Key Articles

PICU Journal Watch
SCCM 2020 Year in Review (Summary by Rahul Damania, MD)

ArticleAuthorJournalDateMajor Results 
 Lung Protective Ventilation  Amato et alNEJM 1998 RCT of 53 patients with ARDS demonstrating improved 28 day survival and higher rates of weaning from mechanical ventilation in the lung protective arm (6 cc/kg) vs the conventional arm (12 cc/kg). 
  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 
 ROSE (NMB in ARDS) Trial PETAL NEJM  2019PETAL network, in contrast to ACURASYS, finds no differences in outcomes comparing early NMB (cisatracurium) to standard sedation in adult patients with moderate/severe ARDS (PF<150) 
 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 Pediatric ARDS  Willson et alJAMA  2005 Initial study of calfactant in pediatric ARDS (RCT of 153 patients) demonstrating improved oxygenation and mortality with calfactant (15/77 vs 25/75 
 Surfactant in Pediatric ARDS Willson et al PCCM2013Followup of initial study originally intended to be larger and  have a more homogenous population. RCT 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)
 Extubation Readiness     
  Weaning and Extubation Readiness in Pediatric Patients Newth et al PCCM 2009 Review of extubation readiness and weaning in pediatric patients. 
Septic Shock      
  Surviving Sepsis Guidelines Rhodes et al CCM2016  
 Pediatric Sepsis Guidelines  Weiss et alPCCM and ICM2020 
 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.
 ADRENAL Trial (steroids septic shock) Venkatesh et al  NEJM 2018RCT of 3800 adult patients with septic shock receiving mechanical ventilation demonstrated no difference in 90 day mortality between those receiving hydrocortisone (200 mg/day) vs. placebo, including in 6 predefined subgroups. There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renalreplacement therapy, and the incidence of new-onset bacteremia or fungemia. 
 ALBIOS: 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 not 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).
 Factors Associated with Bleeding/Thrombosis on ECMO  Dalton et alARJCCM 2017 Prospective observational cohort study off pediatric patients receiving ECMO showing bleeding occurred in 70.2%, including intracranial hemorrhage in 16%, and was independently associated with higher daily risk of mortality. Circuit component changes were required in 31.1%, and patient-related clots occurred in 12.8%. Laboratory sampling contributed to transfusion requirement in 56.6%, and was the sole reason for at least one transfusion in 42.2% of patients. Pump type was not associated with bleedingthrombosis, hemolysis, or mortality. Hemolysis was predictive of subsequent thrombotic events. Neither hemolysis nor thrombotic events increased the risk of mortality. 
 Referral to ECMO Center H1N1 Noah et al  JAMA2011 Propensity matching study showing for that adults with ARDS from H1N1, referral to an ECMO center was associated with lower mortality. 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching. The hospital mortality rate was 23.7% for ECMO-referred patients (69 of 80 received ECMO) vs 52.5% for non-ECMO-referred patients (relative risk [RR], 0.45 [95% CI, 0.26-0.79]; P = .006) when individual matching was used; 24.0% vs 46.7%, respectively (RR, 0.51 [95% CI, 0.31-0.81]; P = .008) when propensity score matching was used; and 24.0% vs 50.7%, respectively (RR, 0.47 [95% CI, 0.31-0.72]; P = .001) when GenMatch matching was used. The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated. 
 ECMO for Pediatric ARDS  Barbaro et alAJRCCM  2018Using the RESTORE database, this study used individual case matching and propensity matching to compare children with pediatric ARDS supported by ECMO vs those not supported by ECMO. There were no differences found in mortality (25% in both groups for individual matching and 25% vs 30% (ECMO vs non-ECMO) for propensity matching (p=0.70) nor in any secondary outcomes.  
 EOLIA: ECMO for Severe ARDS  Combes et al NEJM 2018This randomized multicenter RCT of 249 adult patients with severe ARDS (P/F <50 for 3 hours, P/F <80 for 6 hours, or pH <7.25 and pCO2 >60 for 6 hours) demonstrated no significant difference in mortality utilizing VV ECMO vs. conventional mechanical ventilation with crossover (to ECMO) (RR 0.76, 0.55-1.04, p=0.09) 
 Fluids & Nutrition     
 PEPaNIC 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.
