Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Sodium regulates clock time and output via an excitatory GABAergic pathway.

The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water loss during sleep11. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase12-16. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVP neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this information to SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLTGAD→ SCNVP pathway and was prevented by chemogenetic inhibition of OVLTGAD neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.

Dynamic turnover of paused Pol II complexes at human promoters.

Paused RNA polymerase II (Pol II) that piles up near most human promoters is the target of mechanisms that control entry into productive elongation. Whether paused Pol II is a stable or dynamic target remains unresolved. We report that most 5' paused Pol II throughout the genome is turned over within 2 min. This process is revealed under hypertonic conditions that prevent Pol II recruitment to promoters. This turnover requires cell viability but is not prevented by inhibiting transcription elongation, suggesting that it is mediated at the level of termination. When initiation was prevented by triptolide during recovery from high salt, a novel preinitiated state of Pol II lacking the pausing factor Spt5 accumulated at transcription start sites. We propose that Pol II occupancy near 5' ends is governed by a cycle of ongoing assembly of preinitiated complexes that transition to pause sites followed by eviction from the DNA template. This model suggests that mechanisms regulating the transition to productive elongation at pause sites operate on a dynamic population of Pol II that is turning over at rates far higher than previously suspected. We suggest that a plausible alternative to elongation control via escape from a stable pause is by escape from premature termination.

Effect of Hypertonic Saline Solution on the Ventilatory Mechanics of Lungs Donated After Brain Death.

INTRODUCTION: Brain death (BD) compromises the viability of the lung for donation. Hypertonic saline solution (HSS) induces rapid intravascular volume expansion and immunomodulatory action. We investigated its role in ventilatory mechanics (VMs) and in the inflammatory activity of the lungs of rats subjected to BD. METHODS: Wistar rats were divided into four groups: control, n = 10: intact rats subjected to extraction of the heart-lung block; BD, n = 8 (BD): rats treated with isotonic saline solution (4 mL/kg) immediately after BD; hypertonic saline 0 h, n = 9 (Hip.0'): rats treated with HSS (4 mL/kg) immediately after BD; and hypertonic saline 1 h, n = 9 (Hip.60'), rats treated with HSS (4 mL/kg) 60 min after BD. The hemodynamic characteristics, gas exchange, VMs, inflammatory mediators, and histopathological evaluation of the lung were evaluated over 240 min of BD. RESULTS: In VMs, we observed increased airway resistance, tissue resistance, tissue elastance, and respiratory system compliance in the BD group (P < 0.037), while the treated groups showed no impairment over time (P > 0.05). In the histological analysis, the BD group showed a greater area of perivascular edema and a higher neutrophil count than the control group and the Hip.60' group (P < 0.05). CONCLUSIONS: Treatment with HSS was effective in preventing changes in the elastic and resistive pulmonary components, keeping them at baseline levels. Late treatment reduced perivascular and neutrophilic edema in lung tissue.

Comparative-effectiveness study evaluating outcomes for transforaminal epidural steroid injections performed with 3% hypertonic saline or normal saline in lumbosacral radicular pain.

BACKGROUND: Transforaminal epidural steroid injections (TFESI) are commonly employed to treat lumbosacral radiculopathy. Despite anti-inflammatory properties, the addition of 3% hypertonic saline has not been studied. OBJECTIVE: Compare the effectiveness of adding 0.9% NaCl (N-group) vs. 3% NaCl (H-group) in TFESI performed for lumbosacral radiculopathy. METHODS: This retrospective study compared TFESI performed with lidocaine, triamcinolone and 0.9% NaCl vs. lidocaine, triamcinolone and 3% NaCl. The primary outcome was the proportion of patients who experienced a ≥ 30% reduction in pain on a verbal rating scale (VRS; 0-100) at 3 months. Secondary outcome measures included the proportion of patients who improved by at least 30% for pain at 1 and 6 months, and who experienced ≥15% from baseline on the Oswestry disability index (ODI) at follow-up. RESULTS: The H-group experienced more successful pain outcomes than the N-group at 3 months (59.09% vs. 41.51%; P = .002) but not at 1 month (67.53% vs. 64.78%; P = .61) or 6 months (27.13% vs 21.55%: P = .31). For functional outcome, there was a higher proportion of responders in the H-group than the N-group at 3 months (70.31% vs. 53.46%; P = .002). Female, age ≤ 60 years, and duration of pain ≤ 6 months were associated with superior outcomes at the 3-month endpoint. Although those with a herniated disc experienced better outcomes in general with TFESI, the only difference favoring the H-group was for spondylolisthesis patients. CONCLUSIONS: 3% hypertonic saline is a viable alternative to normal saline as an adjunct for TFESI, with randomized studies needed to compare its effectiveness to steroids as a possible alternative. REGISTRATION: Thai Clinical Trials Registry ID TCTR 20231110006.

