Codeine, Potentially Unpredictably Lethal

Frequently used in the pediatric population, codeine is a narcotic analgesic in prodrug form.  In the body, codeine is metabolized to morphine through the CYP2D6 pathway.  In the general population, it is estimated that approximate 10% of codeine undergoes conversion to morphine.

We’re generally familiar with the concept that a certain percentage of the population is ineffective at metabolizing codeine, and therefore receives no additional analgesic effect.  However, the flip side, as these authors report, is a CYP2D6 genotype of over-metabolizers.  In this case series, the over-metabolism of codeine in three post-surgical children likely resulted in supra-therapeutic conversion to morphine, leading to respiratory arrest.

The short summary – when possible, avoid medications that are unpredictably metabolized – such as codeine.

“More Codeine Fatalities After Tonsillectomy in North American Children”
www.ncbi.nlm.nih.gov/pubmed/22492761

Mobile Stroke Units – Probably Not Helpful

Door to needle times too long?  Well, take the needle to the patient, then.

This is an interesting idea that, unfortunately, probably isn’t a good idea.  They loaded a CT scanner, a stroke physician, a paramedic, and a mobile laboratory into a truck, and sent it out to meet acute stroke patients in the field.  The primary endpoint of the study – alarm to thrombolysis time – was great, with a mean time from alarm to therapy decision of 35 minutes.

The authors are very excited about the concept – as they feel the accelerated time scale in terms of acute stroke thrombolysis represents a paradigm shift in management.  Unfortunately, the patient-oriented outcomes – which were not part of the primary endpoint – don’t support their enthusiasm.

All their safety and therapeutic outcomes are underpowered, but, out of their 47 intervention patients and 53 control (in-hospital thrombolysis) patients, 12 vs. 6 were treated stroke mimics and 3 vs. 0 were dead within 7 days.  Comorbidities and stroke severity should have favored the intervention group, so, these outcomes are surprising.  But, it is underpowered, so more data is needed.

“Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial.”
http://www.ncbi.nlm.nih.gov/pubmed/22497929

The Dexamethasone Dose for Croup is 0.15mg/kg

Unfortunately, this is still probably not the trial that convinces everyone.  In fact, it’s been over 15 years since the original single-center trials/reports showing that 0.15mg/kg of dexamethasone was every bit as effective as 0.6mg/kg of dexamethasone.  This makes intuitive sense, considering the steroid equivalencies, and the doses used in studies that have established prednisolone as an adequate treatment for croup, as well.

Regardless, this is a very small – 30-odd patients – with mild croup, randomized to dexamethasone at 0.15mg/kg vs. placebo.  The point of this study was not to test the efficacy of dexamethasone, but rather to show that, despite it’s long half-life, it had immediate effects.  And, I think it’s fair to say this study demonstrates those significant effects in reduction in croup score, gaining statistical significance by 30 minutes.

I don’t know where the attachment came from in terms of the 0.6mg/kg dose of dexamethasone, but it’s just preposterously high.

“How fast does oral dexamethasone work in mild to moderately severe croup? A randomized double-blinded clinical trial.”
http://www.ncbi.nlm.nih.gov/pubmed/22313564

Rivaroxaban and Pulmonary Embolism

This is rivaroxaban, an oral Factor Xa inhibitor, part of the wave of potential warfarin replacements.  This is their phase III EINSTEIN-PE trial, which is a non-inferiority comparison against warfarin for the long-term outpatient management of pulmonary embolism.

Overall, it was slightly less effective at prevention of recurrent venous thromboembolism (2.1% vs 1.8%), but slightly safer with regards to bleeding episodes (10.3% vs. 11.4%).  Adherence to therapy was reasonable compared to other trials regarding the amount of time patients spent with therapeutic INR between 2.0 and 3.0.  So, really, it’s pretty much a wash.
But, of course, when you have a new and expensive therapy that’s essentially similar to the old, cheap option, the conclusion is: “Our findings in this study involving patients with pulmonary embolism, along with those of our previous evaluation involving patients with deep-vein thrombosis, support the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.”  
Of course, if you were expecting a different conclusion from an open-label, manufacturer-sponsored study, you are unfortunately mistaken.
So, make sure your hematology group is on board with PCCs, because there doesn’t seem to be any other possible option for reversing life-threatening bleeding – and rivaroxaban is coming, whether it should be or not.
“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

Is It Reasonable to Keep Using Vasopressin in Shock?

