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(2021) Oh, LawrenceThesisBackground: Cervical spine degenerative conditions effect up to two-thirds of the population and are the most common cause of acquired disability in patients over the age of 50. These disorders commonly present with axial pain, myelopathy, radiculopathy or a combination of these symptoms. Surgical intervention is generally indicated in with failure of conservative management or with evidence of cord compression or myelopathy. Anterior cervical discectomy and fusion (ACDF) is an effective option. It is not well established what factors contribute to dysphagia and recurrent laryngeal nerve palsy complications following ACDF surgery. Objective: 1. To determine the rates of dysphagia and recurrent laryngeal nerve complications following ACDF reported in the literature and potential associated factors. 2. To determine rates of dysphagia and recurrent laryngeal nerve injuries in a large Australian series of ACDF by a single surgeon. Methods: For the systematic reviews, electronic searches were performed using electronic databases. Relevant studies reporting the rate of dysphagia or recurrent laryngeal nerve injury as an endpoint for patients undergoing ACDF for degenerative disease, myelopathy, cervical canal stenosis or ossification of the posterior longitudinal ligament were identified according to prior inclusion and exclusion criteria. Statistical analysis was performed using odds ratio (OR) as the effective size. I2 was used to explore heterogeneity. For the retrospective chart review, consecutive patients undergoing ACDF from 2015 to 2019 for cervical radiculopathy and/or myelopathy were included. Univariate logistic regression analysis was performed to identify risk factors of RLN palsy, swallowing problems and adjacent-level ossification disease (ALOD). Results and conclusions: We found that based on pooled analysis that there was a higher rate of dysphagia for multiple-level ACDF (6.6%) compared with single-level ACDF (4%). The pooled incidence of recurrent laryngeal nerve palsy from the literature was 1.2%, with no difference between multiple- and single-level ACDF. These rates were similar to analysis of our retrospective series, with 1.8% patients having recurrent laryngeal nerve palsy and 4.0% with clinical dysphagia. We confirm based on our series that multi-level operation was associated with higher rate of RLN palsy, but this was not affected by other factors including age, gender, and the use of plate, internal fixation or number of screws.
Flucloxacillin concentrations and clinical outcomes in Staphylococcus aureus bacteraemia, and the impact of renal impairment on flucloxacillin pharmacokinetics(2021) Duckworth, AndrewThesisBackground: Methicillin sensitive staphylococcus aureus bacteraemia (SAB) is a common cause of bacteraemia with substantial associated mortality. Flucloxacillin is one of the first line antibiotics used in the treatment of this condition. The relationship between serum flucloxacillin concentrations below the minimum inhibitory concentration (MIC) of the pathogen and clearance of bacteraemia based on blood cultures remains uncertain. In addition, flucloxacillin is renally cleared by active tubular secretion, however the current Australian dosing guidelines do not recommend dose adjustment until the eGFR is <10 ml/min/1.73m2. We investigated the impact of estimated glomerular filtration rate (eGFR) on the serum flucloxacillin concentration. Methods: Two retrospective observational studies are presented. In the first study, 138 episodes of SAB between January 2015 and December 2018 were analysed. Inclusion criteria were age > 16 years and a positive blood culture for methicillin sensitive staphylococcus aureus. Of these, there were 30 and 41 episodes in which appropriately timed trough and mid-dosage estimated free flucloxacillin concentrations [FLX]efree, respectively, were obtained within 7 days of the initial MSSA blood culture. Differences between the persistent (blood cultures positive >72 hours) and non-persistent (<72 hours) bacteraemia groups in age, sex, focus of infection and risk factors for complicated clinical course were determined. In the second study, we analysed 396 serum flucloxacillin concentrations [FLX]total, restricted to the first per hospital admission or outpatient encounter and those simultaneously co-measured with creatinine. Inclusion criteria were age > 16 years and a serum flucloxacillin concentration measured at the study institution between May 2015 and June 