COVID-19: more than a cytokine storm

 

COVID-19: more than a cytokine storm

 

by Giovanni Riva, Vincenzo Nasillo, Enrico Tagliafico, Tommaso Trenti, Patrizia Comoli and Mario Luppi 

 

Critical Care volume 24, Article number: 549 (2020)

 

In these first months of coronavirus disease-19 (COVID-19) pandemic, a mainstream pathogenetic hypothesis, likely stemming from early clinico-therapeutic observations, has been suggesting that severe COVID-19 may represent a sort of hyperimmune disorder, akin, in particular, to secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS) [1,2,3]. In this view, COVID-19-associated cytokine storm, with elevated plasma levels of IL-6, IL-1, and TNF-α, as well as ferritin and other inflammatory biomarkers, has been considered as a typical sign of sHLH/MAS, but the other “key feature” of COVID-19—the progressive lymphopenia with T cell exhaustion [4,5,6]—has largely been neglected. Of note, both CD4+ and CD8+ T lymphocytes were found to be remarkably decreased in severe cases (median 177.5 and 89.0 × 106/L, respectively), when compared to moderate ones (median 381.5 and 254.0 × 106/L, respectively), thus suggesting T cell lymphopenia may constitute a potential prognostic marker to be included in the monitoring of COVID-19 patients [4]. Frequencies of IFN-γ-producing CD4+ T cells (i.e., cytotoxic Th1 subset) tended to be lower in severe than in moderate illness (median 14.1% versus 22.8%, respectively), possibly indicating a progressive skew of the Th1/Th2 balance toward a tolerogenic response [4]. In addition, the percentages of both memory Th cells and regulatory T cells were found to decrease in severe cases [5].

Mechanical Ventilation During the Coronavirus Disease 2019 Pandemic: Combating the Tsunami of Misinformation From Mainstream and Social Media*

 

Mechanical Ventilation During the Coronavirus Disease 2019 Pandemic: Combating the Tsunami of Misinformation From Mainstream and Social Media*

 

by Savel, Richard H.; Shiloh, Ariel L.; Saunders, Paul C.; Kupfer, Yizhak 

 

Critical Care Medicine: September 2020 - Volume 48 - Issue 9 - p 1398-1400

 

In this issue of Critical Care Medicine, Auld et al (1) present some important data regarding ICU and hospital mortality of critically ill patients with coronavirus disease 2019 (COVID-19). Focusing on these results for their mechanically ventilated (MV) patients, we would begin by stating that their study was able to account for 147 of 165 or 89% of the patients, meaning that only 18 patients (11%) remained in hospital (ICU or otherwise) to potentially change the mortality results. This fact alone allows us to place significant weight in their results.

In terms of more detail, for patients on MV, ICU mortality was 33.9% (56/165), while their hospital mortality was similar at 35.8% (59/165). This is in dramatic contrast to recent studies demonstrating significantly higher mortality related to MV in COVID patients (2–4). Although there are multiple reasons as to why ICU and hospital mortality of MV patients is lower than that which has been reported in other COVID literature, we believe these are the key sentences of their article: “During the study period, ICU capacity enabled the timely admission of all patients requiring critical care to a COVID-ICU. Further, all patients admitted to a COVID-ICU were cared for by a traditional ICU care team led by a critical care-trained attending physician with standard (i.e., pre-COVID) ICU staffing ratios. There were no critical shortages in medications, ventilators, dialysis machines, or other critical care equipment.” Their medical system was not overwhelmed. The standard of care that was applied did not change, and it was not a mass casualty situation such as happened in other part of the world where ICU capacity needed to increase by a factor of three or greater. What are some of the relevant points to be raised?

The importance of airway and lung microbiome in the critically ill

 

The importance of airway and lung microbiome in the critically ill

 

by Ignacio Martin-Loeches, Robert Dickson, Antoni Torres, Håkan Hanberger, Jeffrey Lipman, Massimo Antonelli, Gennaro de Pascale, Fernando Bozza, Jean Louis Vincent, Srinivas Murthy, Michael Bauer, John Marshall, Catia Cilloniz and Lieuwe D. Bos

 

Critical Care volume 24, Article number: 537 (2020)

 

During critical illness, there are a multitude of forces such as antibiotic use, mechanical ventilation, diet changes and inflammatory responses that could bring the microbiome out of balance. This so-called dysbiosis of the microbiome seems to be involved in immunological responses and may influence outcomes even in individuals who are not as vulnerable as a critically ill ICU population. It is therefore probable that dysbiosis of the microbiome is a consequence of critical illness and may, subsequently, shape an inadequate response to these circumstances.

