Rebound hyperkalemia in a dog with albuterol toxicosis after cessation of potassium supplementation.

OBJECTIVE: To describe the presentation of rebound hyperkalemia as a delayed side effect of albuterol toxicity in a dog. CASE SUMMARY: A 3-year-old female neutered mixed-breed dog was presented for albuterol toxicosis that led to a severe hypokalemia, hyperlactatemia, and hyperglycemia. The dog also experienced sinus tachycardia and generalized weakness. Treatment was instituted with intravenous fluid therapy and potassium supplementation, and the dog was monitored with a continuous electrocardiogram. Resolution of hypokalemia was documented 12 hours after initial presentation, at which time fluid therapy and potassium supplementation were discontinued. There were no further periods of sinus tachycardia, but instead the dog developed ventricular ectopy with rapid couplets (instantaneous rates of 300/min). An echocardiogram revealed normal cardiac size and function. Twenty-four hours after presentation, the patient developed severe hyperkalemia, despite discontinuation of fluids and potassium supplementation for 12 hours. Serial venous and urinary electrolytes were performed for determination of the fractional excretion of electrolytes. These data confirmed rebound hyperkalemia (7.0 mmol/L), consistent with a markedly increased fractional excretion of potassium, and secondary to the release of potassium from inside the cells. Fluid therapy with dextrose supplementation was provided until 36 hours postpresentation. The hyperkalemia resolved, and the dog was discharged after 44 hours of hospitalization. NEW OR UNIQUE INFORMATION PROVIDED: This case documents rebound hyperkalemia following treatment of albuterol toxicosis in a dog. This case highlights the importance of understanding the distribution of total body potassium when treating serum hypokalemia. Transcellular shifts of potassium, as in the case of albuterol toxicosis, can lead to rebound hyperkalemia even after discontinuation of potassium supplementation. This case further explores the utility of fractional excretion of electrolytes in elucidating the etiology and management of electrolyte disturbances.

Clinical standards for the diagnosis and management of asthma in low- and middle-income countries.

BACKGROUND: The aim of these clinical standards is to aid the diagnosis and management of asthma in low-resource settings in low- and middle-income countries (LMICs).METHODS: A panel of 52 experts in the field of asthma in LMICs participated in a two-stage Delphi process to establish and reach a consensus on the clinical standards.RESULTS: Eighteen clinical standards were defined: Standard 1, Every individual with symptoms and signs compatible with asthma should undergo a clinical assessment; Standard 2, In individuals (>6 years) with a clinical assessment supportive of a diagnosis of asthma, a hand-held spirometry measurement should be used to confirm variable expiratory airflow limitation by demonstrating an acute response to a bronchodilator; Standard 3, Pre- and post-bronchodilator spirometry should be performed in individuals (>6 years) to support diagnosis before treatment is commenced if there is diagnostic uncertainty; Standard 4, Individuals with an acute exacerbation of asthma and clinical signs of hypoxaemia or increased work of breathing should be given supplementary oxygen to maintain saturation at 94-98%; Standard 5, Inhaled short-acting beta-2 agonists (SABAs) should be used as an emergency reliever in individuals with asthma via an appropriate spacer device for metered-dose inhalers; Standard 6, Short-course oral corticosteroids should be administered in appropriate doses to individuals having moderate to severe acute asthma exacerbations (minimum 3-5 days); Standard 7, Individuals having a severe asthma exacerbation should receive emergency care, including oxygen therapy, systemic corticosteroids, inhaled bronchodilators (e.g., salbutamol with or without ipratropium bromide) and a single dose of intravenous magnesium sulphate should be considered; Standard 8, All individuals with asthma should receive education about asthma and a personalised action plan; Standard 9, Inhaled medications (excluding dry-powder devices) should be administered via an appropriate spacer device in both adults and children. Children aged 0-3 years will require the spacer to be coupled to a face mask; Standard 10, Children aged <5 years with asthma should receive a SABA as-needed at step 1 and an inhaled corticosteroid (ICS) to cover periods of wheezing due to respiratory viral infections, and SABA as-needed and daily ICS from step 2 upwards; Standard 11, Children aged 6-11 years with asthma should receive an ICS taken whenever an inhaled SABA is used; Standard 12, All adolescents aged 12-18 years and adults with asthma should receive a combination inhaler (ICS and rapid onset of action long-acting beta-agonist [LABA] such as budesonide-formoterol), where available, to be used either as-needed (for mild asthma) or as both maintenance and reliever therapy, for moderate to severe asthma; Standard 13, Inhaled SABA alone for the management of patients aged >12 years is not recommended as it is associated with increased risk of morbidity and mortality. It should only be used where there is no access to ICS.The following standards (14-18) are for settings where there is no access to inhaled medicines. Standard 14, Patients without access to corticosteroids should be provided with a single short course of emergency oral prednisolone; Standard 15, Oral SABA for symptomatic relief should be used only if no inhaled SABA is available. Adjust to the individual's lowest beneficial dose to minimise adverse effects; Standard 16, Oral leukotriene receptor antagonists (LTRA) can be used as a preventive medication and is preferable to the use of long-term oral systemic corticosteroids; Standard 17, In exceptional circumstances, when there is a high risk of mortality from exacerbations, low-dose oral prednisolone daily or on alternate days may be considered on a case-by-case basis; Standard 18. Oral theophylline should be restricted for use in situations where it is the only bronchodilator treatment option available.CONCLUSION: These first consensus-based clinical standards for asthma management in LMICs are intended to help clinicians provide the most effective care for people in resource-limited settings.

