1. Early Goal-Directed Therapy (EGDT) – Rivers et al., 2001
The EGDT trial, published in The New England Journal of Medicine in 2001, was a landmark study that changed the approach to early sepsis resuscitation. It introduced structured hemodynamic targets in the first 6 hours of sepsis management, leading to a significant reduction in mortality.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock |
| Objective | To determine if structured hemodynamic resuscitation within the first 6 hours of sepsis improves survival compared to usual care. |
| Study Type | Single-center, randomized controlled trial (RCT), unblinded |
| Location | Henry Ford Hospital, Detroit, USA |
| Time Period | March 1997 – March 2000 |
| Number of Patients | 263 (EGDT: 130, Standard Care: 133) |
| Setting | Emergency Department (ED) – patients presenting with early severe sepsis or septic shock |
| Follow-up Duration | 60 days |
| Primary Endpoint | In-hospital mortality |
📌 Why Was EGDT Needed?
- Before EGDT, sepsis mortality was ~46%, and no structured resuscitation protocol existed.
- Delayed fluid resuscitation, vasopressor use, and transfusions contributed to poor outcomes.
- The trial tested whether early, aggressive hemodynamic resuscitation improves outcomes.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Suspected or confirmed infection – Systolic BP <90 mmHg OR Lactate ≥4 mmol/L (signs of hypoperfusion) – Identified within 6 hours of ED presentation |
| Exclusion Criteria | – Acute pulmonary edema (fluid restriction needed) – Active GI hemorrhage (requiring blood products) – DNR status, pregnancy, age <18 years – Already received >1L IV fluids before arrival |
📌 Key Point: Patients included had severe sepsis or early septic shock but had not yet received aggressive resuscitation.
3. Intervention Arms & Protocols
| Feature | EGDT Group (Structured Resuscitation) | Standard Care Group |
|---|---|---|
| Fluids (First 6 Hours) | 30 mL/kg IV crystalloid bolus, then guided by CVP | Fluids given at clinician discretion |
| CVP Target | 8–12 mmHg | No specific target |
| MAP Target | ≥65 mmHg (fluids → vasopressors if needed) | No strict MAP goal |
| ScvO₂ Target | ≥70% (if low, added dobutamine or transfusion if Hct <30%) | Not measured |
| Urine Output Goal | ≥0.5 mL/kg/hr | No strict target |
| Vasopressors | Given if MAP <65 after fluids | Used based on clinician discretion |
| Blood Transfusion | If hematocrit <30% | Given if judged necessary |
| Dobutamine Use | If ScvO₂ <70% despite fluids | Rarely used |
📌 Why 30 mL/kg Fluids?
- This volume was chosen to rapidly restore intravascular volume and improve perfusion.
- A CVP target of 8–12 mmHg was used to guide additional fluids.
📌 Why ScvO₂ Monitoring?
- ScvO₂ (central venous oxygen saturation) measures oxygen delivery vs. demand.
- If ScvO₂ <70%, it suggests inadequate oxygen delivery → requiring inotropes (dobutamine) or transfusions.
4. Key Results & Outcomes
4.1 Fluids & Interventions Received
| Parameter (First 6h) | EGDT Group | Standard Care | Difference |
|---|---|---|---|
| Total IV Fluids | 4.9L (IQR: 3.5–6.3L) | 3.5L (IQR: 2.5–5.0L) | +1.4L in EGDT |
| Blood Transfusions (%) | 19% | 4% | +15% in EGDT |
| Dobutamine Use (%) | 13.7% | 0.8% | More frequent in EGDT |
📌 EGDT patients received more fluids, blood transfusions, and inotropes than the standard care group.
4.2 Mortality Results
| Outcome | EGDT | Standard Care | Difference |
|---|---|---|---|
| 28-Day Mortality | 30.5% | 46.5% | −16.0% (P = 0.009) |
| 60-Day Mortality | 33.3% | 49.2% | −15.9% (P = 0.01) |
📌 EGDT reduced mortality by ~16%, making it one of the most impactful sepsis trials ever conducted.
5. Key Clinical Implications
✅ EGDT proved that early, aggressive sepsis resuscitation saves lives.
✅ Hemodynamic targets (CVP, MAP, ScvO₂) improved oxygen delivery and reduced multi-organ dysfunction.
✅ A structured resuscitation protocol should begin within the first 6 hours of sepsis recognition.
6. Limitations & Controversies
🔹 Single-Center Study → Conducted only at Henry Ford Hospital (concerns about generalizability).
🔹 Control Group Received Suboptimal Care → Standard care patients may have been under-resuscitated.
🔹 ScvO₂ Monitoring is Invasive & Outdated → Later trials showed that ScvO₂ isn’t necessary for good outcomes.
🔹 PROCESS, ARISE, & PROMISE Trials (2014–2015) failed to replicate the mortality benefit → Questioning the necessity of strict EGDT protocols.
7. EGDT vs. Modern Practice (2024 Update)
| EGDT (2001) | Modern Sepsis Management (2024) |
|---|---|
| 30 mL/kg fluids → CVP target (8–12 mmHg) | 30 mL/kg fluids → Dynamic assessment (PLR, VTI, IVC) |
| ScvO₂ monitoring with central line | Capillary refill time, lactate clearance instead |
| Dobutamine if ScvO₂ <70% | Echocardiography-based cardiac function assessment |
| Blood transfusions if Hct <30% | Less reliance on transfusions unless Hb <7 g/dL |
📌 Key Change: EGDT’s aggressive protocol is no longer required, but the concept of early, structured resuscitation remains critical.
8. Final Take-Home Message
💡 “EGDT revolutionized sepsis care by proving that aggressive early resuscitation saves lives. However, modern sepsis management has evolved, focusing on dynamic assessments rather than fixed resuscitation targets.”
Next Trial: PROCESS (2014) – The First Major Challenge to EGDT
2. PROCESS Trial (2014) – Challenging EGDT
The PROCESS (Protocolized Care for Early Septic Shock) trial, published in The New England Journal of Medicine in 2014, was the first major study to challenge EGDT. It aimed to determine whether a structured, EGDT-like approach was superior to usual care in modern sepsis management.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Protocolized Care for Early Septic Shock (PROCESS) |
| Objective | To compare EGDT vs. protocolized resuscitation vs. usual care in early septic shock |
| Study Type | Multicenter, RCT, unblinded, noninferiority trial |
| Location | 31 centers (USA) |
| Time Period | March 2008 – May 2013 |
| Number of Patients | 1,341 |
| Setting | Emergency Departments (ED) – patients presenting with early septic shock |
| Follow-up Duration | 60 days |
| Primary Endpoint | 60-day mortality |
📌 Why Was PROCESS Needed?