2020. Free flucloxacillin concentrations [FLX]efree were estimated from total concentrations using a Michaelis-Menten model for serum albumin binding. We analysed the proportion of episodes with [FLX]efree below the upper limit oxacillin MIC for methicillin-susceptible Staphylococcus aureus (1mg/L) in this cohort, and [FLX]total>125.1mg/L - a previously identified neurotoxicity threshold, respectively, by GFR quintile. Results: In the first study, the persistent and non-persistent bacteraemia groups were found to be similar in age, sex and types of infection. Sub-MIC trough concentrations were identified in 3/17 cases of persistent bacteraemia, as compared with 0/13 cases of non-persistent bacteraemia (OR 0.0; 95% CI 0.0 to 1.4; p=0.24). Sub-MIC mid-dosage concentrations were identified in 3/22 cases of persistent bacteraemia, as compared with 0/19 cases of non-persistent bacteraemia (OR 0.0; 95% CI 0.0 to 1.28; p=0.24). In the second study, of the 396 [FLX]total samples, 242 [64.7%]) were from hospital ward inpatients, 70 (18.7%) samples were obtained from patients in ICU or HDU care, while 62 (16.6%) were from outpatients. In a multivariable regression analysis, [FLXfree] negatively correlated with eGFR. Flucloxacillin concentrations stratified by GFR quintiles were determined. The proportion of episodes with [FLXfree]<1 mg/L was significantly lower in the lower GFR quintiles when compared with the higher GFR quintile (p<0.001 for trend). Conversely, [FLX] above a previously identified neurotoxicity threshold was found to be significantly more common in lower GFR quintiles as compared with higher GFR quintiles (p<0.001 for trend). Conclusions: Sub-MIC trough or mid-dosage estimated free flucloxacillin concentrations were not associated with a lower rate of persistent bacteraemia, however the wide confidence intervals include a clinically important effect, and larger studies are warranted. Flucloxacillin concentrations were significantly negatively correlated with eGFR. Potentially subtherapeutic concentrations were more common in patients in higher eGFR quintiles, while potentially neurotoxic concentrations were more common in patients in lower eGFR quintiles but above the current threshold for dose adjustment.
(2022) Sandery, BlakeThesisAcute kidney injury (AKI) occurs commonly in hospitalised children and carries an increased risk of morbidity and mortality. This thesis investigates the relationship between AKI and baseline kidney function, as this has not been well explored. We studied children exposed to acyclovir, and children with cancer, as these groups both have an increased risk of AKI. Children with cancer have been shown to have high baseline kidney function, known as glomerular hyperfiltration (GH), which is poorly understood. GH is a glomerular filtration rate above normal, which we define as a measured glomerular filtration rate (NMGFR) ³160mL/min/1.73m2. In a retrospective review of 150 children treated with acyclovir, 27 (18%) developed AKI. The only factor associated with AKI on multivariable analysis in this cohort was higher baseline estimated GFR (p=0.013). We reviewed the records of 202 children who underwent allogeneic haematopoietic stem cell transplant (HSCT) for haematological malignancy. In the first 100 days post-HSCT, 173 (85.6%) children developed AKI and stage 3 AKI occurred in 58 (28.7%). Factors significantly associated with stage 3 AKI on multivariable analysis were use of ciclosporin (vs. tacrolimus) (p=0.02), total body irradiation (p=0.01), early AKI on or before day 10 post-HSCT (p=0.001), ³10% creatinine increase 24 hours after AKI onset (p=0.001), and higher pre-HSCT NMGFR (p=0.03). At 1-year, patients with stage 3 AKI had greater reduction in estimated GFR than other children (-53.9 vs -18.8mL/min/1.73m2; p=0.0002). Analysis of the above cohort combined with the records of 91 children who underwent NMGFR at time of solid organ cancer diagnosis revealed that 16% had GH. GH was more common in young children (p=0.0055) and those with acute myeloid leukaemia (p=0.02), and was associated with higher weight gain (a surrogate for fluid accumulation) post-HSCT (p=0.02). Most children with GH pre-HSCT returned to a normal GFR. Development of GH at 1-year post-HSCT was associated with prior acute GVHD. This research is among the first to demonstrate that GH is associated with an increased risk of AKI. Our results suggest that GH occurring before HSCT may have a different underlying cause to hyperfiltration occurring post-HSCT and warrants further investigation.