Bystander Naloxone for Opioid Overdose

November 3, 2016

Background:  In the USA, overdose has surpassed MVCs as the leading cause of injury death with approximately 43,000 deaths in 2013.  Over 80% of these were unintentional, and 37% involved opioids.

One option for intervention is to provide naloxone rescue kits to drug users and their friends/families.  This approach has been endorsed by the WHO, the American Public Health Association, state legislatures and public health departments.

Arguments against:  Will users consider naloxone a “safety net” and choose to actually increase their drug use?  Can drug users and community members be trusted to safely respond to overdoses?  These articles are representative of the data responding to these questions.

Article 1.  Doe-Simkins M, Quinn E et al.  Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs:  a restrospective cohort study.  BMC Public Health 2014. 14:297.

This retrospective cohort study from 2006-2010 examines the impact of a well-established Massachusetts based initiative consisting of 8 agencies that provide overdose education and naloxone distribution (OEND).  Authors aimed to compare success of rescues from trained vs. untrained bystanders, and to determine if naloxone distribution changed heroin use.

“Trained” participants received training from the program, and “untrained” participants were contacts of the trained participants, so should have been exposed to some information about OEND.

Authors reviewed results of 599 rescue reports from 4,926 substance using participants (295 trained and 78 untrained).  There were no significant differences in help-seeking, rescue breathing, staying with the victim or in the success of naloxone administration between trained and untrained participants.  There were also no significant changes in the use of heroin when comparing use over at least 30 days in drug users who presented to different centers over time, although more participants increased rather than decreased benzodiazepine and barbituate use.

Although technically a negative study with regards to differences in overdose rescue management between trained and untrained participants, the authors conclude that as there are no significant differences in behaviors overall between these groups and there is no significant increase in heroin use, the results support an expansion of OEND programs with naloxone potentially becoming an over the counter medication.  

Limitations?  No systematic collection of data, potential bias that participants may provide incomplete or selected information that they feel investigators want to hear.  Other societal confounders may have affected drug use patterns over the study period.

Bottom line from discussants: OEND programs are likely making meaningful impact in communities, although gathering data to prove this is challenging.  

Article 2:  Giglio RE, Guohua L, DiMaggio CJ et al.  Effectiveness of bystander naloxone administration and overdose education programs:  a meta-analysis. Injury Epidemiology 2015. 2:10.

This meta-analysis of the literature on the effectiveness of OEND included 9 articles using pre-defined criteria with the aims of 1) evaluating odds of recovery after overdose and 2) impact of training on overdose recognition and knowledge of management of overdose.

Results:  bystander naloxone administration was associated with a significantly increased odds of recovery from overdose compared to no naloxone administration (OR = 8.58, 95% CI = 3.90 to 13.25).  Training led to improved knowledge regarding overdose recognition and management (standardized mean difference = 1.35, 95% CI = 0.92 to 1.77).

Limitations:  The meta-analysis did not include a robust discussion of study quality.  Outcomes of the relatively small number of witnessed overdoses (n=66) was largely based on self-report.  There was lots of study heterogeneity, and the pre/post knowledge data were limited with very short term follow-up of knowledge retention.  Three studies did not report duration of training; details of training curriculum and evaluation tools were also lacking.

Bottom line from discussants:  education/training may not be very helpful, butbystander naloxone itself is life saving.

Article 3:  McDonald R, Strang J.  Are take-home naloxone programmes effective ?  Systematic review utilizing application of the Bradford Hill criteria. Addiction 2016;111:1177-1187.

Aims:  to review the impact and safety of take-home naloxone.

This systematic review used narrative synthesis of 22 observational studies to assess the effects of take-home naloxone programs on overdose mortality as well as take-home naloxone safety.  Bradford Hill criteria are used in public health to assess causality when only observational data are available, and include the following 9 factors:  strength of association, consistency, specificity, temporality, dose-response relationship, plausibility, coherence, experimental evidence and analogy.   The authors determined that the included studies met all of these criteria, supporting the conclusions that take-home naloxone reduces overdose related mortality with a low rate of adverse effects.  

Limitations:  studies again rely on self report, there is a lack of systematic followup, a high level of study dropout, selection for participants with good experiences (survived), details of training are limited, and the most important Bradford Hill criterion, experimental evidence, was only represented by one study that used a quasi-experimental research design.

Bottom line from discussants: again, poor quality data which are overwhelming in favor of naloxone distribution and bystander use.

What’s the downside?  In Illinois there are no legal ramifications for physicians to prescribe naloxone.  Although data are never going to be high quality for this type of public health intervention, results consistently demonstrate positive outcomes and the potential to save many lives.  Naloxone is safe, with the most common side effect being precipitation of opioid withdrawal.  Opioid overdose kills, and as Christian stated, can also cause tremendous morbidity from respiratory depression and brain hypoxia.  

Analogy of epipens:  we prescribe potentially dangerous medication without thinking twice, studies have shown only about 10% of epipen users use it correctly.  Analogy of CPR instruction:  years may go by without bystanders doing CPR on a cardiac arrest patient, but heroin user has a high likelihood of being at the site of an overdose.

October 2016 EMRAP also discussed that naloxone may save not only the patient in front of you, but their support system:  friends, family, other users, as heroin is often used socially in groups....trickle down effect.  

What is available in Illinois?   Individuals can go to Marianos or Walgreens and obtain intranasal naloxone without a prescription, along with 1:1 private counseling from a pharmacist.  Cost approximately $140 at Marianos, Walgreen’s about 80$.  Covered by many insurance plans.  Also coupon available online for Ezvio (www.ezvio.com), the$$$$ talking naloxone auto-injector.  A cheap alternative-Mike Kennedy: price of 0.4 mg vial of naloxone 10$.

Liz Regan:  “Lali’s Law” PA99-0480, passed in 2015 in Illinois, named after a teenager who died from opioid/benzo overdose, allows trained pharmacists to dispense naloxone to individuals at risk of opioid overdose, their friends/family, first responders, and school nurses.  This comprehensive reform bill also provides criminal immunity for health care professionals who prescribe and dispense naloxone pursuant to the law, and protection from civil liability for both pharmacists who dispense naloxone and laypersons who administer naloxone in good faith.  http://www.ilga.gov/legislation/publicacts/99/PDF/099-0480.pdf

At ACMC?  Michael Cirone and Kyle Bernard will be speaking with hospital administration regarding training interested PharmDs, physicians and nurses to dispense naloxone kits obtained from the Chicago Recovery Alliance (anypositivechange.org).  Kudos to both for moving this important effort forward.

Ted:  consider tailoring discharge instructions to patient’s insurance, and use Medical Social worker.  Harwood and McKean:  this is an opportunity for institutional control/policy; standardize treatment so patients leave informed and with naloxone in pocket.  Overcome the barriers to care.

ICH and TBI

July 14, 2016

Journal Club Synopsis:  ICH and TBI:  Challenging Standard Management

A big thank you to Harwood for another peaceful summer escape to the marshlands and forest.  Also big thanks to presenters Patrick Holland, Dan DeWeert, Jenny Denk, Dan Nejak, Nate West (barbarian), and Mike Stanek (wizard).

1.      Qureshi AI, et al: Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med  2016 June 8.

Although evidence has suggested that hematoma expansion and morbidity/mortality in hypertensive patients with ICH might be reduced with early reduction in SBP, there has been no consensus for blood pressure targets in these patients.  In this RCT of 1000 adult patients with ICH and elevated BP presenting to 110 international sites (including ACMC; go E. Kulstad and Stanek!), 500 patients were randomized to a SBP target of 110-139 mm Hg (intensive treatment) and 500 to a SBP target of 140-179 mm Hg (standard treatment).  Inclusion criteria were at least one initial SBP of ≥ 180, supratentorial ICH with hemorrhage volume < 60 cm3, GCS ≥ 5, and initiation of antihypertensive treatment within 4.5 hours after symptom onset.  Primary outcome was death or disability defined as modified Rankin scale score of 4-6 at 3 months.  Secondary outcomes included scores on a health state index and ICH expansion at 24 hours.  Serious adverse events and safety outcomes including neurologic deterioration and renal adverse events were also recorded.  Nicardipine was used as the first-line antihypertensive, and if needed, labetolol was the preferred second-line agent.

Results:  The primary outcome of death or disability was observed in 39% of the intensive-therapy group, and in 38% of the standard-treatment group (no significant difference).  There were no significant differences in health state index scores.  Interestingly, although there was a trend towards more expansion of ICH in the standard treatment group, this did not translate to higher morbidity/mortality for these patients.  The rate of serious adverse events and early neurologic deterioration was higher in the intensive treatment group.  There was a significantly higher rate of renal adverse events within 7 days in the intensive treatment group (9% intensive, 4% standard). 

Systolic blood pressure was relatively tightly controlled for both groups, resulting in a study that really compared SBP of 140s to SBP of 120s.  It is therefore unclear if a maintaining a higher SBP, e.g. SBP 160-170, would result in the same outcomes.  Points were also made that the majority of patients presented with a GCS of 15, limiting the external validity in a sicker patient population, and that the best goal may be a smooth maintenance of blood pressure, rather than a forced low target that results in significant SBP variability.  Not surprisingly, there were many more treatment failures (inability to achieve/maintain target SBP) in the intensive treatment group.  There was a trend favoring intensive treatment in patients presenting with low GCS scores (3-11).

Bottom line:  a target SBP of 140s resulted in similar death/disability compared to a target SBP of 120s in patients with relatively small volume ICH and overall high initial GCS scores.  Tight SBP control was associated with a trend toward more serious adverse events as well as a significantly higher rate of adverse renal events.  Aggressive reduction of SBP in patients with ICP does not demonstrate a death/disability benefit and is associated with increased incidence of serious adverse events. 

2.      Baharoglu MI, et al:  Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.  Lancet  2016 25;387:2605-2613.

Ok, so aggressive BP control doesn’t work in ICH.  How about platelet transfusion for patients taking anti-platelet agents?  People taking anti-platelet agents have increased mortality after ICH, and it’s intuitively attractive to transfuse platelets in this population.  In this small study (41 sites, 6 years...190 patients-ouch!), adults presenting within 6 hours of symptom onset after supratentorial non-traumatic ICH symptom with a GCS score of ≥ 8, who had received anti-platelet therapy for at least 7 days prior, were randomized open label to either receiving standard care or standard care + platelet transfusion within 90 minutes of brain imaging. Most patients were taking aspirin and if randomized to platelets received one platelet concentrate (5 donor units).  Those taking ADP receptor inhibitors such as clopidogrel (Plavix) and randomized to platelets received two platelet concentrates.  Primary outcome was a shift towards death or dependence rated on the modified Rankin Scale at 3 months.

Results:  The odds of death or dependence were significantly higher in the 97 patients in the platelet group as compared with the 93 patients in the standard care group (odds ratio 2.05, 95% CI 1.18-3.56). Serious adverse events were more frequent in the platelet group (42% vs. 29%) including significantly increased rates of serious adverse events due to ICH, and hospital mortality was higher in the platelet group as well (24% vs. 17%). 

Limitations:  an unknown number of patients were eligible for the trial, and the small trial size with limited enrollment over 6 years are threats to the external validity of the study.  There were also a number of patients enrolled who met an exclusion criteria, or protocol violation.  This trial specifically evaluated patients not heading to the OR; future study would be necessary to evaluate outcomes in surgical patients with ICH.  This study did not assess platelet function.

Bottom line: mortality and morbidity were higher in patients receiving platelet transfusions after non-traumatic ICH than in patients receiving standard care.   This may be due to potential inflammatory and pro-thrombotic effects of platelet transfusion.

3.      Patanwala AE, et al:  Succinylcholine Is Associated with Increased Mortality When Used for Rapid Sequence Intubation of Severely Brain Injured Patients in the Emergency Department.  Pharmacotherapy  2016;36(1):57-63.

A youtube video should be imminent, as of course this article interpretation was performed using LARP (Live Action Role Playing).  For a less dramatic synopsis, this was a chart review from a single academic center.  A total of adult 233 patients with TBI requiring intubation were either intubated with succinylcholine (149 patients) or rocuronium (84 patients).  Agent choice was by provider preference.  Mortality was 23% in both groups, with the same first-pass success rate.  Groups were similar except for a higher rate of hypotension in the succinylcholine group.

 When stratified by “Head Abbreviated Injury Score,” rocuronium mortality was 22% in the low score group and 23% in the high score group, while succinylcholine mortality was 14% and 44%.  Authors therefore attempt to draw the conclusion that in more severely brain injured patients, rocuronium is the preferred neuromuscular blocker.  The only problem with this conclusion is that overall mortality rates for the 2 agents were identical, implying that for the lesser brain injured patients, succinylcholine should therefore be the safer agent.  This indeed was the trend, although it didn’t reach statistical significance.  Especially in this retrospective trial, sub-group analysis by Head AIS should be hypothesis generating. 

Rocuronium needs to be given at 1.5 mg/kg IV to provide similar intubating conditions to succinylcholine, and if dosed correctly, provides several potential advantages (avoid theoretical increase in ICP and hyperK with succinylcholine, longer paralysis facilitates multiple imaging studies, etc).  What’s the downside to rocuronium?  Medical staff forget to initiate a long active sedative immediately after intubating, leading the horrible potential of awake but paralyzed patients.  In addition, for certain clinical conditions such as seizures, a shorter acting paralytic allows for earlier repeat neurologic exams. 

Bottom line, for the stated primary outcome of in-hospital mortality, the 2 agents performed equally well.  The “head AIS” is not meant as an initial injury scoring scale, and GCS, which can be determined at presentation quickly, did not discriminate between rocuronium and succinylcholine.  If only for simplicity and to decrease cognitive load, rocuronium should usually be your neuromuscular blocking agent of choice.

Journal Club bottom lines:

1.      In patients with ICH and hypertension, lower SBP to 140s.  Maintaining smooth BP control is more beneficial than an aggressively low target SBP in the 120s.

2.      Platelet transfusions in patients with non-traumatic ICH who are taking anti-platelet agents is associated with increased rates of death or dependence. 

3.      Use rocuronium at 1.5 mg/kg IV instead of succinylcholine.  Except maybe in seizure patients who need early neuro-rechecks.  Just remember to start a long acting sedative right away!!

Journal Club Potpourri

Journal Club Summary, May 2016: Revisiting antibiotics for abscess; Reconsidering the diagnostic evaluation of Acute Heart Failure; the Power of the probe in diagnosing undifferentiated hypotension.

Many thanks to Mike and Karen Lambert for hosting on a beautiful evening, and to Matt DeStefani, Frank Lee, Mike Stanek, Mike Kennedy, Liz Regan and Bristol Schmitz for their cogent, concise article analyses.

Article 1: Talan DA, et al: Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. N Engl J Med 2016;374:823–832.

Brief background; CA-MRSA abscess is the culprit behind the huge spike in SSTIs seen in our emergency departments over the past 20 years. While historically abscesses have been successfully treated with I/D alone, CA-MRSA is virulent and pesky, and small studies have suggested a role for antibiotics in addition to I/D, both for improved resolution of infection and to help prevent abscess recurrence. These studies have been underpowered, as the I/D success rate even in the age of CA-MRSA is around 80%, making it difficult to demonstrate small differences in cure rates in small studies. The most recent 2015 IDSA guidelines on SSTI recommend I/D and no antibiotics for simple, uncomplicated abscess.

So, a shout out to Dave Talan and Greg Moran, UCLA EM, for publishing this double blind RCT of 1265 patients &gt;12 yo who presented with uncomplicated abscess to 5 US emergency departments and who were treated as outpatients. While immunosuppression was an exclusion criteria, 11% of included patients did have diabetes and 8% had prior MRSA. About half of wound cultures grew MRSA. Average abscess size was 2.5 x 2 cm, with an average area of erythema of 7 x 5 cm.

The primary endpoint was clinical cure of abscess 7-14 days after end of treatment with either 7 days of 2 DS Bactrim bid or placebo. Clinically important secondary outcomes included the need for surgical drainage, hospitalization, development of new infection in patient or household contacts, and invasive infections.

Results: Clinical cure was 80.5% in the Bactrim group, 73.6% in the placebo group; an ARR 7% for cure with a NNT of 14. There was still a high cure rate even without antibiotics...likely even higher assuming those lost to follow-up were clinically cured. Bactrim was superior to placebo for most secondary outcomes, including a 7% ARR in skin infections at new sites (10.3% vs. 3.1%). Subsequent invasive infections were rare in both groups. Adverse events were mild and most commonly GI (43% in Bactrim group vs 36% in placebo group). No C. difficile was reported.

So why not just give everyone with an abscess Bactrim after the I/D? Well, for starters, the majority of abscesses still resolved without antibiotics. Somehow, they didn’t see any, but you have to consider C. difficile. Also cost, the nuisance of non-specific GI side effects, and the potentiation of other medications, especially drug/drug interactions for Bactrim with Coumadin and oral hypoglycemics. They also didn’t see Stevens Johnson Syndrome, which is a rare but potentially life threatening complication of Bactrim. Antibiotic resistance is always a concern.

Maybe this is a time for shared decision making? Pretty simple talking points; 7% ARR for cure or recurrence, but baseline at least 74% cure. They didn’t look at subgroups...maybe push more for antibiotics in a patient with DM or with a large area of cellulitis? Could consider a “wait and see” prescription, although treatment failures may need additional I/D and should probably be re-seen.

NB, if prescribing antibiotics, remember they used 2 Bactrim DS bid for 7 days. Current IDSA guidelines say either 1 or 2 DS tabs bid is acceptable.

Show of hands? A minority of people in the room would take the Bactrim if they had an uncomplicated abscess. Interestingly, nobody in the room admitted to ever having a MRSA abscess....hmmmm.

Article 2: Martindale JL, et al: Diagnosing Acute Heart Failure in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med 2016;23(3):223-42

It’s an age old question...how to accurately diagnose acute heart failure?