Thoracic Society of Australia and New Zealand position statement: The safe clinical use of sputum induction for bio-sampling of the lower airways in children and adults.

Sputum induction is widely used in clinical settings for collection of biological samples from the lower airways. However, in recent years sputum induction has been associated with serious adverse events and even death. This position statement was commissioned by the Thoracic Society of Australia and New Zealand to address major adverse events of two deaths associated with sputum induction that have occurred in Australia in 2021, and outlines best practice for the safe use of sputum induction. The statement resulted from systematic literature searches by a multi-disciplinary group including respiratory physicians, nurses and physiotherapists (paediatric and adults focused). Consumers had input to an advanced draft of the position statement. The position statement covers indications for sputum induction, informed consent, scope of practice of personnel administering the procedure, infection control considerations, details about the sputum induction procedure, safety considerations and risk assessment in clinical settings.

Isotonic balanced fluid versus 0.9% saline in patients with moderate to severe traumatic brain injury: A double-blinded randomised controlled trial.

BACKGROUND AND IMPORTANCE: Traumatic brain injury (TBI) is a global health concern with significant economic impact. Optimal fluid therapy aims to restore intravascular volume, maintain cerebral perfusion pressure and blood flow, thus preventing secondary brain injury. While 0.9% saline (NS) is commonly used, concerns about acid-base and electrolyte imbalance and development of acute kidney injury (AKI) lead to consideration of balanced fluids as an alternative. OBJECTIVES: This study aimed to compare the outcomes of patients with moderate to severe TBI treated with Sterofundin (SF) versus NS. DESIGN, SETTINGS AND PARTICIPANTS: A double-blinded randomised controlled trial of patients aged 18 to 65 years with TBI was conducted at the University Malaya Medical Centre from February 2017 to November 2019. INTERVENTION OR EXPOSURE: Patients were randomly assigned to receive either NS or SF. The study fluids were administered for 72 h as continuous infusions or boluses. Participants, investigators, and staff were blinded to the fluid type. OUTCOMES MEASURE AND ANALYSIS: The primary outcome was in-hospital mortality. Relative risk (RR) with 95% confidence interval (CI) was calculated. MAIN RESULTS: A total of 70 patients were included in the analysis, with 38 in the NS group and 32 in the SF group. The in-hospital mortality rate were 3 (7.9%) in the NS group vs. 4 (12.5%) in the SF group, RR = 1.29 (95% CI, 0.64 to 2.59; p = 0.695). No patients developed AKI and required renal replacement therapy. ICP on day 3 was significantly higher in the SF group (18.60 ± 9.26) compared to 12.77 ± 3.63 in the NS group, (95% CI, -11.46 to 0.20; p = 0.037). There were no significant differences in 3-day biochemical parameters and cerebral perfusion pressure, ventilator-free days, length of ICU stay, or Glasgow Outcome Scale-Extended (GOS-E) score at 6 months. CONCLUSIONS: In patients with moderate to severe TBI, the use of SF was not associated with reduced in-hospital mortality, development of AKI, or improved 6-month GOS-E when compared to NS.

Effect of continuous hypertonic saline infusion on clinical outcomes in patients with traumatic brain injury.

Osmotic therapy has been recognized as an important treatment option for patients with traumatic brain injury (TBI). Nevertheless, the effect of hypertonic saline (HTS) remains unknown, as findings are primarily based on a large database. This study aimed to elucidate the effect of HTS on the clinical outcomes of patients with TBI admitted to the intensive care unit (ICU). We retrospectively identified patients with moderate-to-severe TBI from two public databases: Medical Information Mart for Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during ICU stay. Trajectory modeling based on the intracranial pressure evolution pattern allowed for the identification of subgroups. Overall, 130 (6.65%) of 1955 eligible patients underwent HTS. MSCM indicated that the HTS significantly associated with higher infection complications (e.g., urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)) and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect of HTS on GCS was found in subgroups with medium and low intracranial pressure. Our study revealed no significant difference in mortality between patients who underwent HTS and those who did not. Increased occurrence rates of infection and electrolyte imbalance are inevitable outcomes of continuous HTS infusion. Although the study suggests slight beneficial effects, including better neurological outcomes, these results warrant further validation.

