Key Articles

ArticleAuthorJournalDateMajor Results 
  ARDSNET Tidal Volume ARDSNET NEJM 2000 RCT of 861 adults with ARDS, Vt of 6 cc/kg with plateau pressure <30 cmH20 associated with 9% absolute mortality decrease (31 vs 40%, p =0.007, NNT=11) and a 2 day increase in ventilator free days. 
 Pediatric Prone Positioning Curley et al JAMA 2005  102 pediatric patients with ALI randomized to prone vs. supine positioning (20 hours/day for maximum 7 days) did not demonstrate any difference in ventilator free days or other clinical outcomes at 28 days.
 PROSEVA Prone Positioning ARDS Guerin et al NEJM 2013466 adults with ARDS, prone positioning associated with reduced 28d mortality (16 vs 32.8%, p<0.001) and reduced 90 day mortality (23.6 vs 41%,  p<0.001) 
 ACURASYS NMB in ARDS  Papazian et alNEJM 2010 340 adults with severe ARDS, those randomized to 48 hrs cisatracurium vs placebo had decreased risk for death at 90 days (after adjustment for P/F, plateau pressure, APACHE score) HR0.68, p=0.04. No difference in rate of ICU acquired paresis 
 Berlin Definition ARDS Ranieri et al JAMA 2012 Berlin definition for adult ARDS: P/F <100= severe, 100 to <200 = moderate, 200  to <300= mild 
 PALICC Pediatric ARDS Consensus Conference PALICC PCCM2015  Pediatric ARDS definitions with oxygenation index as the defining variable with mild ARDS being an OI of 4 to <8, moderate being 8 to <16 and severe being an OI of >16
 ARDSNET High vs Low PEEP ARDSNET NEJM 2004 549 adults with ARDS, when ventilated at 6 cc/kg with plateau pressure limit of 30 cmH2O, no difference in outcomes between low PEEP (~8) and high PEEP  (~13) 
ARDSNET NEJM 2006 RCT of 180 adults with ARDS showing no difference in mortality with the use of solumedrol for ARDS and increased mortality in those who started steroids at least 14 days after the onset of ARDS. 
 Meduri Steroids for ARDS Meduri et al JAMA 1998 Small trial of 24 adult patients with ARDS demonstrated improved lung injury scores, MODS scores, and mortality with a regimen of 2mg/kg solumedrol for 32 days. 
  FACCTARDSnet NEJM 2006  RCT of 1000 adults with ALI utilizing conservative or liberal fluid therapy (-136 cc vs +7L over 7 days, respectively) demonstrating no difference in mortality but increased ventilator free days in the first 28 days in the conservative group.
 Surfactant in ARDS Wilson et al PCCM 2013RCT of 110 pediatric patients with ALI/ARDS randomized to surfactant or placebo showed no significant differences (except hospital free days, favoring placebo) and was stopped by the sponsor for futility. 
  Driving Pressure in ARDSAmato et al NEJM 2015 Using multilevel mediation analysis to analyze data from 3562 patients from ARDS trials, delta P found to be the ventilation variable that best stratified risk with decreases in delta P  being strongly associated with increased survival 
  OSCARYoung et al NEJM 2013 Multicenter RCT of 795 adult patients with early ARDS showing no difference in 30 day mortality between HFOV vs. conventional ventilation.  
 OSCILLATE Ferguson et al NEJM 2013 Multicenter RCT of 548 adult patients with ARDS (stopped early) showed increased mortality with HFOV (47 vs 35% relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005) vs. conventional ventilation. Those in the HFOV group received more NMB, midazolam, and vasoactive agents.   
 LungSAFE Bellani et al  JAMA 2016 International, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents demonstrating poor recognition of ARDS (51.3-78.5% for mild to severe, respectively) as well as suboptimal use of best practices (i.e. low tidal volume strategy, prone positioning, etc)
Septic Shock      
  Surviving Sepsis Guidelines Rhodes et al CCM2016  
 Pediatric Sepsis Guidelines  Davis et alCCM 2017 
 EGDT Rivers et al  NEJM2001 RCT of 263 adults demonstrating 30.5% mortality vs 46.5% mortality utilizing EGDT. Recent trials (PROMISE, ARISE, PROCESS) have had differing results. 
 Steroids in Septic Shock  Annane et al JAMA 2002RCT of 300 septic patients failing to respond to 250 mcg cosyntropin stimulation treated with hydrocortisone (50 mg IV q6) and fludrocortisone daily had reduced mortality compared to nonresponders given placebo (53 vs 63%). No benefit for steroids in cosyntropin responsive patients.  
