Key Articles

Major Results

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).

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.

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.

466 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)

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 for adult ARDS: P/F <100= severe, 100 to <200 = moderate, 200 to <300= mild

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

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)

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.

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.

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.

Initial study of calfactant in pediatric ARDS (RCT of 153 patients) demonstrating improved oxygenation and mortality with calfactant (15/77 vs 25/75

Followup 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.

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

Multicenter RCT of 795 adult patients with early ARDS showing no difference in 30 day mortality between HFOV vs. conventional ventilation.

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.

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)

Review of extubation readiness and weaning in pediatric patients.

RCT of 263 adults demonstrating 30.5% mortality vs 46.5% mortality utilizing EGDT. Recent trials (PROMISE, ARISE, PROCESS) have had differing results.

RCT 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.

RCT 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.

RCT 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.

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.

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.

RCT of 1260 adult patients with septic shock demonstrating no difference in outcome for EGDT vs. standard care

RCT of 1341 adults with septic shock, no difference in outcome for EGDT vs. standard care

RCT of 1600 adults with septic shock demonstrating no difference in outcome for EGDT vs. standard care

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)

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.

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

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)

Multicenter RCT of 1679 adults with septic shock demonstrating no differences in 28 day mortality, although there was increased arrhythmias in the dopamine group.

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.

A 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.

Meta-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 (i.e.no benefit for EGDT in various subgroup analyses).

International point prevalence study studying Pediatric Severe Sepsis showing ~8% prevalence and 25% in-hospital mortality (both in developed and resource-limited settings).

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).

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 bleeding, thrombosis, hemolysis, or mortality. Hemolysis was predictive of subsequent thrombotic events. Neither hemolysis nor thrombotic events increased the risk of mortality.

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 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.

Using 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.

This 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)

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.

Pragmatic multicenter RCT of 7942 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)

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)

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)

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.

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)

Multicenter 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.

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.

Multicenter (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.

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.)

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)

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.

Blinded RCT comparing fresh (<8d) to standard blood in 2510 critically ill adults with no differences in mortality or secondary clinical outcomes.

Essentially 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.

RCT of 77 pediatric patients with TBI (stopped for futility) demonstrated no significant difference in clinical outcomes comparing hypothermia vs. normothermia.

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)

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. Trauma.org's summary of the available literature states "there is no evidence to support the use of steroids in the management of spinal cord injury"

At 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%.

In 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).

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).

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).

Multicenter 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).

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.

RCT 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%)

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)

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)

Use 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 references of important articles for CVICU

30 useful references for CVICU

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%).

Single 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).

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).

Multicenter 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.

Sibling matched cohort study of infants exposed to anesthesia vs. their sibling pairs who had not been exposed show no differences in neurodevelopmental outcomes.

Multicenter 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.

Systematic 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).

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.

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).

National 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.

Randomized 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.

Multicenter cluster randomized trial of 21 patients demonstrates no difference in all cause hospital mortality with use of PEWS (pediatric early warning system).

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)