Practices in Triage and Transfer of Critically Ill Patients: A Qualitative Systematic Review of Selection Criteria.

OBJECTIVES: To identify and appraise articles describing criteria used to prioritize or withhold a critical care admission. DATA SOURCES: PubMed, Embase, Medline, EBM Reviews, and CINAHL Complete databases. Gray literature searches and a manual review of references were also performed. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. STUDY SELECTION: We sought all articles and abstracts of original research as well as local, provincial, or national policies on the topic of ICU resource allocation. We excluded studies whose population of interest was neonatal, pediatric, trauma, or noncritically ill. Screening of 6,633 citations was conducted. DATA EXTRACTION: Triage and/or transport criteria were extracted, based on type of article, methodology, publication year, and country. An appraisal scale was developed to assess the quality of identified articles. We also developed a robustness score to further appraise the robustness of the evidence supporting each criterion. Finally, all criteria were extracted, evaluated, and grouped by theme. DATA SYNTHESIS: One-hundred twenty-nine articles were included. These were mainly original research (34%), guidelines (26%), and reviews (21%). Among them, we identified 200 unique triage and transport criteria. Most articles highlighted an exclusion (71%) rather than a prioritization mechanism (17%). Very few articles pertained to transport of critically ill patients (4%). Criteria were classified in one of four emerging themes: patient, condition, physician, and context. The majority of criteria used were nonspecific. No study prospectively evaluated the implementation of its cited criteria. CONCLUSIONS: This systematic review identified 200 criteria classified within four themes that may be included when devising triage programs including the coronavirus disease 2019 pandemic. We identified significant knowledge gaps where research would assist in improving existing triage criteria and guidelines, aiming to decrease arbitrary decisions and variability.

Data initiatives supporting critical care research and quality improvement in Canada: an environmental scan and narrative review.

PURPOSE: Collection and analysis of health data are crucial to achieving high-quality clinical care, research, and quality improvement. This review explores existing hospital, regional, provincial and national data platforms in Canada to identify gaps and barriers, and recommend improvements for data science. SOURCE: The Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group undertook an environmental survey using list-identified names and keywords in PubMed and the grey literature, from the Canadian context. Findings were grouped into sections, corresponding to geography, purpose, and patient sub-group initiatives, using a narrative qualitative approach. Emerging themes, impressions, and recommendations towards improving data initiatives were generated. PRINCIPAL FINDINGS: In Canada, the Canadian Institute for Health Information Discharge Abstract Database contains high-level clinical data on every adult and child discharged from acute care facilities; however, it does not contain data from Quebec, critical care-specific severity of illness risk-adjustment scores, physiologic data, or data pertaining to medication use. Provincially mandated critical care platforms in four provinces contain more granular data, and can be used to risk adjust and link to within-province data sets; however, no inter-provincial collaborative mechanism exists. There is very limited infrastructure to collect and link biological samples from critically ill patients nationally. Comprehensive international clinical data sets may inform future Canadian initiatives. CONCLUSION: Clinical and biological data collection among critically ill patients in Canada is not sufficiently coordinated, and lags behind other jurisdictions. An integrated and inclusive critical care data platform is a key clinical and scientific priority in Canada.

The safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T mutation, supports a Phase 1/2 clinical study.

INTRODUCTION: SPL84 is an inhaled antisense oligonucleotide (ASO) in development for the treatment of cystic fibrosis (CF) patients carrying the 3849 + 10kb C->T (3849) mutation. To support the initiation of the first clinical study, a full battery of safety and toxicology studies were performed. RESEARCH DESIGN AND METHODS: SPL84 was administered by inhalation to mice and monkeys to determine the no observed adverse effect level (NOAEL) and establish sufficient safety margins for the starting clinical dose. RESULTS: There were no preclinical safety findings with SPL84; no related clinical signs, nor any effect on body weight, food consumption, or clinical pathology. The microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled compounds. Systemic exposure in both species was low. The NOAEL for mice and monkeys was the highest administered dose in both species, resulting in safety margins ~ 40X the proposed starting clinical dose. CONCLUSION: These successful results supported the initiation of a phase 1/2 clinical study of SPL84 (ongoing), assessing the safety, tolerability, and pharmacokinetics of a single ascending dose in healthy subjects to be followed by assessment of safety, tolerability, pharmacokinetics, and preliminary efficacy of multiple ascending doses in CF patients carrying the 3849 mutation.