Hyperosmolar therapies for neurological deterioration in mild and moderate traumatic brain injury: towards new research.

The scoping review by Nicolò Marchesini and colleagues about the use of hyperosmolar therapies (HTs) in patients with traumatic brain injury (TBI) points out a significant gap in scientific literature regarding this topic. Although there are few high-quality recommendations, it is important to provide care under certain physiologic parameters. Through this letter we comment on the importance of guidelines to administer and monitor the use of HTs in the Neuro-ICU.

Hypertonic Saline Versus Other Intracranial-Pressure-Lowering Agents for Patients with Acute Traumatic Brain Injury: A Systematic Review and Meta-analysis.

Acute traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Intracranial pressure (ICP)-lowering is a critical management priority in patients with moderate to severe acute TBI. We aimed to evaluate the clinical efficacy and safety of hypertonic saline (HTS) versus other ICP-lowering agents in patients with TBI. We conducted a systematic search from 2000 onward for randomized controlled trials (RCTs) comparing HTS vs. other ICP-lowering agents in patients with TBI of all ages. The primary outcome was the Glasgow Outcome Scale (GOS) score at 6 months (PROSPERO CRD42022324370). Ten RCTs (760 patients) were included. Six RCTs were included in the quantitative analysis. There was no evidence of an effect of HTS on the GOS score (favorable vs. unfavorable) compared with other agents (risk ratio [RR] 0.82, 95% confidence interval [CI] 0.48-1.40; n = 406; 2 RCTs). There was no evidence of an effect of HTS on all-cause mortality (RR 0.96, 95% CI 0.60-1.55; n = 486; 5 RCTs) or total length of stay (RR 2.36, 95% CI - 0.53 to 5.25; n = 89; 3 RCTs). HTS was associated with adverse hypernatremia compared with other agents (RR 2.13, 95% CI 1.09-4.17; n = 386; 2 RCTs). The point estimate favored a reduction in uncontrolled ICP with HTS, but this was not statistically significant (RR 0.52, 95% CI 0.26-1.04; n = 423; 3 RCTs). Most included RCTs were at unclear or high risk of bias because of lack of blinding, incomplete outcome data, and selective reporting. We found no evidence of an effect of HTS on clinically important outcomes and that HTS is associated with adverse hypernatremia. The included evidence was of low to very low certainty, but ongoing RCTs may help to the reduce this uncertainty. In addition, heterogeneity in GOS score reporting reflects the need for a standardized TBI core outcome set.

Bronchiolitis.

Viral bronchiolitis is the most common cause of admission to hospital for infants in high-income countries. Respiratory syncytial virus accounts for 60-80% of bronchiolitis presentations. Bronchiolitis is diagnosed clinically without the need for viral testing. Management recommendations, based predominantly on high-quality evidence, advise clinicians to support hydration and oxygenation only. Evidence suggests no benefit with use of glucocorticoids or bronchodilators, with further evidence required to support use of hypertonic saline in bronchiolitis. Evidence is scarce in the intensive care unit. Evidence suggests use of high-flow therapy in bronchiolitis is limited to rescue therapy after failure of standard subnasal oxygen only in infants who are hypoxic and does not decrease rates of intensive care unit admission or intubation. Despite systematic reviews and international clinical practice guidelines promoting supportive rather than interventional therapy, universal de-implementation of interventional care in bronchiolitis has not occurred and remains a major challenge.

Emulated trial investigating effects of multiple treatments: estimating combined effects of mucoactive nebulisers in cystic fibrosis using registry data.

