ABC!
- Four-center trial included 335 patients requiring mechanical ventilation
Randomized patients to intervention (SAT+SBT) or control (SBT alone) - SAT (sedation awakening trial) – all sedation and analgesics (unless needed for active pain) held until eye opening to verbal stimuli or if respiratory failure criteria occurred. Sedatives were restarted at 50% previous dose
- SBT (spontaneous breathing trial) – T-piece or pressure support trial for 120 minutes
- Primary endpoint (days without mechanical ventilation over 28 days) was improved with intervention (14.7 vs. 11.6 days, p=0.02)
- ICU length of stay was decreased with intervention (9.1 vs. 12.9 days, p=0.01)
- There was no difference in 28-day mortality, but 90-day mortality was lower with intervention (44% vs. 58%, p=0.01, NNT 7)
- Self-extubation was more common with intervention (10% vs. 4%, p=0.03, NNT 17), but there was no difference in the need for reintubation
TBL
“A sedation awakening trial (SAT) and a spontaneous breathing trial (SBT) used together were superior to SBT alone for reducing duration of mechanical ventilation and 90-day mortality. The combination of SAT+SBT was associated with more self-extubation, but not more reintubation following self-extubation.”
ACURASYS
- Included 339 patients with early (within 48 hrs), severe ARDS (PaO2:FiO2 < 150).
- Most patients were randomized within 16 hours of meeting criteria.
- Randomized to placebo vs. cisatracurium (15 mg bolus + 37.5 mg/hr x 48 hrs)
Open-label, 20 mg cisatracurium allowed if sustained plateau pressure > 32 mmHg- Primary outcome (90-day mortality) was reduced with cisatracurium (crude rate 31.6% vs. 40.7%, p=0.08). After pre and post-hoc Cox regression adjustments for baseline PaO2:FiO2, SAPS II, and plateau pressures, the hazard ratio was 0.68 (p=0.04)
- Analysis indicated mortality benefit specifically in the subgroup of patients with PaO2:FiO2 < 120
- Pneumothorax more common in placebo group (4.0% vs. 11.7%, p=0.01, NNT 13)
- No difference in ICU-acquired paresis, although it is important to note that study drug was only given for a 48-hour period
- Mortality benefit was not significant until both pre-hoc and post-hoc Cox regression analysis corrected for baseline characteristics. The study would have been stronger if randomization and a larger sample size had more balanced baseline characteristics
TBL
In patients with severe ARDS, cisatracurium for 48 hours decreased 90-day mortality, although the analysis was limited by unbalanced baseline characteristics.
AKIKI
- Included 620 French ICU patients with KDIGO stage 3 (elevated serum creatinine or oliguria/anuria), acute kidney injury most likely due to acute tubular necrosis, and were receiving vasopressors and/or were mechanically ventilated
- Excluded patients with a compelling need for dialysis (eg, BUN > 112 mg/dL, K > 6 mg/dL, pH < 7.15 with metabolic acidosis, pulmonary edema with hypoxia despite mechanical ventilation and diuretics)
- Randomized patients to early dialysis (beginning at the time of randomization) or delayed dialysis (where dialysis was only initiated once the patient had a compelling need or if oliguria persisted beyond 72 hours)
- Primary endpoint (60-day mortality) was not different between early and delayed groups (48.5% vs. 49.7%, p=0.79)
- The study met pre-specified power to detect a 15% absolute difference in risk in the primary endpoint. The primary endpoint 95% confidence interval included an 18% decrease to a 29% increase in 60-day mortality for delayed dialysis versus early dialysis.
- Patients randomized to early dialysis were more likely to have catheter-related bloodstream infections (10% vs. 5%, p=0.03, NNH 20)
- Patients randomized to delayed dialysis were more likely to receive diuretics (36.5% vs. 1.3%), medical treatment for hyperkalemia (22.9% vs. 5.5%), and medical treatment for acidosis (16.7% vs. 6.8%)
- There were no differences in length of stay, mechanical ventilator-free days, vasopressor-free days, or dependence of renal replacement therapy at 28 or 90 days
98% of early dialysis patients actually received dialysis, but only 51% of delayed dialysis patients actually required dialysis - All aspects of the type and dose of hemodialysis were left to the discretion of the study site. Intermittent dialysis was used as the initial therapy in 50% of patients, and continuous renal replacement therapy was used exclusively in only 30% of patients
- The results of AKIKI are discrepant versus the ELAIN trial. AKIKI was multicenter (not single center), enrolled patients later (KDIGO stage 3 instead of stage 2), enrolled almost all medical patients (not surgical), waited to initiate dialysis in the delayed group until they had a compelling indication (instead of KDIGO stage 3 alone), and was pragmatic in allowing any type of renal replacement therapy and dose (instead of specifying CVVHDF at an effluent rate of 30 mL/kg/hr)
TBL
Among critically ill patients with acute kidney injury without an urgent need for dialysis, early renal replacement therapy did not improve mortality versus a delayed strategy but did increase the risk of catheter-associated bloodstream infections.
