Critical CARE Landmark Trials 

P ICU patients (6,997 Patients)

I Albumin (N=3,479) 

C Normal saline (N=3,500) 

O The primary outcome measure was death from any cause during the 28-day period after randomization.

T 28 days

R There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P=0.87). 

C In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.

P ICU patients with hypovolemic shock (n=2857 Patients)

I  Colloids (gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) (n=1,414)

C Crystalloids (isotonic or hypertonic saline or Ringer lactate solution) (n=1,443)

O  Primary outcome: All-cause mortality at 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy.

T 90 days

R Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group ( P = 0.26).  Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (P = 0.03) 

C Among ICU patients with hypovolemia, the use of colloids compared with crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy.

P Patients admitted to the intensive care unit (ICU).  (n=2278 Patients)

I  Buffered crystalloid  (n=1162) 

C Saline (0.9% sodium chloride) (n=1116) 

O The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality.

T 90 days

R In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, -2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, -0.1% [95% CI, -1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, -1.0% [95% CI, -3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40).

C Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality. 

P Non-critically ill patients  (n=13347 Patients)

I  Balanced crystalloid : lactated Ringer’s (95.3%), with the remainder as Plasmalyte (4.7%)   (n=6708) 

C 0.9% saline for intravenous fluid therapy (n=6639) 

O  The primary outcome was hospital-free days (days alive after discharge before day 28).   Secondary outcomes included major adverse kidney events within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction.

T 28 days

R The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41)  Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).  

C At 28 days Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline.

P Adult patients admitted to the ICU (n=15802 Patients)

I  Balanced crystalloid (n=7860)

C Saline (n=7942)

O  The primary outcome was a major adverse kidney event within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction

T 30 days

R Among patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04)  In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08). The incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60). 

C  Intravenous administration of balanced crystalloids rather than saline had a favorable effect on the composite outcome of death, new renal-replacement therapy, or persistent renal dysfunction. 

P Mechanically ventilated patients (365 patients)

I Dexmedetomidine (n=244) 

C 

Midazolam (n=122)  

O Percentage of time within target RASS range

T 30 days

R There is no difference regarding the primary outcome which is the percentage of time within target RASS range (score -2 to +1) (P=0.18).

C  There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia.

P Critically ill adult patients on mechanical ventilation  (n=430 Patients)

I  Protocolized sedation plus daily sedation interruption (n=214) 

C Continuous opioid and/or benzodiazepine infusions and random allocation to protocolized sedation (n=209) 

O  Primary outcome: Time to successful extubation. Secondary outcomes included duration of stay, doses of sedatives and opioids, nurse and respiratory therapist clinical workload ( on a 10-point visual analog scale [VAS]). 

T 28 days

R There was no difference in median time to successful extubation. p=0.52 Duration of ICU stay (median [IQR], 10 [5-17] days vs 10 [6-20] days; P = .36) and hospital stay (median [IQR], 20 [10-36] days vs 20 [10-48] days; P = .42) did not differ between the daily interruption and control groups, respectively. However, Nurse workload was significantly higher in the intervention group  (VAS score, 4.22 vs 3.80; mean difference, 0.41; 95% CI, 0.17-0.66; P = .001). 

C For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay. 

P Septic patients on mechanically ventilated (422 patients)

I Dexmedetomidine (N=214) 

C Propofol (N=208) 

O The primary end point was days alive without delirium or coma during the 14-day intervention period.  Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire at 6 months. 

T 90 days

R No difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26). Ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). 

C Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol.

P Patients with early, severe ARDS (n=340 Patients)

I  Cisatracurium besylate (n=178) 

C Placebo (n=162) 

O The primary outcome was in-hospital mortality rate

T 90 days

R The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04).

C In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. 

P Patients with moderate-to-severe ARDS  (n=1006 Patients)

I  Continuous infusion of cisatracurium with concomitant deep sedation (n=501) 

C Without routine neuromuscular blockade and with lighter sedation targets (n=505) 

O The primary end point was in-hospital death from any cause at 90 days 

T 90 days

R At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between- group difference, −0.3 percentage points; 95% confidence interval, −6.4 to 5.9; P=0.93). 

C Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. 

P Critically ill patients in septic shock (499 Patients)

I Hydrocortisone (n=251) 

C Placebo (n=248) 

O At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. 

T 28 days

R Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group).  At 28 days, there was no significant difference in mortality (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock.

C Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed.

