Hemodynamic Resuscitation and Monitoring in Early Sepsis
Conditions: Septic Shock
Sponsor: Tata Memorial Centre

 
 
Version No 1.0 dated 09 July 2019 
Study Protocol  
 
 
Hemodynamic Resuscitation 
and Monitoring in Early 
Sepsis (HERMES Study) 
 
An ISCCM research project 
 
 
 
Principle Investigator: 
Prof. Sheila Nainan Myatra 
Tata Memorial Hospital, Mumbai, INDIA 
Email : sheila150@hotmail.com Cell : 9820156070 
 
 

 
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Hemodynamic Resuscitation and Monitoring in Early Sepsis 
(HERMES Study) 
 
INTRODUCTION  
 
Septic shock is the most commonly occurring of all types of shock. (1) 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 (2−7). Developed separately from the guidelines publication by the SSC, the bundles 
have been the cornerstone of sepsis quality improvement since 2005 (8−12). An updated version 
was published in 2016 “Surviving Sepsis Campaign: International Guidelines for Management of 
Sepsis and Septic Shock” (13, 14). 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 (15, 16). The important relationship 
between the bundles and survival was confirmed in a publication from this initiative (17).  
 
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.  

 
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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. We 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. We would like to study 
the hemodynamic resuscitation and monitoring performed in these patients. In addition, we 
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 patients presenting with early sepsis and hypotension to Indian ICUs  
 To determine various factors associated with improved survival in patients with sepsis 
and septic shock  
 To determine factors associated with achieving the goals of the one hour SSC sepsis 
bundle within one, three and six hours in patients with sepsis and septic shock  
 
 
METHODS 
 
Study design  
 
Prospective observational multi–center national cohort study.  
 
 
 
 
 
 

 
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Primary outcome  
 ICU Mortality  
 Completing the elements of the one hour SSC sepsis bundle in one 1 hour  
Secondary outcomes  
 Hospital mortality  
 28-day mortality  
 Completing the elements of the one hour SSC sepsis bundle in one, three and six hours  
 
Inclusion criteria 
1. Adult patients (≥ 18 years old)  
2. Presenting to ICU with suspected sepsis  
3. 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 
 
1. Patient likely to be in shock due to reason other than sepsis (e.g. cardiogenic or 
hemorrhagic shock) 
2. Decision taken for not intubating / ventilating /aggressive resuscitation prior to ICU 
admission 
3. Patient transferred from another ICU OR another hospital (only if stay >7 days) 
 
 
 
 
 
 
 
 

 
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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.        

 
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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  
 
1. There will be no direct patient contact or intervention. Local coordinators will guarantee the 
integrity of data collection and ensure timely completion of CRFs. Date related to the 
following will be collected prospectively from the charts:  
2. Patient demographic data e.g. age, sex, comorbidities, likely source of sepsis  
3. Total number of ICU patients, patients with sepsis and septic shock admitted to the ICU in 
the 60 days period  
4. Patient clinical examination findings and severity of illness  
5. 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  
6. Antibiotics administered and details of microbiology examinations  
7. Adjunct therapies initiated for sepsis  
8. ICU, hospital and 28-day mortality 
 
 
 
 
 

 
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Proposed Study Timelines  
 First email invitation - 11th July 2019  
 Earliest date to start recruitment -1st August 2019  
 Window period - 60 days from the start date of recruitment  
 Last date of recruitment – 14th December 2019  
 Data cleaning/analysis – by 31st January 2020 
 Study ends - 29th February 2020 
 Presentation at CRITICARE 2020 –Feb /March 2020  
 Publication in 2020  
 
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 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, we will take a sample size of at least 450 patients. We plan to recruit 50 -
100 centers nationwide. Each center will be asked to collect data from at least 10 patients, hence 
we 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 we will use the Fisher’s exact 

 
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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. 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, NY: IBM Corp and R studio (version 1.2).  
 
 
STUDY REGISTRATION  
 
The Principle Investigator (PI) will register the study on clinical trials.gov on behalf of all the 
investigators. The registration number will be provided to all investigators as soon as it is 
available.  
 
 
 
 
INSTITUTIONAL ETHICS COMMITTEE (IEC) APPROVAL  

 
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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 PI 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 PI will have ownership of the data. The data will be stored in the PIs department at Tata 
Memorial Hospital, Mumbai for 10 years.  
 
 
 
 
 
PUBLICATION AND AUTHORSHIP POLICY  

 
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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 PIs 
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 PIs from 
the top 3 centers with highest number of patient recruitment.  
 
The PI and Co PI 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 
 
 
REFERENCES 

 
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