Conservative vs. liberal fluid management in ARDS
- Included 1,000 patients with early onset ALI/ARDS (within 48 hrs)
- Randomized to conservative (net even balance) vs. liberal (fluid-positive) fluid management strategies according to a strict treatment protocol
- Primary endpoint (60-day mortality) was not different between groups
(25.5% vs. 28.4%, p=O.30)
- Conservative management had more 28-day ventilator-free days (14.6 vs. 12.1 days, p<0.001) and 28-day ICU free days (13.4 vs. 11.2 days, p<0.001)
- Over 7 days, fluid balances were -136 mL (conservative strategy) vs. +6992 mL (liberal strategy)
- Conservative strategy has higher incidence of metabolic alkalosis (serum bicarbonate > 40 mEq/L) and electrolyte imbalances (serum sodium 150 mEq/L, potassium < 3 mEq/L)
Compared to liberal fluid management in ALI/ARDS, conservative strategies did not improve 60-day mortality, but did improve ventilator-free days and ICU length of stay.
rFVIIa for acute ICH
- Included 841 patients with spontaneous intracranial hemorrhage (ICH) within 3 hrs of onset
- Excluded deep coma (Glasgow < = 5), aneurysm, AV malformation, trauma, known coagulopathy, and a history of thromboembolic disease
- Randomized to receive 20 or 80 mcg/kg recombinant activated factor VII (rFVIIa) or placebo.
- Treatment was given within 4 hours of symptom onset
- Baseline characteristics were NOT well balanced, with the rFVIIa group being sicker (more intraventricular hemorrhage, more LV hypertrophy, and coma)
- Primary endpoint (90-day death or disability according to Rankin scale) was not different between 40 mcg/kg rFVIIa or 80 mcg/kg rFVIIa and placebo (26% vs. 300/0 vs. 24%)
- Percent hematoma growth from baseline at 24 hrs was reduced with 80 mcg/kg rFVIIa compared to placebo (11% vs. 26%, p>0.001, NNT 7)
- Absolute hematoma growth from baseline at 24 hrs was reduced with both 20 mcg/kg rFVIIa (4.9 mL) and 80 mcg/kg (3.7 mL) compared to placebo (7.5 mL)
- Arterial thromboembolic events (primarily MI and CVA) were more common with rFVIIa 80 mcg/kg compared to placebo (8% vs. 4%, p=O.04, NNH 25)
- Risk factors for thromboembolic events included age (OR 1.1 per 5 years of age) and previous use of antiplatelet therapy (OR 1.9)
- Study screened 8886 patients, only enrolling about 10% of patients, highlighting the specific type of ICH examined in this study and the poor external validity to all types of ICH
- Mortality findings in this study are in conflict with a smaller phase 11b study
- Possible explanations for the discrepancy may be the imbalance in baseline characteristics, better outcomes among the placebo group, or higher incidence of arterial thromboembolic events
Recombinant activated factor VII reduced hematoma growth at 24 hours, but did not have a clinical benefit (death or disability at 90 days). Arterial thromboembolic events were more common with rFVIIa.
Fluid boluses in African children with severe infection
- Included 3141 children (median 24 months of age) in sub-Saharan Africa with severe febrile illness with altered mental status or respiratory distress AND impaired perfusion (delayed capillary refill, weak pulse, cold extremities, or tachycardia)
- The majority of patients (57%) had malaria as a cause of their acute illness.
- Randomized in 1:1:1 ratio to 20 mL/kg bolus of normal saline, 20 mL/kg bolus of 5% albumin, or nom fluid resuscitation (“control” group).
- Treatment could be repeated in 1 hour (20 mL/kg) if impaired perfusion persisted.
- Primary endpoint (48-hour mortality) was higher with normal saline versus control (10.5% vs. 7.3%, p=O.01, NNH 31) and with albumin versus control (10.6% vs. 7.3%, p=O.008, NNH 30).
- There was no difference between normal saline and albumin groups (p=0.96).
- Mortality at four weeks was also higher with normal saline versus control (12% vs. 8.7%, p=O.01, NNH 30) and albumin versus control (12.2% vs. 8.7%, p=O.01, NNH 29)
- No beneficial effect of bolus therapy was demonstrated on any subgroup of patients
- At 8 hours, the median cumulative fluid volume was 40 mL/kg (albumin
and normal saline) versus 10.1 mL/kg (control).
