TCS Weeks 1-5 Bible PDF

Bachelor of Medical Studies MEDICST3502 - Transition to Clinical Studies T.C.S Bible LRH Health and Society Week 1 – Aboriginal Community Controlled Health Sector Learning Objectives Describe Aboriginal and Torres Strait Islander holistic concepts of wellbeing and Aboriginal and Torres Strait Islander health models, including programs and Aboriginal and Torres Strait Islander specific interprofessional healthcare teams that can enhance patient health outcomes (H&S LO). Describe Aboriginal and Torres Strait Islander models of health care, including community and sociocultural strengths (S&S LO). Describe best practice approaches that lead to improved and sustained positive Aboriginal and Torres Strait Islander health and wellbeing outcomes (S&S LO). Aboriginal health is far from limited to physical well-being, instead refers to the social, emotional and cultural well-being of the whole community in which everyone is able to achieve their full potential as a human being. Subsequently, this results in improved well-being of the entire community. It is a whole of life view and includes the cyclical concept of life-death-life. One of the key bodies in South Australia supporting indigenous primary care is the Aboriginal Health Council of South Australia. This team is responsible for representing the Aboriginal community-controlled health services and the substance misuse services. They act as a health voice for all ATSI in South Australia. They are a state affiliate of the national aboriginal community-controlled organisation (NACCHO) which is the peak national body. Community control is the ability for the people who are going to use the health service to participate in their planning, implementation and evaluation. AHCSA Programs include: These services also form a major employer of indigenous people, promotes intersectoral collaboration, focuses on comprehensive primary care and is highly cost effective. Aboriginal health workers and practitioners provide a range of clinical and non-clinical comprehensive primary care, AHPs are registered with AHPRA and provide culturally based health services that are based on lived experience with racism, colonisation etc. This was particularly evident in the ACCHO COVID-19 Response which led to outstanding care and prevention in COVID-19. Main challenges include funding, competitive tendering, excessive reporting requirements and fragmented funding, short term contracts and body part funding (opposed to general health funding). There are 8 key characteristics of indigenous primary health service delivery: 1. Culture 6. Flexible approach to care 2. Accessible 7. Holistic health care 3. Community participation. 8. Self-determination and 4. Continuous quality improvement empowerment. 5. Culturally appropriate and skilled workforce Week 3 – Transmission Dynamics of Vector Borne Disease Learning Objectives Describe the relationship between climate change and vector-borne disease transmission. Recall and apply the Ross-McDonald model of malaria transmission. Explain a range of control measures for vector-borne diseases and describe how they can be evaluated Transmission of viral/vector borne disease is dependent on four overarching factors. 1) Probability of a trasnsmission in a contract between an infected individual and a susceptible one. 2) Frequency of contracts in the population and contact patterns. 3) Duration of infectiousness 4) Proportion of the population that are already immune and not susceptible. The basic reproductive rate of infectious disease is denoted as: 𝑅0 = 𝛽 × 𝜅 × 𝐷 Where: - B = Risk of transmission per contact (decreased by condoms, facemasks ect. - K = Average number of contacts per time unit. - D = duration of infectiousness measured by the same time units are K. Ross-Macdonald model is used to monitor transmission of vector borne disease. 𝑅0 = 𝑚𝑎2 𝑏𝑐𝐷𝐻 𝐷𝑀 Where: - M=number of mosquitos per person. o E.g. fumagating, sterilisation. - A = mosquito biting rate - B = mosquito to human probability per bite. - C = Himan to mosquito transmission probability per bite - DH = Duration of human infection o Medications etc. - DM = Duration of mosquito infection. As a result of a being to the second power, interventions (such as mosquito nets etc) will have the greatest impact on infection rates as it will quarter the infection rate, whereas the rest to a ratio of 2. Control measures should be evaluated by: 1) Cost effective? 2) How well will it work? 3) Is it safe? 4) Who will have access to the benefits? 5) Is the infrastructure available? 6) Will the benefits be sustained. Week 4 – Health Economics Learning Objectives Describe the role of economic evaluation in the context of making a decision about providing healthcare to society, using the concepts of scarcity, choice and opportunity cost. Scarcity Health economics broadly is how individuals, business, governments and societies drive decisions about what we do with what is available. Essentially driving choices between alternate options. - The study of how scarce resources are allocated among alternative uses for the care of sickness and the promotion, maintenance and improvement of health, including the study of how health care and health related services, their costs and benefits and health itself are distributed among individuals and groups in society – BMJ. Ensures efficiency and effectiveness in health whilst ensuring affordability. Whilst wants in healthcare are essentially unlimited, there is constraints given scarcity of resources, both financial and physical. Scarcity is also driven by real inputs required to produce goods and services (Labor, energy and other physical resources), even if money is unlimited. Opportunity Cost The theory that every choice made under scarcity had a opportunity cost, whereby the potential benefit that is loss through the decision to fund one option over another. Whereby if the opportunity cost is greater than the benefit gained, this suggests a poor allocation of resources. Conversely, should a decision result in opportunity cost less than of the benefits gained, it is a good decision. The theory of opportunity cost is far from limited to monetary gain/loss. In health, estimating opportunity cost is difficult, particularly in public health given that the opportunity cost may result in divestment from other government funded areas (e.g. education, military). Factors that may impact health related funding includes: - Diagnostic capabilities/treatment capabilities etc. - Frequency f use. - Distance to the next-nearest hospital and what is their current available technology/treatment etc. - Potential monetary benefits. - Training requirements. - Surrounding population demographics and health priorities Resource allocation must also consider the overall budget and the priorities of that given health system. Another consideration is that there are some areas at which healthcare funding shortages cannot address, for example, money cannot buy necessary organ transplants. Decisions in Health Decision makers in health include: - Personal level – decisions about treatments and monitoring are often made by the patient and a healthcare worker in consultation. - Institutional and societal level, whereby these people are in positions of authority who decide what healthcare products and services will be made accessible and whether or not it will be publicly funded. These decisions about the availability of products or services are denoted as regulatory decisions. These restrict the availability of products and services out of concern for public safety. Often relating to laws, regulations and rules. The two major bodies responsible for this are the TGA and AHPRA. There are also state authorities responsible for overseeing hospital and other heath regulation. Whilst public safety is priotised over economic efficiency, it is often the case that regulatory decisions impact both. Economical decisions are better described as reimbursement decisions. These decisions are typically made after regulatory bodies have decided that the product is safe. This is based on: - Does the service provide good value for money. - Is it affordable, both in the short term and the long term. These decisions are made by the MSAC and PBAC. At a state level, thereare various committees that determine the regulatory and reimbursement decision making roles. Economic efficiency or cost effectiveness relies on the value (in this case the health outcomes) being greater than the healthcare resources required to obtain the service and product. It is up to those funding the good or service to decide whether it is cost- effective. In health this is particularly complex, mainly for service, as there is not just the net equipment expenditure, but also the staffing, training etc. Good-value, Is a subjective measure of whether this product or service is viable. These assessments are always comparative and always involves an alternate course of action (e.g. watchful waiting etc). Health Economic Costs It is important to denote that human costs are not classified as costs in economic evaluation and are considered health outcomes consequential of the economic outcome. Health costs are strictly a measure of healthcare resources use. Resources often fall into: - Labour - Land - Capital (either physical or monetary) In most cases, market has already been established and a recognised price for any of these elements has already been produced. Rarely are costs needed to be assigned to a product. Costs may also occur at different points of time for a product or service that may be upfront, downstream or averted costs. Costs should be reported with the types of resources used, the number of units of each type and the unit price. This should estimate total economic cost of an intervention. Currency and setting are also notable factors that may further impact these results. A health outcome is simply of a measure of health that is quantifiable based on a individual or population basis. E.g. pain score. Outcomes may include health events, time period of events or health states. There are four types: 1. Surrogate Outcomes: Proxy indicators of health and they are measures that a clinician can measure or assess easily and objectively. These are great for cause-effect outcomes. They may differ in various circumstances or events. 2. Intermediate and disease specific outcomes. E.g. Cases of MI, or changes in pain score. a. Intermediate outcomes are an earlier manifestation of disease but may also be a surrogate outcome for final or patient relevant outcomes. b. Disease specific are a type of intermediate outcomes. 3. Final Outcomes are irreversible and will not change with later observation or more follow up. E.g. survival or life years gained as a result of ann intervention. 