Month: February 2014

Droperidol Never Killed Anyone

The bearer of a black box and the scourge of Pharmaceutical and Therapeutics committees, droperidol has a long history – a history where, for the most part, it is used safely for decades.

This is a small case series from a prospective trial of treatment for acute agitation in the Emergency Department.  In this study, patients requiring treatment for agitation received 10mg of IM droperidol as an initial dose, followed by a second dose within 15 minutes as needed, and further doses of droperidol as needed and in consultation with a toxicologist.  An ECG was obtained, and continuous telemetry monitoring was applied as soon as safely possible.

42 patients qualified for droperidol in this study, 29 of whom received 10mg of droperidol, 11 received 20mg, 3 received 30mg, and 3 received 40mg.  Of these, 4 patients receiving 10mg or 20mg had prolonged QT observed on ECG – to a maximum of 534ms.  The authors write, then, in their conclusion: “QT prolongation was observed with high-dose droperidol.”

A more accurate conclusion, however, would probably be: “In a limited case series, no dose-dependent relationship between droperidol and QT prolongation was observed.  QT prolongation of uncertain clinical significance was noted in a small number, but confounding co-ingestants limit the reliability of this finding.”

There ought to be, at this point, little legitimate concern over the clinical significance of the QT prolonging effects of these medicines in nearly all clinical situations.  Thanks to Ariel Cohen for sending this in!

“High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings”
http://www.ncbi.nlm.nih.gov/pubmed/24168079

2-Handed BVM – Many Hands Make Light Work

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

I’ve been teaching ACLS and airway workshops for years and I always make a point of focusing on the proper technique for bag-valve-mask (BVM) ventilation. I’ve always taught people both the 1-handed and the 2-handed techniques and said that they’re basically equivalent as long as you feel like you’re getting a good seal. This study brings the efficacy one-hand BVM into question.

The authors performed an interesting study. They took a group of providers (EM residents, attendings, nurses, paramedics and ICU nurses) and had them hold face masks on simulation mannequins with 1-handed and 2 different 2-handed techniques. A ventilator provided a 600 ml tidal volume and then measured the volume returned. Since this is a closed circuit, the volume returned should be equal to the set tidal volume – whatever leaked around the “seal” created by the provider.
What they found was surprising. For the 1-handed only 31% of the set tidal volume was expired while that number was 85% for both of the 2-handed techniques. This difference was found to be statistically significant and I imagine it would also be clinically significant. A study done earlier last year by Hard et al had similar findings.1
So what stands in the way of us completely stopping the teaching and application of 1-handed BVM (unless necessary due to staffing) and embracing 2-handed BVM? Unfortunately, the study is done on simulation mannequins and not on people. What we prefer is to see the application of the study to human patients. But this isn’t always possible. In the same issue of Annals, Wang and Yealy comment in an editorial that not only would it be virtually impossible to do this study in real human patients but also that it’s likely unnecessary.2 BVM is a technique that lends itself well to being studied in a simulation model.
What we have here are two studies showing benefit of a 2-hand BVM technique on mannequins that requires no increased equipment and a minimal increase in necessary resources. Using a 2-hand system is likely a better way to bring the mandible forward and open the nasopharynx allowing for nasal oxygenation. Since we’re unlikely to see a study done on actual patients, this should be enough to change practice.
Article:
“Comparison of Bag-Valve-Mask Hand-Sealing Techniques in a Simulated Model.”
References:
1. “Face Mask Ventilation: A Comparison of Three Techniques.”
2. “Emergency Airway Research: Using All Tools to Bridge the Knowledge Gaps.”

The Rat Around Your Neck

Physicians as plague carriers – but, rather than rats, as in the Middle Ages, suppose it may be our stethoscopes.

In this observational study out of Ethiopia, 176 stethoscopes belonging to healthcare workers and students in a hospital were swabbed and cultured.  Naturally, the authors were able to grow bacteria off 86% of these, half of which were pathologic strains such as S. aureus, Klebsiella, Citrobacter, Proteus, and P. aeruginosa.  The swabs taken from the ICU harbored the greatest percentage of isolates for pathogenic strains.  Most strains demonstrated some level of antibiotic resistance, such as 27% of S. aureus which proved methicillin-resistant.

