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Top 10 Practice Changing Trials in Intensive Care
Dr Swapnil Pawar
Dr Swapnil Pawar & Dr Jose Chacko
The ARDS-net low tidal volume (ARMA) study
In this multicentric randomized controlled trial (RCT), patients with acute lung injury and acute respiratory distress syndrome (ARDS), (based on pre-Berlin definitions) were enrolled. The study was conducted across 10 university hospitals in the USA for a 3-year period between 1996-99. Patients were ventilated with a tidal volume of 12 ml/kg predicted body weight at a plateau pressure of 50 cm H2O or less, and compared with 6 ml/kg predicted body weight at a plateau pressure of 30 cm H2O or less. The trial was stopped early at the fourth interim analysis after enrolment of 861 patients.
Main findings
The study revealed that ventilation with low tidal volumes of 6 ml/kg reduced mortality and the duration of mechanical ventilation.
| Outcome | 6 ml/kg | 12 ml/kg | P value |
| Death before discharge home with unassisted breathing | 31% | 39.8% | 0.007 |
| Unassisted breathing at 28 days | 65.7% | 55% | < 0.001 |
| Ventilator-free days at 28 days | 12±11 | 10±11 | 0.007 |
How did the study change practice?
The study was hailed as a landmark in the field of critical care practice. However, criticisms were levelled against the authors for comparing extremes of tidal volumes compared to a more conventional standard of care. Although slow to take up, the findings of the ARMA study led to a paradigm shift in the ventilation strategy of ARDS patients.
The TRICC trial enrolled 838 critically ill patients with hemoglobin levels <9.0 gm/dl within 72 hour of ICU admission. Eighty-two percent of patients were on mechanical ventilation. Of these, 418 patients received a restrictive transfusion strategy; red cells were transfused if the hemoglobin levels dropped below 7 g/dl, with maintenance of levels between 7–9 g/dl. In the liberal group, red cells were transfused if the hemoglobin levels dropped below 10 g/dl, aiming for a target hemoglobin of 10–12 g/dl. The overall 30-day mortality (the primary outcome) was not significantly different; however, the hospital mortality was lower with a restrictive strategy. The 30-day mortality was also significantly lower in less severely ill patients (APACHE II score <20) and in the younger age group (<55 years old).
| Outcome | Restrictive | Liberal | P value |
| 30-day mortality | 18.7% | 23.3% | 0.11 |
| Hospital mortality | 22.2% | 28.1% | 0.05 |
| APACHE II <20 | 8.7% | 16.1% | 0.03 |
| <55 years old | 5.7% | 13.0% | 0.02 |
| Cardiac disease | 20.5% | 22.9% | 0.69 |
How did the study change practice?
The TRICC trial was a well-conducted study that came up with important new findings that would change transfusion practice among critically ill patients. However, a large number of patients were excluded as the treating clinicians considered transfusion necessary. The study was underpowered as the final sample size did not reach the planned target. However, it clearly demonstrated that a transfusion trigger of 7 gm/dl with a range 7–9g/dl would have no adverse impacts in a heterogenous group of critically ill patients. The authors advised caution with a low transfusion threshold in critically ill patients with myocardial ischemia.
The NICE-SUGAR study was conducted across 42 ICUs in Australia, New Zealand, and North America.6 In the intervention arm, the blood glucose levels were maintained between 81–108 mg/dl, while a higher level of up to 180 mg/dl was allowed in the control arm. A total of 6104 patients underwent randomization, with 3054 in the intensive glucose control arm and 3050 in the conventional arm. The study revealed a significantly lower 90-day mortality with a more conventional blood glucose target of 180 mg/dl among critically ill patients.
| Outcome | Intensive control | Conventional | P value |
| 90-day mortality | 27.5% | 24.9% | 0.02 |
| 28-day mortality | 22.3% | 20.8% | 0.17 |
| Hypoglycemia(Blood sugar 40mg/dl or less) | 6.8% | 0.5% | <0.001 |
There was no significant difference between groups in the number ventilation, ICU, or hospital days, the onset of new organ dysfunction or the requirement for renal replacement therapy.
How did the study change practice?
The NICE-SUGAR study clearly demonstrated that aiming for “tight” control of blood glucose levels may result in significant hypoglycemia and worsen clinical outcomes. It quelled the initial enthusiasm towards maintaining lower blood glucose levels in critically ill patients.
