The benefits of colloids vs crystalloids for fluid resuscitation has been long debated. The FLASH trial examined the effect of Hydroxyethyl starches (HES) 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery. The study was conducted in France involving 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery across 20 centers. The study was a multicenter, double-blind, parallel-group, randomized clinical trial. Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9%saline (n = 389) or 0.9%saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day. The group examined as a primary outcome death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, hospital and ICU length of stay and all-cause mortality at postoperative days 28 and 90.
Among 826 patients enrolled (mean age, 68years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group relative risk, 1.10 [95%CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (IQR, 750-2000 mL) in the HES group and 1500 mL (IQR, 750-2150 mL) in the saline group (median difference, 250 mL [95%CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3%of patients had died in the HES and saline groups, respectively relative risk, 1.76 [95%CI, 0.79-3.94]; P = .17). Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9%saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients. The study was limited by the restriction of the fluid protocol to the first 24 hours post-op and the exclusion of patients with a low risk of morbidity.
Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. The PEPTIC investigators compared in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis. Secondary outcomes examined were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. The study was a cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. The study included adult patients requiring invasive mechanical ventilation within 24 hours of ICU admission and were followed up for 90 days at the hospital. The study compared two stress ulcer prophylaxis strategies. Each ICU used a prophyalxis strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs. A total of 13,436 patients were randomized by site to PPIs and 13,392 patients were randomized by site to H2RBs.
Among 26,982 patients who were randomized, 154 opted out, and 26,828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26,771 patients (99.2%) included in the mortality analysis; 2459 of 13,415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13,356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95%CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95%CI, −0.01 to 1.88] percentage points; P = .054). Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95%CI, 0.57 to 0.92]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different. The study concluded that among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3%vs 17.5%, respectively, a difference that did not reach the significance threshold. The study was limited by patients with upper GI bleed having been excluded from the study, some of these patients subsequently were found to have lower GI bleeds. Investigators were able to choose route of administration of the ulcer prophylaxis drug which may have altered findings.
The CRASH-2 trial published in 2013 established the use of tranexamic acid (TXA) in the management of patients suffering from hemorrhagic shock. Based on these results, the investigators of CRASH-3 sought to determine if the administration of TXA might positively affect mortality and morbidity in patients with traumatic brain injury.
The study was an international, multi-center, randomized, placebo-control trial. The original inclusion criteria were adult patients presenting within 8hrs of injury with evidence of intracranial blood on CT scan OR with a GCS ≤12, IF the referring physician had clinical uncertainty about the usefulness of TXA administration (in other words, the patient has no other hemorrhagic source from which they might benefit from TXA or vice versa, a contraindication to TXA). Enrollment began in July 2012, and in Sept 2016, based on external information, the inclusion criteria was shortened from TXA administration within 8hrs of injury to within 3hrs. The primary endpoint was head injury-related in-hospital mortality at 28 days. They prespecified a sensitivity analysis which excluded patients with severe TBI (those who presented with GCS 3 or with bilateral unreactive pupils), as these patients were likely to have a poor outcome regardless of TXA administration. Secondary outcomes included: head injury-related death within 24hrs, all cause and cause specific mortality, disability, vascular occlusive events (VOE), seizures, complications, any neurosurgery, ICU length of stay and adverse events. VOE included myocardial infarction, stroke, deep vein thrombosis (DVT) and pulmonary embolus (PE)). DVT and PE were diagnosed on imaging or post-mortem. They originally powered the study to detect a 15% relative reduction in overall mortality leading them to need 10,000 patients. However, they changed overall mortality to be head injury-related mortality and therefore increased their sample size to 13,000 patients.