The authors of this meta-analysis seem to think so.
Unfortunately, they identify a very heterogenous set of evidence for analysis, which reduces the statistical power of every comparison.  They identify only a couple studies of vasopressin vs. placebo, and most of their studies are vasopressin vs. an increased dose of norepinephrine.
It’s hard to generate any unreasonable conclusion from this data – the error bars cross one, so you can either take this as permission to drop vasopressin from your usage patterns because its use has no measurable mortality benefit, or you can continue to use vasopressin because it doesn’t seem to be harmful, and allows you to reduce the dose of norepinephrine.
I’d really like to see more vasopressin vs. control – there’s only one reasonably sized vasopressin vs. placebo trial – and it heavily, but non-significantly, favors control with a risk ratio for mortality of 1.94 (0.74 to 5.10).
More to be done!
“Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis”

Ketamine + Propofol = Ketofol

Combining propofol, a beloved agent for procedural sedation for its rapid onset, quick recovery times, and titratable levels of sedation with ketamine, the world’s safest agent for unmonitored anesthesia, has been shown in case series to be as safe and effective as expected.

This small, randomized trial is a direct comparison between ketofol and propofol, with the primary outcome measure being the proportion of patients experiencing an adverse respiratory event using the standardized Quebec Criteria.  The authors are testing the hypothesis that use of ketofol will result in fewer adverse respiratory events, which they believe to be one of the weaknesses of propofol, and one of the strengths of ketamine.

With ~120 patients in each group, there is essentially no clinical or statistical difference between outcomes of the two groups.  Clinicians provided transient assisted ventilation for three ketofol patients and one propofol patient – which is not statistically different.  Secondary outcomes were similar, although a handful of ketofol patients experienced recovery agitation, some of which required treatment.

It seems odd to me that the authors would be testing the respiratory adverse events of ketofol – both ketamine and propofol are so profoundly safe, with already extremely low rates of assisted ventilation, and unplanned intubation rates of ~1 in 5,000 or more.  Ketofol has been similarly already shown to be extremely safe in terms of respiratory events, primarily in retrospective case series.  They’ve essentially set themselves up to test something that’s almost already conclusively expected to generate insignificant differences.  What is more interesting to clinicians now, when considering agents for sedation, is the secondary effects – hypotension, hypersalivation, vomiting, myoclonus, agitation – and how that affects procedural success and time to disposition.  Ketofol is a great combination – but its value seems to be in the mitigation of the non-airway adverse events.

“Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia:  A Randomized Double-Blind Trial”
http://www.ncbi.nlm.nih.gov/pubmed/22401952

Please Stop Using Azithromycin Indiscriminantly

There is a time and a place for a macrolide with a long half-life, and it is not empirically for pharyngitis.

And, it’s even less appropriate empirically for pharyngitis now that it’s been overused to the point where it’s nearly in the drinking water – because it can no longer be considered second-line for group A streptococcus for your penicillin allergic patients.

This is a case report and evidence review from Pediatrics that discusses two cases of rheumatic fever, both of which presented after treatment of GAS pharyngitis with azithromycin.  While rheumatic fever has been almost completely wiped out – there are so few of the RF emm types in circulation, that it’s almost nonexistent in the United States – there are still sporadic cases.  Macrolides are listed as second-line therapy for GAS, but single-institution studies have shown macrolide resistant streptococcus in up to 48% of patients.  Macrolide resistance varies greatly worldwide, from a low of 1.1% in Cyprus to 97.9% in Chinese children.

Why is macrolide resistance so high?  Azithromycin is the culprit; because it has such a long-half life, it spends a long time in the body at just below its mean inhibitory concentration, and preferentially selects for resistant strains.

Please stop using azithromycin.  Use doxycycline, or another alternative, when possible.  There has never been reported resistance to pencillin in GAS.

“Macrolide Treatment Failure in Streptococcal Pharyngitis Resulting in Acute Rheumatic Fever”
http://www.ncbi.nlm.nih.gov/pubmed/22311996

Zolpidem and Benzodiazepines Will Kill You

Apparently!

Especially if you’re elderly.

It’s an interesting observational, statistically matched-control study using Electronic Health Records to monitor prescriptions of zolpidem (Ambien) and other benzodiazepines (Temazepam), commonly used as sleep aids, particularly in the shift-work population.

I think this graph pretty well sums up their results:

Blue lines are hypnotic-free, orange lines are patients taking hypnotics.  Downward slopes – exaggerated by the vertical scale – are bad.  An increased hazard for cancer was also found in patients prescribed hypnotics.