THE INFLUENCE OF SPELEOTHERAPY ON BRONCHI PASSAGE IN CHILDREN WITH BRONCHIAL ASTHMA USING A PHARMACO-FUNCTIONAL TEST WITH SALBUTAMOL.

OBJECTIVE: The aim: To investigate the reaction of the bronchi to inhalation of salbutamol in children with different severity of bronchial asthma under the conditions of speleotherapy. PATIENTS AND METHODS: Materials and methods: 40 children aged 6-15 years were examined, 20 of them had an intermittent course of the disease, 20 had a mild course, and the children were in the inter-relapse period. Determining the function of external respiration (FER) with a pharmaco-functional test (PFT) with salbutamol was carried out in the dynamics of observation before and after treatment and compared with the indicators of 40 healthy children. Speleotherapy was performed based on the children's department of the Ukrainian Allergological Hospital of the village Solotvino. RESULTS: Results: A decrease in increased bronchial tone and restoration of bronchial patency at all levels of the bronchi in all patients with an intermittent course of the disease and a partial decrease in bronchial hyperreactivity with the improvement of bronchial patency in children with a mild course of bronchial asthma under the influence of speleotherapy was established. CONCLUSION: Conclusions: Thus, speleotherapy contributes to a positive reaction of the bronchi to inhalation of salbutamol, which is reflected in the normalization of disturbed bronchial tone and the restoration of bronchial patency at all levels of the bronchi, in all patients with an intermittent course and partially with a mild course of the disease.

Effect of inhaled albuterol on whole blood potassium concentrations in dogs.

BACKGROUND: Albuterol by inhalation (IH) is a common treatment for hyperkalemia in humans but its effect on blood potassium concentrations in dogs is unknown. OBJECTIVE: Determine whether albuterol (IH) decreases blood potassium concentrations in healthy normokalemic dogs and if effects are dose-dependent. ANIMALS: Ten healthy dogs. METHODS: Prospective, crossover experimental study. Albuterol sulfate was administered at a low-dose (90 µg) in phase I and, 7 days later, high-dose (450 µg) in phase II. Blood potassium and glucose concentrations (measured via blood gas analyzer) and heart rates were obtained at baseline and then 3, 5, 10, 15, 30, 60, 90, 120, 180, and 360 minutes after inhaler actuation. RESULTS: Blood potassium concentrations decreased rapidly after albuterol delivery with a significant reduction compared to baseline within 30 minutes in both phases (P = .05). The potassium nadir concentration of phase I occurred at 60 minutes (mean, SD; 4.07 mmol/L, 0.4) and was significantly decreased from baseline, (4.30 mmol/L, 0.3; t(9) = 2.40, P = .04). The potassium nadir concentration of phase II occurred at 30 minutes (mean, SD; 3.96 mmol/L, 0.39) and was also significantly decreased from baseline, (4.33 mmol/L, 0.4; t(9) = 2.22, P = .05). The potassium nadir concentration decreased by 0.1 mmol/L for each 10 µg/kg increase in dose of albuterol (P = .01). Five dogs had ≥1 hyperglycemic measurement (ie, >112 mg/dL). No median heart rate was tachycardic nor was any mean blood glucose concentration hyperglycemic at any time point. CONCLUSION AND CLINICAL IMPORTANCE: Albuterol IH decreases blood potassium concentrations in a dose-dependent manner without clinically meaningful alterations to heart rate or blood glucose concentrations in healthy dogs. The mean decrease in potassium concentration at the high-dose of albuterol was modest (0.38 mmol/L).

Efficacy of salmeterol and magnesium isoglycyrrhizinate combination treatment in rats with chronic obstructive pulmonary disease.

