ECASS III

821 enrolled within 3-4.5 hrs of ischaemic stroke with bleeding criteria as exclusions
Included (Not in NINDS) –
- Age>80
- High stroke severity
- Stroke and diabetes
Primary end-point 3 month favourable outcome by modified Rankin Score
- Improved by alteplase Vs Placebo (52.4% Vs 45.2%, p=0.04, NNT=14)
- !! Symptomatic ICH more frequent with TPA (2.4% Vs 0.3%, p=0.008, NNH=48)
No mortality difference

TBL

Patients with stroke presenting within 3-4hrs who received alteplase had a better 3 month favourable outcome than those who received placebo. But there was an increase rate of symptomatic ICH.

See the paper here

EDEN

1000 mechanically ventilated patients meeting ALI criteria within 48h P:F ratio >300 and bilateral pulmonary infiltrates / no heart failure
Randomised to trophic (10-20ml/hr ) OR full enteral feeding for 6 days
Primary end-point ventilator free days in 1st 28 days
- No difference Trophic Vs normal (14.9 Vs 15 days, p=0.89)
Also no difference in 60 day mortality, organ failure free days, ICU free days, incidence of infection
Trophic feed patients experienced fewer GI intolerances (regurge, vomiting, diarrhoea etc) although low incidences
Trophic feed patients got less calories over 6 days (400 Vs 1300kcal/day, p=0.001)
87% of patients excluded according to their criteria though!! Limits external validity

TBL

Amongst a selective group of patients with ALI, vent free days and other endpoints were no different between trophic and full enteral feed over a 6 day period.

See the paper here

ELAIN

In critically unwell patients with acute kidney injury, does early initiation of renal replacement therapy (RRT) compared to delayed initiation reduce all cause mortality at 90 days?

Population

Included 231 patients with KDIGO stage 2 (majority were cardiac and abdominal surgical patients with:
1. - 2-fold increase in serum creatinine from baseline, or urine output <0.5ml/kg/hr for ≥12 hrs despite optimal resuscitation (PCWP>12, CI >2.6, MAP>65, IAP<15)
  - At least one of the following conditions:
    - Severe sepsis
    - Catecholamines (noradrenaline/adrenaline) >0.1mcg/kg/min
    - Refractory fluid overload (worsening pulmonary oedeoma, P/F <300mgHg, fluid balance >10% body weight)
    - Development or progression of non-renal organ dysfunction (SOFA organ system score ≥2
    - Age between 18 and 90

Intervention

Initiation of RRT within 8 hours of confirmation of KDIGO stage 2 [100% got this]
- Median time to RRT was 6.0 hours (IQR 4.0–7.0)

Control

Inititation of RRT within 12 hours of either [91% got this]
- KDIGO stage 3 criteria
  - Creatinine rise >3 fold increase from baseline, or oliguria <0.3ml/kg/hr for ≥24 hours or serum creatinine > 4mg/dl (353.6 μmol/l) with an acute increase of at least 0.5mg/dl (44.2μmol/l) within 24 hours
- Absolute indication for RRT
  - Urea >100mg/dl
  - Potassium >6mmol/l and or ECG abnormalities
  - Magnesium >4mmol/l and/or anuria/absence of deep tendon reflexes
  - Blood pH <7.15
  - Urine production <200ml/12hr or anuria
  - Organ oedema in the presence of AKI resistant to diuretic treatment (defined as one trial of furosemide)
    - Median time to RRT was 25.5 hours (IQR 18.8–40.3)

Outcome

Primary outcome: 90 day mortality
- Early group 39.3% vs Delayed group 54.7%
  - Hazard ratio 0.66 (95% CI 0.45 to 0.97; P=0.03)
  - Absolute risk reduction 15.34% (95% CI 2.62% to 28.06%; P= 0.025)
  - NNT=7
  - Fragility Index=3
Secondary outcome: early vs delayed
- Median duration of RRT: 9 days vs 25 days (P = 0.04, HR 0.69 [95% CI 0.48–1.00])
- Enhanced recovery of renal function at day 90: 53.6% vs 38.7% (P = 0.02, OR 0.55 [95% CI: 0.32–0.93])
- Median duration of mechanical ventilation: 125.5 hrs vs 181.0 hrs (P = 0.002)
- Length of hospital stay: 51 days vs 82 days (P < 0.001, HR 0.34 [95% CI 0.22–0.52])
No significant differences seen in
- Requirement of RRT at day 90
- Length of ICU stay
- Adverse events, fluid balance, and RRT modality
- Subgroup analysis of those who reached KDIGO stage 3 vs those who achieved absolute RRT requirement
Exploratory analysis:
- 24 hours post randomisation: significantly lower IL-6 and IL-8 in early group compared to delayed group (100% of early group and 21.8% of late group had received RRT but this time point)