There are, of course, flaws with this study – but it is consistent with other published literature suggesting harms associated with hypnotic use.  The huge limitation of a study like this is controlling retrospectively for all the comorbid cofounders.  They attempt to do this statistically with a small set of comorbid disease, but it remains a limitation.

“Hypnoticsassociation with mortality or cancer: a matched cohort study”
http://bmjopen.bmj.com/content/2/1/e000850

Is Midazolam Really Superior to Lorazepam?

Or, more accurately, is it reasonable to perform an intramuscular injection of midazolam rather than an intravenous injection of lorazepam for seizure-like activity in the prehospital setting?

Almost certainly.

In fact, some folks are taking this article and claiming that intramuscular midazolam is superior to intravenous lorazepam, that it’s a “game changer.”

Well, let’s not go crazy here.

As with any piece of literature, the more vocal the giddiness I see perpetuated about the internet, the more cautious I am with rushing to judgement.  It is, of course, a very well-designed, prospective, double-dummy, randomized, non-inferiority comparison between midazolam and lorazepam.  The aim of the study is, essentially, to show that, even though midazolam is not typically as rapidly effective at terminating seizures, the time difference is made up by intramuscular route versus the time required for an IV start.

What’s kind of odd that I see in this article is that nearly a third of the lorazepam group did not receive the benzodiazepine portion of the intervention – and they compare it to the midazolam group in which all but 5 patients received the intervention.  When their primary outcome is the number of folks who arrived seizure-free in the Emergency Department – it seems as though the 7% absolute difference between the two groups could be easily explained by the fact that a third of the lorazepam group didn’t receive an intervention.  Most of the lorazepam group had the intervention withheld because they stopped seizing of their own accord at the time of enrollment, with a minority having the intervention withheld because IV access could not be obtained.

And, the differences favoring midazolam are hard to pin down whether it’s actually medication superiority, or something different about the seizures.  42 patients in the lorazepam group failed to stop seizing after additional therapy, compared with only 22 in the midazolam group – is this a difference in efficacy, or a difference in the underlying disease process – which appears to be more resistant to any therapy, including rescue, in the lorazepam group?

But, in any event, this just nitpicking against the superiority argument, and not the non-inferiority argument.  From a clinical standpoint, it is clearly safe and effective to use intramuscular midazolam for seizures in the prehospital setting.  However, what I’d prefer to see is a similarly powered trial of intranasal midazolam, which takes all the injection risks for patient and provider out of the equation during the seizure.  This is a good first step, but I think we can make effective treatment even safer if intranasal can be shown non-inferior as well.

“Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus”
http://www.nejm.org/doi/full/10.1056/NEJMoa1107494

Ketamine For Acute Pain Control

So, there’s effective.  And then there’s effective, but insane.  I am aware that low-dose continuous infusions of ketamine are excellent adjunctive therapies to decrease narcotic use in trauma and orthopedic patients, but I have never seen ketamine used in bolus form to treat acute pain in the out-of-hospital setting.

But, that’s what we have.  After an initial 5mg IV bolus of morphine, patients were randomized to receive either additional morphine or ketamine boluses – 1 to 5mg of morphine every five minutes, or 10 to 20mg of ketamine every three minutes.  Pain medication was given per protocol until relief or adverse events.  And, the ketamine group was superior – pain scores dropped 5.6 points on the numerical verbal scale with ketamine and 3.2 with morphine.

However, the ketamine group also had a 39% incidence of adverse effects, compared with 14% of the morphine group.  The morphine group had mostly nausea, with one patient exhibiting a change in level of consciousness.  However, the ketamine group had multiple patients with decreased consciousness, disorientation, and emergence phenomena.  So, while the editor capsule summary states “Supplementing out-of-hospital opiods with low-dose ketamine is an effective strategy to mitigate trauma pain” he is technically correct, but the insanity of this strategy is trying to make an evidence-based decision about intracranial imaging after iatrogenically altering your patients prehospital.

What I appreciate best about this paper is how aggressive the paramedics were with treating pain – the patients receiving morphine averaged 14.4mg, with a standard deviation of 9.4mg!  I see my residents ordering 2mg at a time and it drives me nuts.

“Morphine and Ketamine Is Superior to Morphine Alone for Out-of-Hospital Trauma Analgesia: A Randomized Controlled Trial”
www.ncbi.nlm.nih.gov/pubmed/22243959