The most classic treatment recommended in the current chronic obstructive pulmonary disease (COPD) guidelines is glucocorticoid and ß2 receptor agonist combination, such as salmeterol xinafoate and fluticasone propionate (Sal/Flu), causing many adverse reactions due to hormones. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating chronic inflammation, contributing to its structure is similar to steroidal anti-inflammatory drugs. In this study, we successfully established COPD rat model by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction, as characterized by lung function decline. We discovered that salmeterol xinafoate/MgIG combination could alleviated lung inflammation infiltration, airway wall thickness (AWT) and the secretion of bronchial mucin MUC5AC of COPD rats more than salmeterol xinafoate, MgIG, or salmeterol xinafoate and fluticasone propionate treatment did, as well as reduced inflammatory cells (white blood cells, neutrophils and lymphocytes) accumulation in bronchoalveolar lavage fluid and decreased TNF-α, IL-6 and IL-1ß production in the serum of COPD rats. Finally, we found that Moreover, the mechanism involved might be related to the suppression of JAK/STAT signaling pathway. Overall, our studies suggested that MgIG might be a potential alternative adjuvant drug for fluticasone propionate for the clinical treatment of patients with COPD.

Retrospective evaluation of acute salbutamol (albuterol) exposure in dogs: 501 cases.

OBJECTIVE: To determine the common clinical signs, with onset and duration, treatments given, and outcome in dogs with acute, accidental exposure to salbutamol. DESIGN: Retrospective study. ANIMALS: Five hundred and one canine cases reported to the UK's Veterinary Poisons Information Service (VPIS). MEASUREMENTS AND MAIN RESULTS: A review of all records in the VPIS database for dogs exposed to salbutamol was carried out. After applying inclusion and exclusion criteria, the records of 501 dogs were further analyzed. The most common clinical signs were tachycardia (80.6%), tachypnea (32.9%), depression (21.0%), and vomiting (19.2%). The dose was unknown in most cases as the dogs typically pierced a salbutamol inhaler. The blood potassium concentration was measured in at least 142 dogs and hypokalemia was reported in 21.2% (106/501), 18 (17%) of which had associated weakness, twitching, or collapse. Three dogs had paralysis probably as a result of hypokalemia, although no potassium concentration was reported in these cases. Arrhythmias occurred in 17 dogs (3.4%), and 7 required pharmacological intervention. There were no reports of persistent cardiac injury or thermal injury from the compressed gas present in some salbutamol products. Signs were rapid in onset, generally within 1-3 h, and, where time to outcome was recorded (n = 172), 78% of dogs recovered within 24 h. Of the 501 dogs, no treatment was required in 27.9%. Beta-blockers were used in 39.5%, intravenous fluids in 28.7%, and potassium supplementation in 15.8%. Overall, 30 dogs remained asymptomatic (6.0%), 469 recovered (93.6%), and 2 dogs (0.4%) died. CONCLUSIONS: Most dogs exposed to salbutamol rapidly develop clinical signs; these were commonly increased heart and respiration rates. Hypokalemia and arrhythmias (particularly ventricular arrhythmias) are potential complications. Any dog that chews a salbutamol inhaler should be assessed promptly for signs of toxicosis. Prognosis in dogs with acute salbutamol exposure is good, but more guarded in those with severe tachycardia and at risk of cardiac injury.

Effect of Aerosolised Salbutamol Administration on Arterial Potassium Concentration in Anaesthetised Horses.

Aerosolized salbutamol has been associated with hypokalemia in horses undergoing colic surgery. The objective of this study was to evaluate the effect of aerosolized salbutamol on arterial potassium concentration ([K +]) in healthy anaesthetized horses undergoing elective surgery. Anesthetic records were reviewed from healthy adult horses undergoing elective surgery over a 3-year period with two complete sets of arterial electrolyte (sodium [Na +], potassium [K +], chloride [Cl -], calcium [Ca 2+]) concentration measurements. Records were excluded if intra-operative electrolyte supplementation, antimicrobial administration or noncrystalloid fluid administration were documented or if salbutamol was administered prior to electrolyte measurement. Sixty records which fulfilled inclusion criteria were divided into two groups depending on whether or not aerosolized salbutamol (2µg kg -1) (to treat hypoxemia) was administered after baseline electrolyte measurement and before the second electrolyte measurement. Aerosolized salbutamol was administered (Group S) in 22 horses and not administered (group NS) in 38 horses. There was a significant reduction in [K +] and [Ca 2+] between baseline and the second electrolyte measurement in both groups (P< .001). The reduction in [K +] between baseline and the second electrolyte measurement was significantly greater in group S (12.3%) compared to group NS (6.9%) (P= .017) and was significantly associated with salbutamol administration (P= .04). The results of this study indicate that monitoring [K +] is important in anaesthetized horses, particularly after aerosolized salbutamol administration.

Reducing Unnecessary Treatments for Acute Bronchiolitis Through an Integrated Care Pathway.

