Landmark Trials

Clinical question

Does very intensive systolic blood-pressure reduction improve outcome compared with standard reduction in acute spontaneous intracerebral hemorrhage?

What the trial found

Targeting SBP 110–139 mmHg was not superior to a 140–179 mmHg target for death or disability after acute ICH.

Clinical interpretation

Supports smooth BP control while avoiding routine overshoot below the contemporary 130–150 mmHg maintenance range in suitable mild-to-moderate ICH.

Clinical question

How does dexmedetomidine compare with midazolam for prolonged sedation in mechanically ventilated ICU adults?

What the trial found

Dexmedetomidine did not improve time at target sedation but reduced delirium prevalence and ventilation duration compared with midazolam.

Clinical interpretation

Supports non-benzodiazepine sedation strategies when light, interactive sedation and delirium reduction are priorities.

Clinical question

Is dexmedetomidine noninferior to midazolam or propofol for prolonged light-to-moderate ICU sedation?

What the trial found

Dexmedetomidine was an effective alternative to midazolam and propofol for prolonged light-to-moderate sedation.

Clinical interpretation

Supports dexmedetomidine as a useful light-sedation agent rather than implying universal superiority over propofol for every ICU patient.

Clinical question

In patients with ceftriaxone-resistant E. coli or Klebsiella pneumoniae bloodstream infection susceptible to both study drugs, is definitive piperacillin-tazobactam noninferior to meropenem for 30-day mortality?

What the trial found

For ceftriaxone-resistant E. coli or Klebsiella pneumoniae bloodstream infection, piperacillin-tazobactam did not meet the noninferiority criterion compared with meropenem and had higher observed 30-day mortality.

Clinical interpretation

MERINO supports carbapenem therapy for serious ESBL-producing Enterobacterales bloodstream infection rather than relying on piperacillin-tazobactam as definitive treatment, while susceptibility method, source, inoculum and newer beta-lactam/beta-lactamase inhibitor options still matter clinically.

Clinical question

Do high-dose corticosteroids improve survival after clinically significant traumatic brain injury?

What the trial found

High-dose corticosteroids increased mortality after traumatic brain injury and should not be used to treat acute TBI.

Clinical interpretation

The CRASH result is a major harm signal and is the reason corticosteroids are contraindicated as a treatment for traumatic brain injury itself. Steroids may still be indicated for a separate coexisting condition, but not to improve TBI outcome.

Clinical question

Does PAV+ shorten time to successful liberation compared with pressure-support ventilation?

What the trial found

PAV+ did not accelerate successful liberation compared with pressure support.

Clinical interpretation

PAV+ may be used for selected physiology/interaction goals, but should not be taught as improving liberation or survival compared with protocolized pressure support.

Clinical question

Does early automated closed-loop ventilation improve ventilator-free days?

What the trial found

Automated closed-loop ventilation did not improve patient-centered liberation outcomes compared with protocolized conventional ventilation.

Clinical interpretation

Automation can improve process measures but should not be presented as proven to reduce ventilation duration or mortality.

Clinical question

Does targeting SpO2 90% (88–92%) reduce 90-day mortality compared with usual oxygen therapy?

What the trial found

A routine SpO2 target around 90% did not improve survival in unselected mechanically ventilated adults.

Clinical interpretation

Avoid both hypoxemia and unnecessary hyperoxemia; UK-ROX does not support universally lowering oxygen targets to 88–92% in all ventilated ICU adults.

Clinical question

Do more frequent readiness screening or pressure-supported SBTs shorten time to successful extubation?

What the trial found

Neither more frequent screening nor pressure-supported SBTs universally shortened successful extubation.

Clinical interpretation

Daily protocolized readiness assessment remains reasonable; do not teach one SBT technique or increased screening frequency as universally superior.

Clinical question

Does selective digestive decontamination reduce hospital mortality in mechanically ventilated ICU patients?

What the trial found

SDD did not significantly reduce in-hospital mortality.

Clinical interpretation

Do not present SDD as a routine mortality-improving VAP-prevention strategy; potential infection/ecologic effects must be balanced with local antimicrobial-resistance considerations.

Clinical question

Do adjunctive corticosteroids reduce mortality in HIV-negative immunocompromised adults with PJP and acute hypoxemic respiratory failure?

What the trial found

The trial did not demonstrate a statistically significant 28-day mortality benefit from routine adjunctive corticosteroids in HIV-negative hypoxemic PJP.

Clinical interpretation

Do not automatically apply the established HIV-associated PJP steroid rule to non-HIV PJP; individualize adjunctive corticosteroids and avoid assuming higher doses improve outcomes.

Clinical question

Does minimally invasive hematoma evacuation within 24 hours improve 180-day functional outcome compared with guideline-based medical management in selected spontaneous ICH?

What the trial found

In carefully selected patients treated within 24 hours, minimally invasive evacuation improved the prespecified utility-weighted functional outcome; the observed benefit was driven by lobar hemorrhage.

Clinical interpretation

ENRICH supports early minimally invasive evacuation as a selective strategy for appropriate lobar ICH rather than routine surgery for all spontaneous ICH.

Clinical question

Is 7 days of antibiotic therapy noninferior to 14 days for selected hospitalized patients with bloodstream infection?

What the trial found

Seven days was noninferior to 14 days for mortality in the trial's selected bloodstream-infection population.

Clinical interpretation

Supports shorter therapy for appropriately selected uncomplicated bloodstream infection after source control and clinical improvement; it does not justify 7 days for S. aureus bacteremia, endovascular infection, inadequately controlled foci, or other syndromes that require longer treatment.

Clinical question

Does primary alpha-2 agonist sedation shorten time to successful extubation compared with propofol-based sedation?

What the trial found

Alpha-2 agonist–based sedation was not superior to propofol for time to successful extubation.

Clinical interpretation

Choice among propofol and dexmedetomidine should be phenotype- and adverse-effect-driven; dexmedetomidine should not be taught as universally superior for ventilator liberation or delirium prevention.

Clinical question

Does objective early PPH detection plus a bundled first-response treatment strategy reduce severe bleeding outcomes after vaginal birth?

What the trial found

A systems approach coupling objective blood-loss detection with prompt bundled treatment improved important PPH outcomes.

Clinical interpretation

Supports rapid objective recognition and simultaneous first-response therapy rather than waiting for profound blood loss or sequential treatment failure.

Clinical question

Does prophylactic TXA shortly after vaginal birth prevent PPH in women with moderate or severe anemia?

What the trial found

Routine prophylactic TXA immediately after vaginal birth did not reduce clinically diagnosed PPH in women with moderate or severe anemia.

Clinical interpretation

Do not extrapolate the WOMAN treatment benefit in established PPH into universal postpartum TXA prophylaxis.

Clinical question

Is once-weekly rezafungin noninferior to daily caspofungin for candidemia/invasive candidiasis?

What the trial found

Once-weekly rezafungin provided efficacy noninferior to daily caspofungin in the studied candidemia/invasive-candidiasis population.

Clinical interpretation

Rezafungin is a newer echinocandin option, but FDA labeling is restricted to patients with limited or no alternative treatment options; it does not make conventional echinocandins obsolete.

Clinical question

Can clinically individualized VAP antibiotic courses of 3–7 days be noninferior to usual courses of at least 8 days?

What the trial found

Selected clinically improving VAP patients can receive individualized courses shorter than traditional prolonged therapy without worse death/recurrence outcomes in this trial.

