AVERT-Shock: Does Low Dose Vasopressin Reduce Need for Blood Products in Trauma

Study Design Summary: Double-blind, placebo controlled single center trial of 100 hemorrhagic shock patients comparing vasopressin vs placebo with a primary outcome of blood product transfusion requirements.

Notes: Significant amounts of vasopressin are released during acute hemorrhage and stores diminish with time. Low levels are associated with catecholamine resistant hypotension and increased venous capacitance. Trauma patients are at increased risk of AVP (arginine vasopressin) deficiency within the first 48 hours of resuscitation as their stores diminish, it has a short half life (10-35 minutes) and the shed blood rich in AVP is replaced with AVP poor crystalloid and blood products. When given I physiologic doses (0.04 u/min) to healthy volunteers, AVP does not increase blood pressure, only does it act as a vasopressor when given to AVP deficient patients. AVP also enhances platelet function.

Trauma patients who received 6 units of blood products (pRBC, FFP, platelets) within 12 hours of arrival were enrolled in the study. Cryopreciptate was not considered a unit of blood products in this study. Some important exclusion criteria include prehospital cardiac arrest, ED thoracotomy, chronic renal insufficiency, coronary artery disease, TBI requiring neurosurgery. The AVP arm got a 4 U bolus followed by 0.04u/min infusion, the placebo arm got a similar volume of saline for the bolus and infusion. The bolus and infusions were started after the operating surgeon declared definitive hemorrhage control. The infusion was titrated (0-0.04u/min) to maintain a MAP of 65 mm Hg. Patients received blood products at the discretion of the treating physician, but both patients and health care personnel were blinded to the AVP vs placebo. If patients required pressors, all were titrated and stopped before titrating the study infusion, the study infusion was restarted first if the patient was initially weaned and then requirement MAP support, no open label AVP was permitted. The primary end point was cumulative volume of blood products transfused within the first 48 hours of enrollment. The study was powered at 50 patients per group to detect a 50% reduction in total volume of blood product requirement.

The placebo group had a higher baseline MAP (82 vs 76 mm Hg, p=0.2) at trauma bay admission, but lower mean MAP at time of enrollment (69 vs 71, p=0.38). The patients enrolled were 93% men, with 79% being penetrating trauma. The median amount of cumulative blood product transfused at 48 hours was 1.4 L in AVP group (0.5-2.6L) vs 2.9 L in placebo group (1.1-4.8L) (p=0.01). In the per protocol analysis, all forms of blood products were transfused significantly less in the AVP arm, in the intention to treat analysis, pRBC was not transfused significantly less but all other forms of blood products were. Though the study wasn’t powered for complications, the authors report no difference in the complication rate between the two groups.

Study Conclusion: Addition of low dose vasopressin to patients with hemorrhagic shock reduces blood product requirements.

Fusion Beat Bottom Line Impression: Addition of vasopressin to hemorrhagic shock resuscitation may reduce need for blood product transfusion, however for definitive answer we need a larger study. It is reasonable to reach for AVP in the next trauma patient once blood product resuscitation is underway and you have cognitive and physical bandwidth to support it.

RELAx: Is Lower or Higher PEEP Better in Patients Without ARDS

Study Design Summary: Multicenter, randomized, open label, noninferiority trial of 980 patients without ARDS comparing low vs high PEEP with a primary outcome being number of ventilator free days at day 28.

Notes: Patients included were those who did not have ARDS, were intubated less than 12 hours prior to randomization and not expected to be extubated within 24 hours of randomization. Morbidly obese patients and those with COPD or restrictive lung disease were also excluded from the study. Patients were randomized to a low PEEP group (0-5 cm H2O) and high PEEP group (8 cm H2O). Both groups had similar FiO2 ranges, the low PEEP group had the PEEP titrated down every 15 minutes to a minimum of 0 cm H2O. This was a non blinded study. There was standardized protocol for both groups to respond to hypoxemia and hemodynamic instability, both of which were predefined. In both groups the oxygenation targets were 92% to 96% for SpO2 and 60 to 85mmHg for PaO2.

