Fluids in Septic Shock (FISSH): a Randomized Controlled Trial
Phase: PHASE2
Conditions: Sepsis, Septic Shock
Sponsor: McMaster University

FISSH Full RCT Protocol 4.0 
 
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Fluids in Septic Shock (FISSH) Randomized Control Trial 
 
A multicentre concealed-allocation parallel group blinded randomized controlled trial to examine the 
effect of Ringer’s Lactate as compared to 0.9% normal saline on mortality in patients with septic shock 
 
 
 
PROTOCOL Version 4.0 
 
Version Date: February 8, 2025 
 
NCT03677102 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Background 
Sepsis, a common problem with a worldwide incidence of approximately 200-300 cases per 
year per 100,0001, is defined as life-threatening organ dysfunction caused by a dysregulated host 
response to infection2. In patients with septic shock, defined as sepsis with evidence of organ 
hypoperfusion, hospital mortality rates are estimated at 40%3.  
 
Intravenous fluids are foundational to sepsis management. In septic shock, pathogen-
mediated molecules initiate an inflammatory cascade associated with cytokine release and monocyte, 
lymphocyte and neutrophil aggregation4. This process results in a loss of vascular tone, which in turn 
leads to systemic hypo-perfusion. Therefore, in addition to antimicrobials and vasopressors, 
maintaining organ perfusion and oxygen delivery requires resuscitation of the intravascular space. 
When conducting fluid resuscitation, clinicians may choose from several types of fluid, categorized as 
either crystalloids or colloids. Each fluid has unique properties, including tonicity, pH, and osmolality, 
depending on its electrolyte and molecular composition 5. Colloids are generally not used in the early 
phase of resuscitation as they are more expensive, and their use is not supported by the evidence 6.  
Based on tonicity relative to plasma, crystalloids are classified into hypertonic, isotonic and 
hypotonic solutions. Isotonic crystalloids are those that primarily function as intravenous volume 
expanders. Worldwide, the most commonly used isotonic crystalloid is 0.9% normal saline (saline, 
NS), which contains a supra-physiologic concentration of chloride (154 mM). Other isotonic crystalloid 
solutions (e.g. Ringer’s Lactate [RL]) contain an organic anion (e.g. lactate, maleate, acetate) and 
therefore have a lower chloride content more closely approximate to human plasma. These solutions 
that contain more physiologic chloride content are termed ‘balanced crystalloids’. Compared to 
balanced crystalloid solutions, normal saline is associated with hyperchloremic metabolic acidosis, 
decreased glomerular blood flow, and impaired smooth muscle contractility in animal models 7. 
However, it is unclear whether these adverse effects observed in preclinical models result in worse 
outcomes in critically ill patients.  
There is limited evidence examining the impact of high versus low chloride fluid administration 
in critically ill patients. Fluid administration strategies in patients with sepsis and septic shock, 
including dose and type, remain controversial. The 2016 Surviving Sepsis Campaign Guidelines 
recommend that crystalloid solutions be used as first-line intravenous fluid for patients with septic 
shock, but suggest using either balanced crystalloid or saline 8 until further data are available. Despite 
evidence of the physiologic benefits associated with balanced solutions, saline remains the most widely 
used fluid in the world. Given uncertainty about the impact of lower chloride versus higher chloride 
solutions on mortality, it is unlikely that clinical practice will change without direct randomized 
controlled trial [RCT] evidence. Editorial commentaries in leading critical care journals have 
repeatedly called for RCTs to address this highly relevant clinical question 9-15.  
In a network meta-analysis (NMA) of all fluid types used for resuscitation in patients with 
septic shock 16, our group identified 14 relevant RCTs that reported mortality and 10 that reported the 
use of renal replacement therapy. Results suggested that balanced crystalloids are superior to 0.9% 
saline in improving survival (NMA OR 0.78; 95% Credible Interval (CrI) 0.58-1.05) and decreasing 
the use of renal replacement therapy (RRT) (NMA OR 0.85; 95% CrI 0.56-1.30); however, this was 
based on indirect and low quality of evidence17 18. 
Previously published and ongoing RCTs have important limitations. Since our NMA, the 
SMART trial - the largest RCT to date (n=15,802) addressing this question, conducted at a single 
academic centre in the United States – was designed as an open-label cluster-randomized, multiple 
crossover trial comparing saline with balanced crystalloids in hospitalized patients 19. Investigators 
found that balanced crystalloids were associated with an improvement in the composite primary 
endpoint of death, new RRT or persisting renal dysfunction at 30 days (adjusted OR 0.91, 95% CI 
0.84-0.99) without effect on overall mortality. While only a small proportion of study patients had 