Clinical interpretation

Supports stewardship and response-guided duration; it should not be interpreted as a mandate to stop every VAP course at day 3–5, especially with uncontrolled infection, abscess/empyema, bacteremia, profound immunosuppression or poor response.

Clinical question

Does routine IV levothyroxine increase heart transplantation from hemodynamically unstable potential heart donors after death by neurologic criteria?

What the trial found

Routine levothyroxine did not increase the proportion of donor hearts transplanted.

Clinical interpretation

Do not teach universal thyroid-hormone replacement after death by neurologic criteria as an evidence-based organ-yield intervention; use donor-team protocols and patient-specific indications.

Clinical question

Does pantoprazole prevent clinically important upper GI bleeding without increasing mortality in invasively ventilated ICU patients?

What the trial found

Pantoprazole substantially reduced clinically important upper GI bleeding without a statistically significant effect on 90-day mortality.

Clinical interpretation

For invasively ventilated ICU patients with an indication for stress-ulcer prophylaxis, PPI prophylaxis reduces clinically important upper GI bleeding; reassess and discontinue when the ICU indication resolves.

Clinical question

In critically ill adults with sepsis receiving piperacillin-tazobactam or meropenem, does continuous infusion improve 90-day survival compared with intermittent infusion?

What the trial found

Continuous infusion did not significantly reduce the prespecified primary 90-day mortality endpoint, although clinical cure was higher and the mortality point estimate favored continuous infusion.

Clinical interpretation

Supports prolonged/continuous β-lactam administration as a pharmacokinetically rational option in selected critically ill patients, but it should not be taught as proven to reduce mortality.

Clinical question

Does cefepime vs piperacillin-tazobactam change the risk of acute kidney injury/death or neurologic dysfunction in hospitalized adults with acute infection?

What the trial found

Piperacillin-tazobactam did not increase AKI/death compared with cefepime in this randomized trial; cefepime had more neurologic dysfunction as a secondary outcome.

Clinical interpretation

Challenges the assumption that piperacillin-tazobactam is intrinsically more nephrotoxic than cefepime in all patients, while reinforcing attention to cefepime neurotoxicity, especially with renal dysfunction.

Clinical question

In acute MI with anemia, is a liberal RBC strategy superior to a restrictive strategy?

What the trial found

The trial did not prove superiority of the liberal strategy, but results favored it numerically and informed later ACS guidance.

Clinical interpretation

Do not automatically apply the general ICU Hb 7 g/dL threshold to acute MI; individualize and consider the 2025 ACS guideline position.

Clinical question

Does a liberal RBC threshold improve neurologic outcome after moderate or severe traumatic brain injury?

What the trial found

A liberal strategy did not significantly improve the primary neurologic outcome.

Clinical interpretation

TBI transfusion should not be reduced to a single general-ICU threshold; integrate cerebral physiology, bleeding, ischemia and trial uncertainty.

Clinical question

Does a liberal RBC transfusion threshold improve neurologic outcome in aneurysmal subarachnoid hemorrhage with anemia?

What the trial found

Routine liberal transfusion did not significantly improve long-term neurologic outcome.

Clinical interpretation

Use individualized transfusion decisions in aSAH rather than assuming higher hemoglobin improves neurologic recovery.

Clinical question

Does sodium bicarbonate infusion reduce mortality in ICU patients with severe metabolic acidemia?

What the trial found

The trial was neutral for its primary composite outcome overall. In the prespecified AKIN 2–3 subgroup, bicarbonate was associated with better 28-day survival and less renal replacement therapy; this subgroup result supports selective use rather than routine treatment of all severe acidemia.

Clinical interpretation

The 2018 AKI-subgroup survival signal was hypothesis-generating. BICARICU-2 (JAMA 2025) subsequently found no mortality benefit in severe acidemia with moderate-to-severe AKI, although kidney replacement therapy was reduced. Do not present BICAR-ICU as proving a survival benefit.

Clinical question

In critically ill adults with severe metabolic acidemia and moderate-to-severe AKI, does sodium bicarbonate improve survival?

What the trial found

Bicarbonate did not improve 90-day, 28-day, or 180-day mortality in severe acidemia with moderate-to-severe AKI, but it reduced use of kidney replacement therapy.

Clinical interpretation

Do not claim a mortality benefit from bicarbonate in severe acidemia with AKI. Selective use may still be reasonable to correct severe acidemia and may reduce kidney replacement therapy, balanced against sodium, volume, calcium, and alkalemia risks.

Clinical question

Does adding IV acetazolamide to loop diuretics improve successful decongestion in acute decompensated heart failure?

What the trial found

Adding IV acetazolamide targeting the proximal tubule improves successful decongestion and speeds hospital discharge in congested acute heart failure.

Clinical interpretation

Provides high-quality evidence for sequential nephron blockade using carbonic anhydrase inhibition in loop diuretic resistance.

Clinical question

Does starting empagliflozin after clinical stabilization during an acute heart-failure hospitalization improve 90-day clinical benefit?

What the trial found

Starting empagliflozin in clinically stabilized patients during an acute heart-failure admission improved a 90-day hierarchical composite of survival, heart-failure events and symptoms.

Clinical interpretation

Supports in-hospital initiation of empagliflozin after stabilization; do not extrapolate EMPULSE to dapagliflozin or claim that it independently reduced mortality.

Clinical question

After an acute heart-failure admission, does high-intensity rapid optimization of recommended oral HF therapy with close follow-up improve 180-day outcomes?

What the trial found

Rapid post-discharge optimization of recommended HF therapy with close follow-up reduced the composite of HF readmission or all-cause death at 180 days.

Clinical interpretation

Supports structured, closely monitored rapid optimization after stabilization; it does not prove that every patient should receive immediate four-drug therapy or that mortality alone was reduced by each component.

Clinical question

In severe acute cardiogenic pulmonary edema, does early noninvasive ventilation improve short-term mortality or intubation-related outcomes compared with standard oxygen therapy?

What the trial found

Early NIV improves symptoms and gas-exchange physiology rapidly in acute cardiogenic pulmonary edema, but 3CPO did not establish a mortality or intubation benefit.

Clinical interpretation

Supports symptom/physiology benefits of early NIV while preventing overstatement of 3CPO as a mortality or large intubation-reduction trial.

Clinical question

Does gentle bag-mask ventilation during the interval between induction and laryngoscopy reduce hypoxemia during RSI in the ICU?

What the trial found

Gentle BMV during RSI significantly reduced profound peri-intubation hypoxemia without increasing pulmonary aspiration.

Clinical interpretation

Changed ICU RSI practice: gentle bagging with low pressure/PEEP is now routinely performed during the apneic phase.

Clinical question

Does mechanical thrombectomy improve functional independence in patients with acute ischemic stroke presenting 6-24 hours after last known well?

What the trial found

Mechanical thrombectomy up to 24 hours after last known well in patients with clinical-core mismatch drastically increased functional independence without increasing mortality or intracranial hemorrhage.

Clinical interpretation

Expanded the mechanical thrombectomy therapeutic window from 6 hours to 24 hours in imaging-selected large vessel occlusions.

Clinical question

In critically ill adults with severe (KDIGO stage 3) AKI, does starting RRT immediately, rather than waiting for a strict clinical indication, improve survival?

What the trial found

Starting RRT immediately at KDIGO stage 3, rather than waiting for a strict clinical indication, did not improve 60-day survival. A substantial proportion of patients managed with watchful waiting never required RRT at all.

Clinical interpretation

AKIKI supports a watchful-waiting approach to RRT timing in AKI without an emergent indication — closely monitoring the patient and starting RRT only if a defined indication develops, rather than initiating it pre-emptively at a given AKI stage.

