Adjunctive Vasopressors in Patients with Septic Shock: Protocol for a Systematic Review and Meta-Analysis.

Background: Over one-third of patients with septic shock have adjunctive vasopressors added to first-line vasopressors. However, no randomized trial has detected improved mortality with adjunctive vasopressors. Published systematic reviews and meta-analysis have sought to inform the use of adjunctive vasopressors, yet each published review has limitations that hinder its interpretation. This review aims to overcome the limitations of previous reviews by systematically synthesizing the direct evidence for adjunctive vasopressor therapy use in adult patients with septic shock. Methods: We will conduct a systematic review and meta-analysis of randomized controlled trials evaluating adjunctive vasopressors (vasopressin analogues, angiotensin II, hydroxocobalamin, methylene blue, and catecholamine analogues) in adult patients with septic shock. Relevant studies will be identified through comprehensive searches of MEDLINE, Embase, CENTRAL, and reference lists of previous systematic reviews. Only randomized trials comparing adjunctive vasopressors (>75% of subjects on vasopressors at enrollment) to standard care vasopressors in adults with septic shock (>75% of subjects having septic shock) will be included. Titles and abstracts will be screened, full-text articles assessed for eligibility, and data extracted from included studies. Outcomes of interest include short-term mortality, intermediate-term mortality, kidney replacement therapy, digital/peripheral ischemia, and venous thromboembolism. Pairwise meta-analysis using a random-effects model will be utilized to estimate the risk ratio for the outcomes. Risk of bias will be adjudicated with the Cochrane Risk of Bias 2 tool, and GRADE will be used to rate the certainty of the body of evidence. Discussion: Although adjunctive vasopressors are commonly used in patients with septic shock their effect on patient-important outcomes is unclear. This study is planned to use rigorous systematic review methodology, including strict adhere to established guidelines, in order to overcome limitations of previously-published reviews and inform clinical practice and treatment guidelines for the use of adjunctive vasopressors in adults with septic shock. Systematic review registration: PROSPERO CRD4202327984.

Assessment of Opioid-Induced Immunomodulation in Experimental and Clinical Sepsis.

Opioids remain a standard supportive therapy in patients admitted to the ICU with sepsis. However, as preclinical models indicate an association between opioid exposure and immunosuppression, the use of this class of drugs warrants investigation. The objective of this study was to investigate whether opioid exposure causes immunosuppression in patients with sepsis, and to use a murine sepsis model to determine the effects of opioid exposure on secondary infection. HYPOTHESIS: We hypothesized opioid exposure would be associated with immunosuppression in patients with sepsis and secondary infection in a murine sepsis model. METHODS AND MODELS: This was a two-phase preclinical and clinical study. The clinical phase included a subgroup of patients with sepsis from an existing randomized controlled trial while the preclinical phase used a murine model of sepsis with C57BL/6 mice. In the clinical phase, a post hoc analysis was performed in subjects receiving fentanyl versus no opioid receipt. In the preclinical phase, a murine cecal slurry-induced sepsis model followed by secondary infection was used. Mice were randomized to fentanyl versus no fentanyl concomitantly. RESULTS: In clinical sepsis, a significant decrease in interleukin-23 (IL-23) level in patients with fentanyl exposure was observed and lower IL-23 was associated with mortality (p < 0.001). Other measured cytokines showed no significant differences. Concomitant fentanyl exposure during murine sepsis was associated with a significantly higher bacterial burden (p < 0.001) after secondary infection; however, immune cell counts and plasma cytokine levels were largely unaffected by fentanyl. INTERPRETATION AND CONCLUSIONS: Minimal alterations in cytokines were seen with opioid exposure during clinical sepsis. In a preclinical model, opioid exposure during sepsis was associated with ineffective bacterial clearance upon secondary infection. Further studies are warranted to evaluate the immunomodulatory role of opioids and their implications, especially in the post-sepsis period.

Current Practice Review in the Management of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) presents as an acute inflammatory lung injury characterized by refractory hypoxemia and non-cardiac pulmonary edema. An estimated 10% of patients in the intensive care unit and 25% of those who are mechanically ventilated are diagnosed with ARDS. Increased awareness is warranted as mortality rates remain high and delays in diagnosing ARDS are common. The COVID-19 pandemic highlights the importance of understanding ARDS management. Treatment of ARDS can be challenging due to the complexity of the disease state and conflicting existing evidence. Therefore, it is imperative that pharmacists understand both pharmacologic and non-pharmacologic treatment strategies to optimize patient care. This narrative review provides a critical evaluation of current literature describing management practices for ARDS. A review of treatment modalities and supportive care strategies will be presented.