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sepsis (14.8%), this subgroup appeared to benefit more than any other (adjusted odds ratio for 30-day 
mortality 0.74, 95% CI 0.59-0.93) 20. Limitations of SMART include a heterogeneous population of all 
critically ill patients (not just septic shock), an associated low baseline risk of death (11.1%), exposure 
to only very small amounts of study fluid (mean 1 litre), and more importantly lack of blinding that 
potentially introduced bias in use of co-interventions and outcome ascertainment (other than mortality). 
These limitations severely restrict inferences on the basis of the study’s results. 
There are two ongoing international trials (NCT02721654, NCT0287587) and one Canadian 
trial (NCT02721485) examining a similar research question, however, these trials have important 
limitations regarding generalizability that FISSH attempts to overcome. The design of these trials differ 
from the current proposal in that: (i) one is enrolling all hospitalized patients while the other two enrol 
all critically ill patients – not limited to those with shock. These 3 trials therefore run a high risk of 
false negative results if, as is likely, benefits of balanced crystalloid are restricted to patients with 
shock; and/or (ii) these trials evaluate a more expensive, less available, and less studied balanced 
crystalloid comparator (Plasmalyte) as opposed to FISSH which is using the widely available RL; 
and/or  (iii) enrol patients later in their disease course as compared to FISSH, with greater upfront open 
label fluid contamination (further increasing the likelihood of a false negative result); and/or (iv) do not 
include a translational component.  
Therefore, FISSH will be the only critical care fluids trial to specifically examine patients with 
sepsis and those anticipated to receive a large volume of fluid resuscitation (patients with established 
shock) using a blinded intervention along with employing proven strategies aimed at minimizing non-
study fluid resuscitation. Thus, if – as is probable – the benefits of balanced crystalloid are limited to 
patients with septic shock in whom contamination with other fluid solutions is minimized, the current 
proposal is the only trial with a high likelihood of demonstrating the benefit. 
We have proven feasibility. We successfully completed a 50 patient pilot trial assessing the 
feasibility of conducting a larger trial 21 and are confident we have the expertise and experience to 
execute this trial in a cost-efficient and timely manner. Based on these feasibility results, we were 
funded through the Physician Services Incorporated (PSI) Foundation New Investigator Grant for a 
further 200 patient provincial trial. Given a similar design between the provincial trial and this 
protocol, we will include these patients who have already been enrolled in the final analysis.  
 
 Research Question 
Specific Aims: To examine the effect of NS versus RL on: 1) 30-day mortality; 2) other outcomes 
important to patients including receipt of advanced life support (renal replacement therapy [RRT], 
invasive mechanical ventilation, vasopressors), ICU and hospital length of stay and acute kidney injury 
(AKI). 
 
Hypothesis: In patients with septic shock, administering RL instead of NS will improve survival, 
reduce the incidence of AKI, reduce the use of life support. 
 
Trial design. This is a multi-centre stratified concealed and blinded RCT with a primary outcome of 30-
day mortality. We also include a translational biology sub-study examining serum cell-free DNA 
levels. We will enrol 1096 patients from 29 hospitals across Canada and Saudi Arabia. We may enrol a 
few additional patients to account for lost to followup and post-randomization exclusions. 
 
In patients with septic shock, what is the impact of administering 0.9% Normal Saline versus 
Ringer’s Lactate on 30-day mortality and other patient important outcomes including acute 
kidney injury, need for advanced life support, and ICU/hospital length of stay? 