The ED diagnosis of AHF based on history, exam, CXR and ECG is discordant with the final discharge diagnosis in nearly one out of four cases.

In this review of 57 studies with 18,000 patients, 46% of whom were diagnosed with AHF, the authors examined the test characteristics of history and physical exam findings, ECG, CXR, BNP, Ultrasound, Echo, and Bioimpedence devices in patients presenting to the ED with dyspnea.

Not surprisingly, history and exam don’t do so well. There are many overlapping historical and exam features in our patients who often have multiple co-morbidities causing dyspnea. Unfortunately, authors also looked at each feature independently, instead of considering the power of gestalt of multiple history/exam variable. In any case, S3 has the highest LR (+) of 4, but this is found in only 13% of patients with AHF.

ECG: not helpful.

CXR: pulmonary edema on CXR has an LR (+) of 4.8, but CXR has a known poor sensitivity for AHF and a normal CXR does not help rule out CHF.

Echo: if reduced EF, echo can be helpful, except it doesn’t take into account 50% of CHF patients with preserved EF...also may be able to get the EF from recent echo/EMR, so may not add new information. Reduced EF as determined by visual estimation had a LR (+) of 4.1.

BNP was useful as a rule out, with a LR (-) of 0.11 when BNP was &lt; 100 pg/ml. BNP had a LR (+) of 7 when BNP was &gt; 1000 pg/ml, but values in between had unreliable LRs. Point made in the article that dichotomizing a continuous variable such as BNP is not the optimal use of the test. Also, most of the studies evaluating BNP excluded patients with renal failure, leading to fewer false-positives and inflating the test’s specificity.

There have been limited studies of Bioimpedence devices, with heterogeneity in the data analysis, but some initial promising results with segmental bioelectrical impedence analysis.

The overall winner....Lung Ultrasound with a LR (+) of 7.4 when B lines were visualized in multiple lung zones (hint, Mike Lambert likes using the windows at the medial costosternal articulations) and LR (-) of 0.16 when B-line pattern was absent.

Biggest limitation of this paper (beyond its mind numbing length)? Gold/criterion standard diagnosis of AHF is still clinical and consensus based, incorporating the clinical data and objective test results...leading to potential incorporation bias (study evaluates features that are also used to define the final diagnosis).

Bottom line: Use Ultrasound, to both rule in and rule out AHF. Gestalt history and physical may be helpful, but no individual H/P finding except for the elusive S3 is reliable. Very low or very high BNPs can help. Low EF on echo is useful, but misses 50% of patients with EF preserved AHF.

Article 3: Shokoohi H, et al: Bedside Ultrasound Reduces Diagnostic Uncertainty and Guides Resuscitation in Patients With Undifferentiated Hypotension. Crit Care Med 2015;43:2562-9.

In an ideal world, as the ultrasound probe becomes your sixth digit, and a rapid US protocol for the patient with undifferentiated shock will improve diagnostic accuracy and certainty.

In this single center study, attendings trained in critical care US or US fellows performed ultrasounds (4 view cardiac, 8 view lungs, IVC @ hepatic vein, & FAST/Aorta scan) on 118 adult ED patients with undifferentiated shock defined as SBP &lt; 90 mm Hg after at least 1 liter NS IV. Patients with obvious sources of hypotension, or trauma-related hypotension were excluded. Clinicians caring for patients completed a pre/post US form indicating how the results of the protocolized US performed by an independent physician influenced their diagnostic certainty, diagnostic ability, and treatment/resource utilization. Primary outcome  was the change in the treating physician’s diagnostic certainty pre/post US and the concordance of post-US ED diagnosis with final chart review diagnosis.

There was a 28% decrease in diagnostic uncertainty after US, and an increase in the proportion of patients with a definitive diagnosis from 0.8% to 12.7%. Overall, the leading diagnosis after US demonstrated excellent concordance with the final diagnosis. A quarter of patients had significant changes in management after US, and significant changes in diagnostic imaging, consultation, and ED disposition. A subgroup of cases was described where ED US identified serious and time sensitive diagnoses (eg PE, ruptured splenic artery aneurysm, AAA).

Limitations: uncertain how much clinical information was available to physician prior to performing the scans, and this would potentially impact the post-test certainty of diagnosis. Likewise, initial resuscitation measures, including average amount of initial fluids given, was not included. How long do these scans take?? Lambert thinks maybe 10 minutes if you do it a bunch. At the same time, for many patients, after a targeted history, the complete protocol is probably not necessary, and scan time therefore decreases. This study didn’t evaluate the impact on clinical, patient oriented outcomes, including the impact of US on morbidity, mortality, ICU stay, etc. Finally, pre-US protocol diagnosis accuracy and post-US diagnosis accuracy were not directly compared, again likely secondary to lack of standardization of initial clinical information and initial resuscitation measures.

Bottom line: Kerwin-make US a habit. Barounis-it will make you a faster clinician. Team US in general: this is an important subgroup of patients, with potentially time sensitive diagnoses. US: do more, be better, save lives. 

Influenza and oseltamivir

Journal Club Synopsis, January 2016.  Oseltamivir-Prescriptions and Profits.

Many thanks to Branka Milicev for tasty Italian food and beautiful views from her south loop penthouse!

The Tamiflu controversy heated up in 2014.  Turns out Roche, manufacturer of oseltamivir, had suppressed a number of unpublished trials.  A group of researchers went after Roche for several years, and after much public shaming, Roche finalized released these data.  Studies incorporating the unpublished data were published in the April 9, 2014 issue of BMJ as well as our included Family Practice article.  The authors of the BMJ articles also updated the pertinent Cochrane review in 2015, which covers the use of all neuraminidase inhibitors in preventing and treating influenza.

Article 1: (Regan, Navarette)

Ebell MH, et al. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials.  Family Practice 2013; 30:125–133 doi:10.1093/fampra/cms059

This meta-analysis includes published and unpublished double-blinded, placebo-controlled RCTs of oseltamivir in adults with suspected or confirmed influenza that reported the primary outcomes of duration of symptoms, complications, or hospitalizations.  All of these studies were limited to patients presenting within 36 hours of symptom onset.  Pregnant patients were excluded by most of the reporting articles.  Authors were granted access to trial registries maintained by the drug manufacturer.  Eleven studies (3 published, 8 unpublished) with a total of 4769 patients met inclusion criteria. 

For the intention to treat (ITT) population, the mean reduction in duration of symptoms was 21 hours.  There was no significant reduction of symptom duration in the elderly and in patients with chronic disease, two populations felt to be at higher risk.  One study stratified by time of symptoms:  reduction of symptoms by 29 hours if oseltamivir was given within 24 hours of symptom onset, 15 hour reduction if given between 24-36 hours of symptom onset.

Overall, there was no difference in the likelihood of hospitalization and no reduction in the rate of infectious complications requiring an antibiotic when acute bronchitis was excluded.  Authors excluded acute bronchitis as current guidelines do not support the use of antibiotics for acute bronchitis.  The risk of pneumonia was reduced in the population with PCR confirmed influenza infection (NNT = 111), but not in the general ITT population.  There was only one death reported, in the placebo group. 

Downsides to Tamiflu?  Cost is about 100$.  Side effects of oseltamivir were not specified in this meta-analysis, but other reports state rates of nausea and vomiting between 5-10%.  There are less common neuropsychiatric and renal complications as well as headache.  An additional concern is the expected increase in drug resistance with liberal oseltamivir use.  Authors also comment on the questionable motivations of the manufacturer not publishing multiple studies, and the break in the public trust when patients are recruited and enrolled in studies whose results are never used for the intended purpose of advancing medical care.

Limitations of the meta-analysis include the limited reporting of complications in the ITT population.  Existing literature includes only small numbers of hospitalizations and serious complications, which limits comparisons, especially for high-risk patients.

From our presenters: they are less likely to prescribe Tamiflu.   One more day of flu has different meanings to different people, depending on their income, work situation, future exposures, comorbidities.   

Bottom line:  In this large meta-analysis of published and unpublished studies, there is no evidence that oseltamivir reduces the likelihood of hospitalization or acute infectious complications.  There is a small reduction in the risk of pneumoniabut this was only seen in lab confirmed influenza (NNT =111).  There is a reduction of about one day in duration of symptoms if oseltamivir is given within the first 36 hours of illness, but treatment is associated with side effects of nausea and vomiting.

Article 2: (Einstein, Ede)

Muthuri SG et al. Eff ectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014;2: 395–404.

So, if oseltamivir doesn’t help prevent infectious complications or hospitalizations in outpatients, does it at least help in sicker patients with flu who require hospitalization? 

This is a meta-analysis of retrospective, observational data from the 2009-2010 Influenza A H1N1 pandemic.  It included data for 29,234 patients from 78 studies worldwide, who were admitted to hospital with clinical or lab confirmed influenza A H1N1.  Primary outcome was the association between neuraminidase inhibitor treatment and mortality, adjusted for treatment propensity and confounders.  Although the authors state in their methods that they attempted to include both observational studies and RCTs, in their conclusions they refer to using retrospective, observational data and in the appendix, there is no further clarity regarding the methodology of studies included. 

In adults, neuraminidase inhibitor treatment was associated with mortality risk reduction, adjusted odds ratio 0.81; 95% CI 0.70-0.93.  Treatment within 2 days of symptom onset vs. late treatment, treatment within 2 days vs. no treatment, and treatment of pregnant women and critically ill adult patients were all associated with even greater mortality risk reductions.  If treatment was started within 2 days, NNT (to save a life of an admitted pt) was 31.

Combining all subgroups, there was no mortality benefit with treatment delayed more than 2 days after symptom onset; however there was still benefit of delayed treatment in patients admitted to ICU.  The association with reduced mortality was not statistically significant in pediatric patients. 

What are the problems with this study?

First, funding was by Hoffman –La Roche, makers of oseltamivir, and the main author was a paid consultant for Pharma and former employee of Roche.  As seen from the first article, there have been big issues with suppressed data and overstatement of treatment effect with this drug.

The data were retrospective and observational, implying potential for lots of residual confounders and missing information.  Although 401 centers were contacted to contribute, only 78 centers were included.  Finally, the quality of the included studies has been described as “medium to poor,” with “clear evidence of unadjusted biases.” (theNNT.com).

Bottom line:  In this meta-analysis with significant limitations, oseltamivir treatment within 2 days of symptoms was associated with a mortality reduction in hospitalized adults, with the greatest benefit seen in pregnant women and critically ill patients.

Article 3: (Hart, West)

Lenzer J. Why aren’t the US Centers for Disease Control and Food and Drug Administration speaking with one voice on flu? BMJ 2015;350:h658 doi: 10.1136/bmj.h658

Ok, I’ll get a little political.

From “Tamiflu, a Nice Little Earner:-BMJ, 2014.

Since its launch in 1999, oseltamivir has generated cumulative sales in excess of $18 billion for Roche. Half of the total expenditure was by governments and companies around the world for stockpiles for pandemic preparations. The US alone spent more than $1.3 billion buying a strategic reserve of antivirals.  Most have never been used, and today the US stockpile consists of more than 65 million treatments. 

Back to the Lenzer’s editorial:

The FDA disagrees with the CDC  “Take 3” campaign that claims oseltamivir “saves lives.”  The FDA has stated that oseltamivir “has not been proven to have a positive impact on the potential consequences (such as hospitalizations, mortality, or economic impact) of seasonal, avian, or pandemic influenza.”

CDC director Thomas Friden has made expansive claims about the benefits of neuraminidase inhibitors for non-admitted patients, including the implication of a general mortality benefit.  This approach has been called irresponsible, and an appeal of emotion instead of science.  Oseltamivir costs around 100$, which for many patients is a substantial cost for a marginal benefit.  Sending large numbers of otherwise healthy people to the ED who have influenza but who won’t actually benefit from oseltamivir may actually increase the spread of the virus around crowded ED waiting rooms.

The “CDC Foundation” provides funding to the CDC.  The CDC received a directed donation of $198,000 from Roche (maker of oseltamivir) via the Foundation for the “Take 3” flu campaign.  Step 3 of “Take 3” encourages people to “take flu antiviral drugs if your doctor prescribes them.”  Overall, the CDC receives millions of dollars annually from Big Pharma, channeled through the CDC Foundation.  The reputation of the CDC as being free of industry bias is viewed by some as now compromised.

The CDC cites the Lancet’s 2015 Dobson meta-analysis as demonstrating a reduction in hospitalization after outpatient treatment with oseltamivir.  This study was indirectly sponsored by Roche, and according to Jeanne Lenzer, “all four researchers received industry funding either directly or through industry donations to organizations that directly funded the study (so-called “pass-through” money).”  The Dobson paper’s conclusions are far different than the conclusions from Journal Club’s meta-analysis by Ebell and the 2014 BMJ systematic review by Jefferson, both of which included previously unpublished data from Roche.

Even after the 2014 articles in the BMJ and Family Physician, the CDC’s recommendations regarding neuraminidase treatment for influenza are unchanged.

Really though, if you want the dramatic interpretation, please tune in to youtube and our very own thespians Elise Heeringa and Nathan West.  This was forwarded to Jeanne Lenzer at the BMJ (author of the editorial), who was very impressed J

https://www.youtube.com/watch?v=WpzMS3c2090&feature=youtu.be

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y Journal Club bottom line:  for outpatients, there’s just no data to support treatment with neuraminidase treatment to prevent serious complications, hospitalization, or death.  At best, for outpatients, if treated within 36 hours of symptom onset, you’ll get 21 hrs of decreased illness, for a 100$ drug with up to 10% incidence of N/V.  For adult inpatients, if oseltamivir is started within 2 days, there is likely a mortality benefit.  For admitted kids, overall data says mortality same with/without oseltamivir.  However, there is a December 2013 Pediatrics study (Louie et al) of kids admitted to the ICU that demonstrated a mortality benefit. 

Point of Care Ultrasound

Thanks to Sheila and Ron Bonaguro for the early Thanksgiving feast!!  Outstanding presentations by Ari, Patrick, Natalie, Kennedy and Stephen. 

Pushing the depth of field for point of care ultrasound?  Use of US to predict futility of resuscitation after medical and traumatic cardiac arrest, and as a potential alternative to the trauma pan-scan CT.

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Article 1:  Flato UA, et al:  Echocardiography for prognostication during the resuscitation of intensive care unit patients with non-shockable rhythm cardiac arrest. Resuscitation  2015  Jul; 92:1-6. 

This was a Brazilian prospective, observational cohort study of 49 ICU patients with in hospital asystole or PEA cardiac arrest. Of 88 eligible patients, 39 were excluded. PEA without contractility was classified as electromechanical dissociation (EMD), and PEA with contractility as pseudo-EMD.  Two echo trained intensivists performed transthoracic echos. Rates of ROSC were 70% for pseudo-EMD, 20% EMD, and 24% for asystole.  Good ROSC percentages for all groups, but survival to hospital discharge was only seen in pseudo-EMD patients, and discharge is what counts.  Four patients survived to 180 days, all in the pseudo-EMD group, with CPC of 1, 1, 1, 2.  Echo was feasible, with maximum duration of 10 seconds, so non-disruptive to the ongoing code.  Echo also helped identify underlying etiology of arrest in selected patients, eg unexpected tamponade.  This was a very small study, and conducted in an ICU with a large number of DNR patients who were never entered into study, so different from our ED population.   

This study reinforces our usual practice of using echo to verify presence/absence of cardiac contractility and guide futility of resuscitation.  Blaivas and Fox (go ACMC!!) published a larger study in 2001 demonstrating 100% mortality in patients with asystole or PEA cardiac arrest and no cardiac contractility on bedside echo. This modality helps conserve resources (time and personnel), and may identify the underlying reason for code.  In the future, in young otherwise healthy patients with arrest, an echo demonstrating contractility may help risk stratify for ECMO.

Bottom Line:  Rather than pulse check, consider echo as the more reliable marker for viability.  Also remember end tidal CO2 to guide prognostication.  

(AHA 2015 ACLS guidelines:  “In intubated patients, failure to achieve an ETCO2 of greater than 10 mm Hg by waveform capnography after 20 minutes of CPR may be considered as one component of a multimodal approach to decide when to end resuscitative efforts but should not be used in isolation.”)

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Article 2:  Inaba K et al:  FAST ultrasound examination as a predictor of outcomes after resuscitative thoracotomy: a prospective evaluation. Ann Surg  2015  Sept;262(3):512-8. 

Prospective study between 10/2010 to 5/2014 of 187 trauma patients undergoing resuscitative thoracotomy  (RT) at LAC-USC, and who received FAST before or concurrent with RT.  Thirty-six other patients (16%) received RT but no FAST; these all died.  Median transport time was 33 minutes.  Mechanism was half blunt, half penetrating.  Half lost vital signs at the scene.  FAST was adequate if able to determine presence/absence of cardiac contractility and pericardial fluid.  Seven FAST exams (4%) were inadequate.   Sustained cardiac activity was regained in 48%, but overall survival was only 3.2%, with an additional 1.6% proceeding to organ donation.  Unclear how long FAST took to perform.  Primary outcome measure was survival to discharge or organ donation.  Cardiac motion on FAST was 100% sensitive and 74% specific for the identification of survivors to discharge and organ donors.  The likelihood of survival if pericardial fluid and cardiac motion were both absent was zero. The thought at JC was that authors were trying to stress the importance of pericardial fluid being associated with potentially higher survival, but in reality, the bright line was presence or absence of cardiac contractility:  no contractility =  no survival.  Not entirely similar to our population, as at USC-LAC stab wounds to the box go immediately to the OR, regardless of initial blood pressure, and therefore these patients were not included in the study.  Additionally, we rarely perform RT on blunt trauma.  Interestingly, 4 blunt trauma patients “survived” (did not specify discharge or donor). Four of the six discharged patients were cognitively intact. 