ALBIOS
- Included 1818 patients with severe sepsis or septic shock from 100 centers in Italy
- Randomized patients to receive either 200-300 mL of 20% albumin daily for a serum albumin level less than 3 g/dL or no albumin replacement at all.
- Replacement occurred for up to 28 days or until ICU discharge. Both groups received crystalloids when clinically indicated.
- Primary endpoint (28-day mortality) was not different between albumin replacement and no replacement (31.8% vs. 32%, p=0.94)
- The study was underpowered and at-risk for a type II error — it enrolled the target number of patients, but the power calculation was based on a mortality rate of 45%
- There were no differences in 90-day mortality, new organ failures, length of stay, renal replacement therapy, or duration of mechanical ventilation
- Albumin replacement was associated with slightly better physiologic parameters (lower HR, higher MAP, higher CVP), reduced duration of vasopressor or inotropic support (median 3 vs 4 days, p=0.007), and a lower cumulative net fluid balance (347 mL vs 1220 mL, p<0.001)
- Patients receiving albumin required more cumulative pRBC transfusions (median 600 mL vs 300 mL, p<0.001) and other blood products (900 mL vs 600 mL, p=0.007)
- A post-hoc subgroup analysis of septic shock patients (as defined by a cardiovascular SOFA score of 3-4) suggested a 90-day mortality benefit with albumin replacement.
- This effect was not statistically significant after adjusting for clinically relevant variables (p=0.07). Given that this was a post-hoc subgroup analysis of a secondary endpoint, the relevance of this finding is extremely debatable.
- While the authors draw many comparisons to the SAFE trial, the SAFE trial was a completely different study design examining albumin versus crystalloid resuscitation in a blinded fashion.
- In contrast, ALBIOS studied daily, open-label albumin replacement (not resuscitation) based on serum albumin levels (not based on the need for volume replacement).
TBL
In patients with severe sepsis or septic shock, daily albumin replacement for low serum albumin does not improve mortality or any other clinically relevant endpoints.
ANZICS Dopamine
- Included 328 patients with SIRS, a central line, and at least one indicator of early renal dysfunction (UOP < 0.5 mL/kg over 4 hrs, creatinine > 1.7 mg/dL, or a creatinine increase of > 0.9 mg/dL over 24 hrs)
- Randomized patients to receive dopamine 2 mcg/kg/min or placebo until renal replacement therapy, death, discharge from ICU, or renal dysfunction and SIRS resolved for > 24 hrs
- Most included patients had septic shock and were receiving mechanical ventilation
- Primary endpoint (peak serum creatinine during trial infusion) was not different between dopamine and placebo groups
- Absolute increase in creatinine and the need for renal replacement therapy (21.7% vs. 24.5%) were not different between groups. Similarly, there was no difference in urine output at 1, 24, or 48 hours
- No difference in duration of mechanical ventilation, ICU/hospital length of stay, or mortality
TBL
The use of “renal dose” dopamine did not reduce peak creatinine, the need for renal replacement therapy, ICU length of stay, or mortality.
ARDSnet 2000
- Included 861 patients with early ALI/ARDS (within 36 hrs)
- Randomized traditional tidal volume (12 mL/kg ideal weight) or lower tidal volume (6 mL/kg ideal weight)
- Primary endpoint (death before discharge home or breathing without assistance) was reduced with low tidal volumes (31.0% vs. 39.8%, p=0.007, NNT 11)
- Lower tidal volume also associated with reduction in 28-day breathing without assistance, ventilator-free days, and non-pulmonary organ failures
TBL
In patients with ALI/ARDS, lower tidal volume mechanical ventilation improved mortality compared to traditional tidal volumes.