The primary outcome was number of ventilator free days, however it was designed as as non-inferiority trial. There were a total of 980 patients included in the final study. The high and low PEEP groups were fairly well balanced, however, the high peep group had slightly higher APACHE IV scores (83.5 [IQR 60-103] vs 90 [IQR 67-111]). SOFA scores were similar between the two groups. Time from intubation to randomization was the same for both groups and roughly just under one hour. Only about 30% of patients were intubated because of respiratory failure, others were intubated for surgery or cardiac arrest. More patients in the low PEEP group were intubated for planned post operative ventilation where as the high PEEP group had more intubations for cardiac arrested and depressed mental status.

The low PEEP group had an average PEEP of 4 where as the high PEEP group had an average PEEP of 8. The lower PEEP group had roughly 1 more day of intubation compared to the high PEEP group 17.7 (0-26.6) vs 16.7 (0-26.5), however this did not fall outside of their predefined non-inferiority margin of 10%. More patients in the low PEEP group had atelectasis, hypoxemia, need for recruitment maneuvers and interestingly more pneumothoracies as well. While it wasn’t the primary outcome, the lower PEEP group also had a longer duration of ICU stay with mean days of 8.1 vs 7.2.

Overall, the high PEEP group was sicker and experienced less adverse events such as hypoxemia. This study doesn’t change my practice but does point to the need for a designated RCT looking at whether non-ARDS patients could benefit from higher PEEP.

Some good comments from PulmCrit: “The primary endpoint is the number of ventilator-free days.  This doesn’t really make sense.  Most patients were not intubated due to respiratory failure.  Do we truly expect that a PEEP of 4 cm vs. 8 cm will affect timing of extubation in a postoperative patient, or a patient intubated for airway protection?  Most patients in the study weren’t intubated for respiratory failure – so their timing of extubation is likely to be determined by non-pulmonary considerations. In terms of this study, the low-PEEP arm seems bizarre and unrealistic.  Using zero PEEP (“ZEEP”) is likely to promote atelectotrauma, so ZEEP is generally avoided in critical care practice.  Likewise, 8 cm of PEEP is occasionally used, but this doesn’t seem like usual care either (at least at units that I’ve worked in).  As such, neither arm of this trial resembles standard practice.  A more realistic and clinically useful comparison would be between 5 cm PEEP vs. 8 cm of PEEP.  However, there is less separation between these two groups, so performing a study would be challenging.”

Study Conclusion: In patients without ARDS, lower PEEP is noninferior to higher PEEP with regard to number of ventilator free days at day 28.

Fusion Beat Bottom Line Impression: My current practice of PEEP of 5 cm H2O on most patients increasing as each case demands is unchanged by this study. I do endorse a PEEP of 0 and thus this study does not provide comment on whether PEEP of 5 or 8 is better for clinical outcomes.

Syncope vs Near Syncope 30 Day Serious Adverse Events

Study Design Summary: Multicenter, observational study of 3,500 adults ≥60 years old presenting to ED with syncope or presyncope. Primary outcome was rate of serious adverse events at 30 days compared between the syncope vs near syncope group.

Notes: The goal of the study was to determine if patients presenting with near syncope had similar adverse event rates compare to those presenting with syncope. Patients were included if ≥60 years old, presenting with either syncope or presyncope. Patients were excluded if symptoms caused by events such as intoxication, stroke, head trauma seizure or hypoglycemia, or if medical intervention such as defibrillation was needed. All patients had EKG done with preset criteria to determine if the EKG was considered abnormal. Testing of patients beyond baseline ECG was left up to the treating physician. Physicians were ask to give a probability that the patient would experience a 30 day cardiac event or death. It is unclear at exactly when during the encounter this was sought from the treating physicians.

The final cohort of patients came to 3,581 total patients, from an initial 10,306 screened. While reasons were given to most of the excluded patients, 502 were listed as “other” with no explanation. More patients in the near syncope group had CHF, CAD, dyspnea.