Authors conclude that FAST represents an effective method of determining those patients who do not warrant the risk/resource burden of RT from those who may survive.  It’s a modality to tell you when to stop (NPV), not a modality to tell you when to start (PPV).

Bottom line:  In this study, if FAST had been used to select patients for resuscitative thoracotomy, all survivors would have been identified and RT rate would have been more than cut in half. 

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Article 3.  Dehganzada ZA et al:  Complete ultrasonography of trauma in screening blunt abdominal trauma patients is equivalent to computed tomographic scanning while reducing radiation exposure and cost. J Trauma Acute Care Surg 2015  Aug;79(2):199-205. 

It’s tempting, right? No radiation, portable, quick, relatively inexpensive, and repeatable....there have been numerous efforts to reduce CTs by using physical examination algorithms + US in blunt torso trauma. But as a 2015 Cochrane review discussed, the overall sensitivity for FAST in blunt trauma is low. Trying to incorporate observation periods is challenging too-it’s easy for a busy trauma service to be overwhelmed.   

This study really released the fury of Stephen Jamieson.  Statistical back-fists, jabs at the inconsistent definitions, and an eventual throw-down of all the conclusions-a sight to behold.

In this 11 year retrospective single center study of 19,128 blunt abdominal trauma patients, 66% initially underwent ultrasound, and 34% CT scan.  A “Complete US of Trauma” (CUST) included 7 abdominal regions:  CUST does not equal FAST.  In the CUST group, initially 4% were “positive”, meaning injury confirmed by exploratory laparotomy or CT.  In the CT group, 7.6% positive.  The study defined false negative US as requiring a laparotomy, except when it defined false negative as having an abnormal CT.   Confusing and suspect. Overnight patients received CT.  However, there were also patients who received CT rather than CUST at surgeon discretion regardless of time of day (especially if CUST was poor quality, patient obese, seat belt injury, if hematuria, if significant abdominal pain without operative indications, or if spinal and/or pelvic fractures were suspected-hmmm, higher risk patients shuttled to CT rather than US?  This will change the test characteristics!)  Sensitivity = TP/TP + FN, or for CUST 199/199 + 86 = 70% using abnormal CT following normal US as the definition of FN.  

Mortality was higher in the U/S group (1.8% vs. 1.2%, p = 0.03, NN2Kill=166).  Mortality differences became insignificant when results were conveniently adjusted for age > 65 years or head injury.  Not clear why they felt this was justified, especially as CT group was sicker and with a higher percentage of head injuries-would expect CT group to have higher mortality.

The authors acknowledged that US is lower sensitivity/higher specificity, but then tried to justify US as a rule-out test.  As Kennedy stressed, it should instead be used as a rule-in test:  useful only if abnormal.

UCSD was averaging 4 trauma activations/day (we get about 10), with overall relatively low injury severity scores and <2% laparotomy rate.  As Harwood said, there may be a low risk population where US would be useful as a screening exam, but this study doesn’t help us figure it out.   Conclusions touting cost and radiation savings are also suspect:  no idea if CT is being used appropriately, and as UCSD now has dedicated ultrasonographers for this protocol 24/7, difficult to assess true costs.

Bottom line:  CT is still the winning modality for serious blunt abdominal trauma.  And don’t mess with Jamo.

O2 in MI; O2 Delivery in Hypoxemic Respiratory Failure; ROSC and the Cath Lab.

Journal Club Synopsis September, 2015:  O2 in MI; O2 Delivery in Hypoxemic Respiratory Failure; ROSC and the Cath Lab.

Many thanks to Mike Marynowski for hosting (skyline views and an outdoor big screenTV-what??).  Outstanding synopses by Braden, Elise, Franklin, Dr. Ede, Rachel and Dr. Burns.

Article 1:  We should think of oxygen as a drug, with benefits and harms. There has been suggestion since the 1970s that O2 may be harmful in ACS, through the reduction of coronary blood flow,  increase in coronary vascular resistance, and generation of reactive oxygen species. The latest AHA STEMI guidelines give no clear recommendation for O2 therapy in normoxic patients.

Stub D et al. Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. Circulation  2015;131(24):2143-50.   AVOID Trial.

Editorial:  Nedeljkovic ZS, Jacobs AK:  Oxygen for ST-Segment–Elevation Myocardial Infarction Still Up in the Air.  Circulation  2015;131:2101-3.

In this multicenter, prospective, RCT from Australia, 441 normoxic patients with STEMI received O2 (8 L/min by facemask) or no O2, pre-hospital until admission to cardiac care ward.  Primary outcome was MI size as assessed by degree of cardiac enzyme elevation-troponin and CPK.  Secondary outcomes included recurrent MI, arrhythmia, and MI size assessed by cardiac MRI at 6 months.  There was no significant difference in troponin elevation between the two groups, although there was a significant increase in mean peak CPK in the O2 group compared to the no O2 group.  Rate of recurrent MI was significantly higher in the O2 group (5.5% vs. 0.9%, p=0.006).  The O2 group also had a trend towards higher frequency of cardiac arrhythmias (40% vs. 31%) and significantly increased MI size on cardiac MRI.  The kicker was mortality.  Six-month mortality was 3.8 with O2 vs. 5.9 with air (NNtoKill=48).  This was non-significant statistically, but a concerning trend, and engendered significant discussion at JC, especially as the study’s primary outcome was not clinical/patient oriented.  Troponin/CPK elevation are disease oriented outcomes, and very rough surrogates for outcome and prognosis.  Unfortunately, the trial was not powered for clinical outcomes.  Authors are to be congratulated for completing a challenging study involving delayed consent initiated in the field, but statistical methods were controversial, involving “imputation”, or presumption of results when data were missing (statistics on made up data).  The amount of O2 provided was also questioned, as nasal cannula rather than mask is more the norm in the USA.  The accompanying editorial states that the routine use of oxygen for patients with STEMI remains “up in the air”, and the concerning mortality trend led the majority of folks at JC to vote to continue providing routine O2 to this patient population.  Stay tuned:  a large Swedish Registry randomized trial examining this question is currently enrolling patients, and is powered for both morbidity and mortality.

Article 2:  We all love us some BIPAP in respiratory failure due to COPD or CHF, as noninvasive positive-pressure ventilation reduces intubation and mortality rates in these patients.  However, in patients with non-hypercapnic acute hypoxemic respiratory failure (think really bad pneumonia), noninvasive ventilation is associated with high failure rates and particularly high mortality.  Maybe not such a great idea to always reach for the Darth Vader mask...what’s the optimal O2 delivery in acute hypoxemic respiratory failure?

Frat JP, et al: High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure.  N Engl J Med  2015;372:2185-2196.

In this multicenter, open label RCT trial of 310 ICU pts with non-hypercapnic acute hypoxemic respiratory failure, which excluded patients with CHF, asthma, and COPD, patients received 1 of 3 treatments: high flow O2 via nasal cannula (HFNC), noninvasive positive-pressure ventilation, or standard oxygen therapy via face mask.  Respiratory failure criteria were defined, as were criteria for intubation.  Primary outcome was proportion of patients intubated at 28 days; secondary outcomes included all-cause ICU and 90 mortality rates.  Twenty-eight day intubation rates were 38% vs. 50% vs. 47%, respectively; a non-significant trend favoring HFNC.  Ninety-day all-cause mortality was significantly lower for HFNC (12% vs. 28% vs. 23%, NNT=6 or 9).  ICU complication rates did not significantly differ between the three groups.

This study supports the superiority of HFNC in acute hypoxemic respiratory failure, compared with noninvasive ventilation or O2 by face mask.  Noninvasive ventilation performed poorly.  Caveats?  This was an ICU, rather than an ED study.  We don’t see many patients with respiratory failure from pure pneumonia.  However, for this patient cohort, consider high-flow O2 via NC instead of BIPAP.  Yes, we have it in the ED.  Need to dial in flow rate (max 60 liters/minute, this study used 50 L/min), and FiO2.  HFNC is comfortable, well tolerated, and allows patient to eat, drink, and communicate. 

Article 3:  You have ROSC after cardiac arrest!  Patient is hemodynamically optimized and cooling, O2 sat is 94%, and the ECG shows.....not a STEMI L.    2010 AHA guidelines state: “consideration of emergent coronary angiography may be reasonable even in the absence of STEMI” in post-arrest patients.  Should you push for cardiology to take them to the cath lab?

Kern KB, et al: Outcomes of Comatose Cardiac Arrest Survivors With and Without ST-Segment Elevation Myocardial Infarction: Importance of Coronary Angiography.  JACC Cardiovasc Interv  2015 Jul;8(8):1031-40. 

In this retrospective review of 746 comatose post-cardiac arrest patients including 198 with STEMI (26.5%) and 548 without STEMI (73.5%), overall survival was greater in those with STEMI compared with those without (55% vs. 41%; p = 0.001). However, in all patients who underwent immediate coronary angiography, survival was similar between those with and without STEMI (55% vs. 58%; p = 0.60). A culprit vessel was more frequently identified in those with STEMI, but also in one-third of patients without STEMI. The majority of culprit vessels were occluded (STEMI, 93%; no STEMI, 69%).  An occluded culprit vessel was found in 74% of STEMI patients and in 23% of non-STEMI patients. Among cardiac arrest survivors discharged from the hospital who had presented without STEMI, coronary angiography was associated with better functional outcome (93% vs. 79%; p < 0.003, NNT=7).

Basically, this study attempts to show that early coronary angiography is associated with improved outcomes, regardless if STEMI is present on ECG.  An occluded culprit vessel was found in 23% of non-STEMI patients who went to cath lab.  This is aligned with prior studies demonstrating up to 50% of patients with ROSC after cardiac arrest having an acutely occluded coronary vessel, not well predicted by the presence of STEMI on ECG (Spaulding, 1997, NEJM).

So what’s the problem?  First, this was a study of 6 hospitals, with widely variable cath lab protocols, and additional individual cardiologist variability.  Coronary angiography was only performed in 45% of non-STEMI patients.   The non-STEMI patients who went to cath lab are likely very different from those who didn’t-the fatal flaw of this study.  It’s also a retrospective registry trial, therefore lots of other limitations.  A quarter of the non-STEMI patients who went to cath lab went in a delayed fashion, which has been shown to be of no significant benefit in stable, asymptomatic patients (OAT trial NEJM 2006; 2013 AHA STEMI guidelines).  The AHA STEMI guidelines specifically classify PCI of a non-infarct artery at the time of PCI for STEMI as “Class III-harm”; in other words, PCI should be not be driven by an interventionalist’s oculo-occluded reflex.  If the occluded vessels identified in the 23% of the non-STEMI patients are truly culprit, then positive outcomes may be expected, but the study’s conclusions are not supported by its methodology.  How to improve?  Publish the data for hospitals who take all ROSC patients (STEMI and non-STEMI) to cath lab.

CV Potpourri- Low risk chest pain/CHF treatment

Journal Club Synopsis:  ED treatment of CHF.  Early Discharge of Low Risk Chest Pain

Thanks to Andrea and Keith Carlson for hosting, especially for the wicked ping-pong!

Outstanding critiques of the articles by Nathan West, John Paik, Mike Kennedy, Aris Alexander, Katie Burns and Jessica Ede.

1.  Collins, SP, et al:  Early Management of Patients With Acute Heart Failure: State of the Art and Future Directions—A Consensus Document from the SAEM/HFSA Acute Heart Failure Working Group.  Acad Emerg Med 2015; 22:94–112.

Heart failure results in 1 million ED visits annually.  Based on guidelines from national and international cardiology societies, this consensus document from SAEM and the Heart Failure Society of America discusses best practices for the diagnosis, treatment, and disposition of ED patients with acute heart failure (AHF). 

Unfortunately, literature suggests that there is no historical or exam finding with both high sensitivity and high specificity for the diagnosis of AHF.  Prior HF is the most useful historical feature, but the differential diagnosis of dyspnea remains broad even in these patients.  The elusive S3 gallop has the highest LR+, with modest LR+ for the historical features of PND, orthopnea, and peripheral edema, and for the exam findings of HJR and JVD.  Up to 20% of patients with AHF will have no congestion on their ED CXR, especially in late-stage heart failure.  ECG may suggest underlying precipitants for AHF, and A fib has a high LR+ for AHF.  BNP testing is strongly recommended, although levels can be affected by age, gender, weight and renal function, and can be elevated in other conditions causing myocardial stretch such as ACS and PE.  Patients with HF and preserved LVEF have proportionally lower BNP levels.  Ultrasound can be extremely useful, both to identify AHF (better test characteristics than CXR!), and to use IVC collapse index to evaluate volume status. 

Currently, treatment recommendations vary between societies, reflecting in part the need for high quality ED clinical trials with clinically meaningful outcomes.  Using an algorithm to classify patients, both by initial blood pressure and an assessment of volume status, can help to more effectively tailor treatment to the individual patient.  IV loop diuretics are used frequently, but should be started at relatively low doses, e.g. the IV equivalent of the patient’s usual oral daily dose (DOSE trial).  Although still included in some guidelines, nesiritide is not useful, and low dose dopamine has also not been shown to be helpful (ROSE trial).  Especially in patients presenting with elevated BP, first line treatment should include high dose IV nitrates, as these patients usually have a volume distribution more than volume overload problem.  Early non-invasive ventilation in severe AHF is commonly used and associated with improved symptoms and lower rates of intubation.

Morphine is mentioned as an anxiolytic, however benzodiazepines are more generally ordered for this indication.  Starting inotropes and management decisions about patients in cardiogenic shock will usually be made after early consultation with cardiology.  AHF requiring hospitalization is recognized as a fundamental change in the clinical trajectory of a patient with heart failure.  Our hospital treatment does not lead to clear improvement in survival or re-hospitalization rates. 

Currently 80% of patients with AHF are admitted.  Features including renal dysfunction, low BP, hyponatremia, and elevated troponin or BNP have been associated with increased morbidity and mortality.  However, the absence of high risk features does not equate to the patient being low risk and safe for discharge.  While several decision instruments for early discharge of patients with AHF have been derived, there is no accepted, well-validated published tool.  Our ACMC CHF Observation Protocol is an option in selected patients.  Early follow-up and a stable social situation are key factors to the safe implementation of observation protocols.

2.  Mahler S, et al: Performance of the 2-hour Accelerated Diagnostic Protocol Within the American College of Radiology Imaging Network PA 4005 Cohort. Acad Emerg Med  2015;22:452-60.

Bottom line:  This trial of 1,140 ED patients being evaluated for ACS failed to validate ADAPT as a safe early discharge strategy, however questions were raised about the use of revascularization as a valid endpoint.  Differences in patient populations and health care systems may explain the lower sensitivity of ADAPT in this trial, but further studies are needed.

This was a secondary analysis of 1,369 patients already enrolled in a multi-center CTCA trial in 5 tertiary care US EDs.  Data elements were collected prospectively.  Patients were at least 30 yo, with symptoms suggestive of ACS, and either classified as “low risk” or “at risk” by ADAPT, the 2 hour accelerated diagnostic protocol which includes 0 and 2 hour troponins, ECGs, and a TIMI score.  Eligible patients had initial TIMI scores of 0 to 2, and a non-ischemic ECG on presentation. 

Patients designated low risk and appropriate for early discharge by ADAPT have a TIMI score of 0, ECG with no new ischemic changes, and negative troponin x 2. 

Primary outcome was the rate of MACE (cardiac death, MI, or coronary revascularization) within 30 days of presentation.  Secondary outcomes included the rate of patients identified as safe for early discharge, and abnormal stress or CCTA testing.

Of the 1,140 patients with complete biomarker data, 2.7% had MACE.  ADAPT identified 551 of 1,140 (48%) as low risk and appropriate for early discharge; 5 of these 551 (0.9%, 95% CI=0.3% to 2.1%) had MACE at 30 days.  Of these 5 patients, there were no deaths, one patient with MI, and 5 with revascularizations.  Sensitivity of ADAPT for MACE within 30 days was 84%.  Serial troponins alone were 32% sensitive for MACE. 

These findings conflict with prior very positive studies of the ADAPT strategy. In part this may be due to the inclusion criteria, as the umbrella CCTA trial excluded patients with elevated troponin, whereas prior ADAPT validation studies included patients with elevated troponins who would be identified as “at risk” by ADAPT, thereby boosting the sensitivity of those studies.   In addition, 4/5 of the low risk patients with MACE had revascularization procedures without MI.  The relevance of revascularization as an outcome measure is uncertain.  As discussed at Journal Club, the revascularization rate for patients in the USA is high, and validations of ADAPT in other parts of the world demonstrated much lower percentages of revascularizations in their MACE composite endpoints.  It was also discussed that only 1 of the 5 “missed MACE” patients really appeared to be a true miss.

There were a number of low risk patients with abnormal CCTA or stress testing in this study.  Authors emphasize the importance of early therapy in these patients, reinforcing the need for close follow-up for patients discharged who do not receive higher level diagnostic testing in the ED.

3.  Mahler S, et al: The HEART Pathway Randomized Trial: Identifying emergency department patients with acute chest pain for early discharge.  Circulation Cardiovascular Quality and Outcome  2015:8;195-203.

Bottom line:  Use of the HEART Pathway (HEART score + 2 negative troponins) allowed for a higher rate of early discharge from the ED without stress testing compared with usual care in this study of low risk ED chest pain patients.  No patients identified for early discharge had missed MACE at 30 days.

