Category: Medication Safety

You Can’t Spell “Insanity” Without tPA

When you think you’ve seen it all – a call to administer tPA to acute stroke patients without a prior non-contrast CT.

Indeed, in this “Views & Reviews” article, the authors ask explicitly the question: “Is the administration of alteplase to patients with primary ICH that harmful?”  After much stimulating confabulation, the authors bafflingly conclude: “we cannot argue with confidence that alteplase administration to patients with ICH is harmful”.

Perhaps they’ve never treated patients with alteplase personally, and they further mis-cite or misinterpret the evidence regarding the influence of cerebral microbleeds on symptomatic intracranial hemorrhage.  Despite the clear evidence from multiple meta-analyses that cerebral microbleed burden prior to alteplase administration leads to substantially increased risk of ICH and neurologic worsening, these authors sum up this evidence as “either no increased risk of symptomatic ICH or an increased risk that does not necessarily preclude an overall benefit from alteplase.”

Nonsense.

Even better, the entire purpose of their intellectual exercise boils down to discarding the inconvenience of pre-lytic CT so that alteplase can be delivered pre-hospital.  Yes, rather than clinically correlating the presentation with maximal vascular and perfusion information to consider the safest, most potentially effective (if any) reperfusion therapy – these authors are promoting administration of a $6000 medication in a pre-hospital setting with a paucity of diagnostic expertise or technology available.

Good plan.

“And why not thrombolysis in the ambulance (at least for some)?”
http://www.neurology.org/content/early/2016/06/15/WNL.0000000000002835.short

ENCHANTED – Positive or Negative?

I am probably the last person to comment on ENCHANTED, the trial testing low-dose vs. standard-dose tPA in “Asians”.  When it was released, to some fanfare in the New England Journal of Medicine, I had little to say – it is, frankly, a rather bland contribution to the science.  What has been fascinating, however, is the unusually divergent interpretation of the results.  To wit, the accompanying editorial in the NEJM states:

“ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes.”

This is a relatively reasonable interpretation of the results – hinging on the word “compelling”.  No one’s hearts are to be set a-flutter over these results, but that does a disservice to the ultimate clinical question of which dose is appropriate.  The lay press, however, is here to clear things up – or is it?

“ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke?” 
“ENCHANTED results challenge reduced alteplase dose in Asian stroke patients”
“Low-Dose tPA Not as Effective, Even for Asians”
“Lower Dose of Clot-Busting Drug Reduces Brain Bleeding”
“Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke”
“Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke”

The question, simply, comes down to how easily one interprets “non-inferiority” – a point made nicely by Rory Spiegel in his post – and, further, how one interprets these findings in a Bayesian sense.  The prevailing opinion going into this trial was that low-dose tPA was safer and similarly efficacious in certain ethnic subpopulations on the Asian continent.  The nonsignificant difference (OR 1.09; 95% CI 0.95 to 1.25) in patients having excellent outcomes (mRS 0-1) and the even smaller difference (OR 1.03; 95% CI 0.89 to 1.19) in those having good outcomes (mRS 0-2) does nothing to move the needle on the prevailing clinical hypothesis.  If there is unlikely to be a profound difference in clinical outcomes, what of the safety outcomes?  Here, low-dose alteplase is obviously a winner – significant reductions in hemorrhage and a corresponding decrease in 90-day mortality (p=0.07).

If ECASS failed gloriously due to adverse effects at 1.1 mg/kg, subsequent trials found some favorable risk/benefit at 0.9 mg/kg, and the (supposed) clinical efficacy seems preserved with even greater safety at 0.6 mg/kg, it seems logical to expand interest in lower doses of tPA.  I disagree with those who would dismiss this trial as an unimportant “failure”.

“Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1515510

Try to Avoid tPA When Already Bleeding

Coming to us from the Department of Common Sense: don’t give tPA to stroke patients who already have intracranial hemorrhage.  There’s a little more subtlety here, of course, because in this instance, we’re dealing with cerebral microbleeds – tiny foci of angiographic damage visualized only on MRI.