  CORTICUS (steroids in septic shock) Sprung et alNEJM  2008RCT of 499 adult patients with septic shock showing no mortality benefit of hydrocortisone within 72 hours of sepsis onset, regardless of response to cosyntropin stimulation. Hydrocortisone hastened reversal of shock but also led to more episodes of superinfection.
 Albumin replacement in septic shock Caironi et al NEJM 2014 Multicenter open-label RCT randomized 1,818 patients to daily 20% albumin to maintain a serum albumin > 3 gm/dl plus crystalloids vs. crystalloids alone for the duration of their ICU stay and found no difference in mortality. The albumin group had shorter duration of vasopressor support but duration of mechanical ventilation or need for renal replacement therapy did not differ. 
  SAFE:Albumin vs. SalineFinfer et al NEJM 2004 RCT of 6997 adult patients in the ICU randomized to 4% albumin or normal saline for fluid resuscitation showed no differences in outcomes at 28 days.  
 PROMISEMouncey et al NEJM 2015  RCT of 1260 adult patients with septic shock demonstrating no difference in outcome for EGDT vs. standard care
 PROCESS PROCESS Investigators NEJM 2014 RCT of 1341 adults with septic shock, no difference in outcome for EGDT vs. standard care 
 ARISE  ANZICS Clinical Trials GroupNEJM 2014 RCT of 1600 adults with septic shock demonstrating no difference in outcome for EGDT vs. standard care 
  PROWESS (Activated Protein C Adults)Bernard et al NEJM 2001  Multicenter RCT of 1690 adults with sepsis showed reduced relative risk of death of 19.4% and an absolute reduction in risk of death of 6.1% (p=0.005) with Drotecogin. There was also a higher incidence of serious bleeding in the treatment arm (3.5 vs 2%, p=0.06)
 RESOLVE (Activated Protein C Pediatrics)Nadel et al Lancet 2007 RCT of 477 pediatric patients with sepsis utilizing drotrecogin vs. placebo did now show any difference in clinical outcomes except for more CNS bleeeding in the DrotAA group, particularly in those <60 days.  
 TRISS: Transfusion Septic Shock Holst et al NEJM 2014 998 adult patients with septic shock randomized to Hb threshold of 7 g/dl vs 9 g/dl for transfusion demonstrating no difference in clinical outcomes 
 VASST: Vasopressin vs NE in Septic ShockRussel et al NEJM 2008 Multicenter RCT of 778 adults with septic shock randomized to NE or vasopressin showed no significant differences in outcomes between the two groups (although less 28d mortality in the prospectively defined less severe septic shock with use of vasopressin: 26 vs 35% p=0.05) 
 SOAP-II: NE or dopamine for septic shock DeBacker NEJM 2010 Multicenter RCT of 1679 adults with septic shock demonstrating no differences in 28 day mortality, although there was increased arrhythmias in the dopamine group. 
 SEPSIS-3  Singer et al JAMA2016 Most updated version of adult sepsis definitions. Key finding is that sepsis is now defined as organ dysfunction (change in SOFA of 2 or more) with infection while septic shock is a more severe subset that can be defined as need for vasopressor to maintain MAP of 65 mmHg or greater or serum lactate >2 mmol/L in the absence of hypovolemia.   
  VANISHGordon et al  JAMA 2016A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. Patients randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure–free days. 
 EGDT-PRISM Meta Analysis PRISM Investigators  NEJM 2017Meta-analysis of PROMISE, PROCESS, ARISE trials with 3723 patients showed that EGDT did not result in better outcomes than usual care and was associated with higher costs across a broad range of patient and patient characteristics ( benefit for EGDT in various subgroup analyses).  
  SPROUT (Sepsis Prevalence Outcomes Therapies)Weiss et al  AJRCCM 2015International point prevalence study studying Pediatric Severe Sepsis showing ~8% prevalence and 25% in-hospital mortality (both in developed and resource-limited settings). 

 CESAR Peek et al Lancet 2009 Multicenter RCT of 180 adult patients with ARDS found that referral to an ECMO center (68/90 actually received ECMO in the "refer to ECMO group")  led to higher survival without disability (63 vs 47%, RR= 0.69, p=0.03). Referral also led to gain of 0.03 QALYs at 6 months with cost of QALY of ECMO predicted to be 19,252 British pounds or ~30K USD (2015).
