SGEM#90: Hunting High and Low (Best MAP for Sepsis Patients)

Podcast Link: SGEM90
Date: October 1st, 2014 

Guest Skeptics: Dr. Erin Brennan and Dr. Stuart Douglas. Residents in Emergency Medicine at Queen’s University.

This is another SGEM Journal Club. It was recorded live in Kingston, Ontario at Queen’s University. Thank you to Dr. Heather Murray and all the staff and residents. I had a great time and you have a great program.

JournalClubThere have been two previous SGEM JCs. The first one was at McGill University in Montreal. This is where Dr. William Osler started journal club “for the purchase and distribution of periodicals to which he could ill afford to subscribe”. I am pretty sure Dr. Osler would have been a big fan of FOAMed. SGEM#50 asked whether vasopressin, epinephrine and corticosteroid (VSE) protocol for in-hospital cardiac arrest resuscitation improve survival with favorable neurological outcomes compared to epinephrine alone.

The second episode took place at the home of evidence based medicine, McMaster University. This is where my mentor Dr. Andrew Worster taught me that the answer to any EBM question is “it all depends”. SGEM#55 asked whether an departmental guideline on controlled substance prescriptions reduce opioid abuse?

Case: 74yo man is brought by EMS for altered level of consciousness. He lives alone, family hadn’t heard from him in several days so went to check, found him to be coughing and mildly confused. EMS vitals: HR 115, RR 24, BP 103/70, O2 89% on room air, 99% on non-re-breather mask, T 38.4C and blood glucose is normal. The patient is not intubation, wishes no CPR, but full medical management.

Past medical history includes: COPD, type 2 diabetes, hypercholesterolemia, hypertension and peripheral vascular disease. He is triaged to acute care bed, IV access obtained and bolus 0f 1 liter normal saline provided. ECG shows sinus tachycardia and portable CXR demonstrates right lower lobe infiltrate. Laboratory tests are drawn and sent.

You start Early Goal Directed Therapy (EGDT) by rapidly recognized this man is septic, provided IV fluids and appropriate IV antibiotics for pneumonia. Now you are starting to think about more fluids +/- vasopressors to increase his Mean Arterial Pressure (MAP).

Question: Does a MAP of 80-85mmHg decrease 28 day mortality as compared to a MAP of 65-70mmHg?

Dr. Stuart Douglas and Dr. Erin Brennan

Dr. Stuart Douglas and Dr. Erin Brennan

Background: Sepsis remains a major contributor to ED morbidity, carrying a short-term mortality of approximately 20% (ProCESS). With approximately 750,000 annual cases in the US, recognition and early treatment of severe sepsis and septic shock has become a pillar of Emergency Medicine.

Sepsis can be defined as a “clinical syndrome complicating severe infection characterized by inflammation remote from the site of infection.  Disregulation of the inflammatory response can lead to multiple organ dysfunction.”

There is a continuum of sepsis ranging from SIRS (Systemic Inflammatory Response Syndrome) to septic shock.

  • SIRS – temperature <36 or >38’C, HR >90 RR >20 (or PaCO2 <32mmHg), WBC <4 or >12, or >10% immature forms
  • Sepsis – 2/4 SIRS criteria + infection.
  • Severe sepsis – Sepsis + hypotension end organ failure
  • Septic shock – Sepsis and hypotension refractory to fluid treatment

Mean Arterial Pressure (MAP) is he average arterial pressure during a cardiac cycle, represents the perfusion pressure seen by the organs/tissues.  MAP = (CO x SVR) + CVP, or estimated by MAP = 2/3 Diastolic BP + 1/3 Systolic BP (inaccurate if tachycardic).

Sepsis management involves early recognition with early intervention. Rapid administration of broad spectrum antibiotics (then titrating to pathogen), and a sequential approach to fluid administration to CVP targets, vasopressor administration to MAP targets, and PRBC transfusion to hematocrit and ScvO2 targets has resulted in marked improvements in survival. Recent studies (ProCESS) have indicated that invasive blood pressure monitoring may not be required, as previously thought.

Early Goal Directed Therapy

Early Goal Directed Therapy

There is a hypothesis that a higher MAP may be better than a lower MAP. Dunser et al (2009) found in a retrospective cohort study that MAP below 75mmHg were associated with increased need for renal replacement therapy. Badin et al (2011) found in a prospective cohort study that in patients presenting with septic shock and renal impairment at baseline, MAP targets of 72-82mmHg resulted in less AKI at 72h.

Article: Asfar et al. High versus Low Blood-Pressure Target in Patients with Septic Shock. NEJM 2014

  • Population29 centers in France, 776 patients >18y with septic shock refractory to fluids who required vasopressors at >0.1mcg/kg evaluated within 6h of initiation of vasopressors
    • Defined septic shock – two or more diagnostic criteria of the systemic inflammatory response syndrome, proven or suspected infection and sudden dysfunction of at least one organ
    • Defined refractory – lack of response to the administration of 30ml of NS/kg or of colloids or was determined according to the clinician’s assessment of inadequate hemodynamic results on the basis of values obtained during the right-heart catheterization, pulse-pressure measurement, stroke-volume or ECHO
  • Intervention: Target MAP of 80-85mmHg for max of 5 days
  • Control: Target MAP 60-70mmHg for max of 5 days
  • Outcome: 
    • Primary Outcome:  Death from any cause at 28 days.
    • Secondary Outcome:  90 days mortality, days alive and free from organ dysfunction by day 28, length of stay in ICU and hospital. Serious adverse events classified as ischemic or other.
  • Exclusion Criteria: no consent, not in the French health care system, pregnant, in another study with mortality as the primary end point, investigators decided not to resuscitate.

Authors Conclusions: No significant difference between the two groups in the overall incidence of serious adverse events.

checklist-cartoonQuality Check List for Randomized Control Trials:

  1. The study population included or focused on those in the ED. Unsure. Comment: Dr. Asfar, informed us that about 2/3 of the study population came from the community, with the majority coming through the ED.  The remainder of the patients were already in the ICU
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: No significant difference in the primary outcome between the groups for mortality at 28 days. The mortality rate for the High MAP was 36.6% vs. 34.0% for the Low MAP target. This gave a Hazard Ratio of 1.07 (95% CI 0.84-1.38; p=0.57)

There were 776 patients enrolled in this study. They determined their sample size of 800 patients assuming a death rate of 45%. This was to provide a power of 80% to show a 10% difference in the primary outcome (death at 28days) with a two sided alpha level of 0.05.

There were also no differences detected in the secondary outcome of mortality at 90 days. High 43.8% vs. Low 42.3% HR 1.04 (95%CI 0.83-1.3; p=074).

No difference were found in serious adverse events. High 19.1% vs. Low 17.8%

Comments: Overall, this was a high quality study looking at a clinically relevant topic.  It was good to try and stratify patients based on hypertension. However, the authors noted the challenge in determining patients’ baseline blood pressures. This is important as it may indicate patients who have auto-regulated to a higher baseline MAP, and therefore require a higher MAP in treatment of sepsis to perfuse end-organs.

Lack of clinician blinding is a threat to validity, but unfortunately cannot be overcome in this type of study.  The MAP values exceeded the targets in both groups, but were still significantly different. A large number of patients excluded were excluded from the study. Many they did not get to in less than six hours. Was there any trend in the excluded patients that could have resulted in study bias?

More than 80% of patients in both groups received steroids. This is different from clinical practice in Canada.  In addition, approximately 7% of patients in both groups received Protein C.

Mortality rate was different in this study compared to the ProCESS trial and the original Rivers study. The higher mortalities across groups seen in this French study compared with ProCESS may be because of different infection profiles at inclusion.

Screen Shot 2014-10-02 at 2.47.18 PM

The inclusion of ICU patients in this Asfar study (presumably patients who have already identified themselves as “sick”) could also contribute to the increased mortality. In addition, ProCESS sample was younger, with a larger female proportion. Unfortunately baseline comorbidity scores differed between studies and cannot be used to compare the samples directly.

In patients with hypertension, higher MAP resulted in less renal injury and need for renal replacement therapy.  Results suggest that other than an increased risk of atrial fibrillation in the high MAP group there is no significant difference.

Considering the clinical picture is important in determining target MAP. Patients with uncontrolled hypertension at baseline will require higher MAPs to maintain end organ perfusion.  These results suggest that perhaps there is not an ideal target MAP and support clinical practice of adjusting MAP to target end organ perfusion.

Our Conclusions Compared to Authors: Agree that this study does not demonstrate a 28 day mortality advantage of a higher targeted MAP in patients with septic shock undergoing resuscitation.