Primary outcome was composite outcome of 30 day all cause mortality or any of the predefined serious clinical events. The treating physician determined if the patient had syncope vs near syncope.

There were a total of 658 30-day serious events (18.4%) in the study cohort, with the percentage not different between the syncope (18.2%) vs near syncope (18.7%) groups. Authors report that the major categories of adverse events was similar between the two groups as well. There was also no difference between the groups after multivariate logistic regression analysis. History of arrhythmia, abnormal EKG result, and presence of dyspnea remained the highest predictors of 30-day serious clinical event per the authors.

Study Conclusion: Syncope and near syncope have similar 30 day serious adverse event rates for older patients.

Fusion Beat Bottom Line Impression: This observational study supports the notion that syncope and near syncope should be treated clinically as the same entity when evaluating older patients in the ED.

Is There Benefit to Hospitalization of Older Adults with Unexplained Syncope/Presyncope

Study Design Summary: Multicenter, observational study of hospitalization versus discharge on 3,000 adults ≥60 years old with no serious diagnosis found during index ED visit. Primary outcome was rate of post-ED serious adverse events.

Notes: Patients were included if ≥60 years old, presenting with either syncope or presyncope. Patients were excluded if symptoms caused by events such as intoxication, stroke, head trauma seizure or hypoglycemia, or if medical intervention such as defibrillation was needed. Testing of patients beyond baseline ECG and cardiac biomarker, troponin and BNP, testing was left up to the treating physician. The treating physician was not aware of the troponin and BNP however, but could order their own for review if felt it was needed for evaluation of the patient. Physicians were ask to give a probability that the patient would experience a 30 day cardiac event or death. It is unclear at exactly when during the encounter this was sought from the treating physicians.The researchers compared hospitalized vs discharged patients through propensity matching.

The final cohort of patients came to 2,492 total patients, from an initial 10,306 screened. While reasons were given t most of the excluded patients, 502 were listed as “other” with no explanation. There was 95 patients lost to follow up, which was relatively small. Discharged patients were generally younger, with less having CHF, CAD, or history arrhythmias.

Of the patients in the study, 75% were admitted. Mean length of stay before observation of an adverse event was 7.5 days in the admitted group, vs 13.8 days in the discharged group. The most common serious outcome was cardiac arrhythmia (36.7%). In the unadjusted analysis, the rate of serious event postdischarge was higher in the admitted group (7.4% CI 6.2-8.6 vs 3.2% 1.8-4.6 [since CI did not cross it means statistically significant]) but after propensity adjusting rates were (4.8% 3-6.7 vs 2.8% 1.4-4.2 [since CI did cross it means no statistical significance]). While it isn’t statically significant after matching, both have higher rates for the hospitalized patients, which is what hospitalization is designed to do-find the serious events, not eliminate them.

The authors draw note that the most common adverse event was arrhythmia, and while most admissions last for just a few days, in both groups the average time to serious event was over 1 week.

Study Conclusion: Hospitalization is not associated with improvement in 30 day serious adverse event rates

Fusion Beat Bottom Line Impression: This observation study draws into question whether older patients with unexplained syncope/presyncope benefit from admission. Likely shared decision making and case dependent factors are best considered when making this decision clinically at the bedside.

NoPAC: Does Topical TXA Reduce Need for Anterior Nasal Packing in Spontaneous Epistaxis

Study Design Summary: Double-blind, placebo controlled, multicenter randomized control trial of 496 patients with spontaneous epistaxis that was persistent despite external pressure and topical vasoconstrictors, then randomized to either topical TXA or placebo. The primary outcome was the need for anterior nasal packing.

Notes: The study included patients who presented with spontaneous, non traumatic epistaxis. Patients were excluded if they had traumatic epistaxis, hemodynamic instability, with EMS nasal packing, sent in by ENT clinic, nasopharyngeal cancer, pregnancy hemophilia. They initially received external pressure and ice for at least 10 minutes, if bleeding persisted topical; intranasal vasoconstrictors were used. Choice of agent was left to treating physician. If after 10 minutes there was persistent epistaxis the patients were randomized into the trial and blinded to patient and physician. The decision to move onto further treatment after the TXA or placebo was at the choice of the physician. Primary outcome was need for anterior nasal packing.

