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The Cochrane Database of Systematic... Jun 2023Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review. (Review)
Review
BACKGROUND
Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
OBJECTIVES
To investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Most recent search: 25 April 2022.
SELECTION CRITERIA
We included randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross-over trials we stipulated a one-week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross-over trials, we chose to treat the trials as if they were parallel.
MAIN RESULTS
We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo (stable disease) We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low-certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD -0.60, 95% CI -1.00 to -0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo. Hypertonic saline versus control (acute exacerbation) Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI -14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events. Hypertonic saline versus rhDNase Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV % predicted after three weeks (MD 1.60%, 95% CI -7.96 to 11.16; 1 trial, 14 participants; very low-certainty evidence). At three months, rhDNase may lead to a greater increase in FEV % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low-certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported. Hypertonic saline versus amiloride One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low-certainty evidence). Hypertonic saline compared with sodium-2-mercaptoethane sulphonate (Mistabron®) One trial (29 participants) compared hypertonic saline to sodium-2-mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low-certainty evidence). Hypertonic saline versus mannitol One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-certainty evidence). Hypertonic saline versus xylitol Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV % predicted or median time to exacerbation between groups (very low-certainty evidence). No other outcomes were reported in the review. Hypertonic saline 7% versus hypertonic saline 3% We are uncertain whether there was an improvement in FEV % predicted after treatment with 7% hypertonic saline compared with 3% (very low-certainty evidence).
AUTHORS' CONCLUSIONS
We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.
Topics: Adult; Child; Child, Preschool; Humans; Administration, Inhalation; Amiloride; Cystic Fibrosis; Mannitol; Saline Solution, Hypertonic; Sodium; Xylitol; Infant; Adolescent; Young Adult; Middle Aged
PubMed: 37319354
DOI: 10.1002/14651858.CD001506.pub5 -
Modern Pathology : An Official Journal... Dec 2022Reflex mismatch repair immunohistochemistry (MMR IHC) testing for MLH1, PMS2, MSH2 and MSH6 is used to screen for Lynch syndrome. Recently MMR-deficiency (MMRd) has been... (Meta-Analysis)
Meta-Analysis
Reflex mismatch repair immunohistochemistry (MMR IHC) testing for MLH1, PMS2, MSH2 and MSH6 is used to screen for Lynch syndrome. Recently MMR-deficiency (MMRd) has been approved as a pan-cancer predictive biomarker for checkpoint inhibitor therapy, leading to a vast increase in the use of MMR IHC in clinical practice. We explored whether immunohistochemical staining with PMS2 and MSH6 can be used as a reliable substitute. This two-antibody testing algorithm has the benefit of saving tissue, cutting costs and saving time. PubMed, Embase and Cochrane library were systematically searched for articles reporting on MMR IHC. The weighed percentage of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was analyzed using a random effects model meta-analysis in R. The search yielded 1704 unique citations, of which 131 studies were included, describing 9014 patients. A weighed percentage of 1.1% (95% CI 0.53-18.87, I = 87%) of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was observed. In the six articles with the main aim of investigating the two-antibody testing algorithm all MMRd cases were detected with the two-antibody testing algorithm, there were no cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone. This high detection rate of MMRd of the two-antibody testing algorithm supports its use in clinical practice by specialized pathologists. Staining of all four antibodies should remain the standard in cases with equivocal results of the two-antibody testing algorithm. Finally, educational sessions in which staining pattern pitfalls are discussed will continue to be important.
Topics: Humans; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; DNA-Binding Proteins; Colorectal Neoplasms; DNA Mismatch Repair; Biomarkers, Tumor; Algorithms
PubMed: 36104536
DOI: 10.1038/s41379-022-01149-w -
Journal of Clinical Immunology Aug 2022Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3...
BACKGROUND
Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans.
OBJECTIVES
To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human.
METHODS
We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24 2022.
RESULTS
We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients.
CONCLUSIONS
DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).