OBJECTIVES: To analyze the impact of an integrated care pathway on reducing unnecessary treatments for acute bronchiolitis. METHODS: We implemented an evidence-based integrated care pathway in primary care (PC) centers and the referral emergency department (ED). This is the third quality improvement cycle in the management of acute bronchiolitis implemented by our research team. Family and provider experiences were incorporated by using design thinking methodology. A multifaceted plan that included several quality improvement initiatives was adopted to reduce unnecessary treatments. The primary outcome was the percentage of infants prescribed salbutamol. Secondary outcomes were prescribing rates of other medications. The main control measures were hospitalization and unscheduled return rates. Salbutamol prescribing rate data were plotted on run charts. RESULTS: We included 1768 ED and 1092 PC visits, of which 913 (51.4%) ED visits and 558 (51.1%) PC visits occurred in the postintervention period. Salbutamol use decreased from 7.7% (interquartile range [IQR] 2.8-21.4) to 0% (IQR 0-1.9) in the ED and from 14.1% (IQR 5.8-21.6) to 5% (IQR 2.7-8) in PC centers. In the ED, the overall epinephrine use rate fell from 9% (95% confidence interval [CI], 7.2-11.1) to 4.6% (95% CI, 3.4-6.1) (P < .001). In PC centers, overall corticosteroid and antibiotic prescribing rates fell from 3.5% (95% CI, 2.2-5.4) to 1.1% (95% CI, 0.4-2.3) (P =.007) and from 9.5% (95% CI; 7.3-12.3) to 1.7% (95% CI, 0.9-7.3) (P <.001), respectively. No significant variations were noted in control measures. CONCLUSIONS: An integrated clinical pathway that incorporates the experiences of families and clinicians decreased the use of medications in the management of bronchiolitis.

Repurposing Melt Degradation for the Evaluation of Mixed Amorphous-Crystalline Blends.

Medicine regulators require the melting points for crystalline drugs, as they are a test for chemical and physical quality. Many drugs, especially salt-forms, suffer concomitant degradation during melting; thus, it would be useful to know if the endotherm associated with melt degradation may be used for characterising the crystallinity of a powder blend. Therefore, the aim of this study was to investigate whether melt-degradation transitions can detect amorphous content in a blend of crystalline and amorphous salbutamol sulphate. Salbutamol sulphate was rendered amorphous by freeze and spray-drying and blended with crystalline drug, forming standards with a range of amorphous content. Crystalline salbutamol sulphate was observed to have a melt-degradation onset of 198.2±0.2°C, while anhydrous amorphous salbutamol sulphate prepared by either method showed similar glass transition temperatures of 119.4±0.7°C combined. Without the energy barrier provided by the ordered crystal lattice, the degradation endotherm for amorphous salbutamol sulphate occurred 50°C below the melting point, with an onset of 143.6±0.2°C. The enthalpies for this degradation transition showed no significant difference between freeze- and spray-dried samples (p>0.05). Distinct from convention, partial integration of the crystalline melt-degradation endotherm was applied to the region 193-221°C which had no contribution from the degradation of amorphous salbutamol sulphate. The linear correlation of these partial areas with amorphous content, R2=0.994, yielded limits of detection and quantification of 0.13% and 0.44% respectively, independent of drying technique. Melt-degradation transitions may be re-purposed for the measurement of amorphous content in powder blends, and they have potential for evaluating disorder more generally.

Rapid Detection of Ractopamine and Salbutamol in Swine Urine by Immunochromatography Based on Selenium Nanoparticles.

PURPOSE: The purpose of this study was to establish a lateral flow immunoassay using selenium nanoparticles (Se-NPs) as a probe to detect ractopamine (RAC) and salbutamol (SAL) in swine urine. METHODS: SDS and PEG were used as templates to prepare Se-NPs; anti-RAC monoclonal antibodies or anti-SAL monoclonal antibodies were labelled with Se-NPs; and rapid detection kits were prepared. The sensitivity, specificity, and stability were measured, and actual samples were analysed. RESULTS: The Se-NPs were spherical with a diameter of 40.63 ± 5.91 nm, and were conjugated successfully with an anti-RAC antibody to give a total diameter of 82.33 ± 17.91 nm. The detection limit of a RAC kit in swine urine was 1 ng/mL, and that of a SAL kit was 3 ng/mL. Both procedures could be completed within 5 minutes. No cross-reaction occurred with clenbuterol, bambuterol and phenylethanolamine A. Samples were tested consistently across different batches of kits for swine urine. The results of the kits were identical to those of actual clinical samples analysed by ELISA, and the coincidence rate was 100%. CONCLUSION: The assay kit does not require any special device for reading the results, and the readout is a simple colour change that can be evaluated with the naked eye. It is easy to operate, sensitive, specific, and stable This kit is suitable for the rapid and real-time detection of RAC and SAL residues in swine urine samples. CLINICAL TRIAL REGISTRATION: Swine urines samples were used under approval from the Experimental Animal Ethics committee of the Joint National Laboratory for Antibody Drug Engineering, Henan University.

