Tomographic ventilation-perfusion lung scintigraphy in cardiopulmonary disease

Respiration relies, among other things, on the balance between regional ventilation and perfusion in the lungs. There are many cardiopulmonary diseases, such as pulmonary embolism (PE), chronic obstructive pulmonary disease (COPD) and left heart failure (LHF), which can affect respiration negatively. The diagnosis of PE, COPD and LHF follows separate diagnostic pathways. However, the symptoms that cause the patient to seek medical care are overlapping. This results in a diagnostic dilemma that is complicated by the fact that cardiopulmonary diseases often coexist. Ventilation and perfusion can be imaged with lung scintigraphy. Lung scintigraphy is primarily used to diagnose PE. The introduction of 3-dimensional tomographic lung scintigraphy (V/P SPECT) has resulted in an improved accuracy in the diagnosis of PE. Follow-up with V/P SPECT may lead to better individualization of PE treatment, but has not yet been evaluated. Changes in ventilation and perfusion are also found in COPD and LHF. V/P SPECT may have a clinical role in the diagnosis and characterization of COPD and LHF, but this has been insufficiently studied. Therefore, this thesis focuses on the potential role for V/P SPECT in the follow-up of PE and in the diagnosis and classification of LHF and COPD. In study I, we found that V/P SPECT can be used to diagnose LHF with a high positive predictive value. We developed an algorithm to objectively calculate perfusion gradients and found that an inverted gravitational gradient in the lungs is indicative of LHF. It was also shown that LHF was common among patients with suspected PE. In study II we compared ventilation studies performed with 99mTc-DTPA and 99mTc-Technegas, in patients with and without COPD. This study showed that 99mTc-Technegas, due to a more homogeneous distribution with less focal deposition and better peripheral penetration, should be regarded as the preferred radioaerosol in V/P SPECT studies. Study III indicated an additional value of V/P SPECT in the diagnosis of COPD. V/P SPECT could also be used to characterize the severity of COPD. In study IV, we found that restoration of regional perfusion after acute PE occurred during the first 3 months of treatment, but not thereafter. Follow-up after an episode of PE, using V/P SPECT, seems important since about 20% of the patients in the study had remaining perfusion defects at 3 months after diagnosis, although all were free from symptoms

Congenital and childhood atrioventricular blocks: pathophysiology and contemporary management

Atrioventricular block is classified as congeni- tal if diagnosed in utero, at birth, or within the first month of life. The pathophysiological process is believed to be due to immune-mediated injury of the conduction system, which occurs as a result of transplacental pas- sage of maternal anti-SSA/Ro-SSB/La antibodies. Childhood atrioventricular block is therefore diagnosed between the first month and the 18th year of life. Genetic variants in multiple genes have been described to date in the pathogenesis of inherited progressive car- diac conduction disorders. Indications and techniques of cardiac pacing have also evolved to allow safe perma- nent cardiac pacing in almost all patients, including those with structural heart abnormalities