Spatial and temporal expression of CCR3 and the common beta chain of the IL-3, IL-5 and GM-CSF receptor in the nasal epithelium and lymphoid tissues in a rat model of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) and asthma are closely related conditions that often co-exist, and are characterized by a Th2 inflammatory response where eosinophils occupy a predominant role. Strategies aimed at blocking signaling through the CC chemokine receptor 3 (CCR3) and/or the common beta chain of the IL-3, IL-5 and GM-CSF receptor (ßc) efficiently reduced eosinophilic inflammation in both animal models and in asthmatic patients. This study was therefore aimed at characterizing the spatio-temporal expression pattern of ßc and CCR3 using a rat model of AR. METHODS: Sensitized rats were challenged with ovalbumin and sacrificed at 2h, 8h, 16h or 24h post-challenge. Nasal tissues were microdissected and used for mRNA quantification by QPCR, while histological evaluation determined the presence of eosinophils and mucosubstances. RESULTS: Allergen-induced recruitment of eosinophils in the distal septum and turbinates was maximal at 8h post-challenge, and was correlated with 2-4-fold increase in CCR3 and ßc mRNA. Recruitment of eosinophils was also accompanied by upregulated IL-5, IL-4Rα, TNF-α and IFN-γ mRNA at early time-points. In contrast, IL-13 and MUC5AC mRNA, as well as production of mucosubstances were maximal at 24h. CONCLUSIONS: ßc and CCR3 could play important roles in the modulation of the allergic response, and their inhibition may represent a promising therapeutic approach for AR.

A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice.

BACKGROUND: Recent development in the field of COPD has focused on strategies aimed at reducing the underlying inflammation through selective inhibition of the phosphodiesterase type IV (PDE4) isoform. Although the anti-inflammatory and bronchodilator activity of selective PDE4 inhibitors has been well documented, their low therapeutic ratio and dose-dependent systemic side effects have limited their clinical utility. This study examined the effect of 2'-deoxy-2'-Fluoro-beta-D-Arabinonucleic Acid (FANA)-containing antisense oligonucleotides (AON) targeting the mRNA for the PDE4B/4D and 7A subtypes on lung inflammatory markers, both in vitro and in vivo. METHODS: Normal human bronchial epithelial (NHBE) cells were transfected with FANA AON against PDE4B/4D and 7A alone or in combination. mRNA levels for target PDE subtypes, as well as secretion of pro-inflammatory chemokines were then measured following cell stimulation. Mice were treated with combined PDE4B/4D and 7A AON via endo-tracheal delivery, or with roflumilast via oral delivery, and exposed to cigarette smoke for one week. Target mRNA inhibition, as well as influx of inflammatory cells and mediators were measured in lung lavages. A two-week smoke exposure protocol was also used to test the longer term potency of PDE4B/4D and 7A AONs. RESULTS: In NHBE cells, PDE4B/4D and 7A AONs dose-dependently and specifically inhibited expression of their respective target mRNA. When used in combination, PDE4B/4D and 7A AONs significantly abrogated the cytokine-induced secretion of IL-8 and MCP-1 to near baseline levels. In mice treated with combined PDE4B/4D and 7A AONs and exposed to cigarette smoke, significant protection against the smoke-induced recruitment of neutrophils and production of KC and pro-MMP-9 was obtained, which was correlated with inhibition of target mRNA in cells from lung lavages. In this model, PDE AONs exerted more potent and broader anti-inflammatory effects against smoke-induced lung inflammation than roflumilast. Moreover, the protective effect of PDE4B/4D and 7A AON was maintained when a once-weekly treatment schedule was used. CONCLUSION: These results indicate that inhaled AON against PDE4B/4D and 7A have unique effects on biomarkers that are believed to be important in the pathophysiology of COPD, which supports further development as a potential therapy in this disease.

Improvements in siRNA properties mediated by 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA).

RNA interference (RNAi) has emerged recently as an efficient mechanism for specific gene silencing. Short double-stranded small interfering RNAs (siRNAs) are now widely used for cellular or drug target validation; however, their use for silencing clinically relevant genes in a therapeutic setting remains problematic because of their unfavourable metabolic stability and pharmacokinetic properties. To address some of these concerns, we have investigated the properties of siRNA modified with 2'-deoxy-2'-fluoro-beta-d-arabinonucleotide units (araF-N or FANA units). Here we provide evidence that these modified siRNAs are compatible with the intracellular RNAi machinery and can mediate specific degradation of target mRNA. We also show that the incorporation of FANA units into siRNA duplexes increases activity and substantially enhances serum stability of the siRNA. A fully modified sense 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA) strand when hybridized to an antisense RNA (i.e. FANA/RNA hybrid) was shown to be 4-fold more potent and had longer half-life in serum (approximately 6 h) compared with an unmodified siRNA (<15 min). While incorporation of FANA units is well tolerated throughout the sense strand of the duplex, modifications can also be included at the 5' or 3' ends of the antisense strand, in striking contrast to other commonly used chemical modifications. Taken together, these results offer preliminary evidence of the therapeutic potential of FANA modified siRNAs.