4. Patient reported outcome measures and quality of life based on patient collected data via questionnaires. In health economics, both quality and quantity of life are considered a value hence the health outcome measure of health adjusted life years aims to cover both. Another one is quality adjusted life years (QALY) produced through multiplying number of years of life by the utility value (0 – 1, 0 being worst, 1 being best). This is measured using multi- attribute utility instruments over multiple domains which can be transformed into a linear scale using preference based instruments. Comparative Evaluation Cost Analysis and cost Minimisation Analysis is the most simple form of analysis whereby the costs of a program are subtracted from the overall cost benefit to produce a figure. Cost minimalization analysis is where two alternatives result in equivalent health outcomes and requires good clinical evidence. It establishes that an intervention is least as good as another and is simpler. This assumption however is critical. Cost-Effectiveness Analysis compares cost of an intervention to the benefit it produces forming an incremental cost-effectiveness ratio. This requires identification of the health outcome most important to the patient affected, evidence of quantitative difference in health outcome, estimates of complete resource use. This mainly helps where there is a single most important health outcome and that there are not appreciable differences in other health outcomes and that the alternative options impact the same health outcome. It is limited by the fact that there are often other considerations. Cost utility analysis is a type of cost-effectivness analysis but the outcomes are always translated to QALYs resulting in an incremental cost-effectiveness ratio. Forms cost per QALY gained. This is a well established method of economic evaluation and is used by the MSAC and the PBAC as it captures many health outcomes converted into a single measure. Cost consequence analysis is a comparison of two or more choices but does not attempt to convert different outcomes into a singular meric or use a universal outcome. It describes cost difference between the choices. CCA allows decision-makers to clearly identify multiple differences in outcomes that are not always easy to combine and deliberate over the trade-offs between different consequences and to make decisions based on their priorities. It is good for more diverse and complex outcomes for health interventions. However, interpretation can be difficult. Cost Benefit Analysis is rarely used as it goes substantially further than a cost utility analysis. Instead of translating to QALYs they are translated to monetary value and reports costs and health benefits via monetary means. This is useful in other industries such as finance. Cost Effectiveness analysis and cost-utlity analysis are most useful for health economic evaluations. Health Presentation Type of analysis Costs Advantages Disadvantages outcomes of results Cost Does not reveal Comparison which alternative Not Cost CC partial Monetary. Very simple. is more cost- included. difference. economic effective or the analysis better choice. Health Presentation Type of analysis Costs Advantages Disadvantages outcomes of results Requires evidence of Cost- assumed minimisation equivalent analysis Assumed Cost CMA Monetary. Very simple. outcomes. If this partial equivalent. difference. is not reliable, economic the conclusion analysis may be incorrect. Medium complexity; does not May not require accurately Cost- outcome ICER, $ per capture the effectiveness transformation. In 'natural 'outcome'. overall value if CEA analysis Monetary. Outcome is units'. multiple health full economic patient outcomes are evaluation relevant and affected by the easy for non- decision. health economists to understand. Results presented in a universal Requires more outcome evidence to Cost utility capturing all support analysis ICER, $ per health effects estimation of CUA Monetary. In QALYs. full economic QALY. and outcomes and evaluation comparable transformation across of outcomes to different types QALYs. of interventions. Can describe Can be difficult Variable. all relevant to interpret as For example, outcomes, outcomes may Cost $ per priority quantifiable or run in mixed consequence outcome and Multiple not, and directions, and CCA analysis Monetary. other outcomes. include difficult to full economic outcomes outcomes for compare to evaluation listed, or broader outcomes multiple populations reported for outcomes and in areas other decisions. Health Presentation Type of analysis Costs Advantages Disadvantages outcomes of results reported per $ other than expenditure. health. Universal outcome enabling Cost-benefit comparison of analysis Monetary Net monetary CBA Monetary. cost- full economic value. benefit ($). effectiveness evaluation across decisions from any sector. In health economics, perspectives around the intervention should also be considered. 1. Patient perspective – for costs and benefits experienced directly by the patient. Mostly includes out-of-pocket and private costing but also accessibility perspectives, lost income etc. 2. System perspective is applied most commonly in published economic evaluations and is defined to include the patient and all public healthcare providers and funding bodies. Considers both patient costs but also healthcare system costs. 3. Societal – in that society considers all costs and benefits whether or not it impacts them directly. Examples include herd immunity, family members who is caring for someone with dementia etc. Time horizon is also important as the length of time at which the costs and benefits are estimated must be outlined in the HEE. Ideally this should be a long term horizon that extends for as long as required to meet the condition. Time horizons greater than one year must undergo discounting for time preference process to account for adjustment of costs and outcomes that are incurred in the future as deferred costs. 5% is used per annum for costs and outcomes as recommended by the PBAC and MSAC. Week 5 – Cost-Effectiveness Analysis Framework Learning Objectives Describe the key elements of the Health Economic Evaluation (HEE) decision analytic framework for performing cost-effectiveness analysis. Be able to interpret the results of a cost-effectiveness analysis of a healthcare intervention. PICOC Framework The PICO framework used in a variety of health fields and research to describe and organise element of these studies. The added component of Costs is for economic studies. - Population helps describe individual demographics, disease characteristics and presentations and circumstances of individuals being explored. All of which impact how effective a health intervention may/may not be for a person. In this case, it is best to have a population representitive of how the health intervention will impact local clinical practice of the area being funded. There needs to be consistent populations across the clinicals study evidence, the economic evaluation and its combined analysis. - Intervention describes exactly how and exactly how much an intervention will cost and impact. This may include dosing, route of administration, number of treatments and co-administration of medications. Variation of the intervention will likely impact the effectiveness and/or the costs associated with it and ensuring it remains the same ensures consistency and replicatable results. - Comparators This is dependent on the research question being addressed the required decision-making process. In health economics, this is most commonly the clinical status quo, meaning what wold occur if the proposed intervention is not made avaliable. This may represent an alternative active treatment, watchful waiting, supportive care or no care at all. This may also be a placebo in the context of clinical trials. This may also include treatments on the near-future clinical horizon called near-future comparators to future proof the evaluation. - Outcomes should be selected to best-represent the value of an intervention. This should aim to capture the effect of the intervention and be of importance to the patient. Most commonly in economic evaluation is QALYs. This should, at a minimum represent a final outcome or a highly patient relevent outcome. - Costs ($) monetary expenses associated with resource use such as cost of medications, medical procedures, hospital stays and staff salaries. This is highly dependent on the time horizon of the intervention. Incremental Cost-Effectiveness Ratios Is the final result of a CEA or cost utility analysis where the additional cost of a new intervention compared to a existing one divided by the health benefits gained. 𝐶𝑜𝑠𝑡 𝐴 − 𝐶𝑜𝑠𝑡 𝐵 𝐼𝐶𝐸𝑅 = 𝐸𝑓𝑓𝑒𝑐𝑡 𝐴 − 𝐸𝑓𝑓𝑒𝑐𝑡 𝐵 Where A represents the intervention and B represents the comparator. This must also include the monteary and health outcome as a unit, ie cost per QALY. Ideally interventions should be of low cost for high effect. It may be the case that whilst the intervention is super effective, the cost would be so great that it would not be feasible to fund. Building an Economic Evidence Before building a new evaluation, oner should seek to identify current and avaliable evidence in the field: - Literature Search. - Relevant clinical evidence looking at qualities of interventions. o Should the intervention not change health outcomes, partial analysis such as cost-minimalization analysis will be required. o If effective, then cost-effectiveness analysis is likely appropriate. CEE is designed to answer which of the alternative options is more efficient and can often be denoted with a decision tree. 1. The Population and Problem 2. The Intervention and Comparator 3. Resource use and health associated outcomes. This may be formed of: a. Trial Based Economic Evaluation occurs alongside a clinical trial where the economic data and outcomes are directly observed and measured within a RCT or trial. However usually this is a secondary analysis and thorough economic analysis is often not conducted. It provides high degree of internal consistency, assumptions of clinical pathways are not required and offers statistical analysis. These trials are limited to certain populations and increased cost and complexity due to run the trial and limited outcomes measured and time horizon. b. Modelled Economic Evaluation helps generate estimates of cost and outcomes for alternatives presented that have not been directly measured in a clinical study. This is particularly relevant when the observed data alone is insufficient to predict incremental costs and outcomes for the same population and comparator in this relevant context. i. Conceptual Model – Decision tree or health state diagram sets out disease specific events and processes in a health system that the problem exists. ii. Working model is the actual software, programming and calculations. Extrapolation may be required when clinical studies fail