- Since EGDT (2001) showed a 16% mortality reduction, hospitals adopted CVP-guided resuscitation and ScvO₂ monitoring.
- However, sepsis care had improved overall (early antibiotics, better ICU management), so it was unclear if EGDT was still necessary.
- PROCESS tested whether EGDT still provided a survival benefit over modern usual care.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Suspected infection + lactate ≥4 mmol/L OR persistent hypotension after 1L fluids – Must be randomized within 2 hours of meeting criteria |
| Exclusion Criteria | – DNR status, pregnancy, acute pulmonary edema, active bleeding – >2L fluids already given before randomization |
📌 Key Difference from EGDT: Patients were enrolled within 2 hours (EGDT allowed 6 hours).
3. Intervention Arms & Protocols
| Feature | EGDT (Rivers’ Protocol) | Protocolized Standard Care | Usual Care |
|---|---|---|---|
| Fluids (First 6 Hours) | 30 mL/kg IV crystalloid (CVP-guided) | 30 mL/kg IV crystalloid (MAP-guided) | Fluids given at clinician’s discretion |
| Vasopressors | MAP goal ≥65 mmHg | MAP goal ≥65 mmHg | Used if necessary |
| ScvO₂ Target | ≥70% (via CVC monitoring) | Not required | Not required |
| Dobutamine Use | If ScvO₂ <70% | Rarely used | Rarely used |
| Blood Transfusion | Hematocrit <30% | Hb <7 g/dL | Hb <7 g/dL |
📌 Key Difference from EGDT: The protocolized standard care group received the same volume of fluids but without invasive ScvO₂ monitoring.
4. Key Results & Outcomes
4.1 Fluids & Vasopressor Use
| Parameter (First 6h) | EGDT Group | Protocolized Care | Usual Care |
|---|---|---|---|
| Total IV Fluids | 4.9L | 3.9L | 3.3L |
| Vasopressors Use (%) | 54.9% | 52.2% | 44.1% |
| Dobutamine Use (%) | 8.0% | 1.1% | 0.9% |
| Blood Transfusion (%) | 14.4% | 8.3% | 7.5% |
📌 Key Findings:
- EGDT patients received more fluids, vasopressors, and blood transfusions.
- Despite these interventions, mortality was the same in all three groups.
4.2 Mortality Results
| Outcome | EGDT | Protocolized Care | Usual Care | Difference |
|---|---|---|---|---|
| 60-Day Mortality | 21.0% | 18.2% | 18.9% | No significant difference (P = 0.83) |
| 90-Day Mortality | 31.9% | 30.9% | 34.0% | No significant difference (P = 0.61) |
📌 Key Takeaway: EGDT did not improve survival compared to modern usual care.
5. Key Clinical Implications
✅ EGDT’s structured protocol is not superior to modern usual care.
✅ Early fluids (30 mL/kg) and MAP-guided resuscitation work just as well without ScvO₂ monitoring.
✅ Routine blood transfusions and dobutamine use are unnecessary.
📌 PROCESS showed that modern sepsis care already includes aggressive early resuscitation, making EGDT redundant.
6. Limitations & Controversies
🔹 Unblinded Study → Clinicians knew which group patients were in, which may have influenced treatment.
🔹 Better Overall Sepsis Care → The control group received early antibiotics and fluid resuscitation, unlike the original EGDT trial in 2001.
🔹 Generalizability to Low-Resource Settings? → EGDT might still benefit hospitals without strong sepsis protocols.
7. EGDT vs. PROCESS – What Changed?
| Feature | EGDT (2001) | PROCESS (2014) |
|---|---|---|
| Required ScvO₂ Monitoring? | Yes (central line needed) | No (not necessary) |
| Fluids Given? | 30 mL/kg guided by CVP | 30 mL/kg guided by MAP |
| Vasopressor Use? | Only after fluids | Started earlier if MAP <65 |
| Blood Transfusion? | Hct <30% | Hb <7 g/dL |
| Mortality Benefit? | Yes (16% reduction) | No difference |
📌 Key Change: EGDT’s invasive monitoring and strict protocol were unnecessary when sepsis care improved overall.
8. Final Take-Home Message
💡 “PROCESS proved that modern sepsis care (early antibiotics, MAP-guided fluids, and vasopressors) is just as effective as EGDT. The key takeaway? We don’t need central line-driven ScvO₂ monitoring or rigid protocols anymore—what matters most is early resuscitation and individualized fluid management.”
3. ARISE Trial (2014) – Confirming the Findings of PROCESS
The ARISE (Australasian Resuscitation in Sepsis Evaluation) trial, published in The New England Journal of Medicine in 2014, was a large, multicenter, randomized controlled trial (RCT) designed to determine whether EGDT was superior to modern usual care in early septic shock. It was conducted simultaneously with the PROCESS trial and confirmed that EGDT is not necessary for good outcomes when early antibiotics and fluid resuscitation are provided.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Australasian Resuscitation in Sepsis Evaluation (ARISE) |
| Objective | To determine whether EGDT improves survival compared to usual care in early septic shock |
| Study Type | Multicenter, RCT, unblinded, noninferiority trial |
| Location | 51 centers (Australia, New Zealand, Finland, Hong Kong, Ireland, UK) |
| Time Period | October 2008 – April 2014 |
| Number of Patients | 1,600 |
| Setting | Emergency Departments (ED) – patients presenting with early septic shock |
| Follow-up Duration | 90 days |
| Primary Endpoint | 90-day all-cause mortality |
📌 Why Was ARISE Needed?
- PROCESS (2014) showed EGDT was not superior to usual care, but validation in a different healthcare system was needed.
- The study tested whether EGDT’s strict targets (ScvO₂, CVP, dobutamine use) provided additional survival benefit in an era of early antibiotics, protocolized resuscitation, and ICU care.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Suspected or confirmed infection – Lactate ≥4 mmol/L OR persistent hypotension (MAP <65) after 1L IV fluids – Must be randomized within 6 hours of ED presentation |
| Exclusion Criteria | – DNR status, pregnancy, acute pulmonary edema, active GI bleeding – >1L IV fluids already given before randomization |
📌 Key Difference from PROCESS:
- Patients were enrolled within 6 hours (PROCESS required enrollment within 2 hours).
- More emphasis on early lactate-based screening.
3. Intervention Arms & Protocols
| Feature | EGDT (Rivers’ Protocol) | Usual Care |
|---|---|---|
| Fluids (First 6 Hours) | 30 mL/kg IV crystalloid (CVP-guided) | Fluids given at clinician’s discretion |
| Vasopressors | MAP goal ≥65 mmHg | MAP goal ≥65 mmHg |
| ScvO₂ Monitoring | Yes (≥70%) | Not required |
| Dobutamine Use | If ScvO₂ <70% | Rarely used |
| Blood Transfusion | Hematocrit <30% | Hb <7 g/dL |
📌 Key Difference from EGDT (2001):
- Usual care was already aggressive with early antibiotics and fluids, making additional interventions (ScvO₂ monitoring, dobutamine) unnecessary.