INTRODUCTION: People with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach for people already on DNase is to add hypertonic saline (HS). The effects of DNase and HS used alone have been studied in randomised trials, but their effects in combination have not. This study investigates whether, for people already prescribed DNase, adding HS has additional benefit for lung function or use of intravenous antibiotics. METHODS: Using UK CF Registry data from 2007 to 2018, we emulated a target trial. We included people aged 6 years and over who were prescribed DNase without HS for 2 years. We investigated the effects of combinations of DNase and HS over 5 years of follow-up. Inverse-probability-of-treatment weighting was used to control confounding. The period predated triple combination CF transmembrane conductance regulator modulators in routine care. RESULTS: 4498 individuals were included. At baseline, average age and forced expiratory volume in 1 s (FEV1%) predicted were 21.1 years and 69.7 respectively. During first year of follow-up, 3799 individuals were prescribed DNase alone; 426 added HS; 57 switched to HS alone and 216 were prescribed neither. We found no evidence that adding HS improved FEV1% at 1-5 years, or use of intravenous antibiotics at 1-4 years, compared with DNase alone. CONCLUSION: For individuals with CF prescribed DNase, we found no evidence that adding HS had an effect on FEV1% or prescription of intravenous antibiotics. Our study illustrates the emulated target trial approach using CF Registry data.

Impact of continuous hypertonic (NaCl 20%) saline solution on renal outcomes after traumatic brain injury (TBI): a post hoc analysis of the COBI trial.

BACKGROUND: To evaluate if the increase in chloride intake during a continuous infusion of 20% hypertonic saline solution (HSS) is associated with an increase in the incidence of acute kidney injury (AKI) compared to standard of care in traumatic brain injury patients. METHODS: In this post hoc analysis of the COBI trial, 370 patients admitted for a moderate-to-severe TBI in the 9 participating ICUs were enrolled. The intervention consisted in a continuous infusion of HSS to maintain a blood sodium level between 150 and 155 mmol/L for at least 48 h. Patients enrolled in the control arm were treated as recommended by the latest Brain Trauma foundation guidelines. The primary outcome of this study was the occurrence of AKI within 28 days after enrollment. AKI was defined by stages 2 or 3 according to KDIGO criteria. RESULTS: After exclusion of missing data, 322 patients were included in this post hoc analysis. The patients randomized in the intervention arm received a significantly higher amount of chloride during the first 4 days (intervention group: 97.3 ± 31.6 g vs. control group: 61.3 ± 38.1 g; p < 0.001) and had higher blood chloride levels at day 4 (117.9 ± 10.7 mmol/L vs. 111.6 ± 9 mmol/L, respectively, p < 0.001). The incidence of AKI was not statistically different between the intervention and the control group (24.5% vs. 28.9%, respectively; p = 0.45). CONCLUSIONS: Despite a significant increase in chloride intake, a continuous infusion of HSS was not associated with AKI in moderate-to-severe TBI patients. Our study does not confirm the potentially detrimental effect of chloride load on kidney function in ICU patients. TRIAL REGISTRATION: The COBI trial was registered on clinicaltrial.gov (Trial registration number: NCT03143751, date of registration: 8 May 2017).

Initial Diagnosis and Management of Acutely Elevated Intracranial Pressure.

Acutely elevated intracranial pressure (ICP) may have devastating effects on patient mortality and neurologic outcomes, yet its initial detection remains difficult because of the variety of manifestations that it can cause disease states it is associated with. Several treatment guidelines exist for specific disease processes such as trauma or ischemic stroke, but their recommendations may not apply to other causes. In the acute setting, management decisions must often be made before the underlying cause is known. In this review, we present an organized, evidence-based approach to the recognition and management of patients with suspected or confirmed elevated ICP in the first minutes to hours of resuscitation. We explore the utility of invasive and noninvasive methods of diagnosis, including history, physical examination, imaging, and ICP monitors. We synthesize various guidelines and expert recommendations and identify core management principles including noninvasive maneuvers, neuroprotective intubation and ventilation strategies, and pharmacologic therapies such as ketamine, lidocaine, corticosteroids, and the hyperosmolar agents mannitol and hypertonic saline. Although an in-depth discussion of the definitive management of each etiology is beyond the scope of this review, our goal is to provide an empirical approach to these time-sensitive, critical presentations in their initial stages.

Twenty-one-year follow-up revealed guideline-concordant and non-concordant trends in intensive care of bronchiolitis.