These authors performed a pooled and individual-patient meta-analysis of those undergoing MRI prior to treatment with intravenous thrombolysis.  When stratified by CMB burden, arbitrarily divided into “none”, “1-10”, and “>10”, the obvious is … obvious: patients who are already bleeding are more likely to continue bleeding.  In the unadjusted raw numbers, patients with no CMB had a symptomatic intracranial hemorrhage rate of 4.3%, those with 1-10 CMB had 6.1%, and those with >10 had 40.0%.

There are many technical limitations inherent to the retrospective nature of their study, as well as likely other confounding variables – but, the basic gist: our current practice relying only on non-contrast CT likely misses an important safety indicator in the setting of tPA use.

“Risk of Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke and High Cerebral Microbleed Burden”
https://www.ncbi.nlm.nih.gov/pubmed/27088650

NSAIDs Probably Best for Renal Colic

It has long held that non-steroidal anti-inflammatory treatment is specifically ideal for symptomatic ureterolithiasis – leading to the popularity of such treatments as intravenous and intramuscular ketorolac, diclofenac, and the like.

However, I hadn’t quite seen as large and well-designed comparative efficacy trial as this, as recently published in The Lancet.  This trial, a placebo-control, double-blind, randomized trial compared 75mg intramuscular diclofenac, 1g intravenous paracetamol, and 0.1mg/kg intravenous morphine for patients with acute renal colic.  This means, most impressively, every patient received three injections – one active and two placebo.  The primary outcome was 50% reduction in initial pain score by 30 minutes, with relevant secondary outcomes of persistent pain and need for secondary analgesia.

Based on an analysis only of those who ultimately had confirmed diagnosis of stone on imaging (CT or ultrasound), both diclofenac and paracetamol were similar or superior to morphine, with fewer adverse effects.  Pain scores were halved in 68% of diclofenac, 66% of paracetamol, and 61% of morphine.  Most importantly, need for rescue medication in this trial was only 12% with the intramuscular diclofenac, an important consideration when potentially forgoing an IV start.  The authors actually probably understate the advantage of diclofenac here, as time zero is the time of study medication administration, not time of ED arrival, as an intramuscular injection can be provided much more rapidly than one requiring an IV.

Generalizability may be limited, as it is a single-center study from Qatar in which 80+% of patients were male.  At least however, the nationality of patients were quite diverse, representing Indian, Egyptian, Nepalese, Pakistani, Bangladeshi, Sri Lankan, and many others.

“Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial”
https://www.ncbi.nlm.nih.gov/pubmed/26993881

Acetaminophen is Good, But Morphine is Better

Much has been made recently of the risks and harms of opiates.  The main problem – sometimes they really do work.  Thanks to this study, we again confirm our prior conception of just how well they do work – at least for sciatica.

This trial randomized 300 patients with sciatica to intravenous morphine, paracetamol (acetaminophen), or placebo.  For obvious ethical concerns, all patients received fentanyl rescue at 30 minutes, as needed.  All groups started out around 80 on the pain VAS.  Placebo dropped patients to a mean of 66.  Paracetamol dropped patients to 41.  And morphine dropped patients to 24.  More interestingly, 80% of placebo needed rescue therapy – which implies 20% did not.  Then, 18% of acetaminophen received rescue therapy, followed by 6% of morphine.

So, while morphine is obviously statistically superior to paracetamol, the clinically important difference is less apparent.  The vast majority of patients will have enough relief from paracetamol that additional therapy is unneeded – and, in general, intravenous paracetamol is not likely to have quite the risk of adverse effects.

However, some of the generalizability of this study is limited, as many contexts attempt to manage this pain with oral medications, rather than intravenous.  And, this study may also only be generalizable to your patients based on how similar they are to the typical Emergency Department visitor in Turkey.

“Comparison of Intravenous Morphine vs Paracetamol in Sciatica: A Randomized Placebo Controlled Trial”

Are Antibiotics Back in Favor for Abscesses?

A couple years ago, the IDSA came out with antibiotic treatment guidelines covering uncomplicated cutaneous abscesses.  The simple, straightforward treatment many of us have been advocating: incision and drainage without antibiotics.

Sadly, such days may be finished.

A few years back, a small trial found no statistically difference in clinical cure for patients randomized to trimethoprim-sulfamethoxazole or placebo – but there were concerns regarding whether the study was appropriately powered.  This, larger, multi-center, double-blind, randomized, placebo-controlled trial aims to rectify that flaw.