4. Key Results & Outcomes
4.1 Fluids & Vasopressor Use
| Parameter (First 6h) | EGDT Group | Usual Care | Difference |
|---|---|---|---|
| Total IV Fluids | 4.3L | 4.0L | Not significantly different |
| Vasopressors Use (%) | 76.3% | 67.7% | Slightly more in EGDT group |
| Dobutamine Use (%) | 15.4% | 2.6% | More in EGDT group |
| Blood Transfusion (%) | 13.6% | 7.0% | More in EGDT group |
📌 Key Findings:
- EGDT patients received slightly more fluids, vasopressors, and dobutamine than usual care.
- Despite these additional interventions, mortality was the same in both groups.
4.2 Mortality Results
| Outcome | EGDT | Usual Care | Difference |
|---|---|---|---|
| 90-Day Mortality | 18.6% | 18.8% | No significant difference (P = 0.90) |
| ICU-Free Days | 14.3 days | 14.0 days | No significant difference |
| Ventilator-Free Days | 19.5 days | 19.6 days | No significant difference |
📌 Key Takeaway: EGDT did not improve survival compared to modern usual care.
5. Key Clinical Implications
✅ EGDT’s structured protocol is not superior to modern usual care.
✅ Early antibiotics, aggressive resuscitation, and MAP-guided fluids work just as well.
✅ Routine blood transfusions and dobutamine use are unnecessary.
📌 ARISE confirmed what PROCESS had already shown: EGDT is not needed when early sepsis care is optimized.
6. Limitations & Controversies
🔹 Unblinded Study → Clinicians knew which group patients were in, which could introduce bias.
🔹 Better Overall Sepsis Care → The control group received early antibiotics and fluid resuscitation, unlike in 2001 when EGDT was first introduced.
🔹 Does This Apply to Low-Resource Settings? → EGDT might still help in hospitals without strong sepsis protocols.
7. EGDT vs. ARISE – What Changed?
| Feature | EGDT (2001) | ARISE (2014) |
|---|---|---|
| Required ScvO₂ Monitoring? | Yes (central line needed) | No (not necessary) |
| Fluids Given? | 30 mL/kg guided by CVP | 30 mL/kg guided by MAP |
| Vasopressor Use? | Only after fluids | Started earlier if MAP <65 |
| Blood Transfusion? | Hct <30% | Hb <7 g/dL |
| Mortality Benefit? | Yes (16% reduction in 2001) | No difference in 2014 |
📌 Key Change: EGDT’s invasive monitoring and strict protocol were unnecessary when sepsis care improved overall.
8. Final Take-Home Message
💡 “ARISE confirmed that modern sepsis care (early antibiotics, MAP-guided fluids, and vasopressors) is just as effective as EGDT. The key takeaway? We don’t need central line-driven ScvO₂ monitoring or rigid protocols anymore—what matters most is early resuscitation and individualized fluid management.”
4. PROMISE Trial (2015) – The Final Nail in EGDT’s Coffin
The PROMISE (Protocolized Management in Sepsis) trial, published in The New England Journal of Medicine in 2015, was the third major study—after PROCESS and ARISE—to test whether EGDT improved survival over usual care in early septic shock. Like its predecessors, PROMISE found no survival benefit with EGDT, further cementing the idea that modern sepsis care (early antibiotics, fluid resuscitation, vasopressors) was already optimized without the need for EGDT’s strict protocol.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Protocolized Management in Sepsis (PROMISE) |
| Objective | To determine whether EGDT improves survival compared to usual care in early septic shock |
| Study Type | Multicenter, RCT, unblinded, noninferiority trial |
| Location | 56 centers (United Kingdom) |
| Time Period | February 2011 – July 2014 |
| Number of Patients | 1,260 |
| Setting | Emergency Departments (ED) – patients presenting with early septic shock |
| Follow-up Duration | 90 days |
| Primary Endpoint | 90-day all-cause mortality |
📌 Why Was PROMISE Needed?
- PROCESS (USA) and ARISE (Australia/NZ) both showed EGDT was not superior to usual care, but further validation was needed in a European healthcare system.
- It tested whether EGDT’s structured targets (ScvO₂, CVP, dobutamine use) improved survival in an era of early antibiotics and fluid resuscitation.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Suspected infection + lactate ≥4 mmol/L OR persistent hypotension (MAP <65) after 1L IV fluids – Must be randomized within 6 hours of ED presentation |
| Exclusion Criteria | – DNR status, pregnancy, acute pulmonary edema, active GI bleeding – >1L IV fluids already given before randomization |
📌 Key Similarity to ARISE:
- Patients were enrolled within 6 hours, just like in ARISE.
- Early lactate-based screening was emphasized.
3. Intervention Arms & Protocols
| Feature | EGDT (Rivers’ Protocol) | Usual Care |
|---|---|---|
| Fluids (First 6 Hours) | 30 mL/kg IV crystalloid (CVP-guided) | Fluids given at clinician’s discretion |
| Vasopressors | MAP goal ≥65 mmHg | MAP goal ≥65 mmHg |
| ScvO₂ Monitoring | Yes (≥70%) | Not required |
| Dobutamine Use | If ScvO₂ <70% | Rarely used |
| Blood Transfusion | Hematocrit <30% | Hb <7 g/dL |
📌 Key Similarity to PROCESS & ARISE:
- Usual care already included aggressive early resuscitation, making ScvO₂ monitoring unnecessary.
4. Key Results & Outcomes
4.1 Fluids & Vasopressor Use
| Parameter (First 6h) | EGDT Group | Usual Care | Difference |
|---|---|---|---|
| Total IV Fluids | 4.0L | 3.9L | Not significantly different |
| Vasopressors Use (%) | 53.7% | 46.6% | Slightly more in EGDT group |
| Dobutamine Use (%) | 8.0% | 2.6% | More in EGDT group |
| Blood Transfusion (%) | 8.9% | 7.0% | More in EGDT group |
📌 Key Findings:
- EGDT patients received slightly more fluids, vasopressors, and dobutamine than usual care.
- Despite these additional interventions, mortality was the same in both groups.
4.2 Mortality Results
| Outcome | EGDT | Usual Care | Difference |
|---|---|---|---|
| 90-Day Mortality | 29.5% | 29.2% | No significant difference (P = 0.90) |
| ICU-Free Days | 13.5 days | 13.0 days | No significant difference |
| Ventilator-Free Days | 18.2 days | 18.1 days | No significant difference |
📌 Key Takeaway: EGDT did not improve survival compared to modern usual care.