  SMART: Balanced Crystaloid vs. Saline Semler et alNEJM  2018Pragmatic multicenter RCT of 15802 critically ill adult patients in 5 ICU's demonstrated the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.  (OR 0.91, p=0.04)
 BASICS Fluid Trial  Zampieri et al JAMA 2021Double blind RCT of 75 ICU's in Brazil with 10520 adult critically ill patients did not show a difference between those randomized to balanced fluids vs. saline. 
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.   
 PECARN DKA FLUID Trial Kuppermann et al NEJM  2018Multicenter (13 institutions) RCT of 1255 pediatric patients with DKA (1389 episodes) utilizing a 2x2 factorial design reveals no difference in neurological outcomes when comparing NS vs. 1/2 NS and more aggressive vs. less aggressive fluid resuscitation.  
 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.) 
 TEAM Study  ANZICSNEJM 2022 RCT of 750 adults undergoing mechanical ventilation did not find a difference in mortality at 180 days, or a difference in vent free days between the early mobility and control groups. Adverse events potentially due to mobilization also higher in the intervention group (9.2 vs 4.1%) 
 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%. 
 DECRA Cooper et al NEJM 2011 RCT of 155 adult patients with diffuse TBI and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased ICP and length of stay but was associated with more unfavorable outcomes (death and extended GOS at 6 months-death/vegetative state/severe disability)
  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.  
 PARAMEDIC2- Epinephrine for OHCA  Perkins et al NEJM 2018RCT of 8014 adult patients in the UK with out of hospital cardiac arrest demonstrated improvement in 30 day survival for adults with out of hospital cardiac arrest treated with epinephrine as opposed to placebo (3.2 % vs. 2.4% survival at 30 days, p=0.02) but no difference in survival with favorable neurological outcome (2.2% vs 1.9%, OR 1.18 with CI 0.86 to 1.61) and higher rates of severe neurological impairment (31% vs 17.8%) 
 EXACT Trial      EXACT investigators JAMA2022  RCT of 425 adult patients with OHCA and ROSC randomized to saturation of 90-94% vs 98-100%- no difference in outcomes (and possibly some harm in the intervention lower saturation group)
 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 difference in 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). 
 100 Useful Articles in CVICU Axelrod, DA  PCCM 2013100 references of important articles for CVICU 
 Update: Top 30 Useful articles in CVICU  Uzark K PCCM 2018 30 useful references for CVICU 
 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%).
 ELAIN  Zarbock et al JAMA 2016Single center RCT of 231 patients in adult critical care unit comparing early (within 8 hours of KDIGO stage 2) or delayed (within 12 hours of stage 3 AKI) initiation of RRT. 100% in the early group received RRT while 91% in the late group received RRT. Primary outcome of 90 day mortality with earlier initiation of RRT leading to lower mortality (39% vs 55%) with hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.97] p=0.03. These results contrast with the multicenter RCT AKIKI although the patient populations differed (stage 2 vs. 3 and much more use of RRT in both arms in ELAIN (91% in the delayed group) vs. AKIKI (51% in the delayed group). 
 IDEAL-ICU  Barbar et al NEJM2018 RCT of 488 adult patients with septic shock and renal failure (as defined by RIFLE criteria) comparing whether early (upon diagnosis of renal failure) or delayed (waiting 48 hours) affected outcomes (90 day mortality as primary outcome). There was no difference in overall mortality (58% in early group and 54% in delayed group, p=0.38) and 38% of those in the delayed group did not require renal replacement therapy.  
 STARRT-AKI STARRT AKI group  NEJM2020 Multicenter RCT of  2927 critically ill adult patients with AKI randomized to accelerated (within 12 hours of meeting criteria) or standard (discouraged CRRT until 72 hours or meeting additional criteria) use of CRRT with 90 day mortality as primary outcome. No differences found (43.9% vs 43.7%, p=.92). In addition, patients in the accelerated group were more likely to be on renal replacement at 90 days (10.4 vs 6%) and more likely to have adverse events (23 vs 16.5%).
 PRESERVE Weisbord et al NEJM 2018 2x2 Factorial Designed RCT of 5177 adult patients at high risk for renal complications who were scheduled for angiography who received IV 1.26% Sodium Bicarbonate or Normal saline and oral aceylcysteine or placebo. Primary outcome was a composite of death, need for dialysis, and persistent increase in Cr of at least 50% at 90 days. Secondary outcome was the rate of contrast induced AKI. There was no difference  between groups in either the primary or secondary outcome (sodium bicarbonate nor oral acetylcysteine were both ineffective in reducing rate of AKI or persistent kidney injury/death). 