 Early vs Late TPN Fivez et al NEJM 2016 Multicenter RCT of 1440 critically ill children investigating whether early (first 24 hours of PICU admission) vs late (day 8 of PICU admission) TPN administration affected clinical outcomes (primary outcomes of new infection during ICU stay and duration of ICU dependency). Demonstrated more new infections  (18.5 % vs 10.7%) and longer duration of ICU stay 6.5 vs 9.2 days in the early TPN group compared to the late TPN group.
Tight Gylcemic Control      
 Intensive Insulin Therapy in Critically Ill (Leuven Trial) Van den Berghe et al NEJM 2001 In a single center RCT of 1548 critically ill adults, intensive insulin therapy to achieve glucose of 80-110 (vs 180-200)   resulted in decreased mortality at 12 months (8 vs 4.6%, p <0.04)
 NICE-SUGAR  NICE-SUGAR investigators (UK NHS)NEJM 2009 RCT of 6104 adult patients in the intensive care unit, intensive insulin therapy to achieve glucose of 80-110 vs 110-180 increased mortality (27.5% vs 24.9%, p=0.02) with a 6.8% incidence of severe hypoglycemia in the intensive insulin group vs 0.5% in the conventional group (p<0.001) 
 SPECS : Tight glycemic control after Pediatric Cardiac SurgeryAgus et al NEJM 2012 Multicenter RCT of 960 pediatric patients undergoing surgery with CPB, demonstrating tight glycemic control with BG 80-110 mg/dl was NOT associated with decreased health care associated infections or any other clinical outcome differences. only 3% of patients in the tight glycemic control group had significant hypoglycemia utilizing the continuous glucose meter.  
 CHiP Macrae et al NEJM 2014 Multicenter RCT in England involving 1369 PICU patients (60% cardiac surgery) randomized to tight (72-126) or conventional (<216) glucose control. No differences in clinical outcomes with more hypoglycemia in the tight control vs. conventional control group (7.3 vs 1.5% p= <0.001) 
 HALF-PINT  Agus et alNEJM  2017Multicenter RCT of 713 critically ill pediatric patients (stopped early)  demonstrating no benefit for tight glycemic control (80-110 mg/dl blood glucose) vs. 150-180 mg/dl. Also, there was more severe hypoglycemia (5.2 vs 2% p=0.03) and more healthcare associated infections (3.4 vs 1.1% p=0.04) in the tight glucose control group. 
Risk Factors for Cerebral Edema 
Glaser et al NEJM 2001 Case control utilizing pediatric patients with DKA and cerebral edema showed low PaCO2, high BUN, and treatment with bicarbonate (RR 4.2, 1.5-12.1, p=0.008) to be independently associated with cerebral edema for pediatric patients with DKA.   
 RESTORE Curley et al JAMA 2015 Multicenter RCT of 2449 children in PICU's undergoing mechanical ventilation for acute respiratory failure showed no differences in duration of mechanical ventilation with the use of a nurse driven protocolized sedation (including targeted sedation, arousal assessments, extubation readiness testing, etc.) 
 TRICC: Transfusion Requirements in Critical Care (Adults) Hebert et al NEJM 1999 Multicenter RCT of 838 critically ill adults to transfusion threshold of 7 vs 9.5 g/dl demonstrating increased 30 day mortality in the liberal transfusion group for those less ill (APACHE <20 or younger than age 55). There was no difference in mortality when looked at in aggregate (18.7 vs 23.3% p=0.11). Mortality rate during hospitalization was significantly lower in the restrictive transfusion group (22.2 vs 28.1 %, p=0.05) 
 TRIPICU: Tranfusion Requirements in PICU Lacroix et al NEJM 2007 In RCT of 637 stable critically ill children (no BP <2SD below mean or no alterations in cardiovascular support over 2 hours), a restrictive transfusion threshold of 7 was found to be non-inferior to a liberal transfusion threshold of 9.5 with no significant differences in clinical outcomes.  
 ABLE: Age of Transfused Blood in Critically Ill Adults Lacroix et al  NEJM2015 Blinded RCT comparing fresh (<8d) to standard blood in 2510 critically ill adults with no differences in mortality or secondary clinical outcomes.
 AABB Guidelines for RBC Transfusion Carson et al JAMA  2016Essentially made two recommendations based upon the evidence: 1) Restrictive transfusion thresholds (7 g/dl Hgb in most patients, 8 g/dl for those undergoing orthopedic/cardiac surgery or with preexisting cardiac disease) 2) Use standard issue (rather than fresh) RBC's for all patients, including neonates.