Topics: Antibodies, Antineutrophil Cytoplasmic; Chromatin; DNA; Endodeoxyribonucleases; Humans; Inflammatory Bowel Diseases; Interferon Type I; Interferons; Lupus Erythematosus, Systemic; Lupus Nephritis; Phenotype; Vasculitis
PubMed: 35670985
DOI: 10.1007/s10875-022-01287-5 -
Intestinal and extraintestinal neoplasms in patients with NTHL1 tumor syndrome: a systematic review.Familial Cancer Oct 2022Germline biallelic pathogenic variants (PVs) in NTHL1 have since 2015 been associated with the autosomal recessive tumor predisposition syndrome: NTHL1 tumor syndrome or... (Review)
Review
Germline biallelic pathogenic variants (PVs) in NTHL1 have since 2015 been associated with the autosomal recessive tumor predisposition syndrome: NTHL1 tumor syndrome or NTHL1-associated polyposis. In this systematic review, we aim to systematically investigate the phenotypic and genotypic spectrum of the condition including occurrence of both benign and malignant tumors. The databases PubMed, EMBASE, and Scopus were searched. The search was conducted the 25th of august 2021. We included patients with germline PVs, both heterozygous and homo-/compound heterozygous carriers. Twenty-one papers were selected including 47 patients with biallelic PVs in NTHL1 in 32 families. Twenty-three out of 47 patients (49%) were diagnosed with colorectal cancer (CRC) (mean age: 55, range: 31-73) and 12 out of 22 female patients (55%) were diagnosed with breast cancer (mean age: 49, range: 36-63). Apart from three, all patients who underwent a colonoscopy, had colonic adenomas (93%), and three patients (6%) had duodenal adenomatosis. We also identified 158 heterozygous carriers of germline PVs in NTHL1. Twenty-six out of 68 (38%) heterozygous carriers, who underwent colonoscopy, had colonic polyps or adenomas. Twenty-nine heterozygous carriers (18%) were diagnosed with CRC and 59 (49%) with breast cancer. We observed a high frequency of early onset CRC and breast cancer in patients with NTHL1 tumor syndrome. Subsequently, colorectal, breast, and endometrial cancer screening programs are recommended for NTHL1 biallelic carriers. Trial registry PROSPERO: CRD42021275159.
Topics: Female; Humans; Middle Aged; Adenoma; Adenomatous Polyposis Coli; Breast Neoplasms; Colorectal Neoplasms; Deoxyribonuclease (Pyrimidine Dimer); Genetic Predisposition to Disease; Germ-Line Mutation; Male; Adult; Aged
PubMed: 35292903
DOI: 10.1007/s10689-022-00291-3 -
Pulmonary Pharmacology & Therapeutics Dec 2021Multiple studies describing the benefits of intrapleural fibrinolytic over placebo and DNase therapy have been published, but few have been published on intrapleural... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Multiple studies describing the benefits of intrapleural fibrinolytic over placebo and DNase therapy have been published, but few have been published on intrapleural fibrinolytic and DNase therapy.
OBJECTIVE
Our meta-analysis aims to compare the outcomes of surgical intervention, mortality, and hospital length of stay between intrapleural fibrinolytic and DNase therapy with either intrapleural fibrinolytic or DNase therapy alone in patients with pleural space infections.
METHODS
We searched Pubmed, EMBASE, Web of Science, and Cochrane library databases for observational studies and randomized controlled trials (RCTs) containing comparative data for hospitalized adults and children with pleural infections receiving intrapleural therapy of fibrinolytic and DNase versus those receiving intrapleural fibrinolytic or DNase alone. Meta-analysis was performed using the Review Manager software, and heterogeneity was tested using I statistics.
RESULTS
A total of 2 cohorts and 2 RCTs involving 362 adult and children was included. There was significant reduction in surgical intervention requirement among patients who received intrapleural fibrinolytic and DNase (OR 0.30; 95% CI 0.11-0.83; I = 31%; P = 0.02) than those receiving either intrapleural fibrinolytic or DNase alone. No difference was observed for mortality (OR 0.72; 95% CI 0.31-1.71; I = 0%; P = 0.46) and complication rates (OR 3.09; 95% CI 0.75-12,74; I = 54%; P = 0.12). The hospital length of stay (mean 13.70 vs. 16.67 days; P = 0.19) and duration of chest tube drainage (mean 6.47 vs. 6.30 days; P = 0.58) was similar between the two groups.
CONCLUSION
Combination of intrapleural fibrinolytic and DNase, compared to single-agent intrapleural therapy alone, is associated with a lesser need for surgical interventions. However, no difference was found in mortality, hospital length of stay, and chest tube drainage duration.