Colonization, which has previously been demonstrated on the white coats of physicians, is not proof of transmission – but it is not unreasonable to suspect this may yet occur.  However, only 3% of respondents in this study regularly disinfected their stethoscope after each patient.  Even the mildest improvement in hygiene would likely go a long way towards reducing the theoretical risks.

“Bacterial contamination, bacterial profile and antimicrobial susceptibility pattern of isolates from stethoscopes at Jimma University Specialized Hospital”
http://www.ann-clinmicrob.com/content/12/1/39

Why Observational Data for tPA is Flawed

Much is made of retrospective comparisons derived from registry data in acute ischemic stroke.  The most egregious of these attempt to match a subgroup of tPA-treated folks with a control group not receiving tPA.

This publication, from an Austrian stroke registry, pulls 890 patients from 54,917 with mild (NIHSS <5) symptoms to perform a comparison matched on many clinical features.  In their matched comparison, 41% of tPA-treated patients were better off, 30% were identical on mRS, and 29% favored non-treatment.  Therefore, these authors declare there is an overall shift towards favorable outcome with tPA.

What is wrong with drawing anything but hypothesis-generating conclusions from this data (or, any retrospective, observational data)?  While the authors control for a few factors, there are many pre-existing comorbid conditions influencing treatment or non-treatment with tPA.  For example, a patient with advanced metastatic cancer will almost certainly be excluded from treatment with tPA – and certainly have poor 3-month functional outcomes – but that comorbid state cannot not be captured by this registry.  Then, just as we saw in IST-3, patients who are treated with tPA frequently receive more vigilant initial stroke care.  Adherence to clinical pathways as well as the control of hyperglycemia, fever, and swallowing dysfunction have profound effects on subsequent death and disability far exceeding the effect size supposed for tPA.  This registry, taking place over the course of a decade of evolving stroke care, cannot control for follow-up treatment and therapy.

This is, essentially, why all retrospective, observational comparisons are almost guaranteed to favor the tPA cohort.

Just as an added note – for anyone considering responding directly to the authors in the pages of Stroke – you will be charged $35 for typesetting for an electronic-only publication which then resides behind a paywall.  Traditional scientific journals are for profit, not for science – that’s where FOAMed comes in!

“Thrombolysis in Patients With Mild Stroke: Results From the Austrian Stroke Unit Registry”
http://stroke.ahajournals.org/content/early/2014/01/30/STROKEAHA.113.003827.abstract

My ACEP tPA Policy Critique

As some of you are aware, there is controversy regarding the use of tPA for acute ischemic stroke.  To this end, ACEP has opened up public comment for their recent relevant Clinical Policy Statement.