5. Key Clinical Implications
✅ EGDT’s structured protocol is not superior to modern usual care.
✅ Early antibiotics, aggressive resuscitation, and MAP-guided fluids work just as well.
✅ Routine blood transfusions and dobutamine use are unnecessary.
📌 PROMISE confirmed the findings of PROCESS & ARISE: EGDT is not needed when early sepsis care is optimized.
6. Limitations & Controversies
🔹 Unblinded Study → Clinicians knew which group patients were in, which could introduce bias.
🔹 Better Overall Sepsis Care → The control group received early antibiotics and fluid resuscitation, unlike in 2001 when EGDT was first introduced.
🔹 Does This Apply to Low-Resource Settings? → EGDT might still help in hospitals without strong sepsis protocols.
7. EGDT vs. PROMISE – What Changed?
| Feature | EGDT (2001) | PROMISE (2015) |
|---|---|---|
| Required ScvO₂ Monitoring? | Yes (central line needed) | No (not necessary) |
| Fluids Given? | 30 mL/kg guided by CVP | 30 mL/kg guided by MAP |
| Vasopressor Use? | Only after fluids | Started earlier if MAP <65 |
| Blood Transfusion? | Hct <30% | Hb <7 g/dL |
| Mortality Benefit? | Yes (16% reduction in 2001) | No difference in 2015 |
📌 Key Change: EGDT’s invasive monitoring and strict protocol were unnecessary when sepsis care improved overall.
8. Final Take-Home Message
💡 “PROMISE was the final nail in EGDT’s coffin. It confirmed what PROCESS and ARISE already showed—early antibiotics, MAP-guided fluids, and vasopressors are just as effective as EGDT’s rigid protocol. Today, we focus on individualized resuscitation rather than fixed targets like ScvO₂ and CVP.”
5. CLASSIC Trial (2022) – Liberal vs. Restrictive Fluids in ICU Septic Shock
The CLASSIC (Conservative vs. Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care) trial, published in The New England Journal of Medicine in 2022, was a large, multicenter, randomized controlled trial (RCT) designed to determine whether a restrictive IV fluid strategy improves survival compared to standard (liberal) fluid administration in patients with septic shock in the ICU.
Key Finding: The trial found no significant difference in mortality between restrictive and liberal fluids, suggesting that fluid restriction after initial resuscitation does not improve survival in septic shock.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Conservative vs. Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) |
| Objective | To compare restrictive IV fluids vs. usual-care fluid therapy in ICU patients with septic shock |
| Study Type | Multicenter, RCT, open-label |
| Location | 31 ICUs (Denmark, Norway, Sweden, Finland, Switzerland, the UK, and Belgium) |
| Time Period | December 2018 – September 2021 |
| Number of Patients | 1,554 |
| Setting | ICU patients with septic shock who had already received initial fluid resuscitation |
| Follow-up Duration | 90 days |
| Primary Endpoint | 90-day all-cause mortality |
📌 Why Was CLASSIC Needed?
- Previous studies suggested that excessive IV fluids may worsen outcomes in septic shock by causing fluid overload, pulmonary edema, and organ dysfunction.
- CLASSIC tested whether a restrictive fluid approach improves survival after initial resuscitation.
📌 Key Difference from CLOVERS:
- CLOVERS (2023) studied early resuscitation strategies (ED/Wards), whereas CLASSIC (2022) focused on ICU septic shock patients who had already received fluids and vasopressors.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Septic shock requiring vasopressors for ≥1 hour – Received at least 1L IV fluids before enrollment – Randomization within 12 hours of septic shock onset |
| Exclusion Criteria | – Septic shock duration >12 hours – Major bleeding, acute burns, pregnancy, severe dehydration – ICU admission for non-sepsis reasons |
📌 Key Difference from CLOVERS: CLASSIC excluded patients in the early resuscitation phase and focused on post-resuscitation fluid management.
3. Intervention Arms & Protocols
| Feature | Restrictive Fluid Strategy | Standard Fluid Strategy (Liberal Fluids) |
|---|---|---|
| Fluids Post-Randomization | Minimal fluids unless clear need | Fluids given per standard ICU practice |
| Fluid Triggers | Fluids only for severe hypoperfusion, oliguria, or marked fluid loss | Fluids given at clinician discretion |
| Vasopressor Use | Earlier vasopressors instead of fluids | Fluids first, then vasopressors if needed |
| Rescue Fluids | Allowed if lactate >4 mmol/L, MAP <50, or ScvO₂ <65% | Fluids given more liberally |
| Monitoring | Dynamic assessments | CVP, lactate, bedside clinical signs |
📌 Key Difference from CLOVERS: CLASSIC patients were already in septic shock (on vasopressors), while CLOVERS tested early vasopressors vs. liberal fluids in sepsis-induced hypotension.
4. Fluids, Vasopressor Use, and Other Interventions
| Parameter (First 24h Post-Randomization) | Restrictive Group | Standard Care Group | Difference |
|---|---|---|---|
| Total IV Fluids (First 24h) | 1,798 mL (IQR: 500–3,000 mL) | 2,980 mL (IQR: 1,998–4,000 mL) | -1,182 mL less in restrictive group |
| Cumulative Fluids (First 5 Days) | 1,798 mL | 3,811 mL | -2,013 mL less in restrictive group |
| Vasopressor Use (%) | 100% (all required vasopressors at enrollment) | 100% | No difference |
📌 Key Findings:
- The restrictive group received ~1.2L less fluids within 24 hours and ~2L less over 5 days compared to standard care.
- Both groups used vasopressors equally, suggesting early vasopressors do not necessarily improve survival.
5. Primary & Secondary Outcomes
5.1 Mortality Results
| Outcome | Restrictive Fluids | Standard Fluids | Difference |
|---|---|---|---|
| 90-Day Mortality | 42.3% | 42.1% | No significant difference (P = 0.96) |
| 28-Day Mortality | 34.5% | 34.2% | No difference |
📌 Key Takeaway: Restricting fluids did not improve survival in ICU septic shock.
5.2 Secondary Outcomes
| Outcome | Restrictive Fluids | Standard Fluids | P-Value |
|---|---|---|---|
| Days Alive Without Life Support (Day 90) | 47 days | 47 days | NS |
| Days Alive and Out of Hospital (Day 90) | 33 days | 34 days | NS |
| Serious Adverse Events | No significant difference | No significant difference | NS |
📌 Key Takeaway: Fluid restriction did not reduce ventilator days, organ failure, or hospital stay.
6. Clinical Implications
✅ Restricting fluids after ICU admission does not improve survival in septic shock.
✅ Early vasopressors do not necessarily reduce mortality.
✅ Fluids should be guided by individual patient needs rather than rigid protocols.
