Monitoring of sedation in mechanically ventilated patients using remote technology.

PURPOSE OF REVIEW: Two years of coronavirus disease 2019 (COVID-19) pandemic highlighted that excessive sedation in the ICU leading to coma and other adverse outcomes remains pervasive. There is a need to improve monitoring and management of sedation in mechanically ventilated patients. Remote technologies that are based on automated analysis of electroencephalogram (EEG) could enhance standard care and alert clinicians real-time when severe EEG suppression or other abnormal brain states are detected. RECENT FINDINGS: High rates of drug-induced coma as well as delirium were found in several large cohorts of mechanically ventilated patients with COVID-19 pneumonia. In patients with acute respiratory distress syndrome, high doses of sedatives comparable to general anesthesia have been commonly administered without defined EEG endpoints. Continuous limited-channel EEG can reveal pathologic brain states such as burst suppression, that cannot be diagnosed by neurological examination alone. Recent studies documented that machine learning-based analysis of continuous EEG signal is feasible and that this approach can identify burst suppression as well as delirium with high specificity. SUMMARY: Preventing oversedation in the ICU remains a challenge. Continuous monitoring of EEG activity, automated EEG analysis, and generation of alerts to clinicians may reduce drug-induced coma and potentially improve patient outcomes.

Hyperoxia and modulation of pulmonary vascular and immune responses in COVID-19.

Oxygen is the most commonly used therapy in hospitalized patients with COVID-19. In those patients who develop worsening pneumonia and acute respiratory distress syndrome (ARDS), high concentrations of oxygen may need to be administered for prolonged time periods, often together with mechanical ventilation. Hyperoxia, although lifesaving and essential for maintaining adequate oxygenation in the short term, may have adverse long-term consequences upon lung parenchymal structure and function. How hyperoxia per se impacts lung disease in COVID-19 has remained largely unexplored. Numbers of experimental studies have previously established that hyperoxia is associated with deleterious outcomes inclusive of perturbations in immunologic responses, abnormal metabolic function, and alterations in hemodynamics and alveolar barrier function. Such changes may ultimately progress into clinically evident lung injury and adverse remodeling and result in parenchymal fibrosis when exposure is prolonged. Given that significant exposure to hyperoxia in patients with severe COVID-19 may be unavoidable to preserve life, these sequelae of hyperoxia, superimposed on the cytopathic effects of SARS-CoV-2 virus, may well impact pathogenesis of COVID-19-induced ARDS.

Synapomorphic features of hepatic and pulmonary vasculatures include comparable purinergic signaling responses in host defense and modulation of inflammation.

Hepatosplanchnic and pulmonary vasculatures constitute synapomorphic, highly comparable networks integrated with the external environment. Given functionality related to obligatory requirements of "feeding and breathing," these organs are subject to constant environmental challenges entailing infectious risk, antigenic and xenobiotic exposures. Host responses to these stimuli need to be both protective and tightly regulated. These functions are facilitated by dualistic, high-low pressure blood supply of the liver and lungs, as well as tolerogenic characteristics of resident immune cells and signaling pathways. Dysregulation in hepatosplanchnic and pulmonary blood flow, immune responses, and microbiome implicate common pathogenic mechanisms across these vascular networks. Hepatosplanchnic diseases, such as cirrhosis and portal hypertension, often impact lungs and perturb pulmonary circulation and oxygenation. The reverse situation is also noted with lung disease resulting in hepatic dysfunction. Others, and we, have described common features of dysregulated cell signaling during liver and lung inflammation involving extracellular purines (e.g., ATP, ADP), either generated exogenously or endogenously. These metabokines serve as danger signals, when released by bacteria or during cellular stress and cause proinflammatory and prothrombotic signals in the gut/liver-lung vasculature. Dampening of these danger signals and organ protection largely depends upon activities of vascular and immune cell-expressed ectonucleotidases (CD39 and CD73), which convert ATP and ADP into anti-inflammatory adenosine. However, in many inflammatory disorders involving gut, liver, and lung, these protective mechanisms are compromised, causing perpetuation of tissue injury. We propose that interventions that specifically target aberrant purinergic signaling might prevent and/or ameliorate inflammatory disorders of the gut/liver and lung axis.

More of the Gut in the Lung: How Two Microbiomes Meet in ARDS.

In critically ill patients, lung and gut microbiomes undergo profound changes. Lung microbiome might become enriched with gut-associated microbes as recently demonstrated in sepsis and acute respiratory distress syndrome (ARDS). It has been proposed that in these conditions, bacteria from the gut might enter the lungs via translocation, a process facilitated by increased gut and alveolo-capillary permeability. In patients requiring mechanical ventilation after severe trauma, lung microbiome enrichment with gut-associated microbes was found to correlate with the development of ARDS. The lungs in ARDS are increasingly susceptible to opportunistic infections which can further perpetuate alveolar inflammation and injury. Undoubtedly, more research on the gut-lung crosstalk in critically ill patients is needed to identify causal relationships between the altered microbiome, infections, inflammation, and acute lung injury. With further insights, this area of investigation could lead to the development of novel, microbiome-targeted, and immunomodulation strategies with the potential to improve outcomes of critically ill patients with sepsis, trauma, and ARDS.