Clinical question

In a high-risk, biomarker-enriched population with KDIGO stage 2 AKI, does early RRT initiation improve 90-day survival compared with delayed initiation?

What the trial found

In this single-center trial of a biomarker-enriched, higher-risk KDIGO stage 2 population, early RRT initiation substantially reduced 90-day mortality — a notably larger and more clearly positive effect than any of the larger, later multicenter trials found.

Clinical interpretation

ELAIN is the outlier among the four major RRT-timing trials: its single-center design, biomarker-based patient enrichment, and earlier AKI stage at randomization (stage 2, versus stage 3 in AKIKI) all differ from the larger, more recent, multicenter trials, which found no mortality benefit to early initiation. It has not been replicated at multicenter scale, so it should not be read as outweighing the larger neutral trials for general practice.

Clinical question

In patients with septic shock and severe (RIFLE 'Failure' stage) AKI, does early RRT initiation improve 90-day survival compared with a delayed strategy?

What the trial found

In patients with septic shock and severe AKI specifically, early RRT initiation did not improve 90-day survival compared with a delayed, indication-based strategy.

Clinical interpretation

IDEAL-ICU extends the AKIKI finding to a septic-shock-specific population and reinforces that routine early RRT does not improve survival even in this higher-acuity group — supporting watchful waiting with RRT reserved for a defined indication rather than initiated pre-emptively based on AKI stage alone.

Clinical question

In critically ill adults with severe AKI, does an accelerated RRT initiation strategy improve 90-day survival compared with a standard, watchful-waiting strategy?

What the trial found

In the largest and most rigorously powered trial of RRT timing to date, an accelerated initiation strategy did not improve 90-day survival compared with watchful waiting, and watchful waiting safely avoided RRT altogether in a large minority of patients.

Clinical interpretation

STARRT-AKI is the strongest single piece of evidence against routine early/accelerated RRT initiation in AKI without a specific indication — it reinforces AKIKI and IDEAL-ICU, and its size and rigor argue against generalizing ELAIN's earlier, smaller, single-center positive result to general practice.

Clinical question

Does idarucizumab rapidly and completely reverse the anticoagulant effect of dabigatran in patients with life-threatening bleeding or urgent surgery?

What the trial found

Idarucizumab achieves immediate, complete, and sustained reversal of dabigatran without prothrombotic excess.

Clinical interpretation

Established Idarucizumab (Praxbind) 5 g IV as the definitive specific reversal agent for dabigatran-associated hemorrhage.

Clinical question

Does thoracic endovascular aortic repair (TEVAR) combined with optimal medical therapy improve 5-year aorta-specific survival compared with medical therapy alone in stable uncomplicated Type B dissection?

What the trial found

Prophylactic TEVAR combined with optimal medical therapy in selected patients with stable Type B dissection was associated with improved 5-year aorta-specific survival (6.9% vs 19.3% mortality) and delayed disease progression (27.0% vs 46.1%).

Clinical interpretation

INSTEAD-XL showed that prophylactic TEVAR added to optimal medical therapy in selected, stable patients with favorable-anatomy uncomplicated Type B aortic dissection was associated with improved 5-year aorta-specific survival and delayed disease progression in the population studied. This is foundational RCT / long-term follow-up evidence, not a guideline: it supports individualized consideration of pre-emptive TEVAR in selected high-risk patients, but does not mean every uncomplicated Type B dissection should receive TEVAR — medical therapy remains the default foundational strategy for uncomplicated disease.

Clinical question

Does early, short-course continuous neuromuscular blockade improve survival in severe ARDS?

What the trial found

A 48-hour course of continuous cisatracurium, started early in severe ARDS, improved adjusted survival and time off the ventilator compared with placebo in this single trial.

Clinical interpretation

ACURASYS drove a period of routine early paralysis in severe ARDS, but its mortality finding relied on an adjusted secondary analysis rather than the unadjusted primary comparison, and the later ROSE trial (see Landmark Trials) did not confirm a survival benefit — see Controversies.

Clinical question

Among patients already ventilated with a low-tidal-volume, plateau-pressure-limited strategy, does a higher-PEEP/lower-FiO2 approach improve survival compared with a lower-PEEP/higher-FiO2 approach?

What the trial found

The trial was stopped early for futility: a higher-PEEP strategy produced clinical outcomes statistically indistinguishable from a lower-PEEP strategy once both groups were already receiving lung-protective tidal volumes. It did not show that higher PEEP is harmful, nor that it is beneficial on average.

Clinical interpretation

ALVEOLI does not by itself justify routinely using either a higher- or a lower-PEEP protocol — it shows the two fixed PEEP/FiO2 tables tested performed similarly on average across an unselected ALI/ARDS population. Later individual-patient-data meta-analyses (not reproduced here) suggested a mortality signal favoring higher PEEP specifically in moderate-to-severe disease, which is why current guidance is severity-stratified rather than a flat 'higher is better' or 'no difference' statement.

Clinical question

Does ventilating with a lower tidal volume reduce mortality compared with traditional tidal volumes in acute lung injury and ARDS?

What the trial found

Ventilating with 6 mL/kg predicted body weight and a plateau pressure ceiling of 30 cmH2O lowered mortality compared with 12 mL/kg ventilation, and trial enrollment was stopped early for benefit.

Clinical interpretation

This trial established low tidal volume ventilation as the default strategy for essentially all patients with ARDS, largely independent of severity, and it anchors every major ARDS ventilation guideline written since.

Clinical question

Does an aggressive lung recruitment maneuver strategy with titrated PEEP reduce mortality in moderate-to-severe ARDS, compared with a conventional low-PEEP strategy?

What the trial found

In moderate-to-severe ARDS, an aggressive lung recruitment maneuver and titrated-PEEP strategy resulted in worse 28-day survival (55.3% vs 45.3%, P=0.041), higher 6-month mortality (65.3% vs 59.9%, P=0.04), and increased pneumothorax requiring chest tube drainage (5.6% vs 1.6%, P=0.001).

Clinical interpretation

ART demonstrates that aggressive staircase recruitment maneuvers up to 60 cmH2O and high compliance-titrated PEEP cause hemodynamic collapse and barotrauma that outweigh alveolar recruitment benefit. Routine high-pressure recruitment maneuvers are harmful and not recommended.

Clinical question

In established moderate-to-severe ARDS not related to COVID-19, does early dexamethasone reduce ventilator-free days and mortality compared with usual care?

What the trial found

Early dexamethasone in patients with established, non-COVID moderate-to-severe ARDS increased ventilator-free days and was associated with a large absolute reduction in 60-day mortality in this single-country trial.

Clinical interpretation

This is the most direct RCT evidence for a mortality benefit from corticosteroids in non-COVID ARDS, but it is a single trial, from a single country, stopped early for slow recruitment rather than for benefit — factors that widen uncertainty around the true effect size even though the result was statistically significant. It has not been replicated by an equivalently powered multinational confirmatory trial, so it should be read as an important but not yet definitively confirmed result, distinct from the separately established evidence for corticosteroids (e.g. dexamethasone) in COVID-19-related respiratory failure.

Clinical question

Does early venovenous ECMO reduce mortality in very severe ARDS, compared with continued conventional ventilation with rescue therapies?

What the trial found

Early ECMO in very severe ARDS did not significantly reduce 60-day mortality in the primary intention-to-treat analysis, but substantial crossover to ECMO in the control arm complicates interpreting this as a true null result.