The authors calculated that to detect a 10% difference in packing rate they would need 414 patients total, they then aimed for 450 to account for loss to follow-up. There were 2622 patients initially deemed eligible, 2324 patients were excluded with really poor reasoning. There were 834 excluded, due to no research nurse available, 772 due to “other,” 3325 due to no senior clinical staff and 161 due to “department too busy.” These are way too high to be comfortable with and 772 due to “other” hides a lot of sin. They ended up with 496 patients. First10EM notes that the study is technically underpowered because the power calculations were based on assumption that 95% of patients would require anterior nasal packing but it ended up only being 45%. Method section notes that patients were to be randomized 1:1 but the TXA group ended up with 254 as compared to 242 of placebo. Analyzed in intentional to treat analysis. There was 100% followup for patients that were randomized into the trial.

There were significantly more men in the placebo group, and more patient son anticoagulation in the placebo group. No p values or statical analysis numbers are provided with the demographics table. They did not include a table of the adverse events in the main paper, the authors did state that all serious adverse events were not felt to be secondary to TXA.

The authors address that the TXA dosing in this study is less than in previous studies with the idea that dosing larger than 200 mg are not likely to be fully absorbed into the cotton roll and thus not likely to be fully administered to the patient.

Anterior packing was placed in 100 patients (41%) in the placebo group as compared to 111 (44%) in the TXA group. These differences were not statically significant but it should be noted that the TXA group had more patients receive packing. The hospital admission rate was 110 (45%) in the placebo group as compared to 110 (43%) in the TXA group which seems extremely high-however per First10EM it seems this is standard practice in UK which is where this study took place. There were no difference between the groups in regard to secondary outcomes including hospital admission, blood transfusion requirements, recurrent epistaxis, thrombotic events requiring hospital hospital reattendance within 1 week.

In the discussion section they mention that other previous studies have shown potential benefit to topical intranasal TXA, though they were each looking at different primary endpoints. According to First10EM there are 6 previous RCTs which total to 692 patients, each study had fairly different methods, some using oral and others using topical TXA, which treatment in the control groups also varying. Cochran review rates these studies’ evidence as “moderate to low.” These studies seem to show TXA decreases rebreeding rates.

Given the very high number of patients excluded from the study with poor reasoning, no adverse events table listed in main study, in combination with previous studies which have shown potential benefit, I am very skeptical of the results of this study and do not feel this study can be used to state whether topical TXA should or should not be used for epistaxis. While needing anterior nasal packing is a significant endpoint it may not be the best endpoint to determine TXA effectiveness, this will need to be explored further. St. Emylyns blog notes that this study and the unexpectedly low need of anterior packing the control arm shows that simple and conservative measures work better than we may expect.

Study Conclusion: There was no statistically significant difference in the need for nasal packing in the TXA arm vs the placebo arm.

Fusion Beat Bottom Line Impression: While this study’s results alone show no significant difference in the rates of needing anterior nasal packing after topical TXA vs placebo, given the limitations of this study I feel it does not provide definitive evidence one way or another about topical TXA in epistaxis and I do not think it should alter practice until more data comes out.

COVID-19 Vaccine Pfizer

Study Design Summary: Multinational, placebo controlled trial of 43,448 patient’s who received either a 2 dose COVID-19 vaccine 21 days apart or placebo, with primary outcomes being safety and efficacy against lab confirmed COVID-19 infections.

Notes: The placebo and intervention arm were well balanced in their patient demographics, however, 83% of participants were white and countries such as Brazil and South Africa were included. Patients with HIV and other immune compromised states were included but the specific numbers and outcomes of these subgroups was not included in this paper. The trial did not included children under 16 or pregnant women. Participants reported symptoms of COVID with tested, there is no mention of routine testing, thus this study really only looks at symptomatic cases of COVID-19.