The comment form, however, is a bit of an odd and onerous format.  To spark discussion, to provide inspiration – and for public feedback/comment/correction – here are a few points from the initial draft of my response:
Page 225, Line 3, author list:
Area of Content / Concept – Conflict of Interest in Guideline Development Group (GDG)
The Institute of Medicine publishes recommendations regarding the composition and conflict of interest disclosures of a Clinical Practice Guideline (CPG) writing panel.  This tPA policy statement falls short on several accounts, most importantly:
Standard 2.1:  
The disclosures listed by the authors only narrowly address their direct financial relationships, but do not describe non-commercial, intellectual, and patient/public activities pertinent to the scope of the CPG.  For instance, authors do not fully describe their relationships with FERNE, a pharmaceutical-supported organization, nor other indirect and intellectual activities relevant to the CPG.
Standard 2.3:
The recommendation states members of the GDG should not participate in marketing activities or advisory board of entities whose interests are affected by the recommendations.  This standard does not appear to be met.
Standard 2.4:
Whenever possible, GDG members should not have COI.  If this is not possible, members with COIs should represent only a minority.  The chair, or co-chair, should not have COI.  This standard does not appear to have been met.
Standard 3.1:
The GDG should be multidisciplinary with methodological experts, clinicians, and patients.  The GDG members appear to be primarily clinicians and administrators, rather than patients and methodologic experts.
Standard 7:
The external review process is only briefly described, and the guideline was not open to public comment until this 60-day period.
Additional comments on the integrity of CPG come from a recent BMJ article, “Ensuring the integrity of clinical practice guidelines:  a tool for protecting patients.”  The recommendations from this publication are similar to the IOM recommendations, with the addition the GDG members ought to represent diverse viewpoints regarding the topic in question.  It does not appear this CPG represented any point of view other than a pro-tPA viewpoint.  The ACEP tPA clinical policy was evaluated using the “red flag” methodology by this article and found to be lacking.
Based on the COIs identified in this GDG, the output lacks face validity.
Page 227, Line 23:
Area of Content / Concept – Patient Management Recommendations
The guideline specifies offering IV tPA to acute ischemic stroke patients within 3 hours to be a Level A recommendation.  A Level A recommendation, according to the methodology of the CPG, states this indicates “Generally accepted principles for patient management that reflect a high degree of clinical certainty.”
The evidentiary table cites several articles as Class I evidence specifically relevant to the 3 hour timeframe (NINDS, ECASS II, and ATLANTIS B 0-3).  NINDS, by all accounts, shows benefit, while the effect size is debated by many based on the baseline characteristics of the treatment groups.  ECASS II is a negative trial; it is inappropriate to apply a subgroup analysis consisting of the 158 patients treated within 3 hours as the same level of Class I evidence.  The ATLANTIS B publication cited is also a very small subgroup analysis of a heavily modified trial stopped early for futility, and should not be considered the same level of Class I evidence.
Notably missing from this evidentiary table is ATLANTIS Part A – cited in the text, but apparently not considered as contributory to the CPG.  This is randomized, placebo-controlled evidence stopped early due to patient harms in the tPA cohort.  This merits inclusion in the evidentiary table as evidence of the harms of IV tPA.
The Lees meta-analysis, among others performed prior to 2010, is appropriately level II evidence.  However, it should be noted there are significant methodologic concerns associated with performing a meta-analysis that includes trials stopped early by their sponsors for futility or harms alongside trials allowed by their sponsors to run to their conclusion.  The evidentiary table notes “some of the analyzed studies were industry supported.”  To be more precise, all of the listed studies have substantial COI with industry – including employees of the sponsoring corporations listed among study authors – except NINDS, where the COI is minimized.
The remaining observational evidence is not relevant to a Level A recommendation.  The Hill and Wahlgren Phase IV studies are not placebo-controlled and only offer substantially limited, indirect, adjusted comparisons to a non-tPA treated population regarding safety and effectiveness.
My point, therefore, is NINDS is unique in support of tPA.  It is irresponsible to base a Level A treatment recommendation on a single positive study with a disputed effect size, whose results cannot be considered externally valid to current stroke practice.  NINDS – along with most evidence cited here – describes use in controlled trial environments of academic stroke centers supported by stroke neurologists.  There is insufficient evidence to support its general effectiveness, compared with standard treatment, in community Emergency Medicine.  Additionally, the observational evidence cited in the evidentiary table clearly describes a heterogenous acute stroke population, with varying levels of sICH risk, mortality risk, and capacity to benefit.  A CPG should not make a global recommendation for treating such a heterogenous disease without providing tools for physicians to communicate individualized risks and benefits.  Unfortunately, the placebo-controlled data are of insufficient quantity and quality to guide therapy.
A demonstration of the dangers of basing treatment decisions on small trials and small effect sizes is based in statistical theory.  Dr. Ioannidis demonstrates how “Most published research findings are false”, a hypothesis apparently borne out by “A decade of reversal:  an analysis of 146 contradicted medical practice.”
Furthermore, a Level A recommendation constitutes “generally accepted principles” with a “high degree of clinical certainty”.  If this were, indeed, the case, tPA for acute ischemic stroke would not be a controversial therapy 18 years past its introduction.  Respected U.S. Emergency Medicine experts in critical appraisal and knowledge translation, e.g., Jerome Hoffman, David Schriger, David Newman, Anand Swaminathan, and many others feel tPA for stroke remains an unproven and inadequately described therapy for acute ischemic stroke.  Indeed, Dr. Swaminathan ably debates Dr. Jagoda, one of the authors of this Clinical Policy in podcast, hosted by Scott Weingart.

