HM Medical Clinic

Canadian Society of
Internal Medicine (CSIM)/Rocky Mountain
Conference Report - 24-27 November, 2011, Banff, Alberta Dr. Robert Herman (Chair) Dr. Michael Kenyon Dr. Norm Campbell Dr. Narmin Kassam Dr. Jill Newstead-Angel Rocky Mountain Conference Report Review Committee
Dr. Robert Herman
Dr. P. Timothy Pollak Dr. Kelly B. Zarnke
Dr. Gabriel Fabreau
Dr. Evan Minty
Professor of Medicine Professor of Medicine Head, Division of GIM Internal Medicine Fellow Internal Medicine Fellow University of Calgary University of Calgary University of Calgary University of Calgary University of Calgary Introduction to the 2011
offered to participants to learn from KEYNOTE ADDRESS
Rocky Mountain /ACP
experts in specific topic areas; these well Top 5 Papers in General
General Internal Medicine attended workshops provided a valuable Internal Medicine 2010/2011
opportunity for collegial discussion and Conference
Presented by Dr. Jake Onrot, University of British Columbia Internists from Western Canada As a value-added component and in Every year, hundreds of papers related to gathered in Banff, Alberta for the an effort to enhance the educational general internal medicine are published. annual Rocky Mountain / ACP General opportunities at the meeting, this This makes staying up-to-date on the Internal Medicine Conference held from conference report provides a brief latest evidence a formidable challenge for November 24-27, 2011. This year's summary of topics selected by busy internists. Dr. Jake Onrot selected conference continued its tradition of the scientific committee. A clinical five papers that were published in late offering the more than 200 attendees commentary follows each summary 2010 and in 2011 that he believes have a stellar line-up of speakers from to further reflect on and clarify how had impact on the way internal medicine academic and regional centres. Keynote the findings might impact everyday is practiced. Internists are encouraged presentations and satellite symposia clinical practice. Clinicians are to read these papers and familiarize covered a full array of state-of-the-art encouraged to view and download themselves with the context of each topics in basic and applied research of trial within the overall literature in its the speaker presentations from interest to general internists. Building particular field, to balance the pros and this year's conference at the Rocky cons of each trial, and to apply the trial on their popularity in previous years, a Mountain Conference website at www.
evidence to their own decision-making. series of small-group workshops were Dr. Onrot introduced each of his selected CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. papers by first presenting it in the context fluid balance of 3L at 12 hours in of apixaban to reduce the risk of of a clinical case. The key findings and sepsis patients; a more positive fluid hemorrhagic stroke in patients with conclusions from the five papers are balance at 12 hours and at 4 days was atrial fibrillation with a number- summarized below: associated with significantly increased needed-to-treat (NNT) of 434 compared 1. The randomized controlled to standard therapy with warfarin, and a FEAST trial by Maitland et al. does 3. A randomized controlled trial by Garcia reduced risk of major bleeding (NNT 104).
not support the use of any fluid bolus et al. supports the early use of 5. The POET COPD retrospective cohort (albumin or saline) in critically ill transjugular intrahepatic portosystemic study supports the use of tiotropium children with impaired perfusion in shunt (TIPS) vs. traditional medical versus salmeterol for the prevention resource-limited African countries therapy in patients with cirrhosis who of exacerbations in patients with because both significantly increased were hospitalized for acute variceal moderate-to-severe COPD.
48-hour mortality compared to bleeding and at high risk for treatment 2. A retrospective review of the VASST 4. The large randomized controlled trial by Boyd et al. supports a positive ARISTOTLE trial supports the use Maitland K, Kiguli S, Opoka RO, et al.; FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011; 364(26): 2483-95. Epub 2011 May 26.
Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011; 39(2): 259-65. Garcia-Pagan JC, Caca K, Bureau C, et al.; Early TIPS (Transjugular Intrahepatic Portosystemic Shunt) Cooperative Study Group. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med 2010; 362(25): 2370-9.
Granger CB, Alexander JH, McMurray JJ, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11): 981-92.
Vogelmeier C, Hederer B, Glaab T, et al.; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364(12): 1093-1103.
Paper #1: FEAST trial Paper #2: VASST retrospective review illness severity. Patients with the lowest For pediatric patients in resource-poor The question of optimal fluid manage- CVP had lower mortality. There was an countries where malaria is prevalent, ment in adults with septic shock was interaction between survival, CVP, and clinicians considering fluid manage- assessed in a retrospective analysis of fluid balance: patients with lower CVP ment are faced with choosing between VASST (VAsopressin in Septic Shock Trial). fared better with more fluid administra- guidelines for first-world (i.e., 60 mL/kg While the Surviving Sepsis campaign ad- tion, whereas patients with higher CVP isotonic solution) versus third-world (i.e., vocates for aggressive fluid resuscitation, fared worse with more fluids. Optimal reserve boluses for advanced shock) set- recent literature reports that a more posi- survival occurred in patients with a posi- tings. FEAST randomized 3100 children tive fluid balance is associated with higher tive fluid balance of approximately 3L at with severe febrile illness and impaired mortality. Dr. Onrot reminded the audi- 12 hours. The authors concluded that in perfusion in sub-Saharan Africa to one ence of the double-edged sword of fluid "resuscitated" sepsis, the intravascular of three fluid management strategies: resuscitation: inadequate fluid administra- fluid deficit and tissue hypoperfusion may albumin bolus, saline bolus, or no bolus. tion may worsen tissue hypoperfusion be corrected even though hypotension The primary endpoint of the trial, 48- and ischemia, whereas excessive fluids and organ dysfunction may persist. In this hour mortality, showed a benefit for no may cause volume overload, pulmonary setting, giving more fluid may be harmful. bolus versus either bolus. Malaria (57%) edema, capillary leak, and re-perfusion The unaddressed question remains pre- and anemia were prevalent. This result injury. This prompted the retrospective cisely when to stop administering fluids in contrasts sharply with Rivers et al. (N VASST data evaluation. Hypothesizing that septic shock.
Engl J Med 2001; 345: 1368-77), which both too little fluid AND too much fluid favoured early and aggressive fluid ad- may be harmful, the analysis assessed the ministration in adults with septic shock. relationships between administered fluid FEAST raises questions regarding routine volume, central venous pressure (CVP), administration of fluid boluses in other and mortality. The results showed that patient populations with shock.
a positive fluid balance predicts higher mortality, even after adjusting for baseline CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. more useful in assessing intravascular Further research is needed to volume than is a "normal" or elevated improve our ability to reliably assess These two studies highlight our level and that fluid administration is intravascular volume (e.g., stroke limited knowledge regarding the only one part of an early response volume and pulse pressure variability optimal level of fluid resuscitation to sepsis that includes assessment in response to fluid challenge, and how we use imperfect indices of other markers of tissue perfusion bedside ultrasound [J Intensive Care of tissue perfusion to make (e.g., MAP, urine output, lactate, Med 2009;24:329-37]) and tissue iterative adjustments to our sepsis cognitive performance, central perfusion (e.g. lactate clearance and management strategies. We are venous pO2), early administration measures of oxygen transport).
reminded that a low CVP or JVP is of antibiotics and source control. Paper #3: Early TIPS trial Child-Pugh class C or B liver failure with tially improved in the TIPS group com- Acute and recurrent variceal bleeding is persistent bleeding at the time of endo- pared to standard therapy (ARR = 47%), common in cirrhotic patients with portal scopic band ligation (EBL) on vasoactive as was mortality (ARR = 25%). Dr. Onrot hypertension. The early use of TIPS has drug therapy were randomized to TIPS suggested that TIPS should be considered not been considered a standard part of within 72 hours or to standard therapy in this patient population, arguing that early management in preventing re- (i.e., vasoactive therapy, beta-blockers, we are often reluctant to adopt invasive in- bleeding or death due to concerns about then nitrates as tolerated and serial EBL terventions that may turn out to be better worsening hepatic encephalopathy. The until variceal eradication). The primary than medications.