Topics: Adult; Child; Deoxyribonucleases; Empyema, Pleural; Fibrinolytic Agents; Humans; Pleural Effusion; Thrombolytic Therapy
PubMed: 34571093
DOI: 10.1016/j.pupt.2021.102081 -
Histopathology Oct 2021There has been an increased demand for mismatch repair (MMR) status testing in sarcoma patients after the success of immune checkpoint inhibition (ICI) in MMR deficient...
INTRODUCTION
There has been an increased demand for mismatch repair (MMR) status testing in sarcoma patients after the success of immune checkpoint inhibition (ICI) in MMR deficient tumors. However, data on MMR deficiency in bone and soft tissue tumors is sparse, rendering it unclear if routine screening should be applied. Hence, we aimed to study the frequency of MMR deficiency in bone and soft tissue tumors after we were prompted by two (potential) Lynch syndrome patients developing sarcomas.
METHODS
Immunohistochemical expression of MLH1, PMS2, MSH2 and MSH6 was assessed on tissue micro arrays (TMAs), and included 353 bone and 539 soft tissue tumors. Molecular data was either retrieved from reports or microsatellite instability (MSI) analysis was performed. In MLH1 negative cases, additional MLH1 promoter hypermethylation analysis followed. Furthermore, a systematic literature review on MMR deficiency in bone and soft tissue tumors was conducted.
RESULTS
Eight MMR deficient tumors were identified (1%), which included four leiomyosarcoma, two rhabdomyosarcoma, one malignant peripheral nerve sheath tumor and one radiation-associated sarcoma. Three patients were suspected for Lynch syndrome. Literature review revealed 30 MMR deficient sarcomas, of which 33% were undifferentiated/unclassifiable sarcomas. 57% of the patients were genetically predisposed.
CONCLUSION
MMR deficiency is rare in bone and soft tissue tumors. Screening focusing on tumors with myogenic differentiation, undifferentiated/unclassifiable sarcomas and in patients with a genetic predisposition / co-occurrence of other malignancies can be helpful in identifying patients potentially eligible for ICI.
Topics: Adult; Biomarkers, Tumor; Bone Neoplasms; Brain Neoplasms; Colorectal Neoplasms; DNA-Binding Proteins; Humans; Male; Middle Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplastic Syndromes, Hereditary; Soft Tissue Neoplasms
PubMed: 33825202
DOI: 10.1111/his.14377 -
International Journal of Medical... 2021Neutrophil extracellular traps (NETs) have been implicated in host immune responses. Attempts have been made to examine how NETs affect the pathogenesis of...
Neutrophil extracellular traps (NETs) have been implicated in host immune responses. Attempts have been made to examine how NETs affect the pathogenesis of complications such as autoimmune and vascular disorders. This study aimed to explore the relationship between NETs and vasculitis. The current study entailed the searching of PsycINFO, PubMed, Web of Science, and CINAHL for articles related to the research topic. The search terms and phrases included "vasculitis," "NETs," "neutrophil extracellular traps," "NETosis," and "pathogenesis." The search was limited to articles published between 2009 and 2019. Researchers have shown that NETs contribute to the pathogenesis of vasculitis through different mechanisms and processes, including renal failure and vascular damage. The protective effects of NETs have also been highlighted. Overall, some scholars have shown the effectiveness of using DNase I and the PAD4 inhibitor Cl-amidine to treat vasculitis by restricting NET formation. However, observations have been noted in only animal experimental models. Neutrophil hyperactivity and its role in vasculitis are not yet fully understood. More studies aiming to determine the accurate function of NETs in vasculitis pathogenesis, particularly in humans, should be undertaken. Intensive research on NETs and vasculitis can increase the knowledge of medical practitioners and contribute to the development of new treatment methods to enhance patient outcomes in the future.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Apoptosis; Deoxyribonuclease I; Disease Models, Animal; Extracellular Traps; Giant Cell Arteritis; Humans; Neutrophils; Ornithine; Protein-Arginine Deiminase Type 4; Regulated Cell Death; Takayasu Arteritis
PubMed: 33746569
DOI: 10.7150/ijms.53728 -
The Cochrane Database of Systematic... Mar 2021Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review.
OBJECTIVES
To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 12 October 2020. Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 08 February 2021.
SELECTION CRITERIA
All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance.
DATA COLLECTION AND ANALYSIS
Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence.