Citation:  http://emcrit.org/podcasts/tpa-for-ischemic-stroke-debate/

Lest ACEP consider these objections simply a vocal minority or lunatic fringe, it should be noted active debate continues in the international literature as well.  Just last year, the BMJ posted a “Head to Head” debate regarding the proven efficacy of tPA in acute ischemic stroke.  An unscientific poll accompanying the article reported a slim majority of respondents did not feel tPA was proven effective.

Citation:  http://www.bmj.com/content/347/bmj.f5215

Additionally, there remains disagreement between international professional societies regarding the use of tPA in acute ischemic stroke.  While several countries endorse its use, others, such as Australia and New Zealand, remain concerned the strength of the evidence does not support widespread use.

Citations:
http://bit.ly/1nY6P18
http://bit.ly/1gRpYRs

In summary, the evidence does not support a Level A recommendation for tPA for ischemic stroke within 3 hours.

There is no reasonable justification for anything higher than a Level B recommendation – and even then, a caveat stating this has never been demonstrated as efficacious compared to usual therapy outside of controlled clinical trial environments.  Physicians may consider offering this therapy based on comfort, diagnostic certainty, supporting resources, and institutional commitment, but it should not be considered the standard of care.

Page 227, Line 28:
Area of Content / Concept – Patient Management Recommendations
The Level B recommendation given to IV tPA is inappropriate given the lack of unbiased evidence in support of treatment beyond the 3 hour time window.  This therapy is not approved in the U.S. and the Class I evidence regarding the 3-4.5 hour time window is conflicting.  ECASS, ECASS II, and ECASS III are manufacturer-sponsored studies of which only ECASS III demonstrated benefit.  ATLANTIS, also manufacturer-sponsored, enrolled patients similar to the NINDS criteria and showed harms beyond 5 hours, futility in the 3-5 hour window, and no usable insights in the 0-3 hour timeframe.  As Clark and Madden note, “Keep the three hour tPA window: the lost study of Atlantis” – ECASS III alone is not enough to refute prior evidence of either futility or harm.  There is a reason why the FDA still has not approved IV tPA beyond 3 hours.
ECASS III is also flawed regarding a baseline imbalance of prior stroke included in the placebo arm.  The absolute difference in percentage of patients with prior stroke is identical to the effect size offered by IV tPA.  Even more concerning regarding the internal validity of the findings, ECASS III offers this COI statement:
Supported by Boehringer Ingelheim.
Dr. Hacke reports receiving consulting, advisory board, and lecture fees from Paion, Forest Laboratories, Lundbeck, and Boehringer Ingelheim and grant support from Lundbeck; Dr. Brozman, receiving consulting and lecture fees from Sanofi- Aventis and consulting fees and grant support from Boehringer Ingelheim; Dr. Davalos, receiving consulting fees from Boeh- ringer Ingelheim, the Ferrer Group, Paion, and Lundbeck and lecture fees from Boehringer Ingelheim, Pfizer, Ferrer Group, Paion, and Bristol-Myers Squibb; Dr. Kaste, receiving consulting and lecture fees from Boehringer Ingelheim; Dr. Larrue, receiv- ing consulting fees from Pierre Fabre; Dr. Lees, receiving con- sulting fees from Boehringer Ingelheim, Paion, Forest, and Lund- beck, lecture fees from the Ferrer Group, and grant support from Boehringer Ingelheim; Dr. Schneider, receiving consulting fees from the Ferrer Group, D-Pharm, BrainsGate, and Stroke Treat- ment Academic Industry Round Table (STAIR) and lecture fees from Boehringer Ingelheim and Trommsdorff Arzneimittel; Dr. von Kummer, receiving consulting fees from Boehringer Ingel- heim and Paion and lecture fees from Boehringer Ingelheim and Bayer Schering Pharma; Dr. Wahlgren, receiving consulting fees from ThromboGenics, lecture fees from Ferrer and Boehringer Ingelheim, and grant support from Boehringer Ingelheim; Dr. Toni, receiving consulting fees from Boehringer Ingelheim and lecture fees from Boehringer Ingelheim, Sanofi-Aventis, and Novo Nordisk; and Drs. Bluhmki, Machnig, and Medeghri, being employees of Boehringer Ingelheim.
As I did not mention it previously, the meta-analysis by Lees also supplies this relevant COI statement:
KRL, RvK, DT, MK, and WH report honoraria from Boehringer Ingelheim for their roles in conduct of the ECASS trials. KRL reports honoraria from Lundbeck and Thrombogenics. DT reports honoraria from Novo-Nordisk, Pfizer, Sanofi-Aventis, and Boehringer Ingelheim. EB is an employee of Boehringer Ingelheim. RvK and JCG report being consultants to Lundbeck. GWA reports being a consultant to Lundbeck and Boehringer Ingelheim. SMD reports honoraria from Boehringer Ingelheim.
Confident translation in policy of clinical trial evidence having this level of COI is simply not reasonable.