Weaknesses

Fragility Index 3: a shift of 3 patients would render it non-significant (however, this is greater than the number lost-to-follow-up)
Single centre study: limits its external validation
Not all the treatments were standardised between groups. With the groups also being unblinded, this introduces bias, challenging its internal validity.
External validation further challenged by skewed patient population:
- 216/231 (93.5%) were surgical of which 108 (46.75%) were cardiac surgery patients
- 203 (88%) were mechanically ventilated at time of randomization

TBL

This single centre study demonstrates a significant reduction in 90 day mortality with early (stage 2 KDIGO) initiation of RRT, in a group of almost entirely surgical patients.
However, other studies challenge these conclusions. A larger multi-centre trial including a more mixed ICU patient population is needed in order to validate these data on a larger scale.

See the paper here

ENCHANTED

Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage.

Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian)
935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control.
Low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram) within 4.5 hours after the onset of stroke.
Primary outcome objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, defined by scores of 2 to 6 on the modified Rankin scale
Secondary objectives
- Is low dose superior to the standard dose with respect to symptomatic ICH
- Is the low dose non-inferior in an ordinal analysis of modified Rankin scale scores
The primary outcome occurred 53.2% low dose Vs 51.1% standard-dose (OR 1.09, CI 0.95 to 1.25, P=0.51 for noninferiority).
Low-dose alteplase non-inferior in the ordinal analysis of modified Rankin scale scores (OR 1.00, CI 0.89 to 1.13, P=0.04 for noninferiority)
Symptomatic ICH 1.0% low-dose group Vs 2.1% standard-dose group (P=0.01)
Fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01)
Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07)

TBL

This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose (0.6mg/kg) alteplase to standard-dose (0.9mg/kg) alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase.

See the paper here

EPO-3

Therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions.

Randomized, placebo-controlled trial
1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit were enrolled, with Hb<12
Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days.
Primary end point was the % of patients who received a red-cell transfusion.
Secondary end points
- number of red-cell units transfused
- mortality
- change in hemoglobin concentration from baseline
Epoetin alfa therapy did not result in a decrease in the number of patients who received a red-cell transfusion (46 Vs 48.3%, p=0.34) or the no. of RBC’s transfused
- 4.5±4.6 units in the epoetin alfa group Vs 4.3±4.8 units in the placebo group, (P=0.42).
Hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6±2.0 g per deciliter vs. 1.2±1.8 g per deciliter, P<0.001).
Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10)
- also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72).
- A similar pattern was seen at day 140 particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69).
- As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86).

TBL

The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events.

See the paper here

EPaNIC

In critically ill adult patients, does late supplemental parenteral nutrition (PN), compared with early PN reduce the duration of dependency on intensive care?

Inclusion criteria:
- Adult patient admitted to the ICU
- Nutritionally Risk Screening (NRS) score ≥3 (indicative that the patient was nutritionally at risk)
Exclusion:
- Ketoacidotic or hyperosmolar coma on admission
- BMI < 17 (kg/m2)
- Short Bowel Syndrome
- Pregnancy or lactating
- Taking oral nutrition
- Moribund or coded DNR
- Home mechanical ventilation
- No central catheter
4640 patients randomised
Early Vs Late parenteral nutrition
- Early – 20% dex 2 days then full TPN
- Late – 5% dex 7 days hen full TPN
Primary end point ICU LOS slightly improved in late PN
- 3 Vs 4 days, p=0.02
Secondaries
- No difference in ICU, hospital or 90 day mortality.
- Early had higher new infection rates (22.8 Vs 26.2%, p=0.008, NNH 29)
- Late had lower cholestasis rates (p=0.001), median reduction of 3 days in the duration of renal-replacement therapy (P=0.008) and a 9.7% decrease in the proportion of patients requiring more than 2 days of mechanical ventilation (p=0.006)
- Hospitalisation and total health care cost ($1600 difference)

TBL

Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation.

See the paper here

ESCAPE

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.

Included 433 patients with recent CHF hospitalization (in past year), urgent visit to the ED, or treatment with at least 160 mg furosemide in past month.
Randomized patients to assessment only vs. clinical assessment with a pulmonary arterial catheter (PAC)
Primary endpoint (6-month days alive and out of the hospital) no difference
Other clinical endpoints (mortality, hospitalizations) no difference
- PAC group had a higher incidence of adverse events potentially associated with PACs (21.9% vs. 11.5%, p=O.04, NNH=IO)
- Patients randomized to PACs had superior symptomatic improvement at 1 month, but there was no difference in symptom assessment at 6 months

TBL

The use of a PA catheter (PAC) as an adjunct to clinical judgment alone showed no mortality or hospitalization benefit.

Patients randomized to PACs had a transient improvement in symptoms, but experienced a higher rate of complications as a result of PAC placement.

See the paper here

Early PN

Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial.