study by Garcia-Pagan et al. suggests endpoint of failure to control the acute otherwise. In this study, 63 patients with bleed or re-bleed at 1 year was substan- were baseline differences between Pugh B and C patients at high risk treatment groups, including an of rebleeding, early use of TIPS Reservations have been expressed asymmetry in encephalopathy. should be considered along with regarding the applicability of this However, large benefits were all standard effective and tolerated trial, such as its small size; it is a observed in clinically relevant therapies (somatostatin analogues, single trial showing benefit when outcomes (rebleeding, mortality, antibiotics, EBL, beta blockers and a meta-analysis of related TIPS hepatic function, and time in ICU nitrates) while we await additional research is more equivocal; the and hospital) without adverse subjects were highly screened and effects on encephalopathy. Thus, selected (<20% enrolled); and there in appropriately selected Child- Paper #4: ARISTOTLE trial long-acting inhaled beta-agonists (LABA), to severe exacerbation, and the number To avoid redundancy, ARISTOTLE is sum- based on patient preference, cost, and ad- of moderate and severe COPD exacerba- marized and discussed in another section verse effect profile, whereas patients with tions were all improved with tiotropium of this review.
more severe COPD (FEV1<50%) should be compared to salmeterol. The effects were treated with combination therapy. The consistent across subgroups based on Paper #5: POET COPD trial question therefore remained, for patients age, sex, COPD severity, smoking status, The American Thoracic Society (ATS) rec- with milder COPD, which monotherapy body mass index, and use of concurrent ommends that symptomatic patients with strategy is preferred? The POET COPD inhaled glucocorticoids. Dr. Onrot con- mild or moderate COPD (FEV1/FVC<70%; study directly compared tiotropium to cluded that for mild to moderate COPD 50%<FEV1<80%) should be offered bron- salmeterol in more than 7000 patients requiring monotherapy, a LAAC may be chodilator monotherapy using either long- with COPD exacerbations and FEV1 <70% the preferred choice over a LABA.
acting inhaled anticholinergics (LAAC) or for 1 year. The times to first exacerbation, CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. outcomes observed in POET COPD enthusiastic and tenacious efforts are statistically significant, some to achieve smoking cessation in The POET COPD illustrates the large argue that the absolute size of the patients who consume tobacco (like trial size necessary to compare differences (a few percentage points) almost half of the POET COPD study two active treatments using a is not large. Even a trial of this size population) will achieve a greater meaningful outcome such as is unable to definitively address mortality benefit at a much lower COPD exacerbations, such that the questions of cardiac safety that cost than any or all bronchodilator similarity or small differences can have been raised for both LABA and therapies combined.
be determined with some degree of anti-cholinergic bronchodilators. certainty. While the differences in Finally, we must never forget that AM Edwards Lecture
topic of TB for nearly 30 years. He was born. Over 100 years ago, William Osler invited to present the 2011 AM Edwards said that TB is a social disease with The Early Diagnosis of
Lecture, with the goal of sharing what a medical aspect, and that remains Pulmonary Tuberculosis
is important to know to identify TB true in reserve communities today. Dr. Richard Long, University of Alberta early so that it can be appropriately "Tuberculosis is a very sophisticated Tuberculosis (TB) is frequently included managed. Dr. Long challenged internists pathogen exploiting failures on our as a differential diagnosis for respiratory to link seven key features that lead to a part…. Each generation has failed disorders, yet most internists do not suspicion of TB.
to address social issues that are the encounter the condition frequently Tuberculosis in Canada is largely basis of this disease," Dr. Long opined. enough to be comfortable diagnosing a disease that affects two groups: Factors that converge when there is a TB and managing patients with TB. Indeed, aboriginals from Nunavut and to a lesser outbreak in a reserve community are: 1) in Alberta only 110 to 180 cases of TB extent on reserves across the Prairies and a delay in diagnosis of the source case, are reported annually, meaning that foreign-born people coming from high- 2) large numbers of susceptible contacts internists may not see a case for many incidence countries such as Asia and (e.g., vulnerable children who have never years. Dr. Richard Long, University of Africa. This is important, given that 20% been exposed to the infection), and Alberta, has been an expert on the of the Canadian population is foreign- 3) an environment that is favourable to transmission (e.g., malnutrition, overcrowding, poorly ventilated homes). A combination of organ-specific as well as constitutional symptoms is the next clue for suspecting a case of TB. Dyspnea is uncommon in the early presentation of pulmonary TB because of its ability to interrupt both ventilation and perfusion in parallel. In an acutely infected patient, perfusion and ventilation is redistributed to the remaining healthy lung, leading to preserved function and ultimately, a delay in diagnosis. Typically, symptoms are subacute, occurring over weeks or months and sometimes years. The presence of any high-risk condition, including HIV/AIDS, organ transplantation, dialysis-dependent renal failure and patients on immunosuppressants, including systemic steroids, are another clue to diagnosing CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. TB, as these patients are at risk for half, and assessing for the following in tailoring treatment based on drug primary infection and for reactivating four common patterns: 1) upper lobe susceptibility testing. latent TB infection.
distribution, 2) cavitation, 3) volume In Canadian-born patients, drug-resistant Leukocytosis is typically a feature loss, and 4) endobronchial lesions (fluffy, TB is rare thanks to the practice of of community-acquired pneumonia, poorly defined nodules are present in directly observed therapy, which avoids whereas anemia is a characteristic feature virtually all cases of TB). Finally, cases of compliance issues. Drug resistance is of chronic TB infection. Also, internists suspected TB should be confirmed by more commonly found in foreign-born should not dismiss the value of a plain sputum testing for definitive diagnosis, infected individuals. Fluoroquinolones CXR, which can provide several important with molecular epidemiology to link the are bactericidal and can be lifesaving in diagnostic clues. Dr. Long recommended infection to the source case spatially and cases of highly drug-resistant TB. dividing the lung into an upper and lower temporally. Recovery of the organism through sputum samples is also helpful through a call to the laboratory to gamma release assays (IGRAs) for ensure prompt diagnosis. In Alberta, the diagnosis of latent tuberculosis Despite medical advances, pulmonary all specimens collected are kept (LTBI). These assays are in-vitro tests tuberculosis remains an important for culture of mycobacteria, which of cell-mediated immune response public health issue today. Dr. although notoriously slow remains measuring T cell release of interferon- Long points out that TB has a critically important as it allows for gamma following stimulation by disproportionate representation in fingerprinting of the organism, antigens specific to MTb. Until the vulnerable populations in Canada, susceptibility testing, and banking of advent of these assays, the diagnosis primarily aboriginal populations individual strains.
of LTBI relied solely on the use of and foreign-born immigrants. The traditional tuberculin skin testing importance of its early identification In Dr. Long's second lecture, he (TST), which has known limitations. is compounded by its potential to explained some of the recent IGRAs have been shown to be highly propagate within these communities advances in testing for tuberculosis. specific for LTBI, again 97%, but are and the risk of TB in vulnerable Two novel methods are becoming not reliable in active TB infections groups such as children and widely available and must be (sensitivity 75-90%) and unable the immunocompromised (e.g., understood by internists. The first, to distinguish between latent and HIV/AIDS, patients with solid known as nucleic acid amplification active TB infections. Review of organ transplant, and those on testing (NAAT), is an automated these assays by the Public Health immunosuppressants). The recent molecular test for Mycobacterium Agency of Canada and Canadian decision to withdraw the routine use tuberculosis (MTb), which can be Tuberculosis Committee released BCG vaccine in Canada's First Nations used for rapid diagnosis (within 2h recommendations around their and Inuit communities, which has of collection) and to differentiate use in 2008 (available at http:// been shown to reduce severe forms MTb from other common forms of TB such as CNS and disseminated of mycobacterium such as TB, makes children much more Mycobacterium avian complex php). Although IGRAs will likely vulnerable to infection. This frames (MAC). This test is highly sensitive replace TST for the diagnosis of the importance of early detection and ( 97%) and specific. Moreover, it has LTBI, some important questions prevention of local outbreaks.
also been shown to rapidly identify remain. For example, their utility drug resistant strains of TB through in immunocompromised hosts Once suspected, approaches focus the use of line probe assays, which and in healthcare worker screening on early isolation, preferably airborne is increasingly important as the programs is unknown. Lastly, it is isolation to prevent the spread of incidence of multi-drug resistant not known if a positive IGRA assay TB. The gold standard for diagnosis TB (MDR TB), both globally and will remain positive for the life of the remains recovery and culture of the in Canada, continues to rise. This patient, regardless of treatment for organism. Microscopic detection test was recently endorsed by LTBI. Despite these questions, IGRAs of AFB by stained sputum smears the WHO and its utility shown in represent a major advance in the relates directly to the infectivity of resource poor settings (N Engl J Med diagnosis of latent TB.
a patient and, if clinical suspicion 2010;363:1005–15). The second is high, these should be hastened diagnostic test is the interferon CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc.

