It’s not very often I read an article and decide to I’d like to incorporate it into my practice. EMCrit covered this last month, but I reserved judgement until I had a chance to read the primary literature for myself.
This is the MOPETT trial – half-dose (?”safe dose”) tPA for “moderate” pulmonary embolism. We already know what to do for “massive” PE – full-dose thrombolytics when not otherwise contraindicated. However, the data for full-dose thrombolytics in “submassive” PE is less conclusive.
These authors enrolled relatively ill PE patients – tachypneic, hypoxic, tachycardic patients with >70% thrombotic occlusion of lobar or main pulmonary arteries – but did not apply regularly applied measures of “submassive” – RV dysfunction, elevated troponins, elevated BNP. Their primary outcome was long-term development of pulmonary hypertension, with mortality and bleeding as their secondary outcomes. They dosed tPA at 50mg, rather than 100mg – 10mg bolus and 40mg infusion.
Their two cohorts were rather well matched. Outcomes favored the thrombolysis group, with 16% subsequent pulmonary hypertension compared with 57% in the control group. Mortality, recurrent pulmonary embolism, and bleeding complications were similar and at rates too low to detect a difference given the power of the study.
I’d like to start doing this. I wish they published the troponin/BNP/RV dysfunction rates in the two cohorts to provide better context with the other submassive literature. I also would have preferred to see this study registered with clinicaltrials.gov. But, in a nice change, none of the authors declare any conflicts of interest!
“Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial)”
www.ncbi.nlm.nih.gov/pubmed/23102885
Category: Medication Safety
Etomidate, Safe for Sepsis?
Sadly, the jury is still out. Just months after Critical Care Medicine published the systematic review demonstrating an association between use of etomidate and mortality in sepsis, now they’re back with a retrospective data-mining expedition that draws the opposite conclusion.
This is a multi-center prospective registry of critically ill patients entered into a research database who were retrospectively data-mined for septic, intubated patients. Of the 42,000 patients in the database, approximately 2,000 met this definition, and about half were identified as receiving etomidate as their induction agent. In their cohort, there was no in-hospital mortality difference between the patients who received etomidate and the patients who received a different induction agent for intubation.
Unfortunately, as an observational, retrospective study of imperfectly matched cohorts, there are far too many uncontrolled confounders to base clinical practice on these findings. Studies such as these, even robust, prospective cohorts, are capable of doing little more than suggesting a hypothesis contrary to the findings of prior work.
If you believe etomidate has a chance to harm patients in sepsis, this doesn’t change your practice.
“Single-Dose Etomidate Is Not Associated With Increased Mortality in ICU Patients With Sepsis: Analysis of a Large Electronic ICU Database”
www.ncbi.nlm.nih.gov/pubmed/23318491
New ACEP tPA Clinical Policy
If you’re still skeptical about the use of tPA in stroke patients – too bad. If you’re not on the bus, it would seem now you’re under it. ACEP has published their new Clinical Policy regarding tPA use in the most recent issue of Annals of Emergency Medicine. tPA should be offered to folks in the 0-3 hour window who meet NINDS criteria as a Level A recommendation. This is based on the following Class I evidence:
- Two studies that are negative for benefit (ECASS, ATLANTIS)
- The post-hoc analysis of ATLANTIS B with 61 patients,
- NINDS
The Level B recommendation is that tPA be considered for use off-label in the 3-4.5 hour window, based on ECASS III.
If you’ll travel backwards in time a couple days (by scrolling down), you’ll see I did a quick review of two articles concerning the “trustworthiness” of clinical practice guidelines. The Institute of Medicine names eight criteria – and, for the most part, this guideline does OK. It does, unfortunately, fare less well at the conflict of interests declared:
- Dr. Smith – Served on scientific advisory board for Genentech.
- Dr. Gronseth – Speakers’ bureau for, and honoraria from, Boehringer Ingelheim.
- Dr. Messe – Former speakers’ bureau for Boehringer Ingelheim.
Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.
If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.
“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department”
Pain Control on the Wrong Track
Codeine, the oral narcotic analgesia that is long past its prime. Approximately 8% of the caucasian population cannot metabolize codeine into morphine – and then a small handful are rapid metabolizers that will overdose on an otherwise therapeutic dose. But, this didn’t stop these folks in Montreal from evaluating its efficacy for pediatric musculoskeletal limb pain.
Pediatric pain is a little odd. Overall, the Emergency Department does a poor job of treating pain. Studies in pediatric EDs show significant percentages of injured patients don’t receive any pain control. But, then, we all have the anecdotal experience in which a child is sitting on a stretcher watching TV with a fractured arm denying he’s in any pain at all – why are you bothering me again? Spongebob is on.