to observe outcomes and costs over an adequate duration of time. This however relies on several assumptions around whether treatment effect is likely to continue to increase, stay the same or dimmish. Other Considerations in HEE Equity and Efficiency: - Equity is the concept that there should be fairness in distributing resources, benefits and burdens within a society. It is easy to measure as it pertains to distribution of resources and can use income, home ownership etc as metrics. o Horizontal Equity – Treating all people the same. o Vertical Equity – recognises that individuals have different abilities to pay. - Efficiency refers to hte practical and productive use of resources. In many cases, achieving both requires trade-offs between the two. Equity in health is quite difficult to measure. Despite vast epidemiological data, establishing causality and reasons for disparities is difficult and requires a large amount of data. It is often the case that despite cheaper and greater increases in QALYs, differences in equity (challenges in staffing, transport etc) mean that the cost- per QALY may be higher and hence, cheaper, metropolitan or less equitable interventions are chosen. Productivity is also an important equity issue, as if a treatment can increase a patient's health and ability to work, this may drive increases in cost-effectiveness. Affordability and Sustainability CEA reports on cost per outcome gained but fails to explore toal resource requirements, an essential consideration to determine whether ongoing utilisation of a healthcare intervention is suitable. Financial impact analysis often does not require assessment of the outcomes, rather just the costs associated with intervention. Steps to do so may include: 1. Identify the time period at which the intervention could realistically be produced. 2. Estimate the size of the population who would be eligible. Based on epidemiological data, local patient numbers, replacement of existing product gives great estimates, estimates in change of population. 3. Estiamte the uptake rate and which proportion of the population will utise the intervention. 4. Combine the projected eligible population and uptake rates. 5. Estimate quantity of the intervention per patient. 6. Unit cost and estimate the direct intervention cost. 7. Add the additional costs such as consumables, staffing etc, 8. Subtract costs offsets (e.g. from replacing an intervention) 9. Calculate net costs or savings. As this is projection there may be uncertainty around the size of a population, uptake or average volume of the usage. Hence a sensitivty analysis or scenario analysis must be undertaken to explore these estimates and adjust accordingly. A cost effectiveness plane plots the incremental QALYs and incremental costs in a cartesian plane. Forming several quadrants that describe an intervention: - NW – Less effective and costs more (BAD) - SW – Costs less and less effective (BAD) - NE – Costs more and more cost effective (OK) - SE – Costs less and more cost effective (Ideal) Those in the SW and NE region are variable on which they should be implemented and require trade off. Hence an acceptable trade-off ratio is used to determine the cost effectiveness threshold (lambda). Most real world decisions are in the NE zone and lambda is shifted accordingly. This may be done through. 1. Ranking interventions and fund from the lowest ICER until out of money. 2. Formula relative to GDP per capita for optimal health spend. 3. Adjust ICER depending on national economic outlook, competing budget pressures and political priorities. Uncertainty around an estated ICER is also important, this may be present in the primary sources of data, the modelling methods or assumptions or the interpretation or application of evidence for the final results. - Stochastic – random variability in outcomes between identical patients (error term) - Parameter uncertainty – Uncertainty in the estimation of the parameter (standard error) - Heterogeneity – Variability between patients attributed to their characteristics (beta coefficients) - Structural uncertainty – Uncertainty in the decision modal - Trans locational uncertainty – Around assumptions associated with transforming or extrapolating the economic data. There are two types of sensitivity analysis - Deterministic – describes how an ICER is affected by variation in a specific input parameter. May be univariate or multivariate to produce a tornado chart. Variables are change, usually to present a 95% CI to provide an alternative estimate. - Probabilistic is a simulation of individuals where the value is selected at random from a defined probability distribution. The model is ran 1000s of time to generate sample data which is then used to estimate incremental costs and is plotted. ICERS cannot estimate: - Uncertainty - Applicability at an individual level. - Equity as this is measure of maximising efficiency. - Affordability Science and Scholarship Week 1 – Electrolytes Learning Objectives Outline the physiological mechanisms that maintain electrolyte homeostasis, including the role of the kidneys and regulatory systems in controlling plasma and whole-body levels of sodium, potassium, calcium, and other key electrolytes. Outline the common causes of electrolyte imbalances and understand the physiological consequences associated with deviations from normal levels. Correlate signs and symptoms of electrolyte disorders with laboratory findings to facilitate the diagnosis of electrolyte imbalances. Explain the basis of pharmacological interventions, dietary modifications, and fluid management approaches used to correct electrolyte imbalances. Explain the significance of monitoring for electrolyte levels in patients at risk, and the importance of early detection, intervention, and patient education in preventing severe complications associated with electrolyte imbalance Sodium Sodium Homeostasis Sodium largely exists as an extracellular ion which establishes serum osmolarity. It is a positive cation that is maintained by Na/K ATPase pumps that maintain high ICF potassium levels, and high ECF sodium levels. It is a key regulator of muscular and nerve action potential and governs the speed and excitability of cellular depolarisation. As sodium is a cation, it freely passes the glomerular filtration barriers and passes into the proximal convoluted tubule, it is here that a vast majority of sodium is reabsorbed (65%). 25% is reabsorbed in the thick ascending limb, 5-10% in the distal convoluted tubule and 2% in the collecting duct. Aldosterone is a key regulator of serum aldosterone levels. The macula densa can measure ECF sodium levels to estimate total body fluid volume. Hence if sodium concentration is low, then blood pressure must also be low, as little sodium is being forced through the glomerular membrane into the filtrate to be measured. As a response there is activation of the RAAS system which terminates in the zona glomerulosa releasing aldosterone. Aldosterone increases activity of the Na/K ATPase pumps on the basolateral membrane to pump sodium into the capillaries and remove potassium out of the tubular epithelium. Aldosterone also acts on Epithelial sodium channels on the luminal side to increase sodium reabsorption from the filtrate. Conversely, brain naturetic peptide (BNP) which is released as result of stretch of cardiac muscle acts to inhibit aldosterone release to reduce fluid load on the cardiac muscle and reduce this stretch. Thiazide Diuretics: Na/Cl Channels Loop Diuretics: Na/K/2Cl Channels Potassium Sparing (E.g. Spironolactone): Inhibits aldosterone → Reduces Na/K ATPase expression → reduced sodium resorption without affecting potassium levels. Hyponatraemia (< 135 mmol/L) Given the bodies reliance on sodium to establish serum osmolarity, low sodium levels decrease the osmotic pull of water out of cells forcing increased movement of water into cells. This can cause cellular swelling and subsequent functional disruption and accounts for many of the complications of hyponatraemia (particularly in the nervous system). This also decreases the action potential frequency and amplitude. Patients most at risk of hyponatraemia are: - Aged - Frail - Comorbid – Renal Failure, Diuretic Use - Medication use: Diuretics Causes are roughly summarised into exposure, poor oral intake, fluid excess/restriction or the result of precipitating illness. This can present primarily with neurological symptoms of confusion, irritability, somnolence, coma, seizures, muscle weakness and cerebral oedema. Resulting serum osmolarity is an important diagnostic marker of hyponatraemia, there are two methods of calculating this: - Ordering serum osmolarity levels, whilst this is the most accurate method, it may potentially delay treatment as it takes time. - Calculation: 𝑂𝑠𝑚𝑜𝑙𝑎𝑟𝑖𝑡𝑦 = 2 × [𝑁𝑎+ ] + 𝐺𝑙𝑢𝑐𝑜𝑠𝑒 + 𝑈𝑟𝑒𝑎 This result is usually 10 mosm of the calculated osmolarity. Normal serum osmolarity is 275-295 mosm. Urine sodium levels and osmolarity are also important diagnostic tools for hyponatraemia. Urine sodium is low if less than 40 mmol, and high if greater. Urine osmolarity is low (dilute) if less than 100 mosm, and high (concentrated) if greater than 100 mosm. Causes of Serum Hypo-Osmolar (< 275 mosm), Hyponatraemia (< 135 mmol/L) High Urine Osmolarity (Concentrated) > 100 mosm High Urine Sodium > 40 mmol/L (Sodium Wasting and Water Retention) - SAIDH, causes insertion of too many aquaporin channels which only reabsorb water from the filtrate. - Cerebral Salt Wasting (Hypovolaemia and High Urine Output). Caused by tumours or trauma. Commonly due to aSAH. - Chronic Renal Failure - Thiazide (Stops sodium resorption) - Hypothyroidism (due to high ADH levels from low CO and low peripheral vascular resistance). High Urine Osmolarity (Concentrated) > 100 mosm Low Urine Sodium < 40 mmol/L - True Hypovolaemia - Heart Failure - Cirrhosis - Nephrotic Syndrome (Protein Secretion -> low serum osmolarity, high urine osmolarity without affecting sodium levels) Low Urine Osmolarity (Dilute) > 100 mosm High Urine Sodium > 40 mmol/L (Sodium and Water Wasting) - Renal Sodium Loss - Post-Obstructive Diuresis - Post ATN Diuresis - Acute Renal Failure Low Urine Osmolarity (Dilute) > 100 mosm Low Urine Sodium < 40 mmol/L (Water wasting, Sodium retention) - Polydipsia - Water Administration - Beer Potomania Treatment mainly relies on treating the underlying cause for the hyponatraemia, volume resuscitation in the vent of hypovolaemia and halting contributing medications. Replacement is complex and should only be corrected to maintain safety rather than to normal levels. Rapid correction may cause central pontine myelinolysis, a fatal condition. Total sodium deficit is calculated as follows (0.6 for male, 0.5 for female). 