Effects of antisense oligodeoxynucleotides targeting CCR3 on the airway response to antigen in rats.

Asthma is characterized by airway hyperresponsiveness (AHR) and inflammation, consisting predominantly of eosinophils within the airway lumen and walls. Eosinophil recruitment to the airways is mediated mainly by eotaxin and other chemokines that bind to the CC-chemokine receptor-3 (CCR3), which is highly expressed on eosinophils. This study assessed whether topical inhibition of CCR3 mRNA expression by phosphorothioate antisense oligodeoxynucleotides (AS-ODNs) modifies pulmonary eosinophilia and AHR in an antigen-induced allergic asthma model in Brown Norway (BN) rats. Results show that specific inhibition of CCR3 expression in the lungs by an AS-ODN (AS4) reduced total eosinophil infiltration and the percentage of eosinophils into the airways of ovalbumin challenged rats. Moreover, reduction in CCR3 mRNA levels was correlated with a decrease in CCR3 protein in lung tissue. In addition, AS4 treatment had no effect on circulating eosinophils or on eosinophils in the bone marrow. Finally, AHR was significantly decreased in AS4-treated rats when compared with rats treated with a mismatch AS-ODN. In conclusion, inhibition of the expression of CCR3 decreased pulmonary eosinophilia and reduced AHR after antigen challenge in rats. Topical inhibition of CCR3 expression, using an AS-ODN, could represent a novel approach for the treatment of asthma.

Characterization of antisense oligonucleotides comprising 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA): specificity, potency, and duration of activity.

Antisense oligonucleotides (AON) are being developed for a wide array of therapeutic applications. Significant improvements in their serum stability, target affinity, and safety profile have been achieved with the development of chemically modified oligonucleotides. Here, we compared 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA)-containing AONs with phosphorothioate oligodeoxynucleotides (PS-DNA), 2'-O-methyl-RNA/DNA chimeras and short interfering RNAs (siRNA) with respect to their target knockdown efficacy, duration of action and resistance to nuclease degradation. Results show that two different configurations of FANA/DNA chimeras (altimers and gapmers) were found to have potent antisense activity. Specific target inhibition was observed with both FANA configurations with an estimated EC50 value comparable to that of an siRNA but 20-to 100-fold lower than the other commonly used AONs. Moreover, the FANA/DNA chimeras showed increased serum stability that was correlated with sustained antisense activity for up to 4 days. Taken together, these results indicate that chimeric FANA/DNA AONs are promising new tools for therapeutic gene silencing when increased potency and duration of action are required.

Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector.

We describe the in vitro isolation and expansion of cells capable of forming neurosphere-like aggregates from human adult bone marrow. Cells within these passaged spheroids can differentiate into astrocytes, specific neuronal subtypes, and oligodendrocytes and have gene expression profiles similar to human fetal brain-derived neural stem cells. Genetically modified neural-competent bone marrow-derived cells efficiently migrate toward distant sites of brain injury and tumor in vivo, where they differentiate and express therapeutic transgenes when transplanted into the brains of mice. These studies suggest that adult bone marrow may serve as a large reservoir for autologous neural stem-like cells for future therapeutic strategies.

Targeted delivery in primary and metastatic brain tumors: summary report of the seventh annual meeting of the Blood-Brain Barrier Disruption Consortium.

The November 2000 NIH report of the Brain Tumor Progress Review Group identified delivering and targeting therapeutic agents as a priority in the treatment of malignant brain tumors. For this reason, the seventh annual Blood-Brain Barrier Disruption Consortium meeting, partially funded by an NIH R13 Grant, focused on recent advances in targeted delivery to the central nervous system, clinical trials for primary and metastatic brain tumors using enhanced chemotherapy delivery, and strategies to lessen the toxicities associated with dose intensive treatments, using thiols.

Clinical expert panel on monitoring potential lung toxicity of inhaled oligonucleotides: consensus points and recommendations.

Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs.

Oligonucleotides: a multi-targeted approach for the treatment of respiratory diseases.