Finally, it should also be noted the updated meta-analysis by Wardlaw accompanying the publication of IST-3 no longer shows a statistically significant benefit for alive and independent for the 3-6h time frame – moving from OR 1.17 (1.00 – 1.36) to OR 1.07 (0.96 – 1.20).  This ought to be viewed as regression to the mean as the sample size continues to increase.  Considering thrombolytic trials for myocardial infarction enrolled 140,000 patients, rather than the ~3500 tPA patients from the trials included in the Wardlaw meta-analysis, this should serve as a warning regarding the inadequacy of current evidence.

In summary, treatment beyond 3 hours can only be recommended based on “expert” (e.g., the sponsored mouthpieces of industry) opinion, should be considered only as part of prospective research, and absolutely not be recommended or implied to be standard of care.
Page 232, Line 28:
Area of Content / Concept – NINDS Exclusion Criteria
There is no mention of oral anticoagulation in these treatment recommendations, other than reference to the NINDS exclusion criteria regarding PTT and PT.
The safety of tPA given concomitant use of coumadin and the novel oral anticoagulants (direct thrombin inhibitors, factor Xa inhibitors) is not established.  Contradictory findings from meta-analyses and systematic reviews suggest increased risk of bleeding, even with INR <1.6.  Any CPG recommending offering IV tPA is remiss in excluding mention of these commonly prescribed medications in the population most at risk for stroke.
tPA cannot yet be considered safe when considered in the setting of anticoagulation, despite the NINDS inclusion criteria, in the absence of high-quality data on the subject.
Citations:

All NSAIDs are Created Equally . . . Right?

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

It’s been more than 10 years since Merck made headlines regarding the increased risk of atherothrombotic events with it’s drug rofecoxib (Vioxx) and 3 years since the almost $1 billion settlement regarding the drug. Over this time period, physicians have questioned the use of all non-steroidal anti-inflammatory drugs (NSAIDs) in patients with increased risk of coronary artery disease. Rofecoxib and its brethren were developed in the 1990’s as alternatives to the traditional NSAIDs (tNSAIDs). These newer drugs only inhibited COX-2 and theoretically would lead to less gastrointestinal bleeding since inhibition of COX-1 is believed to lead to this side effect. Based on this pathophysiologic theory and strong marketing, the drugs became widely prescribed. Unfortunately for our patients, saving the gut may compromise the heart. Or is it actually that all NSAIDs, regardless of which COX they inhibit, raises the risk?