𝐷𝑒𝑓𝑖𝑐𝑖𝑡 = 0.6 × 𝑇𝐵𝑊𝑡 × (𝑂𝑝𝑡𝑖𝑚𝑎𝑙 𝑙𝑒𝑣𝑒𝑙 − 𝑁𝑎+ ) This should then be replaced at 1 mmol every 3-4 hours (max 8 mmol per day). Considering 3% saline has 513 mmol of sodium per litre, this is an optimal source for sodium correction. Hypernatremia This may have the opposite effect to hyponatraemia in that it will increase cellular excitability and increase frequency and amplitude of action potentials. This will also force fluid out of the cell due to high serum osmolarity and lead to cellular shrinkage and disruption. Risk factors and timing of this condition are like that of hyponatraemia. The main offending agent for medications is furosemide given that The clinical features are also like that of hyponatraemia. However, this is more likely to call brain shrinkage, potentially causing tearing of dural bridging veins causing subdural and subarachnoid haemorrhages. Causes include: - Excessive sodium intake from iatrogenic causes or excessive saline administration. Also, may be caused by excessive sodium intake. - Excessive water loss in diarrhoea, nausea or vomiting, sweating or urinary (polydipsia, diabetes insipidus). In managing hypernatremia, it is better to correct the water deficit which will subsequently dilute the sodium concentration in the blood. This is calculated as follows (0.6 for men, 0.5 for women). [𝑁𝑎+ ] 𝑊𝑎𝑡𝑒𝑟 𝐷𝑒𝑓𝑖𝑐𝑖𝑡 = 0.6 × 𝑇𝑜𝑡𝑎𝑙 𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 × (( ) − 1) 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 This should then reduce sodium by 8mmol per 24 hours. Often using 5% dextrose, nasogastric water or oral replacement. At risk patients for hypernatraemia include: - Elderly given blunting of thirst responses with age and reduced renal function. - Cardiac and renal patients due to fluid accumulation or diuresis or fluid restriction. - Mental health as thirst response may be altered with anti-psychotics. - Young athletes - Labourers - Hospital patients on diuresis. Sodium derangement should get daily bloods. Anyone on intense correction should get 4-6 hourly checks in initial stages. Blood tests should ideally be drawn away from infusion lines. Calcium Calcium Physiology and Homeostasis 99% of the bodies total calcium volume exists within the bone as a structural source with only 1% remaining in the ECF. 45% of this ECF volume is ionised and the remainder is bound to proteins and anions. Very little calcium exists in the cells at rest with it only really occurring when stored in the sarcoplasmic reticulum. Ionised levels are usually 1.1-1.3 mmol/L and total is 2.2-2.5 mmol/L. It is a large secondary messenger and allows for muscle generation via muscle fibres and allows for myosin binding to actin through removing the troponin cover. It also has roles in triggering fertilisation of oocytes, proliferation of lymphocytes, metabolism within hepatic cells and secretion within the pancreas. Calcium also forms a positive shell around the negative cell membrane and stabilises the cell membrane channels as a result. A vast majority (70%) is reabsorbed in the PCT and 20% in the Thick ascending loop of Henle. The regulated reabsorption occurs with the remaining 10% in the DCT, which is regulated by several hormones: - Parathyroid Hormone (PTH) released in response to hypocalcaemia and hyperphosphatasemia. This predominately drives osteoclast activity to breakdown bone and increase calcium levels but also acts to increase renal resorption. - Calcitriol (Vitamin D derivative) is converted in the kidneys and acts to increase calcium levels in the blood. It increases both renal and GIT reabsorption and reduces osteoclast activity (hence reducing bone breakdown). - Calcitonin from the parafollicular glands reduces renal resorption and inhibits osteoclast activity in periods of hypercalcaemia. Hypocalcaemia This is defined as ionised levels being less than 1.1 mmol/L and total levels being less than 2.2 mmol/L (corrected). What results is increasing membrane irritability as the stabilising calcium border to cells is removed. Furthermore, this reduces muscle contraction due to less neuromuscular junction function and prevents actin-myosin binding. Clinical features include. - Numbness and paraesthesia - Muscle cramps and tetany o Chvostek Sign – Facial nerve tap causing facial muscle spasm. o Trousseau sign – BP Cuff Inflation and tapping the median nerve causing carpal spasm. - Irritability, Confusion, Seizures and Raised ICP. - ECG changes: o Prolonged QT o Arrythmias - Hypotension and cardiac failure. Causes include: - Severe Pancreatitis, the exact mechanism is unclear but may be due to calcium finding to fatty acids being released. Commonly due to gallstones and ethanol use. - Tumour Lysis Syndrome, due to calcium binding to phosphorus. - Renal Failure - Hyperphosphataemia - Hyperlipidaemia - Inadequate intake. Treatment is replacement commonly with oral calcium or vitamin D if the patient is asymptomatic. Symptomatic patients may receive IV supplementation and preferably by central access, if it must be done in a peripheral line, it must be in a large vein with a large proximal vein. - If peripheral – Calcium Gluconate at 2mmol/10mL - If central – Calcium Chloride at 6 mmol/10mL Indicated mainly if ionised < 0.8, symptomatic disease, hyperkalaemia or hypermagnesia. Hypercalcaemia This mainly causes problems due to precipitation in tissues and filtration systems commonly causing the stones, groans and moans symptoms. This may also reduce efficiency of renal water conservation due to inhibition of aquaporin insertion and alters tissue excitability. Features include: - Polydipsia - Stones - Bones (Fractures) - Thrones (Polyuria and constipation). - Psych Overtones (Lethargy, Depression, Delerium) - Cardiac Arrythmias Causes include: - High intake from TPN or calcium salts. - Malignancy (Multiple Myeloma). - Sarcoidosis - Hyperparathyroidism - Thyrotoxicosis - Thiazide Diuretics. Management is via fluid resuscitation or saline diuresis with a loop diuretic, remembering that thiazides retain calcium. Pamidronate can be used to reduce osteoclast activity. Calcitonin is useful for less acute patients as it takes 24 hours to work. Management of the cause is also important. Fluctuations are less than that of sodium and daily monitoring is sufficient. Total calcium can be affected by hypalbuminaemia hence ionised is more clinically useful. Potassium As mentioned above, a vast majority of potassium is intracellular, and the concentration gradient is established by the Sodium-potassium ATPase pumps and normal excretion is entirely dependent on the kidney. It is normally 3.5-5 mmol/L in the serum. Any change in extracellular potassium is compensated for by sequestering or release of intracellular potassium. Its efflux gives cells a negative membrane potential. Hence in hypokalaemia, it hyperpolarises the cells and impairs action potential development, in hyperkalaemia, it hypo=polarises the cell and makes them too excitable. A majority of calcium is resorbed in the PCT (50-60%), and 30% in the thick ascending limb of Henle. It is secreted in the DCT and collecting duct by ROMK channels on the luminal membrane. Aldosterone may increase the activity of these channels to drive potassium secretion and channel expression can be increased by hyperkalaemia and vasopressin. Hypokalaemia Symptoms are very generalised and may cause general muscle weakness. ECG is often the giveaway with characteristics T wave depression and U wave formation. Rarely can cause confusion and paraesthesia. Causes are separated into over-excretion or from inadequate intake: - Over excretion → Furosemide, Polydipsia, Diarrhoea, Vomitting. - Inadequate intake → Malnutrition, refeeding syndrome, hypomagnesaemia or cushings/conns syndrome. Management is simply through ceasing offending medications and management of the underlying cause. If replacement is required, it must be done in combination with magnesium, this may cause venous irritation. - Potassium Chloride 10mmol in 100ml of fluid over 1 hour (max 20 mmol per hour via two peripheral IVDs) - Magnesium Sulfate (10 mmol in 100ml of fluid over one hour). Hyperkalaemia Causes commonly muscle cramping. Again signs are mainly in the ECG showing tented T waves, bradycardia, long PR, QT intervals with a wide QRS. Causes are the opposite of hypokalaemia: - Reduced excretion → Renal failure, Addisions disease, spironolactone use, Pseudo hyperkalaemia (due to lower pH which increases potassium, usually resolving pH will decrease potassium). - Over-replacement via TPN This can be a medical emergency if there are corresponding ECG changes, 10ml of calcium gluconate or chloride can be given to stabilise the myocardium. Insulin Actrapid (10u) in 50ml of 50% of glucose will force potassium into the cells. Salbutamol puffs can also reduce serum potassium. Potassium exchange resin (resonium) can help pull sodium into the bowels and is combined with a laxative to allow for potassium drainage. Dialysis is last resort. Magnesium Like calcium, a large percentage of calcium is stored in the bone (60%), 1% is in ECF and the remaining is in ICF leaving a serum concentration of 0.7-1.1 mmol/L. It forms a key enzymatic co-factor and helps with bone structure, protein function and cell structure. Its main electrochemical function is to oppose calcium and stabilise cell excitability. It is mainly absorbed via paracellular means but can be upregulated in depletion via renal reabsorption (15% PCT, 70% TALH, 15% DCT) which can be upregulated to 100% if needed. Hypomagnesemia commonly causes cramping and muscle spasms, confusion and seizures and may cause Torsade’s. Causes include: - Inappropriate Intake - Diuresis - N/V, diarrhoea - Refeeding Syndrome Can be replaced with oral tablets but this has little value. 