The Tromped, a Means of Prophylaxis for Flight Related Deep Vein Thrombosis

The process of blood flow in the leg, against gravity and towards the heart is instigated by compression of the veins in the foot. Contraction of the calf muscles results in an ejection volume (EV) of blood towards the heart, completing the process. Research studies have shown an association between flight travel and deep vein thrombosis (DVT). Stasis of blood flow can lead to the development of thrombus formation. Deep Vein Thrombosis occurs in situations where people are immobile for long periods of time, whether this is a result of ill health or travel on land or in the air. This alteration in venous haemodynamics may contribute to the development of DVT. A novel prototype design of an in-flight exercise device to stimulate blood flow in the seated position was designed and developed. It consisted of a foot pedal attached to a base by a hinge mechanism and a spring. Four test set-ups, 1 to 4, of differing resistance were evaluated. Calf muscle pump function was assessed by the technique of Air Plethysmogrpahy (APG) in ten healthy volunteers. Ejection Volume Fractions (EVF) and Residual Volume Fractions (RVF) were determined in the standing position (control) and compared to those achieved in the seated position, by compression of the four pedals. The normal EVF is greater than or equal to 60%. It is the volume of blood ejected towards the heart when a participant stood on their tip-toes for five seconds. The normal residual volume (RV), the amount of blood remaining in the veins after exercise, is less than or equal to 35% and is an ideal indicator toward the prevention of venous stasis. Two devices (test set-up 2 and 3) achieved comparable EVF and RVF values to those achieved by the tiptoe control manoeuvre. As Test set-up 3 was more user friendly, its spring parameters were used in the subsequent device designs, namely demonstrator A (DA) and demonstrator B (DB). These prototypes were more streamlined versions designed with the shape of a foot in mind. They had differing dimensions meaning the springs would be positioned differently in relation to the foot. An assessment was conducted to determine if a significant difference existed between the two. DA produced more efficient results and so was used in the follow up study, conducted in Beaumont Hospital, Dublin. The aim of which was to determine if any of the in-flight exercises (advocated by airlines) conducted in the seated position were efficient at creating venous return. This study consisted of two parts. Volunteers first conducted the standard APG assessment, followed by walking, DA and three foot exercises in the seated position. The second part of the study was conducted in the same sequence however participants wore Mediven® Travel Compression Stockings. DA in the seated position was effective at creating venous return however the in-flight exercises did not achieve the required EVF of greater than 60 percent. The concept of the Tromped was integrated into an aircraft footrest. An assessment was conducted with 18 volunteers, six obese, six healthy individuals and with six women taking the contraceptive pill. The four footrest prototypes were compared to tiptoe (control) in the standing position and DA used in an aircraft seat. This seat had an incline of approximately 40mm from the front to the rear of the cushion and differed from previous assessments which were conducted in situ on a level examination couch. Neither of these footrests achieved the required EVF or RVF values. DA was only efficient in the obese group. Further research is recommended, particularly in redesigning the ergonomics of an aircraft seat to specifically enhance venous return in the seated position

Severe COVID-19 and routine biomarker patterns

In acute infectious diseases, the composition of the blood changes. That includes proteins, blood cells and smaller solutes. Routine blood tests have a fundamental role in the diagnosis and follow-up of patients with severe infections. Similar to other severe infections, high levels of inflammatory markers are seen during the acute phase of a SARS-CoV-2 or COVID-19 infection. What distinguished COVID-19 in year 2020 from other viral diseases, was the high pathogenicity increasing the likelihood of affecting other common biomarkers. The aim of this thesis was to investigate the prognostic importance of dynamics and trends of routine electrolyte, coagulation and kidney biomarkers in patients with severe COVID-19 at Karolinska University Hospital during the first phase of the pandemic in Sweden. Study I: A retrospective cohort study of 429 patients. In this study we investigated how trends of platelet counts and D-dimer levels were associated with mortality, thrombosis and difference in anticoagulant treatment routine. We found that increasing platelet levels and decreasing D-dimer levels, during the first week of hospitalization, were associated with improved survival and reduced thrombotic risk and enhanced prophylaxis with LMWH coincided with improved outcomes. Study II: In this retrospective cohort study of 406 patients, we evaluated presence and importance of electrolyte and acid-base imbalance. Hyponatremia was seen in many patients at admittance and was found to be associated with future need of mechanical ventilation. However, development of hypernatremia was common, occurring in 42% of the patients in the cohort, and was associated with increased hospital stay and death. Study III: A retrospective study of 45 patients with COVID-19, undergoing brain magnetic resonance imaging (MRI), which were assessed for the presence/absence of a normal posterior pituitary gland (bright spot). Hypernatremia and polyuria consistent with central diabetes insipidus (DI) were observed in 14 patients (31%), whereof 6 (13%) had a full laboratory workup and fulfilled the diagnostic criteria of DI; all 14 patients with suspected DI lacked the bright spot, suggesting a vasopressin-depleted state. Study IV: In the last study, designed as a retrospective cohort study of 286 patients, we studied acute kidney injury (AKI) and related biomarkers in severe COVID-19. AKI developed in 38% of the patients and a higher mortality was seen in the group with AKI. Discrepant results between eGFR creatinine (eGFRCR) and eGFR Cystatin C (eGFRCYS) was common, especially in the ICU patients, and the development of a pronounced discrepancy was related to poor outcome. To conclude, during hospitalization for severe COVID-19 the biomarker pattern fluctuates depending on improvement or worsening of the disease. In this thesis we describe the changes in some of our common blood tests and how they associate with outcome. Therefore, an evaluation of the dynamics of the biomarkers is an important part in the assessment of disease development, treatment and prognosis

