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Abstract Rationale Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. Objectives To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures. Methods In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (n = 21) or 0.9% IS (n = 21) for 52 weeks. Measurements and Main Results Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (P = 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (−0.6) than in those treated with IS (−0.1; P < 0.05). In addition, weight gain was improved in infants with CF treated with HS (P < 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group. Conclusions Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).

Acute bronchiolitis is the commonest cause for hospitalisation in infancy. Supportive care remains the cornerstone of current management and no other therapy has been shown to influence the course of the disease. It has been suggested that adding nebulised hypertonic saline to usual care may shorten the duration of hospitalisation. To determine whether hypertonic saline does have beneficial effects we undertook an open, multi-centre parallel-group, pragmatic RCT in ten UK hospitals. Infants admitted to hospital with a clinical diagnosis of acute bronchiolitis and requiring oxygen therapy were randomised to receive usual care alone or nebulised 3% hypertonic saline (HS) administered 6-hourly. Randomisation was within 4 h of admission. The primary outcome was time to being assessed as 'fit' for discharge with secondary outcomes including time to discharge, incidence of adverse events together with follow up to 28 days assessing patient centred health related outcomes. A total of 317 infants were recruited to the study. 158 infants were randomised to HS (141 analysed) and 159 to standard care (149 analysed). There was no difference between the two arms in time to being declared fit for discharge (hazard ratio: 0-95, 95% CI: 0.75-1.20) nor to actual discharge (hazard ratio: 0.97, 95% CI: 0.76-1.23). There was no difference in adverse events. One infant in the HS group developed bradycardia with desaturation. This study does not support the use of nebulised HS in the treatment of acute bronchiolitis over usual care with minimal handlings. NCT01469845.

Bronchiectasis guidelines are inconsistent with regard to the effectiveness of mucoactive agents, and their use varies geographically. Large trials are needed to assess safety and effectiveness. For this open-label, randomized, two-by-two factorial trial at 20 sites in the United Kingdom, we enrolled participants with non-cystic fibrosis bronchiectasis who had frequent pulmonary exacerbations and daily sputum production. Current smokers and persons who had recently received mucoactive treatments were excluded. All participants received standard care and were also assigned either to one of three mucoactive-drug groups - hypertonic saline (the hypertonic-saline group), hypertonic saline and carbocisteine (the combination group), or carbocisteine (the carbocisteine group) - or to standard care alone. The comparisons were between hypertonic saline and no hypertonic saline and between carbocisteine and no carbocisteine, with each category consisting of two groups. The primary outcome was the number of pulmonary exacerbations over a 52-week period. Key secondary outcomes were scores on disease-specific health-related quality-of-life assessments, time to next pulmonary exacerbation, and safety. A total of 288 participants underwent randomization. No treatment interactions were found. The mean number of adjudicated fully qualifying pulmonary exacerbations over the 52-week period was 0.76 (95% confidence interval [CI], 0.58 to 0.95) with hypertonic saline as compared with 0.98 (95% CI, 0.78 to 1.19) with no hypertonic saline (adjusted between-group difference in the means, -0.25 [95% CI, -0.57 to 0.07; P = 0.12]) and 0.86 (95% CI, 0.66 to 1.06) with carbocisteine as compared with 0.90 (95% CI, 0.70 to 1.09) with no carbocisteine (adjusted between-group difference in the means, -0.04 [95% CI, -0.36 to 0.28; P = 0.81]). Secondary outcomes and the incidence of adverse events, including serious adverse events, were similar across the groups. In participants with bronchiectasis, neither hypertonic saline nor carbocisteine significantly reduced the mean incidence of pulmonary exacerbations over a period of 52 weeks. (Funded by the National Institute for Health and Care Research Health Technology Assessment Programme and others; ISRCTN Registry number, ISRCTN89040295.).

Inhalation of hypertonic saline has a modest beneficial effect on lung function and the frequency of exacerbations in patients with cystic fibrosis. In this article, the investigators provide in vivo and in vitro data suggesting that this therapeutic effect derives from sustained acceleration of mucus clearance. The investigators provide in vivo and in vitro data suggesting that the therapeutic effect of inhaled hypertonic saline derives from sustained acceleration of mucus clearance. Mucus clearance defends the lung against inhaled bacteria. The efficiency of mucus clearance depends on an adequate volume of airway surface liquid (i.e., hydration). 1 One hypothesis for the pathogenesis of lung disease in patients with cystic fibrosis is that a lack of regulation of sodium absorption and chloride secretion causes depletion of airway surface liquid, slows mucus clearance, and promotes the formation of adherent mucus plaques on airway surfaces. Mucus plaques and plugs obstruct airways and provide the nidus for infection. 2 , 3 On the basis of this hypothesis, therapies that increase the volume of airway surface liquid, and hence mucus . . .