The Bottom Line: The ideal target MAP in septic shock is still unclear – patient factors play a role and care should likely be individualized.

Case Resolution: The patient receives 4 liters of normal saline in the emergency department.  His resuscitation also includes non-invasive positive pressure ventilation, a central line and levophed to support blood pressure. He is then admitted to the ICU for ongoing critical care.

Clinical Application: Reasonable to consider MAP above 65mmHg depending on the case.

What do I tell patients? It looks like you have a serious infection. We are going to give you intravenous fluids, increase your blood pressure with medication if needed, provide broad-spectrum antibiotics, monitor your response to treatment and admit you to the hospital for further care.

Keener Kontest: Winner last week was Jaime Davis from Florida. He knew the core competencies for geriatric fall prevention that emergency medicine residents needed to know graduation based on the guidelines.

  • In patients who have fallen, evaluate for precipitating causes of falls such as medications, alcohol use/abuse, gait or balance instability, medical illness, and/or deterioration of medical condition.
  • Assess for gait instability in all ambulatory fallers; if present, ensure appropriate disposition and follow-up including attempt to reach primary care provider.

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Five Rules of the SGEM Journal Club:

Screen Shot 2014-10-03 at 11.14.32 AM

Upcoming conferences: SkiBEEM 2015 is January 26th-28th in Beautiful Sun Peaks, BC.

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.

SGEM#89: Preventing Falling to Pieces

Podcast Link: SGEM89
Date: October 5th, 2014

Guest Skeptics: Dr. Chris Carpenter. Associate Professor, Emergency Medicine. Director, Evidence Based Medicine, Washington University. C0-Author of Evidence Based Emergency Care- Diagnostic, Testing and Clinical Decision Rules. @SAEMEBM

The goal of the SGEM continues to be to cut the knowledge translation window down from over ten years to less than one year. There are about 3,800 biomedical publications every day on PUBMED alone. Bastian et al published in PloS 2010 that there are about 75 RCT and 11 Systematic reviews released daily. They asked the question “How could anyone every keep up”?

The answer is no one could possibly keep up. No wonder it takes so long for high quality clinically relevant evidence to reach the bedside. A study by Morris et al in 2011 called discusses how it can take an average of 17 years for research evidence to reach clinical practice.

Screen Shot 2014-10-04 at 1.37.08 PM

Seventeen years is more than 10 years as we are always quoting on the SGEM. But we are going to try and shorten that KT window to less than 1 week using the power of Social Media.

The SGEM has entered into an arrangement with Society of Academic Emergency Medicine (SAEM) and the Canadian Association of Emergency Physicians (CAEP) to achieve that goal. SAEM publishes the Academic Emergency Medicine (AEM) Journal and CAEP publishes the Canadian Journal of Emergency Medicine (CJEM). I am calling SGEM Hot Off the Press, or SGEM HOP

Hot off the Press

  1. A paper that has been submitted, peer-reviewd, and ultimately accepted for AEM/CJEM is going to be picked. We will select these papers in conjunction with the Editorial Boards of each journal.
  2. The SGEM will then put a skeptical eye upon the manuscript using the BEEM critical appraisal tool. This is an instrument with published reliability and validity – the only such instrument that I am aware of in any specialty.
  3. One of the authors of the paper will be invited to discuss their work. This will be in order to defend the strengths/weakness/limitations/clinical application of the ideas and data that they propose.
  4. We will do a special SGEM Hot Off the Press podcast that will be posted the week the journal gets published. In essence, this is KT at the speed of social media!
  5. You the audience will get a chance to respond via the blog, twitter or on Facebook. Where else do you have this interactive opportunity to compliment or criticize research with the ear of the original author and the publishing editors?
  6. Another exciting component will be a summary of the SGEM critical appraisal because top social media feedback will be published in a subsequent issue of each journal. This process will leverage the content from original publication, secondary review, podcast dissemination, and social media interactivity and follow-up.

I am very excited about this new series. Just like Swami and the SGEM Classic episodes I hope the SGEM: Hot Off the Press episodes will be just as popular.

Case: 84yo woman (Mrs. C) who lives independently and alone in her own home presents to the emergency department via ambulance with a standing level fall. She was bending over to pick up a letter that had dropped off her desk, lost her balance and hurt her left, non-dominant arm. After the fall she was afraid to stand and could not reach her telephone so she laid on the floor calling for help until a neighbor heard her and called 911. She notes infrequent falls at home with no prior injurious falls. Her past medical history includes hypertension and a remote history of breast cancer, but she does not take anti-platelet or anticoagulant medications. An appropriate physical exam is performed and reveals an isolated left shoulder injury. The x-ray of her left shoulder is negative for any fracture. She is diagnosed with a minor contusion and provided with some acetaminophen. The daughter-in law arrives to take her home, but asks if Mrs. C is at risk for further falls in the future.

Question: Can healthcare personnel accurately identify subsets of geriatric adults at increased risk of falls or injurious falls in the months following an episode of emergency department care?

Background: In the geriatric population (all those over age 65), standing level falls are the #1 cause of traumatic mortality.

A fall can be defined as an unintentional, sudden descent to a lower level. This can be a fall from a bed or chair to the ground or down some stairs to a lower level of the home. In the vast majority of cases, we are not talking about falls from roofs or ladders.

For community dwelling adults over the age of 65 about 1/3 will suffer a standing-level fall. By the time you people reach 80 years of age that increases to half or 50%. Many of these people who fall end up in the ED.

These falls cause a lot of morbidity. They can cause contusions, lacerations and fractures. Fractures can obviously be any bony structure, but commonly include the spine, hip, pelvis, ankle, wrist and humerus. There are about 300,000 hip fractures every year in the US and by 2014 will probably have doubled.

These injuries must cost a lot of health care dollar.  In the USA standing-level falls cost about $19 billion a year.

As mentioned earlier, falls are the leading cause of traumatic mortality in this age group. Older adults who are admitted to the hospital after a fall (the sickest subset) will be readmitted to the hospital within one-year in 44% of cases and 33% will die within one-year.

Article: Carpenter CR, Avidan MS, Wildes T, et al. Predicting Geriatric Falls Following an Episode of Emergency Department Care: A Systematic Review, Acad Emerg Med 2014 (in press)

  • Population: Original prognostic research describing community-dwelling, non-critically ill geriatric adults after an episode of emergency department care.
  • Intervention: Falls and injurious falls risk stratification at 1- to 6-months evaluated in ED settings
  • Control: None
  • Outcome: Prognostic accuracy (sensitivity, specificity, likelihood ratios) for individual risk factors and prediction instruments to predict falls in the months following an episode of ED care.

Authors Conclusions: “This study demonstrates the paucity of evidence in the literature regarding ED-based screening for risk of future falls among older adults. The screening tools and individual characteristics identified in this study provide an evidentiary basis on which to develop screening protocols for geriatrics adults in the ED to reduce fall risk”.

checklist-cartoonQuality Check List for Systematic Review:

  1. The diagnostic question is clinically relevant with an established criterion standard. Yes. Comment: Geriatric falls represent the leading cause of traumatic mortality in older adults. Fall risk assessment is advocated as a geriatric emergency medicine core competency and quality improvement target. It is a key component of Geriatric Emergency Department Guidelines recently approved by the American College of Emergency Physicians, American Geriatrics Society, Society for Academic Emergency Medicine, and Emergency Nurses Association.
  2. The Search for studies was detailed and exhaustive. Yes Used a medical librarian and followed the MOOSE statement and PRISMA guidelines.
  3. The methodological quality of primary studies were assessed for common forms of diagnostic research bias. Yes QUADAS-2 was used to evaluate the overall quality of the trial data
  4. The assessment of the studies were reproducible. Yes
  5. Three was low heterogeneity for estimates of sensitivity or specificity. NO
  6. The summary diagnostic accuracy is sufficiently precise to improve upon existing clinical decision making models. Yes

Key Results: 601 manuscripts with five papers met the inclusion criteria for a full review. Two articles did not include data to do a 2×2 table.  This left you three ED-based studies with 767 patients.

Two of the studies were prospective (660 patients) and one was retrospective (107). The two prospective studies contained 29 individual predictors. These predictors included past falls, number of medications used, self-reported dementia or depression, use of canes or walkers, ability to drive, sense of imbalance, and many others, as well as simple objective physical tests like the chair stand, chair sit, ability to raise feet while walking and turn 180º, and visual and auditory acuity.

The incidence of falls at 6 months was 31% for those who presented with a chief complaint of falls. The incidence of falls was about half (14%) if the chief complaint was something else.