Clinical interpretation

EOLIA is generally read as supportive of ECMO in very severe, refractory ARDS despite the non-significant primary endpoint, given the crossover pattern and subsequent Bayesian reanalyses.

Clinical question

In acute lung injury/ARDS, does a conservative fluid-management strategy targeting an even fluid balance improve outcomes compared with a liberal strategy, once shock has resolved?

What the trial found

A conservative, restrictive fluid strategy after the shock phase did not reduce mortality compared with a more liberal strategy, but it produced more ventilator-free days and a shorter ICU stay, without an increase in shock or need for renal replacement therapy.

Clinical interpretation

FACTT is the basis for a 'dry after resuscitation' approach in ARDS: once a patient is no longer in shock, avoiding a positive fluid balance shortens time on the ventilator and in the ICU, even though it has not been shown to change 60-day survival on its own. It does not address fluid strategy during the initial resuscitation/shock phase, when adequate perfusion still takes priority.

Clinical question

Does early, prolonged prone positioning reduce mortality in severe ARDS?

What the trial found

In patients with severe ARDS ventilated with a lung-protective strategy, adding prone positioning for ≥16 hours/day, started early, substantially reduced mortality compared with staying supine.

Clinical interpretation

PROSEVA is the primary basis for recommending prone positioning specifically in severe ARDS (P/F < 150); the benefit has not been consistently shown in mild-to-moderate disease, so guidelines restrict the strong recommendation to the severe category.

Clinical question

Does routine early continuous neuromuscular blockade improve survival in moderate-to-severe ARDS, compared with a lighter-sedation strategy?

What the trial found

In a larger, more contemporary trial using lighter background sedation in the comparator arm, routine early continuous neuromuscular blockade did not reduce mortality in moderate-to-severe ARDS.

Clinical interpretation

ROSE shifted practice away from routine early paralysis for all patients with severe ARDS; current guidance favors reserving neuromuscular blockade for patients with severe ventilator dyssynchrony or refractory hypoxemia despite adequate sedation, rather than applying it by default.

Clinical question

In trauma patients with or at risk of significant hemorrhage, does tranexamic acid reduce mortality?

What the trial found

Tranexamic acid given within 8 hours of trauma reduced all-cause mortality, with the benefit for death due to bleeding concentrated in patients treated within 3 hours of injury — later administration showed a diminished, and in subsequent analyses potentially reversed, effect.

Clinical interpretation

CRASH-2 established early tranexamic acid as standard of care in trauma with significant hemorrhage, with the specific, time-dependent finding that earlier administration matters — this is the basis for treating TXA as most beneficial within a 3-hour window rather than a drug with a flat benefit regardless of timing.

Clinical question

In severe trauma requiring massive transfusion, does a 1:1:1 plasma:platelet:RBC transfusion ratio improve survival compared with a 1:1:2 ratio?

What the trial found

A 1:1:1 transfusion ratio did not significantly reduce overall mortality compared with 1:1:2, but did reduce early death from exsanguination and improved the rate of achieving hemostasis.

Clinical interpretation

PROPPR is the primary trial basis for balanced-ratio massive transfusion protocols, even though its overall mortality result was neutral — the reduction in early exsanguination and improved hemostasis are read as clinically meaningful secondary findings, though this requires interpreting a non-primary endpoint as practice-changing, which is a real limitation of the trial's design as basis for the current standard.

Clinical question

Does immediate coronary angiography improve 90-day survival compared with delayed angiography in comatose patients after OHCA without ST-segment elevation?

What the trial found

Immediate coronary angiography provided no survival or neurological benefit over delayed angiography in post-cardiac arrest patients without ST-segment elevation.

Clinical interpretation

Supports prioritizing ICU hemodynamic and neuroprotective stabilization over immediate emergent catheterization in non-STEMI post-arrest patients without shock.

Clinical question

Does targeted hypothermia at 33°C improve 6-month survival and functional outcome compared with targeted normothermia (<=37.5°C) with early fever treatment in comatose post-cardiac arrest adults?

What the trial found

Targeted hypothermia at 33°C did not improve survival or functional neurological outcome compared with targeted normothermia and active fever prevention.

Clinical interpretation

Shifted international post-ROSC practice from mandatory 33°C hypothermia toward strict targeted normothermia (<= 37.5°C) with rapid fever prevention.

Clinical question

In acute decompensated heart failure, does the route (bolus vs. continuous infusion) or dose intensity (low- vs. high-dose) of IV furosemide affect symptom relief or renal function?

What the trial found

Neither the route of furosemide administration (bolus vs. continuous) nor the dose intensity (low vs. high) significantly changed symptom relief or renal function at 72 hours, though the high-dose strategy showed trends toward greater diuresis and symptom relief at the cost of a trend toward transient renal function worsening, neither reaching statistical significance.

Clinical interpretation

DOSE supports flexibility in diuretic strategy for acute decompensated heart failure — neither administration route nor dose intensity has been shown to be clearly superior, so the choice can reasonably be guided by institutional practice and individual patient response rather than a single mandated protocol.

Clinical question

In cardiogenic shock with multivessel coronary disease, does culprit-lesion-only PCI (with optional staged revascularization) improve outcomes compared with immediate multivessel PCI?

What the trial found

An initial strategy of treating only the culprit lesion, rather than all significant lesions immediately, reduced 30-day death and severe renal failure in cardiogenic shock with multivessel disease.

Clinical interpretation

This shifted practice away from treating all lesions at the index procedure in cardiogenic shock — the extra contrast load, procedure time, and hemodynamic stress of complete revascularization in an unstable patient appear to outweigh any benefit of immediately opening non-culprit vessels.

Clinical question

In STEMI-related cardiogenic shock, does routine use of a microaxial flow pump (Impella CP) added to standard care improve survival compared with standard care alone?

What the trial found

Routine use of a microaxial flow pump in STEMI-related cardiogenic shock reduced 180-day mortality, at the cost of significantly more bleeding, limb ischemia, and other device-related complications.

Clinical interpretation

This is the first RCT to show a mortality benefit from a mechanical circulatory support device in cardiogenic shock, a genuinely practice-relevant result — but it is a single trial, in a population restricted to STEMI-related shock, with a real and significant complication trade-off. It should not be read as establishing benefit for cardiogenic shock from all causes, or as a device without meaningful downside.

Clinical question

Does routine intra-aortic balloon pump (IABP) support improve survival in MI-related cardiogenic shock undergoing early revascularization?

What the trial found

Routine IABP use did not reduce 30-day mortality in patients with MI-related cardiogenic shock undergoing early revascularization, despite prior registry data and a class I guideline recommendation supporting its use.

Clinical interpretation

This trial reversed a previously guideline-endorsed practice that had been based mainly on registry and observational data — a clear example of randomized evidence overturning weaker prior evidence. IABP is no longer used routinely for MI-related cardiogenic shock.

Clinical question

Does emergency revascularization improve survival compared with initial medical stabilization in cardiogenic shock complicating acute MI?

What the trial found

Emergency revascularization did not significantly reduce mortality at 30 days, but the survival curves separated by 6 months in favor of early revascularization, establishing it as standard of care.

Clinical interpretation

SHOCK established emergency revascularization as the standard approach to MI-related cardiogenic shock, based primarily on its longer-term (6-month) survival benefit rather than a significant 30-day effect — an important nuance often lost in shorthand summaries of the trial.

Clinical question

Is a 5-day course of systemic glucocorticoids non-inferior to a 14-day course in acute COPD exacerbations?

What the trial found

5 days of systemic glucocorticoids is clinically non-inferior to 14 days, significantly reducing steroid exposure.