Background Low-volume hypertonic solutions, such as half-molar lactate (LAC), may be a potential treatment used for fluid resuscitation. This study aimed to evaluate the underlying cardiovascular effects and mechanisms of LAC infusion compared to sodium-matched hypertonic sodium chloride (SAL). Methods Eight healthy male participants were randomized in a controlled, single-blinded, crossover study. Each participant received a four-hour infusion of LAC and SAL in a randomized order. Assessor-blinded echocardiography and blood samples were performed. The primary endpoint was cardiac output (CO) measured by echocardiography. Results During LAC infusion, circulating lactate levels increased by 1.9 mmol/L (95% CI 1.8–2.0 mmol/L, P  < 0.001) compared with SAL. CO increased by 1.0 L/min (95% CI 0.5–1.4 L/min, P  < 0.001), driven primarily by a significant increase in stroke volume of 11 mL (95% CI 4–17 mL, P  = 0.002), with no significant change in heart rate. Additionally, left ventricular ejection fraction improved by 5 percentage points ( P  < 0.001) and global longitudinal strain by 1.5 percentage points ( P  < 0.001). Preload indicators were elevated during SAL infusion compared with LAC infusion. Concomitantly, afterload parameters, including systemic vascular resistance and effective arterial elastance, were significantly decreased with LAC infusion compared with SAL, while mean arterial pressure remained similar. Indicators of contractility improved during LAC infusion. Conclusions In healthy participants, LAC infusion enhanced cardiac function, evidenced by increases in CO, stroke volume, and left ventricular ejection fraction compared with SAL. Indicators of contractility improved, afterload decreased, and preload remained stable. Therefore, LAC infusion may be an advantageous resuscitation fluid, particularly in patients with cardiac dysfunction. Clinical trial registrations https://clinicaltrials.gov/ct2/show/NCT04710875 . Registered 1 December 2020.

Saline (0.9% sodium chloride), the fluid most commonly used to treat diabetic ketoacidosis (DKA), can cause hyperchloremic metabolic acidosis. Balanced crystalloids, an alternative class of fluids for volume expansion, do not cause acidosis and, therefore, may lead to faster resolution of DKA than saline. To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with DKA. This study was a subgroup analysis of adults with DKA in 2 previously reported companion trials-Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). These trials, conducted between January 2016 and March 2017 in an academic medical center in the US, were pragmatic, multiple-crossover, cluster, randomized clinical trials comparing balanced crystalloids vs saline in emergency department (ED) and intensive care unit (ICU) patients. This study included adults who presented to the ED with DKA, defined as a clinical diagnosis of DKA, plasma glucose greater than 250 mg/dL, plasma bicarbonate less than or equal to 18 mmol/L, and anion gap greater than 10 mmol/L. Data analysis was performed from January to April 2020. Balanced crystalloids (clinician's choice of Ringer lactate solution or Plasma-Lyte A solution) vs saline for fluid administration in the ED and ICU according to the same cluster-randomized multiple-crossover schedule. The primary outcome was time between ED presentation and DKA resolution, as defined by American Diabetes Association criteria. The secondary outcome was time between initiation and discontinuation of continuous insulin infusion. Among 172 adults included in this secondary analysis of cluster trials, 94 were assigned to balanced crystalloids and 78 to saline. The median (interquartile range [IQR]) age was 29 (24-45) years, and 90 (52.3%) were women. The median (IQR) volume of isotonic fluid administered in the ED and ICU was 4478 (3000-6372) mL. Cumulative incidence analysis revealed shorter time to DKA resolution in the balanced crystalloids group (median time to resolution: 13.0 hours; IQR: 9.5-18.8 hours) than the saline group (median: 16.9 hours; IQR: 11.9-34.5 hours) (adjusted hazard ratio [aHR] = 1.68; 95% CI, 1.18-2.38; P = .004). Cumulative incidence analysis also revealed shorter time to insulin infusion discontinuation in the balanced crystalloids group (median: 9.8 hours; IQR: 5.1-17.0 hours) than the saline group (median: 13.4 hours; IQR: 11.0-17.9 hours) (aHR = 1.45; 95% CI, 1.03-2.03; P = .03). In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA. ClinicalTrials.gov Identifiers: NCT02614040; NCT02444988.

Hyperosmolar therapy, specifically the use of mannitol, has been employed to improve brain relaxation, but mannitol use may cause hypovolemia and electrolyte imbalance. Given these risks, hypertonic saline was introduced as an alternative; however, data on its efficacy and safety are limited. Researchers conducted a prospective, double-blind, randomized controlled trial. Sixty-six patients with supratentorial or posterior fossa brain tumours undergoing craniotomy were randomized into two groups. Group M received 20% mannitol at 3 ml/kg, and Group H received 3% hypertonic saline at the same dose. These solutions were administered before dural opening. Two masked neurosurgeons immediately assessed the four-point brain relaxation score by direct visual and tactile evaluation after dural opening. Both groups showed no significant difference in brain relaxation scores ( p  = 0.543). There was no significant difference in haemodynamic change, fluid replacement, or serum osmolarity between groups; however, urine output was greater in the mannitol group ( p  = 0.003). Additionally, postoperative neurological outcomes and one-month mortality rates were similar. These findings suggest 3% hypertonic saline can be considered an alternative to mannitol for improving brain relaxation during craniotomy, as it is equally effective with less urine output.