📌 CLASSIC suggests that a restrictive approach is not superior to usual-care fluids. Instead, individualized fluid resuscitation is key.
7. Limitations & Controversies
🔹 Open-Label Study → Clinicians knew which group patients were in, introducing potential bias.
🔹 Exclusion of Severe Hypovolemia → Patients with dehydration or severe fluid losses were excluded, limiting generalizability.
🔹 Did Not Study Early Sepsis → CLASSIC focused on ICU septic shock, not early sepsis (like CLOVERS).
8. CLASSIC vs. CLOVERS – Key Differences
| Feature | CLASSIC (2022) | CLOVERS (2023) |
|---|---|---|
| Setting | ICU patients already in septic shock | Early sepsis in ED/Wards |
| Intervention | Restrictive fluids vs. usual fluids (ICU phase) | Early vasopressors vs. liberal fluids (initial resuscitation) |
| Key Finding | No survival benefit of fluid restriction | No survival difference between early vasopressors & liberal fluids |
📌 Key Takeaway: CLASSIC and CLOVERS both show that fluid strategy matters less than individualized resuscitation based on patient response.
9. Final Take-Home Message
💡 “CLASSIC showed that restrictive fluids do not improve survival in ICU septic shock. The key takeaway? Individualized fluid management is more important than strict liberal or restrictive strategies.”
6. CLOVERS Trial (2023) – Liberal Fluids vs. Early Vasopressors in Sepsis
The CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis) trial, published in The New England Journal of Medicine in 2023, investigated whether an early vasopressor strategy with restricted fluids improves outcomes compared to a liberal fluid strategy in patients with sepsis-induced hypotension.
Key Finding: There was no difference in 90-day mortality between early vasopressors and liberal fluids, suggesting no clear advantage of restricting fluids and starting vasopressors early.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) |
| Objective | To compare early vasopressors with restrictive fluids vs. liberal IV fluids in early sepsis-induced hypotension |
| Study Type | Multicenter, RCT, unblinded |
| Location | 60 centers (USA, National Heart, Lung, and Blood Institute) |
| Time Period | March 2018 – January 2022 |
| Number of Patients | 1,563 |
| Setting | Emergency Department (ED) and hospital wards – early sepsis before ICU admission |
| Follow-up Duration | 90 days |
| Primary Endpoint | 90-day all-cause mortality |
📌 Why Was CLOVERS Needed?
- Sepsis guidelines recommend 30 mL/kg IV fluids initially, but the optimal balance between fluids and vasopressors was unclear.
- Excess fluids can cause organ congestion, but early vasopressors may impair tissue perfusion.
- CLOVERS tested whether early vasopressors with less fluid resuscitation improves outcomes in early sepsis.
📌 Key Difference from CLASSIC (2022):
- CLOVERS studied early sepsis in ED/Wards, whereas CLASSIC studied post-resuscitation septic shock in ICU patients.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Sepsis-induced hypotension (MAP <65 mmHg or SBP <100 mmHg) after 1–3L IV fluids – Suspected or confirmed infection – Randomization within 4 hours of meeting criteria |
| Exclusion Criteria | – Septic shock requiring immediate ICU admission – Severe volume depletion (e.g., GI bleed, pancreatitis) – Active hemorrhage, pregnancy, cardiac arrest, CHF, ESRD on dialysis |
📌 Key Inclusion Criteria: Patients were early in sepsis, before ICU admission, with persistent hypotension despite 1–3L IV fluids.
📌 Key Exclusion: Patients already in septic shock (requiring immediate ICU care) were excluded.
3. Intervention Arms & Protocols
| Feature | Restrictive Fluids (Early Vasopressors) | Liberal Fluids Strategy |
|---|---|---|
| Fluids Post-Randomization | Minimal fluids unless severe hypoperfusion | Aggressive fluid resuscitation (goal 30 mL/kg) |
| Vasopressors | Early norepinephrine infusion if MAP <65 | Started only if fluids failed to restore MAP |
| Fluid Rescue Triggers | Fluids only for lactate >4 mmol/L, severe oliguria, persistent shock | Fluids given as first-line therapy |
| Monitoring | Frequent reassessment for tissue perfusion | Fluids given until perfusion improved |
📌 Key Difference from CLASSIC:
- CLOVERS patients were pre-ICU, testing fluid restriction in early sepsis.
- CLASSIC patients were already in septic shock (ICU phase) and had received initial resuscitation.
4. Fluids, Vasopressor Use, and Other Interventions
| Parameter (First 24h Post-Randomization) | Restrictive (Early Vasopressors) | Liberal Fluids | Difference |
|---|---|---|---|
| Total IV Fluids (First 24h) | 1267 mL (IQR: 555–2279 mL) | 3400 mL (IQR: 2500–4495 mL) | -2,133 mL less in restrictive group |
| Cumulative Fluids (First 5 Days) | 3300 mL | 5400 mL | -2,100 mL less in restrictive group |
| Vasopressor Use (%) | 59% | 37% | Earlier and more common in restrictive group |
📌 Key Findings:
- The restrictive group received ~2L less fluids within 24 hours and ~2.1L less over 5 days.
- Earlier vasopressors were used in 59% of restrictive patients vs. 37% in the liberal group.
5. Primary & Secondary Outcomes
5.1 Mortality Results
| Outcome | Restrictive Fluids | Liberal Fluids | Difference |
|---|---|---|---|
| 90-Day Mortality | 14.0% | 14.9% | No significant difference (P = 0.61) |
| 28-Day Mortality | 10.3% | 11.3% | No significant difference |
📌 Key Takeaway: Restricting fluids and using early vasopressors did not improve survival in early sepsis.
5.2 Secondary Outcomes
| Outcome | Restrictive Fluids | Liberal Fluids | P-Value |
|---|---|---|---|
| Days Free from Organ Support (Day 28) | 21 days | 21 days | NS |
| Ventilator-Free Days | 23.4 days | 22.8 days | NS |
| ICU Length of Stay | 6.5 days | 6.7 days | NS |
| Serious Adverse Events | 10.6% | 10.5% | NS |
📌 Key Takeaway: No difference in ventilator days, ICU stay, or organ failure between groups.
6. Clinical Implications
✅ Restricting fluids in early sepsis does not improve survival.
✅ Early vasopressors are safe but offer no mortality benefit over liberal fluids.
✅ Sepsis resuscitation should be individualized rather than following rigid protocols.
📌 CLOVERS suggests that both fluid-first and early vasopressor-first approaches are reasonable, emphasizing the need for individualized resuscitation.
7. Limitations & Controversies
🔹 Unblinded Study → Clinicians knew which group patients were in, introducing potential bias.
🔹 Excluded ICU Septic Shock Patients → Results do not apply to patients already in severe septic shock.