the risk of stroke in patients with phase III trials evaluating dabigatran, AFib by an impressive 64%. Aspirin rivaroxaban, and apixaban versus Evidence-Based Update in Atrial offers a smaller benefit that only
adjusted-dose warfarin. He noted that Fibrillation: Review of Old and
reaches statistical significance with each of these three trials was relatively New Drugs for Anticoagulation the addition of other agents such as
large, enrolled patients with non-valvular Presented by Dr. L. Brent Mitchell, Calgary clopidogrel. Even then, the benefit of the AFib and risk factors for stroke (i.e., Co-developed by the RM/ACP Annual combination does not approach that of patients who should be receiving an Meeting Committee and Bayer Canada warfarin. Based on these findings, the anticoagulant), defined the primary Anticoagulant therapy in patients with CCS guidelines recommend that only efficacy endpoint as stroke or systemic atrial fibrillation (AFib) is a rapidly patients at very low risk of stroke (i.e., embolism, and utilized major bleeding evolving area of medicine. "New and CHADS2 = 0) should receive aspirin; oral (with varying definitions) as a safety emerging oral anticoagulants are anticoagulant therapy is recommended transformative and will change the for all other patients.
The direct thrombin inhibitor dabigatran way we practice." observed Dr. L. Brent Warfarin's characteristics, including a was evaluated in RE-LY.2 Compared to Mitchell from the Libin Cardiovascular narrow therapeutic window, substantial warfarin, the 150 mg dose reduced the Institute of Alberta as he opened his heterogeneity in individual sensitivity, risk of stroke with a similar risk of major review of the evidence on this topic. and multiple interactions with food, bleeding and the 110 mg dose had a Physicians have been aware of the herbal agents, and other drugs, similar rate of stroke with significantly increased risk of thromboembolic complicate its utilization in the clinical reduced major bleeding. As a result of events associated with AFib for over setting. A recent meta-analysis1 found these findings, the CCS guidelines now 100 years. Accounting for 15 to 20% of that only 48% of patients with AFib were recommend that one of the new oral all strokes, AFib is often undiagnosed treated with warfarin, and of those, anticoagulants such as dabigatran is until after the stroke occurs. Strokes the mean time in therapeutic range preferred over warfarin in most patients associated with AFib are more severe was 55%. As Dr. Mitchell pointed out, who require anticoagulation. The 150 than those occurring in patients without these findings tell us that only one mg bid dose of dabigatran is generally AFib. Importantly, the risk of stroke is quarter of AFib patients are effectively preferred over the 110 mg bid dose equal for paroxysmal, persistent, and anticoagulated, an important care gap except in the elderly or patients with permanent AFib.
that must be resolved. reduced renal function. Warfarin may be preferred over dabigatran in patients The 2010 Canadian Cardiovascular Novel anticoagulants that address many at high risk of an acute coronary event. Society (CCS) guidelines for of warfarin's limitations are at varying [Post-conference note: In 2012, CCS thromboembolism prevention in AFib stages of development. Dr. Mitchell published a focused update to the recommend all patients with AFib be presented the key findings from the guidelines that i) recommends one of assessed for their risk of stroke, using a tool such as the CHADS2 score, and their risk of bleeding, using a tool such as the HAS-BLED score. In principle, patients with a HAS-BLED score of 3 or more are at an increased risk of major bleeding. However, many of the factors in the CHADS2 score are also included in the HAS-BLED score, making the practical interpretation of an elevated HAS-BLED challenging. Dr. Mitchell recommends that in situations where the HAS-BLED is elevated due to the presence of factors included in the CHADS2 score (i.e., hypertension, prior stroke, and age), then the risk of bleeding is secondary to the increased risk of stroke.
Warfarin has been the foundation for prolonged oral systemic anticoagulant therapy for many years and reduces CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. the new agents over warfarin in most 2 risk factors for stroke, a higher risk were also slightly reduced bleeding patients; and ii) removes the preference population than was enrolled in RE-LY. rates. Phase III results for edoxaban are for warfarin over one of the new agents Rivaroxaban was found to be non- expected later this year. in patients at high risk of an acute inferior to warfarin for stroke prevention In considering the overall evidence with similar rates of major bleeding. from these studies, Dr. Mitchell Three Factor Xa inhibitors are in the Apixaban was compared to warfarin emphasized that these new agents late stages of development. [Post- in the ARISTOTLE trial,4 which enrolled are transformative and that healthcare conference note: rivaroxaban received patients at a similar risk for stroke as providers will need to weigh the risks a Notice of Compliance by Health were studied in RE-LY. Apixaban reduced and benefits of each as they pertain Canada for this indication in January, the risk of stroke compared to warfarin, to individual patients when making 2012.] The ROCKET-AF study3 evaluated although the ARR was only 0.34%, treatment decisions. rivaroxaban in patients with at least which is not clinically meaningful. There 1. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-Analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009; 15:244-52.
2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-91. 4. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.
oral anticoagulant agents from which elderly (or to assume that a bleeding to choose, with widely available tests event has the same disutility as a Dr. Mitchell compared and for therapeutic effect and agents stroke), and in so doing, deny them contrasted the three novel oral for rapid reversal of their effects. the benefits of stroke prevention. anticoagulants that will likely Healthcare providers involved in This is especially important when replace warfarin because of their any aspect of thrombosis will need one takes into account the fact convenience and reliability. Although to understand these agents and be that by age 75, CHADS2 score their absolute clinical benefit is familiar with how to use them, and in increases to 1 by definition, at similar to one another and each what populations, in order to provide which point all patients without a is comparable to warfarin, their patients with best care. The relative quantitatively high bleeding risk reduced incidence of intracranial advantages of each agent in any should receive prophylaxis with hemorrhage and practical given patient population have yet to systemic anticoagulation. Hopefully, advantages are moving guideline be worked out in real life practice. the greater consistency of the newer committees to recommend that The adverse cardiac signal seen with agents will lead to fewer bleeding almost all patients with a CHADS2 dabigatran was not seen in the trials complications and increased score of 1 be fully anticoagulated with the Xa inhibitors. Dabigatran confidence in anticoagulating rather than being considered for and apixaban must be dosed twice patients in this age group. This aspirin prophylaxis. daily, whereas rivaroxaban is given new class of agents will change the only once each day. All need to be practice of medicine. Dr. Mitchell correctly points out that dose-adjusted in renal failure. these novel oral anticoagulants are "game-changers." By the end of the Finally, one must be careful not to decade, there will be almost a dozen overestimate bleeding risk in the CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Update on Diabetes:
The benefits and risks of intensive Glycemic variability is another concept Latest Evidence
glycemic control continue to be debated that is generating interest in the Presented by Dr. Stuart Ross, Calgary in the scientific literature. The intensive management of diabetes. Patients who Co-developed by the RM/ACP Annual glycemic control arm in the ACCORD achieve "tighter" glucose control appear Meeting Committee and Lilly/ study (target HbA1c <6%) was stopped to achieve better outcomes than those early due to a higher incidence of death who experience more frequent swings compared to standard management from hyperglycemia to hypoglycemia. In an era where clinical practice is (target 7.0-7.9%). In contrast, the In vitro studies have shown that cells governed by evidence, it can be a ADVANCE study reported a significant exposed to greater variability in glucose challenge to stay up-to-date on the benefit of intensive glycemic control. concentration have higher rates of cell rapidly advancing field of diabetes A sub-analysis of the ACCORD data death than cells exposed to more stable management. Dr. Stuart Ross, Clinical showed that patients in the intensive glucose concentrations. Studies have also Professor of Medicine at the University of management group who died were shown that glycemic variability predicts Calgary, provided an update and a few generally older, had a longer duration mortality in adults in the ICU. A major general conclusions on some of the most of disease, a longer interval between trial called FLAT-SUGAR will prospectively recent evidence in diabetes.