In this study of 282 ED patients with symptoms concerning for ACS, patients were randomized to either the HEART Pathway or Usual Care.  The HEART score includes history, ECG, age, risk factors, and troponin, and a HEART score of 0 to 3 is consistent with low risk.  The HEART Pathway consists of the HEART score + troponins at 0 and 3 hours.  Patients with low risk HEART scores and negative troponins were recommended for discharge without further cardiac testing.  Usual care was based on ACC/AHA guidelines.  The primary outcome was rates of objective cardiac testing (stress or angio) and secondary outcomes included length of stay, early discharge, cardiac related ED revisit, admission, and MACE, all assessed at 30 days. Eligible patients were age at least 21 yo, being evaluated for ACS with ECG and troponin.  Exclusion criteria included STEMI, instability, or additional serious acute medical problems.

Compared with usual care, use of the HEART Pathway significantly decreased objective cardiac testing at 30 days by 12% (69% vs 57%), length of stay by 12 hours, and increased early discharges by 21%.  MACE occurred in 6% of patients overall.

No patients identified for early discharge in either HEART Pathway group or usual care group had MACE at 30 days.  It’s important to note that the primary outcome was objective cardiac testing, rather than a comparison of rates of MACE in the 2 groups, and the study was not powered to detect differences in MACE.  However, the safety of the HEART Pathway has been consistently validated in other trials.

Decision instruments such as the HEART score are useful to support medical decision making, both when having conversations with patients about risk and their disposition preference, and when documenting in the medical record.   Although “gestalt” can be reliable for more senior clinicians, decision instruments in general are particularly useful as an explicit reminder of high-risk features, and help build more reliable heuristics.  

Wellness Topics

Thanks to Dr. John Principe and Dr. Dan Girzadas for hosting the January 2015 Journal Club at Dr. Principe’s WellBeingMD Center.  Appropriately, the topic was wellness, and the delicious and nutritious dinner prepared by the Center’s chef and staff was enjoyed by all.  Outstanding presentations by Drs. Parker, Cirone, Burt, Bamman, Negro and Nejak, as well as the Usastrana demo by Dr. Negro-Namaste.

1.     Shanafelt TD, et al: Burnout and Satisfaction With Work-Life Balance Among US Physicians Relative to the 
General US Population.  Arch Intern Med 2012;172:1377-1385.   

Burnout, including loss of enthusiasm, cynicism, and low sense of accomplishment, has negative professional and personal consequences.  This survey of US physicians from all medical specialties attempted to evaluate rates of burnout and satisfaction with work-life balance.  Of 27,276 physicians invited to participate, 7288 completed the surveys.  Using the Maslach Burnout Inventory, 46% of all physicians reported at least one symptom of burnout, with Emergency Medicine at the top of the list (>60% of EM physicians), followed by Family Medicine and Internal Medicine.  Compared with a sample of US working adults, physicians were more likely to have symptoms of burnout and be dissatisfied with work/life balance.  Limitations:  there was only a 27% overall response rate, and only 333 emergency physicians.  One always has to question motivation of survey respondents, and wonder about the large group who did not respond.

So, how do we avoid/mitigate burnout?  Talk to Cirone, he has it all worked out.  Other voices in the room suggested:  Develop a niche-do something professionally beyond just working your shifts.  Nurture your other passions, outside interests, and relationships.  Retain your sense of humanity; wonder at the amazing intimacy our patients, true strangers, allow us.  You’ll forget more medicine than your patients will ever know-give them a break.  Teach students and residents:  medical, nursing, paramedic.  I didn’t see the movie, but Sam Lam alluded to “Frozen”, and the importance of being pushed to capacity and a little beyond our comfort zone.  Finally, maybe at some point, for some, burnout isn’t bad, but a message that it’s ok to leave, and pursue other interests.

2.     Hall KN, et al:  Factors Associated with Career Longevity in Residency-Trained Emergency Physicians.  Ann Emerg Med 1992;21:291-297.  

This 23-year-old retrospective cohort study of EM residency graduates from 1978-1982 used a mailed (what’s the internet?) questionnaire to identify factors associated with leaving the specialty.  There were 539 responses for a 63% response rate.  Factors associated with remaining in emergency medicine were board certification, working with residents during their EM practice, as well as having an income of more than 100K/year.   Ten-year professional survival rate was 85%.  EM physicians who had left the field were more likely to be board certified in another specialty, and less satisfied with EM as their initial choice of specialty.

A reminder of how far we’ve come.  Less than 40 years ago, during these 4 early years of our specialty, there were a total of only 858 EM residency graduates.  Significant numbers of EM physicians were board certified in another specialty.  It’s difficult to know the reasons those early emergency physicians chose training in EM, and there was no such thing as a medical school rotation in EM.  As of 2014, there were 170 emergency medicine programs, with 1,786 EM residency positions offered in the match.   We have 27 types of EM fellowship training, with EM residency groups and faculty advisors to help guide medical students in their choice of career.   An EM physician will become president of the AMA in June of 2015.

The first sentence of the article’s discussion is telling:  “Previous reports have questioned the ability of emergency medicine to survive as a specialty due to the amount of stress this type of practice generates.”  While no one would deny the stress of our jobs, our specialty has grown and thrived.  It would be hard to extrapolate findings from this study to today’s population of emergency physicians.

3.     Wang X, et al:  Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies.  BMJ  2014;349:g4490.   

“Eat Food, Not Too Much, Mostly Plants.”  

–Michael Pollan, author of The Omnivore’s Dilemma and In Defense of Food, among others

In this stunning meta-analysis of 16 articles including >800,000 subjects and 4.6-26 year followup, it was revealed that your mother is right-eat your fruits and vegetables.  Each additional daily serving of fruits or vegetables was associated with a decrease in all cause and CV mortality.  No change in cancer mortality-perhaps because cancer is so heterogenous in origin depending on organ, with potential for substantial genetic predisposition?  Limitations include the self-report nature of surveys and poor adjustment for other dietary factors.  Not a strong article; as Harwood mentioned, we might not be nodding in agreement so readily if it was advocating cobra venom rather than something so aligned with our common sense....but hey, go eat a rambutan.

If you’d rather not read the meta-analysis, suggest reading something by Michael Pollan (http://michaelpollan.com/books/).

4.     Cramer, H, et al: Effects of yoga on cardiovascular disease risk factors: a systematic review and meta-analysis.  Int J Cardiol  2014 May 1;173(2):170-83. 

Finally, an article after my own heart chakra.  A systematic review of 44 RCTs with >3,000 patients, evaluating the effects of yoga on modifiable cardiovascular risk factors.  Small improvements in BP, HR, RR, waist circumference, cholesterol and HbA1c were noted.  Not sure if any of these differences would be considered clinically relevant, and there was high or unclear risk of bias in most studies.  Many different types of yoga were studied.  In the end however, when yoga was present, even if only for weeks, there were positive and beneficial effects noted in multiple modifiable CV risk factors.

Transfusion in Critical Illness

Thanks to Dave and Heather Collins for a highly entertaining evening, and to J Beckemeyer, Catherine, Elise, Erin, J Remke and Dr. Febbo for their erudite presentations.

Increasingly, data support a more restrictive approach to blood transfusion.  Think of a blood transfusion as a liquid organ transplant, with added risks of TACO, TRALI and other transfusion related immunomodulation. 

BOTTOM LINE FOR JOURNAL CLUB:  7 is the new 10, and 1 is the new 2.  Transfuse at a hemoglobin of 7 g/dl unless unstable/actively hemorrhaging or having ACS, and give 1 unit of pRBCs at a time.  For ACS, current literature is inconsistent but reviewed article favored the more traditional approach of transfusing to 10 g/dl. 

1.     Villanueva C, et al. Transfusion Strategies for Acute Upper Gastrointestinal Bleeding. N Engl J Med 2013; 368:11-21.

In this single center RCT of 921 patients with acute upper GI bleeding, half were randomized to a restrictive strategy (transfuse when hemoblobin < 7 g/dl) and half to a liberal strategy (transfuse when hemoglobin < 9 g/dl).  Patients were included if >18 yo and evidence of acute upper GIB by hematemesis, melena, or both.   Patients with massive exsanguinating bleeding, ACS, symptomatic PVD, and TIA/CVA were excluded.  They also excluded patients with Rockall scores of zero and hemoglobin >12 (wimpy bleeds).  Randomization was stratified according to presence/absence of cirrhosis.  Transfusions were given 1 unit at a time, with reassessment.  Transfusion could also be given for symptomatic anemia, massive bleeding, or need for surgical intervention.  All patients underwent endoscopy within 6 hours.

Primary outcome of survival at 6 weeks was significantly higher in the restrictive (95%) versus liberal (91%) group.  Risk of further bleeding, adverse events, and rescue therapies were significantly lower in the restrictive group. Patients in the liberal group also had significant early rises in portal-pressure gradient (increases risk of rebleeding).  The only subgroup without a significant mortality difference were patients with advanced cirrhosis.

Why does restrictive strategy work in GI bleed?  Authors posit that transfusion may counteract protective splanchnic vasoconstrictive response caused by hypovolemia.  This increased pressure may impair clot formation.  Transfusion may also induce coagulation abnormalities, and for patients with cirrhosis, increased blood volume can increase portal pressure leading to rebleeding.

BOTTOM LINE:  great study looking at a population that makes us nervous, supporting a restrictive transfusion strategy to improve mortality, decrease rebleeding/adverse events, and conserve resources.  It’s a win/win, but remember that they excluded patients with exsanguinating bleeding as well as those with ACS.  Also, transfusion could be given for symptomatic anemia, massive bleeding, or if need for surgery-important caveats.  Finally, these patients all underwent early endoscopy, facilitating early intervention for ulcer, varices, etc.

 

2.     Holst LB, et al:  Lower versus higher hemoglobin threshold for transfusion in septic shock.  N Engl J Med  2014 9;371(15):1381-91. 

In this multicenter, randomized trial, 998 ICU patients with septic shock were randomized to a lower threshold group (transfuse 1 unit pRBCs for hemoglobin < 7 g/dl) or higher threshold group (transfuse 1 unit pRBCs for hemoglobin < 9 g/dl). 

Patients with stable cardiovascular disease were included, but patients with life threatening bleeding or ACS were excluded.  Patients developing life threatening bleeding, ischemia, or need for ECMO or surgery after enrollment could receive transfusion at discretion of treating physician.  Leukoreduced blood was used in an attempt to mitigate immunomodulatory effects of transfusion.

Primary outcome of death by 90 days occurred in 43% of lower threshold group compared with 45% of higher threshold group (RR 0.94; 95% CI 0.78-1.09).  Rates of ischemic events, severe adverse reactions, and life support requirements were also similar in the two groups.  The lower threshold group received half the total number of transfusions as the higher threshold group.  It’s an ICU, not an ED study, but given our boarding, probably still pretty useful information.

BOTTOM LINE: in ICU patients with septic shock, similar mortality and adverse event rates were observed with a lower transfusion threshold (transfuse for hemoglobin < 7 g/dl), with significant savings in the number of units of blood transfused.

3.     Carson JL, et al: Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J  2013;165(6):964.

Ok, so clear that in GI bleed and sepsis (and from the unfortunately named TRICC trial, for critically ill patients in general) a more restrictive blood transfusion strategy is safe and effective.  The holy grail remains...what about patients with ACS??

In this “pilot trial” of 110 patients with ACS or stable angina undergoing cardiac cath, patients were randomized to receive transfusion for hemoglobin < 10 g/dl (liberal strategy), or to transfusion for symptomatic anemia as well as permitted/not required to receive transfusion for hemoglobin < 8 (restrictive strategy).

Patients with active bleeding, hemodynamic instability, symptomatic anemia at time of randomization, or needing surgery were excluded.

Primary outcome was the composite of death, MI, or unscheduled revascularization 30 days after randomization, and occurred in 11% of liberal group and 25.5% of restrictive group (95% CI 0.7% – 29%).  Death at 30 days was 2% in liberal group vs. 13% in restrictive group (95% CI 1.5% – 21%).  These were not significant differences due to small group sizes/large CI, but trends favored liberal transfusion strategy.  All deaths were classified as cardiac.  Most other adverse cardiac outcomes were more frequent in restrictive group.

This study had problems.  First, it’s a small study, so can’t draw practice-changing conclusions.  Also, the restrictive group was on average 7 years older than the liberal group.  Patients with ACS are different from those with stable disease undergoing cath-really these are 2 separate populations.  The study was terminated prior to completing their planned enrollment of 200 patients...not clear why...they do some hand waving about having enough information to plan a larger trial.  Interestingly, the most frequent reason for protocol violation was insufficient time to administer transfusion prior to discharge in the liberal group (wait Mr. Smith...don’t call a taxi yet, let’s give you an [unnecessary?] transfusion).

BOTTOM LINE:  Not a great study, but trends support a more liberal strategy (transfuse for hemoglobin < 10) in patients with ACS. Existing literature for this population is inconsistent, equipoise exists, and a large, well done study still needs to be performed.

Evaluation of the C-spine in Trauma

Journal Club Synopsis-Evaluation of the Cervical Spine in Trauma-September 2014

Many thanks to Trushar and Rupal Naik for hosting, and to Adam, Stephen, Theresa, Natalie K, John P and John M for their insightful analyses.

We see a lot of patients with neck pain after MVCs.  Many can be safely cleared clinically using NEXUS or the Canadian C-spine decision instruments.  When imaging is performed, it’s usually CT rather than Xrays.  We’ve all seen trauma patients hang out for hours/days in c-collars after CT, awaiting either re-assessment when alert, or an MRI.  C-collars cause complications, and this can be a resource utilization challenge.  So, the question on the table...is CT enough?

1. Resnick S, et al:  Clinical Relevance of Magnetic Resonance Imaging in Cervical Spine Clearance A Prospective Study. JAMA Surg 2014; doi:10.1001/jamasurg.2014.867 Published online July 30, 2014.

Just saying, this is the best trial of the three.  It’s a prospective observational study from USC/LAC of 830 awake/alert adults after blunt trauma who had midline tenderness and/or focal neuro deficits (so can’t be cleared with NEXUS) and a negative C-spine CT.  Kenji Inaba of EM:RAP fame is second author.  Primary outcome was clinically significant C-spine (CS) injuries, defined as requiring surgery or a halo.  Overall, 164 (20%) CS injuries were diagnosed, and 23 (3%) were clinically significant.  All clinically significant CS injuries were detected by CT.  CT missed 9% of injuries, i.e., 15 of 681 patients (2.2%) had normal CT but new finding on MRI.  However, none of these injuries required surgery, halo, or change in management based on MRI.  For detecting any CS injury, CT sensitivity was 91% and specificity was 100%.  For clinically significant CS injury, CT sensitivity and specificity were both 100%.  Patients with distracting injuries were excluded.

Limitations:  MRIs were ordered at discretion of attending surgeon or neurosurgeon.  Follow-up was only until day of discharge.  They used advanced 64-slice CT scanners.  Of the 15 patients with normal CT/abnormal MRI, only 6 had neurologic symptoms, and these were all sensory deficits.  Clinically significant injury  in patients with motor deficits were all identified on CT, leading authors to state that MRI “may be indicated” in patients with motor deficit and normal CT scan.

2. Russin JJ, et. al.: Computed tomography for clearance of cervical spine injury in the unevaluable patient. World Neurosurg. 2013;80(3-4):405-413.  

Ok, what about the “unevaluable” blunt trauma patient, defined as GCS < 15, distracting injuries, and/or altered/intoxicated?  This is a higher risk population for cervical spine injury, and there’s a lot of low quality literature out there about this group of patients, with conflicting recommendations.  This was an analysis of 13 articles including patients with negative C-spine CT who also underwent MRI, however only 9 studies included patient management data.  In these 9 studies, 115 of 855 patients with abnormal MRI + negative C-spine CT had change in management.  Three of 855 (0.35%) patients required surgical stabilization (NNT=285), and 57/855 (7%) received “extended time in C-collar.”  

Limitations:  Why were patients chosen to receive an MRI...who knows?  All three of the patients requiring surgical stabilization were from 2 studies by the same author....hmmm.   What’s the meaning/significance of “extended time in C-collar?”  “Missed injuries” had variable treatment depending on the study. Several studies used older generation CT scanners, several were retrospective. There was limited followup/clinical information available for many of these studies. This is a descriptive review, and does not include the statistical methodology of a meta-analysis.  It’s also always imperative to remember the garbage in/garbage out philosophy...if the included studies
(even in a meta-analysis) are of poor quality, then conclusions are dubious. Authors conclude that
CT alone is inadequate in this patient population.  The room was not impressed.

3. Panczykowski DM, et. al.: Comparative effectiveness of using computed tomography alone to exclude cervical spine injuries in obtunded or intubated patients: meta-analysis of 14,327 patients with blunt trauma. J Neurosurg. 2011;115(3):541-549.  

Another attempt to look at the literature on the “unevaluable patient”, this time specifically blunt trauma patients who were obtunded or intubated.  This was a meta-analysis of 17 cohort trials with 14,000+ patients, 12,700+ with negative CT.  Compared to MRI, CT missed 7 unstable injuries (0.05%).  One patient received a halo, 3 received surgical stabilization, 3 were treated with collars (NNT=3000), sensitivity/specificity of CT both >99.9% (95% CI 0.99-1.00).  Much better methodology than Russin, and included only studies with modern CT slice thickness and those reporting patient outcomes.  

Limitations:  Included 10 retrospective trials, and missing significant amount of descriptive demographic data.  There were a variety of reasons listed for ordering MRI, and 1,573 patients didn’t receive MRI.

Final thoughts...in the room, no love for Flex/Ex films.  Reasonable agreement based on discussion, JC articles and background articles that even after negative CT, MRI is important in patients with motor symptoms, and should be considered in the elderly, especially as advancing age is associated with cervical spondylosis.  Other high risk groups include patients with rheumatoid arthritis/ankylosing spondylitis, as these arthritides predispose to cervical spine fracture, and also to ligamentous injury such as atlantoaxial instability. Mechanism and degree of point tenderness will always play a role in imaging decisions.  Evidence for the management of the “unevaluable patient” is still inconclusive, although the third article (Panczykowski) is reassuring.