Clinical interpretation

Established the 5-day oral prednisone 40 mg regimen as the international standard of care in AECOPD.

Clinical question

Does intensive renal replacement therapy reduce mortality in critically ill AKI patients compared with standard therapy?

What the trial found

Intensive dialysis dose or frequency does not improve survival, renal recovery, or reduce organ failure in ICU AKI.

Clinical interpretation

Reaffirmed the standard target effluent dose of 20-25 mL/kg/h for continuous RRT.

Clinical question

Does high-intensity continuous renal replacement therapy improve 90-day survival compared with standard-intensity therapy in critically ill AKI?

What the trial found

Increasing CRRT dose from 25 to 40 mL/kg/h provides no benefit in survival or renal recovery.

Clinical interpretation

Established a delivered CRRT effluent dose of 20-25 mL/kg/h as the global standard of care, avoiding unnecessary filter clogging and nutrient loss.

Clinical question

Is milrinone superior to dobutamine in reducing mortality and adverse events in cardiogenic shock?

What the trial found

Milrinone and dobutamine yielded identical outcomes in cardiogenic shock without significant differences in mortality, arrhythmias, or hospital stay.

Clinical interpretation

Validates inotrope selection based on physiologic context: dobutamine for renal dysfunction or hypotension; milrinone for RV afterload elevation or chronic beta-blocker therapy.

Clinical question

Does referral of severe adult respiratory failure to a specialized ECMO center improve 6-month survival without severe disability compared with conventional ventilation?

What the trial found

Centralized referral to a dedicated ECMO center for severe ARDS significantly improved 6-month survival without severe disability.

Clinical interpretation

Established the clinical paradigm of early transfer to high-volume ECMO centers for refractory ARDS.

Clinical question

Does routine early VA-ECMO reduce 30-day mortality in acute myocardial infarction complicated by cardiogenic shock undergoing early revascularization?

What the trial found

Routine early VA-ECMO did not reduce 30-day mortality in acute MI cardiogenic shock and significantly increased major bleeding and vascular complications.

Clinical interpretation

Argues strongly against routine early VA-ECMO for all infarct-related cardiogenic shock. VA-ECMO remains a selective rescue/bridge strategy for refractory shock or arrest when the expected benefit outweighs bleeding and vascular risk; the trial does not define a single SCAI stage at which ECMO is mandatory or prohibited.

Clinical question

Does sodium zirconium cyclosilicate (ZS-9 / Lokelma) rapidly restore and maintain normokalemia in outpatient and hospitalized hyperkalemia?

What the trial found

ZS-9 acts within 1-2 hours to reliably bind intestinal potassium and achieve normokalemia without causing colonic necrosis.

Clinical interpretation

Supported modern non-absorbed potassium binder therapy over sodium polystyrene sulfonate (Kayexalate).

Clinical question

Does high-flow nasal cannula (HFNC) reduce intubation or mortality compared with standard oxygen or noninvasive ventilation in acute hypoxemic failure?

What the trial found

HFNC reduced 90-day mortality and intubation rates in severe hypoxemic respiratory failure without increasing complications.

Clinical interpretation

Established HFNC as preferred first-line noninvasive support for de-novo hypoxemic respiratory failure.

Clinical question

Does high-flow nasal oxygen reduce 28-day mortality compared with standard oxygen in acute hypoxemic respiratory failure?

What the trial found

HFNO did not reduce 28-day mortality, although intubation occurred modestly less often than with standard oxygen.

Clinical interpretation

Use HFNO for its physiologic and comfort advantages and possible reduction in intubation, but do not teach a proven mortality benefit; reassess frequently for failure.

Clinical question

Does intensive acute blood pressure lowering targeting SBP < 140 mmHg improve outcomes in acute intracerebral hemorrhage?

What the trial found

Intensive BP lowering toward <140 mmHg was safe and did not significantly reduce the primary composite of death or major disability; an ordinal mRS analysis showed a modest shift toward better functional outcome. Hematoma-growth effects were not sufficient to claim reliable prevention.

Clinical interpretation

INTERACT2, together with ATACH-2 and subsequent analyses, informed the later AHA/ASA recommendation to target about 140 mmHg and maintain 130–150 mmHg in selected mild-to-moderate spontaneous ICH, rather than establishing a universal 130–140 target.

Clinical question

Does platelet transfusion improve outcomes in antiplatelet-associated spontaneous intracerebral hemorrhage?

What the trial found

Platelet transfusion in antiplatelet-associated non-operative ICH causes harm and increases mortality.

Clinical interpretation

Reversed empirical practice: routine platelet transfusion is contraindicated in non-surgical antiplatelet-associated ICH.

Clinical question

What is the efficacy and toxicity profile of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory B-ALL?

What the trial found

Tisagenlecleucel achieved durable remissions in relapsed/refractory B-ALL, but was accompanied by high rates of cytokine release syndrome requiring standardized ICU management with tocilizumab.

Clinical interpretation

Pivotal landmark trial establishing the therapeutic reality of CAR T-cell therapy and defining the protocolized management of Cytokine Release Syndrome (CRS) in critical care.

Clinical question

Does high-flow nasal cannula (HFNC) oxygen reduce 28-day mortality compared with standard oxygen therapy in immunocompromised patients with acute respiratory failure?

What the trial found

In critically ill immunocompromised patients with acute hypoxemic respiratory failure, high-flow nasal oxygen did not significantly reduce 28-day mortality or intubation rate compared with standard oxygen.

Clinical interpretation

Demonstrated that while HFNC improves comfort and oxygenation, it does not confer a mortality advantage over standard oxygen in immunocompromised hosts, and close bedside monitoring is essential to avoid delayed emergency intubation.

Clinical question

Does early bifrontotemporoparietal decompressive craniectomy for diffuse TBI with early intracranial hypertension improve functional outcome?

What the trial found

Early decompressive craniectomy for diffuse TBI with intracranial hypertension controlled ICP more effectively than medical management alone but resulted in worse functional outcomes at 6 months.

Clinical interpretation

DECRA demonstrated that successfully lowering ICP does not guarantee a better functional outcome — an important general lesson, not just a craniectomy-specific one. Interpretation is complicated by a baseline imbalance in pupillary reactivity (a strong outcome predictor) between the two groups, and by the relatively low ICP threshold (20 mmHg) and short duration used to trigger the intervention, which is lower/shorter than the refractory threshold used in RESCUEicp.

Clinical question

In TBI with intracranial hypertension refractory to medical therapy, does decompressive craniectomy improve outcome compared with continued medical management?

What the trial found

In refractory intracranial hypertension after TBI, decompressive craniectomy reduced 6-month mortality compared with continued medical management, but this came with an increased rate of vegetative state and severe disability among survivors — the rate of a good functional outcome was not clearly improved.

Clinical interpretation

RESCUEicp shows that decompressive craniectomy trades death for survival with a substantial chance of severe disability in many patients, rather than clearly improving overall outcome — this trade-off should be discussed explicitly in shared decision-making with family, rather than framed simply as 'craniectomy saves lives.'

Clinical question

Does adjunctive dexamethasone improve outcomes in adults with acute bacterial meningitis?

What the trial found

Early dexamethasone significantly reduces death and severe hearing loss/neurological disability in adult pneumococcal meningitis.

Clinical interpretation

Established the mandatory practice of giving 10 mg IV dexamethasone prior to or concurrently with empiric antibiotics.

Clinical question

Does early physical and occupational therapy during daily sedation interruption improve functional independence and delirium in ventilated ICU patients?