With the usual exclusions for patients with serious comorbid disease, these authors enrolled 1,265 to ultimately analyze 1,247.  Acute abscesses of greater than 2.0cm, but still appropriate for outpatient management, were randomized either to 7 days of TMP-SMX or identical-appearing placebo.  There were several different follow-up time frames: for initial clinical improvement, “test of cure”, and for secondary outcomes of abscess recurrence.

There’s not much debate on the outcome – with the TMP-SMX arm generating a fairly consistent ~7% absolute cure rate improvement over placebo.  In the per-protocol population, which excluded patients lost to follow-up, cure rate was 92.9% in the TMP-SMX group versus 85.7% in the placebo cohort.  Furthermore, throughout every meaningful secondary outcome – particularly new skin infection at another site or an infection occurring in a household member – TMP-SMX was favored in proportions of similar absolute magnitude.  Adverse events were similar between each group, without a preponderance of apparent harms from TMP-SMX.

An NNT of ~14 is nothing at which to scoff.  The costs of the intervention are fairly low.  We are definitely missing some of the granular detail in this first publication, and it is difficult to say whether it’s generalizable to smaller abscess or how to manage abscesses with minimal surrounding cellulitis.  I look forward to these follow-up analyses to potentially improve the precision of treatment – but, in the meantime, it may be time to roll back some of our antibiotic stewardship movements in MRSA-endemic regions.

“Trimethoprim–Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess”
http://www.nejm.org/doi/full/10.1056/NEJMoa1507476

Ketamine For Anger Management

From the land of “we still have droperidol”, this case series details the use of ketamine as “rescue” treatment for “agitated delirium”.  In lay terms, the situation they’re describing is the utterly bonkers patient being physically restrained by law enforcement for whom nothing else has worked.

In this case series, which represented only 49 of 1,296 patients with acute agitation, intramuscular ketamine was used as second- or third-line therapy behind droperidol and benzodiazepines.  Target dosing was 4-6 mg/kg, similar to procedural sedation.  Of the 49 requiring rescue ketamine, 44 were effectively sedated within 120 minutes – with a median time to sedation of 20 minutes.  The patients who were not adequately sedated with their initial dose of ketamine almost all received deliberate underdosing out of concern for potential respiratory impairment.

Three patients suffered adverse effects – two with vomiting, and one with desaturation 40 minutes after ketamine.  As with any observational series without a control, particularly a small one, little can be conclusively stated regarding the safety.  However, it is reasonable to consider any potential harms from such large doses of ketamine in the context of the harms of alternative sedating agents or injuries from continued agitation.

It may even be worth trying on the big green guy.

“Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/26899459

Getting Chronic Pain Out of the Emergency Department

This is yet another entry into the parade of narcotic-overuse articles – but, at least, this one shines some light on potential solutions.

Their introduction is full of the standard lovely doom-and-gloom statistics:

  • From 1999 to 2008 there was a concomitant increase in prescription drug abuse with reported opioid overdose deaths tripling.
  • Health care providers wrote 259 million prescriptions for painkillers in 2012, enough for every American adult to have a bottle of pills.
  • Approximately 16,000 deaths in the United States (U.S) are attributed to prescription opioid overdose annually.

Their report is simply a single-center pre- and post-intervention study.  They look backwards at, specifically, 46 patients identified as “high utilizers” with chronic pain and prior documentation of Emergency Department misuse.  Each of these patients was evaluated in concert with their primary care physician or chronic pain specialist, and a specific follow-up plan-of-care was established.  Patients were all informed of their care plan, the most salient portion being narcotics and benzodiazepines would be essentially omitted from any Emergency Department visit.

Patient visits to the ED declined from an average of 6.2 in the six-month pre-intervention period to 2.2 in the post-intervention period.  These data would also indicate a more profound effect excepting for one patient whose change in treatment plan paradoxically increased his ED visits four-fold, resulting in nearly 40 ED visits in the post-intervention period.  Unfortunately, these data only reflect ED use of one hospital, and does not indicate whether visits to other EDs were affected.