Sepsis Treatment Update

Many thanks to Mike and Lisa Anderson for hosting, and to Sola, Dr. Febbo, Jessica, Trale, Adam B. and Natalie H. for their erudite presentations.

Background:  The 2001 NEJM study by Rivers established a new standard for sepsis care, demonstrating a significant improvement in severe sepsis/septic shock mortality using a protocol driven care algorithm during the initial 6 hours of resuscitation.  Since then, there has been ongoing discussion regarding which components of the algorithm are the most impactful.

Bottom line:  Sepsis rates have decreased by nearly 50% since 2000, and this is likely a real finding, in part due to increased awareness and more aggressive treatment of sepsis, as well as to other improvements in critical care. The ProCESS trial reinforces the 4 most crucial elements of successful sepsis management:  early recognition, early and adequate IV fluids, early IV antibiotics, and clinical reassessment of circulation.

Article 1:  Kaukonen K, Bailey M et al.  Mortality Related to Severe Sepsis and Septic Shock Among Critically Ill Patients in Australia and New Zealand, 2000-2012. JAMA.2014;311:1308-1316.

Editorial response:  Iwashyna T, Angus DC.  Declining Case Fatality Rates for Severe Sepsis:  Good Data Brings Good News with Ambiguous Implications.  JAMA.2014;311:1295-1297.

This retrospective observational study and accompanying editorial describe the changes in mortality for severe sepsis with and without shock in 101,064 patients from 171 ICUs in New Zealand and Australia between 2000 and 2012.  The primary endpoint was hospital outcome (mortality and discharge home, to other hospital, or to rehab facility).  Absolute mortality in severe sepsis decreased over this time period from 35% to 18.4%, for an annual average decrease of 1.3%.  Interestingly, mortality also decreased at a similar rate in non-septic ICU patients over this time period.  The annual rate of discharge to home was significantly greater in severe sepsis patients compared to patients with non-sepsis diagnoses. 

As discussed in the editorial, reports of changes in disease incidence or mortality can be misleading and instead reflect increased disease awareness and more liberal testing.  This study demonstrated robust methodology by using consistent international consensus definitions of sepsis over the time frame of the study, prospectively gathered data, and by attempting to control for confounding variables, all lending strength and veracity to its conclusions.  This study points out the importance of taking into consideration overall improvements in care when evaluating new therapies, as a new drug’s “benefit” may be inflated due to an ongoing independent positive trend in outcomes.  Also, short-term mortality by itself is an inadequate outcome metric, as a reduction in short-term mortality may come at the expense of trade-offs in morbidity and mortality.  See Katie Burns for diagrams and an interpretive explanation.

Article 2:  The ProCESS Investigators.  A Randomized Trial of Protocol-Based Care for Early Septic Shock.   NEJM March 18,2014. 

Editorial response:  Lily CM: The ProCESS Trial-A New Era of Sepsis Management. NEJM. March 18, 2014.

ACMC was an enrollment center for the ProCESS Trial, a non-blinded RCT of 1341 patients with septic shock, comparing 3 arms of care:  EGDT (Early Goal Directed Therapy, Rivers algorithm with mandated central line and central hemodynamic monitoring, specific physiologic targets); less aggressive protocol based care (no mandated central line, emphasis on clinical assessment of perfusion); or treating doctor’s “usual care.”  The primary end point was 60 day in-hospital mortality.  Secondary outcomes included longer-term mortality and organ failure/need for organ support.

At 60 days, mortality was 21% in the EGDT group, 18.2% in the less aggressive protocol group, and 18.9% in usual care group.  Protocols were not superior to usual care, and the EGDT protocol was not superior to the less aggressive protocol.  There were also no significant differences in any secondary outcomes, except for a higher need for new dialysis in the less aggressive protocol group (6%) than in the EGDT (3.1%) and usual care (2.8%) groups.

In the initial 6 hours of care, IVF and pressor rates did vary between groups (most IVF in the less aggressive protocol group, more pressors in both protocol groups than in usual care group).  More patients in EGDT group than in other 2 groups received inotropes and blood transfusions.  Antibiotics and steroid use were similar across all groups.

Discussion at JC:  The types of fluid/pressor were not specified, and neurologic outcome was not measured (although percentages of patients discharged to home were similar in the 3 groups).  Patients in both of the protocol groups basically had their own resuscitation doctor for 6 hours as emergency physicians were on call to come to the hospital and provide dedicated care for these 2 groups of patients during the initial 6 hours of the study.  This may reflect even better on the usual care group’s outcomes.  For Febbo, interesting that the group receiving the most crystalloid also had the highest renal failure rate....hyperchloremic metabolic acidosis from high volume Normal Salineàrenal failure??

Although institutions enrolling patients in ProCESS were not supposed to be actively using a sepsis protocol prior to becoming involved in the trial, 70% of participating institutions did have an existing sepsis protocol.  All groups in ProCESS received on average more than 2 liters of IVF prior to randomization, and 76% of patients received antibiotics prior to randomization, reflecting knowledge of EGDT in physicians treating “usual care” patients.

The 18% mortality rate in the “usual care” group of ProCESS is a dramatic improvement in baseline mortality compared with the 46.5% control group mortality in Rivers’ trial.   General improvements in critical care have also likely been impactful, including more liberal transfusion thresholds, lung protective ventilation strategies, and moderate glucose control.

So, do we need sepsis protocols at all?  Critical care resuscitation is complex.  Especially for residents and physicians with infrequent experience treating sepsis, protocols provide useful reminders of treatment goals and therapies.   Moving forward, the traditional EGDT protocol will likely evolve, with less pressure to insert central lines and measure CVP/ScvO2 unless the patient requires vasopressors.  However, reassessing perfusion using serial lactates, Shock Index, and clinical parameters including urine output and mentation remains critical. 

Treatment of Acute Appendicitis-Antibiotics versus Surgery

Many thanks to Sheila and Ron Bonaguro for hosting, and to Catherine, Kasia, Katie B, Erin, Jen B and Lindsay for their excellent discussion of the articles.

As background, there have been numerous low quality studies published dating back to 1959 raising the question of treating acute appendicitis with antibiotics rather than surgery.   This journal club analyzed a meta-analysis of 4 studies (Varadhan), a Cochrane systemic review of 5 studies (Wilms) and probably the best original study on the topic  (Vons).  Surgery is not without risk, and the goal of JC was to evaluate if available literature supports antibiotics as a safe, curative strategy for acute appendicitis.  NB, all literature discussed dealt only with adult patients.

Overall Bottom Line:  The strategy of primary antibiotic treatment appears safe, and may obviate the need for surgery in some patients with acute appendicitis, but at least a quarter of patients will still go on to need surgery within the next year.  Consensus in the room was that for healthy adults, surgery is the preferred treatment.  One contrarian (EK) prefers antibiotics.  For a subset of patients who are poor surgical risks, it would be reasonable to engage the patient/family in patient centered decision making regarding the option for antibiotic treatment.

Future:  there are 2 ongoing prospective trials of antibiotics for appendicitis (APPAC and NOTA), which will likely provide higher quality data down the road.

1.  Varadhan KK, Neal KR, Lobo DN:  Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis : meta-analysis of randomised controlled trials. BMJ  2012; 2156:1–15. 

This meta-analysis illustrates the “garbage in-garbage out” phenomenon of meta-analyses.  This should be an extremely high level methodology for evaluating literature on a topic, but if the trials evaluated are low quality, then the meta-analysis conclusions will be very limited.  Authors evaluated 4 RCTs, with a total of 900 patients (approx half who received antibiotics and half surgery), and concluded that antibiotics are both “effective and safe as primary treatment for patients with uncomplicated acute appendicitis.”  While the antibiotic strategy appeared safe with regards to complications such as perforation, peritonitis and wound infection, 37% of patients receiving antibiotics ultimately required surgery for appendicitis within the following year...not so effective.  One issue with the studies was the variable (or no) imaging used to diagnose appendicitis, calling into question the accuracy of the diagnosis of appendicitis.  If some patients labeled appendicitis didn’t have appendicitis, antibiotics would end up looking very effective.  Overall a number of comments were made about the poor quality of the included studies, including the significant cross-over between groups in one study,  enrollment only of males in another, and significant followup issues.  And, as Chintan pointed out, our established intervention, surgery, is safe and effective (post-op complication rate 9-11%, 10 year adhesion/obstruction rate 3%); we’re not looking for an alternative to a dangerous or inadequate intervention. 

2.  Wilms IM, de Hoog DE, de Visser DC, Janzing HM. Appendectomy versus antibiotic treatment for acute appendicitis. Cochrane Database Systemic Review. 2011;11(11).

So, a plug for Cochrane reviews.  They are usually very high quality, and include a “plain language summary” which provides a quick and dirty conclusion about the topic.  In this review of 5 RCTs/quasi RCTs on antibiotics for acute appendicitis, they performed a non-inferiority analysis to evaluate if antibiotics are as effective as surgery in acute appendicitis.  It included some of the same trials as the meta-analysis.  Total of 901 patients; 73% of patients treated with antibiotics compared to 97% of patients receiving surgery were cured within 2 weeks without major complications at one year.  Study quality was low to moderate, with variability in diagnostic evaluation and use of prophylactic antibiotics.  Due to the pre-defined non-inferiority margin and overlap of confidence intervals for the outcome measures between the 2 groups, their conclusion is that surgery remains the standard treatment for acute appendicitis.  Antibiotics might be ethically studied as a treatment arm in a RCT, or considered in specific patients where surgery is contraindicated.

Side note about non inferiority analysis....these are often performed in drug company trials as the need is only to show that a new treatment is as effective or at least only marginally less effective than the old treatment.   A rather arbitrary margin of non-inferiority is defined by the investigators.  Burden of proof is less than in superiority trials.  For more details, please see Dr. Burns.

3.  Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet 2011; 377(9777):1573–9.

This non-inferiority RCT enrolled 243 adults with acute uncomplicated appendicitis at 6 university hospitals and randomized them to surgery or augmentin x 8 days.  The study was included in both the meta-analysis and the Cochrane review, and is probably the best single trial out there.  All patients received CT scan for diagnosis.  Primary outcome was post-intervention peritonitis within 30 days of treatment, and occurred in 8% of the antibiotic group versus 2% of the surgery group.  In the antibiotic group, 26% of patients had recurrence of appendicitis and required appendectomy between 1 month and 1 year.  Authors concluded that antibiotics were not non-inferior to appendectomy for acute appendicitis, and that surgery remains the gold standard treatment for acute uncomplicated appendicitis.  There were no significant differences between the 2 groups for postintervention complications.  Interestingly, presence of fecalith was predictive both of complicated appendicitis in surgery patients as well as antibiotic failure in the medical group (fecalith = bad).  Plenty of issues with this study as well-no discussion of timing of surgery, all surgery patients also received pre-op antibiotics, and 18% of patients diagnosed with “uncomplicated appendicitis” by CT in the surgery group had complicated appendicitis with peritonitis identified in the OR.  One year followup was missing for 10% of patients.

Lipid Rescue Therapy in Overdose

Journal Club Synopsis November 2013

Lipid Rescue Therapy in Overdose

Many thanks to Abhi and Mala Katiyar for hosting and for the delicious south of the border feast!

Outstanding synopses, analysis, and additional review of the topic by Natalie K, Theresa, John P, Nick, Brian F, and Katie I.

Introduction:

Journal Club at the home of a toxicologist calls for a tox topic...in this case the use of lipid emulsion therapy to treat overdose.  IV lipid emulsions are usually thought of as part of nutritional support (TPN), but case reports of lipid emulsions used as rescue therapy for acute cardiotoxicity from lipophilic drug overdose in humans have been published since 2006.  We’ll call it LRT, or lipid resuscitation therapy moving forward, after the American College of Medical Toxicology guidelines.

Which overdoses?  Most compelling literature in overdose from local anesthetics, (LA) especially bupivacaine.  Also used in other lipophilic drug overdoses including calcium channel and beta blockers, TCAs and other antidepressants.

Mechanism?  3 are proposed:  enhancement of myocardial fatty acid transport  (preferred energy substrate of the heart), expanded intravascular lipid phase or “lipid sink” that alters the volume of distribution of the lipophilic toxin, and restoring cellular calcium transport/function.   Nobody knows for sure.

Risk?  Lipemia (who cares, except temporarily renders some lab results invalid), also possible acute lung injury although low incidence of this in patients receiving nutritional lipids, and critically ill patients after overdose already predisposed to acute lung injury. Need more experience to define scope and degree of risk.

When to use?   Great question.  American College of Medical Toxicology has a guideline that states “there are no standard of care requirements to use, or to choose not to use, LRT.  However, in circumstances where there is serious hemodynamic or other instability from a xenobiotic with a high degree of lipid solubility, LRT is viewed as a reasonable consideration for therapy, even if the patient is not in cardiac arrest.”  This actually is a protective document, allowing clinicians the choice of using/not using without declaring a medicolegally binding standard of care.  AHA 2010 ECC guidelines describe the use of LRT for specifically for LA toxicity.  There are reports of patients responding even after prolonged (up to 52 minutes) of cardiac arrest with LA toxicity.

Dose?  All over the place in the case reports...boluses, drips, repeat boluses.  The American College of Med Tox guidelines recommend 1.5 ml/kg bolus of 20% lipid emulsion over 2-3 minutes IV followed by infusion at a rate of 0.25 ml/kg/minute, with shortest duration of treatment possible until hemodynamic stability restored.  The room at JC agreed that using in unstable patients (not just those in overt cardiac arrest) seems reasonable, and LRT should be initiated immediately in LA toxicity.  There was some support for earlier administration in other overdoses, but concern that early LRT might delay treatment with more accepted therapies, and giving in anticipation of instability may result in unnecessary treatment and possible unnecessary complications.  It is reported that in bupivicaine toxicity, epinephrine administration is associated with a negative outcome, and reduces the efficacy of LRT (maybe because epi irritating to the heart?).  Therefore, as epinephrine hasn’t been shown to help in cardiac arrest anyway, consider avoiding epi or giving a smaller dose in the patient with a LA overdose.

Article 1:  Bologa C, et al.  Lipid Emulsion Therapy in Cardiodepressive syndrome after Diltiazem Overdose-a case report.  Am J Emerg Med. 2013;31:1154e3-1154e4.

Case report of 81 yo female who ingested 5.7 gm of diltiazem in a suicide attempt.  Even after gastric lavage, charcoal, calcium, hyperinsulin/euglycemia, epi drip and aggressive IV fluids patient remained hemodynamically unstable with a Mobitz II second degree AV block.   She received intralipid infusion and become hemodynamically and metabolically stable within 24 hours, and was ultimately discharged home neurologically intact.  Lots of missing information from this case report, but this patient appeared to have a positive outcome temporally related to the intralipid infusion.

Article 2:  Geib AJ, Liebelt E, Manini AF for the Toxicology Investigators’ Consortium (ToxIC). Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse.  J Med Toxicol 2012;8:10-14.

This retrospective chart review described the presentation and management of 9 cases of drug-induced cardiovascular collapse  (cardiac arrest or refractory shock) treated with LRT from 45 centers in 2.5 years.  Five patients (55%) met the main outcome of survival to hospital discharge.  Interestingly there was no significant increase in MAP immediately after LRT infusion (would expect increase in MAP if LRT helps contractility).  A number of possible adverse effects were described, but the scoring system used to assign causality to these events has been faulted as an inappropriate instrument for this purpose.  Again, lots of missing information regarding additional treatments and LRT dosing, no comparison group, and a very small retrospective study.  Also comment that this is likely an incomplete picture of the experience for this number of centers.

Article 3:  Presley JD, Chyka PA.  Intravenous Lipid Emulsion to Reverse Acute Drug Toxicity in Pediatric Patients.  Ann Pharmacother.  2013;47:735-743.

Moving to kids, this article is a brief description of 14 case reports of pediatric patients who received LRT to treat acute drug toxicity (7 cases of LA, 7 from other drugs (Ca channel blockers and other psych drugs).  Thirteen patients did well, one died.  One patient developed hypertriglyceridemia and pancreatitis.  Again, different dosing regimens.

Impressive how well LRT worked in the local anesthetic cases.  Patients received usual ACLS care with successful resuscitation from cardiac instability/cardiac arrest, and in one case resolution of V Tach using only LRT.  As anticipated, the nonanesthetic medication cases were more complicated, and information regarding additional treatment was incomplete.

Sobering that 20 cc of misplaced local anesthetics in 2 teenagers undergoing routine surgeries led to V tach and cardiac arrest.   A plea to be calculate maximum safe doses of local anesthetics, especially in small kids.

Also, point raised that for all of these articles, there is likely significant reporting bias.  Case reports are more likely to be written up and published when they are positive, especially with dramatic outcomes.  A skewed picture results.

EBM teaching point:  You’re not going to find many RCTs in the tox literature.  There are challenges in coordinating trials across multiple centers for what are often sporadic/rare ingestions, and currently there isn’t a good system to organize these research efforts.  Therefore, the level of evidence for many tox questions is low.  A generally accepted hierarchy of levels of evidence is below, and case reports are close to the bottom, but this is what we have to work with for this topic.

Interesting discussion at the end of JC about whether or not we’ve reached clinical equipoise on the question of the use of LRT for LA and other overdoses.  The problem with a drug such as LRT being used without controlled study is that by the time many case reports are published, the genie is out of the bottle.  Consensus in the room was that IRBs would not approve a RCT for LRT in LA use (eg bupivacaine), but that given the weak evidence for LRT in other ingestions (eg calcium channel blockers), there should be further study, ideally through a RCT.  Simply hoping that it might work as a last ditch isn’t a good reason to use it, and medical history is littered with examples of initially popular therapies ultimately shown to have no benefit (or to cause harm).   Even if this is beyond the point of IRB approval for a RCT, it was suggested that a more comprehensive review of national Tox center data would provide a less biased data set than continued publication of case reports.  A plug to call and report all tox cases to Poison Control, even if you are comfortable with management!