ARISE
- Included 1600 patients from several countries (mostly Australia and New Zealand) with septic shock (defined as severe sepsis with refractory hypotension despite 1000 mL of fluid)
- Randomized patients within 6 hours of ED presentation to early goal-directed therapy (EGDT) per Rivers 2001 or “usual care” (no specified resuscitation protocol) for a total treatment duration of 6 hours
- All EGDT patients received a central venous line capable of SCvO2 monitoring (with 90% compliance in the study)
- Clinical decisions for “usual care” were at the discretion of the clinical team; however, SCvO2 monitoring was disallowed during the 6-hour study period
- Primary endpoint (90-day mortality) was no different between EGDT and “usual care” (18.6% vs. 18.8%, p=0.9)
- The study was severely underpowered (anticipating a 90-day mortality rate of 38%), putting the study at risk for a type-II error (not showing a difference between the two groups when one truly exists)
- There were no differences in 28-day mortality (14.8% vs. 15.9%, p=0.53), length of stay (ICU or hospital), mechanical ventilation, or renal replacement therapy
- Within the first 6 hours, EGDT was associated with a slightly greater amount of IV fluid (1964 vs. 1713 mL), use of vasopressors (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7%), and dobutamine (15.4% vs. 2.6%) [p<0.001 for all]
- “Usual care” was associated with a lower ICU admission rate (87% vs. 76.9%, p<0.001) and a reduced frequency of central venous catheter placement (90% vs. 61.9%)
- Compared to the original EGDT trial (Rivers 2001), these patients were much less sick (based on APACHE II and mean lactate, among other markers), but this trial may be more reflective of the “typical” septic shock patient seen in a more modern era
- This trial, in conjunction with ProCESS (a similar, US-based trial in academic hospitals), seriously challenges the concept of EGDT and current guideline recommendations
TBL
Among patients with early septic shock in the emergency department, there was no difference in mortality between usual care (without SCvO2) and early goal-directed therapy (based on the Rivers 2001 protocol).
ATTACH-II
- Included 1000 patients with spontaneous intracerebral hemorrhage with at least one BP reading of 180 mmHg or higher within 4.5 hours of symptom onset.
- The study excluded those with a low Glasgow coma score (GCS 3-5) and those with a blood pressure below 140 mmHg before randomization.
- Randomized to “intensive” BP treatment (goal SBP 110 to 139 mmHg) or “standard” BP treatment (goal SBP 140 to 179 mmHg) for 24 hours.
- The first and second-line antihypertensives were nicardipine (continuous infusion) followed by labetalol (IV push).
- Primary endpoint (severe disability or death at 3 months based on a modified Rankin scale) was not different between intensive therapy and standard therapy (38.7% vs. 37.7%, RR 1.04 [95% CI 0.85 to 1.27], p=0.72)
- Primary endpoint (severe disability or death at 3 months based on a modified Rankin scale) was not different between intensive therapy and standard therapy (38.7% vs. 37.7%, RR 1.04 [95% CI 0.85 to 1.27], p=0.72)
- No differences were detected in other efficacy endpoints between the two groups, including hematoma expansion, neurologic deterioration within 24 hours, death, or quality of life
- Within the first two hours, the average lowest systolic BP was 129 mmHg for “intensive” treatment and 141 mmHg for “standard” treatment.
- Patients randomized to “intensive” therapy were more likely to have renal adverse effects within the first seven days (9% vs. 4%, p=0.002, NNH 20). It is not clear what percent of these adverse events resulted in clinically relevant outcomes (such as dialysis) versus surrogate markers (such as a transient increase in serum creatinine)
- Approximately half of patients presented with a normal Glasgow coma score (GCS of 15). Likely due to this fact, the primary endpoint was much lower than the anticipated rate of 60%, hurting the power of the study.
- Based on the confidence interval of the primary endpoint, the study was able to exclude “intensive” blood pressure management improving outcomes by >15% or worsening outcomes by >27% (relative risk).
- Although the blood pressure goals were < 140 mmHg versus < 180 mmHg, the mean systolic blood pressures between the two groups were around 120-125 mmHg versus 140-145 mmHg during the first 24 hours.
- The treatment effect of intensive BP lowering may have been minimized because the standard of care group was not severely hypertensive.
- Of note, the study only included spontaneous parenchymal hemorrhage (intracerebral). It did not include other types of intracranial hemorrhage such as subarachnoid, traumatic, aneurysmal, or subdural.
- INTERACT2, a study with a similar patient population and study question, indicated a possible benefit of a lower blood pressure in patients with ICH (although the primary endpoint was not significant). Compared to INTERACT2, ATACH-II was different in that it: (a) only specified a blood pressure goal for the first 24 hours (not 7 days), (b) required a quicker time from symptom onset to treatment, (c) had a higher mean BP prior to randomization (about 200 vs. 180 mmHg), and (d) resulted in a lower blood pressure within the first few hours (about 130-140 mmHg vs. 150-160 mmHg).
TBL
Among patients with a spontaneous intracerebral hemorrhage, a lower blood pressure goal (mean systolic BP 129 mmHg) within the first 24 hours did not demonstrate any clinical benefit versus standard of care (mean systolic BP 141 mmHg) and may cause renal adverse effects.