10-20mmol of magnesium sulphate in a 100-200ml bag of saline at 10mmol per hour IV. Hypermagnesemia can cause few signs unless > 3 mmol/L, here it opposes calcium to cause weakness, paralysis, coma and respiratory depression. Causes are usually iatrogenic from TPN or over-replacement. Management is via stopping replacement, optimising renal function and diuresis, severe cases may require dialysis. Phosphate Again, largely exists within bone (85%), only 1% is in ECF, with 45% of this being ionised, 15% protein bound and the remainder complexed with magnesium, sodium and calcium. Its main role is to bind with ADP to form ATP, a key energy substrate. It is absorbed in the intestines and is renally filtered and reabsorbed. PTH increases release from bones and absorption from GIT but decreases renal absorption. Clinical signs include Causes of hypophosphatemia include: malnutrition, refeeding syndrome, diuretics, hypoparathyroidism, proximal tubule dysfunction (Fanconi Syndrome). This is generally treated with replacement with IV 10-20 mmol over 4 hours in 250 ml of fluid. Mild cases can use oral supplementation. Causes of hyperphosphatemia include Renal failure, Hyperparathyroidism, Mass Cell death (Tumour lysis syndrome, rhabdomyolysis, Haemolysis). Treat the underlying condition and optimise renal function ideally. Calcium and aluminium salt phosphate binders can be used in more extreme cases. EUC Derangement Patterns Refeeding Syndrome: Low K, PO4, Mg. These patients should have slow refeeding with aggressive electrolyte replacement. Tumour Lysis Syndrome: High K and PO4, Low Ca. Hydration and dialysis is crucial. Rhabdomyolysis: High PO4 and K, Low Ca. Week 2 – Thoracic Medicine Mediastinum Learning Objectives Describe the boundaries and the divisions of the mediastinum. List and describe the key structures within the mediastinum and review/outline their functions. Recognise the signs, symptoms, and typical features of conditions affecting the mediastinum. Describe the pathophysiology of selected mediastinal pathologies and their complications. Explain the utility of various imaging modalities for visualising the mediastinum, including X-ray, CT and MRI. Identify, at a novice level, normal and abnormal findings within the mediastinum on medical images. Outline the indications, limitations, and potential complications of diagnostic investigations used to confirm and characterise mediastinal diseases. Outline evidence-based management approaches for selected mediastinal disorders. Mediastinal Anatomy The mediastinum is broadly separated into two main areas, the superior and the inferior mediastinum. Both are separated by the sternal angle to the level of the T4 vertebrae. 1) Superior Mediastinum – From the sternal angle toward the superior thoracic aperture. 2) Inferior Mediastinum – From the sternal angle to the diagram. The inferior mediastinum has further subdivisions containing several main structures. The superior mediastinum contains much of the thoracic neurovascular supply, trachea and oesophagus. This includes: 1) The Great Vessels such as the Aortic Arch and subsequent branches including the brachiocephalic artery on the right side, and the left subclavian and common carotid artery. 2) Superior Vena Cava and other superior venous drainage such as the left superior intercostal vein (intercostal veins 2 and 3), the supreme intercostal vein (which drains into the brachiocephalic drain from the first intercostal space) and the azygous vein (from the right posterior intercostal veins). a. Left intercostal veins drain into the hemiazygos and accessory hemiazygos veins before crossing at T7-T9. 3) Left and Right Vagus Nerves a. Right Vagus nerve runs parallel to the trachea and passes posteriorly to the SVC and the right pulmonary bronchus. b. Left Vagus Nerve passes between the left CCA and the Left subclavian arteries descending inferiorly to the aortic arch and behind the left bronchus. 4) Phrenic Nerves from the surface of the anterior scalene muscles There is also other cardiac nerves for the superficial/deep cardiac plexuses and the sympathetic trunk located within this area. As mentioned, there are other structures such as the thymus (anterior), trachea, oesophagus and thoracic duct. The divisions of the inferior mediastinum are the anterior, middle and posterior divisions. The anterior mediastinum is contained within the anterior body of the sternum and the pericardium. It contains lateral borders in the mediastinal pleura. Its contents include very little and contains largely loose connective tissue, some lymphatic vessels and branches of the internal thoracic vessels. In children, the thymus may extend into this area but regresses during adulthood The middle mediastinum is confined to the anterior and posterior borders of the pericardium. It contains the heart and the protective sheath Aswell as the tracheal bifurcation of the left and right main bronchi. The origins of the great vessels can be found here before extending superiorly into the superior mediastinum. This includes: - Ascending Aorta - Pulmonary Trunk - Superior Vena Cava Also contains nerves of the cardiac plexus and the phrenic nerves (left and right). Tracheobronchial lymph nodes can also be found in this area. These nodes are the gathering of the bronchial nodes in the hila of the lungs. The posterior mediastinum is found between the posterior pericardium and the posterior T5-T12 vertebrae. Contents include. 1) Thoracic (descending) Aorta from the arch of the aorta beginning at the edge of the T4 vertebra. It becomes the abdominal aorta at the level of T12. It also contains the several branches of the thoracic aorta that extend anteriorly, laterally and posterolateral. This includes: a. Posterior Intercostal Arteries. b. Bronchial Arteries, the left arise directly from the thoracic aorta whereas the right branch from the right posterior intercostal arteries. These arteries also supply the tracheobronchial tree. c. Oesophageal arteries from the anterior aspect of the aorta. This varies in individuals; most will have two with some having 5 arteries. d. Superior Phrenic Arteries arising also from the thoracic aorta at the aortic hiatus. 2) Oesophagus, which passes posteriorly to the arch of the aorta and initially runs to the right but shifts to the left side before entering the oesophageal hiatus. Branches of the left and right vagus nerve forms the oesophageal hiatus. 3) Thoracic duct allowing return of lymph from most of the body (bar the right superior quadrant) into the left cephalic vein. It originates at the aortic hiatus and runs directly anterior to the T6-T12 vertebrae. It also receives lymph from the intercostal spaces. 4) Inferior portions of the azygous, hemiazygos vein (formed by the left lumbar vein and left subcostal vein) and accessory hemiazygos vein. 5) Sympathetic Trunk There is also multiple lymph nodes involved in draining lymph from the mediastinal contents. They are grouped into main areas and subsequently grouped into stations. - Supraclavicular Zone o Station 1 (Supraclavicular) – Most cranial station, including nodes in the sternal notch, supraclavicular and lower cervical regions. The cricoid cartilage is the upper border of this station and it extends inferiorly to the upper margin of the manubrium and the tops of the clavicle. The midline of the trachea forms 1R and 1L node groups. - Upper zone (Superior Mediastinal Nodes) o Station 2 (Upper Paratracheal), these nodes wrap around the trachea and are separated by the left lateral wall of the trachea (opposed to the midline). The borders includes the apex of the ipsilateral lung and pleural spaces, the upper border of the manubrium. Inferior borders include the inferior margin of the left brachiocephalic veins across the trachea (right) and the left border is the superior border of the aortic arch. o Station 3 (Prevascular and Retrotacheal) ▪ Prevascular (3A) are behind the sternum and anterior to the SVC and the left carotid artery. Superior border is the apex of the chest and extends caudal to the carina. ▪ Retrotracheal nodes (3P) are found posterior to the trachea extending superiorly to the apex of the chest to the carina. o Station 4 (Lower Paratracheal) are found along the distal trachea, found inferior to station 2 and extending to the carina. They are all posterior to the aortic vasculature and like in station two, the midline is the left lateral wall of the trachea to differentiate between 4R and 4L. - Aortopulmonary Zone o Station 5 (Subaortic) are found lateral to the ligamentum arteriosum (remnant of the ductus arteriosus), the upper border is the aortic arch and the lower border is the superior margin of the left pulmonary artery. o Station 6 (Paraaortic) are on the anterior and lateral aspect of the ascending aorta and aortic arch. They are anterior/superior subarotic nodes. Phrenic nerve is a useful landmark - Subcarinal Zone o Station 7 (Subcarinal) are found directly below the carina and between the brainstem bronchi. They are more caudal to the paraoesphageal LN. The origin of the left lower lobe bronchus forms the division of the left and right inferior extensions. - Lower Zone (Inferior Mediastinal Nodes) o Station 8 (paraoesophageal) are inferior to the ST7 subcarinal nodes. They are found along the anterior and lateral aspects of the oesophagus. o Station 9 (Pulmonary Ligament) are found with the pulmonary ligaments (they are not ligaments but are parietal pleural reflections in the pulmonary roots (forming left and right nodes). - Hilar Nodes + Interlobular + Peripheral Zone (Aka Extramediastinal nodes) o Station 10 (Hilar) are in the left and right mainstem bronchi before bifurcation. o Station 11 (Interlobar) are located between the lobar bronchi just immediately distal to the bifurcation of each mainstem bronchi. o Station 12-14 (Peripheral Nodes) aka lobar, segmental and subsegmental nodes depending on if they are located along the lobar, segmental and subsegmental bronchi, as they are difficult to differentiate, they are often denoted as just peripheral lymph nodes in imaging. Lung cancers are staged using TNM staging – nodding is based on regional lymph nodes. - N0 – No regional lymph node metastasis - N1- Metastasis in the ipsilateral pulmonary or hilar nides (10-14) - N2 – Metastasis in ipsilateral mediastinal or subcarinal nodes. - N3 – Metastasis in the contralateral mediastinal, hilar or supraclavicular nodes. Stations 2-4 are in the superior mediastinum, 7-9 in the inferior mediastinum and 5-6 are aortic nodes. Conditions of the Mediastinum Findings of mediastinal pathology are often incidental and asymptomatic. Symptomatic conditions may present with cough, chest pain, fevers and dyspnoea. Symptoms may be suggestive of mass effect such as respiratory compromise, paralysis of the limbs, diaphragm and vocal cords or Horner syndrome. There may be evidence of paraneoplastic syndromes or systemic conditions due to hormone excess, antibiodies or cytokines. Imaging the Mediastinum Conventional Radiography/CXR can appreciate many mediastinal reflections and can show distortion. Computed Tomography (CT) is vital to showing masses of the mediastinum through appreciation of air, fat, water and calcium. High resolution multiplanar reformation images can show detailed anatomical relationships of the tumour and adjacent structures. MRI is ideal for soft tissue contrast and differentiating tumour from normal mediastinal tissue. Good for relationships between pericardium, heart cavities, spinal cord and vascular structures. Diffusion imaging for metabolic and biophysical differences between tissues (as seen in prostate cancer etc). PET for lymphoma and monitoring response to treatment. Tissue Diagnosis Anterior mediastinum is a common site for mediastinal masses. Conditions include: - Thymoma - Teratoma - Germ cell tumour - Lymphoma - Thyroid Tissue Is preferably resected instead of biopsied if there is no evidence of lymphoma and has resectable margins. If it is lymphoma, resection is unnecessary given availability of pharmacological treatments. Middle Mediastinal masses often present as lymphadenopathy within the middle compartment, may include lymphoma, sarcoid or metastatic lung cancer and can be biopsied using mediastinoscopy, endobronchial ultrasound, and endoscopic ultrasound biopsy. 