  Cool Kids (Hypothermia after pediatric TBI)Adelson et al Lancet Neurology 2013 RCT of 77 pediatric patients with TBI (stopped for futility) demonstrated no significant difference in clinical outcomes comparing hypothermia vs. normothermia.
 Hypothermia after Pediatric TBI Hutchison et al NEJM 2008 Multicenter RCT of 225 children with TBI randomized to early (within 8 hours) hypothermia (32.5 C) for 24 hours or normothermia (37 C) demonstrated no improvement in neurologic outcome and may have increased mortality (21 vs. 12%, p=0.06)  
 NASCIS 2 Trial- Naloxone or Methylprednisolone after Acute Spinal Cord Injury   Bracken et alNEJM 1990 RCT of 487 adult patients with acute spinal cord injury comparing methylprednisolone (30 mg/kg bolus followed by 5.4 mg/kg/hr for 23 hours) with naloxone and placebo demonstrated some  improved outcomes in those that received methylprednisolone within 8 hours although this was in post-hoc analysis.'s summary of the available literature states "there is no evidence to support the use of steroids in the management of spinal cord injury"    
 RESCUEicp Hutchison et al NEJM  2016At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. 
  MRC-CRASHCRASH investigators Lancet  2004In a trial of 10008 adult patients with TBI,  compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21·1%] vs 893 [17·9%] deaths; relative risk 1·18 [95% CI 1·09–1·27]; p=0·0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0·22) or time since injury (p=0·05).
 EPO and Transfusion after TBI  Robertson et al  JAMA 2014  In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, −0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009).
Cardiac Arrest      
 THAPCA: Therapeutic Hypothermia after Pediatric Cardiac Arrest (Out of Hospital) Moler et al NEJM 2015 Multicenter RCT of 295 pediatric patients that had undergone out of hospital cardiac arrest demonstrating no significant differences in survival and survival with good outcome (defined as Vineland Adaptive Behavioral Scores-II with a delta of less than 15) between targeted normothermia (T 36.8C) or targeted hypothermia (T 33 C).
 THAPCA: Therapeutic Hypothermia after Pediatric Cardiac Arrest (In Hospital) Moler et al NEJM  2017Multicenter RCT of 257 (329 randomized) pediatric patients that had in-hospital cardiac arrest demonstrates no differences in survival at one year with good nuerologic outcome (defined as Vineland Adaptive Behavioral Scores-II with a score of 70 or higher). 
 HACA: Hypothermia after Cardiac Arrest (adults) Holzer et al NEJM 2002 Multicenter RCT of 275 adults with cardiac arrest secondary to VF or pulseless VT randomized to hypothermia at 32-34C for 24 hours or usual care (normothermia) showing improved neurologic outcomes at 6 months and improved mortality with hypothermia.  
 SVR:Single Ventricle Reconstruction  Ohye et alNEJM 2010 RCT of 549 infants undergoing the Norwood procedure randomly assigned to MBT shunt or RVPA shunt showing transplant free survival at 12 months higher in the RVPA shunt group (74 vs 64%, p=0.01) but with more unintended interventions and complications. No significant transplant free survival at 32 months (p=0.06). Size of treatment effect differed before and after 12 months (p=0.02)
 STARTS-2 Barst et al  Circulation2014 After STARTS-1 (Barst, Circulation 2012) showed safety with sildenafil for pediatric pulmonary arterial hypertension, STARTS-2 showed higher mortality in those children randomized to higher dose sildeanfil (although some criticism in that patients were allowed to cross over at physician's request)
 PRIMACORP Hoffman et al Circulation  2003Use of high dose milrinone (0.75 mcg/kg/min) reduced the risk of LCOS after pediatric congenital heart surgery (relative risk reduction of 55%, p=0.023). 
 AKIKI Gaudry Et al NEJM 2016 French multicenter RCT of 620 adult ICU patients (on vasoactives and/or mechanical ventilation) with KDIGO stage 3 AKI randomized to early or delayed initiation of renal replacement therapy showed no differences in mortality with early vs. delayed initiation (48.5 vs 49.7%, respectively). Furthermore, 49% of the patients in the delayed group did not require renal replacement therapies.It should be noted that a large proportion of patients receiving iHD (>50%) vs CRRT (~30%).
 PANDAS Sun et al  JAMA 2016Sibling matched cohort study of infants exposed to anesthesia vs. their sibling pairs who had not been exposed show no differences in neurodevelopmental outcomes.  
 GAS Davidson et al  Lancet 2016Multicenter international RCT of infants <60 weeks undergoing inguinal hernia surgery showed no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia.