hypotension to Indian ICUs To determine various factors associated with improved survival in patients with septic shock To determine factors associated with achieving the 1 hour, 3 hour and 6-hour resuscitation goals of the sepsis bundle in patients with septic shock METHODS Study design- Prospective observational multi-center national cohort study. Patient Recruitment ISCCM members across India will be contacted to register their ICUs in the study, through emails sent from the ISCCM Research committee. Repeated emails will be sent over a two-month period. Hospitals with more than one ICU can enroll each of their ICUs separately. Each ICU will need to contribute a minimum of 10 adult patients with sepsis and hypotension in a 60 day window period. Each center will designate a maximum of two local coordinators (PI and Co-PI) who will provide scientific and structural leadership in their centers. They will ensure that all local necessary ethical and regulatory approvals are obtained before the start of patient inclusion. Local coordinators will guarantee the integrity of data collection and ensure timely completion of the case record forms. Each center will select a 60 day window period for patient recruitment. The start date may be anytime any time between 1st August to 15th October 2019. Therefore, the recruitment window period will end for a respective centre, anytime between 30th September and 14th December 2019, depending on the start date. All consecutive patients in the 60-day period will be screened and those eligible will be enrolled. Data Collection There will be no direct patient contact or intervention. Local coordinators will guarantee the integrity of data collection and ensure timely completion of CRFs (case record forms). Date related to the following will be collected prospectively from the charts: Patient demographic data e.g. age, sex, comorbidities, likely source of sepsis Total number of ICU patients, patients with sepsis and septic shock admitted to the ICU in the 60 days period Patient clinical examination findings and severity of illness Details of hemodynamic monitoring and other systemic monitoring and therapy performed in ICU e.g. fluid bolus, vasopressor agents, monitoring devices used, hemodynamic variables measured, mechanical ventilation, dialysis etc. in the first 3 days of ICU admission Antibiotics administered and details of microbiology examinations Adjunct therapies initiated for sepsis ICU, hospital and 28-day mortality Sample size The primary endpoint of study was to determine the incidence of ICU mortality in patients with septic shock admitted to Indian ICUs. The sample size calculation was done on the basis of INDICAPS I(Indian Intensive Care Case Mix and Practice Patterns Study-I) Study data (IJCCM April 2016). In this study the ICU mortality incidence was found to be 45% in patients with septic shock. Assuming the incidence rate found in this study, a sample size of 401 produces a two-sided 95% confidence interval with a width equal to 0.100 when the sample proportion is 0.450. Sample size calculation was done using PASS software. To account for attrition, Investigator will take a sample size of at least 450 patients. Investigator plan to recruit 50 -100 centers nationwide. Each center will be asked to collect data from at least 10 patients, hence investigator should be able to meet this target of >450 patients. Statistical analysis The primary objective of the study is to determine the patient characteristics and hemodynamic resuscitation and monitoring practices in patient presenting with early sepsis and hypotension to Indian ICUs which will be analyzed using descriptive statistics. To determine various factors associated with improved survival in patients with septic shock investigator will use the Fisher's exact test or Pearson's χ2 test. Univariable and Multivariable logistic regression models will be developed to assess the independent effects on ICU mortality. To determine factors associated with achieving the 1 hour SSC Sepsis resuscitation bundle in 1 hour, 3 hours and 6-hours in patients with sepsis and septic shock will be assessed by Fisher's exact test or Pearson's χ2 test. Univariable and Multivariable logistic regression models will be developed to assess the independent effects on ICU mortality of the 1 hour, 3 hour and 6-hour resuscitation goals of the sepsis bundle in patients with sepsis and septic shock. The overall performance of the internally validated model will be assessed using Nagelkerke's R2 (R squared in logistic regression). The higher Nagelkerke's R2, the greater the strength of the model. The ability of the models to identify ICU mortality will be quantified as the area under the receiver operating characteristic curve (AUC). The AUC ranges from 50% to 100%, indicating no discriminative capacity to perfect discriminative capacity. The agreement between predicted probabilities and observed frequencies of the outcome will be assessed by visually inspecting the calibration plot. Last, the Hosmer and Lemeshow goodness-of-fit statistic will be computed as a quantitative measure of accuracy. A high outcome of this statistic is related to a low p-value, which indicates a poor fit. All analysis will two sided, and significance will set at a p-value of 0.05. Statistical analyses will be performed using SPSS (the statistical package for social sciences) IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, New York: IBM Corp and R studio (version 1.2). INSTITUTIONAL ETHICS COMMITTEE (IEC) APPROVAL The local hospital investigators should ensure that all necessary local ethical and regulatory approvals are obtained if required, before the start of the study in their institution. CONSENT FOR DATA COLLECTION This is an observational study and involves capture of data from the patient charts. There is no direct patient contact or intervention, hence written, informed consent is not mandatory. However, if required by the institution, consent may be taken from the patients legally accepted representative (LAR). Sample short consent forms for patient data capture will be provided by the PI in English, Hindi and Marathi. This may be translated in various regional languages as required by the local investigator STUDY FUNDING This is an ISCCM Research Committee funded study. The ISCCM will fund the Principal Investigator institution for all expenses related software development, website hosting, secretarial assistance and miscellaneous expenses related to the conduct of the study, data analysis and publication (against actual bills). No funding will be given to the investigators from the various participating centres for contributing data. DATA STORAGE AND OWNERSHIP The Principal Investigator will have ownership of the data. The data will be stored in the Principal Investigators department at Tata Memorial Hospital, Mumbai for 10 years. PUBLICATION AND AUTHORSHIP POLICY The main results of study will be published in a peer-reviewed medical journal. Authorship policy will follow the International Committee of Medical Journal Editors (ICMJE) recommendations. Authorship will be considered based on contributions the study design and protocol development, recruitment of patients, data acquisition and cleaning, analysis and interpretation of the data, manuscript writing and final approval of the version to be published and agreement to be accountable for all aspects of the work, in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Steering Committee - Members of the Steering Committee will include 7 members from the Principal Investigators center and 8 -10 experts from across the country. They will be involved and provide active guidance from inception till publication of the study. Writing committee and main author list - Members of the steering committee and Principal Investigator from the top 3 centers with highest number of patient recruitment. The Principal Investigator and Co-Principal Investigator from each participating ICU will be in the list of study collaborators and their names will be in the publication. The names of all the investigators will be indexed in PubMed depending on the journal policy. SECONDARY ANALYSES After publication of the primary results, on request, the pooled dataset will be available for investigators for secondary analysis, after judgment and approval of scientific quality and validity by the steering committee. Before submission, the final version of all manuscripts related to the study dataset must be approved by the steering committee. The members of the writing committee will be authors of the publications derived from the study dataset.