Contemporary targeted temperature management: Clinical evidence and controversies.

Advancements in cardiac arrest and post-cardiac arrest care have led to improved survival to hospital discharge. While survival to hospital discharge is an important clinical outcome, neurologic recovery is also a priority. With the advancement of targeted temperature management (TTM), the American Heart Association guidelines for post-cardiac arrest care recommend TTM in patients who remain comatose after return of spontaneous circulation (ROSC). Recently, the TTM2 randomized controlled trial found no significant difference in neurologic function and mortality at 6-months between traditional hypothermia to 33°C versus 37.5°C. While TTM has been evaluated for decades, current literature suggests that the use of TTM to 33° when compared to a protocol of targeted normothermia does not result in improved outcomes. Instead, perhaps active avoidance of fever may be most beneficial. Extracorporeal cardiopulmonary resuscitation and membrane oxygenation can provide a means of both hemodynamic support and TTM after ROSC. This review aims to describe the pathophysiology, physiologic aspects, clinical trial evidence, changes in post-cardiac arrest care, potential risks, as well as controversies of TTM.

Major Publications in the Critical Care Pharmacotherapy Literature: 2021.

To summarize the most impactful articles relevant to the pharmacotherapy of critically ill adult patients published in 2021. DATA SOURCE: PubMed/MEDLINE. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critical care patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2021, and December 31, 2021. DATA EXTRACTION: Candidate articles were organized by clinical domain based on the emerging themes from all studies. A modified Delphi process was applied to obtain consensus on the most impactful publication within each clinical domain based on overall contribution to scientific knowledge and novelty to the literature. DATA SYNTHESIS: The search revealed 830 articles, of which 766 were excluded leaving 64 candidate articles for the Delphi process. These 64 articles were organized by clinical domain including: emergency/neurology, cardiopulmonary, nephrology/fluids, infectious diseases, metabolic, immunomodulation, and nutrition/gastroenterology. Each domain required the a priori defined three Delphi rounds. The resultant most impactful articles from each domain included five randomized controlled trials and two systematic review/meta-analyses. Topics studied included sedation during mechanical ventilation, anticoagulation in COVID-19, extended infusion beta-lactams, interleukin-6 antagonists in COVID-19, balanced crystalloid resuscitation, vitamin C/thiamine/hydrocortisone in sepsis, and promotility agents during enteral feeding. CONCLUSIONS: This synoptic review provides a summary and perspective of the most impactful articles relevant to the pharmacotherapy of critically ill adults published in 2021.

Assessment of prescribed vs. achieved fluid balance during continuous renal replacement therapy and mortality outcome.

BACKGROUND: Fluid management during continuous renal replacement therapy (CRRT) requires accuracy in the prescription of desired patient fluid balance (FBGoal) and precision in the attainable patient fluid balance (FBAchieved). Herein, we examined the association of the gap between prescribed vs. achieved patient fluid balance during CRRT (%FBGap) with hospital mortality in critically ill patients. METHODS: Cohort study of critically ill adults with acute kidney injury (AKI) requiring CRRT and a prescription of negative fluid balance (mean patient fluid balance goal of negative ≥0.5 liters per day). Fluid management parameters included: 1) NUF (net ultrafiltration rate); 2) FBGoal; 3) FBAchieved; and 4) FBGap (% gap of fluid balance achieved vs. goal), all adjusted by patient's weight (kg) and duration of CRRT (hours). RESULTS: Data from 653 patients (median of 102.2 patient-hours of CRRT) were analyzed. Mean (SD) age was 56.7 (14.6) years and 61.9% were male. Hospital mortality rate was 64%. Despite FBGoal was similar in patients who died vs. survived, survivors achieved greater negative fluid balance during CRRT than non-survivors: median FBAchieved -0.25 [-0.52 to -0.05] vs. 0.06 [-0.26 to 0.62] ml/kg/h, p<0.001. Median NUF was lower in patients who died vs. survived: 1.06 [0.63-1.47] vs. 1.22 [0.82-1.69] ml/kg/h, p<0.001, and median %FBGap was higher in patients who died (112.8%, 61.5 to 165.7) vs. survived (64.2%, 30.5 to 91.8), p<0.001. In multivariable models, higher %FBGap was independently associated with increased risk of hospital mortality: aOR (95% CI) 1.01 (1.01-1.02), p<0.001. NUF was not associated with hospital mortality when adjusted by %FBGap and other clinical parameters: aOR 0.96 (0.72-1.28), p = 0.771. CONCLUSIONS: Higher %FBGap was independently associated with an increased risk of hospital mortality in critically ill adults with AKI on CRRT in whom clinicians prescribed negative fluid balance via CRRT. %FBGap represents a novel quality indicator of CRRT delivery that could assist with operationalizing fluid management interventions during CRRT.