20% of these masses may be cystic, if they are bronchogenic or enteric they may require resection, and pericardial cysts can be monitored. - Percutaneous biopsy is achieved using CT or ultrasound guidance but has low diagnostic yield of 74-77%. Core biopsy is preferred over FNA for larger tissue sampling. - Ultrasound Guided endobronchial biopsy has a much higher diagnostic yield with lower complication rates. Perioesophageal masses are better accessed with transoesophageal ultrasound guided approaches. Cystic lesions may be at risk of infection if aspirated. Surgical approaches such as mediastinoscopy via anterior approaches (substernal lesions) or cervical approaches for lesions adjacent to the airway (uncommon in days of EBUS). Other approaches include VATS or surgical resection. Common Abnormalities of the Mediastinum Thymoma Originates from the thymic epithelium, often asymptomatic but is the cause of myasthenia gravis in 10% of cases. It can cause compression of adjacent structures. It is diagnosed with imaging (CT and MRI) with histopathological confirmation after biopsy. Preferred surgical resection but adjuvant therapy is considered in low stage, low grade tumours. Prognosis is generally favourable. Post resection surveillance is CT every 6 months for two years followed by annual CT For 5 years if thymic carcinoma. Thymoma is annual for 10 years given risk of late recurrence. Germ Cell Tumours Various types, includes seminomas, non-seminomatous germ cell tumours, embryonal carcinoma, yolk sac tumor, choriocarcinoma and teratoma. Presentation is often limited to compression of adjacent structures but may have endocrinological affects. Diagnosis includes imaging and serum tumour markers (b-hCG, LDH, AFP) and followed by histopathological diagnosis. Requires both surgery, chemotherapy and radiation therapy based on stage, histology, patient factors. Has favourable prognosis with early detection. Mediastinal Cysts Are the result of developmental anomalies or acquired conditions and are categorised as such. These may be bronchogenic, pericardial and oesophageal. Symptoms are the result of compression of adjacent structures or infection. Diagnosed by imaging and histopathology These may be asymptomatic and stable and these are monitored. Complex cysts are surgically resected. As a result, there is good prognosis. Lymphoma Are based on type, stage, and patent factors. These include Hodgkin and non-Hodgkin lymphomas, these are further subclassified based on histology, immunophenotype and genetic features Presentation varies based on type. May cause painless lymphadenopathy, B symptoms and extra nodal involvement. It is imaged and then biopsied (requires slice), sometimes it may require bone marrow biopsy. Treated with chemotherapy, radiation therapy, immunotherapy and targeted therapy. Prognosis varies based on sub-type, but most have good prognosis Sarcoidosis Multisystem inflammation causing formation of non-caseating granulomas, far from limited to the lungs and mediastinum and can affect any organ. The aetiology is unkown but likely a combination of genetic predisposition and environmental triggers. May cause pulmonary symptoms (cough, dyspnoea), lymphadenopathy, skin lesions, ocular involvement and B symptoms. Diagnosed with imaging and histopathology. Treated with corticosteroids initially and immunosuppressive agents. The prognosis is generally favourable however there is risk of relapse and transplantation may be required. Vascular Surgery Learning Objectives Describe the aetiology, risk factors, pathophysiology, clinical features, natural history and progression of peripheral vascular disease and vascular ulcers. Outline the diagnostic techniques and imaging modalities used to diagnose and determine the severity and extent of peripheral venous disease and vascular ulcers, including ankle-brachial index, venous ultrasound and venography. Outline, at a novice level, the management of peripheral vascular disease, including anticoagulation therapy and use of compression stockings. Describe the aetiology, risk factors, natural history, clinical features and progression of aortic aneurysms and aortic dissection. Outline the diagnostic techniques, including imaging modalities, used to diagnose and classify an aortic aneurysm. Outline the management of aortic aneurysms and aortic dissection. Peripheral Vascular Disease PVD is commonly the result of atherosclerotic plaque in the aorta and peripheral arteries leading to episodes of insufficient perfusion. Like with coronary artery disease, this can either result in a demand or supply ischemia. As a result, the presentation of this disease differs greatly. This is often asymptomatic. Intermittent Claudication Intermittent Claudication causes pain, cramping or paraesthesia distal to the area of occlusion. Presentation differs depending on the location of the arterial occlusion. This pain occurs on walking. 1) Femoropopliteal Disease – Calf Claudication. 2) Aortoiliac Disease (Lireche Syndrome) which may be bilateral if at the level of the abdominal aorta causing a triad of bilateral buttock, hip or thigh claudication, erectile dysfunction and absent/dimished femoral pulses. A common investigation used for PVD generally but especially intermittent claudication is the ankle-brachial pressure index. For this test, systolic pressure is measured on the brachial pulse and compared to the calf to produce a ratio. - PVD Cutoff < 0.9 - Mild PVD 0.6-0.9 - Moderate PVD - Severe PVD < 0.4 Similarly, toe pressure can be taken with plethysmography or doppler. - Normal > 70 mmHg - Adequate Perfusion > 50 mmHg - Watershed Zone 30-50 mmHg - Severe Ischemia < 30 mmHg (No wound healing). Patients at risk, but asymptomatic of PVD or have evidence of PVD without symptoms should still undergo lifestyle modification to reduce risk of stroke, MI, death or amputation. Criteria for diagnosis of IC is: - Absence of rest pain. - Thigh, Buttock or Calf Pain - Distance on flat is usually consistent. - Relieved by rest/standing. Important differentials are spinal stenosis (patient will have to sit to relive pain to open the canal) or MSK pain (However this pain is usually severe from the start. Referall is often limited to those with disabling pain as they will require aortiiliac and lower limb DUS. Patients with irritating pain do not require referral and can be adequately managed with risk factor control and exercise. Life-limiting disease can be referred after 3-6 months of risk factor control without improvement (noting if they are smoking, they will not be offered treatment). Risk factor control is preferred and has been found to have a lower risk of amputation when compared to early revascularisation. Critical Limb Ischemia Critical Limb Ischemia is the result of limb-threatening arterial occlusion (supply problem) leading either: rest pain > 2 weeks, non-healing ulcers or gangrene. Often the pain is relieved by allowing the foot to hang out of bed. These patients should undergo a CTA should their renal function be adequate (DUS is second line). These patients will undergo revascularisation (endovascular, bypass or hybrid) or primary amputation. Bypass procedures are either anatomic or extra- anatomic. Acute Limb Ischemia Acute Limb Ischemia is sudden onset, acute lower limb pain. This is either the result of embolus, plaque rupture, aneurysm thrombosis or trauma. Commonly, this causes the 6 P’s: - Painful - Paraesthesia - Pallor - Paralysis - Pulseless - Perishing Cold. May be the result of atrial fibrillation, claudication, or known aneurysm (e.g. AAA). Causes may be derived based on concurrent examination of the other limb: - Pulses in other limb – Embolus. - Pulselessness – Plaque Rupture - Popliteal Aneurysm. Management is based on the extent of salvageability of the limb. - Embolus – Embolectomy +/- Thrombolysis - Acute on Chronic Disease – Embolectomy +/- thrombolysis +/- revascularisation. - Popliteal aneurysm – Bypass Should the limb not be salvageable, then amputation may be required. Diabetic Vascular Disease This either occurs in macrovascular or microvascular areas. - Macrovascular disease predominantly affects tibial vessels that are more difficult to treat and is the result of classical risk factors such as HTN, Hyperlipidaemia. - Microvascular Disease is the result of poor sugar control and involves small vessels of the foot. Often these patients have concurrent kidney disease. Presentations of this are not limited to PVD but may also cause neuropathy. Carotid Artery Stenosis This condition may be largely asymptomatic or symptomatic, with presentations of TIA, Amaurosis Fugax etc. Extent of stenosis is measured based on the percentage compared to the most distal reference diameter to the occlusion. - Mild < 50% - Moderate 50-70% - Severe 70-99% - Occluded These measurements are taken using DUS and CTA. Asymptomatic disease requires risk factor control, there is a 1% risk of stroke per year and endarterectomy is not needed. Symptomatic disease is responsible for approximately 12% of strokes and contributes to many MCA events. Treatment is limited to the following criteria. - 50-99% Stenosis with TIA, Amaurosis Fugax or Stroke (Recovered) - < 3 Months of the event (Ideally within two weeks). Patients with 100% occlusion, free floating thrombi or dissections are not offered treatment. Vertebral artery disease is less common and stenting is not routinely offered. Often presents with dizziness, unilateral limb weakness, dysarthria, headache and N/V. Aneurysms Overview of Aneurysms There are several types of aneurysms: - True Aneurysms – True Diversion and disruption of flow through a lumen. This dilation can be 1.5 times the normal diameter of a vessel. Commonly in the aorta or popiliteal areas and have risk of rupture, embolise, compression of surrounding structures of thrombus. o Saccular o Fusiform (Both Sides of the Vessel) - False Aneurysm – Tissue projection outwards from the vessel without blood flow disruption. False aneurysms can also dissect. Abdominal Aortic Aneurysm (AAA) Defined as aorta size > 3.0 cm (usually 2 cm). It more commonly occurs in males, age > 55, smokers, family history. It is interestingly less likely in diabetics and fortunately its incidence is decreasing. Rupture risk is closely correlated with aneurysm size, with highest risk of rupture at 5.5 – 6.0 cm (1.3% PA). Rupture risk is higher in women. Repair is considered at: - 5.5 cm for men - 5.0 cm for women. Patients are no longer able to drive at 5.5cm and is often the reason for patients to elect for repair. Depending on patient fitness, it may be safer to allow the aneurysm to grow and monitor. Options for AAA Repair Open Repair Endovascular (EVAR) More durable repair and does not require Requires