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Interventions. Patients randomized to high chloride fluid will receive, for all resuscitation and 
maintenance fluid infusions, NS (chloride concentration 154 mmol/L); those in the low chloride arm 
will receive RL (chloride concentration 110 mmol/L). Due to drug-fluid compatibility issues, blood 
products and fluids used for medication infusions (including a dedicated medication line up to 20 
ml/hr) will be exempted. Once a patient is enrolled, study personnel will bring blinded infusion bags of 
study fluids on pre-prepared carts to the patient’s bedside. The timing and amount of fluid infused will 
remain at the discretion of the treating physician. The ICU clinical team will be blinded to fluid type. 
This protocol proved feasible in both the pilot and provincial FISSH trials. Study fluids will be 
administered immediately after randomization and continued until ICU discharge, death, or for 30 days 
after enrolment, whichever comes first.  
Study procedures include minimization of open label fluid use. In rare conditions (e.g., overt 
hypoglycemia, hypernatremia or profound metabolic acidosis), at the request of the treating physician, 
the study fluid infusions may be held and open label fluids (e.g., glucose or bicarbonate containing 
fluid) administered. Blinded study fluid will be resumed as soon as it is deemed safe by the treating 
physician. Research co-ordinators will document all open-label fluid use for the indications mentioned 
above and will document reasons for non-adherence. All other aspects of patient care will be left to the 
discretion of the treating physician.  In the FISSH pilot study, 7 of 50 patients received open label fluid; 
however the volume of non-study fluid administered was small (mean 437 ml/patient). On average, 
94% of fluid that patients received was study fluid.  
Protocol adherence was one of the main reasons for piloting this protocol before moving 
forward with a full RCT. Anticipating this potential challenge within the study protocol, we attempted 
to make use of study fluid as easy as possible through provision of a study cart placed directly at the 
patient’s bedside. Although our feasibility goal for the pilot was a protocol adherence of 75%, we 
achieved a protocol adherence of 94%; meaning on average 94% of total intravenous fluid that each 
patient received during the study period was study fluid. We were able to achieve this compliance 
using strategies such as pre-study education sessions for research and clinical staff and routine clinical 
reminders (including posters, bedside clinical cards and brightly-coloured indicators for patient’s 
charts). We have applied these same tactics in the provincial trial and plan to use the same strategies in 
the full RCT. 
 
Allocation. A trained ICU research co-ordinator at each institution will screen all patients for eligibility 
at the time of ICU admission. We have also empowered physician champions (at least 2-3 per study 
site) in order to facilitate early enrolment. These physician champions are educated on FISSH 
enrolment criteria, randomization processes, and location of the fluid carts. If a potential study patient 
is referred either via the emergency department or ward, it is often the physician that is aware first. Our 
physician champions can either enrol directly into the trial without research co-ordinator support or 
alert the research co-ordinator in a timely manner in order to facilitate early randomization. The 
Methods Center, usually the NPA (Dr. Rochwerg), regularly reaches out to the physician champions at 
each site to assess barriers and facilitators to early randomization. On weekends or after-hours, ICU 
clinical staff will, when available, perform screening, again greatly facilitated by the local physician 
champions. For both the 2-centre pilot study 21 and the provincial trial, centres have been successful in 
operationalizing after-hours remote (off-site) screening and enrolment. In total, 32% of patients from 
the pilot were enrolled outside traditional working hours. This process was facilitated through close 
collaboration with the on-call ICU physician, the research co-ordinator and the research pharmacy. We 
will apply this model and lessons learned from the pilot and provincial trials to this larger FISSH RCT. 
The research co-ordinator will maintain a screening log at each study centre documenting all patients 
reviewed and reasons for exclusion.  
Research co-ordinators will log into the centralized data centre (www.randomize.net) where 
computerized prompts will request preliminary identifying data.  If eligibility criteria are confirmed, 

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the patient will be randomly allocated in a 1:1 schedule to either the NS or RL using undisclosed and 
variable block sizes. Randomization will be stratified by study centre. To expedite study fluid delivery 
to the bedside, and learning from the pilot study, we will provide the unblinded hospital research 
pharmacies with a randomization table prepared by the randomization service. The prepared fluid will 
be placed on a cart that is positioned close to the clinical setting so that it is available when the next 
eligible patient is identified. Fluids are not prepared specifically for study purposes but rather 
commercial fluids that are already stocked in hospital and ‘masked’ for study purposes. The foregoing 
steps were successfully operationalized early in the pilot and in the provincial trial and helped to avoid 
up-front contamination with open label fluids.  
 