Timing of vasoactive agents and corticosteroid initiation in septic shock.

Septic shock remains a health care concern associated with significant morbidity and mortality. The Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock recommend early fluid resuscitation and antimicrobials. Beyond initial management, the guidelines do not provide clear recommendations on appropriate time to initiate vasoactive therapies and corticosteroids in patients who develop shock. This review summarizes the literature regarding time of initiation of these interventions. Clinical data regarding time of initiation of these therapies in relation to shock onset, sequence of treatments with regard to each other, and clinical markers evaluated to guide initiation are summarized. Early-high vasopressor initiation within first 6 h of shock onset is associated with lower mortality. Following norepinephrine initiation, the exact dose and timing of escalation to adjunctive vasopressor agents are not well elucidated in the literature. However, recent data indicate that timing may be an important factor in initiating vasopressors and adjunctive therapies, such as corticosteroids. Norepinephrine-equivalent dose and lactate concentration can aid in determining when to initiate vasopressin and angiotensin II in patients with septic shock. Future guidelines with clear recommendations on the time of initiation of septic shock therapies are warranted.

Pirfenidone in Progressive Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Background: The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical practice guidelines for interstitial lung disease (ILD). Objective: To conduct a systematic review to evaluate existing ILD literature to determine whether patients with progressive pulmonary fibrosis (PPF) should be treated with the antifibrotic pirfenidone. Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through December 2020 for studies using pirfenidone to treat patients with PPF. Data Extraction: Mortality, disease progression, lung function, and adverse event data were extracted. Meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation Working Group approach was used to assess the quality of evidence. Synthesis: Two studies met inclusion criteria. Meta-analyses revealed that changes in forced vital capacity (FVC) percent predicted (mean difference [MD], 2.3%; 95% confidence interval [CI], 0.5-4.1%), the FVC in milliliters (MD, 100.0 ml; 95% CI, 98.1-101.9 ml), and the 6-minute-walk distance in meters (MD, 25.2 m; 95% CI, 8.3-42.1 m) all favored pirfenidone over placebo. The changes in the diffusing capacity of the lung for carbon monoxide (DLCO) in millimoles per kilopascal per minute (MD, 0.40 mmol/kPa/min; 95%, CI 0.10-0.70 mmol/kPa/min) and risk of DLCO declining more than 15% (relative risk [RR], 0.27; 95% CI, 0.08-0.95) also favored pirfenidone. The risks of gastrointestinal discomfort (RR, 1.83; 95% CI, 1.29-2.60) and photosensitivity (RR, 4.88; 95% CI, 1.09-21.83) were higher with pirfenidone. The quality of the evidence was low or very low according to the Grading of Recommendations, Assessment, Development and Evaluation criteria, depending on the outcome. Conclusions: Pirfenidone use in patients with PPF is associated with a statistically significant decrease in disease progression and with protection of lung function. However, there is very low certainty in the estimated effects because of limitations in the available evidence. Primary Source of Funding: Funded by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.