anatomically suitable. surveillance. Higher risk of graft failure. Higher mortality (4.2% vs 1.4%) Requires surveillance. Higher morbidity. Offered to unfit/elderly patients. Offered to young/fit patients (most select EVAR anyway). Ruptures result are surgical emergencies and has extremely high mortality. EVAR is preferred for fast management. These patients may present with collapse, severe abdominal pain or renal colic. Average size for rupture is 7.5cm for men and 6.7 for women. Popliteal Aneurysms Occurs at popliteal size > 12mm (8mm is normal). High association between other known aneurysms (e.g. AAA) and PA. These may embolise or thrombose. These are only repaired at 2.0 – 3.0 cm. Repair is commonly via medial or posterior bypass using vein tissue. Can also be stented (but higher risk of thrombosis). Aortic Dissection Usually isolated to the aortic arch. It is considered a type A aneurysm if it involves the ascending aorta, type B if it involves the descending. Type A dissections require immediate repair, type B has a mortality, but management can occur within 7 days. Discharged alive these patients have relatively good outcomes. Management is via stenting: - Type A – Immediate Surgery - Type B – Conservative unless complicated (rupture, continuing malperfusion or continuing page. Curative treatment is rare due to the presence of distal tears. Peripheral Venous Disease Varicose Veins These are classified based on the shape of the varicies and forms the nomenclature of this condition. - Varices – Dilated, tortuous veins. - Reticular – Blue vein veins in the skin. - Telangiectasia – small intradermal venules (spider veins). These form as the result of venous incompetence within the venous valves. They are mainly cosmetic, rarely they may cause edema, itching, rash, inflammation, pigmentation or phlebitis. Very few pateitns will progress to chronic venous insufficiency Patients with superficial thrombophlebitis will be given 10mg OD rivaroxaban for DVT prophylaxis. VV is commonly investigated with DUS for deep and superficial veins, contains assessment of vein patency and competency + reflux. Treatment: - Surgical – Ligation and stripping. - Heat ablation with laser or radiotherapy (truncal only). - Cyanoacrylate Glue (Truncal) - Ultrasound Guided Foam Sclerotherapy Recurrance is high with VV. Venous Ulceration causes superficial lesions that are often exudative with irregular borders. Caused by chronic venous hypertension causing tissue ischaemia. This can lead to mild pain and dysfunction with variose veins, edema and stasis dermatitis. Lung Cancer Learning Objectives Summarise the main classifications of lung cancer including the distinctions between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Describe the primary aetiological and risk factors contributing to the development of lung cancer, including tobacco smoking, environmental exposures, occupational hazards and genetic predispositions. Explain the cellular and molecular mechanisms underlying the initiation, progression, and metastasis of lung cancer. Recognise the clinical manifestations of lung cancer, including respiratory symptoms, paraneoplastic syndromes, and manifestations of advanced disease. Describe the utility of various imaging modalities (CT, PET), bronchoscopy, and biopsy procedures used to diagnose, classify and stage lung cancers. Identify, at a novice level, normal and abnormal findings on radiographic images of the lungs. Outline the TNM classification of lung cancer staging and its significance for treatment planning. Outline the basis for, benefits of, and potential risks of, various lung cancer treatments, including surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Types of Lung Cancer There are several different types of lung cancer: 1) Non-Small Cell Lung Cancer (NSCLC) ~85% a. Lung Adenocarcinoma’s are located mainly in the peripheral regions of the lung and are the most common form of lung cancer. They are more common in women and non-smokers. They are a glandular tumours with mucin producing cells. b. Lung Squamous Cell Carcinomas (SCC) are centrally located tumours that are most associated with smoking. They form cavitating lesions from the hilar bronchus. They can cause hypercalcaemia as a paraneoplastic syndrome. They are solid, epithelial based tumour with intercellular bridges. c. Large Cell Carcinomas have the poorest prognosis of NSCLC and are more likely to have metastasis and have a poor response to chemotherapy. They are undifferentiated and large celled tumours. 2) Lung Neuroendocrine Tumours, these cells share various histological features such as Kulchitsky cells, rapid growth and tumour markers such as Chromogranin A, Synaptophysin, Neuron-specific enolase. a. Small Cell Lung Cancers are centrally located tumours and are strongly associated with smoking (rare in non-smokers) and are associated with various paraneoplastic syndromes (e.g. Lamber-Eaton Myasthenic Syndrome, Cushings). These are undifferentiated and aggressive. They are associated with L-myc oncogene. b. Large Cell Neuroendocrine Carcinoma are peripherally located tumours with poor prognosis given their high grade. There are several variants that present with characteristic signs. Pancoast tumours are commonly NSCLC tumours of the apical lung causing horner syndrome from cervical sympathetic ganglion compression and compression of the brachial plexus. They may cause hoarseness from compression of the recurrent laryngeal nerve. The lungs are also a common site of metastasis from the breast, prostate, colon etc. Risk Factors Personal Factors - Current or past smoking (90%), there is a 10-30 fold increase in relative risk. - Age - Family History - COPD - Pulmonary Fibrosis - Personal History of Lung Cancer Occupational - Passive smoking. - Air pollution - Occupational exposure (asbestos, silica, diesel) Biology Lung cancer follows similar oncological progression of other cancers in being precipitated by DNA damage from an often-chronic insult causing cellular DNA damage and eventual proliferation of damaged cells. Once this leads to angiogenesis, migration, invasion and metastasis, this is what forms characteristic high-grade cancers. It is this process that also creates lots of genetic targets. Symptoms Lung Cancer: - New or changed cough - Chest or shoulder pain. - Hoarse voice - Loss of weight or appetite - Recurrent chest infection - Lymphadenopathy - Haemoptysis General Cancer Signs: - Fatigue - Weight loss - Night Sweats. There may also be evidence of pleural involvement or metastasis via pleural effusion, chest wall pain and signs of metastasis. Symptoms may also include paraneoplastic syndromes: - Neurological o LEMS o Sensory Neuropathy o Limbic Encephalopathy - Endocrine o Hyponatraemia o Hypercalcaemia o Cushing Syndrome - Dermatomyositis/Polymyositis - Hypertrophic Osteoarthropathy. Investigating Suspected Lung Cancer Serum Investigations may include CBE, MBA 20, LFT, Albumin and Lactate Dehydrogenase. Gold standard imaging is via CT Chest, other scans include CXR and PET. Imaging may also be symptom targeted and may also look for metastasis via CT head, abdomen pelvis. CT gives clinicians important information about the tumour regarding size, progression, spiculation (spikiness), upper lobe involvement, nodule count and type. Other features such as pleural nodularity, lymphatic involvement, endobronchial lesions, consolidation without resolution from pneumonia management, atelectasis. Tumours are also biopsied to identify potential therapeutic targets and genetic mutations. This is accomplished either via bronchoscopy for lung nodules (70.8% diagnostic yield and 2.8% complication rate) or biopsy of lymph nodes (highly diagnostic, up to 92.1%). CT guided transthoracic biopsy also has a high diagnostic yield (92.1%) but has a very high pneumothorax risk (20.5-25%). As mentioned above, these tumours are staged using TNM staging, this has extremely high prognostic value. Stages of NSCLC can be summarised as: 1. Curative – 1A – IIB 2. Intermediate (curative) – IIIA – IIIC. 3. Palliative – IVA and IVB a. IVA – Contralateral lobar mets or pleural mets + a single extrathoracic met (M1B) b. IVB - > 1 Extrathoracic Met Managing Lung Cancer Staging is also great for guiding appropriate management: 1) NSCLC a. Stage 1A-1B – Surgical resection via lobectomy or sub lobar resections. If unfit or is a poor candidate for surgery, stereotactic body radiation therapy or conventional radiotherapy is used. b. Stages II, III, IV – Surgery is often feasible in stage II and III cancers but requires MDT discussion. Adjuvant chemo- and radiotherapy is also required. Known target mutations can be treated with targeted therapy and immunotherapy. 2) SCLC is classified differently depending on extent of involvement. a. Limited Stage SCLC (curative) – Limited to ipsilateral hemithorax and regional lymph nodes are encompassed in a safe radiotherapy field. This can be managed with a combination of chemotherapy and radiotherapy. b. Extensive Stage (palliative) – Occurs when beyond the ipsilateral thorax with involvement of contralateral supraclavicular or hilar lymph node involvement, malignant pericardial or pleural effusion and distant metastasis. Unfortunately, this is the more common form of SCLC. This is managed with chemotherapy +/- immunotherapy. Soon there will be screening available for lung cancer with recurring low-dose CT imaging to screen individuals. Sepsis Week 3 – Infectious Disease Learning Objectives 1. Outline the major classes of antibiotic, antiviral, antifungal, and antiparasitic drugs. 2. Outline the mechanisms of action, spectrum of activity and indications for commonly prescribed classes of antibiotic, antiviral, antifungal, and antiparasitic medications. 3. Summarise the impact of patient variables such as age, organ function, and concomitant medications on treatment outcomes. 4. Outline the potential side effects and adverse reactions associated with the use of antimicrobial medications, considering individual patient factors and the importance of monitoring for drug-related complications. 5. Outline the important principles that underlie the responsible use of antimicrobials. 6. Formulate, at a novice level, evidence-based treatment plans for infectious diseases, considering the principles of antimicrobial stewardship, dosage optimisation, and the importance of avoiding unnecessary antibiotic use. 7. Outline current developments in antimicrobial therapy, including emerging resistance patterns, new classes of drugs and evolving guidelines. Antibiotics Mechanism of Actions Antibiotics are either bactericidal, meaning they selectively kill the bacteria, or bacteriostatic, prevent growth of the bacteria. It is vital that these mechanisms do not produce any or little effect to the host. The mechanisms of these antibiotics can be summarised as follows: 1) Cell Wall Synthesis Inhibitors a. Penicillin-Binding Proteins such as B-Lactams (penicillins, cephalosporins, monobactams, carbapenems). These work via blocking peptidoglycan cross linking. b. Peptidoglycan Subunits (Glycopeptides) c. Peptidoglycan Subunit Transport (Baacitracin) 2) Inhibits Biosynthesis of Proteins a. 30S Subunit Inhibitors (Aminoglycosides, Tetracyclines). b. 50S Subunit Inhibitors (Macrolides, lincosamides, chloramphenicol, Oxazolidinones). 