The study was designed as a 2 injection trial, with the doses 21 days apart. Among patients who had either no known COVID or evidence of COVID infection, COVID was contracted by 9 of the patients in the vaccine arm and 169 in the placebo arm, 0.04% vs 0.84%. Among patients with only no evidence of infection the cases with 8 in the vaccine arm and 162 in the placebo arm.

Interestingly, between the first and second doses of the vaccine the observed efficacy was 51%, and within 7 days of the second dose the efficacy was 91%, with the 95% efficacy being reach at 8 or more days after the second dose. The authors mention that there were 10 severe cases of COVID noted after the first dose and only 1 of those was in the vaccine arm, but no further details are provided.

Adverse events were similar between the placebo and intervention arm, there was more difference in the rate of adverse events after the second dose. The large majority of adverse events were mild to moderate and mainly pain at injection site, muscle aches, fatigue and headache. These adverse events were also more prevalent in the 16-55 year age range, but those over 55 years old had a larger delta increased percentage of patients experience these adverse events after the second dose as compared to after the first dose.

Study Conclusion: Pfizer’s COVID-19 vaccine is both safe and 95% effective at preventing COVID-19 infection.

Fusion Beat Bottom Line Impression: The Pfizer vaccine gives some local site reactions and flu-like symptoms, mainly after the second dose, as compared to placebo, but it is effective in reducing rates of symptomatic COVID-19 in white patients.

SMART: Does Balanced Crystalloid Reduce Major Adverse Kidney Event Rate

Study Design Summary: Single center study of 15,802 ICU patients treated with either saline or balanced crystalloid, with a primary outcome of major adverse kidney event at 30 days or hospital discharge, whichever came first.

Notes: The intervention group (balanced crystalloid) vs saline group were very well balanced in their baseline characteristics. The primary outcome was a composite outcome called “major adverse kidney events” which included death, new RRT, or persistent renal dysfunction (defined as CR greater than or equal to 200% of patient’s baseline Cr) at 30 days or hospital discharge, which ever came first. The study needed 14,000 patients for a 90% power and it had well over this number at 15,802 patients total.

Just like in SALT-ED, fluid administration for patients was coordinated between ER and ICU (or ER and ward in the case of SALT-ED), and was assigned based on the month. Roughly 5% of patients in each group were given both saline and balanced crystalloid due to being in the ICU over the change in month.

The cumulative volume of fluids given to patients in the two groups over the first 7 days was relatively low at roughly around 2-2.5 liters. There was a measurable difference in chloride concentration between the two groups, higher in the saline group, as well as the bicarb concentration, higher in the balanced crystalloid group.

The composite primary outcome was statistically signifiant between the intervention and saline group with 14.3% vs 15.4% for p=0.04. Though none of the individual outcomes were significant on their own; death 10.3% vs 11.1% p=0.06, new RRT 2.5% vs 2.9% p=0.08, persistent renal dysfunction 6.4% vs 6.6% p=0.60. None of the secondary outcomes were statistically significant.

While the primary outcome is a composite outcome and none of the individual outcomes were significant on their own, it is an important outcome and likely more clinically significant than any of the individual outcomes. Lumping death with new RRT though is a bit of a stretch. The study had well over the number of patients needed to be appropriately powered, thus the statistical significance of the study is likely true. The authors note that their conclusion means that using balanced crystalloid instead of saline would result in preventing 1 out of every 94 patients from their primary outcome, which is respectable. They had preplanned subgroup analysis that were not shown in the paper’s tables but discussed, and they note that the difference between the groups were larger when more fluid was administered.