Nintedanib in Progressive Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Background: The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical practice guidelines for interstitial lung disease (ILD). Objective: To conduct a systematic review to evaluate existing ILD literature to determine whether patients with progressive pulmonary fibrosis (PPF) should be treated with the antifibrotic nintedanib. Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through December 2020 for studies using nintedanib to treat patients with PPF. Data Extraction: Mortality, disease progression, and adverse event data were extracted, and meta-analyses performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group approach was used to assess the quality of evidence. Synthesis: Two relevant studies were selected. The annual decline in forced vital capacity was less in the nintedanib arm in the overall study population (mean difference [MD], 107 ml/yr; 95% confidence interval [CI], 65.4 to 148.5 ml/yr) and in the subgroups with usual interstitial pneumonia (UIP) pattern of pulmonary fibrosis (MD, 128.2 ml/yr; 95% CI, 70.8 to 185.6 ml/yr), non-UIP patterns of pulmonary fibrosis (MD, 75.3 ml/yr; 95% CI, 15.5 to 135.0 ml/yr), fibrotic connective tissue disease-related ILD (MD, 106.2 ml/yr; 95% CI, 10.6 to 201.9 ml/yr), fibrotic idiopathic nonspecific interstitial pneumonia (MD, 141.7 ml/yr; 95% CI, 46.0 to 237.4 ml/yr), and fibrotic occupational ILD (MD, 252.8 ml/yr; 95% CI, 79.2 to 426.5 ml/yr), but not fibrotic hypersensitivity pneumonitis (MD, 72.9 ml/yr; 95% CI, -8.9 to 154.7 ml/yr), fibrotic sarcoidosis (MD, -20.5 ml/yr; 95% CI, -337.1 to 296.1 ml/yr), or unclassified fibrotic ILD (MD, 68.5 ml/yr; 95% CI, -31.3 to 168.4 ml/yr) when compared with placebo. Gastrointestinal side effects were common. Quality of evidence for the outcomes ranged from very low to moderate GRADE. Conclusions: Nintedanib use in patients with PPF is associated with a statistically significant decrease in disease progression but increase in gastrointestinal side effects regardless of the radiographic pattern of pulmonary fibrosis. However, limitations in the available evidence lead to low certainty in these effect estimates and make definitive conclusions about the differential effects by subtype of ILD difficult to determine. Primary Source of Funding: Funded by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.

Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.

Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results:1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.

Evaluation of Bivalirudin as the Primary Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation for SARS-CoV-2-Associated Acute Respiratory Failure.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a potential option for the management of severe acute respiratory failure secondary to COVID-19. Conflicting the use of this therapy is the known coagulopathy within COVID-19, leading to an incidence of venous thrombotic events of 25% to 49%. To date, limited guidance is available on optimal anticoagulation strategies in this population. OBJECTIVE: The purpose of this study was to evaluate the utilization of a pharmacist-driven bivalirudin dosing protocol for anticoagulation in the setting of ECMO for COVID-19-associated respiratory failure. METHODS: This was a single-center retrospective chart review over a 9-month period of patients receiving bivalirudin while on ECMO. All patients with acute respiratory failure requiring ECMO with a positive SARS-CoV-2 polymerase chain reaction were included. Bivalirudin was dosed via aPTT monitoring after a starting dose of 0.2 or 0.3 mg/kg/h. RESULTS: There were 33 patients included in this study, all receiving mechanical ventilation. The most common starting dose of bivalirudin was 0.2 mg/kg/h, with an average time to therapeutic range of 20 hours. Compared to previous reports, rates of bleeding were low at 15.1%, and 6.1% of patients developed a new venous thromboembolic event while on ECMO. ECMO survival was 51.5%, with an ICU mortality rate of 48.5%. CONCLUSION AND RELEVANCE: In the first published report of its use within this population, bivalirudin was found to be a viable choice for anticoagulation in those patients on ECMO for severe respiratory failure secondary to COVID-19.

Major Publications in the Critical Care Pharmacotherapy Literature: 2020.

OBJECTIVES: To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2020. DATA SOURCES: The Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update group screened 36 journals monthly for impactful publications. STUDY SELECTION: The group reviewed a total of 119 articles during 2020 according to relevance for practice. DATA EXTRACTION: Articles were selected with consensus and importance to clinical practice from those included in the monthly Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. The group reviewed articles according to Grading of Recommendations, Assessment, Development, and Evaluations criteria. Articles with a 1A grade were selected. DATA SYNTHESIS: Several trials were summarized, including two meta-analyses and five original research trials. Original research trials evaluating vitamin C, hydrocortisone, and thiamine versus hydrocortisone in sepsis, the use of nonsedation strategies, dexmedetomidine in cardiac surgery, remdesivir for severe acute respiratory syndrome coronavirus 2, and thrombectomy in acute ischemic stroke. Two meta-analyses determining the impact of norepinephrine initiation in patients with septic shock and the use of corticosteroids in severe acute respiratory syndrome coronavirus 2 was included. CONCLUSIONS: This clinical review provides summary and perspectives of clinical practice impact on influential critical care pharmacotherapy publications in 2020.

Pharmacotherapy in Coronavirus Disease 2019 and Risk of Secondary Infections: A Single-Center Case Series and Narrative Review.