Bronchoscopic studies have revealed that the carina represents the densest site of bacterial DNA along healthy airways, with a tapering density with further bifurcations. This likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. Though bacterial DNA density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. The dogma of lung sterility also violated numerous observations that long predated culture-independent microbiology.

The body’s resident microbial consortia (gut and/or respiratory microbiota) affect normal host inflammatory and immune response mechanisms. Disruptions in these host-pathogen interactions have been associated with infection and altered innate immunity.

In this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome and ventilator-associated pneumonia.

Conflict Management in the ICU

 

Conflict Management in the ICU

 

by Kayser, Joshua B.; Kaplan, Lewis J. 

Critical Care Medicine: September 2020 - Volume 48 - Issue 9 - p 1349-1357

 

Objectives: To provide a concise review of data and literature pertaining to the etiologies of conflict in the ICU, as well as current approaches to conflict management.

Data Sources: Detailed search strategy using PubMed and OVID Medline for English language articles describing conflict in the ICU as well as prevention and management strategies.

Study Selection: Descriptive and interventional studies addressing conflict, bioethics, clinical ethics consultation, palliative care medicine, conflict management, and conflict mediation in critical care.

Data Extraction: Relevant descriptions or studies were reviewed, and the following aspects of each manuscript were identified, abstracted, and analyzed: setting, study population, aims, methods, results, and relevant implications for critical care practice and training.

Data Synthesis: Conflict frequently erupts in the ICU between patients and families and care teams, as well as within and between care teams. Conflict engenders a host of untoward consequences for patients, families, clinicians, and facilities rendering abrogating conflict a key priority for all. Conflict etiologies are diverse but understood in terms of a framework of triggers. Identifying and de-escalating conflict before it become intractable is a preferred approach. Approaches to conflict management include utilizing clinical ethics consultation, and palliative care medicine clinicians. Conflict Management is a new technique that all ICU clinicians may use to identify and manage conflict. Entrenched conflict appears to benefit from Bioethics Mediation, an approach that uses a neutral, unaligned mediator to guide parties to a mutually acceptable resolution.

Conclusions: Conflict commonly occurs in the ICU around difficult and complex decision-making. Patients, families, clinicians, and institutions suffer undesirable consequences resulting from conflict, establishing conflict prevention and resolution as key priorities. A variety of approaches may successfully identify, manage, and prevent conflict including techniques that are utilizable by all team members in support of clinical excellence.

Position Paper on Critical Care Pharmacy Services (Executive Summary): 2020 Update

 

Position Paper on Critical Care Pharmacy Services (Executive Summary): 2020 Update

 

by Lat, Ishaq; Paciullo, Christopher; Daley, Mitchell J.; MacLaren, Robert; Bolesta, Scott; McCann, Jennifer; Stollings, Joanna L.; Gross, Kendall; Foos, Sarah A.; Roberts, Russel J.; Acquisto, Nicole M.; Taylor, Scott; Bentley, Michael; Jacobi, Judith; Meyer, Tricia A.

 

Critical Care Medicine: September 2020 - Volume 48 - Issue 9 - p 1375-1382

 

Objectives: 

Provide a multiorganizational statement to update the statement from a paper in 2000 about critical care pharmacy practice and makes recommendations for future practice.

Design: 

The Society of Critical Care Medicine, American College of Clinical Pharmacy Critical Care Practice and Research Network, and the American Society of Health-Systems Pharmacists convened a joint task force of 15 pharmacists representing a broad cross-section of critical care pharmacy practice and pharmacy administration, inclusive of geography, critical care practice setting, and roles. The Task Force chairs reviewed and organized primary literature, outlined topic domains, and prepared the methodology for group review and consensus. A modified Delphi method was used until consensus (> 66% agreement) was reached for each practice recommendation. Previous position statement recommendations were reviewed and voted to either retain, revise, or retire. Recommendations were categorized by level of ICU service to be applicable by setting, and grouped into five domains: patient care, quality improvement, research and scholarship, training and education, and professional development.

