Skin-to-deltoid-muscle distance at three recommended sites for intramuscular vaccination in a population with obesity: an observational study.

AIM: Worldwide, immunisation guidelines variably locate the deltoid injection site based on anatomical landmarks. This may influence the skin-to-deltoid-muscle distance and therefore the needle length required to achieve intramuscular injection. Obesity is associated with increased skin-to-deltoid-muscle distance, but it is unknown whether the injection site location chosen in individuals with obesity impacts the needle length required for intramuscular injection. The aim of the study was to estimate the differences in skin-to-deltoid-muscle distance between three different vaccine injection sites recommended by the national guidelines of the United States of America (USA), Australia and New Zealand, in obese adults. The study also explored i) the associations between skin-to-deltoid-muscle distance across the three recommended sites with sex, body mass index (BMI), and arm circumference, and ii) the proportion of participants with a skin-to-deltoid-muscle distance >20 millimetres (mm), in whom the standard 25mm needle length would not ensure deposition of vaccine within the deltoid muscle. METHOD: Non-interventional cross-sectional study in a single site, non-clinical setting in Wellington, New Zealand. Forty participants (29 females), aged ≥18 years, with obesity (BMI>30 kilograms [km]/m[[2]]). Measurements included distance from acromion to injection sites, BMI, arm circumference, and skin-to-deltoid-muscle distance measured by ultrasound at each recommended injection site. RESULTS: Mean (SD) skin-to-deltoid-muscle distances for USA, Australia and New Zealand sites were 13.96mm (4.54), 17.94mm (6.08) and 20.26mm (5.91) respectively, with a mean (95% confidence interval) for the distance between Australia minus New Zealand -2.7mm (-3.5 to -1.9), P<0.001; and USA minus New Zealand -7.6 mm (-8.5 to -6.7); P<0.001. Skin-to-deltoid-muscle distance was greater in females and was positively associated with BMI and arm circumference. The proportions with a skin-to-deltoid-muscle distance >20 mm were 45%, 40% and 15% for the New Zealand, Australia and USA sites respectively. However, the sample size was relatively small, limiting interpretation in specific sub-groups. CONCLUSION: There were marked differences in the skin-to-deltoid-muscle distance between the three recommended injection sites studied. When choosing the required needle length to achieve intramuscular vaccination in obese vaccine recipients, consideration needs to be given to the injection site location, sex, BMI and/or arm circumference, as these factors all influence the skin-to-deltoid-muscle distance. A standard needle length of 25mm may be insufficient to ensure deposition of vaccine into the deltoid muscle in a substantive proportion of adults with obesity. Research is urgently required to determine anthropometric measurement cut-points that can be used to enable appropriate needle length selection to ensure intramuscular vaccination.

When should a longer needle be used for intramuscular injection in obese patients? A combined analysis of New Zealand data.

AIM: To estimate thresholds for Body Mass Index (BMI) and arm circumference above which a longer needle is needed to ensure intramuscular (IM) delivery of a vaccine in the deltoid muscle at the site recommended by New Zealand (NZ) immunization guidelines. METHODS: A combined analysis of two studies, including 442 adults, with measurements of arm circumference, BMI and skin to deltoid muscle distance (SDMD) at the NZ immunization guideline-recommended IM injection site. Receiver Operator Characteristic curves identified arm circumference and BMI cut-points that gave 100% sensitivity for SDMD thresholds. These thresholds were: SDMD of 20 mm, accounting for a minimal penetration of 5 mm into muscle with the standard needle; and 25 mm, which is the length of a standard needle for IM injection, representing the depth this can reach. RESULTS: Cut-point values for arm circumference, at which a longer needle would be required, were higher for males than females: 35 cm versus 30 cm for the 20 mm cut-point, and 40 cm versus 36.7 cm for the 25 mm cut-point respectively. The BMI cut-points were also higher for male than females: 24.6 kg/m2 versus 23.7 kg/m2 for the 20 mm cut-point, and 38.2 kg/m2 vs 31.6 kg/m2 for the 25 mm cut-point respectively. CONCLUSION: Arm circumference and BMI cut-points provide practical measures from which to choose a needle length that increases the chance of successful IM vaccination. Based on our data, an arm circumference of 35 cm for men and 30 cm for women should prompt selection of a longer needle to ensure intramuscular injection at the deltoid site. Thresholds for the different skin to deltoid sites proposed internationally should be determined to enable successful IM vaccination in clinical practice beyond NZ.