Eligibility Criteria.  
Inclusion: We will include patients >16 years of age who meet all of the following: 1) require fluid 
resuscitation for refractory hypotension (systolic blood pressure <90 mmHg or mean arterial blood 
pressure <65 mmHg after 1 Litre bolus of any fluid over 1 hour or less) or organ hypoperfusion (serum 
lactate >4 mmol/L), 2) clinical suspicion of infection; 3) within 6 hours of emergency triage or critical 
care response team or ICU consultation, and 4) are anticipated to require ICU admission. 
Exclusion: Patients will be excluded if they have 1) new intracranial bleed or intracranial hypertension 
at the time of screening; 2) >10% of body surface area acute burn injury; 3) co-existing hemorrhagic 
shock; 4) an imminent plan to transition to palliation; 5) previously been enrolled in FISSH or a 
confounding trial (e.g. a trial examining the effect of other intravenous fluids in septic shock patients); 
6) transferred from another hospital or facility >6 hours since presentation to the first hospital; 7) 
chronic or acute dialysis already in place (whether intermittent or continuous); or 8) admission to ICU 
directly from the operating room or post anaesthetic care unit. 
Justification for Inclusion/Exclusion Criteria: Distributive shock, as seen in sepsis, differs 
fundamentally from other shock syndromes (e.g. cardiogenic, hypovolemic) as the vascular 
endothelium becomes porous in response to inflammatory cytokines, resulting in shift of fluid from the 
intravascular to the interstitial space. This unique and clinically challenging pathophysiologic 
mechanism necessitates a specific treatment plan that differs from other shock etiologies. Consistent 
with this hypothesis, exploratory subgroup analysis from the SMART RCT suggested that benefit of 
balanced crystalloids may have been restricted to patients with sepsis19. The volume of study fluid 
administration in many of the previous fluid studies, including SMART and those included in our 
NMA, was approximately 1-2 Litres; this low fluid dose will also limit the power of ongoing fluid trials 
(NCT02721654, NCT0287587, NCT02721485). To overcome this limitation, and ensure that study 
patients receive an adequate volume of study fluid to demonstrate a difference in outcomes, we will 
only enrol patients with shock or evidence of organ hypoperfusion. This approach was successfully 
employed in our pilot, in which patients received an average of 6.6L of study fluid. Finally, we picked 
a strict 6-hour time window from time of presentation to study enrolment to avoid upfront fluid 
contamination. This has been a significant limitation of previous trials where patients receive large 
volumes (3-4L) of open-label fluid prior to randomization versus only approximately 2L in our FISSH 
pilot. Despite a strict time window, we have been able to meet our monthly recruitment targets. 
 
Consent.  
Given the time-sensitivity of the intervention, the fact that most patients will not be capable to consent 
at the time of study entry, and that both the experimental and control study fluids are currently 
considered the standard of care, we will employ a mixed (a priori and deferred) consent model. This 
model worked well for both the pilot and provincial study centres, ensuring timely enrolment and 
minimizing contamination with non-study fluids. Patients will be enrolled in the study and consent will 
either be obtained immediately (a priori if possible) or study procedures will be initiated and consent 
will subsequently be obtained from the patient, the substitute decision-maker (SDM), or both, ideally 

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within 72 hours. A precedent for using a deferred consent model in studies examining the use of 
emergency intravenous fluids in Canadian centres exists 22, and Clinical Trials Ontario (CTO) has 
approved use of this mixed consent model for the FISSH trial as have local REBs for the 10 provincial 
sites (see Appendix II for approval letter). In the FISSH pilot, 68% of patients were enrolled using 
deferred consent, while 32% were enrolled using an a priori consent model. Using the deferred consent 
model, none of the patients or SDMs refused ongoing study participation. 
 
 
Outcomes. 
The primary outcome is 30-day mortality. We expect that if a difference in survival is demonstrated 
that this will be evident within 30 days. In fluid trials that examined a 90-day endpoint, similar results 
were observed between the 90-day and the shorter time horizon of a 28- or 30-day endpoint 14-16, 
supporting our hypothesis that the predominant effect of the FISSH fluid intervention would most 
likely be identified early in the patient’s trajectory. 
 