Evaluation of Low Risk Chest Pain

Background for the residents: You will be seeing chest pain every day for the rest of your career, and need a straightforward & systematic approach to these patients. The easiest approach is to divide them into 2 or 3 risk categories. Two category system = discharge or admission. Three category system = discharge, chest pain unit, or admission.

If you have a tremendous amount of clinical experience, categorization can be done by clinical gestalt. Otherwise, consider using a decision aid. The HEART score is one of many; expect "new & improved" CP decision aids in the future.



Article 1: Mahler SA, Hiestand BC, Goff DC et at. Can the HEART Score Safely Reduce Stress Testing and Cardiac Imaging in Patients at Low Risk for Major Adverse Cardiac Events? Crit Pathways in Cardiol. 2011;10:128-133.

In this study of registry data, 1070 low-risk ED chest pain patients defined as “low risk CP” by physician assessment and TIMI score < 2 were dichotomized into low vs. high risk “HEART” (History, ECG, Age, Risk factors, Troponin) score groups. Primary outcome was major adverse cardiac events (MACE = death, MI, revascularization) occurring by 30 days. MACE occurred in 0.6% patients with low risk HEART scores compared with 4.2% of patients with high risk scores (odds ratio 8, significant). High risk score was 58% sensitive and 85% specific for MACE. Authors also looked at adding serial troponins to the HEART score. Abnormal serial troponins + high risk HEART = 100% sensitivity to pick up MACE (95%CI 72-100%).

Author conclusion: in low risk chest pain patients, low HEART scores can be used to guide stress testing/cardiac imaging and significantly reduce cardiac testing.

Issues: These are already really low risk patients; only 1.1% of entire cohort had MACE. Low risk HEART score reduces MACE to 0.6%, eg you will still miss 0.5%. Unless you admit everyone, you’ll never get to zero misses. Important societal question concerns our acceptable miss rate. Important to include patient in discussion of risk stratification; personal “acceptable miss rate” will vary among patients. Logistical issues; retrospective registry trial, and 30% of patients were lost to follow-up.

Although serial troponins weren’t part of initial study design, only 2 patients with negative serial troponins had MACE; one went to CABG and the other had sudden cardiac death; could argue that neither of these are true “misses”. Reaffirms importance of serial troponins.

An important caveat about this study: it looked at patients already stratified as low risk, THEN applied the HEART score to help predict MACE and decide who needs stress/cardiac imaging. It was NOT a study of all-comers to an ED who present with chest pain. Authors think of the HEART score like PERC; to be used for additional risk stratification in low risk patients. Finally, this doesn’t address the question of who needs a troponin (low risk vs. no risk).

Bottom line: HEART score useful for new clinicians to help further risk stratify low risk CP patients and decrease ordering of stress tests. Experienced clinicians will likely use gestalt + 2 troponins to reach the same conclusions.

Additional Harwood comments: HEART score of 0-3 = less than 1% chance of MACE with 2 year F/U. HEART score of 0-3 along with a second negative troponin = MACE of 0%. Although it has not been validated prospectively, a heart score of 0 or 1, seems to be safe for discharge with a single negative troponin. HEART score of 4-6 = death/MI risk of 12% in 2 years. These patients would be a candidate for a chest pain unit protocol that accepts intermediate risk patients. HEART score of 7-10 = 65% chance of death/MI (Backus: 2010). Obviously, these patients generally are admitted and will often end up in the cath lab.


Article 2: Ely S, Chandra A, Mani G et al. Utility of Observation Units for Young Emergency Department Chest Pain Patients. JEM 2013;44:306-312.

This retrospective observational study evaluated outcomes of 239 patients ≤ 40 yr old enrolled in an ED observation unit due to suspected ACS. Enrollment required ECG without ST changes, negative trop, normal VS and no dysrhythmias. Primary outcome: to evaluate the rate of abnormal stress tests associated with significant CAD. Five patients had positive stress tests. One additional patient had troponin elevation and a negative cath, but was labeled as +MI. Stress testing identified one patient with intervenable ACS. There was an 80% false positive stress test rate. At one year followup, 2 MI and 1 PCI for overall adverse cardiac outcome rate of 0.8% (95% CI 0.1-2.5%). Author conclusion: observation and stress testing should not be routinely performed in this demographic unless other high-risk features are present.

Issues: didn’t consider cocaine, also didn’t identify why 1/3 of patients didn’t receive stress tests. Nine stress tests were “indeterminate”, without further testing or good followup. Overall lost to followup = 21%.

Bottom line: due to limitations/lack of followup, may not be practice changing, but reinforces results from other studies that stress testing in young CP patients has very low diagnostic utility, with high false positive stress test rates (leading to more unnecessary testing, cost, complications).


Article 3:Shah BN, Balaji G, Alhajiri A, et al. Incremental Diagnostic and Prognostic Value of Contemporary Stress Echocardiography in a Chest Pain Unit Mortality and Morbidity Outcomes From a Real-World Setting. Circ Cardiovasc Imaging. 2013;6:202-209.

Last and least. This retrospective study evaluated outcomes in 811 patients admitted to a chest pain unit with ≥ 2 cardiac risk factors and suspected ACS but nondiagnostic ECG and negative 12 hour troponin who received stress echocardiogram (SE) within 24 hours. Primary outcome was the accuracy of SE for predicting mortality/MI. At one year, 2% rate of death or MI; 0.5% of patients in normal SE vs. 6.6% of patients in abnormal SE group died or had MI. No difference in 30 day re-admission rates between normal/abnormal SE groups. Author conclusions: stress echos are awesome.

Interesting that these were not low risk patients (had cardiac risk factors). 50% of patients received ultrasound contrast agents (not typical practice). Excellent followup (97% followed up at least one year)

Harwood comment: Shah found if patient had normal SE, they had 0 deaths @ 6 month & about 1%/yr for the next 3 yrs. Remember, in Shah's study his pts with a (+) stress ECHO had a 16% death rate after 3 yrs. Mean age was 63 this was a sicker population that is seen in most USA CT angio studies. In Litt's study of 1400 pts, (NEJM 2012) mean age was 49. There were zero deaths @ 30 days.

Big question and fatal flaw: how does this study help us? As Erik stated, for any test, you want to know what information it provides above and beyond what we already know. No demographic information is provided in order to compare patients with abnormal and normal stress tests, and therefore we can’t know if the SE is providing any additional prognostic information. Erik contacted the senior author, who responded but stated that the requested information was not available. Hmmmm.

Additional Harwood comments:

--If the patient has a normal coronary CT angiogram, it appears as though the only a 1% chance of having a MACE the next 5 years. (see March journal club)

--Traditional teaching is that Stress ECHO has 15% False (+) rate & 15% False (-) rate. This is based on studies where all Pt's get Stress & caths (i.e., a very high pretest prob group of CP pts)

Workup for SAH

Journal Club Synopsis: Subarachnoid Hemorrhage (SAH): Do We Still Need the LP?

Thanks to Lisa and Ted Toerne for hosting and for the ridiculous Smoque BBQ, and to presenters Lindsay, Beau, Natalie, Pikul, J Cash, and Brian for their thoughtful critiques.

Background: Headache is the chief complaint for 3% of ED visits. Mixed in with all the benign headaches are 3-4% of patients with headache + normal neuro exam who have serious pathology. One elusive serious diagnosis is the “sentinel bleed” of SAH. Traditional teaching states that a negative CT is not definitive, and debates rage on about how many hundreds of LPs we perform to identify a sentinel SAH. We do plenty of other high volume low yield tests in order to identify rare but life threatening disease (may I have another ECG please), but even putting aside the discomfort and time requirements of LP, there are potential downsides (post LP headache, the rare spinal hematoma/abscess, and the risk of false positive “bloody taps” leading to further unnecessary testing). With the publication of the Perry article in 2011, the question was raised yet again: when considering SAH, is current CT technology finally sensitive enough to obviate the need for LP after a negative CT?

Article #1: Presenters: Lindsay Purnell, Beau Willison
Cortnum, Søren MD, et al: Determining the Sensitivity of Computed Tomography Scanning
in Early Detection of Subarachnoid Hemorrhage. Neurosurgery: May 2010 - Volume 66 -Issue 5 - p 900–905.

In this Danish retrospective study, medical records were reviewed from 499 patients referred to a neurosurgical unit due to suspicion of/confirmed SAH. All patients with a negative CT had a LP performed. Of 296 patients diagnosed with SAH, 295 were diagnosed on CT, and one was diagnosed on day 6 due to a positive LP. Post-LP headache rate was 7.4%. Of patients receiving LPs, 2% were diagnosed with viral meningitis. Authors concluded that CT had a sensitivity of 99.7% (95% CI 98.1-99.99%).

Sounds good. Unfortunately, their methods were horrible. A positive or negative LP was not defined, although they imply that they relied on xanthochromia. They also didn’t define their gold standard for the diagnosis of SAH. It’s unknown who was responsible for reading the CT scans (neurosurgeons ran the study, and did see the scans, but unknown if they were blinded to the study, and if they used an explicit data abstraction form…doubt it). There’s nothing about followup.

Also, there is the issue of referral bias. These are by definition sicker patients than our population, as they were referred to a neurosurgical center, and 60% were diagnosed with SAH. There is an unknown denominator of possible patients who could have been included, and young, healthy patients with bad headaches may not all get referred. Another way to think of it is in terms of spectrum bias, where a test performs differently in different patient populations. CT sensitivity is likely lower in less sick patients.

Bottom line: not practice changing due to poor methods and the referral/spectrum bias. Remember 2% of patients who received LP were diagnosed with viral meningitis-you may identify something besides blood.

Article #2: Presenters: Natalie Kmetuk, Pikul Patel
Jeffrey J Perry, Ian G Stiell, et al: Sensitivity of computed tomography performed within six
hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort
study BMJ 2011;343:d4277.

In this prospective study conducted in 11 tertiary care EDs across Canada, sensitivity of head CT for the diagnosis of SAH was evaluated in 3132 consecutively enrolled neurologically intact adult patients presenting with new acute HA peaking within one hour of onset. SAH rate was 7.7%. Sensitivity of CT for SAH was 92% (95% CI 89-95.5%), with a specificity of 100% (trying to identify specificity is silly here due to incorporation bias-if you define a “positive” using a test you’re evaluating, it has to be 100% specific). The reason this paper has received so much attention is that for the 953 patients receiving CT within 6 hours of HA onset, CT sensitivity was 100% (95% CI 97-100%). All patients were scanned on third generation multi-slice scanners.

Limitations: Only half the patients received LP after negative CT, and the adequacy of follow-up has been questioned. One patient ultimately diagnosed with SAH who had CT within 6 hours of HA onset was sent home after CT was read as negative by the ED physician and a radiology trainee. Additionally, 2292 potentially eligible patients were not enrolled. External validity questioned-will this hold up outside of academic centers?

Bottom line: This article offers support for CT without LP when considering SAH, if CT is performed on a modern scanner within 6 hours of HA onset, and is read by a qualified radiologist. That being said, there are nationally respected emergency physicians with widely divergent opinions on whether this study is enough to change practice.

Article #3: Presenters: Jennifer Cash, Brian Fort
Dustin G. Mark, MD, et al: Nontraumatic Subarachnoid Hemorrhage in the Setting of Negative Cranial Computed Tomography Results: External Validation of a Clinical and Imaging Prediction Rule. ePub2012 / Annals of Emergency Medicine 2012.

This study attempts external validation of a clinical decision instrument identifying high- risk clinical features for SAH in neurologically intact patients with headache. The derivation study was by Perry et al, and published in BMJ in 2010. In that article, they evaluated 1999 patients with max onset headache intensity within one hour (130 cases of SAH), and identified 3 combinations of history and exam findings that were 100% sensitive in identifying SAH. This study by Mark et al attempted to externally validate one of these instruments (investigate patients with any combination of age > 40, neck pain or stiffness, LOC, or HA onset during exertion), as well as the timing of imaging decision instrument described in article #2 (CT within 6 hours of HA onset) using a matched case-control study
of 55 patients over 11 years with normal neuro exam and diagnosis of SAH after (-) CT/ (+) LP. The combination of high-risk clinical features demonstrated a sensitivity of 97.1% (95% CI 88.6-99.7%), specificity of 22.7% (95% CI 16.6-29.8%), and a negative LR of 0.13 (95% CI 0.03-0.61) for the diagnosis of SAH. Twenty percent of SAH cases had negative CT results when performed within 6 hours of headache onset. The authors conclude that the high-risk clinical features may have some Bayesian utility, but that a 6 hour CT cut-off missed 20% of SAH.

Limitations: Retrospective case-control study design, with methodology that started with known SAH patients, rather than with patients presenting with undifferentiated headache. Also, someone was worried enough about these patients to push for an LP after negative CT; it’s not the same as in a prospective study where all patients with negative CT get LP, regardless of how persuasive the clinician was feeling that day.

Bottom line: External validation studies for decision instruments often report lower sensitivities than the initial derivation studies, especially when studies move from academic centers to the community. These decision instruments will need to be re- tested in a number of different practice settings before making definitive conclusions about their accuracy, but the high-risk clinical features may help determine pre/post test probabilities.

____________________________________________________________________________________________

Journal Club bottom line:

There was no consensus. Some in the room are ready to tell neurologically normal patients who are imaged for rule-out SAH within 6 hours of HA onset that if their CT is negative, they need no further evaluation. Others are not convinced, and given the high stakes of missing a sentinel bleed, will tell the same patient there is still up to a 1% of missed bleed (based on LRs, pre/post test probabilities-another discussion), and incorporate the patient’s risk tolerance into decisions about LP/further testing.

Certainly, these articles and the general discussion highlight the importance of “maximal intensity at onset” (within a few minutes) as the most important clinical feature of SAH, even more than “worst HA of life”. They also identify useful high risk clinical features (age > 40, LOC, neck pain or stiffness, HA onset during exertion, vomiting, SBP > 160, DBP > 100) that can help with pre/post test probabilities,
and impact which patients really need the hard sell for the LP after a negative CT, potentially even when CT is within 6 hours of HA onset. Final pearl-beware the patient who isn’t feeling better after analgesics and a negative CT-that’s another high-risk feature.

Wellness

Journal Club Synopsis-Wellness.   November 29, 2012

Kudos to the resident presenters:  Mark Hemming, Maggie Putman, Sola Balogun, Steve Walchuk, Brad Kutka and Bret Negro.  Also, many thanks to Dr. John Principe and his staff at the WellBeingMD Center. 

Article 1:  Mitrou PN, et al: Mediterranean dietary pattern and prediction of all-cause mortality in a US population: results from the NIH-AARP Diet and Health Study.  Arch Intern Med. 2007 Dec 10;167(22):2461-8.

This prospective observational study was a 1995 survey of 380,296 people with no history of chronic disease as part of the National Institutes of Health-AARP Diet and Health Study.  The questionnaire asked about conformity with the Mediterranean dietary pattern (emphasis on vegetables, fruits, nuts, legumes, whole grains, fish, olive oil).  Conformity with the Mediterranean diet was associated with significantly reduced all-cause and cause-specific (cardiac and cancer) mortality at 5 and 10 years.   In men, hazard ratio comparing high to low diet conformity for all-cause mortality was 0.79 (95% CI, 0.76-0.83).   For women, high conformity with the diet was associated with a 20% decreased risk for all-cause mortality.  Multivariate models attempted to adjust for potential confounding mortality risk factors.  Results were maintained in participants who had never smoked, and for both genders.

Both Mark and Maggie mentioned issues of recall bias (how accurately the diet survey was filled out), and Dan stressed that although the trial tried to correct for confounders, there are still likely additional positive choices that people eating a healthy diet make that also contribute to their overall state of health.  Chintan pointed out that participants were only surveyed once, and diet popularity often changes over time; no way of knowing if they complied with the Mediterranean diet for 10 years.  Bottom line for the presenters-the results are consistent with other studies of the Mediterranean diet.  The diet is easy to remember and worth sharing with patients, family.

Article 2:  Kodama S, et al: Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality
and Cardiovascular Events in Healthy Men and Women; A Meta-analysis.  JAMA. 2009;301(19):2024-2035.

This laborious meta-analysis attempts to quantify the relationship between cardiorespiratory fitness (CRF) and all-cause mortality as well as coronary heart disease (CHD)/cardiac events in healthy participants.  Data were obtained from 33 eligible studies of > 185,000 participants.  Compared with participants with high CRF, those with low CRF had a relative risk for all-cause mortality of 1.70 (95% CI , 1.51-1.92; p<0.001) and for CHD/cardiac events of 1.40 (95% CI, 1.32-1.48; p<0.001).   A 1-MET (1 km/hour higher jogging speed) increased level of maximal aerobic capacity was associated with 13% and 15% decreases in risk for all-cause mortality and CHD/cardiac events respectively.  This study suggests that cardiorespiratory fitness could be integrated into the risk factor profile for CHD, and establishes the minimal walking speeds or Bruce protocol performance for men and women at various ages that may help prevent CHD. 

Harwood liked the outcome measure of all-cause mortality:  you don’t want to decrease cardiac mortality but increase the mortality from falling off treadmills.

Stats pearl:  There was a lively discussion of the applications of various study methodologies.  As Barounis stated, a RCT evaluates one variable and one outcome and in general provides the highest level of evidence.  Observational cohort studies don’t examine cause and effect, and can’t account for all confounders.  So, an excellent RCT will trump a meta-analysis and certainly trump an observational trial.   At the same time, for this evening’s clinical questions (diet, exercise), prospective observational cohort trials may be the most appropriate and ethical trial design.  Randomizing anybody to the “high saturated fat sessile lifestyle” arm isn’t going to make it past an IRB.  Another great example from Harwood-you’re not going to perform a RCT on the safety of motorcycle helmets-it’s going to be a population study.