What the trial found

Early mobilization during sedation interruption significantly improves functional recovery at hospital discharge and decreases ICU delirium and ventilator duration.

Clinical interpretation

Core foundational trial supporting early mobilization protocols to prevent and mitigate ICU-acquired weakness (CIP/CIM).

Clinical question

Is IVIG equivalent to plasma exchange, and does combining both provide additional benefit in severe Guillain-Barré syndrome?

What the trial found

IVIG has equivalent efficacy to plasma exchange in severe Guillain-Barré syndrome, and combining both modalities provides no added benefit.

Clinical interpretation

Establishes IVIG (2 g/kg total) and plasma exchange as equally efficacious first-line disease-modifying therapies, with IVIG preferred in many centers due to convenience and ease of administration in ICU.

Clinical question

Does early initiation of parenteral nutrition to supplement enteral nutrition improve recovery compared with withholding parenteral nutrition until day 8?

What the trial found

Withholding supplemental parenteral nutrition during the first week of critical illness accelerates recovery and reduces infectious complications.

Clinical interpretation

Overturned early aggressive parenteral feeding dogma; confirmed parenteral nutrition should be delayed until after day 7 in patients tolerating minimal enteral nutrition.

Clinical question

Does energy-dense enteral nutrition delivering higher caloric intake improve 90-day survival in mechanically ventilated ICU patients?

What the trial found

Higher caloric delivery (100% of target) via energy-dense enteral nutrition did not improve survival and increased gastrointestinal intolerance.

Clinical interpretation

Confirmed that moderate/permissive underfeeding (~70% energy target) during early critical illness is safe and avoids overfeeding complications.

Clinical question

Does treating mild chronic hypertension in pregnancy to target blood pressure <140/90 mmHg reduce adverse pregnancy outcomes without impairing fetal growth?

What the trial found

Treating mild chronic hypertension during pregnancy to a target below 140/90 mmHg reduces severe adverse maternal and perinatal events without impairing fetal growth.

Clinical interpretation

Overturned decades of restrictive blood pressure management, defining blood pressure targets of <140/90 mmHg throughout pregnancy.

Clinical question

Does magnesium sulfate prevent eclamptic seizures and reduce maternal/fetal mortality in women with preeclampsia?

What the trial found

Magnesium sulfate dramatically halves the incidence of eclampsia in preeclampsia without significant maternal or fetal harm.

Clinical interpretation

Definitive landmark trial establishing magnesium sulfate as the global standard of care for seizure prophylaxis and treatment in preeclampsia with severe features.

Clinical question

Does early intravenous tranexamic acid reduce mortality and hysterectomy in postpartum hemorrhage?

What the trial found

Early administration of tranexamic acid within 3 hours of delivery significantly reduces maternal death from postpartum hemorrhage without increasing adverse thromboembolic complications.

Clinical interpretation

Establishes early TXA (1 g IV) as an essential component of obstetric massive hemorrhage resuscitation protocols.

Clinical question

Does a minimally invasive step-up approach reduce complications and mortality compared with primary open necrosectomy in infected necrotizing pancreatitis?

What the trial found

The minimally invasive step-up approach reduced major complications by 43% and avoided open surgery in over one-third of infected necrotizing pancreatitis cases.

Clinical interpretation

Transformed infected necrotizing pancreatitis management from immediate open surgery to initial percutaneous/endoscopic drainage.

Clinical question

Is aggressive fluid resuscitation superior to moderate fluid resuscitation in acute pancreatitis?

What the trial found

Aggressive large-volume fluid loading causes volume overload and harm without improving clinical resolution.

Clinical interpretation

Reversed decades of dogmatic aggressive hydration in acute pancreatitis toward moderate goal-directed therapy.

Clinical question

Does systemic thrombolysis with tenecteplase improve outcomes in intermediate-risk (submassive) pulmonary embolism?

What the trial found

Routine thrombolysis prevents hemodynamic decompensation but markedly increases major hemorrhage and hemorrhagic stroke.

Clinical interpretation

Routine thrombolysis is withheld in submassive PE; close monitoring with rescue thrombolysis if shock develops is the standard of care.

Clinical question

In intermediate-risk acute PE selected for intervention, how does large-bore mechanical thrombectomy compare with catheter-directed thrombolysis?

What the trial found

Among intervention-selected intermediate-risk PE patients, large-bore thrombectomy improved the prespecified hierarchical composite compared with catheter-directed thrombolysis, largely through less deterioration/bailout and ICU use rather than a demonstrated mortality advantage.

Clinical interpretation

PEERLESS supports large-bore thrombectomy as an effective catheter-based option in appropriately selected intermediate-risk PE, but it does not establish a mortality benefit or justify routine intervention for all stable intermediate-risk PE.

Clinical question

Does upfront initial combination therapy with ambrisentan and tadalafil reduce clinical failure compared with monotherapy in treatment-naive PAH?

What the trial found

Initial upfront dual oral combination therapy halves the rate of clinical failure and hospitalization in treatment-naive pulmonary arterial hypertension.

Clinical interpretation

Established a strong evidence base for initial dual oral combination therapy in appropriately selected treatment-naive WHO functional class II-III PAH, while current therapy remains risk-stratified rather than universally identical for every patient.

Clinical question

Does add-on sotatercept improve exercise capacity in symptomatic PAH receiving stable background therapy?

What the trial found

Add-on sotatercept improved exercise capacity and several clinical/hemodynamic measures in symptomatic PAH on background therapy.

Clinical interpretation

Introduced activin-signaling inhibition as an effective additional pathway for PAH therapy; monitor adverse effects including epistaxis/telangiectasia, increased hemoglobin, thrombocytopenia and blood-pressure effects.

Clinical question

Does add-on sotatercept reduce major morbidity/mortality events in high-risk PAH despite maximum tolerated background therapy?

What the trial found

Among high-risk PAH patients on maximum tolerated background therapy, sotatercept substantially reduced the composite of death, lung transplantation or PAH-worsening hospitalization.

Clinical interpretation

Supports escalation with sotatercept in high-risk PAH under specialty care, while the early stopping and composite endpoint require outcome-specific interpretation.

Clinical question

Does add-on sotatercept reduce clinical worsening in intermediate/high-risk PAH diagnosed within the prior year?

What the trial found

Adding sotatercept within the first year after PAH diagnosis reduced clinical-worsening events compared with placebo.

Clinical interpretation

Extends sotatercept evidence earlier in the PAH disease course, but the trial stopped early after prior positive sotatercept results caused loss of equipoise.

Clinical question

Does early hydrocortisone reduce 28-day mortality in severe community-acquired pneumonia admitted to the ICU?

What the trial found

Early continuous hydrocortisone reduced 28-day mortality by nearly half in severe CAP without increasing secondary infections.

Clinical interpretation

Solidified early adjunctive hydrocortisone as a mortality-reducing intervention in severe CAP.

Clinical question

Does a paired protocol of daily Spontaneous Awakening Trials (SAT) plus Spontaneous Breathing Trials (SBT) improve ventilator liberation and survival compared with standard care?

What the trial found

A paired nurse-driven SAT and respiratory therapist-driven SBT protocol drastically reduced ventilator duration, ICU stay, and 1-year mortality.

Clinical interpretation

Established the SAT/SBT paired coordination bundle as the foundational standard for ICU ventilator liberation.

Clinical question

Does early sedation with dexmedetomidine as the primary sedative reduce 90-day mortality compared with standard sedation in mechanically ventilated ICU patients?