P Septic shock patients (799 Patients)

I Vasopressin (n=397)

C Norepinephrine (n=382) 

O The primary end point was the mortality rate 28 days after the start of infusions. 

T 90 days

R There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11).  

C Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors.

P Septic shock patients (1679 Patients)

I Dopamine (n=858)

C Norepinephrine (n=821) 

O The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.

T 28 days

R There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P=0.10).  There were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001).  

C There was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events.

P Adult patients presenting to the emergency department with early septic shock (1600 Patients)

I Receive Early Goal Directed Therapy (EGDT) (n=796) 

C Usual care (n=804) 

O The primary outcome was all-cause mortality within 90 days after randomization 

T 90 days

R At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, −0.3 percentage points; 95% confidence interval, −4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.

C In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. 

P Patients in intensive care units (ICUs) with indisputable or probable septic shock for less than 24 hours (1241 Patients)

I Received Hydrocortisone PLUS Fludrocortisone (n=614) 

C Placebo (n=627) 

O The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180.

T 180 days

R The 90-day mortality was 43.0% in the hydrocortisone-plus-fludrocortisone group and 49.1% in the placebo group (P=0.03). The relative risk of death in the hydrocortisone- plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. 

C Patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. 

P Patients with acute lung injury (n=1000 Patients)

I Conservative strategy of fluid management (n=503) 

C Liberal strategy (n=497) 

O The primary end point was death. Secondary end points included the number of ventilator-free days and organ-failure–free days and measures of lung physiology

T 60 days

R The rate of death at 60 days was 25.5 % in the conservative-strategy group and 28.4 % in the liberal-strategy group (P=0.30; 95 % confidence interval for the difference, −2.6 to 8.4 %).  

C Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non-pulmonary organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. 

P Adult patients with severe respiratory failure (n=180 Patients)

I  Extracorporeal membrane oxygenation (ECMO) (n=90)

C Continued conventional ventilation (pressure control mode with Siemens Servo 300 ventilators) (n=90)

O  The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital.

T 6 months

R 68 (75%) patients received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0·69; 95% CI 0·05–0·97, p=0·03).  Referral to consideration for treatment by ECMO treatment led to a gain of 0·03 quality-adjusted life-years (QALYs) at 6-month follow-up. 

C Transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3·0 or who have a pH of less than 7·20 on optimum conventional management, to a center with an ECMO-based management protocol to significantly improve survival without severe disability. 

P Patients with established moderate-to-severe ARDS (n=277 Patients)

I Receive immediate treatment with dexamethasone (n=139) 

C Routine intensive care (control group) (n=138) 

O Primary outcome was the number of ventilator-free days . Secondary outcome was all- cause mortality 60 days after randomisation.

T 60 days

R The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4·8 days [95% CI 2·57 to 7·03]; p<0·0001). At 60 days, 29 (21%) patients in the dexamethasone group and 50 (36%) patients in the control group had died (between-group difference –15·3% [–25·9 to –4·9]; p=0·0047). The proportion of adverse events did not differ significantly between the dexamethasone group and control group. 

C Early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS.

P Hospitalized patients with COVID-19 (n=6425 Patients)

I  Receive oral or intravenous dexamethasone (n=2104) 

C Receive usual care alone (n=4321) 

O The primary outcome was mortality rate

T 28 days

R Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). 

C In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. 

P Critically ill patients in the medical ICU (6104 Patients)

I Intensive (Target BSL 81-108 mg/dL) (n=3054) 

C Conventional (Target BSL ≤ 180 mg/dL) (n=3050) 

O The primary end point as death from any cause within 90 days after randomization.  

T 90 days

R A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02).  

C Intensive glucose control increased mortality among adults in the ICU: a blood glucose target of ≤ 180 mg/dL resulted in lower mortality than did a target of 81 to 108 mg/dL.

P Patients who had septic shock and a hemoglobin concentration of 9 gm/dL or less (n=998 Patients)

I  Lower hemoglobin threshold ( hemoglobin level was 7 gm/dL or less) (n=502)

C Higher hemoglobin threshold( 9 gm/dLor less)  (n=496)

O  The primary outcome measure was death by 90 days after randomization.

T 90 days

R At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44).

C  Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold. 

P Adults with TBI who were within 3 h of injury, had (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding (n=12737 Patients)

I Receive tranexamic acid (n=6406) 

C Placebo (n=6331) 

O The primary outcome was head injury-related death in hospital within 28 days of injury.

T 28 days

R The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64–0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91–1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). 

C Tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury.