Article 1
Restriction of Intravenous Fluid in ICU Patients with Septic Shock. Shahid A, Fanapour P, Gazmuri RJ. N Engl J Med. 2022 Sep1;387(9):856.
The current Surviving Sepsis Campaign guidelines recommend an initial fixed volume resuscitation of 30 ml/kg of body weight to be given in the first 3 hours from sepsis induced hypoperfusion. This recommendation is based on interventional studies that have described this as usual practice in the early stages of resuscitation and observational data that supports the practice. The average volume of fluid pre-randomization given in the PROCESS and ARISE trials was approximately 30 ml/kg and approximately 2 liters in the PROMISE trial. In some randomized trials involving sepsis and septic shock, high volumes of IV fluids have been associated with harm including worsening kidney injury, respiratory failure, and higher risk of death. This was an interventional randomized multicenter trial comparing restrictive vs. standard IV fluid in patients with septic shock.
The trial enrolled 1554 patients from 31 intensive care units in 8 different countries. The patients enrolled in the trial were critically ill. Septic shock was defined as suspected or confirmed infection, lactic acid level greater than 2, pressor requirements and at least 1 liter of IV fluid in the 24 hours before screening. Patients in the restrictive-fluid group were allowed four exceptions to receive fluid. First, if patients had severe hypoperfusion defined as lactic acid greater than 4, a mean arterial pressure less than 50 despite pressors, had mottling beyond edge of kneecap, or a urine output less than 0.1 ml/kg. Second, IV fluids could be given if there was documented ongoing fluid losses. Third, IV fluids could be given to correct dehydration and electrolyte deficiency if the enteral route was contraindicated. Fourth, IV fluids could be given to ensure a total daily intake of 1 liter. This study found no significant differences in 90-day mortality or serious adverse events of patients who received restrictive fluid therapy comparted to those who received standard therapy. The biggest limitation of this study is that there is not a large difference in the IV fluids given between the restrictive and standard group, a difference of only 2 liters of total fluid volumes after 5 days. This similar fluid administration between the two groups is not due to the liberal administration of fluid in the restrictive group but the relatively prudent use of fluids in the standard group. Compared to the 2016 CLASSIC trial, significantly less fluids were given in this trial. Patients in the standard group in this trial received approximately 2 liters less volume of fluid over the first 5 days than patients in the restricted group received in 2016. This suggests that over the past 6 years, clinicians may have begun to be more judicious in their fluid administration. The takeaway from this study is that judicious administration of IVF is likely not harmful in septic patients.
Article 2
(1->3)-B-D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial.
Bloos F, Held J, Kluge S, Simon P, Kogelmann K, de Heer G, Olaf Kuhn S, Jarczak D, Motsch J, et al. Intensive Care Med. 2022 Jul;48(7):865-875.
The Surviving Sepsis Campaign guidelines give a weak recommendation to use empiric antifungal therapy in patients at high risk of infection. This recommendation is based on studies that demonstrate that sepsis and septic shock due to fungi are associated with poor outcomes and that some observational studies suggested that prompt initiation of appropriate empiric antifungal therapy may be associated with a reduction in mortality. However, both a meta-analysis of empiric antifungal therapy vs no antifungal therapy in critically ill patients and the randomized control trial EMPIRICUS did not find a difference in survival with antifungal empiric therapy. (1à3)-B-D-Glucan (BDG) is an antigen found on multiple fungal agents including Candida, Aspergillus, and Pneumocystis jirovecii. This trial was designed to test whether BDG-guided therapy could more selectively identify those patients at highest risk for fungal infections and shorten the time to antifungal therapy thereby reducing mortality in invasive candida infection (ICI) sepsis.