Or from a Bayesian (E. Kulstad):  it’s situational-for these questions, our pre-test probability is already weighted.  For diet, if the alternative hypothesis is that a McDonald’s diet is the same or better than Mediterranean, well nobody’s saying that.  Even before seeing the data, you have an established pre-test probability. 

So even with their limitations, a prospective observational cohort trial is a satisfactory trial design for certain questions, and as Sola said, a well done meta-analysis of high quality observational trials can provide very useful information.

Article 3:  Bowen S, Marlatt A: Surfing the urge: brief mindfulness-based intervention for college student smokers. Psychol Addict Behav. 2009 Dec;23(4):666-71.

Mindfulness, or an attentive awareness especially of the present moment, is an important part of Buddhist teachings.  More recently, the concept has been incorporated into western therapies for treatment of mental illness and drug addiction.  This RCT examined effects of a brief mindfulness technique on smoking behavior among nicotine-deprived college student smokers.  A total of 123 participants either received instructions on the technique or were advised to use their own coping skills after being deprived of cigarettes for 12 hours and then taunted with cigarettes.  Primary outcome was the number of cigarettes smoked over the 7-day follow-up period, and the intervention group on average smoked 1.5 fewer cigarettes.  How does it work? Bret-it’s all about acceptance, giving up control.  By observing negative feelings or urges without reacting, participants may learn alternative responses to negative experiences.

Lots and lots of problems with the study:  small group sizes, short follow-up, everything was self reported, these were college psychology students with low levels of nicotine addiction and were light smokers (not necessarily externally valid when thinking about our patient population), questionable clinical significance (decrease of 1.5 cigarettes), and they didn't query the intervention group to see if they even used the mindfulness technique.  There is also the well described unconscious desire to please the investigator by providing the “correct” answers on a follow-up survey.  Bottom line-even with the limitations, it’s an intriguing low cost concept, and for our patients, would be interesting to see it studied as part of a more comprehensive smoking cessation program.

Finally, a few comments from Dr. Principe.  He encouraged reinforcement of the positive as a means of sustaining behavior change, rather than emphasizing denial and deprivation.  He advocates mindfulness and appreciating/living in the moment, nutritional education, and exercise as components of overall good health. He stressed the importance of “moving along the spectrum”:  we can’t take our population abruptly to an Ornish or Mediterranean lifestyle.  He recommends the book The Blue Zones by Dan Buettner, published by National Geographic, as an exploration of the factors that contribute to certain populations around the world leading extraordinary long, healthy lives.

Transexamic Acid and Trauma

Journal Club Synopsis: Tranexamic acid:  From the Battlefield to the Trauma Center

Thanks to Branka for hosting at her glam club room, and to all the presenters:  Nick, Paarul, Robbie, Beau, Linsey and Dave.

By way of background, tranexamic acid (TXA) is an inexpensive (about 100 $/dose) synthetic derivative of the amino acid lysine, and inhibits fibrinolysis by blocking lysine binding sites on plasminogen.  In the setting of surgery, it’s been used to help decrease the need for blood transfusion.  More recently, it’s been investigated in trauma patients, as the hemostatic responses to surgery and trauma are thought to be similar.

Article 1:

CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376:23-32.

CRASH-2 was a RCT conducted in 274 hospitals in 40 countries, and included 20,211 adult trauma patients with or at risk for significant bleeding.  Patients were randomized to either TXA or placebo.  The primary outcome was all cause mortality at 4 weeks, and was significantly reduced in the TXA group (14.5% TXA versus 16.0% placebo, RR 0.91, 95% CI 0.85-0.97; p = 0.0035).  This absolute risk reduction in mortality of 1.5% translates to a NNT of 67.  There was also a significant reduction in the risk of death due to bleeding (4.9% TXA, 5.7% placebo).  As the mechanism of action of TXA is inhibition of fibrinolysis, question possibility of increased clotting risk, but there was no significant difference in the rate of thrombosis in the 2 groups.

So what are the criticisms?  First, many of the centers involved are in developing countries, and likely do not have the same level of trauma care as in the US.  The CRASH-2 investigators attempted to address this by performing an outcomes analysis by continent, and stated that the positive effects of TXA persisted. 

Stats pearl:  CRASH-2 is a pragmatic trial, rather than an explanatory trial.  We’re much more used to explanatory trials in the medical literature.  They are performed under tightly controlled conditions, with many inclusion/exclusion criteria, usually in academic centers using smaller sample sizes and strictly defined control treatments.  The downside is that they tend to overestimate benefits, and the results are never as good when applied to the real world (limited external validity).  Pragmatic trials are the real world.  Large sample sizes, broader entrance criteria, accept more variation, often performed across many centers, and with easy to generalize results.  One way to think about it is that explanatory trials are specialized studies for information/efficacy, and pragmatic trials are real-world studies to help make decisions/determine effectiveness.  Expect to see more pragmatic trials in the future, especially in emergency medicine.

In CRASH-2, only half the patients received blood, and only half went to the OR.  The decision to enroll patients was the responsibility of the treating doctor.  Again, this reflects the pragmatic nature of the trial.  This relatively low percentage of patients receiving blood or an operation actually biases the results against TXA, as many patients received TXA who weren’t actually having significant bleeding.  It is encouraging that they found a treatment benefit in this “real world” scenario.

Another question raised about the trial is the blood transfusion requirements between the 2 groups.  If TXA helps stop bleeding, why did the TXA group have the same transfusion rate as the placebo group?  This was examined in a secondary analysis of CRASH-2 (Lancet 2011), that demonstrated the importance of early administration of TXA, with a 2.4% decrease in mortality from bleeding if TXA was given in the first hour (early clot stabilization proposed as the mechanism of benefit) and a 1.3% increase in the mortality from bleeding if TXA was given after 3 hours.  In addition, the transfusion rate equivalence is likely an example of survivor bias (second stats pearl!).  If your primary outcome (survival) shows significant benefit, then the extra survivors in the treatment group survive to receive more blood products, decreasing differences seen in secondary outcomes such as the number of units of blood transfused. 

Comments from the reviewers/audience:

Barounis:  Highest benefit when given early-stressed the goal of administration within first hour after injury.  Still uncertain about optimal patient population.

Kerwin favors use in hemorrhagic shock, while Den Ouden sees this as the “aspirin of trauma” J

Harwood: In EM, we ask 2 questions:  how do you diagnose, and how do you treat.  For therapies, we balance number needed to treat, number needed to harm, and cost.  With this treatment, NNT = 67, NNH = 0, and costs per life save is < $ 7,000 (100$ per dose x 67).  From a population health perspective, anything less than $20,000 per life saved is a good option.

Both Nick and Paarul were concerned about the lack of carefully defined enrollment criteria, and would like a better sense of the population that will benefit, although as this is a pragmatic trial, it was designed to rely on physician judgment when choosing eligible patients, and found a mortality benefit when using these “real world” criteria.

Sam Lam:  “all cause mortality” as primary outcome is especially appropriate in this study, as many times cause of death will be unknown in the developing world.

Article 2:

Morrison JJ, Dubose FF, Rasmussen TE, Midwinter MJ.  Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113-119.

This retrospective observational study from a surgical hospital in Afghanistan compared mortality, coagulopathy, and thromboembolic complications in 896 post-operative patients receiving at least 1 unit of pRBCS, 293 of whom also received TXA.  Primary outcome was all cause mortality.  Secondary endpoints included transfusion requirements, coagulation parameters, and thrombotic complications. The TXA group had lower mortality than the no-TXA group (17.4% versus 23.9%, p = 0.03, NNT = 15).  The mortality benefit was even greater in patients receiving massive transfusion (14.4% versus 28.1%).  Based on PT/aPTT measurements, there was a decrease in the percentage of hypocoagulable patients in the TXA group.  Interestingly, transfusion requirements were higher for the TXA group, and the rate of PE/DVT was also higher in the TXA group.  The TXA group had a higher Injury Severity Score and a higher percentage of patients with severe extremity injury.  Also, as it was a retrospective, observational study, it is difficult to draw causal conclusions regarding the blood transfusion/thrombotic complication differences.  Survivor bias may also impact the secondary outcomes.

Comments from the reviewers/audience:

Beau:  external validity-patients were men in their 20’s.  Matches our trauma population?  Bottom line-would use TXA.

Robbie:  liked that they checked coags, could see improvement in coag parameters in TXA group.  ARR 6.5%, NNT = 15.  For massive transfusion, even better ARR 13.7%, NNT = 7.  Increased risk of 2.4% in PE group, NNH = 42 (again, retrospective study, limited information on thrombotic complications/significance).  Authors hypothesize that anti-inflammatory effects of TXA also beneficial.  Bottom line-would use TXA.

E. Kulstad:  horse is out of the barn for any future RCT on TXA given these 2 studies.

Harwood:  Mechanism of injury was explosions for majority of patients-severe force.  Would have liked more specifics on how TXA administered; non-standardized dosing.

Sam Lam:  Retrospective (always issues), Patients who die early don’t get TXAàaffects results (another form of survivor bias), and noted that protocol for giving TXA changed halfway through study-unknown if other components of trauma care also changed.

Article 3:

CRASH-2 Collaborators, Intracranial Bleeding Study. Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study). BMJ 2011;343:d3795 doi: 10.1136/bmj.d3795.

Historically, anti-fibrinolytics have not been recommended in aneursymal SAH due to concerns about increased cerebral ischemia.  Recent data are more positive, but patients with isolated head trauma were excluded from CRASH-2 due to this concern.  There were still 270 patients from CRASH-2 who had multi-trauma including traumatic brain injury, and this study evaluated the intracranial hemorrhage growth in these patients as a primary outcome, comparing the 133 patients receiving TXA to the 137 patients randomized to placebo.  While the study did not find significant differences in the primary or secondary outcomes, there were consistent trends favoring TXA:  decreased ICH growth, decreased mortality, and decreased new focal cerebral ischemic lesions.  The historical concern of increased ischemia when using TXA in patients with intracranial hemorrhage was not seen in this study.

Consensus bottom line for this Journal Club from the group:

TXA is safe and inexpensive, and likely to be of benefit to trauma patients anticipated to require blood transfusion, especially if given within the first 3 hours after injury.  TXA is particularly useful in developing countries where blood products may not be safe and are less available.

What’s the future?  Locally, Erik Kulstad and Nick Kettaneh will be representing the ED in the ACMC Pharmacy and Therapeutics meeting at the end of the month to discuss adding TXA to our formulary.  Worldwide, look for studies evaluating the use of TXA to treat head injury (CRASH-3), post partum hemorrhage (WOMAN), and GI bleeding (HALT IT).

The Dispo of Patients with Upper GI Bleed

The goal for this JC was to discuss 2 commonly used scoring systems for patients with upper GI bleeds in an effort to identify patients who can be safely discharged from the ED. Both the Glasgow-Blatchford (GBS) and Rockall scores use clinical criteria, and the “full” Rockall also incorporates endoscopic findings.

Article 1: Stanley AJ, Ashley D, Dalton HR et al. Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective validation. Lancet. 2009;373:42-47.

This 2 part multi-center UK study used receiver-operating characteristic (ROC) curves to compare the ability of Glasgow-Blatchford (GBS) and Rockall scores (both pre and post-endoscopy Rockall) to predict need for clinical intervention (blood transfusion, endoscopic treatment, surgery) or death for 676 consecutive patients presenting with upper GI bleed. The area under the ROC curve was best for GBS (0.90 [95%CI 0.88-0.93), followed by full Rockall (0.81 [95% CI 0.77-0.84]), then pre-endoscopy Rockall (0.70 [95% CI 0.65-0.75]). In the second part of the study they prospectively identified 123 of 491 (22%) patients as low risk using a GBS of 0, of whom 84 (68%, or 15% of total cohort) were managed as outpatients, all without adverse events.

Bottom line article 1: A GBS of zero (BUN < 18, Hgb at least 13 for men/12 for women, SBP at least 110, Pulse < 100, absence of melena, syncope, CHF, liver dz) identifies a significant number of patients presenting with upper GI bleed who can safely be managed as outpatients.

Issues:

• Not a biggie, but Blatchford was one of the authors.

• In phase 2, only 40% of patients underwent outpatient endoscopy. They did have 6 month follow-up through chart review and contact with patient/PMD and verified no readmissions for GI hemorrhage or death.

• Louis-UK study, did not include demographic data on patients, and missing endoscopy on large percentage of patients treated as outpatients.

• McKean-wanted to see information about age (concern about sending home old patients) and other demographics. Needs more external validation, especially with diverse patient groups.

Comments from the sages:

Harwood: As residents move forward in their careers, there will be an increasing emphasis on conserving resources and saving money in medicine. GBS could be a useful tool used in a dichotomous fashion (“home or admit”) to avoid unnecessary admissions, but needs more external validation.

Rogu: Likes GBS-it’s easy to use. Also, developing decision instruments is usually a multi-step process: derivation study followed by a validation study and then an impact analysis. This is a nice example of a study that both validates the GBS decision instrument and in part 2 examines its clinical impact.

Kulstad C: Think about GBS like PERC: it's helpful in avoiding a work-up, but a positive shouldn’t be followed blindly disregarding the specific clinical situation.

Article 2: Stephens JR, Hare NC, Warshow U et al. Management of minor upper gastrointestinal haemorrhage in the community using the Glasgow Blatchford Score. Eur J Gastroenterol Hepatol 2009;21:1340-1346.

In this two part UK study, GBS was first prospectively calculated on 232 patients admitted to a teaching hospital with upper GI bleed in order to identify a low risk cut-off score. All patients were offered next day or emergent endoscopy as indicated. GBS ≤2 and age <70 successfully predicted favorable  outcome (no need for endoscopic therapy, blood transfusion or surgery, or death) in all 52 of 232 (22%) patients with this score.

They then used this cut-off (GBS ≤2, age <70) to prospectively identify 104 of a second cohort of 304 patients (34%) as low risk, and considered outpatient management of these patients. Importantly, only 32 of these 104 (31% of low risk group, 10.5% of entire group) were actually managed as outpatients. Low risk patients were still admitted if there were concerns about social situation/support, active comorbidities, if taking warfarin or had suspected varices. All patients managed as outpatients were offered next weekday endoscopy, and nearly all completed endoscopy. All low risk patients in this cohort (both those admitted and those managed as outpatients) had good outcomes-no need for interventions, no deaths. In addition, 91% of patients managed as outpatients expressed a strong preference for this option.

Important-lack of need for acute intervention does not equal lack of findings on endoscopy- outpatient management still mandates availability of next working day endoscopy.

This is also a small study, and didn't include sensitivity/specificity/confidence intervals, and should be replicated with more patients and in other patient populations.

Bottom line for article 2: by using a GBS ≤2 with an amendment for age < 70, a set of low risk patients with upper GI bleed (10% % in this study) can be identified for consideration of safe outpatient management, but next-day endoscopy must be available.

Issues:

• As Erik often points out, there was no figure identifying how many potentially eligible patients were missed. If patients are enrolled M-F 9-5, the missed patients may constitute a different group with potentially different outcomes.

• Janna: hard to set up endoscopy for all patients in our system. Liked that this approach reflects patient preference. Important observation in the study: rate of significant endoscopic findings dramatically increased with age (8% increase by decade of life).

• Maletich: Even those admitted did well, although significant findings at endoscopy (18% vs. 9% findings in outpatient endoscopies)- reiterated challenge of outpatient endoscopy in US. This does help corroborate your decision to send some patients home.

Comments from the sages:

Harwood: Rockall score does not include hemoglobin. GBS includes hemoglobin. If one outcome measure is need for transfusion, then including hemoglobin introduces bias and favors your score.

Barbara: Treat seniors carefully!

Joan: NHS does not equal US health system-access to care and followup, availability of endoscopy much different.

Article 3: Chandra S, Hess EP, Agarwal D et al. External validation of the Glasgow-Blatchford Bleeding Core and the Rockall Score in the US setting. AJEM 2012;30:673-679.

In the last article, the authors attempt to externally validate the GBS and Rockall scores in the United States. In this retrospective study, 171 patients were identified with a diagnosis of upper GI Bleed. Primary outcome was need for endoscopic intervention, blood transfusion, angiography, surgery or death within 30 days. GBS outperformed pre-endoscopy Rockall (area under ROC curve 0.79 vs. 0.62), but was similar to post-endoscopy/full Rockall (area under ROC curve 0.72).

A GBS of 0 had a sensitivity of 99% (95% CI 93-100%) and specificity of 6% (95% CI 2-14%). For both the GBS and Rockall scores, at higher score cutoffs with greater specificity, the sensitivities were suboptimal.

Interestingly, 20 (12%) of cohort were discharged and managed as outpatients based on clinical gestalt, and only 2 required endoscopic intervention within 30 days (and no deaths), suggesting that EP decision making with appropriate consultation by GI is already safe and effective .

Bottom line for article 3: The prognostic accuracy of GBS and post-endoscopy Rockall were similarly high. Although the sensitivity of a GBS of 0 was excellent in this study, the low specificity of both GBS and Rockall prevents the authors from recommending either score as the sole means to identify patients safe for discharge/outpatient management.

Issues:

• Matt: Limitations of retrospective chart review. Also, study only included residents of Olmsted County, as all inpatient and outpatient medical records for these patients are available through a searchable data set. This excluded a large number of otherwise potentially eligible patients.

• Jako: This retrospective relatively small study alone not strong enough to support use of GBS, and low specificity limits usefulness. Needs external validation beyond one county in Minnesota.