Long story short, this study randomized children to receive either ibuprofen alone or ibuprofen plus codeine. At each time point, the difference in pain scales was no different between groups. Pain scores weren’t that high to begin with, and had moderate improvement after either treatment.
For minor pain, acetaminophen and ibuprofen are adequate options. For more severe pain, intravenous narcotics, intranasal narcotics, or even intramuscular ketamine are probably better options.
“Efficacy of an Ibuprofen/Codeine Combination for Pain Management in Children Presenting to the Emergency Department With a Limb Injury: A Pilot Study”
www.ncbi.nlm.nih.gov/pubmed/23232154
Pouring Money Into Prehospital Stroke Thrombolysis
Staying consistent with the “brain attack!” slogan folks developed for stroke, the innovations in treatment continue to progress in their attempts to mimic myocardial infarction. In myocardial infarction, a great deal of focus has been placed on rapid diagnosis and either thrombolysis or interventional catheterization. This extends to the prehospital arena, with experimentation with ECG transmission, pre-hospital lytics, and pre-hospital cath lab activations.
For stroke, they’re still trying to replicate this pre-hospital diagnosis and treatment – made slightly more complex because the diagnostics involved requires CT scanning. However, with enough funding from telehealth and imaging industry, “mobile stroke units” have been created for feasibility evaluations.
And, these authors have certainly demonstrated that it is feasible, diagnosing 48 acute strokes in the prehospital setting and giving half of them thrombolysis. One patient given rt-PA had sepsis rather than an acute stroke, which is of uncertain significance in an underpowered feasibility case series such as this.
However, there’s a difference between can and should. I’m uncertain whether we should even be exploring the can portion in this pilot, considering should means a grossly excessive allocation of resources for a therapy of uncertain benefit. Given the small absolute benefits seen in the handful of trials that even showed a benefit, I can’t possibly see how trials of pre-hospital lytics could favor anything but surrogate endpoints, rather than patient-oriented endpoints. 30 minutes faster to TPA? At what cost, and did outcomes change?
I won’t fault the authors for their interesting experiment – as long as they don’t seriously propose it as The Future based on our current evidence.
“Prehospital thrombolysis in acute stroke : Results of the PHANTOM-S pilot study”
www.ncbi.nlm.nih.gov/pubmed/23223534
Next Up – Apixaban!
The latest installment of propaganda in the NEJM comes from Pfizer and Bristol-Meyers Squibb, the joint venture behind apixaban. Along with rivaroxaban, apixaban is an oral Factor Xa inhibitor, another option in the procession of potential warfarin replacements. The Xa inhibitors, while they’ve had their problems, improve upon their main competitor – dabigatran – because they can be reversed in the emergency setting using prothrombin concentrate complexes (PCCs). Dabigatran, as we all know, has no practical reversal strategy.
This is AMPLIFY-EXT, the extended treatment option from AMPLIFY – where apixaban is continued for an additional 12 months for prophylaxis against recurrent venous thromboembolism. In isolation, looks great! The placebo group had an 8.8% VTE recurrence in the study period vs. 1.7% in either of the two apixaban doses. And, major bleeding in the placebo group exceeded the apixaban groups – 0.5% vs. 0.2% and 0.1%. More effective and safer than a sugar pill!
So, what’s the problem? Well, this is the third apixaban trial to be published in the NEJM in the last two years. The first one, apixaban for acute coronary syndrome, showed no benefit and increased bleeding. The next, apixaban for stroke prevention in non-valvular atrial fibrillation (ARISTOTLE), showed non-inferiority to warfarin – but the rate of major bleeding in that study was 2.1% per year. Then, the NEJM also has a recent article regarding aspirin for the prevention of recurrent VTE – where the placebo group only had a VTE recurrence risk of 6.5% rather than the 8.8% observed in AMPLIFY-EXT.
You can’t directly compare trial populations, of course, but it doesn’t make any sense that bleeding would be reduced compared to placebo. And, it’s a straw man comparison with placebo – the correct comparison is rather head-to-head against a potentially efficacious agent, such as low-dose aspirin. After all, low-dose ASA is pennies a day, rather than the ~$10 per day for apixaban.
Can’t blame the pharmaceutical companies for selling, can only blame the suckers for buying.
“Apixaban for Extended Treatment of Venous Thromboembolism”
http://www.nejm.org/doi/full/10.1056/NEJMoa1207541
Dabigatran: Hidden Danger in the Home
The flaws with dabigatran have been well-described on this blog – mostly focusing on its lack of realistic reversal options. However, less obvious are the unanticipated ways patients end up in situations requiring such reversal.