What the trial found

An early dexmedetomidine-primary strategy did not reduce 90-day mortality compared with usual-care sedation; supplemental sedatives were frequently needed.

Clinical interpretation

Dexmedetomidine is a useful non-benzodiazepine sedative for selected light-sedation goals, but SPICE III does not justify calling it universally superior or outcome-improving.

Clinical question

In mechanically ventilated adults with septic shock, does a continuous hydrocortisone infusion reduce 90-day mortality?

What the trial found

Continuous hydrocortisone infusion did not reduce 90-day mortality compared with placebo, though it resolved shock faster and shortened initial ICU stay.

Clinical interpretation

ADRENAL and APROCCHSS tested different steroid regimens (hydrocortisone alone vs hydrocortisone plus fludrocortisone, with some protocol differences) and reached different conclusions about mortality — this is a genuine, unresolved tension in the corticosteroid evidence base, not a case where one trial should be read as simply correct and the other wrong. See Controversies.

Clinical question

In adults with septic shock, does hydrocortisone plus fludrocortisone reduce 90-day mortality?

What the trial found

Hydrocortisone combined with fludrocortisone reduced 90-day mortality compared with placebo in adults with septic shock.

Clinical interpretation

APROCCHSS and ADRENAL tested meaningfully different regimens (combined mineralocorticoid/glucocorticoid vs. glucocorticoid alone, with differing severity thresholds for enrollment) and reached different mortality conclusions. Current practice and the 2026 SSC's conditional, low-certainty recommendation reflect this unresolved tension rather than treating either trial as definitively settling the question — see Controversies.

Clinical question

Do balanced crystalloids reduce major adverse kidney events or mortality compared with saline in the ICU?

What the trial found

Balanced crystalloids produced a small reduction in the MAKE30 composite compared with saline. Mortality benefit was not statistically significant in the overall trial; sepsis subgroup/secondary analyses suggested lower mortality and informed later guideline preference for balanced crystalloids.

Clinical interpretation

Supported preferential use of balanced crystalloids over saline in many critically ill patients; the absolute MAKE30 difference was small and the sepsis mortality finding was a prespecified subgroup result. SSC 2026 therefore suggests, rather than mandates, balanced crystalloids over saline for sepsis resuscitation (with saline favored in sepsis plus TBI).

Clinical question

Does using vasopressin as an early, primary vasopressor (rather than adding it after norepinephrine) reduce kidney failure in septic shock?

What the trial found

Using vasopressin as an early, primary vasopressor did not improve kidney failure-free days or reduce mortality compared with norepinephrine as the primary vasopressor.

Clinical interpretation

VANISH tested vasopressin as an early, primary agent rather than as an add-on for norepinephrine-refractory shock, which is a different clinical question from how vasopressin is actually used in current practice — it does not argue against the current guideline-endorsed role of vasopressin as an adjunct in escalating norepinephrine requirements.

Clinical question

In septic shock already requiring norepinephrine, does adding low-dose vasopressin instead of continuing to titrate norepinephrine alone improve mortality?

What the trial found

Adding vasopressin to norepinephrine did not significantly reduce 28-day mortality compared with norepinephrine alone in the overall trial population. A pre-specified subgroup analysis suggested a possible mortality benefit in patients with less severe shock (lower baseline norepinephrine dose), but subgroup findings in a formally neutral trial are hypothesis-generating, not confirmatory.

Clinical interpretation

VASST is the main trial-level basis for using vasopressin as an add-on agent in septic shock rather than as a norepinephrine replacement, but it did not establish a mortality benefit for the overall population — the rationale for adding it (reducing norepinephrine dose requirements, catecholamine-sparing) is physiologic and practical rather than a demonstrated survival benefit.

Clinical question

Does capillary refill time (CRT)-guided resuscitation improve outcomes compared with lactate-guided resuscitation in septic shock?

What the trial found

CRT-guided resuscitation did not significantly reduce the primary 28-day mortality endpoint but was associated with modestly less organ dysfunction at 72 hours.

Clinical interpretation

Supports CRT as a rapid bedside perfusion marker within a multimodal resuscitation strategy; it should not be presented as proven mortality-superior to lactate-guided care.

Clinical question

Is norepinephrine or dopamine superior as the first-line vasopressor in undifferentiated shock?

What the trial found

Dopamine caused significantly more arrhythmias overall than norepinephrine. In the prespecified cardiogenic shock subgroup, dopamine was associated with increased 28-day mortality, whereas mortality did not differ in septic or hypovolemic shock.

Clinical interpretation

Supports norepinephrine over dopamine as the first-line vasopressor in shock, primarily driven by lower arrhythmogenicity and safety in cardiogenic shock.

Clinical question

In benzodiazepine-refractory status epilepticus, is any one of levetiracetam, fosphenytoin, or valproate more effective as second-line therapy than the others?

What the trial found

None of the three second-line agents was superior to the other two for terminating benzodiazepine-refractory status epilepticus, and adverse event rates (including hypotension and need for intubation) were similar across arms.

Clinical interpretation

ESETT did not identify a preferred second-line agent on efficacy or safety grounds — choice among levetiracetam, fosphenytoin, and valproate can reasonably be guided by other factors (infusion time, side-effect profile in a specific patient, drug availability, renal/hepatic considerations) rather than by an expected difference in seizure termination.

Clinical question

Is intramuscular midazolam via autoinjector non-inferior to intravenous lorazepam for terminating prehospital status epilepticus?

What the trial found

IM midazolam terminates prolonged seizures faster than IV lorazepam by eliminating the delay required for intravenous line placement.

Clinical interpretation

Established IM midazolam 10 mg as the preferred first-line agent when IV access is not immediately established.

Clinical question

Does early tranexamic acid reduce head injury-related mortality in patients with acute traumatic brain injury?

What the trial found

Early tranexamic acid administration within 3 hours reduces head injury mortality in mild-to-moderate TBI without increasing thromboembolic risk.

Clinical interpretation

Supports early TXA for non-severe TBI presenting within 3 hours of injury.

Clinical question

Is a restrictive RBC transfusion strategy (transfuse when Hb < 7.0 g/dL) as safe and effective as a liberal strategy (transfuse when Hb < 10.0 g/dL) in critically ill patients?

What the trial found

A restrictive threshold (Hb < 7.0 g/dL) was at least as effective as and potentially superior to a liberal threshold (Hb < 10.0 g/dL) in critically ill patients, cutting blood use by 54%.

Clinical interpretation

Foundational trial establishing Hb < 7.0 g/dL as the standard restrictive transfusion trigger in critical care.

Clinical question

Does a restrictive hemoglobin threshold of 7.0 g/dL improve or preserve outcomes compared with 9.0 g/dL in septic shock?

What the trial found

Patients with septic shock managed with a restrictive threshold (Hb <= 7.0 g/dL) had identical 90-day mortality and ischemic complications while avoiding 50% of transfusions.

Clinical interpretation

Provided randomized-trial support for a restrictive transfusion threshold in the studied septic-shock population, without establishing that one threshold applies to every ICU subgroup.

Clinical question

Does a restrictive transfusion strategy improve outcomes compared with a liberal strategy in acute upper GI bleeding?

What the trial found

Restrictive transfusion significantly improved 45-day survival and reduced rebleeding, particularly in cirrhotic patients.

Clinical interpretation

Firmly established the restrictive transfusion threshold (Hb < 7.0 g/dL) in acute UGIB.

Clinical question

Does early surgery (within 48 hours) reduce death and embolic events in severe left-sided infective endocarditis with large vegetations?