Magnesium sulphate for treating acute bronchiolitis in children up to two years of age.

BACKGROUND: Acute bronchiolitis is a significant burden on children, their families and healthcare facilities. It mostly affects children younger than two years of age. Treatment involves adequate hydration, humidified oxygen supplementation, and nebulisation of medications, such as salbutamol, epinephrine, and hypertonic saline. The effectiveness of magnesium sulphate for acute bronchiolitis is unclear. OBJECTIVES: To assess the effects of magnesium sulphate in acute bronchiolitis in children up to two years of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, and two trials registries to 30 April 2020. We contacted trial authors to identify additional studies. We searched conference proceedings and reference lists of retrieved articles. Unpublished and published studies were eligible for inclusion. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs, comparing magnesium sulphate, alone or with another treatment, with placebo or another treatment, in children up to two years old with acute bronchiolitis. Primary outcomes were time to recovery, mortality, and adverse events. Secondary outcomes were duration of hospital stay, clinical severity score at 0 to 24 hours and 25 to 48 hours after treatment, pulmonary function test, hospital readmission within 30 days, duration of mechanical ventilation, and duration of intensive care unit stay. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE methods to assess the certainty of the evidence. MAIN RESULTS: We included four RCTs (564 children). One study received funding from a hospital and one from a university; two studies did not report funding sources. Comparator interventions differed among all four trials. Studies were conducted in Qatar, Turkey, Iran, and India. We assessed two studies to be at an overall low risk of bias, and two to be at unclear risk of bias, overall. The certainty of the evidence for all outcomes and comparisons was very low except for one: hospital re-admission rate within 30 days of discharge for magnesium sulphate versus placebo. None of the studies measured time to recovery, duration of mechanical ventilation, duration of intensive care unit stay, or pulmonary function. There were no events of mortality or adverse effects for magnesium sulphate compared with placebo (1 RCT, 160 children). The effects of magnesium sulphate on clinical severity are uncertain (at 0 to 24 hours: mean difference (MD) on the Wang score 0.13, 95% confidence interval (CI) -0.28 to 0.54; and at 25 to 48 hours: MD on the Wang score -0.42, 95% CI -0.84 to -0.00). Magnesium sulphate may increase hospital re-admission rate within 30 days of discharge (risk ratio (RR) 3.16, 95% CI 1.20 to 8.27; 158 children; low-certainty evidence). None of our primary outcomes were measured for magnesium sulphate compared with hypertonic saline (1 RCT, 220 children). Effects were uncertain on the duration of hospital stay in days (MD 0.00, 95% CI -0.28 to 0.28), and on clinical severity on the Respiratory Distress Assessment Instrument (RDAI) score at 25 to 48 hours (MD 0.10, 95% CI -0.39 to 0.59). There were no events of mortality or adverse effects for magnesium sulphate, with or without salbutamol, compared with salbutamol (1 RCT, 57 children). Effects on the duration of hospital stay were uncertain (magnesium sulphate: 24 hours (95% CI 25.8 to 47.4), magnesium sulphate + salbutamol: 20 hours (95% CI 15.3 to 39.0), and salbutamol: 24 hours (95% CI 23.4 to 76.9)). None of our primary outcomes were measured for magnesium sulphate + epinephrine compared with no treatment or normal saline + epinephrine (1 RCT,120 children). Effects were uncertain for the duration of hospital stay in hours (MD -0.40, 95% CI -3.94 to 3.14), and for RDAI scores (0 to 24 hours: MD -0.20, 95% CI -1.06 to 0.66; and 25 to 48 hours: MD -0.90, 95% CI -1.75 to -0.05). AUTHORS' CONCLUSIONS: There is insufficient evidence to establish the efficacy and safety of magnesium sulphate for treating children up to two years of age with acute bronchiolitis. No evidence was available for time to recovery, duration of mechanical ventilation and intensive care unit stay, or pulmonary function. There was no information about adverse events for some comparisons. Well-designed RCTs to assess the effects of magnesium sulphate for children with acute bronchiolitis are needed. Important outcomes, such as time to recovery and adverse events should be measured.

Cervical stitch (cerclage) in combination with other treatments for preventing spontaneous preterm birth in singleton pregnancies.