The reduction in ED visits is certainly apparently favorable – but, better yet, the median number of narcotic pills, as recorded in the state database, prescribed to each patient dropped from 664 to 471.  Changes in pill use, however, were much more heterogenous – and could be confounded by pill prescribing in closely neighboring states.  And, regardless of the improvement, pain management clearly continued to consist of fairly robust quantities of narcotics.

It’s at least a start, and, definitely some improvement.  If your system has the resources to develop care plans for individual patients, the benefits likely outweigh the drawbacks.

“Impact of a Chronic Pain Protocol on Emergency Department Utilization”
http://www.ncbi.nlm.nih.gov/pubmed/26910248

Let’s Replace: Droperidol; With: Olanzapine

The U.S. has been suffering acute droperidol-emia for quite some time, now.  Around the time ondansetron was exclusively on-patent, the FDA “coincidentally” published a “black box” for this otherwise universally beloved medication.  This led to restrictions in use at many institutions.  Then, recently, it’s simply no longer available from any local manufacturer.  It is a sad world, indeed.

At times, I have replaced its use with haloperidol.   Droperidol and haloperidol are, of course, both typical butyrophenone antipsychotics – but the complex metabolism of haloperidol leads to some unpredictability in sedation and effect.  Despite being approved only for oral and intramuscular use, I have occasionally used olanzapine intravenously for headache in the Emergency Department – and, now, the fine folks at Hennepin County have published their robust experience.

This is simply a retrospective review of its use at their institution, with an eye towards safety events, not effectiveness.  Six months of data, comprising 713 patients, were manually reviewed by two co-authors.  The most common usages for olanzapine were agitation (34.4%), abdominal pain (23.1%), headache (17.0%), nausea & vomiting (15.0%), and non-specific pain (8.4%).  Many patients reviewed also received co-administration of olanzapine with other sedating medications, including opiates, benzodiazepines, and ketamine.

Unfortunately, this study ultimately does not provide terribly insightful data regarding olanzapine use.  Only 20 patients had an EKG before and after administration, and median increase in QTc was 12ms.  Four patients suffered akasthisia “likely” or “possibly” related to olanzapine.  About 10% of patients required supplemental oxygen for respiratory depression and hypoxia.  Then, seven patients required intubation and two patients died during their subsequent hospitalizations.  Each of these serious adverse outcomes was multifactorial.

So, there is no simple answer regarding olanzapine.  Just like the case series behind the black box for droperidol, olanzapine was used in many patients with significant comorbid physiology or pharmacology.  Without a control or comparator group, this study cannot address the comparative efficacy and safety of any potential alternative agents.  It is probably reasonable to consider olanzapine as an option in situations where droperidol was previously used, but its effectiveness and true safety remains unknown.

“A Large Retrospective Cohort of Patients Receiving Intravenous Olanzapine in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/26720055

When Procedural Sedation Goes Wrong

Like any typical Emergency Physician, procedural sedation is a frequent part of my practice.  Each procedure, of course, is preceded by discussion of informed consent – the balance of risks, benefits, and alternatives to the procedure.  The risks of many procedures in medicine are, luckily, quite rare – but just how rare are these risks in procedural sedation?

That’s why I love systematic reviews like these – so I can be substantially more precise in such discussions.  Moreso, if you love forest plots – you’ll really love this article.

The high points:

  • Agitation associated with procedural sedation is almost entirely the domain of ketamine, at 16% pooled incidence.  “Ketofol” brings it down to 4.8%, and the remainder are ~1 in 1000.
  • Aspiration was observed once in a pooled multi-agent sample of 2,370 patients.
  • Bradycardia was witnessed essentially only in one study using etomidate – otherwise ~1 in 250.
  • Hypotension is most frequent with propofol, but still only 2%.  The rest fall around 1% or less.
  • Hypoxia was a little harder to pin down, with most agents’ results skewed by outlier studies.  5% is probably reasonable for propofol, while ketamine-containing protocols are probably ~1% or lower.
  • Laryngospasm was witnessed ~1 in 1,500.

It’s worth scanning through their detailed visualizations of their results to get a feel for how different agents compare.  For what its worth, these data general support my practice of using mostly propofol, ketamine, or combinations of each.

“Incidence of Adverse Events in Adults Undergoing Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis”
http://www.ncbi.nlm.nih.gov/pubmed/26801209