What the trial found

Early surgery within 48 hours in patients with left-sided infective endocarditis and large vegetations (>10 mm) significantly reduced embolic complications without increasing operative mortality.

Clinical interpretation

Defines the standard of care for urgent surgical consultation and intervention in patients with large vegetations and severe valvular dysfunction before embolic stroke or annular destruction occurs.

Clinical question

Is TAVR non-inferior or superior to surgical aortic-valve replacement in patients with severe aortic stenosis at low surgical risk?

What the trial found

TAVR demonstrated lower 1-year rates of death, stroke, and rehospitalization compared to SAVR across the surgical risk spectrum.

Clinical interpretation

Solidifies TAVR as an established therapeutic alternative to open surgery in critical AS, including emergent transcatheter rescue procedures in hemodynamic instability.

Clinical question

Does an ultra-slow low-dose tPA infusion achieve successful lysis with minimal hemorrhage in obstructive prosthetic valve thrombosis?

What the trial found

Slow infusion of low-dose tPA (25 mg over 25 hours) without a bolus effectively dissolves obstructive mechanical valve thrombi with exceptionally low major bleeding and embolic risk.

Clinical interpretation

Establishes slow-infusion low-dose fibrinolysis as the preferred first-line medical rescue regimen for critically ill patients with obstructive prosthetic valve thrombosis who are poor surgical candidates or have right-sided valve thrombosis.

Clinical question

Does NIV preoxygenation reduce peri-intubation hypoxemia compared with an oxygen mask in critically ill adults?

What the trial found

NIV preoxygenation substantially reduced peri-intubation hypoxemia.

Clinical interpretation

Use NIV preoxygenation when clinically appropriate and not contraindicated, especially in patients at high risk of desaturation.

Clinical question

Does ketamine rather than etomidate improve survival for critically ill adults undergoing emergency tracheal intubation?

What the trial found

Ketamine did not improve survival compared with etomidate and was associated with more peri-intubation cardiovascular collapse in this trial.

Clinical interpretation

Choose induction drugs according to patient physiology and contraindications; do not teach ketamine as universally hemodynamically safer than etomidate in critically ill adults.

Clinical question

After initial fluids, does an early restrictive fluid/vasopressor-prioritized strategy improve outcomes compared with liberal fluids?

What the trial found

A vasopressor-prioritized restrictive approach was not superior to a liberal fluid approach for mortality.

Clinical interpretation

Avoid dogmatic fluid strategies; individualize additional fluid using perfusion, responsiveness, tolerance, and shock phenotype.

Clinical question

Does landiolol-guided heart-rate reduction improve organ failure in persistent tachycardic septic shock?

What the trial found

Routine landiolol for persistent tachycardia in established septic shock was not supported.

Clinical interpretation

Do not use beta-blockade routinely simply to normalize heart rate in vasopressor-dependent septic shock.

Clinical question

Does high-dose protein improve discharge alive in high-nutritional-risk mechanically ventilated ICU patients?

What the trial found

Aggressive high-dose protein did not improve outcomes and may harm selected high-risk patients.

Clinical interpretation

Avoid routine very-high early protein dosing, particularly in AKI/high organ failure.

Clinical question

Does augmented enteral protein improve days alive and free of hospital?

What the trial found

Augmenting enteral protein did not improve patient-centered outcomes.

Clinical interpretation

Do not present aggressive protein augmentation as a proven outcome-improving priority.

Clinical question

Is an 8-day course of antibiotic therapy as effective as a 15-day course for microbiologically confirmed ventilator-associated pneumonia?

What the trial found

An 8-day antibiotic course for VAP produces equivalent clinical cure and survival while markedly reducing antibiotic exposure and multidrug-resistant pathogen emergence.

Clinical interpretation

Established the short 7-8 day antibiotic duration as standard of care in VAP.

Clinical question

Does adding caplacizumab, an anti-von Willebrand factor nanobody, to plasma exchange speed recovery and reduce TTP-related complications in acquired TTP?

What the trial found

Among patients with acquired TTP, caplacizumab led to faster normalization of the platelet count (2.69 vs 2.88 days). The composite of TTP-related death, recurrence or a thromboembolic event during treatment was 12% with caplacizumab vs 49% with placebo, recurrence at any time was 12% vs 38%, and no caplacizumab-treated patient developed refractory disease vs three on placebo. Patients on caplacizumab needed less plasma exchange and a shorter hospital stay. Mucocutaneous bleeding was more common (65% vs 48%).

Clinical interpretation

HERCULES made caplacizumab an add-on to plasma exchange and immunosuppression that protects against early exacerbation and ischemic events while the underlying autoimmune ADAMTS13 deficiency is treated. It does not replace plasma exchange or immunosuppression, and the bleeding signal needs monitoring.

Clinical question

Does terlipressin plus albumin reverse type 1 hepatorenal syndrome compared with placebo plus albumin?

What the trial found

Verified reversal of HRS occurred in 63 of 199 patients (32%) on terlipressin and 17 of 101 (17%) on placebo. More adverse events occurred with terlipressin, including abdominal pain, nausea, diarrhea and respiratory failure; death within 90 days from respiratory disorders was 11% vs 2%. At day 90, death had occurred in 51% vs 45% and liver transplantation in 23% vs 29%.

Clinical interpretation

CONFIRM shows terlipressin plus albumin improves renal function in HRS-AKI but does not by itself show a survival benefit, and the respiratory-failure signal means selection and monitoring (volume status, oxygenation) matter. It is a bridge to recovery or transplant, not definitive therapy.

Clinical question

Does plasma volume expansion with intravenous albumin, added to antibiotic treatment, prevent renal impairment and death in cirrhosis with spontaneous bacterial peritonitis?

What the trial found

Infection resolved in 94% on cefotaxime alone and 98% on cefotaxime plus albumin (not significant). Renal impairment developed in 33% vs 10%, in-hospital death occurred in 29% vs 10%, and three-month mortality was 41% vs 22%, all favoring albumin. Patients treated without albumin had higher plasma renin activity.

Clinical interpretation

The trial is the basis for giving intravenous albumin with antibiotics in SBP to protect the kidneys by supporting effective arterial volume. It also underpins the later logic of recognizing and treating HRS-AKI early in cirrhosis with infection.

Clinical question

Is dabigatran as effective and safe as dose-adjusted warfarin for preventing recurrent venous thrombosis after cerebral venous thrombosis?

What the trial found

No recurrent venous thromboembolic events were seen in either group. One major bleed (intestinal) occurred on dabigatran and two (intracranial) on warfarin, with one further clinically relevant non-major bleed on warfarin. Recanalization occurred in 60.0% on dabigatran and 67.3% on warfarin.

Clinical interpretation

RE-SPECT CVT found both anticoagulants carried a low risk of recurrence and bleeding, supporting dabigatran as a reasonable alternative to warfarin after initial heparin in stable patients. Because it was small and exploratory, it cannot show equivalence on efficacy.

Clinical question

Does adding endovascular treatment to standard medical care improve functional outcome in severe cerebral venous thrombosis?

What the trial found

At 12 months, 22 of 33 patients (67%) in the endovascular group and 23 of 34 (68%) in the standard-care group had an mRS of 0 to 1. Mortality was 12% vs 3% and symptomatic intracerebral hemorrhage 3% vs 9%, neither statistically significant.

Clinical interpretation

TO-ACT does not support routine endovascular treatment in severe CVT; anticoagulation-based care remains the foundation. Because the trial was small and stopped for futility, a benefit in a highly selected group cannot be excluded.