This case report from the Rocky Mountain Poison Center describes an elderly male on dabigatran who does something commonly seen in the elderly: he suffers acute renal failure from a minor medical illness. Unlike warfarin, dabigatran is renally excreted, and should not be used by patients with reduced glomerular filtration rates – these patients were excluded from the Phase III trials. In the presence of renal failure, the half-life increases from 12-17 hours to 18-27 hours, depending on the severity of the renal dysfunction. This leads to supratherapeutic levels.
This patient was noted to have a dabigatran plasma concentration nearly triple the therapeutic mean and developed spontaneous, unremitting gastrointestinal hemorrhage. Despite resuscitation, blood products, and emergency dialysis – which halved the dabigatran concentration within four hours – the patient expired.
Clinicians using dabigatran, therefore, need be acutely aware of any clinical changes in their patients that may reduce renal function.
“Fatal dabigatran toxicity secondary to acute renal failure”
www.ncbi.nlm.nih.gov/pubmed/23158612
Make Ketamine Work For You
Along with droperidol and dexamethasone, ketamine is on my short list of favorite medications for use in the Emergency Department. As this correspondence from authors at Highland Hospital summarizes, it’s a floor wax and a dessert topping:
– Use as peri-procedural pain control/anxiolytic to assist with subcutaneous infiltrative local anesthesia.
– Use as adjunctive pain control in patients who are failing high-dose narcotics.
– Use as pain control/anxiolytic in patients with significant supratentorial comorbidities.
These authors state “In clinical practice, chronic pain, psychologic distress, and behavioral disorders frequently overlap”, and I couldn’t agree more. Sub-disassociative doses of ketamine (0.1 to 0.3 mg/kg) have an excellent safety profile and represent an ideal option for multiple common clinical situations in the ED.
If your ED restricts the use of ketamine, you need to make that stop.
“Emerging applications of low-dose ketamine for pain management in the ED”
www.ncbi.nlm.nih.gov/pubmed/23159425
Don’t ß-Blockade Cocaine Chest Pain
Or, specifically, ignore this evidence that says you can.
There may be some mythology to the hypothesis that non-selective ß-receptor blockade is contraindicated in the setting of cocaine chest pain. After all, the supporting evidence consists only of small, laboratory case series – and other outcomes-oriented data suggests ß-blockade is cardioprotective, as we already know. However, this study is a perfect example of inappropriately extending a conclusion from retrospective data.
These authors identified 378 patients from retrospective chart review, selecting patients with chief complaints of chest pain and positive toxicology tests for cocaine. Unfortunately, urine toxicology tests for cocaine stay positive for days following the initial episode of cocaine use. Therefore, there is no way from these chart review methods to reliably differentiate the acuity of the cocaine intoxication.
This is important because a major flaw in retrospective reviews, such as this, is a confounding selection bias. If all cocaine chest pain patients are not created equal – the neurohormonal effects of cocaine last on the minutes to hours while their drug tests are positive for days – then providers may be selecting patients for beta blocker use/non-use based on acuity information this review cannot detect. If providers are excluding patients from beta-blockers based on the acuity of their intoxication – as many sensible providers might – and only using beta-blockers in non-acute presentations, then this study may not include any of the population of interest.
The authors’ statement of “We have found that BB use in the acute management of cocaine-associated chest pain did not increase the incidence of MI” cannot be defended as accurate, as it is based on indefensible assumptions.
“Safety of β-blockers in the acute management of cocaine-associated chest pain”
http://www.ncbi.nlm.nih.gov/pubmed/23122421
PCA in the ED is Brilliant and Horrible
Management of acute pain in the Emergency Department is frequently inadequate. Considering the practice environment, the ebb and flow of workload, and the heterogenous presentations, this is not surprising. On the inpatient side of things, many patients with acute, severe pain receive patient-controlled analgesia. So, this is a randomized, controlled trial of PCA vs. conventional, untitrated boluses in the ED.
And, they were successful in demonstrating significant trends towards better, faster pain control and increased patient satisfaction with the PCA. Both groups received the same total amount of morphine, but the dynamics by which patients were able to self-titrate their pain control resulted in improved pain relief.
Unfortunately, there are some flaws with this study. This multi-center study only managed to enroll 96 patients in a one-year timeframe – probably the number we could aggressively enroll at my institution in a week. There is no mention of adverse events – which is significant, because PCA medication variances are renowned on the inpatient side as significant sources of morbidity. And, finally, they don’t measure any of the other operational variables that are important – cost, time to set up, etc.
Patient-controlled analgesia may yet have a role in the ED – and studies like this help keep the flame alive – but significant hurdles remain.
“A Randomized Controlled Trial of Patient-Controlled Analgesia Compared with Boluses of Analgesia for the Control of Acute Traumatic Pain in the Emergency Department”
www.ncbi.nlm.nih.gov/pubmed/23068783