BACKGROUND: Preterm birth (PTB) remains the foremost global cause of perinatal morbidity and mortality. Thus, the prevention of spontaneous PTB still remains of critical importance. In an attempt to prevent PTB in singleton pregnancies, cervical cerclage, in combination with other treatments, has been advocated. This is because, cervical cerclage is an intervention that is commonly recommended in women with a short cervix at high risk of preterm birth but, despite this, many women still deliver prematurely, as the biological mechanism is incompletely understood. Additionally, previous Cochrane Reviews have been published on the effectiveness of cervical cerclage in singleton and multiple pregnancies, however, none has evaluated the effectiveness of using cervical cerclage in combination with other treatments. OBJECTIVES: To assess whether antibiotics administration, vaginal pessary, reinforcing or second cerclage placement, tocolytic, progesterone, or other interventions at the time of cervical cerclage placement prolong singleton gestation in women at high risk of pregnancy loss based on prior history and/or ultrasound finding of 'short cervix' and/or physical examination. History-indicated cerclage is defined as a cerclage placed usually between 12 and 15 weeks gestation based solely on poor prior obstetrical history, e.g. multiple second trimester losses due to painless dilatation. Ultrasound-indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation for transvaginal ultrasound cervical length < 20 mm in a woman without cervical dilatation. Physical exam-indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation because of cervical dilatation of one or more centimetres detected on physical (manual) examination. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (26 September 2019), and reference lists of retrieved studies. SELECTION CRITERIA: We included published, unpublished or ongoing randomised controlled trial (RCTs). Studies using a cluster-RCT design were also eligible for inclusion in this review but none were identified. We excluded quasi-RCTs (e.g. those randomised by date of birth or hospital number) and studies using a cross-over design. We also excluded studies that specified addition of the combination therapy after cervical cerclage because the woman subsequently became symptomatic. We included studies comparing cervical cerclage in combination with one, two or more interventions with cervical cerclage alone in singleton pregnancies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts of all retrieved articles, selected studies for inclusion, extracted data, assessed risk of bias, and evaluated the certainty of the evidence for this review's main outcomes. Data were checked for accuracy. Standard Cochrane review methods were used throughout. MAIN RESULTS: We identified two studies (involving a total of 73 women) comparing cervical cerclage alone to a different comparator. We also identified three ongoing studies (one investigating vaginal progesterone after cerclage, and two investigating cerclage plus pessary). One study (20 women), conducted in the UK, comparing cervical cerclage in combination with a tocolytic (salbutamol) with cervical cerclage alone in women with singleton pregnancy did not provide any useable data for this review. The other study (involving 53 women, with data from 50 women) took place in the USA and compared cervical cerclage in combination with a tocolytic (indomethacin) and antibiotics (cefazolin or clindamycin) versus cervical cerclage alone - this study did provide useable data for this review (and the study authors also provided additional data on request) but meta-analyses were not possible. This study was generally at a low risk of bias, apart from issues relating to blinding. We downgraded the certainty of evidence for serious risk of bias and imprecision (few participants, few events and wide 95% confidence intervals). Cervical cerclage in combination with an antibiotic and tocolytic versus cervical cerclage alone (one study, 50 women/babies) We are unclear about the effect of cervical cerclage in combination with antibiotics and a tocolytic compared with cervical cerclage alone on the risk of serious neonatal morbidity (RR 0.62, 95% CI 0.31 to 1.24; very low-certainty evidence); perinatal loss (data for miscarriage and stillbirth only - data not available for neonatal death) (RR 0.46, 95% CI 0.13 to 1.64; very low-certainty evidence) or preterm birth < 34 completed weeks of pregnancy (RR 0.78, 95% CI 0.44 to 1.40; very low-certainty evidence). There were no stillbirths (intrauterine death at 24 or more weeks). The trial authors did not report on the numbers of babies discharged home healthy (without obvious pathology) or on the risk of neonatal death. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to evaluate the effect of combining a tocolytic (indomethacin) and antibiotics (cefazolin/clindamycin) with cervical cerclage compared with cervical cerclage alone for preventing spontaneous PTB in women with singleton pregnancies. Future studies should recruit sufficient numbers of women to provide meaningful results and should measure neonatal death and numbers of babies discharged home healthy, as well as other important outcomes listed in this review. We did not identify any studies looking at other treatments in combination with cervical cerclage. Future research needs to focus on the role of other interventions such as vaginal support pessary, reinforcing or second cervical cerclage placement, 17-alpha-hydroxyprogesterone caproate or dydrogesterone or vaginal micronised progesterone, omega-3 long chain polyunsaturated fatty acid supplementation and bed rest.

Long-acting dual bronchodilator therapy (indacaterol/glycopyrronium) versus nebulized short-acting dual bronchodilator (salbutamol/ipratropium) in chronic obstructive pulmonary disease: A double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Most guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. METHODS: This was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 µg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. RESULTS: A total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0-6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. CONCLUSION: Among patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

Development and validation of a HPLC method for quantifica-tion of degradation impurities of salbutamol sulfate with following long-term stability studies in multicomponent cough syrup.