🔹 Low Vasopressor Use in Restrictive Group → Only 59% received vasopressors, raising concerns about protocol adherence.
8. CLOVERS vs. CLASSIC – Key Differences
| Feature | CLOVERS (2023) | CLASSIC (2022) |
|---|---|---|
| Setting | Early sepsis (ED/Wards, pre-ICU) | Septic shock (ICU, post-resuscitation) |
| Intervention | Restrictive fluids with early vasopressors vs. liberal fluids | Restrictive fluids vs. usual fluids |
| Key Finding | No survival difference between fluid-first and vasopressor-first | No survival benefit of fluid restriction in ICU septic shock |
📌 Key Takeaway: Both trials emphasize individualized fluid management over rigid strategies.
9. Final Take-Home Message
💡 “CLOVERS showed that early vasopressors are not superior to liberal fluids in early sepsis resuscitation. The key takeaway? Sepsis resuscitation should be individualized, balancing fluids and vasopressors based on patient needs.”
7. FACTT Trial (2006) – Liberal vs. Conservative Fluids in ARDS
The FACTT (Fluid and Catheter Treatment Trial), published in The New England Journal of Medicine in 2006, was a landmark study that investigated whether a liberal or conservative fluid strategy improved outcomes in patients with acute respiratory distress syndrome (ARDS).
Key Finding: A conservative fluid strategy improved lung function, reduced ventilator days, and shortened ICU stays—without increasing shock or worsening organ perfusion.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | Fluid and Catheter Treatment Trial (FACTT) |
| Objective | To compare liberal vs. conservative fluid management strategies in ARDS |
| Study Type | Multicenter, RCT, 2×2 factorial design |
| Location | 20 ARDS Network hospitals (USA) |
| Time Period | June 2000 – October 2005 |
| Number of Patients | 1,000 |
| Setting | ICU patients with ARDS (ventilated) |
| Follow-up Duration | 60 days |
| Primary Endpoint | 60-day mortality |
📌 Why Was FACTT Needed?
- ARDS is a severe lung injury often caused by sepsis, pneumonia, or trauma, with high mortality (~40%).
- Fluid overload worsens pulmonary edema and oxygenation, but aggressive fluid removal could impair perfusion.
- FACTT tested whether a conservative fluid strategy could improve lung function without harming circulation.
📌 Key Unique Feature:
- FACTT used a 2×2 factorial design, testing fluid strategies (liberal vs. conservative) AND catheter monitoring (CVP vs. PA catheter).
- However, the PA catheter results were neutral, so the main focus was liberal vs. conservative fluid management.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – ARDS diagnosis (PaO₂/FiO₂ ≤ 300 mmHg, bilateral infiltrates, non-cardiogenic cause) – Mechanical ventilation required – Randomization within 48 hours of ARDS onset |
| Exclusion Criteria | – Severe CHF, chronic lung disease, CKD, cirrhosis – High risk of volume depletion (GI bleeding, acute pancreatitis) |
📌 Key Inclusion: Patients had confirmed ARDS and required ventilation.
📌 Key Exclusion: Severe CHF and CKD patients were excluded to avoid confounding due to volume status.
3. Intervention Arms & Protocols
| Feature | Conservative Fluids | Liberal Fluids |
|---|---|---|
| Daily Fluid Goal | Maintain CVP <4 mmHg | Maintain CVP 10–14 mmHg |
| Diuretic Use | Aggressive diuresis allowed | Minimal diuretics |
| Vasopressor Use | Allowed if needed to maintain MAP | Fluids first, then vasopressors if needed |
| Monitoring | CVP or PA catheter to guide fluids | Same |
📌 Key Difference: The conservative group received fewer fluids and more diuretics to actively remove excess fluid, while the liberal group received fluids to maintain higher CVP.
4. Fluids, Vasopressor Use, and Other Interventions
| Parameter (First 7 Days Post-Randomization) | Conservative Fluids | Liberal Fluids | Difference |
|---|---|---|---|
| Total IV Fluids (7 days) | 1.0L (median) | 7.0L (median) | -6.0L less in conservative group |
| Fluid Balance (7 days) | -136 mL (net fluid loss) | +6,992 mL (net fluid gain) | ~7L difference |
| Diuretic Use (%) | 68% | 21% | More frequent in conservative group |
| Vasopressor Use (%) | 66% | 57% | Slightly more in conservative group |
📌 Key Findings:
- The conservative group received 6L less fluids over 7 days and had a net negative fluid balance.
- Vasopressors were used slightly more in the conservative group but without harm.
5. Primary & Secondary Outcomes
5.1 Mortality Results
| Outcome | Conservative Fluids | Liberal Fluids | Difference |
|---|---|---|---|
| 60-Day Mortality | 25.5% | 28.4% | No significant difference (P = 0.30) |
| ICU Mortality | 16.9% | 19.7% | No significant difference |
📌 Key Takeaway: Conservative fluids did NOT reduce mortality compared to liberal fluids.
5.2 Secondary Outcomes
| Outcome | Conservative Fluids | Liberal Fluids | P-Value |
|---|---|---|---|
| Ventilator-Free Days (Day 28) | 14.6 days | 12.1 days | P < 0.001 |
| ICU-Free Days (Day 28) | 13.4 days | 11.2 days | P < 0.001 |
| Oxygenation (PaO₂/FiO₂ at Day 7) | +23 mmHg improvement | No significant change | P < 0.001 |
| Acute Kidney Injury (AKI) | 10% | 14% | P < 0.05 (fewer AKI in conservative group) |
📌 Key Takeaway: Conservative fluids improved lung function, reduced ventilator days, and lowered ICU stay without increasing AKI.
6. Clinical Implications
✅ A conservative fluid strategy improves lung function and shortens ICU stay in ARDS.
✅ Conservative fluids reduce ventilator days without harming circulation.
✅ Excess fluids worsen lung function, oxygenation, and ICU outcomes.
📌 FACTT changed ARDS management by promoting conservative fluids and diuresis.
7. Limitations & Controversies
🔹 Did Not Assess Long-Term Outcomes → Follow-up was limited to 60 days.
🔹 Excluded Severe Hypovolemia → Results may not apply to septic shock patients needing aggressive fluids.
🔹 Higher Vasopressor Use in Conservative Group → More patients required vasopressors, though this did not worsen mortality.
8. FACTT vs. CLOVERS & CLASSIC – Key Differences
| Feature | FACTT (2006) | CLOVERS (2023) | CLASSIC (2022) |
|---|---|---|---|
| Setting | ICU patients with ARDS | Early sepsis (ED/Wards) | ICU septic shock |
| Intervention | Restrictive vs. Liberal fluids in ARDS | Early vasopressors vs. fluids in sepsis | Restrictive vs. usual fluids in septic shock |
| Key Finding | Restrictive fluids improved lung function & reduced ICU stay | No survival benefit of early vasopressors | No survival benefit of fluid restriction |
📌 Key Takeaway: FACTT supports conservative fluids in ARDS, while CLOVERS & CLASSIC suggest individualized fluid management in sepsis.