- Fluid volume in the control group was primarily attributed to blood transfusion and maintenance IV fluids.
- The primary hypothesis for increased mortality is that bolus therapy worsened hemodilution and delayed receipt of blood transfusion.
- Approximately 33% of patients presented with a hemoglobin below 5 g/dL. Blood transfusion within the first hour was much more common in the control group compared to the bolus groups (20% versus 2 to 4%), suggesting that clinicians delayed blood products in favor of bolus therapy.
- Although the trial lacks external validity to “first world” countries (in which malaria and severe anemia are rare and access to ICU care with mechanical ventilation is common), the FEAST trial does challenge the dogma of aggressive fluid resuscitation in children with severe sepsis
Among children in sub-Saharan Africa presenting with severe infection and impaired perfusion, aggressive fluid resuscitation with either albumin or normal saline increased mortality compared to a no-bolus strategy.
High-flow nasal cannula for acute hypoxemic respiratory failure
- Included 310 patients in France and Belgium with a respiratory rate > 25 bpm, hypoxia (Pa02:Fi02 ratio < 300 on 10 Ipm or less of oxygen), and no hypercapnia (PaC02 < 45 mmHg)
- Excluded those with chronic respiratory failure, COPD, asthma
exacerbations, cardiogenic pulmonary edema, hypotension requiring vasopressors, altered mental status (GCS of 12 or less), and those with an urgent need for endotracheal intubation
- Randomized patients in an open-label fashion to high-flow nasal cannula (“high-flow NC”), a non-rebreather oxygen mask (“standard oxygen”), or noninvasive positive pressure ventilation (“NIPPV”).
- In all three groups, the supplemental oxygen device was titrated to a target Sp02
of 92% or higher.
- The majority of the patients had hypoxemia due to pneumonia (75%), most had bilateral infiltrates (80%), and most had severe hypoxia with an Fi02:Pa02 ratio below 200 (77%)
- Primary endpoint (intubation rate by day 28) was not different between high-flow NC, standard oxygen, and NIPPV (38% vs. vs. 50%, p=O.18)
- In a post-hoc analysis of patients with severe hypoxia (Pa02:Fi02 < 200), high-flow NC was associated with a lower primary endpoint (intubation by day 28) than standard oxygen (HR 2.14, Cl 1.08-4.22) and NIPPV (HR 2.6, Cl 1.36-4.96)
- Ventilator-free days by day 28 was higher (better) with high flow NC than standard oxygen or NIPPV (24 days vs. 22 days vs. 19 days, p=0.02)
- Crude ICU mortality was similar between high-flow NC and standard oxygen (HR 1.85, Cl 0.84-4.09), but was lower with high-flow NC after adjustment (HR 2.55, Cl 1.07-6.08)
- Both crude and adjusted ICU mortality were lower with high-flow NC versus NIPPV (crude HR 2.55, Cl 1.21-5.35)
- At 90 days, mortality was lower with high-flow NC compared to standard oxygen (HR 2.01, Cl 1.01-3.99) and NIPPV (HR 2.5, Cl 1.31-4.78)
- At one hour, patients with high-flow NC had superior improvement in respiratory discomfort as measured by a visual analog scale and subjective assessment of dyspnea compared to standard oxygen and NIPPV (p<0.001)
- The primary endpoint of the trial was underpowered. The study was
designed for an intubation rate among standard oxygen of 60% (instead of
- Because the primary endpoint failed to show benefit, all secondary endpoints and post-hoc analyses should be viewed with caution.
- Further, imbalances in baseline characteristics prompting statistical adjustments (such as ICU mortality) further weaken the impact of these secondary endpoint results.
- The inclusion and exclusion criteria of the study selected for a very small subpopulation of patients with respiratory failure (about 6% of those screened with respiratory failure were included), which limits the external validity of the study to a broad patient population
Among a select group of patients with hypoxemia and without chronic respiratory failure or cardiogenic pulmonary edema, high-flow nasal cannula did not reduce the risk of intubation compared to a non- rebreather mask or non-invasive positive pressure ventilation, although it did show benefit for a number of secondary endpoints including 90-day mortality.