This was a randomized multicenter trial comparing BDG-guided antifungal therapy vs standard of care in patients with sepsis at high risk of developing ICI in 18 German ICUs. Risk for ICI was defined as needing TPN, abdominal surgery within the last 7 days, previous antimicrobial therapy for more than 48 hours and previous renal replacement therapy. BDG-samples and blood cultures were taken concomitantly. The study had two arms. One arm was standard therapy. In the standard therapy arm, diagnosis of ICI was based on cultures only. BDG levels were taken in the standard arm, but they were not expedited or used to guide treatment. In the second arm, any patient with a BDG concentration >80pg/mL was treated with antifungals suitable for ICI. When culture results became available, patients with positive blood cultures were treated regardless of BDG results. Patients with two BDG positive results were treated regardless of blood culture results. Treatment was discontinued in patients with negative blood cultures with only one BDG positive sample. Empirical antifungal therapy was discouraged in both groups. The patients in this study were critically ill. Based on APACHE/SOFA/SAPS II scores patients in the study had a 40-50% mortality rate. The most frequent ICI risk factor for the patients in this study that led to patient inclusion was recent abdominal surgery (approximately 70%); however, the authors did not define the abdominal surgery by location. The trial’s lower than expected rate of ICI may be explained if the patients included did not have abdominal operations specific to the upper gastrointestinal tract. The rate of culture diagnosed ICI in the study was approximately 14% for both groups. While there was a twofold increase in frequency of antifungal therapy in the BDG group (99 of 172 vs 46 of 167), there was no significant mortality difference between the groups. Specificity of BDG was low in this trial. Various factors trigger false positives for BDG results including administration of antimicrobials and blood products including albumin. In the future, further studies with a higher cut-off may increase the specificity of the test to make it more useful or BDG may be used similarly to procalcitonin as a surrogate for withdrawal of empirically started antifungal treatment rather than early initiation. In conclusion, this study does not support BDG guidance for initiation of antifungal therapy.
Article 3
Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, Cook DJ, Battista MC, Day AG, et al. N Engl J Med. 2022 Jun 23;386(25):2387-2398.
Adjuncts for the treatment of sepsis have previously been sought. Recombinant activated protein C, use of HMG Co-A reductase inhibitors and now Vitamin C have all been trialed as additional therapy to the standard practice of volume resuscitation and vasopressor use in septic shock as outline in the Surviving Sepsis Campaign. Beginning in 2017, Marik et al published results suggestive of reduced mortality and preserved organ function when a cocktail of intravenous Vitamin C, corticosteroids and thiamine were used. Subsequent studies failed to demonstrate similar results. The CITRIS-ALI Trial (multi center double blinded placebo-controlled study) did not reach similar findings as Marik’s original study, no significant improvement in organ dysfunction or alterations in biochemical markers. Furthermore, recent meta-analyses have given mixed results. This trial was an interventional randomized blinded multi-center study comparing high dose IV Vitamin C to placebo in patients with septic shock.
This trial enrolled 863 patients from 35 adult medical- surgical ICU in 3 countries with all patients receiving vasopressors and having a proven or suspected infection as primary diagnosis as well as being admitted to the ICU no longer than 24 hours. Patients were randomized in a 1:1 ratio to receive with high dose Vitamin C or placebo. All involved study personal minus on site pharmacist were blinded. The intervention group received a bolus of Vitamin C of 50mg/kg in a 50ml solution of dextrose 5% in water or normal saline, with doses administered over 30 to 60 minutes every 6 hours (200 mg/kg/day) for the first 96 hours if the patient remained in the ICU for that duration. The control group received a matched placebo dose of dextrose 5% in water or normal saline. Additional care, was provided at the discretion of the local treatment team, including the use of corticosteroids and/or thiamine. This study found composite death or persistent organ dysfunction, defined as ongoing vasopressor use, mechanical ventilation or new need for renal replacement therapy on trial day 28, were significantly higher in the Vitamin C infusion group 44.5% (191/429) vs 38.5% (167/434, risk ratio, 1.21; 95% CI, 1.04-1.40; P=0.01). Secondary outcomes of death at 6 months, median number of days without organ dysfunction, SOFA scores, Health related Quality of life at 6 months and biomarkers at days 1,3, and 7 were not significantly different. Furthermore, safety outcomes of Stage 3 acute kidney injury, acute hemolysis and hypoglycemia were not significantly different and no subgroup differences. Limitations of this study are inherent to the primary outcome of composite death. 9 patients also failed to contribute data after randomization and no data regarding ARDS or underlying pathogens or treatment of the underlying infection were recorded. Additionally, the unlike the CITRIS-ALI, the current study did not specifically address ARDS, but included analysis of both organ dysfunction and biomarker derangement. Given the outcomes of both the CITRIS-ALI and this study, the use of Vitamin C in sepsis does not have a role.