A sited relative contraindication to using balanced crystalloid was hyperkalemia and brain injury, and so clinicians could opt to not follow protocol for these patients. With that taken into account, potshot analysis showed that the difference between the intervention and saline groups were equal or favored balanced crystalloid in all subgroups of which ICU type the patient was in (MICU, SICU, burn ICU…), balanced fluids were better in patients with sepsis and patients without TBI but also better in the neurosurgical ICU. This NICU vs TBI contrast maybe due to the allowance for deviation from protocol for TBI patients. The intervention and saline group were equal for the primary outcome in all levels of kidney function, though favoring balanced crystalloid, except if patients had previous RRT then balanced crystalloid was favored.

According the First 10 in EM, the fragility index of this study is 0, meaning it is not clinically significant and the p value for the primary outcome is actually 0.06. Most other FOAM sites agreed with the authors’ conclusion.

Of note, no APACHE II scores are given.

Study Conclusion: Among critically ill adults, use of balanced crystalloid resulted in lower rate of major adverse kidney events than use of saline.

Fusion Beat Bottom Line Impression: Use of balanced crystalloid does result in less composite death, RRT and persistent renal dysfunction in critically ill patients as compared to saline.

ICU-ROX: Does Conservative Oxygen Therapy in the ICU Increase Ventilator Free Days

Study Design Summary: Randomized trial of 1,000 patients of patients with less than 2 hours of invasive or noninvasive mechanical ventilation. Separated into 2 groups of conservative vs usual oxygen therapy groups. Primary outcome was ventilator free days, secondary outcomes included death at 90 and 180 days as well as others.

Notes: There were many patients excluded from this trial, some for reasons that seem like the investigators were quite selective, including 254 patients excluded for “severe morbidity.” Overall the intervention and control groups were not the most balanced but were balanced enough.

Both the intervention and control group used SpO2 of 90% as the lower acceptable limit. The control group of “usual oxygen therapy” had no other specific requirements but FiO2 of less than 0.3 was discouraged. The intervention group of “conservative oxygen therapy” targeted a SpO2 of less than 97%. Alarms were set on both groups to alert staff if the SpO2 was out of goal range. Clinicians could deviate from protocol if they felt it was necessary.

There was no difference in between the intervention and control group in terms of both the primary outcome of ventilator free days (15.5 vs 16.0) as well as secondary outcomes including death at 90 days, 180 days, vasopressor free days and number of patients required renal replacement therapy.

There were no real difference in adverse outcomes between the two groups listed, but it is mentioned in the paper. Previous studies have shown improved mortality and ventilator free days with conservative oxygen therapy. This study notes that previous papers with that conclusion have had very liberal oxygen strategies for the control groups and as opposed to the “usual oxygen therapy” in this group, meaning previous papers’ control groups had higher hyperoxia than the control group in this study.

Study Conclusion: The use of conservative oxygen therapy as opposed to usual care did not increase the number of ventilator free days.

Fusion Beat Bottom Line Impression: This study supports the conclusion that conservative oxygen therapy does not increase the number of ventilator free days, but given previous papers showing harm from hyperoxia, and the low adverse outcomes demonstrated with conservative oxygen therapy in this study, overall targeting normoxia is likely best.

MOPETT: Does Low Dose tPA for Pulmonary Embolism Reduce Pulmonary Hypertension

Study Design Summary: Prospective, single center, unblinded study of 121 patients with a predefined “moderate” pulmonary embolism were given either half dose tPA with anticoagulation or only anticoagulation. Primary outcome was pulmonary hypertension at 28 months and a composite of pulmonary hypertension and recurrent PE at 28 months.

Notes: The study predefined a “moderate” PE and in an unblinded fashion randomized patients to either half dose tPA with anticoagulation or only anticoagulation. Anticoagulation choice was either UFH or LMWH with preference for LMWH. 79% of patients in the tPA group and 81% in the AC only group received LMWH as opposed to UFH. Pulmonary embolism was imaging confirmed. The dosing for tPA was 0.5mg/kg up to 50mg with 10% as bolus over 1 minute followed by the remaining 90% over 2 hours.