Since the onset of the coronavirus disease 2019 pandemic, immune modulators have been considered front-line candidates for the management of patients presenting with clinical symptoms secondary to severe acute respiratory syndrome coronavirus 2 infection. Although heavy emphasis has been placed on early clinical efficacy, we sought to evaluate the impact of pharmacologic approach to coronavirus disease 2019 within the ICU on secondary infections and clinical outcomes. DATA SOURCES: PubMed (inception to March 2021) database search and manual selection of bibliographies from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles relevant to coronavirus disease 2019, management of severe acute respiratory syndrome coronavirus 2-associated respiratory failure, and prevalence of secondary infections with pharmacotherapies were selected. The MeSH terms "COVID-19," "secondary infection," "SARS-CoV-2," "tocilizumab," and "corticosteroids" were used for article identification. Articles were narratively synthesized for this review. DATA SYNTHESIS: Current data surrounding the use of tocilizumab and/or corticosteroids for coronavirus disease 2019 management are limited given the short follow-up period and conflicting results between studies. Further complicating the understanding of immune modulator role is the lack of definitive understanding of clinical impact of the immune response in coronavirus disease 2019. CONCLUSIONS: Based on the current available literature, we suggest prolonged trials and follow-up intervals for those patients managed with immune modulating agents for the management of coronavirus disease 2019.

The immunomodulatory effects of opioids and implications for intensive care unit populations.

Analgesia within the intensive care unit (ICU) is often achieved via the utilization of opioids in alignment with current guidelines. Recent evidence has not only demonstrated the potential impact of opioids in suppression of immune function, but also the potential harm of immunosuppression of patients within the ICU. Despite the potential immunosuppression seen with opioids in this at-risk population, their use remains frequent. In this review, we highlight the potential immunomodulatory impact of opioids within the critically ill and considerations for their use.

Comparison of fixed dose versus train-of-four titration of cisatracurium in acute respiratory distress syndrome.

PURPOSE: To compare the ventilatory and clinical outcomes associated with a fixed-dose cisatracurium infusion versus a titrated infusion strategy in patients with Acute Respiratory Distress Syndrome (ARDS). MATERIALS AND METHODS: Single-center, retrospective, cohort study in a medical ICU of a tertiary care academic medical center. Adult patients ≥18 years old with a continuous infusion of cisatracurium for ≥12 h for treatment of ARDS were included. The primary outcome was the PaO2 /FiO2 ratio assessed at 24 and 48 h following cisatracurium initiation. Secondary outcomes included amount of average dose of drug administered, 28-day ventilator-free days, LOS, and hospital mortality. RESULTS: 167 patients were included; median baseline PaO2/FiO2 was 97 (76-146), median SOFA score of 9 (7-11), and ICU mortality was 71/167 (43%). In a mixed-effects model, fixed dose and titrated cisatracurium associated with similar changes in PaO2/FiO2 assessed at 24 and 48 h (p = 0.316). Fixed-dose was associated with a >3-fold increase in drug exposure (average dose 6.4 (5.4-8.0) vs. 2.0 (1.5-2.8) mcg/kg/min; p < 0.001, respectively). No differences were observed in secondary clinical endpoints. CONCLUSION: Fixed-dose cisatracurium was associated with similar ventilatory and clinical outcomes compared to titrated strategy, yet it was associated with a 3-fold increase in dose administered.

Evaluation of Evidence, Pharmacology, and Interplay of Fluid Resuscitation and Vasoactive Therapy in Sepsis and Septic Shock.

ABSTRACT: We sought to review the pharmacology of vasoactive therapy and fluid administration in sepsis and septic shock, with specific insight into the physiologic interplay of these agents. A PubMed/MEDLINE search was conducted using the following terms (vasopressor OR vasoactive OR inotrope) AND (crystalloid OR colloid OR fluid) AND (sepsis) AND (shock OR septic shock) from 1965 to October 2020. A total of 1,022 citations were reviewed with only relevant clinical data extracted. While physiologic rationale provides a hypothetical foundation for interaction between fluid and vasopressor administration, few studies have sought to evaluate the clinical impact of this synergy. Current guidelines are not in alignment with the data available, which suggests a potential benefit from low-dose fluid administration and early vasopressor exposure. Future data must account for the impact of both of these pharmacotherapies when assessing clinical outcomes and should assess personalization of therapy based on the possible interaction.