Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial

Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems. Keywords: automated clinical care; clinical; clinicians; closed-loop; computers; decision-support

Total and subgenomic RNA viral load in patients infected with SARS-CoV-2 Alpha, Delta, and Omicron variants

Background: SARS-CoV-2 genomic and subgenomic RNA levels are frequently used as a correlate of infectiousness. The impact of host factors and SARS-CoV-2 lineage on RNA viral load is unclear. Methods: Total nucleocapsid (N) and subgenomic N (sgN) RNA levels were measured by RT-qPCR in specimens from 3,204 individuals hospitalized with COVID-19 at 21 hospitals. RT-qPCR cycle threshold (Ct) values were used to estimate RNA viral load. The impact of time of sampling, SARS-CoV-2 variant, age, comorbidities, vaccination, and immune status on N and sgN Ct values were evaluated using multiple linear regression. Results: Ct values at presentation for N (mean ±standard deviation) were 24.14±4.53 for non-variants of concern, 25.15±4.33 for Alpha, 25.31±4.50 for Delta, and 26.26±4.42 for Omicron. N and sgN RNA levels varied with time since symptom onset and infecting variant but not with age, comorbidity, immune status, or vaccination. When normalized to total N RNA, sgN levels were similar across all variants. Conclusions: RNA viral loads were similar among hospitalized adults, irrespective of infecting variant and known risk factors for severe COVID-19. Total N and subgenomic RNA N viral loads were highly correlated, suggesting that subgenomic RNA measurements adds little information for the purposes of estimating infectivity. Keywords: SARS-CoV-2; subgenomic RNA; variants of concern; viral load

Obesity does not alter the pharmacokinetics of drotrecogin alfa (activated) in severe sepsis.

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was \u3e135 kg were excluded from th

Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.

BACKGROUND: In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had

mRNA Vaccine Effectiveness Against COVID-19 Hospitalization Among Solid Organ Transplant Recipients

Background: The study objective was to evaluate 2 and 3 dose COVID-19 mRNA vaccine effectiveness (VE) in preventing COVID-19 hospitalization among adult solid organ transplant (SOT) recipients. Methods: 21-site case-control analysis of 10,425 adults hospitalized March-December 2021. Cases were hospitalized with COVID-19; controls were hospitalized for an alternative diagnosis (SARS-CoV-2 negative). Participants were classified as: SOT recipient (n=440), other immunocompromising condition (n=1684), or immunocompetent (n=8301). VE against COVID-19 associated hospitalization was calculated as 1-adjusted odds ratio of prior vaccination among cases compared with controls. Results: Among SOT recipients, VE was 29% (95% CI: -19 to 58%) for 2 doses and 77% (95% CI: 48 to 90%) for 3 doses. Among patients with other immunocompromising conditions, VE was 72% (95% CI: 64 to 79%) for 2 doses and 92% (95% CI: 85 to 95%) for 3 doses. Among immunocompetent patients, VE was 88% (95% CI: 87 to 90%) for 2 doses and 96% (95% CI: 83 to 99%) for 3 doses. Conclusion: Effectiveness of COVID-19 mRNA vaccines was lower for SOT recipients than immunocompetent people and those with other immunocompromising conditions. Among SOT recipients, vaccination with 3 doses of an mRNA vaccine led to substantially greater protection than 2 doses. Keywords: COVID-19; SARS-CoV-2; immunocompromised; solid organ transplantation; vaccination; vaccine effectiveness

Prognostic Language in Critical Neurologic Illness: A Multicenter Mixed-Methods Study

Background and objectives: There are no evidence-based guidelines for discussing prognosis in critical neurologic illness, but in general, experts recommend that clinicians communicate prognosis using estimates, such as numerical or qualitative expressions of risk. Little is known about how real-world clinicians communicate prognosis in critical neurologic illness. Our primary objective was to characterize prognostic language clinicians used in critical neurologic illness. We additionally explored whether prognostic language differed between prognostic domains (e.g., survival, cognition). Methods: We conducted a multi-center cross-sectional mixed-methods study analyzing de-identified transcripts of audio-recorded clinician-family meetings for patients with neurologic illness requiring intensive care (e.g., intracerebral hemorrhage, traumatic brain injury, severe stroke) from seven U.S. Centers: Two coders assigned prognostic language type and domain of prognosis to each clinician prognostic statement. Prognostic language was coded as probabilistic (estimating the likelihood of an outcome occurring, e.g., 80% survive ; She\u27ll probably survive ) or non-probabilistic (characterizing outcomes without offering likelihood; e.g., She may not survive ). We applied univariate and multivariable binomial logistic regression to examine independent associations between prognostic language and domain of prognosis. Results: We analyzed 43 clinician-family meetings for 39 patients with 78 surrogates and 27 clinicians. Clinicians made 512 statements about survival (median 0/meeting [IQR 0;2]), physical function (median 2[IQR 0;7]), cognition (median 2[IQR 0;6]) and overall recovery (median 2[IQR 1;4]). Most statements were non-probabilistic (316/512 [62%]), 10/512(2%) of prognostic statements offered numeric estimates, and 21% (9/43) of family meetings only contained nonprobabilistic language. Compared to statements about cognition, statements about survival (OR 2.50[95% CI 1.01, 6.18]; p=0.048) and physical function (OR 3.22[1.77, 5.86]; p\u3c0.001) were more frequently probabilistic. Statements about physical function were less likely to be uncertainty-based than statements about cognition (OR 0.34 [95% CI 0.17-0.66]; p=0.002). Discussion: Clinicians preferred not to use estimates (either numeric or qualitative) when discussing critical neurologic illness prognosis, especially when they discussed cognitive outcomes. These findings may inform interventions to improve prognostic communication in critical neurologic illness