The groups were equal in their baseline characteristics such as age, past medical history, history of previous unprovoked PE/VTE, hormone therapy, smoking history. The intervention vs control group had a mean pulmonary artery systolic pressure of 50 vs 51 mm Hg on admission, this quickly diverged after treatment with final numbers at 28 months of 28 vs 43 mm Hg (p<0.001). In the intervention vs control group there was 9 vs 32 patients with pulmonary hypertension at 28 months (p<0.001) and 9 vs 35 with composite of pulmonary hypertension and recurrent PE at 28 months (p<0.001). The secondary outcomes of mortality, hospital stay in days and recurrent PE all favored the tPA group. There was no bleeding in either group which does raise question, especially considering this wasn’t a blinded study.

Since the study was unblinded, only moderately sized and with unique definitions of size of PE rather than conventional massive/submassive/non-massive the results are hard to extrapolate to current practice but they do show decent results that even patients without massive PE can benefit from tPA and that half dose tPA may be safe. The authors offer up the explanation that since the lungs are the only organ to receive 100% of the cardiac output that half dose tPA is effective and can reduce bleeding complications-which the results of their study also seem to support. Although the study was unblinded to the patients and the treating clinicians, the cardiologists reading the ECHOs were blinded.

Due to the composite outcome we cannot definitely stay if it reduces recurrent PE. The study does not direct address mortality as a primary outcome thus no conclusion can be drawn about this outcome either.

Study Conclusion: “Safe” dose tPA is safe and effective in reducing pulmonary hypertension and recurrent PE at 28 months for patients with “moderate” PE.

Fusion Beat Bottom Line Impression: Half dose tPA reduces rates of pulmonary hypertension at 28 months and does not increase risk of bleeding compared to anticoagulation alone.

SALT-ED: Does Balanced Crystalloid Reduce Time to Hospital Discharge Compared to Saline

Study Design Summary: Single center study of 13,347 non-critically ill patients treated with either balanced crystalloid or saline in the emergency department, with a primary outcome of hospital free days.

Notes: The two groups of saline vs balanced crystalloid (lactated ringers or plasma-lyte A) were balanced in their baseline characteristics including baseline serum Cr and electrolytes. Both groups got a mean volume of fluids around 1.6 L and a median volume of 1 L. The study was patients who received at least 500cc of fluid in the ED and were admitted. The trial only included ED squid administration and did not extend to what fluids the patients got once admitted. This study also included only patients admitted to general medical wards, patients admitted to the ICU were examined separately in the SMART trial. Only 84% of the patients in the balanced crystalloid group received as compared to the 93% in the saline group.

The primary outcome was hospital free days to day 28 from randomization. For this outcome there was no difference between the groups. There were predefined secondary outcomes that mainly centered on kidney function. There were more adverse kidney events in the saline group (5.6% vs 4.7% p=0.01). In hospital was similar between the two groups.

While the study was negative and is reported as such, it is important to note that the study fluids were only the fluids administered in the ED and once the patients were admitted that fluid was no longer controlled. Also, a large percentage of the balanced crystalloid group received saline. The primary outcome of hospital free days is a complex endpoint and is not the best primary outcome for this study. If they had controlled the fluid throughout the hospital stay then this primary outcome would be more appropriate. The median and mean amount of fluid for each group was less than 2 liters. The secondary outcomes suggesting more adverse kidney events in the saline group is hypothesis generating only and does not provide any direct evidence. Also, as noted by REBEL EM, 35% of patients had an unknown baseline Cr thus a true analysis of adverse kidney events is not known as a large percentage had unknown baseline and in the study these patients were assumed to have normal Cr at baseline.

Study Conclusion: There is no difference in hospital free days among non-ICU patients treated with saline as opposed to balanced crystalloid.

Fusion Beat Bottom Line Impression: There is no difference in hospital free days in non-critically ill patients who receive saline or balanced crystalloid in the ED. This study does not support balanced crystalloid or saline as a superior resuscitation fluid when given in the ED.

ADRENAL: Does Hydrocortisone Reduce Mortality in Septic Shock

Study Design Summary: Multicenter, double-blind trial of 2658 patients with septic shock randomized to either hydrocortisone or placebo for 7 days, with primary outcome all cause mortality at 90 days.