Secondary outcomes include:  
• Acute kidney injury – development of stage 2 or worse acute kidney injury (AKI) according to 
KDIGO guidelines17 based strictly on serum creatinine criteria. Stage 2 AKI is defined as serum 
creatinine 2.0-2.9 times baseline. For the purposes of analysis, baseline creatinine will be an 
outpatient reading within 365 days of the current admission date. If multiple pre-hospitalization 
values are available, the value closest to the date of hospital admission will be used. If an 
outpatient pre-hospitalization value is not available, the lowest creatinine value obtained during 
the current hospitalization will be considered baseline 18. 
• Hospital and ICU mortality 
• Hospital and ICU length of stay 
• Ventilator-free days - defined as cumulative number of days alive without receiving greater 
than or equal to 2 hours of mechanical ventilation, censored at 30 days; patients who die prior to 
30 days will be assigned -1 
• Vasopressor-free days - defined as the cumulative number of days alive without requiring 
greater than or equal to 2 hours of intravenous vasopressor support, censored at 30 days; 
patients who die prior to 30 days will be assigned -1 
• Change in organ failure score - calculated using the SOFA score, defined as the net change in 
SOFA from day 1 until ICU discharge or death 
• Biochemical abnormalities during study period (any serum blood test results showing 
hyperchloremia, hyperkalemia, hypernatremia, or acidosis) 
• Serious adverse events related to study fluid19 – critically ill patients are admitted to the ICU for 
life-sustaining therapies and medical complications are likely to occur in this population 
consistent with severity of illness. Due to these unique morbidity and mortality expectations, we 
don’t collect generic adverse events but instead focus on study-related SAEs that the attending 
physician believes related to the study fluid with plausible time sequence and biological 
plausability 
 
Data collection. All outcome data will be collected prospectively at the ICU bedside. The study CRFs 
were pre-tested (via the FISSH pilot work) and edited for clarity and ease-of-use prior to the original 
study initiation. Trained research staff at each study centre will record the data onto paper case report 
forms (CRFs), which they will transcribe into web-based e-CRFs (REDCap – http://www.project-
redcap.org) that are encrypted and password-protected. The online database fully complies with FDA 
and Health Canada rules for electronic data management. Baseline data will include eligibility criteria, 

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baseline demographic data, admitting diagnosis, SOFA score and APACHE II admission prognosis 
score (see Appendix IV for CRF sample). While patients remain in the ICU, daily data collection will 
include measures of organ dysfunction, ventilator requirements, hemodynamics, all fluid administered 
(including study, non-study and blood products), use of renal replacement therapy, and other daily 
relevant blood test values. Co-interventions will also be captured including but not limited to use of 
bicarbonate, vasopressors/inotropes, corticosteroids, vitamin C, and diuretics. Vital status will be 
documented during the 30-day follow-up period (discharge, readmission, death). The web-based CRF 
allows for real-time consistency checks and frequent audits of entered data to ensure they are complete 
and accurate. The paper CRFs will be stored as backup, when needed. The centralized data centre will 
be responsible for managing the database and quality assurance using anomaly searches and logic 
checks. Immediate data entry will ensure missing data are identified quickly and issues are resolved in 
a timely manner. Centre staff will initiate inquiries to study centres that are slow to enter data or enter 
inconsistent data with helpful remediation recommendations offered. Study documents and CRFs will 
be kept for the duration required by local regulatory bodies. The screening log (maintained by the local 
research co-ordinator) will be transcribed to the e-CRF on a daily basis to ensure consistency with the 
information at the centralized data centre. We will use random source data verification to monitor data 
integrity and ensure data fidelity. We will plan site monitoring visits as necessary and for any site-
specific issues. 
 
Sample Size. 
The baseline risk of mortality in septic shock based on the existing literature is approximately 35-40% 
3. Our FISSH pilot trial results were consistent with these estimates, with a 30-day mortality rate of 
35%. To detect an 8% absolute risk reduction of mortality with the use of RL, as compared with NS, 
from a baseline rate of 35%, we determined that 548 patients per group (total 1096 patients) would 
provide a power of 80% with alpha=0.05 and 2-sided testing. This 8% absolute risk reduction in 
mortality was determined based on other interventional RCTs in patients with septic shock including 
those examining different intravenous fluids25 26 34 (range in targeted absolute risk reduction in 
mortality of 5-10%), the administration of corticosteroids35 (targeted absolute risk reduction in 
mortality of 10%), and different blood pressure management strategies36 (targeted absolute risk 
reduction in mortality of 10%).  
 