Main Results: 

There are 82 recommendation statements: forty-four original recommendations and 38 new recommendation statements. Thirty-four recommendations were made for patient care, primarily relating to critical care pharmacist duties and pharmacy services. In the quality improvement domain, 21 recommendations address the role of the critical care pharmacist in patient and medication safety, clinical quality programs, and analytics. Nine recommendations were made in the domain of research and scholarship. Ten recommendations are in the domain of training and education and eight recommendations regarding professional development.

Conclusions: 

The statements recommended by this taskforce delineate the activities of a critical care pharmacist and the scope of pharmacy services within the ICU. Effort should be made from all stakeholders to implement the recommendations provided, with continuous effort toward improving the delivery of care for critically ill patients.

Conservative oxygen therapy for mechanically ventilated adults with suspected hypoxic ischaemic encephalopathy

 

Conservative oxygen therapy for mechanically ventilated adults with suspected hypoxic ischaemic encephalopathy

 

Intensive Care Medicine (2020) 18 August 2020

 

Purpose

Liberal use of oxygen may contribute to secondary brain injury in patients with hypoxic-ischaemic encephalopathy (HIE). However, there are limited data on the effect of different oxygen regimens on survival and neurological disability in HIE patients.

Methods

We undertook a post-hoc analysis of the 166 patients with suspected HIE enrolled in a trial comparing conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary endpoint for the current analysis was death or unfavourable neurological outcome at day 180. Key secondary outcomes were day 180 mortality, and cause-specific mortality.

Results

Patients with HIE allocated to conservative oxygen spent less time in the ICU with an SpO2 ≥ 97% (26 h [interquartile range (IQR) 13–45 vs. 35 h [IQR 19–70], absolute difference, 9 h; 95% CI − 21.4 to 3.4). A total of 43 of 78 patients (55.1%) assigned to conservative oxygen and 49 of 72 patients (68.1%) assigned to usual oxygen died or had an unfavourable neurological outcome at day 180; odds ratio 0.58; 95% CI 0.3–1.12; P = 0.1 adjusted odds ratio 0.54; 95% CI 0.23–1.26; P = 0.15. A total of 37 of 86 patients (43%) assigned to conservative oxygen and 46 of 78 (59%) assigned to usual oxygen had died by day 180; odds ratio 0.53; 95% CI 0.28–0.98; P = 0.04; adjusted odds ratio 0.56; 95% CI 0.25–1.23; P = 0.15. Cause-specific mortality was similar by treatment group.

Conclusions

Conservative oxygen therapy was not associated with a statistically significant reduction in death or unfavourable neurological outcomes at day 180. The potential for important benefit or harm from conservative oxygen therapy in HIE patients is not excluded by these data.

Neurological outcome after extracorporeal cardiopulmonary resuscitation for in-hospital cardiac arrest: a systematic review and meta-analysis

 

Neurological outcome after extracorporeal cardiopulmonary resuscitation for in-hospital cardiac arrest: a systematic review and meta-analysis

 

by Benjamin Yaël Gravesteijn, Marc Schluep, Maksud Disli, Prakriti Garkhail, Dinis Dos Reis Miranda, Robert-Jan Stolker, Henrik Endeman and Sanne Elisabeth Hoeks

 

Critical Care volume 24, Article number: 505 (2020)

 

Background

In-hospital cardiac arrest (IHCA) is a major adverse event with a high mortality rate if not treated appropriately. Extracorporeal cardiopulmonary resuscitation (ECPR), as adjunct to conventional cardiopulmonary resuscitation (CCPR), is a promising technique for IHCA treatment. Evidence pertaining to neurological outcomes after ECPR is still scarce.

Methods

We performed a comprehensive systematic search of all studies up to December 20, 2019. Our primary outcome was neurological outcome after ECPR at any moment after hospital discharge, defined by the Cerebral Performance Category (CPC) score. A score of 1 or 2 was defined as favourable outcome. Our secondary outcome was post-discharge mortality. A fixed-effects meta-analysis was performed.