9. Final Take-Home Message
💡 “FACTT revolutionized ARDS management by proving that conservative fluid strategies improve lung function, reduce ventilator days, and shorten ICU stay—without increasing mortality. The key takeaway? Avoid fluid overload in ARDS and use diuresis when needed.”
8. ANDROMEDA-SHOCK (2019) – Capillary Refill vs. Lactate-Guided Resuscitation in Sepsis
The ANDROMEDA-SHOCK trial, published in JAMA in 2019, was a multicenter randomized controlled trial (RCT) designed to compare capillary refill time (CRT)-guided resuscitation vs. lactate clearance-guided resuscitation in patients with septic shock.
Key Finding: CRT-guided resuscitation led to less fluid administration and faster resolution of shock, without increasing mortality.
1. Study Design & Rationale
| Feature | Details |
|---|---|
| Full Name | ANDROMEDA-SHOCK (ANDROmeda Sepsis SHOCK) |
| Objective | To compare capillary refill time (CRT) vs. lactate clearance for guiding fluid resuscitation in septic shock |
| Study Type | Multicenter, RCT, open-label |
| Location | 28 ICUs (Argentina, Chile, Colombia, Ecuador, Uruguay) |
| Time Period | March 2017 – March 2018 |
| Number of Patients | 424 |
| Setting | ICU patients with septic shock |
| Follow-up Duration | 28 days |
| Primary Endpoint | 28-day all-cause mortality |
📌 Why Was ANDROMEDA-SHOCK Needed?
- Septic shock resuscitation traditionally relied on lactate clearance to guide fluids and vasopressors, but lactate is slow to normalize and affected by non-hypoperfusion factors (e.g., liver dysfunction).
- Capillary refill time (CRT) is a simple bedside test that reflects microcirculatory perfusion and responds more rapidly to changes in circulation.
- ANDROMEDA-SHOCK tested whether CRT-guided resuscitation could reduce fluid overload while maintaining adequate perfusion.
📌 Key Novel Feature:
- First major RCT to test CRT vs. lactate as a bedside tool for guiding resuscitation in septic shock.
2. Inclusion & Exclusion Criteria
| Criteria | Details |
|---|---|
| Inclusion Criteria | – Septic shock requiring vasopressors after ≥20 mL/kg IV fluids – Lactate ≥2 mmol/L |
| Exclusion Criteria | – Acute hemorrhage, severe trauma, acute pulmonary edema, DNR status – Severe liver failure (Child-Pugh C), chronic kidney disease (CKD), pregnancy |
📌 Key Inclusion: Patients had persistent septic shock despite initial fluid resuscitation.
📌 Key Exclusion: Conditions where CRT or lactate might be unreliable (e.g., liver failure, acute bleeding).
3. Intervention Arms & Protocols
| Feature | CRT-Guided Resuscitation | Lactate-Guided Resuscitation |
|---|---|---|
| Perfusion Target | CRT ≤3 seconds | Lactate decrease by ≥20% every 2 hours |
| Fluids (After Randomization) | Fluids stopped if CRT normalized | Fluids continued if lactate remained high |
| Vasopressor Use | Adjusted based on CRT response | Adjusted based on lactate response |
| Monitoring | Reassessed every 30 minutes | Lactate rechecked every 2 hours |
📌 Key Difference: CRT was reassessed every 30 minutes (fast response), while lactate took longer (every 2 hours).
4. Fluids, Vasopressor Use, and Other Interventions
| Parameter (First 8h Post-Randomization) | CRT-Guided Group | Lactate-Guided Group | Difference |
|---|---|---|---|
| Total IV Fluids (8h) | 1.4L (IQR: 0.9–2.1L) | 1.8L (IQR: 1.2–2.6L) | -400 mL less in CRT group |
| Cumulative Fluids (First 24h) | 2.4L | 3.2L | -800 mL less in CRT group |
| Vasopressor Use (%) | Higher in CRT group (faster escalation to norepinephrine) | Delayed vasopressors in lactate group |
📌 Key Findings:
- The CRT group received ~400 mL less fluids in 8 hours and ~800 mL less over 24 hours.
- CRT-guided resuscitation resulted in earlier vasopressor use but less fluid administration.
5. Primary & Secondary Outcomes
5.1 Mortality Results
| Outcome | CRT-Guided Resuscitation | Lactate-Guided Resuscitation | Difference |
|---|---|---|---|
| 28-Day Mortality | 34.9% | 43.4% | No significant difference (P = 0.06) |
📌 Key Takeaway: CRT-guided resuscitation did not significantly reduce mortality, but there was a trend toward benefit (P = 0.06).
5.2 Secondary Outcomes
| Outcome | CRT-Guided Resuscitation | Lactate-Guided Resuscitation | P-Value |
|---|---|---|---|
| Organ Failure-Free Days | 14.5 days | 13.0 days | P = 0.045 |
| ICU-Free Days | 10.0 days | 8.5 days | P = 0.04 |
| Vasopressor-Free Days | 17.0 days | 15.0 days | P = 0.04 |
| Ventilator-Free Days | 16.5 days | 14.0 days | P = 0.03 |
📌 Key Takeaway: CRT-guided resuscitation led to faster shock resolution, fewer organ failures, and earlier ICU discharge.
6. Clinical Implications
✅ CRT is a simple bedside tool that rapidly reflects tissue perfusion.
✅ CRT-guided resuscitation reduced fluid administration and improved organ recovery.
✅ Lactate clearance alone may lead to excessive fluid resuscitation.
📌 ANDROMEDA-SHOCK suggests that CRT should be included in septic shock resuscitation strategies.
7. Limitations & Controversies
🔹 Underpowered for Mortality → The trial was not powered to detect mortality differences (P = 0.06 trend toward CRT benefit).
🔹 Open-Label Design → Clinicians knew the resuscitation strategy, potentially influencing decisions.
🔹 Excluded Severe Hypovolemia → Results may not apply to patients needing aggressive volume resuscitation.
8. ANDROMEDA-SHOCK vs. PROCESS, ARISE, PROMISE – Key Differences
| Feature | ANDROMEDA-SHOCK (2019) | PROCESS (2014) | ARISE (2014) | PROMISE (2015) |
|---|---|---|---|---|
| Setting | ICU patients with septic shock | Early sepsis (ED/Wards) | Early sepsis (ED/Wards) | Early sepsis (ED/Wards) |
| Intervention | CRT vs. lactate for resuscitation | EGDT vs. usual care | EGDT vs. usual care | EGDT vs. usual care |
| Key Finding | CRT led to faster shock resolution with less fluids | EGDT not superior to usual care | EGDT not superior to usual care | EGDT not superior to usual care |
📌 Key Takeaway: ANDROMEDA-SHOCK showed that CRT is a fast, effective bedside tool for guiding resuscitation, while prior sepsis trials focused on structured protocols vs. usual care.