The best positive likelihood ratio (+LR) was found in one of the two studies and had a result of 6.55 (95% CI 1.41-30.38). However, when that was combined in the meta-analysis gave a +LR of 2.54 (95% CI 1.62-3.98).

The best negative likelihood ratio (-LR) was if the patient could cut their own toenails –LR 0.57 (95% CI 0.38-0.86).

We described the Tiedemann and Carpenter fall-risk prediction instruments. Both instruments use a simple scoring system based upon two to four fall-risk factors. A Tiedmann score of three had a +LR 3.76 and a –LR 0.46 In contrast, the Carpenter score of >1 gave a similar +LR score, but proved much more useful to distinguish subsets at lower risk of falls with –LR of 0.11.

We opine that “although our results fail to provide a definitive fall screening strategy, the quantitative summary estimates of fall incidence and risk factor accuracy and reliability provide an evidence basis on which clinicians, nursing leaders, administrators, educators, policy-makers, and researchers can build.”

Dr. Chris Carpenter

Dr. Chris Carpenter

Comments: Clearly there is a need to figure out who is a greater risk in this geriatric population. These types of falls cause significant morbidity/mortality, cost a lot of money, and we simply lack the resources to treat every older adult as high-risk for future falls.

Risk assessment in aging adults is advocated by multiple professional organizations and licensing bodies. Nonetheless, geriatric patients rarely receive guideline directed care for falls following an episode of ED care.

Multiple barriers exist between contemporary ED management of community-dwelling senior citizens and optimal injurious falls prevention. The first and most prominent obstacle is the lack of ED-validated risk stratification instruments to distinguish low-risk from non-low-risk for falls. If we cannot identify the “at-risk”, how can we efficiently and cost-effectively proactively work to prevent future falls? Funding agencies need to recognize this conundrum, too.

There are some non-EM guidelines committees and prominent funding agencies opine that fall-risk stratification risk factors and instruments from office-based settings, hospital wards, and nursing homes ought to extrapolate to the ED. However, evidence based medicine proponents argue that validation in the ED is essential. The current meta-analysis from the Academic Emergency Medicine Evidence Based Diagnostics series takes an essential first step toward this objective.

One limitation of this study was its English only search. This was due to lack of funding resources.  The English search did identified  601 abstracts to review. Dr. Carpenter did attended the International Association of Gerontology and Geriatrics meeting in Seoul Korea in June 2013. This meeting brought together the world’s medical and non-medical experts in the care of an aging population. He sought expertise in ED-based falls prevention, cognitive assessment, frailty, and functional vulnerability during my week in Korea. Dr. Carpenter also serve as the Chair of the American College of Emergency Physicians Geriatric Section and founding member of the International Consortium for Emergency Geriatrics. Based upon these exposures and leadership positions, he is not convinced that there is a novel EMERGENCY DEPARTMENT based fall-risk stratification protocol somewhere else in the world.

  • Why limit the systematic review to only the English language?  My research lab lacks funding or capacity to translate hundreds of abstracts in dozens of languages to find the few manuscripts that might require translation. Remember that our English-language only search identified 601 abstracts to review. In addition, I attended the International Association of Gerontology and Geriatrics meeting in Seoul Korea in June 2013. This meeting brought together the world’s medical and non-medical experts in the care of an aging population. I sought expertise in ED-based falls prevention, cognitive assessment, frailty, and functional vulnerability during my week in Korea. I also serve as the Chair of the American College of Emergency Physicians Geriatric Section and founding member of the International Consortium for Emergency Geriatrics. Based upon these exposures and leadership positions, I’m not convinced that there is a novel EMERGENCY DEPARTMENT based fall-risk stratification protocol somewhere else in the world.
  • Limited search of the “grey” literature? We did conduct a hand search of unpublished abstracts in Academic Emergency Medicine and Annals of Emergency Medicine. Admittedly, we could have hand-searched various other scientific assembly research abstracts including the Journal of the American Geriatrics Society, Canadian Association of Emergency Physicians, and the European Society for Emergency Medicine.
  • Where you disappointed in the quantitative conclusions of this systematic review? I was disappointed for clinicians and educators seeking a definitive answer on the question. However, I strongly feel the results are still useful. More importantly, this research ought to serve as a siren song to emergency medicine investigators and funding agencies that we need to devote more time, energy, and resources to solving older adult acute care questions. If we cannot accurately identify older adults at increased risk for the #1 cause of traumatic mortality, what else are we missing: dementia, delirium, frailty, functional decline, etc.?
  • Why do you think that these results are still useful? We explored 29 commonly referenced risk factors across two prospective ED-based studies. None of the risk factors, including objective tests of function like the elements of the “get-up-and-go test”, accurately predicted falls at 6-months. However, two risk prediction instruments were described. One (Carpenter Rule) significantly reduced the post-ED fall risk with a negative likelihood ratio 0.11 (95% CI 0.06-0.20).
  • Why do you think you got unsatisfactory results? The reasons are likely multifactorial. Falls represent a complex relationship between an aging individual’s senescent physiology interacting with intrinsic and extrinsic stressors. The risk of falls for an individual are neither static from day-to-day nor comparable to the next patient of similar age and illness severity. Furthermore, existing trials did not use STARD criteria, including the lack of an explicit and uniformly accepted definition of “falls”. Future trials must do so, while employing more definitive gold standards for fall occurrence, including smart-phone fall detectors.

The Bottom Line: Persons 65 years or older are an increasing percentage of the total population. These people fall, get injured and even die. We do not have good ED evidence to help us predict accurately or reliably who is at risk of falling. High quality research is need for healthcare providers, funders, and guideline developers to use in deriving screening protocols.

Case Resolution: This lovely 84yo woman (who was my grandmother in 1995) is treated conservatively for her minor contusions and is discharged home with her daughter-in law. She is advised to follow- up with her PCP in the next week and return to the ED if she has increasing pain, decreasing function or is otherwise concerned. Of concern, Sirois et al noted that 15% of these patients (community dwelling geriatric standing level fall, discharged home from the ED with minor injuries) will experience significant functional decline at 3-months

Clinical Application: ED-based fall-risk screening for older adults should use the most accurate risk-stratification instruments available until better tools are developed and validated in ED settings. Using other instruments like STRATIFY or HENDRICH II in the ED leaves clinicians, patients, payers, and policy-makers without valid, evidence-based estimates of post-ED fall risk. Funding agencies and researchers should more aggressively pursue more definitive and clinically useful fall-risk stratification.

What do I tell patients/families: Standing level falls are very common and can even cause death in people over age 65. There is about 1/3 chance your mother-in law will fall again in the next 6 months. Unfortunately, there is no single fall risk factor that we know of that can predict who will or will not fall. However, there is some information I can give you to try and prevent another fall. Click on this link to get the document downloaded. SGEM falling to pieces Figures

Keener Kontest: Last weeks winner was Loice Swisher from Ambler PA.  She knew the major adverse effects of procainamide to watch for were cardiac in nature. Specifically watching for hypotension and prolonged QRS and QT intervals. The infusion should be stoped if the QRS or QT prolongs by more than 50% from baseline.

Listen to the podcast for this weeks Keener question. Sent your answer to TheSGEM@gmail.com. Put “keener” in the subject line. The first correct answer will receive a cool sceptical prize.

Upcoming conferences: SkiBEEM January 26th-28th in Sun Peaks BC

 

Stay tuned for the next episode of the SGEM-HOP with Dr. Chris Bond and the Canadian Journal of Emergency Medicine.

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.

SGEM#88: Shock Through the Heart (Ottawa Aggressive Atrial Fibrillation Protocol)

Podcast Link: SGEM88a
Date:  September 23rd, 2014 

Guest Skeptics: Dr. Anand Swaninathan or Swami as his is better known. Swani is an assistant program director at NYU/Bellevue Hospital in the department of EM. He is also part of the REBEL EM Alliance.

Case Scenario: A 35-year-old woman presents to the ED with palpitations. She states that she woke up this morning and went for a run and began feeling her heart race. She stopped and rested but her heart rate wouldn’t come down and it felt irregular. This all started about 2 hours ago. Her vitals are unremarkable except that her heart rate is 140 bpm and irregular.

Question: What is the effectiveness and safety of the Ottawa Aggressive Protocol to perform rapid cardioversion and discharge of patients with these arrhythmias?

d5c7a8d36ae3db4dc1874640a99379e7Background: Atrial fibrillation is one of the most common dysrhythmias encountered in the ED. Patients with chronic AF often present with increased heart rates, chest pain and weakness among other presentations. There has been a debate going on for a number of years as to which is the best strategy to address these patients, rate or rhythm control.  This debate has raged for years with little end in site.