MAIN RESULTS
The searches identified 74 trials, of which 19 (2565 participants) met our inclusion criteria. 15 trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years. Dornase alfa compared to placebo or no treatment Dornase alfa probably improved forced expiratory volume at one second (FEV) at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed treatment may make little or no difference in quality of life. Dornase alfa probably reduced the number of pulmonary exacerbations in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa: daily versus alternate day One cross-over trial (43 children) found little or no difference between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence). Dornase alfa compared to other medications that improve airway clearance Results for these comparisons were mixed. One trial (43 children) showed dornase alfa may lead to a greater improvement in FEV compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported little or no differences in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found dornase alfa may improve quality of life compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found little or no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence). When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash.
AUTHORS' CONCLUSIONS
There is evidence to show that, compared with placebo, therapy with dornase alfa may improve lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer, probably due to treatment. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.
Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Disease Progression; Expectorants; Forced Expiratory Volume; Humans; Infant; Mannitol; Placebos; Randomized Controlled Trials as Topic; Recombinant Proteins; Saline Solution, Hypertonic; Vital Capacity
PubMed: 33735508
DOI: 10.1002/14651858.CD001127.pub5 -
The Cochrane Database of Systematic... Mar 2021Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.
OBJECTIVES
To determine whether the timing of dornase alfa inhalation (in relation to airway clearance techniques or morning versus evening inhalation) has an impact on objective and subjective measures of clinical efficacy in people with cystic fibrosis.
SEARCH METHODS
Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, the Physiotherapy Evidence Database (PEDro), clinical trial registries and international cystic fibrosis conference proceedings. Date of the most recent search: 12 October 2020.
SELECTION CRITERIA
Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the trial with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. We assessed the quality of the evidence using GRADE.
MAIN RESULTS
We identified 115 trial reports representing 55 trials, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials (98 participants) compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second (very-low quality evidence). Similarly, forced vital capacity (low-quality evidence) and quality of life (very-low quality evidence) were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small trials in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant. In one trial (25 participants), morning versus evening inhalation had no impact on lung function or symptoms (low-quality evidence).
AUTHORS' CONCLUSIONS
The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and trials with variable follow-up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alfa inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.
Topics: Administration, Inhalation; Adolescent; Child; Combined Modality Therapy; Cystic Fibrosis; Deoxyribonuclease I; Drug Administration Schedule; Forced Expiratory Volume; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Therapy; Time Factors; Vital Capacity; Young Adult
PubMed: 33686652
DOI: 10.1002/14651858.CD007923.pub6 -
European Journal of Hospital Pharmacy :... May 2022Airway mucus obstruction is a major challenge in children admitted to the paediatric intensive care unit (PICU). We aimed to evaluate the evidence and contemporary use... (Review)
Review
OBJECTIVES
Airway mucus obstruction is a major challenge in children admitted to the paediatric intensive care unit (PICU). We aimed to evaluate the evidence and contemporary use of the mucolytic medication dornase alfa for non-cystic fibrosis conditions in the PICU.
METHODS
(1) We performed a systematic review with searches in PubMed, EMBASE, and the Cochrane Library. for quality assessment and data synthesis, we included only randomised controlled trials (RCTs) that compared dornase alfa to standard care or placebo in critically-ill paediatric patients (<18 years of age) in the PICU. However, non-randomised controlled studies and case series are also discussed. data were extracted independently by multiple reviewers using data extraction forms. The primary outcome was duration of mechanical ventilation. The GRADE approach was used for quality assessment. No meta-analysis could be performed. (2) A national cross-sectional survey among all seven PICUs in the Netherlands was also performed.
RESULTS
The systematic review yielded only one RCT, comparing dornase alfa with normal saline in children after cardiac surgery. In this study, dornase alfa led to a reduction in duration of mechanical ventilation by approximately 1 day (36% reduction). In addition, we found nine retrospective observational and case studies. The survey revealed high current use of dornase alfa in Dutch PICUs: 42% of the respondents reported prescribing dornase alfa at least once every week. Only 4% of the respondents reported having access to a local PICU dornase alfa protocol.
CONCLUSIONS
The off-label use of dornase alfa in the PICU is frequent without strong evidence or local protocols, highlighting the need for further research on the effectiveness of this mucolytic agent.
Topics: Child; Cross-Sectional Studies; Cystic Fibrosis; Deoxyribonuclease I; Expectorants; Humans; Intensive Care Units, Pediatric; Recombinant Proteins
PubMed: 33122405
DOI: 10.1136/ejhpharm-2020-002507