To evaluate the management of bronchiolitis in the paediatric intensive care unit (PICU) before and after publication of the national bronchiolitis guidelines in June 2015. All infants treated between 2016-2020 for bronchiolitis in the PICU of Tampere University Hospital at < 12 months of age were included. The data were retrospectively collected from electronic patient records. The current results reflecting the post-guideline era were compared with previously published results for the pre-guideline 2000-2015 period. These two studies used identical protocols. Forty-six infants treated in the PICU were included. During the post-guideline era, inhaled adrenaline was given to 26 (57%), salbutamol to 7 (15%), and hypertonic saline inhalations to 35 (75%) patients. Forty-three patients (94%) received high-flow oxygen therapy (HFOT). Seventeen patients (37%) were treated with nasal continuous positive airway pressure (CPAP) and 4 (9%) with mechanical ventilation. CONCLUSION: When post-guideline years were compared with pre-guideline years, the use of bronchodilators decreased in agreement, but the use of inhaled saline increased in disagreement with the guidelines. The use of respiratory support increased, evidently because of an introduction of the non-invasive HFOT treatment modality. WHAT IS KNOWN: • Oxygen supplementation and respiratory support, when needed, are the cornerstones of bronchiolitis treatment. • Medicines are frequently given to infants with bronchiolitis, especially if intensive care is needed, although evidence of their effectiveness is lacking. WHAT IS NEW: • Nearly all (94%) infants who needed intensive care were treated with HFOT and 37% with nasal CPAP, and finally, only 9% were intubated, which reflects the effectiveness of non-invasive techniques. • When pre- and post-guideline eras were compared, use of racemic adrenaline decreased from 84 to 57%, but use of hypertonic saline increased up to 75%, which disagrees with the current guidelines.

Nebulised hypertonic saline solution for acute bronchiolitis in infants.

BACKGROUND: Airway oedema (swelling) and mucus plugging are the principal pathological features in infants with acute viral bronchiolitis. Nebulised hypertonic saline solution (≥ 3%) may reduce these pathological changes and decrease airway obstruction. This is an update of a review first published in 2008, and updated in 2010, 2013, and 2017. OBJECTIVES: To assess the effects of nebulised hypertonic (≥ 3%) saline solution in infants with acute bronchiolitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, Embase, CINAHL, LILACS, and Web of Science on 13 January 2022. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 13 January 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs using nebulised hypertonic saline alone or in conjunction with bronchodilators as an active intervention and nebulised 0.9% saline or standard treatment as a comparator in children under 24 months with acute bronchiolitis. The primary outcome for inpatient trials was length of hospital stay, and the primary outcome for outpatients or emergency department (ED) trials was rate of hospitalisation. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and assessment of risk of bias in included studies. We conducted random-effects model meta-analyses using Review Manager 5. We used mean difference (MD), risk ratio (RR), and their 95% confidence intervals (CI) as effect size metrics. MAIN RESULTS: We included six new trials (N = 1010) in this update, bringing the total number of included trials to 34, involving 5205 infants with acute bronchiolitis, of whom 2727 infants received hypertonic saline. Eleven trials await classification due to insufficient data for eligibility assessment. All included trials were randomised, parallel-group, controlled trials, of which 30 were double-blinded. Twelve trials were conducted in Asia, five in North America, one in South America, seven in Europe, and nine in Mediterranean and Middle East regions. The concentration of hypertonic saline was defined as 3% in all but six trials, in which 5% to 7% saline was used. Nine trials had no funding, and five trials were funded by sources from government or academic agencies. The remaining 20 trials did not provide funding sources. Hospitalised infants treated with nebulised hypertonic saline may have a shorter mean length of hospital stay compared to those treated with nebulised normal (0.9%) saline or standard care (mean difference (MD) -0.40 days, 95% confidence interval (CI) -0.69 to -0.11; 21 trials, 2479 infants; low-certainty evidence). Infants who received hypertonic saline may also have lower postinhalation clinical scores than infants who received normal saline in the first three days of treatment (day 1: MD -0.64, 95% CI -1.08 to -0.21; 10 trials (1 outpatient, 1 ED, 8 inpatient trials), 893 infants; day 2: MD -1.07, 95% CI -1.60 to -0.53; 10 trials (1 outpatient, 1 ED, 8 inpatient trials), 907 infants; day 3: MD -0.89, 95% CI -1.44 to -0.34; 10 trials (1 outpatient, 9 inpatient trials), 785 infants; low-certainty evidence). Nebulised hypertonic saline may reduce the risk of hospitalisation by 13% compared with nebulised normal saline amongst infants who were outpatients and those treated in the ED (risk ratio (RR) 0.87, 95% CI 0.78 to 0.97; 8 trials, 1760 infants; low-certainty evidence). However, hypertonic saline may not reduce the risk of readmission to hospital up to 28 days after discharge (RR 0.83, 95% CI 0.55 to 1.25; 6 trials, 1084 infants; low-certainty evidence). We are uncertain whether infants who received hypertonic saline have a lower number of days to resolution of wheezing compared to those who received normal saline (MD -1.16 days, 95% CI -1.43 to -0.89; 2 trials, 205 infants; very low-certainty evidence), cough (MD -0.87 days, 95% CI -1.31 to -0.44; 3 trials, 363 infants; very low-certainty evidence), and pulmonary moist crackles (MD -1.30 days, 95% CI -2.28 to -0.32; 2 trials, 205 infants; very low-certainty evidence). Twenty-seven trials presented safety data: 14 trials (1624 infants; 767 treated with hypertonic saline, of which 735 (96%) co-administered with bronchodilators) did not report any adverse events, and 13 trials (2792 infants; 1479 treated with hypertonic saline, of which 416 (28%) co-administered with bronchodilators and 1063 (72%) hypertonic saline alone) reported at least one adverse event such as worsening cough, agitation, bronchospasm, bradycardia, desaturation, vomiting and diarrhoea, most of which were mild and resolved spontaneously (low-certainty evidence). AUTHORS' CONCLUSIONS: Nebulised hypertonic saline may modestly reduce length of stay amongst infants hospitalised with acute bronchiolitis and may slightly improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation amongst outpatients and ED patients. Nebulised hypertonic saline seems to be a safe treatment in infants with bronchiolitis with only minor and spontaneously resolved adverse events, especially when administered in conjunction with a bronchodilator. The certainty of the evidence was low to very low for all outcomes, mainly due to inconsistency and risk of bias.