Dr. Ian Stiell and colleagues published an article in 2011 in Annals looking at variation in Recent-Onset atrial fibrillation management in Canada and found a ton of variability. Rhythm control was selected in 42-85% of patients across hospitals and electricity was chosen as the primary strategy for rhythm control in 7-69%. Lots of diffing opinions.

In the USA there’s a lot of fear of cardioversion. Actually, the fear is of cardioverting and the patient throws a clot. What happens is that a lot of patients are rate controlled, admitted and we let cardiology sort it out.  With all this variability in practice, Stiell and colleagues sought to show that their protocol was both effective and safe.

Lauren Westafer and Jeremy Faust from FOAMCast recently did an excellent job covering the background on atrial fibrillation and flutter. Don’t FOAM it alone. While you are at it check out their new word “Rosenalli”. This is the melding of core Emergency Medicine texts, Rosen’s and Tintinalli.

Article: Stiell IG et al. Association of the Ottawa Aggressive Protocol with Rapid Discharge of Emergency Department Patients with Recent-Onset Atrial Fibrillation or Flutter. CJEM 2010; 12(3): 181-91

  • Population: 660 Consecutive, retrospective cohort of ED patients presenting with a primary diagnosis of recent-onset atrial fibrillation or flutter. Ottawa Hospital Civic Campus ED between June 2000-June 2005
    • Exclusions: Chronic or persistent/longstanding AF, patients with symptoms longer than 48 hours or unknown duration, and patients with another diagnosis necessitating admission.
  • Intervention: Ottawa Aggressive Protocol (Box 1) Basically, rate control if very symptomatic or not being cardioverted. Otherwise, procainamide infusion 1 gram over 60 min IV and if this failed, electrical cardioversion. Of note, procainamide held if patient unstable or had hx of failing procainamide in past.
  • Comparison: None
  • Outcome: Conversion to sinus rhythm, discharge from the hospital, discharge in atrial fibrillation 

Authors Conclusions: “The Ottawa Aggressive Protocol is effective, safe and rapid and has the potential to significantly reduce hospital admissions and expedite ED care.”

Peace_Tower-OttawaOttawa Aggressive Atrial Fibrillation Protocol: Once the patient is assessed and it’s determined that their symptoms began  <48 hours prior to presentation, they were entered into the protocol. Rate control was given if either the patient was highly symptomatic while awaiting cardioversion or if cardioversion was not going to be pursued. Rhythm control was then initiated with an infusion of procainamide 1000 mg over 60 minutes. If procainamide worked, great the protocol was completed. If it didn’t work, the patient moved on to electrical cardioversion. Chemical cardioversion was skipped in patients who were unstable or they had a history of AF with failure of procainamide. They then go on to discuss anticoagulation and disposition.

Screen Shot 2014-09-23 at 8.26.22 AM

checklist-cartoonCritical Appraisal Check List for Cohort Study:

1. Did the review ask a clearly focused question? – Yes. Is it safe and efficacious to implement the Ottawa Aggressive Protocol in patients with new onset atrial fibrillation.

2. Did the authors use an appropriate method to answer the question? – Yes, for the question that was asked.  They weren’t looking to compare rhythm control versus rate control for a patient centered outcome but simply to evaluate the efficacy of this approach. It would of course be great to see a RCT to answer the real question: “What is better rate or rhythm control”?

3. Was the cohort recruited in an acceptable way? – Yes. Recruitment was of consecutive patients. No one aside from the predetermined exclusions was left out.

4. Was the exposure accurately measured to minimize bias? – Yes. An objective outcome measure was looked at here – was the patient in sinus rhythm or not? Was the patient discharged or not? Although discharge does take into account a more subjective evaluation.

5. Was the outcome accurately measured to minimize bias? – Yes. Hard to bias whether the patient in sinus or not.

6. Have the authors identified all important confounding factors and were these taken into account in the design? – Yes.

7. Was the follow up of subjects complete and long enough? – The primary endpoint was simply looking at whether the patient converted or not. The also looked at 7-day relapse rates. We can argue whether 7 days is long enough or if they should have looked at 14, 30 or 60 days instead. Often when you read cardiology literature they have a 30d outcome. There are a couple of questions with the length of follow-up. How long do you feel responsible for someone you discharged from the emergency department? And from a medical legal standpoint, how long should you be held accountable?

8. What are the results of this study? – As stated previously, they found that 96.8% of patients were discharged home and 90% were discharged in sinus rhythm. The relapse rate at 7 days was 8.6%.

9. How precise are the results? Little unsure, they calculated descriptive statistics using proportions, means or medians with intra quartile ranges. It would have been nice to see some 95% confidence intervals around some of the key results.

10. Do you believe the results? – Yes. I think the endpoint they were focused on was a hard one. Did this protocol lead to rhythm control and the answer is that it did in 90% of patients who were eligible to enter the protocol. Additionally, the safety outcome is a hard one as well – did anyone have a thromboembolic event? Easy to figure out.

11. Can the results be applied to the local population? -  Yes. One interesting thing I found here was that a lot of these patients had been cardioverted for atrial fibrillation in the past. That may not be everyone’s typical population although it is mine. Yes, I too have seen patients more than once in the emergency department for atrial fibrillation and cardiverted them back to normal sinus rhythm.

12. Do the results of this study fit with the available evidence? – Yes. There’s other literature that shows similar conversion rates so this isn’t far outside of what we’d expect.

Key Results:

  1. 660 patients recruited
  2. 95.2% with atrial fibrillation, 4.9% with atrial flutter
  3. Procainamide conversion rate was 58.3%
  4. Of the 243 patients who underwent electrical cardioversion, 91.7% success rate
  5. 96.8% of patients were discharged home and 93.3% of them were in sinus rhythm upon discharge.
  6. Adverse events were seen in 7.6% and there were no cases of torsades de pointes or CVA or death.
  7. Median LOS: 4.9 hours. 3.9 hours in those converting with procainamide, 6.5 hours in those requiring electrical cardioversion.
Dr. Anand Swaminathan

Dr. Anand Swaminathan

Does this Change What We Do? – Hard to say. I still think at least in the US, there’s a lot of concern about converting someone and throwing an embolism. There was a recent letter in JAMA that questioned whether the cutoff for cardioversion should be 48 hours or 12 hours. They found that the risk of thromboembolic event was 0.3% in the group converted at < 12 hours and 1.1% from 12-48 hours. Even though this rate is still quite low, it’s probably higher than we’d like to see. It is important to note that in patients with 3 weeks of anticoagulation who are then cardioverted, the thromboembolic rate is still up to 0.8%. I know this was plastered all over Social Media when it came out and Ian Stiell himself said that his group is looking into these numbers as this may change recommendations.

Aside from the limitation of thromboembolic phenomena, I think many US EPs would rather defer the procedure, along with the procedural sedation, to the cardiologists and inpatient guys. But I think this is the wrong reason to not cardiovert. The other day, we had a young guy come in with recent onset AF of about 2 hours and we had him sedated and cardioverted within 15 minutes. It just doesn’t take that long to do this.

It is these controversial issues in medicine that often teach us the most. When there is no clear answer on what is the best approach it makes us think even harder. New onset rapid atrial fibrillation is one of those areas.

We all want to give the best care to patients based on the best evidence. However, sometimes the best evidence is weak. This is truly a “classic” example of…we need more information. Until we have that more definitive study it motivates us to know both sides of the argument. To understand why some evidence supports rate control and other evidence supports rhythm control as an optimal strategy.

Screen Shot 2014-01-28 at 12.27.19 PMRemember that evidence based medicine is not just about literature. EBM was originally defined as the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The literature is just one part of EBM. It also involves clinical expertise and the patient’s unique situation and personal values. It is where these three important things over lap that you get the “best” care.

EBM is about increasing patient’s choices not decreasing choices. And this is done using shared decision-making. So ultimately, the EBM answer to any clinical question, as my mentor Dr. Anderw Worster taught me so well is…it all depends.

Bottom Line: The Ottawa Aggressive Protocol appears to be highly effective in converting patients with recent onset atrial fibrillation or flutter back to sinus rhythm. In this cohort of 660 patients, there were no thromboembolic events and the relapse rate was 8.6% at 7 days.

Case Resolution: You discuss the options with your patient and she elects for chemical cardioversion. After the administration of procainamide, she is still in atrial fibrillation. She then elects for electrical cardioversion. You perform procedural sedation and convert the patient with 150J biphasic and she converts to sinus rhythm. 1 hour after the procedure, you discharge home for follow up with your local cardiologist.