3) Disrupts Membranes a. Lipopolysaccharide such as Polymyxin B, Colistin, Daptomycin 4) Inhibit Nucleic acid Synthesis a. RNA – Rifamycin b. DNA – Fluoroquinolones 5) Antimetabolites a. Folic Acid Synthesis – Sulphonamides, Trimethoprim b. Mycolic Acid Synthesis Enzyme – Isonicotinic Acid Hydrazide. 6) Mycobacterial Adenosine Triphosphate (ATP) Synthase Inhibitor (Diarylquinoline) Beta-Lactams Contains beta-lactam ring crucial to its bactericidal effect in preventing peptidoglycan cross-linking. They have partial CNS penetration but only during meningeal inflammation to allow for increased BBB permeability. Primarily renal excretion. Penicillins 1. Natural Penicillins a. Types: Penicillin G (IV, IM), Penicillin V b. Coverage i. Gram Positive Aerobes (Streptococcus Pyogenes, Streptococcus Pneumoniae. ii. Gram Negative cocci (Neisseria Meningitis) iii. Spirochetes (Treponema Pallidum) iv. Some Gram-Positive Anaerobes. c. Side Effects i. Hypersensitivity ii. Haemolytic Anaemia Positive direct Coombs tet iii. Drug Induced Interstitial Nephritis iv. Seizures d. Mechanism of Resistance is via cleavage of the beta-lactam ring by B- Lactamases. Penicillin binding protein mutations prevent penicillin binding. 2. Penicillinase Resistant Penicillins, their resistance comes from addition of large side chains to prevent b-lactamase binding. a. Examples (Oral or IV), Nifcillin, Dicloxacillin, Oxacillin, Floxacillin, Methicillin. b. Use: i. Non-MRSA S. Aureus. ii. Not effective against streptococcu viridans, enterococci or listeria. c. Risk of interstitial nephritis (predominantly with methicillin) d. Whilst they are resistant to b-lactamases, changes in the PBP site may produce resistance. 3. Aminopenicillins a. Types: i. Amoxicillin (+/- Clavulanate) (Oral or IV) ii. Ampicillin (+/- Sulbactam) (IM or IV). b. Spectrum: These are considered extended-spectrum penicillins and covers a large range including gram positive aerobes and gram negative rods. Commonly used for: i. H. Pylori ii. H. Influenzae. iii. E. coli iv. Listeria Monocytogenes v. Proteus Mirabilis vi. Shigella vii. Enterococci viii. Spirochetes c. Amoxicillin/Ampicillin may cause diarrhoea, pseudomembranous colitis, hypersensitivity reactions, rash and rarely acute interstitial nephritis. Carbapenems There are various types, these include imipenem, meropenem, ertapenem and doripenem. All are available in IV formulations. Imipenem is given in combination with cilastatin to inhibit human dehydroeptidase 1. These drugs are last resort given high amount of adverse effect. They have a broad spectrum and work against intrinsic beta-lactamase resistance. They cover gram positive cocci, gram negative rods (including pseudomonas) and Anaerobes. Adverse effects include secondary fungal infections, CNS toxicity (may reduce seizure threshold), GIT upset, rash, thrombophlebitis. Monobactams Includes IV Aztreonam, it specifically binds to the PBP3 protein and is less susceptible to b-lactamases. These are only effective against gram negative bacteria and has no affect on gram positibe rods or anaerobes. This is often used as an alternative to aminoglycosides in renal impairment. Broad spectrum coverage can be achieved if given with vancomycin or clindamycin. Cephalosporins There are several generations of cephalosporins all with varying sensitivities and formulations. Generation 1st 2nd 3rd 4 th 5th Examples Cephalexin Cefuroxime, Cefixime Cefepime Ceftaroline (PO) Cefaclor (PO) (PO) (IV) Cefazolin Cefuroxime, Ceftrixone, (IV/IM) cefocitin, Cefotaxime, cefotetan (IV) (IV) Ceftriaxone (IM) G+ +++ ++ + +++ +++ G- Proteus Proteus + + + Mirabilis E. coli. E. Coli Haemophilus Klebsiella Klebsiella Neisseria MRSA - - - - + Listeria - - - - + Pseudomonas - - + + - Enterococcus - - - - + Atypicals - - - - - There is a potential for cross-reactivity in patients with penicillin allergies. Some small risk of autoimmune haemolytic anaemia, vitamin K deficiency, increases nephrotoxicity of aminoglycosides, neurotoxicity and hyperbilirubinemia (ceftriaxone) in neonates. Glycopeptides Commonly available by vancomycin, teicoplanin or topical bacitracin. These are also inhibitors of cell wall synthesis and are bacterial death and is bacteriostatic against C. Difficle. Again only CNS penetration in meningeal irritation and is renally cleared. Main clinical uses are against gram-positive: - MRSA - S. Epidermidis - Enterococci (not VRE) - C. Difficle. There some adverse effects associated with nephrotoxicity, ototoxicity, thrombophlebitis, flushing reaction, DRESS syndrome, neutropenia. These are bata - lactamase resistant. Lipopeptides Main drug is daptomycin. Which incorporates potassium channels into the cell membrane of gram-positive bacteria causing rapid membrane depolarisation and loss of membrane potential causing inhibition of DNA, RNA and protein synthesis causing a bactericidal effect. Gram positive cover, staph. Aureus + MRSA and good for skin and skin structure infections + endocarditis. Also used in VRE. It is inactivated by surfactant. Is can cause reversible myopathy, rhabdomyolysis and allergic pneumonitis. Aminoglycosides Several examples: - Gentamicin (IV or IM) - Neomycin (PO) - Amikacin (IV or IM) - Capreomycin - Tobramycin (IV or IM) - Kanamycin - Streptomycin (IM or IV) It is a 30S subunit of bacterial ribosome to cause irreversible inhibition and inhibits bacterial protein synthesis. This leads to misreading of mRNA and blocking of translocation. It is synergistic with b-lactams as it allows for aminoglycoside entry through the cell wall. There is poor CNS penetration, and it is cleared renally. It is good for severe gram negative rod infections but is not good against anaerobes (as aminoglycosides have oxygen dependent absorption by cells). Adverse effects are nephrotoxicity and namely ototoxicity and vestibulotoxicity: - Tinnitus - Ataxia - Vertigo And this is worsened when combined with loop diuretics. It can also cause neuromuscular blockage and teratogenicity. MG, botulism and pregnancy is a contraindication. Tetracyclines Examples include minocycline (IV or PO), tetracycline (IV or PO), Doxycycline (PO), Demeclocycline. Binds 30S subunit on amino-acyl-tRNA is blocked from binding to ribosome acceptor site -> Inhibition of bacterial protein synthesis causing a bacteriostatic effect with poor CNS penetration. Route of elimination is renal. Clinical uses include: - Cells which lack a cell wall (e.g. Mycoplasma Pneumoniae, Ureaplasma) - Intracellular Bacteria such as Rickettsia, Chlamydia, Anaplasma - Borrelia Burgdoferi - Other: Cholerae, Francisella tularensis. - Cutibacterium Acnes (topical for acne). - Community acquired MRSA Adverse effects: - Hepatotoxicity - Deposition within teeth and bones can cause bone growth issues and discolouration. - Damage to mucous membranes (esophagitis, GI upset). - Photosensitivity - Fanconi Syndrome if Degraded - Pseudotumor cerebri. Contraindications include children < 8 YO, pregnant women, breastfeeding, renal failure and hepatic dysfunction. Macrolides Examples include erythromycin, azithromycin and clarithromycin (IV or Oral) and Roxithromycin (Oral). It binds to the 23S Ribosomal RNA molecule of the 50S subunit that blocks bacterial protein synthesis (bacteriostatic). It is biliary cleared and used mainly for: - Atypical Pneumonia -> Mycoplasma Pneumona, Legionella, - Bordetella Pertusis - STIs by Chlamydia - Gram Positive Cocci – Good for streptococci infections in penicillin allergies. - Neisseria Spp. Dual therapy with ceftriaxone for N. Gonorrhoeae - Mycobacterium Avium - H. Pylori Adverse effects include increased GIT motility, QT interval prolongation, acute cholestatic hepatitis, eosinophilia, rash etc. Can increase risk of hypertrophic pyloric stenosis in infants < 6 weeks. Erythromycin enhances the effect of oral coagulants. - Contraindicated in pregnant women. - Hepatic failure (azithromycin and clarithromycin). - Cautious in breastfeeding. Resistance occurs due to methylation of the 23S rRNA prevents macrolide binding. Lincosamides Examples include mainly clindamycin; it binds to the 50S subunit causing blockage of peptide translocation → Bacteriostatic effect. There is poor CNS penetration and is cleared renally and biliary. It is used in: - Anaerobes such as bacteroides Spp o Aspiration Pneumoniae o Lung Abscesses o Oral Infections - Group A Streptococcus. - Partial effectiveness against gram positive aerobes. Adverse effects: - GIT Upsets - Pseudomembranous colitis - Fever - Teratogenicity. Oxazolidinones The main example is linezolid. It blocks the 50s subunit of the bacterial ribosome forming a bacteriostatic with good CNS penetration. Has both renal and biliary elimination with hepatic metabolism. Its main use is reserved for multi-drug-resistant gram-positive bacteria such as VRE and MRSA. Adverse effects: GIT upset, pancytopenia, peripheral neuropathy, serotonin. Contraindications include concurrent use with SSRIs. Amphenicols The main drug in this case is chloramphenicol, it binds to the 50S subunit causing blockage of peptidy transferease causing reduced bacterial protein synthesis (bacteriostatic effect). It also has good CNS penetration and is mainly used in meningitis caused by H. Influenzae, N. Meningitis or S. Pneumoniae. Is also used in rickettsia infections. It does have some inhibitory effect on CYP450 and can cause subsequent side effects if combined with other CYP450 inhibitory medications. There is also risks of: - Dose Dependence bone marrow suppression - Gray Baby Syndrome Hence is contraindicated in infancy pregnancy. Fluoroquinolones Examples include several generations: - First Generation: Nalidic Acid (oral) - Second Generation: Norfloxacin, Ciprofloxacin, Ofloxacin (oral). - Third Generation: Levofloxacin (Oral or IV) - Fourth Generation: Moxifloxacin, Gemifloxacin These inhibit prokaryotic topoisomerase II (DNA Gyrase) causing DNA Supercoiling causing DSDNA breaks and inhibition of DNA replication and transcription. Uses include: - Norfloxacin, Ciprofloxacin and Ofloxacin: o Gram Negative Rods (UTI and GIT Infection) o Some Gram Positives o Neisseria Gonorrhea/Chylamdia Trachomatis/Ureaplasma Urealyticum - Levofloxacin, Moxifloxacin and Gemifloxacin o Atypical Bacteria (legionella, mycoplasma). o Anaerobes o Gemifloxacin against penicillin-resistant pneumococci o Moxifloxacin: Is a second line treatment of TB patients if they cannot tolerate standard TB treatment o

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