Abstract Background: The role of hyaluronic acid plus hypertonic saline (HA+HS) as a mucoactive treatment in patients with bronchiectasis is still unknown. This study evaluated whether HA+HS solution enhances similar sputum quantity with better safety profile than HS alone in patients with bronchiectasis. Methods: In this double-blind randomized crossover trial, three solutions (7% HS; 0.1% HA +7%HS; and 0.9% isotonic saline, IS) were compared in outpatients with bronchiectasis and chronic sputum expectoration. Participants inhaled each solution across four consecutive sessions. All sessions, except on session 3, also included 30 minutes of airway clearance technique. A 7-day washout period was applied. Sputum weight was collected during the sessions (primary outcome) as well as during a 24-hour follow-up. The Leicester Cough Questionnaire (LCQ) and lung function were measured before/after each treatment arm. Safety was assessed by the monitoring of adverse events (AEs). Results: Twenty-eight patients with bronchiectasis (mean age of 64.0 (17.9) and FEV1% 60.9 (24.6) of predicted) were recruited. HS and HA+HS promoted similar expectoration during sessions, both being greater than IS [median difference HS vs. IS 3.7 g (95% CI 0.5–6.9); HA+HS vs. IS 3.2 g (95%CI 0.5–5.9)]. Sputum expectorated exclusively during the ACT period was similar across all treatment arms [HS vs. IS −0.3 g (95% CI −1.7 to 0.9); HA+HS vs. IS 0.0 g (95% CI −1.3 to 1.4); HS vs. HA+HS 0.0 g (95% CI −1.2 to 0.4)]. Sputum collected over the 24-hour follow-up tended to be lower for HS and HA+HS compared with IS [HS vs. IS −1.7 g (95% CI −4.2 to 0.0); HA+HS vs. IS −1.1 g (95%CI −3.6 to 0.7)]. No differences in LCQ or lung function were observed. Most severe AEs were reported using HS. Conclusion: HS and HA+HS were more effective on sputum expectoration than IS in patients with bronchiectasis, reporting HA+HS better safety profile than HS.

Background This prospective, randomized trial aimed to compare the efficacy and safety of different intravenous diuretic regimens in acute decompensated heart failure (ADHF) patients. Methods ADHF patients were enrolled and randomized into three groups: continuous intravenous furosemide infusion (cIV), bolus furosemide injection (bI), and furosemide plus hypertonic saline solution (HSS). Clinical outcomes were assessed over 48 h. Results In a study involving 1276 patients admitted for ADHF, three therapeutic regimens (T × 1, T × 2, and T × 3) were compared. T × 1 administered an 80 mg furosemide intravenous bolus infusion twice daily to 479 patients, while T × 2 involved a continuous 16‐h infusion of 160 mg furosemide daily to 420 patients. T × 3 treated 377 patients with 160 mg furosemide combined with 150 mL of HSS containing 1.95% NaCl over 30 min. Yet, overall changes in renal markers such as BUN, Na, K, and serum creatinine did not differ significantly. Analysis of prespecified study endpoints revealed notable variations in hospitalization length among the treatment arms. T × 1 demonstrated a significantly shorter hospital stay (3.7 days) compared to T × 2 (6.6 days) and T × 3 (7.9 days). Conversely, alterations in serum creatinine at 48 h, overall changes in serum creatinine, body weight loss, and serum potassium levels did not significantly differ among the treatment groups. Conclusion While intravenous bolus of furosemide showed potential benefits in reducing hospitalization duration, limitations such as a small sample size and short‐term observation emphasize the need for larger studies to validate these outcomes further. While no significant differences were observed in renal function or fluid removal among continuous intravenous furosemide infusion, bolus furosemide injection, and furosemide plus HSS groups, the continuous infusion without HSS exhibited a notably shorter hospital stay. These findings suggest a potential benefit of continuous intravenous furosemide infusion as an effective strategy in reducing hospitalization duration.

Background and aimsSensitive outcome measures to assess the efficacy of therapeutic interventions in patients with cystic fibrosis (CF) with mild lung disease are currently lacking. Our objective was to study the ability of the lung clearance index (LCI), a measure of ventilation inhomogeneity, to detect a treatment response to hypertonic saline inhalation in paediatric patients with CF with normal spirometry.MethodsIn a crossover trial, 20 patients with CF received 4 weeks of hypertonic saline (HS) and isotonic saline (IS) in a randomised sequence separated by a 4 week washout period. The primary end point was the change in the LCI due to HS versus IS.ResultsBaseline characteristics including the LCI were not significantly different between both study periods. Four weeks of twice-daily HS inhalation significantly improved the LCI compared with IS (1.16, 95% CI 0.26 to 2.05; p=0.016), whereas other outcome measures such as spirometry and quality of life failed to reach statistical significance. Randomisation order had no significant impact on the treatment effect.ConclusionsThe LCI, but not spirometry was able to detect a treatment effect from HS inhalation in patients with CF with mild disease and may be a suitable tool to assess early intervention strategies in this patient population.Clinical trial numberNCT00635141.