Towards cytoprotection in the peritransplant period.

As a consequence of ischemia-reperfusion injury of whole organ transplants and hypoxia-anoxia of cell transplants, transplantation unavoidably triggers adverse, cytodestructive inflammation within the allograft. Interventions that dampen adverse inflammation may limit the extent and duration of this injury, and preserve tissue function. Moreover, these interventions should create a milieu that guides many donor-activated T cells into a tissue-protective phenotype, thus promoting graft acceptance or even tolerance. Hence, it is useful, maybe crucial, to identify the measures that minimize deleterious consequences of acute and chronic inflammation upon allograft. Several therapies that inhibit activity of certain proinflammatory cytokines or expression of tissue "danger signals", while sustaining or potentially enhancing the expression of tissue-intrinsic anti-inflammatory and cytoprotective genes, are awaiting clinical trials or are already approved for the treatment of immuno-inflammatory disorders. If applied in the peritransplant period, such cytoprotective regimens may increase the pool of donor organs suitable for transplantation, reduce the overall requirements for maintenance immunosuppression and perhaps foster transplant tolerance.

Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival.

The promise of islet cell transplantation cannot be fully realized in the absence of improvements in engraftment of resilient islets. The marginal mass of islets surviving the serial peritransplant insults may lead to exhaustion and thereby contribute to an unacceptably high rate of intermediate and long-term graft loss. Hence, we have studied the effects of treatment with alpha 1-antitrypsin (AAT) in a syngeneic nonautoimmune islet graft model. A marginal number of syngeneic mouse islets were transplanted into nonautoimmune diabetic hosts and islet function was analyzed in control and AAT treated hosts. In untreated controls, marginal mass islet transplants did not restore euglycemia. Outcomes were dramatically improved by short-term AAT treatment. Transcriptional profiling identified 1,184 differentially expressed transcripts in AAT-treated hosts at 3 d posttransplantation. Systems-biology-based analysis revealed AAT down-regulated regulatory hubs formed by inflammation-related molecules (e.g., TNF-α, NF-κB). The conclusions yielded by the systems-biology analysis were rigorously confirmed by QRT-PCR and immunohistology. These data suggest that short-term AAT treatment of human islet transplant recipients may be worthy of a clinical trial.

Pulmonary natural killer T cells play an essential role in mediating hyperoxic acute lung injury.

Critically ill patients are routinely exposed to high concentrations of supplemental oxygen for prolonged periods of time, which can be life-saving in the short term, but such exposure also causes severe lung injury and increases mortality. To address this therapeutic dilemma, we studied the mechanisms of the tissue-damaging effects of oxygen in mice. We show that pulmonary invariant natural killer T (iNKT) cells are unexpectedly crucial in the development of acute oxygen-induced lung injury. iNKT cells express high concentrations of the ectonucleotidase CD39, which regulates their state of activation. Both iNKT cell-deficient (Jα18(-/-)) and CD39-null mice tolerate hyperoxia, compared with wild-type control mice that exhibit severe lung injury. An adoptive transfer of wild-type iNKT cells into Jα18(-/-) mice results in hyperoxic lung injury, whereas the transfer of CD39-null iNKT cells does not. Pulmonary iNKT cell activation and proliferation are modulated by ATP-dependent purinergic signaling responses. Hyperoxic lung injury can be induced by selective P2X7-receptor blockade in CD39-null mice. Our data indicate that iNKT cells are involved in the pathogenesis of hyperoxic lung injury, and that tissue protection can be mediated through ATP-induced P2X7 receptor signaling, resulting in iNKT cell death. In conclusion, our data suggest that iNKT cells and purinergic signaling should be evaluated as potential novel therapeutic targets to prevent hyperoxic lung injury.

CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease.