ALLEN 1983
- Included 121 patients with aneurysmal (not traumatic) subarachnoid hemorrhage within 96 hours with normal neurological exam (A&O x 3, allowed for some confusion or isolated cranial nerve palsy)
- Randomized patients to receive nimodipine 0.7 mg/kg PO bolus, then 0.35 mg/kg (28 mg for 80 kg patient) PO Q4h vs. placebo x 21 days
- Primary endpoint (per-protocol neurologic deficit or death from vasospasm at 21 days) was improved with nimodipine (13.3% vs. 1.8%, p=0.03, NNT 9)
21-day mortality was numerically reduced with nimodipine (11.7% vs. 5.4%, no p value given)
- Primary endpoint (per-protocol neurologic deficit or death from vasospasm at 21 days) was improved with nimodipine (13.3% vs. 1.8%, p=0.03, NNT 9)
- Study does not report the incidence of vasospasm (only reports neurologic deficits secondary to vasospasm)
- Safety analysis was non-existent within study
- Major limitations to study: only included patients with normal neurologic function at study entry (poor external validity for severe SAH), per-protocol analysis, endpoint was neuro deficit caused by vasospasm (etiology of deficit may be subjective)
TBL
Among patients with aneurysmal subarachnoid hemorrhage, nimodipine reduced neurologic deficit and mortality secondary to vasospasm.
Andriulli
- Included 474 patients with upper GI bleed and successful endoscopic treatment of an ulcer with epinephrine and optional thermal or mechanical therapy
- Excluded severe coagulopathy (platelet < 100,000 or INR > 1.5) and those receiving PPI therapy before index endoscopy
- Randomized patients to omeprazole or pantoprazole IV (based on investigator preference) at either “high-dose” (80 mg bolus, then 8 mg/hr x 72 hours) or “standard-dose” (40 mg once daily). Both groups switched to an oral PPI after 72 hours (20 mg PO BID)
- Primary endpoint (30-day recurrent bleeding) was no different between high-dose and standard-dose patients (11.8% vs. 8.1%, p=0.18). Recurrent bleeding was most common during the first 72 hours.
- Rebleeding rates between treatment groups were no different for any subgroups examined (gastric vs. duodenal, ulcer size, active vs. non-bleeding ulcers, Rockall score)
- Independent predictors of rebleeding were Rockall score ≥ 6 at presentation (HR 2.14, 95% CI 1.15-3.98) and active index bleeding (HR 1.88, 95% CI 1.02-3.49)
- There was no difference in number of units of blood transfused, length of hospitalization, or mortality
- Among patients with rebleeding, there was no difference in a second event of rebleeding or need for surgery between high-dose and standard-dose therapy
- The sample size in this trial was 80% powered for a rebleeding rate of 15% in the standard arm and 7% in the high-dose arm.
- Of note, the standard-dose patients were generally sicker at baseline (more shock at baseline, more severe comorbidities, more with Rockall score ≥ 6) compared to high-dose patients
- Within a 72-hour study period, high-dose patients would have received 656 mg of PPI compared to standard-dose’s 120 mg (an 82% decrease in total drug use
TBL
In patients with an upper GI bleeding ulcer and successful endoscopic treatment, a standard-dose IV PPI used significantly less drug and did not result in different rebleeding rates compared to a high-dose infusion.
Annamenini 2002
- Included 299 patients with septic shock and mechanical ventilation within 3-8 hours of meeting study criteria (CORTICUS enrolled within 72 hours)
- Compared placebo vs. hydrocortisone 50 mg IV Q6h + fludrocortisone 50 mcg PO daily x 7 days (no taper)
- All patients were stim tested (250 mcg cosyntropin) and classified as “responders” or “non-responders” (less than 9 mcg/dL increase in cortisol)
- Primary endpoint (28-day survival among non-responders) was improved with steroid therapy (63% vs. 53%, p=0.04, NNT=10)
- No clinical effect seen in responders, but cohort was underpowered (N=70, 23% entire study)
- Steroid therapy reduced median duration of vasopressor therapy (9 vs. 7 days, p=0.01)
- Over 80% of screened patients were ineligible for study inclusion (1026 of 1326 screened), many due to very quick enrollment period from onset of septic shock — limits external validity
TBL
Among patients with very early septic shock who were non-responders to a cosyntropin stim test, hydrocortisone/fludrocortisone therapy improved 28-day survival. Furthermore, steroid therapy reduced duration of vasopressor therapy in all patients (regardless of stim test response).