The PROSEVA trial included patients from 27 ICUs in France and Spain. All patients had severe ARDS with a PaO2/FiO2 ratio of less than 150, while on an FiO2 of 0.6 or more, and a PEEP of 5 cm of H2O or higher. In the intervention arm, patients remained in the prone position continuously for at least 16 hours; in the control arm, they remained semi-recumbent in the supine position. A total of 237 patients underwent prone positioning, while 229 were maintained supine, semi-recumbent.
| Outcome | Prone | Supine | P-value |
| 28-day mortality | 16% | 32.8% | <0.001 |
| 90-day mortality | 23.6% | 41% | <0.001 |
| Successful extubation at 90 days | 80.5% | 65% | <0.001 |
The study found a significant reduction in the 28- and 90-day mortality with prone ventilation. The number of ventilation-free days was significantly more in patients who underwent prone positioning. There was no difference in the ICU length of stay, need for non-invasive ventilation, or tracheostomy between groups.
How did the study change practice?
After several years and many RCTs that failed to show benefit, the PROSEVA study established improved survival among patients with severe ARDS, with a PaO2/FiO2 ratio of less than 150. In today’s world, most centers would prone ventilate severely hypoxic patients before considering more advanced modalities of care, including extracorporeal support.
Targeted temperature management (TTM) post cardiac arrest
Nielsen et al. conducted a multicentric, international RCT. Unconscious survivors of out-of-hospital cardiac arrest were assigned to targeted temperature management at 36 vs. 33°C. A total of 939 patients were included, 473 to the 33°C and 466 to the 36°C arm.11 The all-cause mortality until the end of the study, with a mean follow-up period of 256 days, was similar between groups.
| Outcome | 33°C | 36°C | P value |
| Death at the end of the study period | 50% | 48% | 0.51 |
| Cerebral Performance Category score (180 days): Severe cerebral disability, coma or vegetative state, or brain death | 54% | 52% | 0.78 |
| Modified Rankin score (180 days): Moderately severe disability, severe disability, or death | 52% | 52% | 0.87 |
| Death at 180 days | 48% | 47% | 0.92 |
How did the study change practice?
It was remarkable that basic life support measures were established within a median duration of 1 min in the TTM study; it remains unclear whether in the real-world setting of more delayed resuscitation, a lower target temperature level would be of benefit.
However, the TTM study strongly suggested that maintenance of normothermia in the post cardiac arrest period may be equally effective in optimizing clinical outcomes as reducing the temperature to lower levels.
The ANZICS trial – Low dose dopamine as Renal Protective agent
In a multicentric placebo controlled RCT conducted across ICUs in Australia, 324 patients were included. The inclusion criteria were 2 or more features of the systemic inflammatory syndrome (SIRS) over a 24 h period with early renal dysfunction based on urine output and creatinine levels. The investigators found no difference in peak creatinine levels between groups through the study period.
| Outcome | Dopamine | Placebo | P value |
| Peak serum creatinine (mg/dl) | 2.77 (1.63) | 2.82 (1.66) | 0.93 |
| Renal replacement therapy | 21.7% | 24.5% | Not significant |
| ICU stay | 13 (14) | 14 (15) | 0.67 |
| Hospital stay | 29 (27) | 33 (39) | 0.29 |
The number of survivors to ICU discharge (108 vs 105; p=0·61) and hospital discharge (92
vs 97 patients; p=0·66) was not significantly different between groups.
How did the study change practice?
This study shelved the use of dopamine as a “renal protective” strategy in critically ill patients. Except in a few cardiac units, it is unusual to see dopamine being methodically titrated to protect the kidneys.
The multicentric, placebo controlled RCT was carried out in 274 centers across 40 countries. Patients with significant hemorrhage and hypotension or those who were deemed to be at a high risk of significant hemorrhage were included, within 8 hours of injury. In the intervention arm, tranexamic acid was administered in a dose of 1 g intravenously over 10 min, following by 1 g over 8 hours; a matching placebo was administered in the control arm. In the final analysis, 10060 patients were included in the tranexamic acid arm and 10067 patients in the control arm. The use of tranexamic acid was associated with a significant reduction in hospital mortality at 4 weeks; death due to bleeding was also significantly less with tranexamic acid therapy.
| Tranexamic acid | Control | P value | |
| Hospital mortality within 4 weeks | 14.5% | 16% | 0.0035 |
| Death due to bleeding | 4.9% | 5.7% | 0.0077 |
How did the study change practice?