diagnosis and treatment initiation, a evaluate the link between glycemic The currently accepted glycemic target history of cardiovascular disease, rapid variability and cardiovascular outcomes of HbA1c ≤7% was derived in large part correction of elevated HbA1c, had using continuous glucose monitoring.
from the UKPDS study, which showed episodes of hypoglycemia, and continued Dr. Ross concluded his presentation that this level of control was associated poor glycemic control. In other words, with a brief discussion of diabetic with significant reductions in several intensive management had failed in nephropathy, which continues diabetes-associated microvascular these particular patients, even though to be one of the most significant complications. In a post-trial follow- the mean HbA1c of the entire intensive microvascular complications in diabetes up of patients 10 years after the trial control arm was 6.5%. These findings patients. Renal impairment increases was completed, patients who had support the concept that optimal the risk of hypoglycemia and some been randomized to intensive control management of diabetes depends on oral hypoglycemic agents, such as retained a significant advantage over the "age and stage" of each patient. metformin, are not recommended in the conventional group, even if glycemic Reaching a glycemic target of ≤7% patients with impaired renal function. control had deteriorated. This "legacy in older patients with long-standing However, evidence from a Cochrane effect" suggests a major benefit of diabetes and associated complications review suggests the risk of lactic acidosis early intensive glycemic management may be more difficult – and potentially associated with metformin is low and for both microvascular and harmful – compared to achieving this this drug can be safely used in patients macrovascular outcomes. target in younger patients with less with minor reductions in renal function. advanced disease. Sulfonylureas remain the recommended second-line therapy, but are also renally eliminated. Third-line treatment is insulin. DPP-4 and GLP are alternative 3rd line agents in patients who cannot take or refuse insulin. The DPP-4 inhibitors are excreted renally and dose adjustments are necessary in patients with impaired renal function (with the exception of linagliptin, which is excreted primarily through the bile). Finally, Dr. Ross advised that an appropriate glycemic target for an elderly patient with heart disease may not be <7%. "Common sense must remain a big part of clinical acumen." CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. potentially long lasting beneficial 4. High variability in blood glucose effects in reducing complications levels (glycemic variability) is Diabetes continues to represent a (the "Legacy Effect"). HbA1c targets potentially harmful despite very large burden of disease with of <7% should ideally be achieved achieving HbA1c targets <7%.
associated cost and morbidity in within one year of diagnosis of Canada. Review of Canadian data in 5. The therapeutic pyramid should diabetes care reveals discouraging include metformin as the first line results with respect to achieving 2. Simultaneous management of all agent, sulfonylureas as second combined targets of glycemic control, cardiovascular risk factors, line, and insulin as third line. blood pressure and lipid control including hypertension and Insulin is a more effective therapy (Can J Cardiol 2010;26(6):297–302). dyslipidemia, is paramount.
than oral agents and internists Dr. Ross' review offered five very need to be more willing to initiate practical and evidence-based 3. Elderly patients with a long history this therapy in hopes of achieving recommendations for internists to of diabetes and difficulty achieving glycemic targets earlier in the manage their diabetic patients: glycemic targets may be harmed disease process.
by overly aggressive management 1. Early management in newly of blood sugar control.
diagnosed patients offers Update on Lipids:
on biomarkers and new evidence linking mediators have a major role in the Cardiovascular Disease
atherosclerosis with inflammation.
pathophysiology of atherosclerosis, Prevention - A Look Ahead
Studies suggest that for each 1 mmol/L and patients with chronic inflammatory Presented by Dr. Jacques Genest, reduction in LDL-C there is a 2% absolute disorders such as rheumatoid arthritis McGill University risk reduction in major atherosclerotic and psoriatic arthritis have a 2- to 5-fold Co-developed by the RM/ACP Annual events, regardless of the lipid-lowering higher incidence of cardiovascular Meeting Committee and Merck Canada agent employed. Whereas evidence disease. Emerging evidence suggests that cholesterol crystallization may Canadian guidelines for the diagnosis and continues to accumulate supporting the be an early inflammatory trigger of treatment of dyslipidemia and prevention benefits of aggressive LDL-C lowering, atherosclerosis. Current models propose of cardiovascular disease are updated strategies involving modulation of HDL-C that cholesterol crystals activate the every 3 years. It is expected that the 2012 mass and function have not borne inflammasome to generate interleukin version of the guidelines will be largely consistently positive results. The results unchanged in terms of cardiovascular risk of ongoing studies evaluating the effects β, triggering production of CRP by the liver and ultimately resulting in assessment and LDL-cholesterol (LDL-C) of niacin, dalcetrapib, and anecetrapib on vascular inflammation. The potential treatment targets. Dr. Jacques Genest, cardiovascular event are eagerly awaited.
involvement of the inflammasome and McGill University, reviewed some of the Dr. Genest predicted that vascular ongoing studies that may influence future β pathway opens the door to new inflammation may play an increasing role molecular targets for the treatment of guideline recommendations with a focus in atherosclerosis research. Inflammatory atherosclerosis. function may be more important than written, HPS-2 THRIVE and AIM-HIGH its mass. This was a hard learned (N Eng J Med 2011;365:2255–67) Dr. Genest's talk is an excellent lesson in ILLUMINATE (torcetrapib) (N give credence to the current focus resource to general internists as Eng J Med 2007;357:2109–22), and on getting LDL to target. The first they navigate this dynamic field. one that has informed forthcoming advice to pass on to our patients: Eat The signal in JUPITER (Circulation studies of the next generation food. Mostly plants. Not too much 2010;121:143:50) regarding hs-CRP of CTEP inhibitors, namely DAL (Pollan M. The Omnivore's Dilemma: indicate that the protein itself is not OUTCOMES (dalcetrapib) and REVEAL A Natural History of Four Meals. New likely a causal factor in coronary (anacetrapib). Although the next York, New York: Penguin, 1996).
artery disease. Modulation of HDL chapter for niacin remains to be CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc.

CRT in the Treatment of
in the primary composite endpoint of but there was no significant benefit of CRT Heart Failure
total mortality or heart failure events added to ICD in this subgroup of patients. Presented by Dr. Anthony Tang, Victoria, was demonstrated in Class I-II patients However, there was a trend towards a and Dr. Jonathan Howlett, Calgary receiving CRT plus an implantable cardiac reduction in hospitalization due to heart Co-developed by the RM/ACP Annual defibrillator (ICD) compared to ICD alone failure (hazard ratio 0.58, p=0.052). A Meeting Committee and Medtronic in the MADIT-CRT study; however, the small Italian study suggests that CRT can difference was driven by the reduction in be effectively applied in patients with While clinical trial evidence supporting heart failure events, with no significant AF who undergo AV junction ablation. A cardiac resynchronization therapy (CRT) difference in mortality. Both studies subsidiary study is now being planned to initially accumulated for the treatment reported a significant reduction in left address this particular group of patients.