We have increased the sample size by 2% (to achieve a total target sample size of 1118) to account for 
randomization errors, informed consent withdrawals, and lost to followup. 
 
Trial 
Targeted ARR for Mortality 
VISEP – Fluid trial 25 
10% 
ALBIOS – Fluid trial 26 
7.5% 
CRISTAL – Fluid trial 28 
5% 
APROCCHS – Steroids in septic shock 35 
10% 
SEPSISPAM – Blood pressure targets in septic shock 36 
10% 
 
Data Analysis.  
A biostatistician blinded to study group identification will conduct all analyses based on intention-to-
treat principle. The baseline characteristics comparing balanced fluid and unbalanced fluid groups will 
be reported using means (and standard deviations), medians (and inter-quartile ranges) or proportions 
as indicated. Dichotomous outcomes, such as the primary outcome of mortality, compared between 
randomized groups will be reported using risk ratio and 95% confidence intervals and calculated using 
the Mantel-Haenszel approach to account for stratification variables. For non-normally distributed data 

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such as ICU and hospital length of stay, we will try to log-transform the data and retain a parametric 
approach or, if this is not possible, use the non-parametric Wilcoxon rank sum test. These continuous 
variables will be censored at 30 days. An independent t-test will be used to compare the means of the 
electrolyte values (serum K, Na, pH) between the 2 groups and mean difference with 95% confidence 
intervals and p-values will be reported. A two-sided p<0.05 will be considered statistically significant 
for all outcomes. Since all data are collected in hospital, we anticipate very little missing data. For 
dichotomous and continuous outcomes with data missing for more than 5% of patients (eg. SOFA 
score), we will perform multiple imputation using chained equations and will combine using Rubin’s 
rule 25. 
In collaboration with the Data Safety and Monitoring Board (DSMB), we developed a DSMB 
Charter that included a conservative stopping criteria (e.g. O’Brien-Fleming multiple testing procedure 
26) to avoid inappropriately stopping the trial early27. As both the trial intervention and comparator are 
considered standard of care interventions conferring low risk of harm, we performed a single interim 
analysis for safety when outcome data were available for 50% of patients. The FISSH Trial team and 
trial investigators were blinded to the interim analysis results which were only reviewed only by the 
DSMB.   
Five planned subgroups include: patients < 65 years of age versus patients  65years of age  
(hypothesizing that older patients will benefit more from low chloride fluid) 28; patients with a baseline 
Sequential Organ Failure Assessment (SOFA) score <10 versus  10 (hypothesizing that those that are 
sicker will benefit more from low chloride fluid); patients who receive < 2 Litres of fluid pre-
randomization versus those that receive  2 Litres (hypothesizing that those that receive more fluid pre-
randomization will show less benefit with low chloride fluids); patients with KDIGO stage 2 AKI or 
higher at baseline pre-randomization versus those without AKI at baseline (hypothesizing that those 
with AKI will show more benefit with low chloride fluids); and male versus female patients (no 
explicit hypothesis). We will perform these subgroup analyses only for the primary outcome. Each 
analysis will test for an interaction between treatment and subgroup to ascertain whether effects differ 
significantly. For those that have a statistically significant interaction, we will examine subgroup 
credibility using the ICEMAN tool29. 
 
Knowledge Translation and Exchange. We will publish study findings in a high-impact journal and 
present them at national (Canada Critical Care Forum) and international (Society of Critical Care 
Medicine Congress [SCCM]) conferences. Drs. Rochwerg, Lamontagne and Alhazzani are heavily 
involved as methodologists supporting societal clinical practice guidelines, including the Surviving 
Sepsis Campaign6 and BMJ Rapid Recommendations40, and will ensure the results of the FISSH trial 
are appropriately incorporated into future guidelines and healthcare policy. We will use avenues such 
as Twitter (www.twitter.com), online medical education blogs and the CCCTG network of 
dissemination (www.ccctg.ca) to increase awareness of trial results. 
 