9. Final Take-Home Message
💡 “ANDROMEDA-SHOCK proved that capillary refill time is a simple, rapid, and effective bedside tool for resuscitation in septic shock. CRT-guided resuscitation reduces fluid overload and improves organ recovery—without compromising perfusion.”
CLOVERS vs. CLASSIC Trial: Detailed Comparison
Both CLOVERS (2023) and CLASSIC (2022) are major randomized controlled trials that investigated restrictive vs. liberal fluid resuscitation strategies in septic shock. However, they differ in patient population, timing of intervention, volume of fluids given, and outcomes.
1. Study Design & Objectives
| Feature | CLOVERS Trial (2023) | CLASSIC Trial (2022) |
|---|---|---|
| Full Name | Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis | Conservative vs. Liberal Approach to Fluid Therapy in Septic Shock |
| Objective | Early resuscitation: Compare restrictive (early vasopressors) vs. liberal (more fluids) approach in sepsis-induced hypotension | ICU fluid management: Compare restrictive vs. standard care in septic shock patients already admitted to the ICU |
| Study Type | Multicenter, RCT, open-label | Multicenter, RCT, open-label |
| Location | 60 centers (USA) | 31 ICUs (Europe) |
| Patients Included | Sepsis-induced hypotension (early phase, pre-ICU) | Septic shock in ICU (post-initial resuscitation phase) |
| Timing of Intervention | Early septic shock (ED & wards, within 4h of meeting criteria) | Late septic shock (ICU, after initial resuscitation) |
| Primary Hypothesis | Early vasopressors with restrictive fluids improves survival | Restricting fluids after ICU admission improves survival |
🔹 Key Difference:
- CLOVERS studied early sepsis resuscitation (first few hours in ED/Wards).
- CLASSIC studied post-resuscitation phase (ICU patients who had already received fluids).
2. Inclusion & Exclusion Criteria
| Feature | CLOVERS | CLASSIC |
|---|---|---|
| Inclusion Criteria | Suspected infection + hypotension after 1–3L fluids (MAP <65 mmHg, SBP <100 mmHg) | Septic shock requiring vasopressors after receiving ≥1L of IV fluids |
| Exclusion Criteria | >4h since hypotension, >3L fluids given, severe fluid overload, pregnancy | >12h septic shock, >4L fluids before enrollment, major bleeding, severe burns |
🔹 Key Difference:
- CLOVERS patients were in the early hours of sepsis.
- CLASSIC patients were already admitted to ICU and receiving vasopressors.
3. Intervention Protocols
| Feature | CLOVERS | CLASSIC |
|---|---|---|
| Restrictive Fluids Group | – Fluids limited after initial 1–3L – Early vasopressors started to maintain MAP | – Fluids minimized after ICU admission – Additional fluids given only if signs of hypoperfusion |
| Liberal/Standard Fluids Group | – Initial 2L fluid bolus, then fluids as needed – Vasopressors started only if fluids failed | – Fluids given at clinician discretion (standard ICU practice) |
🔹 Key Difference:
- CLOVERS: Tested early vasopressor use vs. aggressive fluids.
- CLASSIC: Tested ongoing restrictive fluids vs. usual care in ICU patients already on vasopressors.
4. Fluids and Vasopressor Use
| Feature | CLOVERS Restrictive | CLOVERS Liberal | CLASSIC Restrictive | CLASSIC Standard |
|---|---|---|---|---|
| Fluids in First 6h | 500 mL (IQR: 130–1097) | 2300 mL (IQR: 2000–3000) | 1798 mL (IQR: 500–3000) | 2980 mL (IQR: 1998–4000) |
| Fluids in First 24h | 1267 mL (IQR: 555–2279) | 3400 mL (IQR: 2500–4495) | 1798 mL (IQR: 500–3000) | 2980 mL (IQR: 1998–4000) |
| Total Fluids (including pre-trial fluids) | 3300 mL | 5400 mL | 4900 mL | 5700 mL |
| Vasopressor Use | 59% | 37% | 100% (all required vasopressors at enrollment) | 100% |
🔹 Key Difference:
- CLOVERS: Liberal group got ~2L more fluids within 6h; restrictive group got earlier vasopressors.
- CLASSIC: Both groups were on vasopressors; restrictive fluids led to ~1L less fluid over 24h.
5. Outcomes & Mortality
| Outcome | CLOVERS Restrictive | CLOVERS Liberal | CLASSIC Restrictive | CLASSIC Standard |
|---|---|---|---|---|
| 90-Day Mortality | 14.0% | 14.9% | 42.3% | 42.1% |
| Ventilator-Free Days | 23.4 days | 22.8 days | 19.3 days | 19.5 days |
| ICU-Free Days (28d) | 22.8 days | 22.7 days | 12.5 days | 13.0 days |
| RRT Use | 3.3% | 3.3% | 22.5% | 20.8% |
| Serious Adverse Events | 10.6% | 10.5% | No difference |
🔹 Key Takeaways:
- Neither trial found a significant mortality difference between restrictive and liberal fluids.
- Restricting fluids did NOT improve survival in either early sepsis (CLOVERS) or ICU septic shock (CLASSIC).
- CLASSIC showed slightly fewer ventilator-free days with restrictive fluids, but this was not statistically significant.
6. Clinical Implications & Take-Home Messages
Key Similarities Between CLOVERS & CLASSIC:
✅ Restricting fluids does not improve survival.
✅ Liberal fluids do not significantly increase harm.
✅ Early vasopressors are safe but not clearly superior.
✅ Both trials suggest that individualized fluid management is the best approach.
Key Differences Between CLOVERS & CLASSIC:
🔹 CLOVERS tested early resuscitation (first few hours), CLASSIC tested ICU patients post-resuscitation.
🔹 CLOVERS tested early vasopressors vs. fluids, CLASSIC tested post-resuscitation fluid restriction.
🔹 CLOVERS patients received less fluid overall; CLASSIC patients were already on vasopressors.
7. Final Take-Home Message
💡 “CLOVERS and CLASSIC both show that restrictive fluid strategies do not improve survival in septic shock. CLOVERS tested early vasopressors in ED patients, while CLASSIC tested fluid restriction in ICU patients. The key takeaway? Individualized fluid therapy based on dynamic assessment is more important than strict liberal vs. restrictive strategies.”
Review of Critical Care Medicine 