Included 1372 ICU patients in Australia and New Zealand with central venous access admitted within the past day who were not expected to receive nutrition within the next 24-48 hours
Randomized patients to parenteral nutrition (with protein, glucose, lipids, and electrolytes) or standard of care (leaving all nutritional decisions to physician discretion)
Primary endpoint (60-day mortality) was not different between early parenteral nutrition and standard of care (21.5% vs. 22.8%, p=O.6)
At 60-days, there was no statistical or clinical difference in quality of life, performance status, or physical functioning status
There was no difference in infection rate, hospital length of stay, or hospital mortality
Early PN patients required fewer days of mechanical ventilation (7.26 vs. 7.73 days per 10-patient-ICU-days, p=0.01) and trended towards a shorter ICU length of stay (8.6 vs. 9.3 days, p=0.06)
Early parenteral nutrition patients received a mean of 6 days of parenteral nutrition and 3.1 days of enteral nutrition while in the ICU
Standard of care patients remained unfed for a mean of 2.8 days after randomization, with 40.8% of patients not receiving any form of nutrition during the mean 3.72 days of ICU care
**Unlike the EPaNIC trial, which targeted a broad variety of ICU patients, this study focused on a narrow cohort of patients with short-term relative contraindications to early enteral feeding and (somewhat surprisingly) did not exclude malnourished patients

TBL

Early TPN among patients recently admitted to an ICU with relative contraindications to enteral nutrition decreased duration of mechanical ventilation but did not impact other clinically meaningful endpoints. Early TPN was not associated with an increased risk of infection.

See the paper here

Esteban 2004

Noninvasive ventilation after extubation failure

Included 221 patients following elective extubation who demonstrated the onset of respiratory failure within 48 hours (eg, hypercapnia, hypoxia, increased work of breathing)
Randomized patients to medical therapy (supplemental oxygen, respiratory physiotherapy, bronchodilators) or noninvasive positive pressure ventilation with a full face mask
Primary endpoint (ICU mortality) was higher with noninvasive ventilation than medical therapy (25% vs. 14%, p=0.048, NNH 9)
Trial halted early (planned to enroll 167 more patients)
Mortality was primarily driven by patients requiring re-intubation who received noninvasive ventilation (38% noninvasive vs. 22% medical, p=O.06)
There was no difference in re-intubation rates (48% in both groups) or ICU length of stay
The authors hypothesize that the increase in mortality rate may have been due to a longer interval between respiratory failure and re-intubation in the noninvasive ventilation group (median 12 vs. 2 hours, p=0.02).
- The contribution to mortality was likely multifactorial, but may have included cardiac ischemia, respiratory muscle fatigue, aspiration pneumonitis, or complications of emergent intubation.
Crossover to noninvasive ventilation occurred in 26% patients assigned to medical therapy.
- Of those receiving crossover noninvasive ventilation, 25% required re-intubation
Prior studies have demonstrated that extubation failure was independently associated with mortality, and that noninvasive ventilation may avert the need for re-intubation (thus reducing mortality rate).

TBL

In patients with the onset of respiratory failure after extubation, noninvasive positive-pressure ventilation was associated with increased mortality, likely due to delayed reintubation, compared to conventional medical therapy.

See the paper here

Eurotherm 3235

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury

Included 387 patients with a closed traumatic brain injury within 10 days and a sustained intracranial pressure >20mmHg
Randomized to “control” (standard care with hyperosmolar therapy and inotropes) or “hypothermia” to 32-35 deg C (cooling with standard of care only if hypothermia did not reduce ICP <20 mmHg)
Hypothermia was initiated with chilled saline and maintained by the usual cooling technique at each site for at least 48 hours until ICP was no longer elevated
Primary endpoint (death or disability based on the 8-point Extended Glasgow Outcome Scale [GOS-E] at 6 months) was worse with hypothermia than control (OR of worse score =1.53, p=O.04)
The trial was stopped early (before a target enrollment of 600 patients) due to concern of harm
A favorable outcome (GOS-E of 5 to 8) was more common with control than hypothermia (36.5% vs. 25.7%, p=O.03, NNH 9) The risk of death was higher with hypothermia than control (26.6% vs. 34.9%, OR 1.45, p=O.047, NNH 12)
Mean daily ICP was similar between control and hypothermia, although control patients were more likely to use require barbiturate coma for persistently elevated ICPs (21.4% vs.10.3%)
It is not clear whether hypothermia is harmful or if delaying or deferring other therapies (hypertonic saline, mannitol, barbiturates) is harmful.
The study did not collect data regarding hyperosmolar therapy usage, and those randomized to hyperthermia were less likely to receive a barbiturate coma
The study was a pragmatic design in which centers could use any cooling technique. It is possible that certain cooling techniques could have either caused harm or benefit, but there was no analysis of how patients were cooled.