The absolute reduction in mortality was just 1.5%; besides, the study also found that tranexamic acid use was not associated with a reduction in the transfusion of blood products. The absolute risk reduction in mortality with the use of tranexamic acid in trauma patients was very small. Besides, it did not reduce the amount of blood products administered. A subsequent exploratory analysis revealed that tranexamic acid should be administered within the first 3 hours to bleeding trauma patients. Later use is less effective and possibly harmful.15
The SAFE study included a heterogenous group of 6997 critically ill patients. They were randomized to receive 4 percent albumin or normal saline as resuscitation fluid for 28 days. There were 3497 patients in the albumin group and 3500 in the saline group. There was no difference between groups in the 28-day mortality, the primary outcome of the study.
| Outcome | 4% albumin | Normal saline | P value |
| 28-day mortality | 20.9% | 21.1% | 0.87 |
| New organ failure | 47.3% | 46.7% | 0.85 |
| ICU days | 6.5±6.6 | 6.2±6.2 | 0.44 |
| Hospital days | 15.3±9.6 | 15.6±9.6 | 0.30 |
| Ventilation days | 4.5±6.1 | 4.3±5.7 | 0.74 |
| Renal replacement therapy | 0.5±2.3 | 0.4±2.0 | 0.41 |
On subgroup analysis a higher relative risk of death was noted with 4% albumin in trauma patients; this was due to a higher mortality among patients with traumatic brain injury. The use of 4% albumin suggested benefit in patients with severe sepsis. There was no difference in the relative risk of death in patients with ARDS. The study concluded that the use of 4% albumin as resuscitation fluid led to similar clinical outcomes compared to normal saline. The use of 4% albumin may be detrimental in patients with trauma, particularly with traumatic brain injury.
How did the study change practice?
The SAFE study contradicted the findings of the 1998 Cochrane meta-analysis and showed that albumin resuscitation may be equally safe compared to normal saline. However, the study established that normal saline may be equally effective as a resuscitation fluid. The ratio of the volume albumin to that of saline administered during the initial four days of treatment was 1:1.4. This finding challenged the conventional dogma that the volume of crystalloids administered must be 2–3 times higher for equivalent efficacy.
This RCT was conducted across five countries in 69 medical-surgical ICUs. Adult patients with a documented or suspected focus of infection with two or more criteria of the systemic inflammatory response syndrome (SIRS) and requiring pharmacological support for maintenance of blood pressure for at least 4 hours were included in the study. Hydrocortisone was administered as a continuous infusion of 200 mg/day. The control group received a matching placebo. The final analysis included 1853 patients who received hydrocortisone and 1860 patients who received placebo.
The 90-day mortality, the primary endpoint, was not different between groups. There was a statistically significant, reduced time to resolution of shock by one day, reduced time to cessation of mechanical ventilation and a lower requirement for blood transfusion.
| Outcome | Hydrocortisone | Placebo | P value |
| 90-day mortality | 27.9% | 28.8% | 0.50 |
| 28-day mortality | 22.3% | 24.3% | 0.13 |
| Time to shock resolution (days) | 3 (2–5) | 4 (2–9 | <0.001 |
| Time to ICU discharge (days) | 10 (5–30) | 12 (6–42) | <0.001 |
| Days alive and out of ICU (days) | 58.2±34.8 | 56.0±35.4 | 0.047 |
| Time to cessation of ventilation (days) | 6 (3 to 18) | 7 (3 to 24) | <0.001 |
| Blood transfusion | 37% | 41.7% | 0.004 |
There was no significant difference in the incidence of recurrent shock, days alive and out of hospital, re-initiation of mechanical ventilation, use of renal replacement therapy, days alive and free of renal replacement therapy, and new-onset bacteremia or fungemia.
How did the study change practice?
The ADRENAL study was by far the largest study on the use of steroids in septic shock. It adds to the body of knowledge corticosteroids may reduce the time to resolution of shock, but may not improve survival.
A total of 7000 patients were randomized to receive 6% HES (130/0.4, Voluven) or normal saline as resuscitation fluid until 90 days after randomization, ICU discharge or death. The final analysis included 3315 patients in the 6% HES group and 3336 patients in the normal saline group.
| HES 6% | Normal Saline | P value | |
| 90-day mortality | 18% | 17% | 0.26 |
| Renal replacement therapy | 7% | 5.8% | 0.04 |
| Adverse events | 4.6% | 3.3% | 0.006 |
Patients in the risk (R) and injury (I) categories of the RIFLE score were higher in the normal saline group; however, there were more patients with failure (F) in the HES 6% group. There was no difference between groups in the 28-day mortality, death in ICU, or in hospital. The duration of mechanical ventilation, renal replacement therapy, stay in ICU and hospital were not different between groups.
How did the study change practice?
The era of synthetic colloid use came to an end after the publication of The CHEST and the 6S trial. The latter study showed an 8% absolute increase in mortality at 90 days and a 6% absolute increase in the requirement for renal replacement therapy with the use of HES,18 thus corroborating the findings of the CHEST study.
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