 
Trial Management. 
CLARITY at McMaster University (Clinical advances through research and information translation) 
will act as the coordinating Methods Centre (http://www.clarityresearch.ca/). Dr. Rochwerg is one of 
the CLARITY faculty members. CLARITY, under Dr. Rochwerg’s direction, will be responsible for 
data management, data queries, data analysis, and for providing progress and data reports to the 
Steering Committee. Dr. Rochwerg, Peggy Austin (trial co-ordinator), and Lisa Buckingham (trial data 
manager) will oversee day-to-day management for the study and report back regularly (at least 
monthly) to the Steering Committee. 
 

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Steering Committee 
Dr. Bram Rochwerg is the principal investigator. Dr. Rochwerg has published over 225 peer-reviewed 
manuscripts. He has co-authored 7 textbook chapters. He has acquired over $1.8 million in grant 
support as principal investigator and over $25 million dollars as a collaborator. Dr. Rochwerg holds 
leadership positions as the Grants and Manuscript chair for the CCCTG and the Director of Knowledge 
Translation for the Canadian Critical Care Society. He routinely supervises Health Research 
Methodology (HRM) Master’s students, and clinical residents and fellows in their research projects. 
Dr. Rochwerg will lead the Steering Committee that includes senior and experienced ICU trialists, a 
trial manager (Peggy Austin), an experienced biostatistician (Diane Heels-Ansdell), a data manager 
(Lisa Buckingham), and other local and international experts in ICU research methodology and fluid 
resuscitation. Current members of the Steering Committee include Drs. Deborah Cook, Maureen 
Meade, Gordon Guyatt, Michelle Zeller, Sangeeta Mehta, Frederick D’Aragon, and Francois 
Lamontagne. Drs. Cook, Meade and Mehta are internationally recognized ICU trialists who have led a 
number of large multinational CIHR funded studies 41-44. Dr. Cook has also provided mentorship for 2 
other trials of fluid resuscitation 22 45. Dr. Gordon Guyatt is an internationally acclaimed methodologist 
with extensive RCT expertise. Dr. Francois Lamontagne is a mid-career clinician-investigator with 
experience running RCTs in the area of resuscitative medicine 46.  
Quarterly meetings of the Steering Committee will occur either in person or via teleconference. 
In addition to Steering Committee meetings, Dr. Rochwerg meets with Drs. Cook, Meade and Guyatt at 
least monthly for research-related discussion. This ensures ongoing opportunities for training and 
mentorship in order to maintain Dr. Rochwerg’s continued development and success as a Clinician-
Scientist. The Steering Committee will be responsible for monitoring study recruitment and targets, 
monitoring issues with data collection and missing data, and making decisions on new centre 
recruitment. Dr. Rochwerg meets with the trial manager weekly, and will be responsible for overall 
start-up and study management. Site principal investigators (PIs) have been identified at each centre 
and they will be responsible for all local procedures in conjunction with Dr. Rochwerg. This includes 
local REB approval, hospital approval, enlisting pharmacy cooperation and ensuring all parties are not 
only properly trained, but have suitable ongoing research oversight. The Steering Committee and 
central Methods Center staff will closely support local PIs. At the time of centre initiation all relevant 
paperwork and standard operating procedures (SOPs) will be supplied to the local PI. Dr. Rochwerg 
and the trial manager will provide on-site training sessions for the local PIs and research co-ordinators 
on the study protocol and data collection procedures. Research meetings with all research staff from all 
centres will take place at least twice a year with relevant study updates, recruitment numbers and 
motivational messages. Dr. Rochwerg, or a Steering Committee member, will be available 24 hours a 
day, 7 days a week if problems or questions arise. The FISSH Trial has been registered on 
clinicaltrials.gov (NCT03677102). 
 
 
 
 
References: 
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2. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for 
Sepsis and Septic Shock (Sepsis-3). JAMA : the journal of the American Medical Association 
2016;315(8):801-10. doi: 10.1001/jama.2016.0287 [published Online First: 2016/02/24] 
3. Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality 
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5. Rochwerg B, Wludarczyk A, Szczeklik W, et al. Fluid resuscitation in severe sepsis and septic 
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