of Class III and IV heart failure patients, ventricular (LV) volume and increased recent studies have shown benefits in Dr. Jonathan Howlett, Clinical Professor ejection fraction (EF) from baseline – so mildly symptomatic patients. Indeed, of Medicine at the University of Calgary, called ‘reverse remodeling' of ventricular the REVERSE, MADIT-CRT and RAFT used a case-based approach to review the studies support a reduction in morbidity, recently updated Canadian Cardiovascular mortality, and disease progression in Class The RAFT trial, which was largely a Society (CCS) heart failure guidelines I or II heart failure patients. Dr. Anthony Canadian study, supports a significant with a focus on CRT. The guidelines Tang, Professor of Medicine at the reduction in a composite endpoint of strongly recommend the use of CRT in University of British Columbia, reviewed mortality or hospitalization due to heart combination with an ICD for heart failure the clinical trial evidence for CRT in the failure in Class II-III patients receiving patients on optimal medical therapy with management of patients with mild-to- ICD plus CRT. The RAFT trial showed a Class II symptoms, LEVF <30% and QRS moderate heart failure. significant benefit in terms of all-cause duration of 150 ms.
mortality, with an absolute reduction The REVERSE study demonstrated a trend Dr. Howlett pointed out several patient of 6% over 5 years of follow-up. A toward less worsening of a composite features that should be considered prespecified subgroup analysis showed endpoint that included all-cause mortality, when selecting patients for CRT referral, that patients with a wider QRS duration heart failure hospitalization and heart including the severity of heart failure (i.e., or left bundle branch block (LBBB) derived failure worsening in Class I-II heart failure ejection fraction, symptoms, rhythm, greater benefit from the addition of CRT.
patients receiving CRT compared to those QRS width and morphology, likelihood of with an implanted but inactive device (16% Patients with permanent atrial fibrillation successful pacing) as well as comorbidities vs. 21%, p=0.10). A significant reduction (AF) were also included in the RAFT study and patient preference. Internists should keep in mind that studies to date have not included patients with planned surgical or interventional procedures, recent myocardial infarction, known cardiomyopathies, end stage renal failure, dementia, or other significant life-limiting co-morbidities. Therefore the benefits and risks of CRT in these patients remain unknown. In conclusion, Dr. Howlett summarized some of the points that argue for and against CRT.
CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Features that argue for CRT
Features that argue against CRT
Lower ejection fraction Ejection fraction closer to 35% Lack of sinus rhythm, lack of pacing potential (e.g., large posterior infarct) QRS closer to 150 ms QRS closer to 120 ms Stable, chronic heart failure Extremes of symptoms • Use of inotropes • Female gender? • Acutely worsening or intermittent symptoms there was a 3.7 % absolute reduction EF < 30% and a QRS duration > 150 in mortality. These numbers are quite msec be considered for placement of A recently published systematic respectable. However, because of the CRT-ICD clearly have not examined review and meta-analysis on the high mortality and morbidity in this all of the economic issues relevant subject of CRT (J Cardiac Fail cohort, 3-6 times more people died to implementing such a costly new 2011;17:860-6) cites 5 studies or were admitted to hospital for heart technology in this sizable population that compare CRT to medical failure despite having the device than of patients. Will there be more money management of heart failure alone benefited from it. for this exciting new technology, in patients with Class II - IV heart or is the verdict in from the 3 trials failure. Summarily, these studies The authors of the 2011 CCS presented and it's Code BLUE on show a 4.5% absolute reduction in Heart Failure Guidelines statement CRT? Perhaps there is a subset of mortality over the 1-2 years of the suggesting that all patients with patients with heart failure where CRT running of the trials. Also, in 6 RCTs NYHA Class II-IV heart failure despite or some better treatment will help comparing CRT-ICD versus ICD alone optimal medical treatment with an them live longer, healthier lives.
Short Snappers
(those with previous stroke, or pre- example, the recent HYVET-COG study existing cognitive impairment). While showed that aggressive blood pressure Dementia: A Disease of the
this association would be expected for reduction (i.e., -15 mmHg) in very elderly vascular dementia, it also applied to patients significantly reduced their risk Presented by Dr. Tom Jeerakathil, patients with Alzheimer's disease (AD). of dementia. The curves continued University of Alberta The findings are also consistent with to diverge over time, suggesting that Stroke and other vascular risk factors the 1997 Nun Study, which showed dementia might be delayed or prevented are associated with an increased risk that in the presence of microinfarcts, by controlling blood pressure over of future dementia. How this occurs smaller plaque burden produced more several decades.
and the extent to which cardiovascular significant cognitive impairment. Other While more definitive evidence linking risk factors and small vessel disease cardiovascular risk factors have also been dementia with small vessel disease contribute to dementia is less well associated with a higher risk of dementia continues to emerge, Dr. Jeerakathil established. The findings of a recent and cognitive changes, particularly suggested that internists should consider meta-analysis of prospective longitudinal hypertension. adopting quick screens for cognition into studies that examined the impact of If dementia is a disease of the routine practice. The Mini-Cog test (Int J white matter changes on outcomes microcirculation, can controlling Geriatr Psychiatry 2000;15:1021–7) was including cognitive decline, dementia, cardiovascular risk factors modulate highlighted as a screen that takes 2 to 4 stroke and mortality support an disease outcomes? The literature minutes to administer and correlates well association between small vessel disease shows mixed results, but there is a with MMSE and MoCA scores.
and dementia in the general population, signal suggesting that modulation although not in ‘high risk' subgroups of risk factors may be protective. For CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. and in gross pathology between to consider increasing their use of vascular dementia and AD may, in neurocognitive screening tools given Dr. Jeerakathil's talk raises the fact, reflect a common etiological the prevalence of vascular risk factors interesting hypothesis that the origin with respect to microvascular within our patient population.
overlap that is seen both clinically health. General internists may want Use of Hypertonic Saline in
Therefore, guidelines suggest empiric acceptable. Reasonable limits for the treatment with hypertonic saline. There treatment of acute severe hyponatremia Presented by Dr. Irene Ma, are at least four formulae available to are to increase sodium by 1-2 mEq/L/hr University of Calgary guide the amount of hypertonic saline to for the first 3-4 hours, never exceeding administer, with the Androgue-Madias 3/hr, with a daily maximum of 8-12 The treatment of hyponatremia involves formula being the most commonly used. mEq/L. balancing the risks of cerebral edema While the equation seems deceptively from undertreatment and the risks of While there is clearly potential harm simple, it can be difficult to recall when osmotic demyelination syndrome (ODS) to correcting an acute drop in sodium a patient is actively seizing and requires with over-aggressive treatment. Evidence too rapidly, correcting sodium levels immediate care. Dr. Ma recommended guiding the optimal management of too slowly can also result in negative a simpler method that yields the same hyponatremia is limited and is based outcomes. In acute hyponatremia, a answer as using a formula, but that does primarily on consensus from expert correction rate of 2 mmol/hr has been not require any memorization on the panels. Nonetheless, when confronted associated with greater survival than internist's part. The method involves with a patient with symptomatic severe correcting sodium more slowly. Studies logically working through the following hyponatremia, few internists would argue suggest that end sodium values are against the use of hypertonic saline.
overestimated about 75% of the time 1. How much sodium is in the patient using the available formulae. Dr. Ma Hypertonic saline is any solution with right now? [TBW (L) x existing serum argued that clinicians should no longer a higher sodium concentration than sodium concentration (mEq/L)] be surprised when patients are over- the body's normal level of 140 mEq/L. corrected, but rather, they should expect Typically, hypertonic saline solutions are 2. How much sodium will be in the this to be the case. There are multiple 3% (513 mEq/L) and 5% (856 mEq/L), but patient if 1L of 3% hypertonic saline is reasons that may account for over- they can range as high as 29%. The use administered? [#1 above + 513 mEq] correction using formulae. For example, of hypertonic saline is generally guided 3. What would the patient's end sodium formulae do not account for ongoing by symptoms. Patients who are most concentration be? [#1 above + 513] urine and gastrointestinal sodium losses, likely to do poorly if undertreated include mEq / [TBW + 1] L dietary intake, and more importantly, those with an acute drop in their sodium, 4. How quickly do you want to achieve for water diuresis. This makes ongoing women, children, and patients who are this end concentration? laboratory testing and monitoring essential in the management of acute In order to avoid overtreatment of Hyponatremia can be worsened if the hyponatremia. When sodium is over- hyponatremia and the risk of OSD, saline solution administered does not corrected, hypotonic solutions can be there are recommended limits based have a higher sodium concentration administered (e.g., 1-2 μg IV/SC DDAVP) on human data from different sources. than that in the urine. However, when with monitoring of urine sodium levels While these vary, Dr. Ma suggested internists are confronted with an acute every 1-2 hours to ensure they remain in that for undifferentiated symptomatic case of severe hyponatremia, urine the normal range.