Notes: Patients were fairly similar in their baseline characteristics, there was slightly more epinephrine used in the hydrocortisone group, more patients in the control group had pulmonary source infection where as more patients with skin/soft tissue infection were in the hydrocortisone group but overall percentages for sites in each group were relatively similar. Time to randomization was pretty much similar, more patients in the 18-24 hour range (the latest range) came from the placebo group, thus favoring any potential positive benefit in the hydrocortisone group.

The primary outcome of all cause mortality showed no difference between the two groups. There were many secondary outcomes, most were not different between groups however there were some. Intervention vs control: shorter time to resolution of shock in steroid group (3 vs 4 days p<0.001), median time to discharge from ICU (10 vs 12 days p<0.001), number of days alive and out of the ICU (58 vs 56 days p=0.047). Other statically significant differences were more blood transfusions in the control group and shorter time to initial removal of ventilation in the steroid group. The authors note that while the steroid group did have a shorter time to initial vent discontinuation, there was more reintubation and the overall number of days on the ventilator between groups did not differ. In regards to the listed positive secondary outcomes, a day earlier or shock resolution but no mortality benefit (including 28 day all cause mortality as one of the secondary outcomes) doesn’t;t seem significant. Early ICU discharge is interesting in the steroid group but no real conclusions can be drawn from this secondary outcome. The 2 day difference of days alive out of the ICU isn’t impressive when its 58 vs 56 days. There were more adverse events in the steroid group but some of these included leukocytosis and hyperglycemia, which are likely of small to no clinical significance. Overall the secondary outcomes point towards possible promising trends and 90 day/28 day all cause mortality is likely an appropriate end point here, which showed no difference between the groups.

Study Conclusion: Hydrocortisone does not lower 90 day all cause mortality in patients with septic shock.

Fusion Beat Bottom Line Impression: This study does not demonstrate a 90 day or 28 day mortality benefit of steroids in septic shock.

SAFE: Does Resuscitation with Albumin Confer a Mortality Benefit Over Saline

Study Design Summary: Multicenter, double-blind trial of 6,997 ICU patients to receive 4% albumin or saline as choice of resuscitation fluid while in the ICU, with primary outcome as all cause mortality at 28 days.

Notes: The study intervention was specifically resuscitation fluid, patients were placed on the physicians’ choice of maintenance fluids. The authors do no list time from admission/presentation to randomization, but patients were included for 28 days or until death. Noteably, once patients left the ICU they were no longer controlled as to which resuscitation fluid was given, but the rates of patients receiving resuscitation fluid outside of the ICU between the control and intervention group was the same.

The groups were similar in their baseline characteristics including age, source of admission to the ICU (ED, OR, hospital ward…), APACHE II scores, organ failure, percentage of patients on the vent, CRRT, and physiological variables such as HR, MAP, CVP, urine output and serum albumin.

Patients in the intervention group received significantly less fluids on the first 3 days after randomization and significantly more pRBC on the first 2 days. The control group had a significantly higher net positive fluid balance on the first 3 days after randomization by roughly 1/2 liter per day. MAP and HR did not different significantly between the groups. There was a significant difference in the serum albumin concentration between the two groups, higher in the intervention group as expected.

There was no difference between the groups in all cause mortality at 28 days, length of ICU stay, length of hospital stay, duration of mechanical ventilation, duration of CRRT, or rate of new organ failure. In predefined subgroups there was a trend towards improvement in mortality in the saline group in trauma patients. This in combination with the significantly more pRBC given to the intervention group was explained by the authors as possibly due to greater hemodilution from the albumin as a known improved volume expander, with possible changes in coagulation in the albumin group. The authors note this is a secondary outcome and would need a more directed study to asses for any true mortality difference.

Study Conclusion: There is no difference in 28 day all cause mortality for patients receiving 4% albumin vs saline fluids.

Fusion Beat Bottom Line Impression: There is no mortality benefit to choosing albumin vs saline as resuscitation fluid.