Official Title
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Hemodynamic Resuscitation and Monitoring in Early Sepsis

Conditions
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Septic Shock

Intervention / Treatment
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* Other: No Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Adult patients (≥ 18 years old) Presenting to ICU with suspected sepsis Presence of hypotension (Systolic BP ≤ 90 mmHg / Mean arterial pressure (MAP) ≤ 65mmhg or patient with Systolic BP > 90 mmHg / MAP >65mmHg on vasopressor. Exclusion Criteria Patient likely to be in shock due to reason other than sepsis (e.g. cardiogenic or hemorrhagic shock) Decision taken for not intubating / ventilating /aggressive resuscitation prior to ICU admission Patient transferred from another ICU OR another hospital (only if stay >7 days)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: No Intervention|No Intervention|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU Mortality | Overall ICU Mortality due to septic shock with hypotension | throughout ICU stay till discharge (up to 2 months) | 
| Completing the elements of the one hour SSC sepsis bundle in one 1 hour | Identify factors associated with improved outcomes and fulfilling the goals of the one hour Surviving Sepsis Campaign (SSC) bundles within one, three and six hours in patients with sepsis and septic shock and to identify compliance with the one hour SSC bundle guidelines The Surviving Sepsis Campaign released an updated one-hour sepsis bundle, which combines recommendations listed in the three-hour and six-hour bundles. This includes 5 elements: 1. measuring lactate levels 2. obtaining blood cultures before administering antibiotics 3. administering broad-spectrum antibiotics 4. fluid resuscitation for hypotension or lactate level ≥ 4 mmol/L and 5. use of vasopressors for hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg | 1 hour after admission upto 60 days from the study start date in respective study site (60 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital mortality | Over all mortality during the hospital stay | throughout the hospital stay till discharge in the respective study site (up to 3 months) | 
| 28-day mortality | Over all mortality from ICU admission day to till 28 day | From ICU admission to 28 days in the respective study site (up to 3 months) | 
| Completing the elements of the one hour SSC sepsis bundle in one, three and six hours | Identify factors associated with improved outcomes and fulfilling the goals of the one hour Surviving Sepsis Campaign (SSC) bundles within one, three and six hours in patients with sepsis and septic shock and to identify compliance with the one hour, three hour and six hour SSC bundle guidelines The Surviving Sepsis Campaign released an updated one-hour sepsis bundle, which combines recommendations listed in the three-hour and six-hour bundles. This includes 5 elements: 1. measuring lactate levels 2. obtaining blood cultures before administering antibiotics 3. administering broad-spectrum antibiotics 4. fluid resuscitation for hypotension or lactate level ≥ 4 mmol/L and 5. use of vasopressors for hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg | 1 hour, 3 hour and six hour after admission upto 60 days from the study start date in the respective study site (60 days ) |