Cardiac Arrhythmias

Cardiac arrhythmias are common triggers of emergency admission to cardiology or high-dependency departments. Most cases are easy to diagnose and treat, while others may present a challenge to healthcare professionals. A translational approach to arrhythmias links molecular and cellular scientific research with clinical diagnostics and therapeutic methods, which may include both pharmacological and non-pharmacologic treatments. This book presents a comprehensive overview of specific cardiac arrhythmias and discusses translational approaches to their diagnosis and treatment

Ambulance-delivered transdermal glyceryl trinitrate versus sham for ultra-acute stroke: rationale, design and protocol for the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) trial (ISRCTN26986053)

Rationale: Vascular nitric oxide levels are low in acute stroke and donors such as glyceryl trinitrate have shown promise when administered very early after stroke. Potential mechanisms of action include augmentation of cerebral reperfusion, thrombolysis and thrombectomy, lowering blood pressure, and cytoprotection. Aim: To test the safety and efficacy of four days of transdermal glyceryl trinitrate (5 mg/day) versus sham in patients with ultra-acute presumed stroke who are recruited by paramedics prior to hospital presentation. Sample size estimates: The sample size of 850 patients will allow a shift in the modified Rankin Scale with odds ratio 0.70 (glyceryl trinitrate versus sham, ordinal logistic regression) to be detected with 90% power at 5% significance (two-sided). Design: The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is a multicentre UK prospective randomized sham-controlled outcome-blinded parallel-group trial in 850 patients with ultra-acute (4 h of onset) FAST-positive presumed stroke and systolic blood pressure 120 mmHg who present to the ambulance service following a 999 emergency call. Data collection is performed via a secure internet site with real-time data validation. Study outcomes: The primary outcome is the modified Rankin Scale measured centrally by telephone at 90 days and masked to treatment. Secondary outcomes include: blood pressure, impairment, recurrence, dysphagia, neuroimaging markers of the acute lesion including vessel patency, discharge disposition, length of stay, death, cognition, quality of life, and mood. Neuroimaging and serious adverse events are adjudicated blinded to treatment. Discussion: RIGHT-2 has recruited more than 500 participants from seven UK ambulance services. Status: Trial is ongoing. Funding: British Heart Foundation. Registration: ISRCTN26986053

Coagulation Monitoring Devices: Past, Present, and Future at the Point of Care

Automated technologies have revolutionised the monitoring of coagulation disorders in the central hospital laboratory setting, allowing for high throughput testing, improved accuracy and precision, accompanied by a marked reduction in human error. However, they still require trained operators and sample transportation. With the advent of point of care (POC) testing, the working principle of traditional coagulometers was used as the foundation for the development of miniaturised devices. A number of POC coagulation devices have been commercially available for many years now, allowing the patient to assume more control over the management of their own medication, e.g. warfarin. While POC devices for measuring anticoagulation have relied principally on clotting time tests, novel platelet function tests, and factor-specific assays based on enzymatic or immunoassay principles are becoming available, driven by the emergence of new anticoagulant drugs, in addition to the inability of clotting tests to accurately detect many thrombotic disorders. This review highlights recent progress in the development of POC coagulation monitoring technologies and examines their future potential in clinical diagnostics

Can smartphone technology improve patient care?