Nebuliser systems for drug delivery in cystic fibrosis.

BACKGROUND: Nebuliser systems are used to deliver medications to the lungs, to control the symptoms and the progression of lung disease in people with cystic fibrosis (CF). There are many different nebulised-medications prescribed for people with CF and there are many different types of nebuliser systems. Some of these nebulised medications are licenced for, and can be taken via only one type of nebuliser system; some are licensed for, and can be taken via more than one type of nebuliser system. This is an update to a previous systematic review. OBJECTIVES: To assess the time efficiency, effectiveness, safety, cost and impact of use (e.g. burden of care, adherence, quality of life (QoL)) of different nebuliser systems, when used with different inhaled medications for people with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching of relevant journals and abstract books containing conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data. We also searched online trial registries. Date of the most recent search: 9 August 2023. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing nebuliser systems, including conventional nebulisers, vibrating mesh technology (VMT) systems, adaptive aerosol delivery (AAD) systems and ultrasonic nebuliser systems. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third review author assessed studies where agreement could not be reached. They assessed the certainty of the evidence using GRADE. MAIN RESULTS: The search identified 216 studies with 33 of these (2270 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic saline and other solutions through the different nebuliser systems in children and adults with CF. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. The certainty of the evidence ranged from low to very low. Some conventional nebuliser systems providing higher flows, higher respirable fractions, and smaller particles decrease treatment time, increase deposition (the amount of drug reaching the lung), and may be preferred by people with CF, as compared to other conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Newer nebuliser systems using AAD, or VMT (or both) reduce treatment time compared to conventional systems. Deposition (as a percentage of priming dose) with AAD is greater than with conventional systems. VMT systems may give greater deposition than conventional systems when measuring sputum levels. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved and that individuals prefer AAD or VMT systems, but also that some nebuliser systems using VMT may be subject to increased system failures. There is limited, unclear evidence on the impact of different nebuliser systems on lung function and a lack of data on the impact of different nebuliser systems on our outcomes of quality of life (QoL), adverse effects, respiratory exacerbations and related implications, adherence, satisfaction, cost and device reliability. AUTHORS' CONCLUSIONS: Newer technologies e.g. AAD and VMT have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, preference and adherence. Data are lacking for all varieties of medications which are used in CF care, including different inhaled antibiotics or hypertonic saline, with all delivery (nebuliser system) possibilities. Long-term RCTs are needed to evaluate different nebuliser systems to determine patient-focused outcomes (such as QoL and burden of care), safe and effective dosing levels of a wide variety of medications, clinical outcomes (such as hospitalisations and need for antibiotics), and an economic evaluation of their use. There are insufficient data to establish whether one nebuliser system is better than another overall. Clinicians should be aware of the variability in the performance of different nebuliser systems, compatibility with specific nebulised medication, and they must work with their patients to choose the best nebuliser system for each individual. This is likely to be an ongoing process as the needs and circumstances of each individual change over time.