Comments from the sages:

Sam: Low specificity means higher number of false positives. Clinical judgment may perform better. Trying to explain the poorer fit of the ROC curves in this study compared to study 1, likely in part due to the methods of chart review, eg if patients with a small amount of bleeding are diagnosed with “gastritis” and discharged, they wouldn’t be picked up and counted, and it’s a group that likely would be GBS 0 with excellent outcomes.

Stats blurb: Receiver Operating Characteristic (ROC) curves.
Y axis is True Positive Rate = True positives/All positives = sensitivity. X axis is False Positive Rate = False positives/All negatives = 1 – specificity.

The area under the curve is a measure of text accuracy and shows the tradeoff between sensitivity and specificity. The closer the curve follows the left-hand border and then the top border of the ROC space, the more accurate the test. A perfect test with a sensitivity and specific of 100% would have an area under the curve of 1.0 In general, 0.9 is excellent, 0.8 is good, 0.7 is fair, and 0.5 is a straight line at 45 degrees which is worthless. ROC curves are also often used to determine an optimal cut off value for a test. The optimal cut-off point on the curve will vary depending on whether the clinical situation demands a high sensitivity or high specificity.

Journal club bottom line:
The Glasgow Blatchford Score is easy to use and a score of zero appears to help predict a low risk group of patients with upper GI bleed who can be considered for outpatient management. A score of GBS ≤2 and age <70 is another reasonable cut-off, and incorporates age. Outpatient management for a patient with a GBS of 0 is only a safe option if excellent follow-up and next day endoscopy is assured. Respect age as a predictor of more serious underlying pathology and risk for bad outcomes-nobody in the room was comfortable sending home elderly patients with GI bleeds. And while the GBS is useful, it should be an adjunct to your clinical judgment: remember to consider co-morbidities and the social situation of the patient.

Novel Anti-coagulants

A brief rundown of the players:

Dabigatran (Pradaxa) is a direct thrombin inhibitor, FDA approved in October 2010 for the prevention of CVA in patients with Afib.  In December 2011, the FDA initiated an investigation into reports of higher than expected rates of serious bleeding events.  Rates of dyspepsia and GI bleed are also concerning, and a small but significant increase in MI has been shown in safety outcome data from multiple trials.

Rivaroxaban (Xarelto) is a direct Factor Xa inhibitor, FDA approved July 2011 for DVT prophylaxis, and in November 2011 for prevention of CVA in patients with Afib.

Apixaban (Eliquis), another direct Factor Xa inhibitor, will likely be FDA approved in June 2012 for prevention of CVA in patients with Afib. 

This journal club examined the 3 major studies published in NEJM used to support the use of these novel anticoagulants in the prevention of CVA in patients with Afib.  Interestingly, these drugs are struggling when studied in ACS; APPRAISE-2 (study of apixaban + antiplatelet therapy after ACS) was stopped early in 2011 due to increase in major bleeding without significant reduction in recurrent ischemic events.  One other general note:  in all three of these studies, ICH (the bleeding complication that counts) was significantly less with the study drug as compared to warfarin.  All 3 of these drugs do ok in these non-inferiority studies-the important question is how they will perform in the real world, and it may be several years before safety conclusions and community effectiveness data give us the answer.

1.  Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-1151.  (RE-LY)

Dabigatran 150mg BID or 110mg BID (blinded) vs Dose adjusted warfarin (unblinded)

Randomized, noninferiority trial of 18,113 patients, median follow-up 2 years.

Condition: AF within 6 months prior to randomization + 1 risk factor for CVA.  Use of                antiplatelets acceptable.  Mean CHADS2 score 2.1.  Intention to treat.

Primary endpoint: Stroke or systemic embolism

• Warfarin 1.7%
• Dabigatran 110mg 1.5% (p=0.34)
• Dabigatran 150mg 1.1%   (p<0.001 for superiority)

Major Bleeding

• Warfarin 3.4%
• Dabigatran 110mg 2.7% (p=0.003)
• Dabigatran 150mg 3.1% (p=0.31)

ICH

• Warfarin 0.74%
• Dabigatran 110mg 0.23% (p<0.001)
• Dabigatran 150mg 0.3% (p<0.001)

Conclusion: Lower dose dabigatran similar to warfarin for preventing stroke/systemic embolism and caused less major bleeding than warfarin.  Higher dose dabigatran superior to warfarin for preventing stroke with similar rates of major bleeding to warfarin (trade off with dosing between benefit and bleeding).  Both doses of dabigatrin with significantly less ICH than warfarin.  Significantly higher rate of GI bleeding in higher dose dabigatran group as compared with warfarin.

Comments:  Tony-higher discontinuation rate with dabigatran, likely from dyspepsia rates.  What happens with the effectiveness of these drugs in the real world (external validity) when people don’t take them due to side effects, and there is no monitoring such as INR to reinforce compliance?  Also likely to see less of a difference between the drugs in motivated patients on warfarin with very well controlled INRs.  In real world, INR is maintained in therapeutic range only about 55% of the time.  You can improve warfarin safety and effectiveness if you use point of care monitoring and have motivated patients.  Brad-bottom line, concern about increased MI and GI bleed rates, and no easy reversal agent.

2.  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011;365(10):883-891.  (ROCKET)

Rivaroxaban 20mg QD vs Dose adjusted Warfarin

Randomized double blind, noninferiority trial of 14,000 patients, median follow-up 707 days.

Condition: AF within 6 months prior to randomization + at least 2 risk factors for CVA.  Mean          CHADS2 score 3.5.

Primary endpoint: Stroke and systemic embolism

• Warfarin  2.4%
• Rivaroxaban 2.1% (ITT p=0.12 for superiority, p<0.001 for noninferiority)

Major Bleeding

• Warfarin 3.4%
• Rivaroxaban 3.6% (p=0.58)

ICH

• Warfarin 0.7%
• Rivaroxaban 0.5% (p=0.02)

Conclusion:  Rivaroxaban non-inferior to warfarin in the prevention of stroke/systemic embolism with no significant difference in major bleeding events and less ICH.

Comments:  Mark-patients in this study with higher CHADS2 scores-more like our patients.  Also noted the increased risk for thrombotic events after stopping rivaroxaban.  This is also something seen with clopidogrel (Plavix).  Brian noted the heavily subsidized authors. Three statistical analyses used in this study:  intention to treat, per-protocol and as treated safety analyses.  Superiority was achieved only in the as treated safety analysis.  It seems like a lot of data torturing to find a way to demonstrate superiority.

Statistics Rant about noninferiority studies.  We commonly read superiority studies-attempts to show that drug A is better than drug B.  Why do a noninferiority study?  It’s a logical choice when you can’t use a placebo arm, and want to show drug A is as “good as” drug B.  Also, choosing the noninferiority margin, or how close the results for drug A need to be to drug B in order to conclude that they are similar, is arbitrary.   Pick a margin, and if you’re dealing with FDA approval, you just need to pick a margin that the FDA will swallow in order to approve your drug.  For the apixaban study, if apixaban was shown to be at least 50% as good as wafarin, it was judged noninferior.  In general the requirements for noninferiority studies are much more lax than for superiority studies, making them attractive to Big Pharma.  Also, in the end, if you able to demonstrate and report superiority, your results looks even better.  As far as analyzing results, in randomized studies trying to demonstrate superiority, intention to treat (ITT) is the best approach.  With non-inferiority studies, it’s actually preferable to do both ITT and per-protocol analyses, as per-protocol analyses bias against demonstrating significant differences (is a stronger analysis).  When in doubt though, as Erik always stresses, look at effect size (number needed to treat, absolute risk reduction), the comparison between benefits and harms, and expense…not statistics, and certainly not p values.

3.  Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011;365(11):981-992.  (ARISTOTLE)

Apixaban 5mg BID vs Dose adjusted Warfarin

Randomized double blind noninferiority trial of 18,201 patients, median duration of followup                1.8 years.  Mean CHADS2 score 2.1.

Condition: AF within 6 months prior to randomization + at least 1 risk factor for CVA

Primary endpoint: Stroke or systemic embolism

• Apixaban 1.3%
• Warfarin 1.6% (p<0.001 for noninferiority, p=0.01 for superiority)

Major Bleeding

• Apixaban 2.1%
• Warfarin 3.1% (p<0.001)

ICH

• Apixaban 0.2%  
• Warfarin 0.5% (p<0.001)

Conclusion: Apixaban superior to warfarin in preventing stroke/systemic embolism with less major bleeding and lower rates of ICH.

Comments:  Paarul-questioned the costs of these agents.  Paarul and Pikul both felt the drug is promising, but have concerns about external validity, as there were significant inclusion/exclusion criteria.  Dabigatran costs 8 $/day, warfarin is 30 cents.  Need to factor in costs of INR testing, and as Mary pointed out, also costs of bridging with enoxaparin (Lovenox) if INR subtherapeutic.  Christine pointed out that the study stressed relative risk reduction, which can sound good, but is less appropriate than using absolute risk reduction.  Kelly wondered about the outcomes of the patients who bled-not discussed in the paper.  Harwood pointed out that although results superior to warfarin, small effect size:  NNT to prevent stroke/embolism 303, NNT to prevent a major bleed 104, NNT to save a life 238, and outside of carefully monitored study setting, real world effect size will likely be even less.

In my humble opinion, this is the strongest study of the three.  Then again, apixaban isn’t even FDA approved yet-unlike iPhones, there are potentially big downsides to being the early adopter for new drugs…meaningful safety conclusions are still years in the future.

BONUS!!  AVERROES - Apixaban in Patients with Atrial Fibrillation (this was a background article, but interesting as it compared Apixaban to ASA; relevant for patients who aren’t candidates for warfarin)

Apixaban 5mg BID vs ASA

5,600 patients

Condition: AF within 6 months prior to randomization + 1 risk factor for CVA

Primary endpoint: Stroke and systemic embolism

• ASA 3.9%
• Apixaban 1.7% (p<0.001)

Major Bleeding

• ASA 1.2%           
• Apixaban  1.4% (p=0.33)

ICH

• ASA 0.3%           
• Apixaban  0.4% (p=0.83)

Conclusion: Apixaban superior to aspirin with similar rate of major bleeding and ICH. Study stopped early due to benefit of apixaban over aspirin.

Pediatric IVF

Background:  Our current intravenous fluid (IVF) orders for pediatric patients follow an equation first published in 1957 (Holliday and Segar).  Electrolyte composition of IVF are based on average sodium content in low solute infant formula, with the untested assumption that oral requirements translate to a safe and appropriate IV solution.

Over time, case reports of iatrogenic hyponatremia in pediatric patients have been described, some leading to permanent neurologic impairment or death.  The hyponatremia is attributed to the use of hypotonic IVF such as 0.45 NS and 0.2NS.  The mechanisms are not fully elucidated, but likely are related to the temporarily high arginine vasopressin (AVP) levels seen in children hospitalized with many common disorders (asthma, infection, post-op, dehydration, etc), and an impaired clearance of electrolyte-free water.   Proponents of the status quo cite concerns about isotonic fluids leading to hypernatremia, hypertension, interstitial fluid overload and tissue damage from extravasation.

In 2007, the National Patient Safety Agency in the UK warned against the use of hypotonic IVF fluids in children, followed by similar warnings by the Institute for Safe Medication Practices in Canada in 2008 and the United States in 2009, yet many hospitals continue to use hypotonic IVF for their pediatric patients.

Article #1:

Montanana PA, Alapont M, Ocon AP et al. The Use of Isotonic Fluid as Maintenance Therapy Prevents Iatrogenic Hyponatremia in Pediatrics: A Randomized, Controlled Open Study,Pediatr Crit Care Med 2008;9:589 –597. 

In this non-blinded RCT, 128 PICU patients received either isotonic IVF (NaCl = 140 mEq/L) or hypotonic IVF (NaCl < 100 mEq/L).  Patients were followed for 24 hours, with electrolytes, glucose and BP measured at 0, 6, and 24 hours.  Baseline Na levels were similar in the two groups.  The primary outcome was hyponatremia (Na < 135) at 6 and 24 hours.   All eligible patients consented to be in the study (whoah, what’s going on with informed consent in Spain…and Australia in article 3-also 100% compliance!).   They did lose a number of patients, mostly because IVF were no longer required, but 8 patients discontinued the study due to hyponatremia.  At 24 hours, 20.6% of the hypotonic IVF group were hyponatremic, compared to 5.1% in the isotonic IVF group:  NNH (number needed to harm) with hypotonic fluids = 7.  There was no significant difference in adverse events or hypernatremia between the 2 groups.

Statistics Rant:  this study included a Bayesian analysis, which is worth a comment.   In a nutshell, there are two types of probability:  Bayesian and Frequency.  Frequentists rely on objective probabilities defined through well defined random experiments….think p values.  Bayesians interpret probability using their degree of belief in a hypothesis.  It’s more of a “how do we feel” about the statistics, rather than an arbitrary “p < 0.05 = truth”.   Many current journals are getting away from p values entirely.  A large effect size, combined with prior knowledge about the topic, can be more persuasive than a statistically significant p value in isolation.  Bayesians are all about pre-test and post-test probability; how does additional new information change your view of the likelihood of an event?

Discussion:  McKean brought up the excellent point that the study is not blinded, and therefore open to confounders.  It would also be preferable to use clinical, or patient oriented outcomes, rather than surrogate markers like sodium level, but clinical complications are going to be rare in this situation.  Although the number of patients with moderate or severe hyponatremia was low, they were all in the hypotonic fluid group and this is potentially more clinically relevant.

Article #2:

Choong K, Arora S, Cheng J et al. Hypotonic Versus Isotonic Maintenance Fluids After Surgery for Children: A Randomized Controlled Trial. Pediatrics 2011:128;857-864.

In this blinded study 258 post-op kids either received hypotonic (0.45NS) or isotonic (0.9NS) IVF for 48 hours.  Baseline characteristics in the two groups were similar.  Primary outcome was acute hyponatremia, defined as Na < /= 134.   Secondary outcomes included severe hyponatremia (Na < /= 129 or symptomatic), hypernatremia (Na >/= 146), and adverse events attributable to fluid choice or sodium level.   The risk of hyponatremia was significantly greater in the hypotonic group (40.8% vs 22.7 %; RR: 1.82 [95%CI:1.21-2.74]).  Eight patients in the hypotonic group developed severe hyponatremia as compared with 1 patient in the isotonic group.  In Harwood’s view, this is a study of 9 kids with severe hyponatremia (the most clinically concerning patients), and all but one received hypotonic fluids.  The risk of hypernatremia was not significantly different between the two groups, nor was the rate of adverse events.   NNT with isotonic IVF to prevent one case of hyponatremia = 6.

Discussion:   As Jess mentioned, there was a safety officer who alerted physicians if predetermined Na levels were met.  If electrolyte values were persistently abnormal, physicians could change the study solution to an open label IVF.   More patients in the hypotonic group were changed to open label IVF, with hyponatremia being the most commonly stated reason for the change.  This methodology likely decreased the rate of harmful outcomes and diluted the magnitude of the primary outcome (anticipate more harm and even more significance in the outcomes if the above safety choices hadn’t been made).

Article #3:

Neville KA, Verge CF, Rosenberg AR et al. Isotonic is Better than Hypotonic Saline for Intravenous Rehydration of Children with Gastroenteritis: a Prospective Randomised Study.Arch Dis Child 2006;91:226–232. 

The final study evaluated dehydrated children diagnosed with acute gastroenteritis.  In this study, a total of 102 children with acute gastroenteritis (AGE) received either D2.5 0.9NS or D2.5 0.45NS for 4 hours, with electrolytes measured in both blood and urine at 0 and 4 hours.  Results were analyzed according to whether patients started the study with a normal Na or if they began hyponatremic (Na < 135).  Physicians chose between two different rehydration rate protocols.  Patients were similar at baseline except for a higher rate of baseline hyponatremia in the isotonic fluid group.  The primary outcome was the change in serum sodium at 4 hours.  Thirty-six percent of the children were hyponatremic at the start of the study, and these patients were more likely to have been ill longer than patients with baseline normal serum sodiums.   The IV infusion rate did not affect the change in serum sodium, which is important as proponents of hypotonic fluids have argued that the rate rather than the type of IVF determines the risk of hyponatremia.  At 4 hours, in the hypotonic fluid group patients initially hyponatremic did not demonstrate a significant change in serum sodium, but patients initially normonatremic had a small drop in serum sodium.  In the isotonic group, at 4 hours those initially hyponatremic had a small increase in serum sodium, while those initially normonatremic had overall unchanged serum sodiums.  In other words, isotonic fluids appeared to prevent hyponatremia and did not cause any cases of hypernatremia.

Discussion:  Beau pointed out that this is a non-blinded study, but it did look at a “hard” outcome, serum sodium, that shouldn’t have been affected by blinding.  He also mentioned that the study did not address complications, length of stay, etc, and did not specify prior interventions such as anti-emetic administration.   As Jim Maletich discussed, this really was only a four-hour study, although for the subset of patients followed longer, the few cases of hyponatremia identified were all in the hypotonic fluid group.  Urine biochemical analysis reiterated Harwood’s point:  kids can handle sodium, but they aren’t good at handling (excreting) free water. 

Bottom line consensus from the group:  it’s time to change our practice.  Except for rare situations when children present with profound hypo or hypernatremia (for example patient with DI), the IVF of choice is 0.9NS, usually with KCl and dextrose added after any necessary initial resuscitation boluses have been given.  It’s the medically appropriate choice, should be financially equivalent to current practice, and makes our lives easier (bonus!).    Our pediatric colleague Patty, who managed to sit through 2 journal clubs on this topic in one day, voiced similar conclusions from the Department of Pediatrics discussion.

There’s always a caveat…

There is a potential concern for the induction of metabolic acidosis when administering IVF with equal chloride and sodium ion concentrations.   As Harwood pointed out, none of the three studies evaluated chloride or pH.   LR contains less chloride than NS, but is still hypotonic.  Future studies.