Purinergic signaling and associated ectonucleotidases, such as CD39 and CD73, have been implicated in the pathogenesis of inflammatory bowel disease (IBD). CD39 is known to be a Treg memory cell marker, and here we determine the phenotype and function of CD73(+) CD4(+) T lymphocytes in patients with IBD. We describe elevated levels of CD73(+) CD4(+) T cells in the peripheral blood and intestinal lamina propria of patients with active IBD. The functional phenotype of these CD73(+) CD4(+) T cells was further determined by gene expression, ecto-enzymatic activity, and suppressive assays. Increased numbers of CD73(+) CD4(+) T cells in the periphery and lamina propria were noted during active inflammation, which returned to baseline levels following anti-TNF treatment. Peripheral CD73(+) CD4(+) T cells predominantly expressed CD45RO, and were enriched with IL-17A(+) cells. The CD73(+) CD4(+) cell population expressed higher levels of RORC, IL-17A, and TNF, and lower levels of FOXP3 and/or CD25, than CD73(-) CD4(+) T cells. Expression of CD73 by peripheral CD4(+) T cells was increased by TNF, and decreased by an anti-TNF monoclonal antibody (infliximab). In vitro, these peripheral CD73(+) CD4(+) T cells did not suppress proliferation of CD25(-) effector cells, and expressed higher levels of pro-inflammatory markers. We conclude that the CD73(+) CD4(+) T-cell population in patients with active IBD are enriched with cells with a T-helper type 17 phenotype, and could be used to monitor disease activity during treatment.

An examination of sedation requirements and practices for mechanically ventilated critically ill patients with COVID-19.

PURPOSE: Preliminary reports suggest that critically ill patients with coronavirus disease 2019 (COVID-19) infection requiring mechanical ventilation may have markedly increased sedation needs compared with critically ill, mechanically ventilated patients without COVID-19. We conducted a study to examine sedative use for this patient population within multiple intensive care units (ICUs) of a large academic medical center. METHODS: A retrospective, single-center cohort study of sedation practices for critically ill patients with COVID-19 during the first 10 days of mechanical ventilation was conducted in 8 ICUs at Massachusetts General Hospital, Boston, MA. The study population was a sequential cohort of 86 critically ill, mechanically ventilated patients with COVID-19. Data characterizing the sedative medications, doses, drug combinations, and duration of administration were collected daily and compared to published recommendations for sedation of critically ill patients without COVID-19. The associations between drug doses, number of drugs administered, baseline patient characteristics, and inflammatory markers were investigated. RESULTS: Among the study cohort, propofol and hydromorphone were the most common initial drug combination, with these medications being used on a given day in up to 100% and 88% of patients, respectively. The doses of sedative and analgesic infusions increased for patients over the first 10 days, reaching or exceeding the upper limits of published dosage guidelines for propofol (48% of patients), dexmedetomidine (29%), midazolam (7.7%), ketamine (32%), and hydromorphone (38%). The number of sedative and analgesic agents simultaneously administered increased over time for each patient, with more than 50% of patients requiring 3 or more agents by day 2. Compared with patients requiring 3 or fewer agents, patients requiring more than 3 agents were of younger age, had an increased body mass index, had increased serum ferritin and lactate dehydrogenase concentrations, had a lower Pao2:Fio2 (ratio of arterial partial pressure of oxygen to fraction of inspired oxygen), and were more likely to receive neuromuscular blockade. CONCLUSION: Our study confirmed the clinical impression of elevated sedative use in critically ill, mechanically ventilated patients with COVID-19 relative to guideline-recommended sedation practices in other critically ill populations.

Standard Sedation and Sedation With Isoflurane in Mechanically Ventilated Patients With Coronavirus Disease 2019.

OBJECTIVES: To describe sedative and analgesic drug utilization in a cohort of critically ill patients with coronavirus disease 2019 and compare standard sedation with an alternative approach using inhaled isoflurane. DESIGN: This was a retrospective cohort study designed to compare doses of sedatives between ICU patients receiving standard IV sedation and patients receiving mixed sedation including inhaled isoflurane. Data were obtained from electronic medical records. SETTING: ICU at large academic medical center where mechanical ventilation was delivered with Draeger Apollo (Draeger Medical, Telford, PA) anesthesia machines. PATIENTS: Consecutive adult patients (≥ 18 yr) with confirmed coronavirus disease 2019 admitted to ICU between April 2, 2020, and May 4, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-five mechanically ventilated patients were included in the study, with a mean (sd) age of 59.4 (12.8) years. Twenty-three patients (65.7%) were men. Seventeen patients (48.6%) received standard IV sedation, whereas 18 (51.4%) also received isoflurane. The mean duration of mechanical ventilation (sd) was 23.3 (11.6) days in the standard sedation group and 23.8 (12.5) days in the isoflurane group. Mean (sd) duration of isoflurane exposure was 5.61 (2.99) days, representing 29.1% of total sedation time (sd, 20.4). Cumulative opioid exposure did not differ between the standard sedation and isoflurane sedation groups (mean morphine milligram equivalent 6668 [sd, 1,346] vs 6678 [sd, 2,000] mg). However, the initiation of isoflurane in patients was associated with decreased utilization of propofol (mean daily amount 3,656 [sd, 1,635] before vs 950 [sd, 1,804] mg during isoflurane) and hydromorphone (mean daily amount 48 [sd, 30] before vs 23 [sd, 27] mg). CONCLUSIONS: In the subjects that received isoflurane, its use was associated with significant decreases in propofol and hydromorphone infusions.