What variables should inform needle length choice for deltoid intramuscular injection? A systematic review.

OBJECTIVES: (1) Assess the distribution of skin-to-deltoid-muscle distance (SDMD) at the deltoid intramuscular (IM) injection site; (2) its relationship with demographic and anthropometric variables and (3) Consider the findings in relation to clinical guidance on IM injection, such as COVID-19 vaccines. DESIGN: Systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL and SCOPUS between June and July 2021 with no publication date limit. ELIGIBILITY CRITERIA: Studies reporting measurements of the SDMD in living adults aged 16 years and older, at the deltoid IM injection site, published in English were considered. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed each stage of screening, data extraction and quality assessments using the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross sectional studies. RESULTS: 16 105 papers were identified, of which 11 studies were suitable for review, representing 1414 participants. Heterogeneity in the definition of the deltoid IM injection site, locations measured and methods of measurement precluded meta-analysis. Evidence from ultrasound SDMD measurements demonstrated some patients in all but 'underweight' body mass index (BMI) categories, may require needles longer than 25 mm for successful IM injection. Calliper measurements overestimated SDMD compared with ultrasound. Female sex, higher BMI categories and greater weight in women were associated with greater SDMD. CONCLUSIONS: The reviewed evidence was insufficient to inform definitive needle length 'cut points' for IM injection based on demographic or anthropomorphic variables. Contemporary clinical guidance currently based on this evidence, including the site of injection and choice of needle length, may result in subcutaneous administration in a small proportion of recipients, particularly if obese or of female sex. PROSPERO REGISTRATION NUMBER: CRD42021264625.

COVID-19 vaccination and the skin to deltoid MUSCLE distance in adults with diabetes.

Objectives: To estimate the proportion of adult diabetics with a skin to deltoid muscle distance (SDMD) of > 25 mm, representing a distance greater than the standard needle length used for intramuscular COVID-19 vaccination, and to assess whether anthropometric measurements predict ultrasound SDMD measurements. Design: Non-interventional cross-sectional study. Setting: Single site, non-clinical setting, Wellington, New Zealand. Participants: One hundred participants (50 females) aged at least 18 years diagnosis with diabetes. All participants completed the study. Main outcome measures: The proportions of participants with a SDMD > 25 mm and a SDMD > 20 mm (indicating that the needle would not have penetrated at least 5 mm into the deltoid, which is considered necessary to ensure deposition of vaccine into muscle); the relationship between anthropometric measurements (body weight, body height, body mass index (BMI), skinfold thickness, arm circumference) and SDMD measured by ultrasound. Results: The proportion (95 %CI) of participants with a SDMD > 25 mm was 6/100; 6 % (2.2 to 12.6), and the proportion with a SDMD > 20 mm was 11 % (5.6 to 18.8), of which 9/11 had a BMI ≥ 30 kg/m2 and 9/11 were female. The strongest relationships between anthropometric measurements and SDMD were with arm circumference (r = 0.76, P < 0.001) and BMI (r = 0.73, P < 0.001). Arm circumference and BMI were the best predictors of SDMD measurements with AUC for ROC curves of 0.99 and 0.94 above the 25 mm cut point, 0.97 and 0.89 above the 20 mm cut point respectively. Conclusions: The standard needle length of 25 mm is likely to be insufficient to ensure deposition of COVID-19 vaccine within the deltoid muscle in a small but important proportion of obese adults with diabetes. Arm circumference and BMI are simple measurements that could identify those that need a long needle to ensure successful intramuscular vaccine administration. Funding: Ruth Maud Ring Spencer Estate; Health Research Council of New Zealand (Independent Research Organisation).

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Cannabis in Palliative Care: A Systematic Review of Current Evidence.

CONTEXT: Palliative care aims to improve the quality of life in patients with incurable illness. Medicinal cannabis (MC) has been used in the palliative care setting to address multiple symptoms in patients. OBJECTIVES: To evaluate the full scope of available literature investigating the effects and potential harms of MC on symptom management and quality of life in palliative care. METHODS: PubMed, Embase, The Cochrane Library and clinicaltrials.gov were searched for eligible articles, published between 1960 and September 9, 2021. Quality of the evidence was assessed in accordance with Grading of Recommendations, Assessment, Development and Evaluations. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for non-randomized trials. RESULTS: Fifty-two studies (20 randomised; 32 non-randomised) with 4786 participants diagnosed with cancer (n = 4491), dementia (n = 43), AIDS (n = 235), spasticity (n = 16), NORSE syndrome (n = 1) were included. The quality of evidence was 'very low' or 'low' for all studies, and low for only two randomised controlled trials. Positive treatment effects (statistical significance with P < 0.05) were seen for some MC products in pain, nausea and vomiting, appetite, sleep, fatigue, chemosensory perception and paraneoplastic night sweats in patients with cancer, appetite and agitation in patients with dementia and appetite, nausea and vomiting in patients with AIDS. Meta-analysis was unable to be performed due to the wide range of cannabis products used and the heterogeneity of the study outcomes. CONCLUSION: While positive treatment effects have been reported for some MC products in the palliative care setting, further high quality evidence is needed to support recommendations for its use in clinical practice.