Keener Kontest: Last weeks winner was Dr. Matt Hallanger a PGY-2 in EM at Mercy St. Vincent Medical Center, Toledo, Ohio. He knew that paracetamol or acetaminophen abandoned as a drug for nearly 60 years after its first Patient trial 1899 for fear that it induced methemoglobinemia (which it does not).

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.

 

SGEM#87: Let Your Back Bone Slide (Paracetamol for Low-Back Pain)

Podcast Link: SGEM87
Date:  September 17th, 2014 

Guest Skeptics: Dr. Pal Ager-Wick is from Norway. Consultant at Legevakten in Drammen, which is a GP run ED handling most things except major trauma. Keen interest in everything evidence based especially ultrasound. Pal is bringing Matt and Mike from the Ultrasound podcast to Norway.

Case Scenario: 35 year old man presents to ED with mechanical back pain after doing some heavy lifting on the weekend. He has not “red flags”.

Question: Does paracetamol improve time to recovery from pain compared to placebo in patients with low-back pain?

Background: The leading cause of disability worldwide is low-back pain. Guidelines recommend paracetamol (acetaminophen) as the first-line agent. There have been no randomized control trials comparing paracetamol vs. placebo for low-back pain.

rred-flags

1) Cancer Related Red Flags with Low Back Pain

  • History of cancer
  • Unexplained weight loss >10 kg within 6 months
  • Age over 50 years or under 18 years old
  • Failure to improve with therapy
  • Pain persists for more than 4 to 6 weeks
  • Night pain or pain at rest

2) Infection Related Red Flags with Low Back Pain

  • Persistent fever
  • History of intravenous drug abuse
  • Severe Pain
  • Lumbar spine surgery within the last year
  • Recent bacterial infection
  • Immunocompromised states

3) Cauda Equina Syndrome Related Red Flags with Low Back Pain

  • Urinary Incontinence or retention
  • Saddle anesthesia
  • Anal sphincter tone decreased or Fecal Incontinence
  • Bilateral lower extremity weakness or numbness
  • Progressive neurologic deficit

4) Significant Herniated Nucleus Pulposus

  • Major Muscle Weakness (strength 3 of 5 or less)
  • Foot drop

5) Vertebral Fracture Related Red Flags with Low Back Pain

  • Prolonged use of Corticosteroids
  • Age greater than 70 years
  • History of Osteoporosis
  • Mild trauma over age 50 years (or with Osteoporosis)
  • Recent significant trauma at any age

6)  Abdominal Aortic Aneurysm Red Flags with Low Back Pain

  • Abdominal pulsating mass
  • Atherosclerotic vascular disease
  • Pain at rest or nocturnal pain
  • Age greater than 60 years

Article: Williams CW et al. Efficacy of paracetamol for acute low-back pain:
a double-blind, randomized controlled trial. Lancet Published online July 24, 2014

  • Population: 1,652 patients from Australia and New Zealand
    • Inclusion: adults who sought care for low-back pain directly or in response to a community advertisement. New episode with pain between 12th rib and buttock. Shorter than 6 weeks duration with the month prior having no pain. No leg pain. Pain had to be of at least moderate intensity (measured by a evaluation tool)
    • Exclusions: Suspected serious spinal pathology, current use of full, regular does of analgesics, spinal surgery in last 6 months, contraindications to paracetamol, psychotropic drugs, pregnancy or planned to get pregnant.
  • Intervention: Paracetamol as needed and paracetamol as regimen
  • Comparison: Placebo
  • Outcome:
    • Primary outcome was time to pain free (VAS 0 or 1) maintained for 7 days
    • Secondary outcomes were pain intensity, disability, function, global rating of symptom change, sleep quality, and quality of life. Process measures consisted of adherence to drug (daily and at 4 weeks); concomitant treatment use and work absenteeism (at 4 and 12 weeks); adverse events (at 1, 2, 4, and 12 weeks); and treatment satisfaction and patient masking (at 12 weeks).

Authors Conclusions: Our findings suggest that regular or as-needed dosing with paracetamol does not affect recovery time compared with placebo in low-back pain, and question the universal endorsement of paracetamol in this patient group.

checklist-cartoonQuality Check List for Random Control Trials:

  1. The study population included or focused on those in the ED? NO 
    • 235 primary care clinicians (181 general practitioners, 50 pharmacists, and four physiotherapists) across Sydney, Australia, screened consecutive patients who sought care for low-back pain directly or in response to a community advertisement
  2. The patients were adequately randomized? YES
  3. The randomization process was concealed? YES
  4. The patients were analyzed in the groups to which they were randomized? YES
  5. The study patients were recruited consecutively (i.e. no selection bias)? YES
  6. The patients in both groups were similar with respect to prognostic factors? YES
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation? YES
  8. All groups were treated equally except for the intervention? YES
  9. Follow-up was complete (i.e. at least 80% for both groups)? YES
  10. All patient-important outcomes were considered? YES
  11. The treatment effect was large enough and precise enough to be clinically significant? NO

Key Results:

  • 550 regular paracetamol group
  • 549 to the as-needed paracetamol group
  • 553 to the placebo group

Was there a difference in their primary outcome of time to recovery from low-back pain? Just to remind everyone that was defined as self-reporting 0-1 on a pain VAS (pain free) for 7 days.

There was no difference in median time to recovery between the three groups. Regular 17 days (95%CI 14-19), As-needed 17 days (95% CI 15-20) and placebo 16 days (95% CI 14-20).

Ok, so there was not a difference in their primary outcome. It took a median time of between two and three weeks for all groups to be “pain free” for their low-back pain.

They also expressed this as a hazard ratio (HR):

  • Regular vs. Placebo HR 0.99 (95%CI; 0.87-1.14)
  • As-Needed vs. Placebo HR 1.05 (95% CI 0.92-1.19)
  • Regular vs. As-Needed HR 1.05 (95% CI; 0.92-1.20)

What about secondary outcomes? They looked at pain intensity, disability, function, global rating of symptom change, sleep quality, and quality of life, adherence to drug, concomitant treatment use and work absenteeism, adverse events, treatment satisfaction and patient masking. Surely there must have been some differences in these parameters?

Short answer is NO. Table 3 in the manuscript details the change in secondary outcomes. They did longitudinal mixed models and did not demonstrate any differences between groups for any of the secondary outcomes.

Pal

Pal Ager-Wick

Commentary: This is a large and well designed study which aims to see if paracetamol is an efficacious treatment for uncomplicated lower back pain with no red flags. It is important to note that the time to self reported VAS 0-1 for one week was the primary outcomes. Both as needed and a regular dosing of paracetamol does not seem to make for a more speedy recovery.

It was a very well done study but I have some concerns that 1/3 of the patients approached declined to participate. There are also issues with external validity to the ED setting. Are people who mainly present to the General Practitioners office different from those that present to the ED in Australia and New Zealand?

In addition, how is low-back pain perceived in Australia and New Zealand? There can be differences perceptions, approaches, management between counties when it comes to various conditions. It would be interesting hear from someone down under. If you are a SGEM listener from Australia or New Zealand send me an email (TheSGEM@Gmail.com) I would love to hear and share your thougths.

Naproxen was used as a rescue medication, and as this study was industry sponsored this study might later be used as support for naproxen as standard for lower back pain.

So you are not just a skeptic but you are also a cynic. But the drug company that sponsored this trial makes paracetamol so you would think the bias would be towards finding an effect?

Anybody who had read Ben Goldacre’s book Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients would become cynical towards the pharmaceutical industry.

I think the lack of effect says more about the complex nature of low back pain in our society than the treatment. When there are multiple modalities all claiming to have great effect for the same condition I am skeptical that anything really works well (medical, manipulative, non-science based, etc).

I would interpret the data saying the natural history of acute low back pain with no underlying serious pathology is a self-limiting condition. We should not expect acetaminophen to effect time to recovery in this type of situation.

There is a strong placebo effect involved in the treatment of low back pain. If the placebo effect is large and the active treatment effect is small it may be hard to distinguish the signal (treatment) from the noise (placebo). Patients who believe in the treatment modality will more likely get benefit. So I think when it comes to treating non-serious low back pain, it all depends…

Comment on authors conclusion compared to our conclusion: Agree with their conclusions based on the data presented and encourage being skeptical of the universal endorsement of paracetamol for these types of patients.

Bottom Line: It appears that paracetamol does not improve time to recovery compared to placebo for out-patients with low-back pain.