From July 2012 to Jan 2019, they enrolled 12,737 patients from 175 hospitals in 29 countries. 72% of patients (9,202) had TXA administered within 3hrs and 9,127 patients had outcome data. There were no significant differences in baseline characteristics. Head injury-related mortality for patients treated with TXA was 18.5% vs. 19.8% in patients receiving placebo (Risk Ratio (RR) 0.94 CI: 0.86-1.02). Excluding severe TBI, mortality for patients treated with TXA was 12.5% vs. 14.0% in patients receiving placebo (Risk Ratio 0.89; CI 0.80-1.00). Neither of these comparisons are statistically significant. When stratified by GCS, patients with mild to moderate injury (GCS 9-15) did see a survival benefit in the group treated with TXA (RR 0.78; CI: 0.64-0.95) versus placebo (RR 0.99; CI 0.91-1.07). When stratifying risk of death by time to administration, mild and moderate injury patients did show survival benefit (p=0.005) with maximal benefit occurring with earlier administration. TXA offered no survival benefit in the severely injured patients (p=0.73) regardless of time of administration. They also evaluated risk of head injury-related death by World Bank income group and did not find a statistical difference between high-income vs. low income and middle-income countries. The RR of head injury-related death within 24hrs in the entire cohort was 0.81 (95% CI: 0.69-0.95) and in the sub-group which excluded patients with GCS of 3 or bilateral unreactive pupils the RR fell to 0.72 (95% CI: 0.56 – 0.92). This was statistically significant and showed a survival benefit for TXA administration, though this benefit was lost by the 28-day mark when mortality was no longer different between the groups (primary endpoint). Disability, vascular occlusive events and seizure incidence were similar in patients receiving TXA vs. receiving placebo (VOE RR 0.98; CI: 0.74 – 1.28; Seizure RR 1.09, CI 0.90 – 1.33).
The authors conclude that the administration of TXA within 3 hours of injury reduced head injury-related death, with no adverse effects or complications. This is a broad statement. In actuality, the primary end-point was negative: there was no statistical difference for head injury-related mortality at 28 days in patients given TXA vs. placebo for the entire cohort, or in their pre-specified subgroup analysis (excluding patients with GCS 3 or nonreactive pupils). The study was able to demonstrate that a sub-group of patients may benefit: patients with mild-moderate head injury (GCS 9-15, equal pupils) who are able to have early administration of TXA (≤ 3hrs). TXA did not adversely affect disability at 28 days, vascular occlusive events or seizure incidence. Strengths of the study are the large size making it well powered for its primary end point. It also has a good randomization scheme and excellent follow-up, helping eliminate bias. Weaknesses include the fact that the survival benefit was shown in a subgroup analysis only, for which the study was not powered. DVT and PE were only captured if recorded positive on imaging or post-mortem study, and this may have led to an underestimation of their incidence. There is also no information about the patient’s coagulation profile on arrival, which could be a confounding variable as well.
This is a multicenter, blinded, parallel group, randomized clinical trial. The primary purpose was to determine if achieving 100% of recommended caloric intake “during critical illness would increase quality of life scores, return to work, or key life activities and reduce death and disability six months later.” This study is the pre-specified 6 month follow up to TARGET (The Augmented versus Routine Approach to Giving Energy Trial) which evaluated 90-day mortality in 4,000 patients randomized to energy dense or routine enteral nutrition. The TARGET study found no statistically significant difference in 90-day mortality. In this study they divided the outcomes into several key groups, based on the patient’s pre-hospital functional status: <65 years of age and in the labor force, <65 years and not in the labor force, >65 years and living independently, >65 yrs and living at home with supports, >65 yrs and living in long term health care facility. The subgroups each had different metric tools by which their return to their pre-hospital condition was assessed.
By day 180, 29.6% of the patients in the energy-dense group and 28.1% of the patients in the routine enteral nutrition group had died, which was not statistically different. Mortality was not different for any of the subgroups, except for a strong trend in the group age ≥ 65yrs living at home with support, and this trend was in the direction of harm for those patients receiving energy-dense nutritional support. The quality of life scores, utilizing the EuroQol five dimensions five-level questionnaire (EQ5D5L) visual analogue scale, were not different overall or for any of the subgroups. For patients ≤ 65 yrs and in the labor force, there was no difference in the percentage of patients returning to work, the hours worked, the shift missed at work, effectiveness at work or major changes in the kind of work done.
This is a negative study, and there was no long-term benefit in achieving 100% of caloric requirements during critical illness. Despite a negative result, the study is nonetheless important, and again illustrates the high mortality in patients who survive their acute critical illness. ~30% of patients in both groups surviving to 90 days in the original TARGET study were subsequently dead at 6 months in this study. Interventions to mitigate this mortality risk are of paramount importance. While clinicians know that nutrition is extremely important for the critically ill patient, the physiology of the benefit of nutrition and starvation in critical illness is not yet elucidated and the timing of initiation and full support remains elusive. It is important to note that this study did engage enteral nutrition early, and each patient was treated for a median of 6 days (ranging from 3 – 11). Volume and protein delivered were similar, but calories varied depending on the carbohydrate and fat content. Of note, most of these patients (73%) had non-surgical reasons for admission to the ICU, making generalization to the surgical population difficult.