Repeated dose budesonide/formoterol compared to salbutamol in adult asthma: A randomised cross-over trial.

OBJECTIVE: To determine the comparative bronchodilator, systemic beta2-agonist, cardiovascular and adverse effects of salbutamol 200 µg and budesonide/formoterol 200/6 µg when taken repeatedly in stable asthma. METHODS: This open-label, cross-over, single-centre, controlled trial, randomised adults with asthma to different orders of two treatment regimens: salbutamol 200 µg via MDI at t=0, 30, 60, 90 min, then salbutamol 2.5 mg via nebuliser at t=120, 140, 160 and 420 min; or budesonide/formoterol 200/6 µg one actuation via Turbuhaler at t=0, 30, 60, 90 min, two actuations at t=120, 140, 160 and 420 min. The primary outcome measure was FEV1 after 180 min. Secondary outcomes included repeat measures of FEV1, serum potassium, heart rate, and adverse events RESULTS: Of 39 patients randomised, two withdrew due to adverse events (QTCF prolongation and T wave abnormalities) after the first intervention with salbutamol. The mean (sd) change from baseline FEV1 180 min after randomisation for salbutamol and budesonide/formoterol regimens was 0.71 (0.46) L, N=38, and 0.58 (0.45) L, N=37, respectively; with a mean (sd) paired difference of -0.10 (0.40) L, N=37, and a model-based estimated difference (95% CI) -0.12 (-0.25 to 0.02) L, p=0.088. In the main secondary analysis, salbutamol resulted in significantly greater FEV1 from 30 to 240 min, but lesser FEV1 at 360 and 420 min. Salbutamol resulted in a significantly lower serum potassium, and a higher heart rate and number of adverse events. CONCLUSION: The comparative bronchodilator responses of repeated administration of salbutamol 200 µg dose-1 and budesonide/formoterol 200/6 µg differed depending on the time of measurement. Salbutamol caused greater systemic beta2-agonist and cardiovascular effects and more adverse events.

Underestimation of COVID-19 mortality during the pandemic.

BACKGROUND: There has been considerable international variation in mortality during the COVID-19 pandemic. The objective of this study was to investigate the differences between mortality registered as due to COVID-19 and the excess all-cause mortality reported in countries worldwide during the COVID-19 pandemic. METHODS: Ecological analysis of 22 countries compared 5-year historical all-cause mortality, reported all-cause mortality and expected all-cause mortality (calculated as historical mortality plus the reported deaths attributed to COVID-19). Data available from the first week of January 2020 to that most recently available were analysed. RESULTS: Compared to the preceding 5 years, there was an excess of 716 616 deaths, of which 64.3% were attributed to COVID-19. The proportion of deaths registered as COVID-19-related/excess deaths varied markedly between countries, ranging between 30% and 197% in those countries that had an excess of deaths during the period of observation. In most countries where a definite peak in COVID-19-related deaths occurred, the increase in reported all-cause mortality preceded the increase in COVID-19 reported mortality. During the latter period of observation, a few countries reported fewer all-cause deaths than the historical figures. CONCLUSION: The increases in all-cause mortality preceded the increase in COVID-19 mortality in most countries that had definite spikes in COVID-19 mortality. The number of deaths attributed to COVID-19 was underestimated by at least 35%. Together these findings suggest that calculation of excess all-cause mortality is a better predictor of COVID-19 mortality than the reported rates, in those countries experiencing definite increases in mortality.

Medicinal applications of cannabis/cannabinoids.