Clinical Application: This is just one randomized clinical trial looking into the issue and is not strong enough evidence for me to abandon recommending this treatment modality. I would like to see the study replicated in my practice environment. Specifically, a study looking at consecutive patients presenting to the emergency department with low-back pain.

What do I tell my patient? You appear to have a mechanical injury to your low-back. There are no “red flags” to suggest anything more serious is going on right now. The natural history of this condition is for it to resolve with or without treatment. Has anything worked well for you in the past? Different treatments have different potential benefits and harms. Taking paracetamol has not been shown to speed up how fast you get better.  Most people get better within a few weeks. You should try to stay active and see your primary care doctor in a couple of weeks if the pain is not resolving. Please return to the emergency department if your pain is getting worse, you develop any of those red flags we discussed or are otherwise concerned.

Keener Kontest: Last weeks winner was Loice Swisher from Philadelphia. They knew the name of the ECG manifestation of pericarditis named after Dave Spodick? Spodick’s Sign is downward sloping of the TP segment is suggestive of pericarditis and reported to occur in as much as 80% of the patients.  It can be essentially the entire QRST segment and lead II has been reported to be usually the best lead to see this in.

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

BEEM LogoUpcoming conferences:

  • QueBEEM Quebec City September 29th and 30th

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.

 

SGEM#86: Achy Breaky Heart (Colchicine for Acute Pericarditis)

Podcast Link: SGEM86
Date:  August 26th, 2014 

Guest Skeptics: Dr. Chris Bond. Chris is a clinical lecturer and emergency physician at the University of Calgary, #FOAM blogger, dogma basher, wine and food supergeek. Chris has a blog called SOCMOB, is part of the REBEL-EM Alliance and did a blog entry on colchicine for pericarditis.

Case Scenario: 33 year old woman presents to ED with sharp RSCP which is pleuritic in nature. Well’s low and PERC negative. ECG consistent with acute pericarditis. Other lab investigations normal.

Question: Is colchicine more effective in combination than standard anti-inflammatory therapy for acute pericarditis, than standard anti-inflammatory therapy alone?

Background: Pericarditis is inflammation of the pericardium, most often from an infectious or idiopathic cause.  There are also other less common etiologies like neoplastic, autoimmune, drugs, trauma and radiation.

The classic history is positional, pleuritic chest pain radiating to the trapezius muscles.  The pain is worsened by lying flat and relieved sitting forward.  Other historical clues would be concurrent or recent infectious symptoms, eg. low grade fever, cough, general weakness.

On exam there are two important diagnostic findings: a pericardial friction rub, and a pericardial effusion on bedside U/S.Screen Shot 2014-08-28 at 11.29.32 AM

For investigations, the ECG is the diagnostic test of choice, which should show widespread ST elevation, and PR depression inferiorly and PR elevation in aVR.  However, this is a very simplified description of the pericarditis ECG, and I would highly recommend listeners check out Amal Mattu’s pericarditis EKG videos.

For blood tests, the WBC and CRP are insensitive and non-specific.  The troponin is used to look for myocardial involvement (myopericarditis), however, with the new high-sensitivity troponins, we may be calling myopericarditis more in the future.Screen Shot 2014-08-28 at 11.30.29 AM

To summarize, there are generally 4 consensus diagnostic criteria:

  1. Classic Chest Pain
  2. Friction Rub
  3. Effusion on Ultrasound
  4. ECG Changes

Colchicine is a plant derived alkaloid that functions as a microtubule inhibitor.  It comes from the autumn crocus or meadow saffron plant.  It is one of the oldest anti-inflammatories and has been used to treat rheumatic diseases for about 2500 years.  Traditional uses include treatment of familial Mediterranean fever, Behcet’s disease and gout.

Unfortunately, colchicine also has a pretty narrow therapeutic window, so you can imagine that there was quite a bit of colchicine toxicity back in the day.

For some good information as background material check out Controversial Issues in the Management of Pericardial Disease. Imazio et al Circulation 2010;121:916-928

Article: Imazio, et al. A Randomized Trial of Colchicine for Acute Pericarditis. NEJM 2013;369:1522-8. PubMed ID: 23992557

  • Population: 240 adult patients were enrolled from from five general hospitals in Northern Italy. All were diagnosed with a first episode of acute pericarditis. This was defined as at least two of the following; typical chest pain (pleuritic, improved sitting up and forward), pericardial friction rub, ST elevation or PR depression, new or worsening pericardial effusion.
  • Intervention: Colchicine (0.5 – 1.0 mg) daily for 3 months in conjunction with conventional anti-inflammatories.
  • Comparison:
    • ASA 800 mg or ibuprofen 600 mg every 8 hours for 7 to 10 days, followed by a taper for 4 weeks.
    • Prednisone (0.2-0.5 mg/kg) daily was given to patients with contraindications to aspirin therapy (allergy, peptic ulcer disease, anticoagulant use i.e patient’s with high risk of bleeding).
    • All patients in both groups received gastroduodenal prophylaxis with proton-pump inhibitors.
  • Outcome:
    • Primary Outcome:  Incessant or recurrent pericarditis.  Recurrent pericarditis was defined by symptom-free interval of 6 weeks or longer after the initial episode of pericarditis.  Recurrence was documented by recurrent pain and one or more of the following signs:  pericardial friction rub; ECG changes; pericardial effusion on echocardiography; or elevation in WBC or ESR or C-reactive protein.
    • Secondary Outcome: Symptom persistence at 72 hours, remission within 1 week, number of recurrences, the time to first recurrence, disease-related hospitalization, cardiac tamponade, and constrictive pericarditis.
  • Exclusions:TB, neoplastic, or purulent pericarditis; severe liver disease or current aminotransferase levels >1.5x upper limit of normal; serum creatinine >2.5 mg/dL; skeletal myopathy or serum creatinine kinase level above the upper limit of the normal range; blood dyscrasia; inflammatory bowel disease; hypersensitivity to colchicines or other contraindication to its use; current treatment with colchicines; life expectancy of 18 months or less; pregnant or lactating women. Also patients with evidence of myopericarditis, as indicated by an elevation in the serum troponin level.

Authors Conclusions: The use of colchicine in addition to standard anti-inflammatory therapy with GI prophylaxis in the treatment of acute pericarditis reduced the rate of refractory or recurrent episodes and increased the time to recurrence when compared to placebo.

checklist-cartoonQuality Check List for Random Control Trials:

  1. The study population included or focused on those in the ED? Unsure

    • Comment: Comment: Patients were recruited consecutively through 5 major hospitals but it was not clear how they presented (through the ED, clinic, ward). There were many exclusion criteria.
  2. The patients were adequately randomized? Yes 
  3. The randomization process was concealed? Yes
  4. The patients were analyzed in the groups to which they were randomized? Yes 
  5. The study patients were recruited consecutively (i.e. no selection bias)? Yes 
  6. The patients in both groups were similar with respect to prognostic factors. Yes 
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes 
  8. All groups were treated equally except for the intervention. Yes 
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Pericarditis NEJM curve Key Results: Based upon the data presented the NNT for the primary outcome to prevent the one case of recurrent or incessant pericarditis was 4.8 (95% CI 3-11). Figure2 in the manuscript showed the Kaplan-Meier Survival Curves for freedom from incessant or recurrent pericarditis.

nerd glasses

Talk Nerdy To Me

 

 

 

Kaplan-Meier survival curve is the probability of surviving in a given length of time while considering small time intervals. It is a standard way of expressing the number of subjects living for a certain amount of time after treatment from clinical trials.

Screen Shot 2014-08-28 at 11.32.11 AM

  • Secondary Outcomes:
    • Symptom persistance 72hrs (ARR 20.8%, NNT=5)
    • Recurrence frequency (ARR 31%, NNT=3)
    • Hospitalizations (ARR 9.2%, NNT=11)
    • Remission 1 week (ARR 26.7%, NNT=4)
    • Prolonged time to first recurrence (24.7 weeks vs. 17.7 weeks)
Dr. Chris Bond

Dr. Chris Bond

Comments: This was a well done RCT with excellent adherence to drug regimens (95%) and no losses to follow-up. The effects of colchicine was seen early and the benefits were sustained out to 18 months. Benefits were seen both in the primary and secondary outcomes.

The authors reported a NNT of 4 but recomputed the NNT is 4.8 with 95% CI 3-11, so actual applied NNT is 5.

This paper was funded by the pharmaceutical industry, as disclosed via a non-influence statement in the article.

As with many RCT the study was powered to show benefit but underpowered to detect rare adverse effects.