Results

Our search yielded 1215 results, of which 19 studies were included in this systematic review. The average survival rate was 30% (95% CI 28–33%, I2 = 0%, p = 0.24). In the surviving patients, the pooled percentage of favourable neurological outcome was 84% (95% CI 80–88%, I2 = 24%, p = 0.90).

Conclusion

ECPR as treatment for in-hospital cardiac arrest is associated with a large proportion of patients with good neurological outcome. The large proportion of favourable outcome could potentially be explained by the selection of patients for treatment using ECPR. Moreover, survival is higher than described in the conventional CPR literature. As indications for ECPR might extend to older or more fragile patient populations in the future, research should focus on increasing survival, while maintaining optimal neurological outcome.

Letter: High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection

 

Letter: High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection

 

by Adriana Françozo de Melo and Mauricio Homem-de-Mello 

 

Critical Care volume 24, Article number: 500 (2020) 

 

The complete mechanism of action of the SARS-CoV-2 remains unclear. The severity of the disease is probably linked to the “cytokine storm” that leads to the acute respiratory distress syndrome. Cytokine storm is an overwhelming increase of several inflammatory markers at once, and it is a cause of severity in some conditions such as sepsis, acute pancreatitis, and multiple sclerosis, among others.

These conditions, characterized by a variety of inflammatory etiologies, have the common prognostic of hemodynamic abnormalities, multiple organs failure, and high mortality rates. Treatment of cytokine storm associated syndromes usually focuses in this environment: intensive care of hemodynamic parameters, uphold of damaged organs, and supervision of coagulopathy. The main cause of the cytokine induction, however, must yet be treated and is the main reason why in bacterial sepsis antibiotics are used.

High doses of intravenous vitamin C, higher than 6 g per day (however, even 15 g/day, or more, are reported), have demonstrated efficacy in treatment of sepsis and acute pancreatitis [1, 2]. To the best of our knowledge, oral formulations cannot exert the same effects.

In parenteral administration of high doses, vitamin C may decrease several inflammatory parameters (cytokines, cellular response, and homeostatic control), already observed in human and animal models. As adverse effect, ascorbic acid may cause oxalate accumulation in the kidneys that can be prevented with the concomitant use of thiamine.

Recovery Trial [3] recently finished its dexamethasone arm in severe COVID-19 patients and has shown decrease in mortality among patients that requires mechanical ventilation and support of oxygen. We are convinced about a possible synergistic effect of vitamin C and this corticosteroid.

Recently, Dr. Carr commented [4] about a new clinical trial in development in China, using intravenous vitamin C in high dose. This trial, registered by Dr. Peng (Wuhan University), is now closed, since new severe cases became rare in Wuhan. (Confirmed by Dr. Peng by e-mail, even if in clinicaltrials.gov the status of the trial is yet as “recruiting”).

Dr. Hernández and colleagues proposed a protocol including vitamin C in high dose to be used in COVID-19 patients [5]. However, the manuscript is in Spanish, decreasing the accessibility of the information.

The protocol using intravenous high dosage of vitamin C, thiamine and a glucocorticoid (as dexamethasone) seems to be useful, not expensive, with low risk of severe adverse effects. The aim is providing further discussion about the recovery of complicated cases of cytokine storm associated to the SARS-CoV-2.

Personalized Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome: Comparison Between Optimal Distribution of Regional Ventilation and Positive Transpulmonary Pressure

 

Personalized Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome: Comparison Between Optimal Distribution of Regional Ventilation and Positive Transpulmonary Pressure

by Scaramuzzo, Gaetano; Spadaro, Savino; Dalla Corte, Francesca; Waldmann, Andreas D.; Böhm, Stephan H.; Ragazzi, Riccardo; Marangoni, Elisabetta; Grasselli, Giacomo; Pesenti, Antonio; Volta, Carlo Alberto; Mauri, Tommaso

Critical Care Medicine: August 2020 - Volume 48 - Issue 8 - p 1148-1156

Objectives:

Different techniques exist to select personalized positive end-expiratory pressure in patients affected by the acute respiratory distress syndrome. The positive end-expiratory transpulmonary pressure strategy aims to counteract dorsal lung collapse, whereas electrical impedance tomography could guide positive end-expiratory pressure selection based on optimal homogeneity of ventilation distribution. We compared the physiologic effects of positive end-expiratory pressure guided by electrical impedance tomography versus transpulmonary pressure in patients affected by acute respiratory distress syndrome.