Regulatory approvals for Epidiolex (purified cannabidiol) in the treatment of childhood drug resistant epilepsy have set a precedent for the use of cannabinoids as a prescribed medicine. Two common reasons cited for the use and prescription of cannabis-based products are pain and insomnia. Unlike drug resistant epilepsy, the level of evidence of efficacy in pain is poorly developed. The lowest quality trials with the greatest methodological shortcomings suggest some benefit, a level of evidence that is inconsistent with widespread prescribing. The evidence in insomnia is scant. Ongoing trial development and critical review of the literature should not be overshadowed by increasing permissiveness towards cannabis use and anecdotal reports of efficacy.

A systematic review of the label accuracy of cannabinoid-based products in regulated markets: is what's on the label what's in the product?

OBJECTIVES: To review the literature regarding label accuracy and contamination of medical cannabinoid-based products. METHODS: A systematic review with meta-analysis following PRISMA guidelines. This study is registered with PROSPERO (CRD42019131565). RESULTS: Five studies reported label accuracy data ranging between 17% and 86%. Four studies reported contaminants, including pesticides, solvents and AB-FUBINACA. Meta-analysis was limited to the proportion of pesticide-contaminated samples found in two studies (0.25 (95% CI [0.10, 0.40])) and displayed significant heterogeneity. CONCLUSIONS: Label inaccuracies and contaminants are found across a spectrum of cannabinoid-based products. The review highlights the paucity and heterogeneity of research relating to cannabinoid-based products in light of changing global legislation. Further robust research is required to support ongoing pharmacovigilance and patient safety.

Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Insomnia is associated with significant comorbidity, disability and impact on quality of life and, despite advances in pharmacotherapy and psychotherapy, remains a significant burden to society. Cannabinoids are gaining acceptance for use as medicines in the treatment of insomnia disorder. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the efficacy of cannabinoids in the treatment of insomnia disorder. METHODS: We performed a systematic review of the PubMed, Cochrane Library, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature Complete databases from inception to 5 December 2019, and again prior to data abstraction, for studies of cannabis-based products for the treatment of insomnia disorder in adults. Inclusion criteria were (1) clinical studies, (2) participants aged ≥ 18 years, (3) insomnia disorder either formally diagnosed against contemporaneous diagnostic criteria or quantified with validated instruments and (4) compared cannabis-based products with the standard of care, placebo or a sedative. No language restrictions were imposed. Non-primary research, animal studies and studies of cannabis-induced insomnia were excluded. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials (RCTs) and Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for non-randomized trials. Heterogeneity was assessed with the I2 statistic. RESULTS: A total of five studies (two RCTs and three non-randomised studies) with 219 study participants were included, of which three could be combined. The three non-randomised studies contributed data on the Pittsburgh Sleep Quality Index Questionnaire score, showing a favourable effect of cannabinoids at ≤ 4 weeks of follow-up (mean difference - 1.89 [95% confidence interval {CI} - 2.68 to - 1.10]; n = 176) and at 8 weeks of follow-up (mean difference - 2.41 [95% CI - 3.36 to - 1.46]; n = 166). One double-blind crossover RCT (n = 32) reported that, compared with amitriptyline, nabilone-a synthetic analogue to tetrahydrocannabinol (THC)-improved Insomnia Severity Index scores after 2 weeks of treatment (adjusted difference - 3.25 [95% CI - 5.26 to - 1.24]) and resulted in a more restful sleep as a sub-measure of the Leeds Sleep Evaluation Questionnaire (LSEQ) (difference 0.48 [95% CI 0.01-0.95]) but with no effect on overall sleep quality as measured by the LSEQ. In a single ascending-dose RCT (n = 9), THC reduced sleep-onset latency compared with placebo at 10 mg, 20 mg and 30 mg doses (mean difference - 43.00 min [95% CI - 82.76 to - 3.24], - 62.00 [95% CI - 103.60 to - 20.40] and - 54.00 [95% CI - 103.93 to - 4.07], respectively). All the included studies were assessed as poor quality, mainly due to small sample sizes, short treatment periods, uncertain clinical significance and high risk of bias. CONCLUSIONS: Few studies have examined the efficacy of cannabinoids in the treatment of insomnia disorder. Despite some possible signals for efficacy, the heterogeneity of participants, interventions, efficacy outcomes and results, and the high risk of bias across included trials, do not reliably inform evidence-based practice. This review highlights shortcomings in the existing literature, including lack of diagnostic clarity, poorly defined participant groups, non-standardised interventions and studies of inappropriate design, duration and power to detect clinically meaningful outcomes. Further research in the form of high-quality RCTs are required before drawing any conclusions about the efficacy of cannabinoids in the treatment of insomnia disorder. TRIAL REGISTRATION: PROSPERO registration number, CRD42020161043.