hyponatremia, <12 mEq/L/day is indices are not always readily available. CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. the response to your sodium with 0.9% saline. First, and this was discussed by Dr. Ma, if the Is there any risk to giving 100 ml of tonicity (osmolality) of the urine 3% NaCl (or 2 ml/kg in smaller adults What about using normal (0.9%) is higher than the tonicity of the or children) over 5-10 min, repeating saline for correction of hyponatremia? solution you are using to correct the serum sodium and thereby If you know the concentration of the hyponatremia, rehydrating/ devising an ‘on-the-go' replacement solute in a bag and can correctly correcting with 0.9% saline may drive strategy? This can be continued until calculate the amount and the rate the sodium lower and worsen the the patient is asymptomatic (usually at which you wish to administer it hyponatremia. Second, given that after a correction in serum sodium (information needed regardless of the 0.9% saline has inherently more water by 4-6 mEq/l), following which no solution you are choosing), the only than 3% saline, you risk correcting further sodium correction or a slower difference in giving 100 mEq of Na+ the volume deficit before correcting rate of sodium administration can as 0.9% NaCl or 100 mEq of Na+ as the sodium deficit. The stimulus be undertaken depending upon the 3% NaCl is in the amount of water you causing ADH secretion is lost (ADH is cause of the hyponatremia (Curr are providing along with that solute. appropriately elevated in hypovolemic Opin Crit Care 2011;17:581-93). The clinical question becomes ‘How hyponatremia) in which case the In no instance should the daily much water would I like to give to this kidney starts excreting large volumes correction be greater than 10 mEq/l patient who is already hyponatremic?' of dilute urine thereby self-correcting in the first 24 hours and 18 mEq/l This, of course, relates to the the hyponatremia, irrespective of over 48 hours. Indeed, given the overriding cause of the hyponatremia your best efforts to control solute and frailties of assessing volume, most and to the risks inherent in water administration. Incidentally, the experts now suggest giving repeated same problem awaits glucocorticoid small boluses of hypertonic saline If the patient has hypovolemic administration in hyponatremia and repeatedly measuring serum hyponatremia, and so is deplete due to adrenal insufficiency. Thus, sodium to all symptomatic patients of both sodium and water but hypertonic saline should be the that require sodium correction (Acta proportionally more sodium than principal replacement solution early Anaesthesiol Scand 2011; 55:139- water, 2 conditions may complicate in the treatment of most cases of 48). The key is, and this cannot your correction, particularly when hyponatremia, irrespective of the be overemphasized, choosing the choosing to rehydrate/correct correct solution and reassessing Exercise in health promotion
osteoporosis, diabetes, coronary heart Current exercise recommendations call Presented by Dr. Mark Roberts, disease, colorectal cancer, breast cancer, for at least 30 minutes of moderately University of British Columbia hypertension, and many others. Given intense physical activity at least 5 days the health benefits of physical fitness per week, and preferably every day. These Current epidemiological reports suggest and exercise, it might be expected that recommendations are based on evidence that low fitness levels are responsible for healthcare professionals would routinely suggesting that the benefits of exercise more deaths in Canada and the USA than advise their patients on this important extend beyond weight control and weight chronic diseases such as hypertension, matter. Yet studies suggest this is not loss. Physicians should therefore be obesity and smoking that are expensive the case. Indeed, in a study of 330 family actively recommending the minimum to treat and garner much more attention. physicians across Canada, only 11% amount of exercise to all of their patients. In Canada, it is estimated that 30,000 counselled their patients on the benefits While higher amounts of exercise may be deaths can be attributed to the "sedentary of exercise, and more alarmingly, only necessary in some circumstances, such as death syndrome." Low fitness is not only 43% felt they should be counselling their endurance training, there are undeniable an important risk factor for mortality, it patients on this topic. Not surprisingly, health benefits from meeting just the is also associated with a host of other the major barriers against counselling minimum requirements for physical chronic conditions including dementia, were time and education about exercise.
activity each day.
CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Roberts' talk, the American College of scenario, where limiting our daily Preventative Medicine has noted that sitting / laying to 23.5 hours proves Dr. Roberts presented discouraging the health benefits of regular physical too ambitious, a recent analysis of statistics regarding physician activity extend beyond weight loss. the INTERHART study offers some advocacy for exercise despite the General Internists may want to avail hope that even mild to moderate existing evidence about its benefits, themselves of this fact to help keep occupational activity is protective (Eur and the cost effectiveness of physical patients motivated in the absence of Heart J 2012;33:452–66). See you all activity interventions (Br J Gen Pract a demonstrative change in physical in the stairwell.
2011;61:e125-33). As cited in Dr. appearance. In the worst case Workshops
can all be well visualized with bedside Dr. McDermid utilizes U/S-guided U/S. Studies suggest that non-cardiology bedside diagnosis 3 to 4 times during a Ultrasound Guided Bedside
intensivists can reliably perform goal- typical night on call. "My practice revolves Diagnosis & Procedures
directed U/S. For example, a study of around U/S because I can get information Presented by Dr. Rob McDermid, six intensivists who received ten 1-hour fast. It helps me improve the care of my University of Alberta sessions of U/S training were found to patients." Guidelines are currently in Ultrasound (U/S) technology has the perform with 84% accuracy. Moreover, development for the training and optimal potential to assist physicians with a host the information obtained by bedside U/S use of bedside U/S. Meanwhile, the of procedures and diagnostics, including resulted in a change in management availability and portability of U/S devices central venous access, thoracentesis, strategy in 37% of cases. Trainees at all is increasing while the development of and many others. Bedside U/S has levels can learn how to apply bedside accurate and affordable U/S probes is been shown to be particularly useful U/S-guided diagnosis with appropriate an ongoing area of innovation. A hand- for identifying cardiac abnormalities training. For example, first-year medical held U/S device is now available for (low ejection fraction, high pulmonary students have been taught to use pressure, pericardial effusion, and severe bedside U/S to augment diagnosis. valvular regurgitation or stenosis). These are safer when guided by U/S. But, practices. Training programs with how extensively should internists established curricula (both U/S theory Will bedside US become the new not formally trained in diagnostic and learning of specific skills) exist. stethoscope of the 21st century? imaging be using this modality of However, the occasion would be rare This technology has great potential investigation? While very limited that a bedside U/S replaces formal to augment our physical exam skills research in this area is supportive of and complete diagnostic imaging, and to enhance the safety of some the capacity for health care providers when indicated. This technology of our common bedside procedures. at many levels to learn very specific is undoubtedly useful for many For example, physical exam findings U/S skills, there is much to learn applications and is evolving rapidly such as thyroid enlargement or regarding optimal introduction of – for example, the hand held-device nodules or the presence of a pleural this new technology into practice. cited above. As internists, it behooves effusion or ascites can be confirmed ED physicians and intensivists us to keep up to date not only in our at the bedside. Central venous have moved ahead of internists on knowledge base but also evolving catheterization and thoracocentisis introduction of bedside U/S into their diagnostic skills.
CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Infection in Pregnancy
no associated medical conditions. The Finally, Dr. Castillo advocated for the pathogens most often associated with recognition of pregnancy as a window Presented by Dr. Eliana Castillo, University of Calgary maternal sepsis leading to mortality of opportunity to promote routine include Group A Streptococcus, E. coli, vaccination. Immunization against Pregnancy can be considered as a and influenza. Furthermore, almost influenza can significantly reduce "controlled" or contained form of 50% of women who died did so within maternal morbidity and mortality, and systemic inflammatory response 24 hours of admission, supporting the it can also protect newborns from syndrome (SIRS) whereby heart rate concept of rapid deterioration when death in the early days of life. Mothers is >90 bpm, respiratory rate is >20 decompensation occurs. These data expressing concerns regarding the breaths/min, PaCO2 is <32 mmHg, suggest a failure of taking routine theoretical risks of vaccination during white blood cell count is >12,000, and observation, asking for specialist advice pregnancy can be reassured that the risk temperature is higher than 38˚C or less early, and importantly, starting empiric of adverse pregnancy outcomes due to than 36˚C. These are normal physiologic antibiotic treatment in pregnant women vaccine-preventable infections is much changes in pregnancy and women often when sepsis is suspected. Dr. Castillo's higher. The World Health Organization feel fine despite their presence. own data involving 75 cases of sepsis recommends routine vaccinations Infections are common complications among pregnant women admitted to during pregnancy including influenza of pregnancy, occurring in 1 to 10% the British Columbia Women's Hospital and DTap, as well as specific vaccines of pregnant women. In the setting of suggest that SpO2 was measured in only based on maternal comorbid medical contained SIRS, a pregnant woman can 42% of cases, urine output was recorded conditions. Despite this recommendation usually compensate for an infection for only 20% of the time, and lactate was and the recognized risks of influenza a while. However, if she decompensates, ordered <1% of the time. infection during pregnancy, only 15% it tends to happen rapidly. Sepsis is Recommendations include considering of all pregnant women are immunized, often not recognized soon enough tachypnea and/or an SpO suggesting an educational need for in pregnant patients because the than 94% on room air to be red flags, patients and physicians alike.
physiology of pregnancy can mimic ensuring that perfusion goals (urine the pathophysiology of sepsis. Sepsis output, lactate) are met, directing continues to rank among the top three investigations toward identifying a source causes of maternal morbidity in the (nasopharyngeal swabs and sputum), and United Kingdom and Canada, where tailoring appropriate antibiotic treatment. data on maternal deaths are tracked With the exception of fluoroquinolones, and compiled every 3 years. This rich any antibiotic that would typically be source of epidemiologic information used for the treatment of respiratory suggests that the median age of women infections in non-pregnant patients (e.g., who die from sepsis during pregnancy macrobid, azithromycin, 3rd generation is 34 years, and about half of these cephalosprins) can be considered for women were otherwise "healthy" with pregnant women.
Dr. Castillo gave an informative and insightful presentation on this subject and we would encourage participants to review her slide set on the RM website.
CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Osteoporosis for General
life) and the healthcare system (i.e., loss or family history of hip fracture, Internists
about $1 billion per year in Canada).
which increases the absolute 10-year Presented by Dr. Bill Leslie, The new guidelines endorse the use of risk by 9%. Spinal imaging can be University of Manitoba the CAROC risk assessment tool that useful in moderate-risk patients; if any undiagnosed vertebral fractures are The Osteoporosis Canada clinical is based on national fracture mortality identified, the patient is re-categorized practice guidelines for the diagnosis data and has been tested and validated into a high-risk group that warrants and management of osteoporosis were in Canadian cohorts. This simple tool treatment. There is strong evidence to updated in 2010. Although they continue emphasizes just three risk categories support osteoporosis treatment in high- to emphasize T-scores and bone mineral (low, moderate and high) and three risk risk patients (10-year risk >20%). There density (BMD) for the characterization factors (age, sex and BMD), which are are several first-line therapies available of osteoporosis, the new guidelines also generally sufficient to inform appropriate to choose from. Dr. Leslie noted that recognize that this disease is complex treatment decisions. Alternatively, Dr. while serious adverse events such as and multifactorial, and that more than Leslie suggested using the World Health osteonecrosis of the jaw and atypical one single risk factor predicts fracture Organization's FRAX system, which femur fractures have been associated risk. Therefore, the new guidelines have considers additional risk factors. A with bisphosphonate therapy, these increased their focus on fractures and the Canadian version is available, which has events are very rare and the risk-benefit clinical impact of fragility fractures. been directly validated in a Canadian population. Both tools estimate 10- ratio remains favourable in high-risk There continues to be an enormous care year fracture risk, which aligns with patients. New anabolic treatments gap in post-fracture care and treatment the Osteoporosis Canada treatment that regulate osteoclast function are in of high-risk patients to prevent secondary guidelines, and are available on the development and Dr. Leslie predicted fractures. This is in stark contrast to Osteoporosis Canada website (www.
that "these new drugs will change how other chronic health conditions. For we treat osteoporosis in the next 5 to example, 80% of patients who suffer a heart attack are discharged from Patients with a low 10-year risk of Calcium and vitamin D supplementation hospital with a prescription for beta- fracture (<10%) are unlikely to benefit as well as weight-bearing exercise blockers, whereas only 15% of people from treatment; lifestyle counselling remain important components of who fracture are diagnosed and treated should be dispensed and the patient management for patients with low for osteoporosis. The consequences of reassessed in 5 years. Patient preference bone mass. Current recommendations under-recognition of osteoporosis can guides treatment decisions for the suggest an upper limit of 1200 mg/d of be considerable to both patients (e.g., moderate risk (10-20%) group. These calcium from both dietary sources and subsequent fracture, hospitalization, patients should be evaluated for supplements, a reduction from previous institutionalization, reduced quality of additional risk factors, including height recommendations of 1500 mg/d. Some studies have suggested that calcium supplements may cause a surge in serum calcium levels that can increase the risk of cardiovascular disease. However, Dr. Leslie cautioned that the evidence for this association is limited to one large study that found a signal using a very narrow definition of myocardial infarction, but the association disappeared when adjudicated definitions were used. Dr. Leslie is comfortable recommending 1200 mg/d, whereas there is no evidence for benefit above this level. He advises vitamin D supplementation at 1000-2000 IU/d, although guideline recommendations vary between 800-4000 IU/d.
A Quick Reference Guide for the 2010 Osteoporosis Canada guidelines is available online at CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. formal assessment of osteoporosis active life style that includes weight- risk in all patients with fractures as a bearing exercise and to consider an Efforts to reduce the clinical and first step to avoiding repeat breaks. intake of 1000-2000 IU/d of Vitamin financial costs of osteoporosis Both the CAROC risk assessment tool D as well as a total food/supplement continue to be frustrated by the and the World Health Organization's intake of 1200 mg/d of calcium. inability of any single intervention FRAX system provide a 10-year By the time the bone becomes to have a major impact on this fracture risk, validated for the osteoporotic enough to fracture, multi-factorial problem. However, a Canadian population. Those with a > it may be too late to fully regain systematic approach to diagnosis, 20% risk merit strong consideration its integrity. Therefore, as in many categorization and treatment will still for bisphosphonate therapy. medical diseases, prevention is far be needed for there to be any hope of more desirable than cure. improving the situation. Dr. Leslie's workshop also reminds us that the most prudent therapy is The new Osteoporosis Canada preventive. Younger patients need guidelines start by recommending encouragement to participate in an Update on Perioperative
event surveillance, and dispensing (American Society of Anesthesiologists) Medicine
general medical advice. Dr. Bruce Fisher physical status classification system, Presented by Dr. Bruce Fisher, reviewed the benefits – and potential Lee criteria, and the revised Cardiac Risk University of Alberta harms – of performing preoperative Index (rCRI) are the most commonly cardiac risk assessment and preoperative employed. Dr. Fisher discussed some Preoperative consultations are commonly management of medications in patients of the benefits and limitations of risk conducted for patients undergoing undergoing non-cardiac surgery.
assessment tools, which are summarized major non-cardiac surgery. This task in the table on the opposite page.