Article 4
Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. Finfer S, Micallef S, Hammond N, Navarra L, Bellomo R, Billot L, Delaney A, Gallagher M, Gattas D, et al. N Engl J Med. 2022 Mar 3;386(9):815-826.
Fluid resuscitation of critically ill patients is a cornerstone of therapy administered in the ICU. The selection of fluid type and volume infused have all be linked to patient outcomes, thus multiple studies have examined both. As normal saline is the most utilized solution globally, any alternative fluid choice which exhibited improved clinical outcomes would result in significant practice changes. Several recent studies have suggested that there is an increased risk of acute kidney injury and in some cohorts’ death. These risks have translated into more balanced multielectrolyte solutions (BMES) being used in resuscitation although the literature (BaSICS trial, SMART trial, SPLIT trial and SALT trials) is homogenous with respect to the outcomes. This trial was an interventional double blinded randomized multi center study comparing 90-day mortality between critically ill patients who received BMES versus saline.
5037 patients were enrolled from 53 ICUs from Australia and New Zealand. Inclusion included patient whom required fluid resuscitation and were expected to be in the ICU for at least 3 days. Exclusion criteria were traumatic brain injury, patients who had specific fluid requirements, received disqualifying resuscitation (>500mL, was initially any volume but was amended), were at risk for imminent death or had a preexisting life expectancy <90 days. Treatment fluid was supplied in identical 1000ml bags which were indistinguishable from each other. For the following 90 days the patients received the assigned fluid for all resuscitate and needed crystalloid therapy in the ICU. Volume and rates of fluid administration was at the direction of the local treatment teams. Once discharged from the ICU fluid type was not directed by trial protocol. Primary outcome of unadjusted 90-day mortality was not different between groups, 21.8% BMES vs 22.0% saline. There are 530 deaths in each group. Unadjusted absolute risk reduction was -0.15 95% CI -3.6-3.3, with secondary analyses failing to demonstrate any change in primary outcome when those patients whom received >500ml of fluid either prior to or in the ICU post randomization. Adjusted analysis including gender, APACHE II, presence of sepsis and source of ICU admission did not demonstrate a difference. Secondary outcomes of new renal replacement therapy, need for vasopressor support, ventilator free days, days alive and maximum or increased creatinine level showed no significant difference. Subgroup analysis did not yield any difference for Age>65, AKI, Sepsis or APACHE II>25. The limitations of this study are related to enrollment and protocol adherence. As the authors note the initial recruitment size was adjusted as a result of the COVID 19 pandemic. The additional limitations were secondary to fluid administration and fluid type administered. There were a large number of lack of adherence to study protocol with 10.8% and 11.5% of patients in the BMES and saline groups respectively receiving non protocol fluid during resuscitation and 6.1% and 5.7% for maintenance fluid. The authors accommodated the deviations from the protocol utilizing post hoc probability weighting, which continued to demonstrate no difference in survival. Furthermore, once patients were discharged from the ICU fluid administration was off protocol and not recorded. This study when taken in toto with the additional studies comparing BMES to saline, demonstrates that the use of BMES is no different than saline with respect to 90-day mortality.