Introduction The emergence of evidenced-based medicine (EBM) has led to an ever-increasing plethora of guidelines to follow in order to best deliver this high standard of care. Compliance with such guidelines remains sub-optimal and novel methods of guideline dissemination have become popular. Two patient safety areas of major morbidity and, potentially, mortality for patients are venous thromboembolism (VTE) and sepsis. Prophylaxis is available to minimise risk of VTE and early resuscitation bundles for sepsis, such as Sepsis Six have become widely promoted. Both of these areas have local guidelines that should be followed but compliance is poor. At the start of this period of research Sepsis Six had not yet been rolled-out in the surgical department at the RAH, Paisley. This provided a golden opportunity to look at guideline dissemination for one area, using a variety of modalities. Smartphone technology has become ubiquitous in the past few years. The reasons for this are examined and the role for smartphones, and their applications (apps) in delivering assistance to doctors involved in front-line care is discussed. Potential regulatory issues are reviewed. Aims The aims of this thesis are: To assess prevalence of smartphones in the doctor population in a three-site hospital board area and these doctors’ attitudes to smartphone technology for clinical uses. To design and implement novel apps for thromboprophylaxis and Sepsis Six as a supplemental modality for guideline dissemination. To assess the impact of the introduction of these apps on guideline compliance, including assessing for fatiguing of interest. Materials and Methods A SurveyMonkey questionnaire was emailed to all 456 doctors across the three hospitals in the GGC Clyde sector asking about smartphone ownership and usage and their views on the roles of apps for clinical care. Native smartphone apps were designed and developed for both iPhone and android platforms for both VTE prophylaxis and Sepsis Six. Once these had been field-tested, and pre-app audit of current guideline compliance undertaken they were manually deployed to the surgical junior doctors at the Royal Alexandra Hospital, Paisley. Concurrently, while the Sepsis Six app was being developed the concept of Sepsis Six was rolled out using standard posters, presentations and tutorials. After each modality introduction for both VTE prophylaxis and Sepsis Six audit was undertaken both early, and some time later, to try and assess possible fatiguing of interest and compliance. Results There was a good response to the survey, revealing very high smartphone ownership levels at virtually 90%, with 100% ownership in doctors in the early years of training. Further analysis revealed that doctors in the middle of their training, rather than at either extreme, were the most likely to use a smartphone for clinical care. Doctors preferentially own iPhones rather than Android based smartphones which is out-of-keeping with worldwide, and indeed UK statistics, strongly favouring Android. VTE prophylaxis at baseline audit was better than expected. This meant it was difficult to show any improvement on addition of the smartphone app. There were transient improvements in the correct prescribing of anti-embolic stockings however but generally results suggested that the app simply wasn’t being used. Sepsis bundle compliance at baseline was poor but slowly improved over the seven audit points. There were no sharp improvements in Sepsis Six bundle compliance to suggest that either the traditional methods or the app were particularly good at improving guideline compliance. Conclusions Electronic patient care is fast becoming universal and smartphone/ tablet technology will be at the forefront of this. Despite disappointing results here,the use of an app for more complex patient-specific guidelines is likely to become increasingly popular, as long as accuracy of the information provided by the app can be guaranteed

Common medications in the risk and prognosis of lymphoid neoplasms and epidemiology of primary CNS lymphoma

Lymphoid neoplasms are malignancies arising from the lymphocyte, and include lymphoma subtypes, chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). It is a heterogenous group of diseases, with different molecular pathogenesis, clinical characteristics, treatments and outcome. There is increasing understanding that risk factors may differ between the subtypes. The incidence of the non-Hodgkin subtypes of lymphoma (NHL) increased rapidly for several decades during the end of the 20th century, for mostly unknown reasons. Concurrently the use of many prophylactic medications such as statins and aspirin became common in Europe and North America. Anti-carcinogenic properties have been described in both these medications, but for statins there has also been concern about a potential conflicting effect of statins in lymphoma treatments that include the widely used monoclonal antibody rituximab. In study I and II we investigated the association between statin use and disease-specific mortality in lymphoid neoplasms. We assessed statin exposure in 6-month periods before and after diagnosis of a lymphoid neoplasm in cohort studies, and at any time during follow-up in nested case-control studies. We assessed the dose-response relationship by categories of intensity of statin use (according to American College of Cardiology/American Heart Association guidelines as low, moderate and high intensity) and duration. In study I, we found that among patients with MM, statin use was associated with improved myeloma- specific mortality in all time-windows assessed. There was however no significant trend for dose intensity or duration. In study II, we found no association between statin use and lymphoma-specific survival in NHL overall or in CLL and other subtypes. We found improved lymphoma-specific survival in Burkitt lymphoma and in CLL patients that used statins for >2 years, but these findings could also be due to chance. We found no evidence of reduced efficacy of rituximab treatment for patients with statin use, which is reassuring. In study III we used the American cohort the Nurses’ Health Study to assess detailed information on aspirin use over 25+ years and risk of NHL and its subtypes. We investigated both cumulative average quantity and duration of aspirin use. We found no association between aspirin use and risk of NHL overall, but there was an increased risk of follicular lymphoma for users of large quantities of aspirin (5+ tablets/week), as well as a significant trend across increasing categories of quantity. In study IV we investigated the incidence of primary central nervous system lymphoma (PCNSL), a rare NHL subtype located in the CNS. PCNSL has traditionally had a dismal prognosis, but many new treatment schemes have been introduced lately. We found an increasing incidence primarily in the elderly (70+) that was consistent with an increasing trend of brain tumors of all types in the same age group, suggesting that this can, at least in part, be due to increased diagnostic procedures and reporting. We did not find any improvement in survival during the study period, indicating that the new treatments have not yet improved the prognosis in a population-based setting