involves risk stratification, risk reduction, Several cardiac risk stratification tools are available, among which the ASA Risk assessment tool Benefits
ASA physical status • Widely used and • Not explicitly developed as a risk assessment tool classification system • Clinical acumen required • Derived in a non-contemprary patient population • Derived from a large, • Becoming "stale" (developed 12 years ago) prospective study • Underestimates risk • Widely used and • Included only two types of surgical patients (does not reflect orthopedic population) • Does not predict vascular risk very well VSG-CRI (Vascular Study • Recently developed • Complicated model Group of New England – (2010) Cardiac Risk Index) • Derived from a large • Limited utility for internists who are less likely to consult on vascular surgery patients rCRI (Erasmus model) • Stratifies risk by age • ROC increased from Cardiac Risk Calculator • Recently developed (2011) • Not a research trial • Derived from a large • No preoperative and postoerative evaluations database of 250,000 • Average age of cohort 10 years younger than rCRI cohort • Only included hard cardiac endpoints (MI and cardiac arrest) • Medical chart review • 1/3 were low risk surgeries (laparoscopy, breast surgery) with high quality data not normally candidates for preoperative consultation • ASA classification embedded in the score (i.e., "a model within a model") • Low sensitivity ROC: receiver-operator curve CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Dr. Fisher noted that the simple and that it is not "ready for prime time" yet. A sensitivity analysis showed that risk rapid Ankle-Brachial Index (ABI) correlates More definitive data on how to make use of was increased only when the consultation well with the rCRI, and is probably this biomarker is eagerly awaited from the was carried out by specialists rather than worth doing to ensure a patient does ongoing VISION trial, with results expected generalists and when the consultation not have undeclared vascular disease. was within 7 days of surgery, suggesting Among the newer tools and tests on the Dr. Fisher concluded his workshop by a narrower focus of the consultation and horizon to improve risk stratification is reviewing data from a retrospective cohort more aggressive interventions close to brain natriuretic peptide (BNP). While study that evaluated outcomes in more surgery may increase the risk for harm studies to date suggest this easy-to- than 270,000 patients undergoing major to patients. Dr. Fisher concluded that measure biomarker may offer additional elective non-cardiac surgery in Ontario "Before you do stuff, you should ask prognostic information for mortality and from 1994 to 2004. In this cohort, 39% of yourself what you'll do with the results, cardiac events after major non-cardiac patients had a preoperative consultation and give yourself enough time to have surgery, this benefit is offset by the lack at a median of 15 days prior to surgery. the intervention work." For example, of understanding regarding what to do Using matched propensity analysis, the smoking cessation often takes longer than with the information. Furthermore, there investigators showed that patients who 2 weeks, beta-blocker initiation within has been substantial variability between received preoperative risk assessment and 1-2 weeks of surgery can be dangerous, studies evaluating BNP and pro-BNP (e.g., management had higher 30-day and 1-year and statins require several weeks to have types of surgeries, patients' risk level, mortality, longer hospital stay, increased an appreciable effect on blood lipids. mortality rates, etc.) and a threshold BNP preoperative testing and pharmaceutical "As advocates for our patients, we need level has yet to be defined. While BNP may interventions, compared to patients who to actively lobby to stop last-minute be a tantalizing idea, Dr. Fisher concluded did not receive a preoperative consultation. management strategies." it for communication between increased in magnitude when physicians. Perhaps more impactful only consultations performed by Dr. Fisher pointed out that several was his discussion of the paper by specialists or within 1 to 7 days of the tools used to predict patient Duminda et al (Arch Intern Med of surgery were considered." This risk in the perioperative period 2010;170:1365-74). The discussion suggests that the last minute pre- were not developed for that of that paper points out that: "In operative consultation achieves little purpose, but rather to categorize sensitivity analyses, the association benefit and interventions may carry of consultation with mortality was more risk than benefit. CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. CONFIDENTIAL - Distribution or use of this document and the contents is prohibited without the express written permission of EBM Consulting Inc. Please join us at the 2012 CSIM Annual Scientific Meeting.
2012 CSIM Annual Scientific Meeting
In collaboration with ASMIQ
October 17-20, 2012 - Quebec City, QC
Program and registration information will be posted at For more information please contact [email protected] Please join us at the 2012 Rocky Mountain Conference of General Internal Medicine.
2012 Rocky Mountain Conference
November 22-25, 2012 - Banff Park Lodge, Banff AB
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P 905 607 4201 F 905 607 3163
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Bai, et al. "rapid and high throughput detection of hbv ymdd mutants with fluorescence polarization"

P.O.Box 2345, Beijing 100023,China World J Gastroenterol 2003;9(10):2344-2347Fax: +86-10-85381893 World Journal of Gastroenterology E-mail: [email protected] Copyright © 2003 by The WJG Press ISSN 1007-9327 • BRIEF REPORTS • Rapid and high throughput detection of HBV YMDD mutants withfluorescence polarization Yui-Jie Bai, Jin-Rong Zhao, Guan-Ting Lv, Wen-Hong Zhang, Yan Wang, Xiao-Jun Yan


Indonesia (see also ) Abused domestic worker is homeAn Indonesian domestic worker, Ceriyati Dapin, 33, who fled from her abusive Malaysian employer, was reunited with her family on 22 June. Indonesian Foreign Ministry spokesman Kristiarto Legowo said that the government would facilitate her trip back to Malaysia to pursue her legal case. Malaysian police have arrested the employer and charged her with unlawful confinement and causing injury with a dangerous weapon. Following the incident, Indonesia and Malaysia have agreed to revise the MOU on migrant workers. Both countries will form a committee to revise the articles to ensure better working conditions for Indonesian workers in Malaysia. Indonesian Minister for Manpower and Transmigration Eman Suparno argued that the provision permitting employers to hold the passports of workers in the informal sector render workers vulnerable and increases their risk of detention during immigration raids. According to data from the Ministry of Manpower and Transmigration, Indonesia deployed some 3.9 million workers, with as many as 1.2 million going to Malaysia. Migrant workers should keep their passportsParticipants in a seminar on human trafficking, organized by the US Embassy, agreed that Indonesian workers abroad are abused because they do not have their passports with them. There are some 1.2 million regular and 500,000 irregular Indonesian workers in Malaysia. Endang Sulistyaningsih, director of promotion at the National Agency for the Placement and Protection of Indonesian Overseas Workers, said that the government asked the Malaysian government to permit Indonesian workers to keep their passports at a renegotiation of the bilateral MOU on migrant workers in Surabaya on 28 and 29 June. Also under discussion are a wage raise, a day off, and basic requirements employers should meet, such as no criminal record and a certain income level. Wahyu Susilo, founder of Migrant Care, said that Malaysia would not be able to meet Indonesia's demand for workers to keep their passports because Malaysia's law stipulates that employers must keep their workers' passport. Indonesians arrested in the USOn 19 June, US immigration authorities arrested 81 irregular immigrants – 76 Indonesians and four Malaysians – at Iridium Industries Inc., a plastics factory in Pennsylvania. Iridium's plant manager, Wayne Migliaccio, said his company uses several recruitment agencies and it is their responsibility to check workers' immigration status. The Indonesian government has demanded access to the Indonesian migrants 76 Indonesians to ensure that they get legal assistance, said a Foreign Ministry spokesman Kristiarto Legowo. The workers allegedly overstayed their visas. 3 Indonesians to be deportedThree irregular Indonesian workers, identified as Bambang Heri, Lestari Budiman and Hans Woworuntu, currently detained at the Lackawanna County detention center, Pennsylvania are to be deported. They arrived in the US in 2000 and were arrested in April this year. Another Indonesian, identified as Suratman, is still consulting his lawyer on whether he would accept deportation or try to extend his stay permit in the US. Indonesian in US detention drugged for deportationTwo immigrants, from Indonesia and Senegal, claiming they were forcibly drugged for deportation sued the US Department of Homeland Security. The American Civil Liberties Union of Southern California filed the suit, demanding a federal court prohibit authorities from drugging deportees taking commercial flights unless a physician prescribes it is necessary. Raymond Soeoth, a 38-year-old Indonesian, was given the drugs Haldol and Cogentin in December 2004 at a Los Angeles detention center. The organization filed the suit said he had no history of mental illness and was not examined by a doctor before being drugged. Deported migrants maltreated by authorities at home