 Epidemiology of AKI in Critically Ill Children Kaddourah et al NEJM  2017Multicenter prospective study of AKI (using KDIGO criteria) in 4683 pediatric patients demonstrating AKI in 26.9% and severe AKI in 11.6% with severe AKI associated with an increased risk of poor outcomes, including mortality.  
 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.
 In House Attending Coverage     
 Physician Staffing Models and Clinical Outcomes in Critically Ill Patients Provonost et al  JAMA 2002Systematic analysis of data from 1994-2001 regarding high intensity (mandatory intensivist consult or closed unit) vs. low intensity (no intensivist or elective intensivist consult) staffing models in critical care and association with clinical outcomes. gh-intensity staffing was associated with lower hospital mortality in 16 of 17 studies (94%) and with a pooled estimate of the relative risk for hospital mortality of 0.71 (95% confidence interval [CI], 0.62-0.82). High-intensity staffing was associated with a lower ICU mortality in 14 of 15 studies (93%) and with a pooled estimate of the relative risk for ICU mortality of 0.61 (95% CI, 0.50-0.75). 
 Association of In House Attending Coverage with Outcomes in Children Undergoing Heart Operations      Gupta et alATS 2016 Using propensity matching, mortality at ICU discharge was lower among the patients treated in hospitals with 24/7 coverage (24/7 versus No 24/7, 2.8% versus 4.0%; p = 0.002). The use of extracorporeal membrane oxygenation (ECMO), the incidence of cardiac arrest, extubation within 48 hours after operation, the rate of reintubation, and the duration of arterial line and central venous line use after operation were significantly improved in the 24/7 group. When stratified by surgical complexity, survival benefits of 24/7 coverage persisted among patients undergoing both high-complexity and low-complexity operations. 
 Impact of 24/7 Attending Coverage on Outcomes in Pediatric Intensive Care Gupta et al  AJRCCM2016 Care provided in PICU's with 24/7 in-house coverage associated with improved overall patient survival and survival after cardiac arrest. After adjusting for patient and center characteristics, the 24/7 group was associated with lower mortality in the intensive care unit (ICU) (24/7 vs. no 24/7; odds ratio [OR], 0.52; 95% confidence interval [CI], 0.33-0.80; P = 0.002), a lower incidence of cardiac arrest (OR, 0.73; 95% CI, 0.54-0.99; P = 0.04), lower mortality after cardiac arrest (OR, 0.56; 95% CI, 0.340-0.93; P = 0.02), a shorter ICU stay (mean difference, -0.51 d; 95% CI, -0.93 to -0.09), and shorter duration of mechanical ventilation (mean difference, -0.68 d; 95% CI, -1.23 to -0.14).
Duty Hours      
 FIRST Trial  Bilimoria et al NEJM 2016National cluster-randomized RCT of 117 general surgery residency training programs comparing standard duty hour restrictions to a flexible policy that waived rules regarding maximum shift lengths and time off between shifts and compared 30 day rate of postoperative death or serious complications. As compared with standard duty-hour policies, flexible, less-restrictive duty-hour policies for surgical residents were associated with noninferior patient outcomes and no significant difference in residents’ satisfaction with overall well-being and education quality. 
 iCompare (Internal Medicine Residents)  Desai et alNEJM  2018Randomized trial of 63 internal medicine residencies, shows no difference in amount of times intern spent on direct patient care and education between the standard work hour group and the flexible policy cohort. Interns in the flexible policy group were less satisfied with their educational experience than their peers in the standard group. The opposite was true for program directors. Accompanying NEJM editorial.
Early Warning Scores      
 EPOCH Trial Parshuram et al JAMA 2018 Multicenter cluster randomized trial of 21 centers demonstrated no difference in all cause hospital mortality with use of PEWS (pediatric early warning system). 
 Palliative Care     
 Early Palliative Care for Patients with Metastatic Non Small Cell Lung Cancer  Temel et al NEJM  2010 RCT of 151 adult patients with metastatic non small cell lung cancer demonstrated those in the early palliative care group had improved quality of life, improved mood,  and less depression compared to standard oncologic care alone. Despite undergoing less aggressive care, those in the early palliative care group actually had longer survival as well (11.6 vs 8.9 months, p=0.02)