Medicines containing both a herbal extract and a synthetic substance are in high demand due to their beneficial effects and synergism. The novel combination of salbutamol sulfate and Hedera helix extracts seems to be prospective in terms of pharmacological activity. But for quality assurance, impurities of the synthetic component have to be determined and quantified. Plant extracts consist of various phytochemical components, therefore, it is more complicated to develop a selective analytical method due to the sample matrix. To prove the safety and efficacy of the dosage form, a new HPLC method for analysis of salbutamol sulfate impurities was developed and validated. The method was used to estimate the safety of the novel syrup by performing long-term stability studies for 24 months. Obtained results indicated the absence in both significant reducing of the main components content and increasing of related substances level. Also, force degradation was carried out to prognosticate the possibility of impurities producing.

Reducing Albuterol Use in Children With Bronchiolitis.

OBJECTIVES: In 2014, the American Academy of Pediatrics published bronchiolitis guidelines recommending against the use of bronchodilators. For the winter of 2015 to 2016, we aimed to reduce the proportion of emergency department patients with bronchiolitis receiving albuterol from 43% (previous winter rate) to <35% and from 18% (previous winter rate) to <10% in the inpatient setting. METHODS: A team identified key drivers of albuterol use and potential interventions. We implemented changes to our pathway and the associated order set recommending against routine albuterol use and designed education to accompany the pathway changes. We monitored albuterol use through weekly automated data extraction and reported results back to clinicians. We measured admission rate, length of stay, and revisit rate as balancing measures for the intervention. RESULTS: The study period included 3834 emergency department visits and 1119 inpatient hospitalizations. In the emergency department, albuterol use in children with bronchiolitis declined from 43% to 20% and was <3 SD control limits established in the previous year, meeting statistical thresholds for special cause variation. Inpatient albuterol use decreased from 18% to 11% of patients, also achieving special cause variation and approaching our goal. The changes in both departments were sustained through the entire bronchiolitis season, and admission rate, length of stay, and revisit rates remained unchanged. CONCLUSIONS: Using a multidisciplinary group that redesigned a clinical pathway and order sets for bronchiolitis, we substantially reduced albuterol use at a large children's hospital without impacting other outcome measures.

A Respiratory Therapist-Driven Asthma Pathway Reduced Hospital Length of Stay in the Pediatric Intensive Care Unit.

BACKGROUND: Asthma is a common reason for admissions to the pediatric intensive care unit (PICU). Since June 2014, our institution has used a pediatric asthma clinical pathway for all patients, including those in PICU. The pathway promotes respiratory therapist-driven bronchodilator weaning based on the Modified Pulmonary Index Score (MPIS). This pathway was associated with decreased hospital length of stay (LOS) for all pediatric asthma patients; however, the effect on PICU patients was unclear. We hypothesized that the implementation of a pediatric asthma pathway would reduce hospital LOS for asthmatic patients admitted to the PICU. METHODS: We retrospectively reviewed the medical records of all pediatric asthma subjects 2-17 y old admitted to our PICU before and after pathway initiation. Primary outcome was hospital LOS. Secondary outcomes were PICU LOS and time on continuous albuterol. Data were analyzed using the chi-square test for categorical data, the t test for normally distributed data, and the Mann-Whitney test for nonparametric data. RESULTS: A total of 203 eligible subjects (49 in the pre-pathway group, 154 in the post group) were enrolled. There were no differences between groups for age, weight, gender, home medications, cause of exacerbation, medical history, or route of admission. There were significant decreases in median (interquartile range) hospital LOS (4.4 [2.9-6.6] d vs 2.7 [1.6-4.0] d, P < .001), median PICU LOS (2.1 [1.3-4.0] d vs 1.6 [0.8-2.4] d, P = .003), and median time on continuous albuterol (39 [25-85] h vs 27 [13-42] h, P = .001). Significantly more subjects in the post-pathway group were placed on high-flow nasal cannula (32% vs 6%, P = .001) or noninvasive ventilation (10% vs 4%, P = .02). CONCLUSION: The implementation of an asthma pathway was associated with decreased hospital LOS, PICU LOS, and time on continuous albuterol. There was also an increase in the use of high-flow nasal cannula and noninvasive ventilation after the implementation of this clinical pathway.

Anti-asthmatic activity of alkaloid compounds from Pericarpium Citri Reticulatae (Citrus reticulata 'Chachi').