Design: Cross-over prospective physiologic study.

Setting: Two academic ICUs.

Patients: Twenty ICU patients affected by acute respiratory distress syndrome undergoing mechanical ventilation.

 Intervention: Patients monitored by an esophageal catheter and a 32-electrode electrical impedance tomography monitor underwent two positive end-expiratory pressure titration trials by randomized cross-over design to find the level of positive end-expiratory pressure associated with: 1) positive end-expiratory transpulmonary pressure (PEEPPL) and 2) proportion of poorly or nonventilated lung units (Silent Spaces) less than or equal to 15% (PEEPEIT). Each positive end-expiratory pressure level was maintained for 20 minutes, and afterward, lung mechanics, gas exchange, and electrical impedance tomography data were collected. Measurements and Main Results: PEEPEIT and PEEPPL differed in all patients, and there was no correlation between the levels identified by the two methods (Rs = 0.25; p = 0.29). PEEPEIT determined a more homogeneous distribution of ventilation with a lower percentage of dependent Silent Spaces (p = 0.02), whereas PEEPPL was characterized by lower airway—but not transpulmonary—driving pressure (p = 0.04). PEEPEIT was significantly higher than PEEPPL in subjects with extrapulmonary acute respiratory distress syndrome (p = 0.006), whereas the opposite was true for pulmonary acute respiratory distress syndrome (p = 0.03).

Conclusions: Personalized positive end-expiratory pressure levels selected by electrical impedance tomography– and transpulmonary pressure–based methods are not correlated at the individual patient level. PEEPPL is associated with lower dynamic stress, whereas PEEPEIT may help to optimize lung recruitment and homogeneity of ventilation. The underlying etiology of acute respiratory distress syndrome could deeply influence results from each method.

Biomarkers in critical care nutrition

 

Biomarkers in critical care nutrition

by Christian Stoppe, Sebastian Wendt, Nilesh M. Mehta, Charlene Compher, Jean-Charles Preiser, Daren K. Heyland and Arnold S. Kristof

Critical Care volume 24, Article number: 499 (2020) 

The goal of nutrition support is to provide the substrates required to match the bioenergetic needs of the patient and promote the net synthesis of macromolecules required for the preservation of lean mass, organ function, and immunity. Contemporary observational studies have exposed the pervasive undernutrition of critically ill patients and its association with adverse clinical outcomes. The intuitive hypothesis is that optimization of nutrition delivery should improve ICU clinical outcomes. It is therefore surprising that multiple large randomized controlled trials have failed to demonstrate the clinical benefit of restoring or maximizing nutrient intake. This may be in part due to the absence of biological markers that identify patients who are most likely to benefit from nutrition interventions and that monitor the effects of nutrition support. Here, we discuss the need for practical risk stratification tools in critical care nutrition, a proposed rationale for targeted biomarker development, and potential approaches that can be adopted for biomarker identification and validation in the field…

Letter: Blood type A associates with critical COVID-19 and death in a Swedish cohort

 

Letter: Blood type A associates with critical COVID-19 and death in a Swedish cohort

Critical Care volume 24, Article number: 496 (2020) 

Coronavirus disease 2019 (COVID-19) is primarily associated with respiratory failure, but both renal and circulatory failure is common in patients that require critical care or die of the disease [1]. A recently published GWAS showed a strong association between severe COVID-19 and the ABO blood group locus in a cohort from Italy and Spain, with a higher risk for patients with blood group A [2]. This is consistent with data on susceptibility to COVID-19 being associated with blood group in Chinese [3]. Although the GWAS dataset did not include data on mortality, there is a preliminary report in an American cohort that blood group A is associated with both severity of COVID-19 and death [4]…