The main side effects in both groups were gastrointestinal (GI) disturbances, and were statistically insignificant between groups (9.2% in the colchicine group, compared to 8.3% in the placebo group, P=0.67). It is possible the side effects were caused by the standard therapies (ASA, ibuprofen, corticosteroids) all despite prophylactic GI protection with proton pump inhibitor.

The Bottom Line: Adding colchicine to usual anti-inflammatory management with GI prophylaxis prevents recurrence or refractory pericarditis symptoms with a NNT of 5. The most common side effect being diarrhea. Strict exclusion criteria limits application to uncomplicated pericarditis without systemic manifestations or evidence of elevated cardiac biomarkers (including non-specific troponitis).

Case Resolution: This 33year old woman diagnosed with pericarditis was given a prescription for ibuprofen 600mg TID for 7 days followed by a tapering dose over 1 month, colchicine 0.5mg daily for three months and proton pump inhibitor for 3 months. She was also referred to cardiology for on-going follow-up.

Clinical Application: Colchicine (0.5-1.0mg) daily for three months in conjunction with conventional anti-inflammatories and GI prophylaxis can be used for acute non-suppurative pericarditis to prevent recurrence or refractory symptoms.

What do I tell patients: You have inflammation around your heart called pericarditis. Anti-infammatory drugs like ibuprofen and ASA can help treat your symptoms. An additional medicine called colchicine has been shown to prevent prolonged symptoms. Colchicine has also been shown to prevent pericarditis from happening again. These two type of medications can be hard on the stomach so we are going to give you something to protect your gut. The most common side effect to these effective pericarditis treatments is diarrhea.

Keener Kontest: Marcus Prescott knew that Sussman and Fitch published the first study on thrombolysis in stroke in 1958. Thrombolysis with fibrinolysin in cerebral arterial occlusion. JAMA. 1958 Aug 2;167(14):1705–1709.

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

BEEM LogoUpcoming conferences:

  • QueBEEM Quebec City September 29th and 30th
  • EuroBEEM Prague  December 5th and 6th

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.

 

SGEM#85: Won’t Get Fooled Again (tPA for CVA)

Podcast Link: SGEM85
Date:  September 5th, 2014 

Guest Skeptics: Dr. Ryan Radecki is an Assistant Professor of Emergency Medicine – The University of Texas Medical School at Houston. He has an amazing blog called Emergency Medicine Literature of Note. It is billed as musings on publications and studies relevant to EM & otherwise. You can follow Ryan on Twitter @EMLitofNote.

This is the first episode of season#3 of the Skeptics’ Guide to Emergency Medicine. The goal continues to be to cut the knowledge translation window from 10 years down to 1 year. The SGEM does this by using social media to provide you with high quality, clinically relevant, critically appraised, evidence based information. It is all part of the Free Open Access to Meducation movement. FOAM – Medical education for anyone, anywhere, anytime.

Fonzie Jumps the Shark

I was warned by Jeremy Faust and Lauren Westafer of FOAMCast that season threes can be dangerous. Let me assure the SGEM listeners there will be no jumping of the shark.

We will continue to provide a weekly podcast critically reviewing a recent publication. The validated and reliable Best Evidence in Emergency Medicine (BEEM) appraisal tool will be used to review the manuscripts. Guest skeptics will be invited on to help and give a variety of opinions. There will be more SGEM Classics with the Swami on historic, must know emergency medicine papers. Cheesy theme music mostly from the 1980’s will be selected to help with the edumatainment factor. And of course, cool skeptical prizes will be awarded to the keenest listener who answers the trivia question at the end of each podcast.

I am also working on an exciting new segment for the SGEM tentatively called “Hot Off the Press”. Can’t provide details right now but I hope it will help cut the KT window to less than one week.

So let us start season#3 by addressing one of the most hotly debated issues in emergency medicine, thrombolysis for acute CVA. The SGEM does not shy away from controversial issues it just follows the data.

Thrombolytic therapy for acute ischemic stroke does remains widely controversial.  A “pro/con” debate in the BMJ was accompanied by a non-scientific poll with results split nearly 50/50 regarding whether the benefits of tPA were adequately proven.  Many professional organizations have recommended thrombolytic therapy, with treatment under 3 hours preferred, but treatment up to 4.5 hours accepted.  Other professional societies, primarily in Emergency Medicine, have been less enthusiastic about tPA.

The Australasian College of Emergency Medicine suggests additional evidence is necessary, and the Council of the American College of Emergency Physicians recently voted to revise a pro-tPA Clinical Policy statement.  Alternatively, many stroke neurologists feel tPA to be beneficial in many patients currently excluded from treatment.  This includes the very elderly (>80 years), mild strokes (NIHSS < 5), and time windows up to six hours from onset.

Active clinical trials are underway addressing each of these questions, as well as trials evaluating the utility of advanced imaging to select patients even further from the onset of symptoms.

Case Scenario: 78 year old man presents to ED with right leg and arm for the last 4 hours.  He has a history of hypertension and dyslipidemia. His vitals are unremarkable except for a blood pressure of 165/95. A non-contrast CT head is performed that shows no acute intracranial pathology. Your stroke team asks you to administer thrombolysis and admit.

Question: Is thrombolysis safe and effective treatment in patients who present with signs of an ischemic stroke of less than 6 hours duration?

Background: Acute ischemic strokes represent the leading cause of disability in our society and the third most common cause of death. There have been many studies performed looking at thrombolysis for acute CVA.

We have covered the original 1995 NINDS article on Episode#70. The bottom line from that manuscript was I was skeptical that thrombolysis has benefit for acute stroke.

I presented 12 major trials for thrombolysis in CVA at the Swedish National Emergency conference early this year at SweetBEEM. To summarize there were four trials stopped due to harm or futility, six showing no benefit, and only two showing benefit. This was not enough proof for me to reject the null hypothesis.

Screen Shot 2014-03-26 at 8.40.10 PM

Citation: Wardlaw JM et al. Thrombolysis for Acute Ischemic Stroke (Review).  Cochrane Database Syst Rev. 2014 Jul 29;7:CD000213. doi: 10.1002/14651858.CD000213.pub3. PubMed ID: 25072528

  • Population: 27 randomised trials, involving 10,187 patients, with definite ischemic stroke.
    Intervention: Any thrombolytic agent – urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase.
  • Comparison: Placebo.
  • Outcome: Functional independence at long-term follow up, with safety outcomes of spontaneous intracerebral hemorrhage and death.

Authors Conclusions: Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up).

checklist-cartoonQuality Checklist for Systematic Reviews:

  1. The clinical question is sensible and answerable. Agree.
  2. The search for studies was detailed and exhaustive.  Agree. 
  3. The primary studies were of high methodological quality. Uncertain.
  4. The assessments of studies were reproducible. Disagree.
  5. The outcomes were clinically relevant.  Agree.
  6. There was low statistical heterogeneity for the primary outcome. Disagree.
  7. The treatment effect was large enough and precise enough to be clinically significant. No.

Key Results: In evaluating 27 trials, the authors perform 39 analyses, some with multiple sub-analyses.  They also tend to focus primarily on those involving rt-PA, or alteplase, as the approved and guideline-recommended therapy.

  • Thrombolytic therapy, up to six hours, dead or dependent – 23 trials, 9,318 participants
    • 2679/4891 (54.7%) allocated thrombolysis vs. 2608/4427 (58.9%) allocated control
    • OR 0.85 (95% CI 0.78 to 0.93), with significant heterogeneity (I2 = 39%, P = 0.03)
  • Thrombolytic therapy, up to six hours, risk of symptomatic intracranial hemorrhage – 25 trials, 10,186 participants:
    • 402/5372 (7.4%) allocated thrombolysis vs. 84/4814 (1.7%) allocated control
    • OR 3.75 (95% CI 3.11 to 4.51), without heterogeneity (I2 = 7%)
  • Thrombolytic therapy, up to six hours, risk of death from all causes – 28 trials, 10,187 patients
    • 1043/5372 (19.4%) allocated thrombolysis vs. 856/4815 (17.7%) allocated control
    • OR 1.18 (95% CI 1.06 to 1.30), with significant heterogeneity (I2 = 48%, P = 0.003)

These trials included urokinase, streptokinase, and desmoteplase – and modern thrombolytic therapy is typically undertaken with alteplase, or rt-PA. How about the results for just the rt-PA trials?