Pericarpium Citri Reticulatae (PCR, Citrus reticulata 'Chachi', Guangchenpi in Chinese) is one of the most famous Chinese citrus herbal medicines. The in vivo anti-asthmatic activity of 'Chachi' PCR was investigated using a histamine-induced experimental asthma model in Guinea pigs. Two alkaloid-type compounds, synephrine and stachydrine, were analyzed and identified in the 'Chachi' PCR alkaloid fraction. The alkaloid fraction and synephrine protected Guinea pigs against histamine-induced experimental asthma in a dose-dependent manner. The respective application of high, middle, and low doses of the 'Chachi' PCR alkaloid fraction significantly increased specific airway resistance by 284%, 328%, and 355%, and decreased dynamic compliance by 57%, 67%, and 75%. A similar change was observed for synephrine. The expression of eosinophils in bronchoalveolar lavage fluid (BALF) and serum IgE, IL-4, and IL-5 levels in histamine-induced experimental asthmatic Guinea pigs were significantly downregulated by the 'Chachi' PCR alkaloid fraction and synephrine compared to the control group, whereas stachydrine did not impart a statistically significant effect on the expression of tested inflammatory cells (leucocytes, eosinophils, neutrophils, and lymphocytes), immunoglobulin (IgE), or cytokines (IL-4 and IL-5). Pathological changes in lung tissues in each treatment group included the infiltration of inflammatory cells around the bronchia.

Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways.

Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200 mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator.

Evaluation of the anti-asthmatic and antitussive potentials of methanol leaf extract of Napoleona vogelii in rodents.

Napoleona vogelii is used in ethnomedicine for the treatment of asthma and cough. This study evaluated antiasthmatic and antitussive properties of its methanol leaf extract (NVE) in rodents. Phytochemical screening was conducted using established methods. Acute oral toxicity test was done in mice and guinea pigs. Ovalbumin (OA)-sensitized guinea pigs were orally pretreated with 100, 200 or 400 mg/kg/day of NVE or 0.5 mg/kg/day of salbutamol for 14 days before exposure to 0.2% histamine aerosol. Latency to preconvulsive dyspnea (PCD), tracheal fluid volume (TFV), flow rate (FR), and tracheal morphometry (TM) were evaluated. Tracheal rings from sensitized guinea pigs were tested in organ baths for antispasmodic and spasmolytic effects. Citric acid and ammonium hydroxide cough models were used to evaluate antitussive effects in guinea pigs and mice respectively. Tannins, alkaloids, flavonoids, and phenolic substances were found in NVE. LD50 values in mice and guinea pigs were greater than 5000 mg/kg. NVE caused a significant (P < 0.05) increase in the latency to PCD and a decrease in TFV in the group treated with 200 mg/kg. TM indicated a reduction in airway narrowing in NVE-treated groups. The presence of NVE significantly attenuated responses of tracheal rings to carbachol. Its addition to carbachol precontracted rings resulted in significant relaxation. Emax for calcium concentration-response was significantly (P < 0.01) decreased in the presence of NVE. Cough bouts dose-dependently decreased significantly (P < 0.05) in guinea pigs and mice. We conclude that NVE seems safe and possesses anti-asthmatic effect that involves inhibition of calcium influx. It also has antitussive properties that may be peripherally mediated.

Development of novel gastroretentive salbutamol sulfate-loaded sodium alginate-pectin bubble beads prepared by co-axial needle air-injection method and in vivo clinical evaluation by ultrasound studies.

In the present study, the salbutamol sulfate-loaded sodium alginate-pectin (SS-loaded SA-PEC) bubble beads have been optimized and evaluated for drug loading, in vitro drug release, in vivo floating behavior in the stomach, etc. Nine batches (F1-F9) of bubble beads with different SA and PEC contents were prepared by novel co-axial needle air-injection method and related to their percent drug loading efficiency (%DLE) and percent drug release at 4 h (%R4h) as response factors. The multivariate analysis has shown the effect of SA/PEC ratio, total polymer content, as well as their interaction on %DLE and %R4h. In the quantitative modeling, the satisfactory adjustment of the linear models (along with interaction terms) with the experimental data for both %DLE and %R4h has confirmed the findings of the multivariate analysis. The optimized SS-loaded SA-PEC bubble beads based on 2D (contours), 3D, desirability, and overlay plots has exhibited %DLE of 87.35 ±â€¯2.48% (n = 3 and error = 2.94%) and %R4h of 85.79 ±â€¯2.98% (n = 3 and error = 0.25%). The in vitro drug release studies have shown almost complete (≥85%) SS release from all the batches within 4-6 h in simulated gastric fluid (SGF) pH 1.2. The in vivo clinical findings by ultrasound studies have shown excellent floatation (>6 h) behavior of bubble beads in the upper gastrointestinal tract (GIT) and efficient stomach-specific gastroretention.