This research group performed a meta-analysis of a large number of trials looking at both NSAIDs vs. placebo (280 trials) and one NSAID vs. another NSAID (474 trials). All of the studies look at length of use of at least four weeks but many had longer treatment durations. So, what did they find? When compared to placebo, coxibs (COX-2 inhibitors), diclofenac and ibuprofen all increased the risk of major coronary events but naproxen did not:
Coxibs RR (CI)
Diclofenac RR (CI)
Ibuprofen RR (CI)
Naproxen RR (CI)
Major Vascular Events
1.37 (1.14 – 1.66)
1.41 (1.12 – 1.78)
1.44 (0.89 – 2.33)
0.93 (0.69-1.27)
Major Coronary Events
1.76 (1.31-2.37)
1.70 1.19-2.41)
2.22 (1.10 – 4.48)
0.84 (0.52 – 1.35)
Gastrointestinal Complications
1.81 (1.17-2.81)
1.89 (1.16-3.09)
3.97 (2.22-7.10)
4.22 (2.71-6.56)

Additionally, it didn’t matter which coxib they looked at: all of them increased major coronary events. The coxibs did, however, do what they were supposed to do; the risk of gastrointestinal bleeding was lower in comparison to tNSAIDs like ibuprofen and naproxen.

Does this change what we should do? Can we give NSAIDs to older patients without fearing a major coronary event or death from an MI? The numbers here are small but important. For every 1000 patients allocated to a coxib, three more had major vascular events and one of these events would be fatal. That’s an absolute increase of 0.1% in comparison to placebo. Small increased risk but avoidable. Why not give naproxen instead? In fact, NSAIDs like ibuprofen interfere with the binding of aspirin negating its cardioprotective effects if the two are taken together. Naproxen doesn’t have this issue.
The relative safety in terms of major vascular events associated with naproxen versus ibuprofen was recently written about by the FDA and reported by the Associated Press here –

http://hosted.ap.org/dynamic/stories/U/US_PAIN_RELIEVERS_SAFETY?SITE=AP&SECTION=HOME&TEMPLATE=DEFAULT

I think the bottom line here isn’t much of a surprise. If you can, avoid NSAIDs in patients with cardiac risk factors. Ibuprofen isn’t a safe alternative. If you need to give an NSAID for whatever reason, use naproxen and use short courses of therapy.
“Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials”

Appendicitis Week Continues

As compared to the previously critiqued publication, I am rather pleased with the protocol described by these authors.

This is a clinical pathway for appendicitis from Children’s in Memphis prospectively evaluated for diagnostic accuracy.  They’ve taken the idealist route – risk-stratification, followed by discharge, ultrasound, or pediatric surgery evaluation.  These authors use the Pediatric Appendicitis Score, dropping patients into buckets based on scores 1-3, 4-7, and 8-10.  Most interestingly, there is no role for CT scanning in this pathway unless specifically requested by the consulting surgeon.

In this study, 196 children completed the full clinical pathway – 44 were in the low-risk group, 119 in the moderate-risk, and 33 in the high-risk group.  Almost all the low-risk patients were discharged from the Emergency Department with a telephone call follow-up, and only one patient had a callback – for what was eventually diagnosed as an omental infarct.  In the high-risk group, all 33 patients were admitted, and all 28 patients who were taken to the OR by surgery had appendicitis.  The 119 patients in the moderate-risk group are much more interesting.  33 of 119 ultimately had ultrasounds supporting a diagnosis of appendicitis, and all were confirmed in the OR.  However, the remainder of these patients either were discharged without ultrasound, or had negative ultrasounds.  There were, ultimately, 5 cases of appendicitis in the moderate-risk group, despite a negative ultrasound.

This is the main flaw in external validity of their protocol – what to do with a moderate-risk patient with a negative ultrasound?  Per the authors, the more concerning cases were admitted – either to surgery or pediatrics, depending on level of suspicion for an alternative diagnosis – or discharged with telephone follow-up.  I think many folks, when faced with this level of uncertainty, proceed to CT scan – but, amazingly, only 13 kids in this cohort were subjected to diagnostic or therapeutic radiation.  This statistic alone validates the protocol – and the cultural and operations changes necessary to make it work.  By having a safety net of follow-up calls in place for patients discharged from this clinical pathway, the pressure for an immediate diagnosis is eliminated.

It is a small sample size, and it requires providers to increase their comfort level with diagnostic uncertainty – but it certainly seems rational and promising.

“Prospective Evaluation of a Clinical Pathway for Suspected Appendicitis”
http://www.ncbi.nlm.nih.gov/pubmed/24379237