  • rt-PA, up to six hours, dead or dependent – 8 trials, 6729 participants
    • 1830/3372 (54.2%) allocated rt-PA vs. 1947/3357 (57.9%) allocated control
    • OR 0.85 (95% CI 0.77 to 0.93), with significant heterogeneity (I2 = 45%, p = 0.04)
  • rt-PA, within 3 hours, dead or dependent – 6 trials, 1779 participants
    • 531/896 (59.2%) allocated rt-PA vs. 603/883 (68.3%) allocated control
    • OR 0.65 (95% CI 0.54 to 0.80), without heterogeneity

The authors therefore lead their published abstract conclusion with the sentence:  Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people.”

Dr. Ryan Radecki

Dr. Ryan Radecki

Commentary: This Cochrane Review update the 2009 version through the addition of the Third International Stroke Trial (IST-3), the largest stroke trial to date.  To remind listeners, IST-3 enrolled patients up to six hours, and specifically enrolled those who were not eligible for tPA under the current European license, but where the treating clinician believed tPA was promising therapy.

A minimal initial number were enrolled double-blind, but following the approval of tPA in Europe, Boehringer Ingelheim ceased supply of the study medication.  This resulted in transition to an open-label design, in which both the treating clinician and the patient were aware of treatment allocation.

This introduces several forms of bias, including alteration of the type or intensity of other initial treatment based on allocation, a placebo effect after being given the “promising” therapy, and a nocebo effect if randomized to no additional treatment.

Outcome assessments at 6 months were blinded to allocation, but many occurred via telephone or postal mail, relying on un-blinded patients or family members to report functional status.  This trial is subject to substantial limitations to internal validity, and its inclusion in this updated Cochrane Review – comprising over half the total number of patients treated with thrombolytic therapy – diminishes the reliability of the analysis as a result of bias in favour of thrombolytics.

There were a number of problems with IST-3:

  • Pragmatic, open-label (blinding)
  • Small blinded (300) favored control
  • Only patients doctors thought would benefit (bias)
  • Missed target by ~50% for enrollment
  • After 7 years they seemed to move the goal post
  • Another statistician was brought in to “persuade”
  • Came up with secondary outcome with ordinal logistic regression analysis
  • Primary end point was NEGATIVE
  • Reported as a positive study -  “despite the early hazards, thrombolysis within 6h improved functional outcome. Benefit did not seem to be diminished in elderly patients.

The SGEM did a critical review of IST-3 on Episode#29. The bottom line from that review was treatment with tPA harmed (death) 1 in 25 early, the fatal and non-fatal bleed rate when up significantly and there was no benefit seen at 6 months in the primary outcome.

The authors appropriately note many of these threats in their reporting of potential sources of bias.  Only 14 of 27 included trials met criteria for high-grade concealment.  Other than IST-3, most were double-blind, placebo-controlled trials – although, the authors note saline placebo is not identical in appearance to tPA, and prolonged incidental bleeding from venipuncture or gingiva in tPA patients could serve to un-blind patients or clinicians.  Blinding of follow-up assessment was only explicitly declared in seven trials, which may have resulted in clinicians aware of acute phase events performing the follow-up assessment.

We mentioned earlier that several trials were stopped prematurely as a result of safety, futility, or enrolment issues.  ATLANTIS A was stopped after 142 patients due to an excess of symptomatic intracranial haemorrhage.  ATLANTIS B was stopped after 619 patients due to futility, and the authors note data has only been publicly presented on 547 of them.

ASK, MAST-E, MAST-I, and MELT were stopped early by their data monitoring committees.  AUST was discontinued after slow recruitment.  The authors do not acknowledge the distorting effect of early termination when weighting results for pooled analysis.

The authors also downplay the potential bias resulted to trial funding and author affiliation.  They note “8/27 trials were run by companies that make the clot-dissolving drugs”, but go on to state most participants come from trials funded by Government or charity sources.  However, this statement is only true based on the inclusion of IST-3.  The majority of trials comprising the remaining participants, including most trials evaluating tPA, were funded by Genentech and Boehringer Ingelheim.  All tPA trial reports were co-authored by individuals declaring conflict-of-interest with one of the two manufacturers.

All trials were performed in specialized stroke centers, and patients were assessed by expert neurologists prior to enrolment and treatment.  The generalizability of any of these findings to many practice settings is limited, and observational studies show mixed results regarding safety and rate of treatment of stroke mimics.

The simple summary of this review boils down to the reliability of the evidence, rather than the analyses of the authors.  However, after nearly two decades of tPA, most clinicians’ opinions are fully crystalized.  Regardless of the conclusions or analyses in this article, few will change practice.

Comment on authors conclusion compared to our conclusion: The authors write:Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment.

In fact, those treated with tPA after three hours derived NO benefit, according to their analyses.  Analysis 1.19 reports death or dependency at follow-up with an OR of 0.93 (95% CI 0.83 to 1.04) versus control.  Therefore, even accepting the data at face value, the authors present a misleading conclusion through inappropriate partitioning of data.

Screen Shot 2014-09-05 at 2.17.34 PM

The remaining author conclusions, regarding a definite increase in symptomatic intracranial hemorrhage, deaths at 7 to 10 days, and deaths at final follow-up, accurately reflect consistent harms present across all trials.

The authors also call for additional trials aimed at identifying the latest time window, treatment population, reduction in harms from intracranial hemorrhage, and the appropriate environment for practice.  However, it may be more appropriate to perform additional studies to narrow the treatment population to maximize benefit, rather than expand the treatment population to the very limits of risk/benefit balance.

Screen Shot 2014-04-08 at 2.57.04 PMThe Bottom Line: No true believers – on either side of the issue – are harmed by this publication. Thrombolysis for CVA…I remain skeptical

Case Resolution:  You reassess the patient and he seems to be improving clinically. You discuss the potential benefits and risk of thrombolysis. By now it is now over 4.5hrs and the treatment window has closed. The patient is not given tPA and admitted for further care.

This is a challenging case and we are clearly in a realm of uncertainty. There are few risk stratification and prognostic tools out there to predict outcome with tPA. But this patient is far from that idea patient population. His age, hypertension and dyslipidemia are clinical features likely increasing his chance of intracranial hemorrhage.

In these trials in a typically younger population the symptomatic intracranial hemorrhage rate was 7.4%. Just roughly estimating his chance of ICH after tPA is probably 10-12% or even higher with a corresponding increase in mortality.

His unilateral weakness is improving. Is this a transient event? It is difficulty to say so close to the onset of symptoms. Stroke mimics and TIAs also do great with tPA but they also do great without treatment. The level of disability is an important consideration. A patient with some weakness might be reasonable to expect to regain some function with rehabilitation, whereas profound hemiparesis is almost certain to be completely disabled for the remained of his life.

Many individuals will actually make the decision to take that substantial risk of bleeding in order to gain an even smaller chance of independent living. Assessment of pre-stroke functional status is also an important consideration. Then as you say this patient’s presents near the end of this proposed therapeutic window. In general, and in this specific case, I would say the risks even exceed the theoretical benefits.

Clinical Application: I will continue to offer tPA, as recommended by the American Heart Association guidelines, and tacitly mandated by medicolegal consequences if not offered.  The manner in which patients are provided informed consent for this therapy dramatically influences their likelihood of electing to receive treatment.

What do I tell my patient? Thrombolytic therapy for acute ischemic stroke is controversial.  The risks – severe bleeding and with neurologic worsening – are consistent and known, occurring in about 1 in 12 patients.  The benefits are uncertain, and most studies suggestive of benefit were sponsored by drug companies or otherwise biased.  Other trials showing harm or no benefit were stopped early when hoped-for results did not materialize.  However, a number of patients in all trials using tPA – about 1 in 10 – received noticeable functional benefit from this therapy when given quickly after a stroke.  Doubts persist about the reliability of this data, and, unfortunately, it is unclear which patients have the greatest chances of benefit or harm from this therapy.  The choice to receive this therapy remains an individual patient decision.

Keener Kontest: Who did the first study for thrombolysis is stroke and when was it published?

If you know the answer than send me an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

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Upcoming conferences:
  • QueBEEM Quebec City September 29th and 30th
  • EuroBEEM Prague  December 5th and 6th

Thank you to Dr. Ryan Radecki for being the first guest skeptic on Season3 of the SGEM. I hope this was a good way to launch Season#3. You can look forward to a weekly skeptical review of the EM literature. As mentioned, Swami will be back with some Classic papers, expect more great skeptical guests, I will be recording SGEM Journal Club at Queen’s University next month, there will be the occasional 10,000 foot view of an EM/MedEd/EBM issue and a brand new SGEM segment coming soon.

Remember to be skeptical of anything you learn,

even if you heard it on the Skeptics’ Guide to Emergency Medicine.