Nebulised hypertonic saline for cystic fibrosis.

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 (FEV1) % 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 FEV1 % 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 FEV1 % 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 FEV1 % 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 FEV1 % 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 FEV1 % 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 FEV1 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.

Administration of 3% hypertonic saline via peripheral route: Is it really safe?

BACKGROUND: Administration of 3% sodiumchloride through a peripheral venous catheter is associated with risk of infusion-related adverse events (IRAE) due to its high osmolarity. Given this concern and the paucity of data regarding these events,many hospitals have policies that require central line administration of 3% sodiumchloride. OBJECTIVE: The objective of this analysis was to evaluate the incidence of IRAE associated with peripheral administration of 3% sodium chloride. METHODS: This analysis included patients who received 3% sodium chloride via a peripheral venous catheter between May 2017 and August 2019. The major endpoint of this analysiswas the overall incidence of IRAE, defined as the documentation of infiltration or phlebitis. Amultivariable logistic regression was performed to identify potential risk factors (e.g., age, infusion rate, infusion duration, peripheral venous catheter location, and needle gauge) for development of IRAE. RESULTS: A total of 706 administrations in 422 patientswere included. Seventy-four (10.5%) administrations were associated with a documented event. Based on the Infusion Nurses grading scale for infiltration or phlebitis, 48% of the events in this analysiswere grade 1 in severity. Duration of infusion of 3% sodiumchloride was found to be associated with an increased odds of an IRAE (OR per 1 h 1.02, 95% CI 1.01-1.02) in the multivariable analysis. Age, infusion rate, peripheral venous catheter location, and needle gauge were not independently associated with an increased risk of an IRAE. CONCLUSION: These data suggest that IRAE occurred more frequently when 3% sodium chloride was administered over a longer duration and themajority of events weremild with no permanent tissue injury. Itmay be reasonable to consider peripheral administration of 3% sodium chloride in the acute care setting for a short duration, although additional studies are needed to continue to evaluate its safety.

Safety of peripheral 3% hypertonic saline bolus administration for neurologic emergency.

BACKGROUND/OBJECTIVE: Hypertonic sodium chloride (HTS) is used for emergent treatment of acute cerebral edema and other neurologic emergencies. Central access is not commonly available in emergent situations and 3% HTS is utilized peripherally. Many studies have shown the safety of its administration at rates up to 75 mL/h, but there is a lack of data to establish the safety of peripherally administered, rapid bolus dosing in emergent situations. The objective of this study is to describe the safety of rapid, peripherally administered (≥ 250 mL/h) 3% HTS for neurologic emergencies. METHODS: This is a retrospective, cohort study including adult patients receiving 3% HTS via a peripheral IV site for elevated intracranial pressure, cerebral edema, or other neurological emergencies at a rate of at least 250 m/h between May 5, 2018 - September 30, 2021. Patients were excluded if they simultaneously received another hypertonic saline fluid. Baseline characteristics collected included HTS dose, rate and site of administration, indication for use and patient demographics. The primary safety outcome was incidence of extravasation and phlebitis within one hour of HTS administration. RESULTS: There were 206 patients receiving 3% HTS who were screened, and 37 patients met inclusion criteria. The most common reason for exclusion was administration at a rate < 250 m/h. The median age was 60 (IQR 45, 72) with 51.4% being male. The most common indications for HTS were traumatic brain injury (45.9%) and intracranial hemorrhage (37.8%). The most common administration location was the emergency department (78.4%). The median IV-gauge (n = 29) was 18 (IQR 18, 20), with the most common placement site being antecubital (48.6%). The median dose of HTS was 250 mL (IQR 250, 350), with a median administration rate of 760 mL/h (IQR 500, 999). There were no episodes of extravasation or phlebitis noted. CONCLUSIONS: Rapid, peripheral administration of 3% HTS boluses is a safe alternative for treatment of neurologic emergencies. Administration at rates up to 999 mL/h did not result in extravasation or phlebitis.