Reversing inflammatory lung disease remains the foremost challenge in treating respiratory diseases such as asthma and chronic obstructive pulmonary disease. Reducing (or modifying) the underlying inflammatory process with mono-target drugs has proven challenging. The era of designing 'one target for one disease' has evolved such that a growing body of evidence suggests a single drug that is capable of specifically targeting multiple targets and pathways would be better at arresting progression of these respiratory diseases and be an important advancement in current therapy. Oligonucleotide-based drugs represent an emerging class of drug candidates. Their properties, a broader range of targets over conventional small-molecule drugs and recent clinical proof-of-concept support their development as novel multi-targeting agents for the treatment of respiratory diseases.

Oligonucleotides: New therapeutic approaches for asthma and chronic obstructive pulmonary disease.

Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases. There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action. Oligonucleotides may be divided in two groups based on their main mechanism of action: (i) RNA-targeting; and (ii) protein-targeting. Antisense oligonucleotides and siRNAs, both of which belong to the RNA-targeting group, and the immunostimulatory sequence-based drugs, which are members of the protein-targeting group, are progressing through clinical trials. In principle, the development of these agents is facilitated by a series of significant advantages, such as those associated with delivery to the lung via inhalation, and targeting to the site of action, resulting in reduced levels of systemic exposure. Although no oligonucleotide-based drug has been approved for the treatment of asthma or COPD, this class of compounds holds significant promise in the treatment of these two diseases. Several oligonucleotide drug candidates have been evaluated in the clinic with no significant adverse safety findings, while clinical proof of concept based on short-term inhalation protocols in challenge models in humans has also been established.

TPI 1020, a novel anti-inflammatory, nitric oxide donating compound, potentiates the bronchodilator effects of salbutamol in conscious guinea-pigs.

Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.

Emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease.

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are disorders of the airways largely related to the presence of persistent inflammation. The approval of inhaled corticosteroids in the early 1970s pioneered a new age of therapy in treating chronic inflammatory airway diseases. This was the first time that an anti-inflammatory product was available to reduce the characteristic lung inflammation in airways and the associated obstruction, inflammation and hyper-responsiveness. Fast forward 40 years: corticosteroids are still an important therapeutic intervention; however, they exhibit limited use in moderate to severe asthma and COPD. Oligonucleotide therapies are an emerging class which include the antisense, the RNAi (siRNA and miRNA), the immunomodulatory, the aptamer and the decoy approaches. As these approaches are rather recent in the respiratory field, most are still early in development. Nevertheless, with limitations of current small molecule therapies and the hurdles faced with biologics, the use of oligonucleotides is relevant and the door is open to the development of this category of therapeutics. This review focuses on the major classes of oligonucleotides that are currently in late stage preclinical or clinical development for the treatment of asthma and COPD, and discusses the implications for their use as therapies for respiratory diseases.

Advantageous toxicity profile of inhaled antisense oligonucleotides following chronic dosing in non-human primates.

TPI ASM8 and TPI 1100 are two products containing modified phosphorothioate antisense oligonucleotides (AONs), which are undergoing development for the treatment of asthma and chronic obstructive pulmonary disease (COPD), respectively. TPI ASM8 is comprised of two AONs, one targeting the human chemokine receptor 3 (CCR3) and the other targeting the common beta-chain of the IL-3/IL-5/GM-CSF receptors. TPI 1100 is also a dual-AON compound targeting the phosphodiesterase (PDE) 4 and 7 isotypes. For both products, the AONs are present in a 1:1 ratio by weight. Both products will be administered by inhalation to patients, and TPI ASM8 is currently undergoing Phase 2 clinical trials. As part of the safety assessment of both products, the toxicity and disposition (i.e., pharmacokinetics of the AON components in plasma and tissues) were investigated in 14-day inhalation studies in monkeys at doses ranging from 0.05 to 2.5mg/kg/day. Results indicated that both products were safe and well tolerated at all dose levels. Reversible treatment-related alterations were only observed at the high dose levels tested and were limited to changes in the respiratory tract which were characterized primarily by the presence of alveolar macrophages in the absence of a generalized inflammatory response. Plasma pharmacokinetic profiles showed very low plasma concentrations, and no plasma accumulation was observed after repeated doses. While significant amounts of the AONs of both TPI ASM8 and TPI 1100 were measured in trachea and lung, only limited amounts of the AONs could be measured in kidney and liver, which, in combination with the low plasma level data, is indicative of very low systemic exposure. Taken together, these results demonstrate that these two new AON-based products are safe and that delivery via the inhaled route achieves localized deposition in the pulmonary tract with very limited systemic exposure and reduced toxicity compared to other routes of AON administration.