Do you shenfu? Shenfu injection for septic shock.

There is probably better quality evidence for shenfu injection for sepsis than the recent craze over Vitamin C… pretty sad considering this awful paper.

Shenfu…?

It’s a “well-known traditional Chinese formulation restoring Yang from collapse, tonifying Qi for relieving desertion…” (It’s made from ginseng and aconite.)

So if you need your Yang restored and your Qi tonified then Shenfu is for you! Especially if you are feeling a bit septic?

Back to this randomized placebo controlled trial…

157 patients with sepsis were randomized to either shenfu injection vs. placebo in addition to usual care.

Inclusion criteria relied on the Third International Consensus Definition for sepsis and septic shock published in 2016… even though this study was conducted from June 2010 to November 2012. Perhaps shenfu makes you see into the future…?

The primary outcome was lots of things… something to do with cellular immunity, CD4, CD8 counts, mHLA-DR expression, ex-vivo endotoxin LPS induced TNF, IL 6 and IL 10 cytokines, length of ICU stay, vasopressor use, illness severity, etc.

Why didn’t they just measure the Yang and Qi?

Believe it or not, the authors state the study was powered to the secondary outcome of mortality at 28 days. They were looking for a “holy shit!” difference of 20% and as such only needed low numbers of patients.  (Could it be they changed their original primary outcome to a secondary one after no difference was found? No….)

Results?

Shenfu was great! (except for mortality… but who cares)

The authors conclude, “these findings suggest that shenfu injection can enhance the cellular immunity of patients with septic shock and could be a promising adjunctive treatment for patients with septic shock.”

So for all of you out there giving Vitamin C for sepsis, perhaps you should mix it with a little shenfu… shouldn’t hurt?

Covering:

Zhang N, Liu J, Qiu Z, Shenfu injection for improving cellular immunity and clinical outcome in patients with sepsis or septic shock. Am J Emerg Med 2017;35:1-6.

Geckos & Watermelons: Association Between Tracheal Intubation During Adult In-Hospital Cardiac Arrest and Survival

Generally speaking, what do you get when you perform an observational study based on registry data?

Not much.

Nevertheless, this study does pose an interesting research question. Is intubation beneficial for in-hospital cardiac arrest? Or should we just use other means of ventilation and resuscitate accordingly.

To really answer this question, one would ideally like to see a randomized trial so that confounders are equal amongst the two groups. Otherwise we might be comparing geckos to watermelons.

Back to the study...

This was an observational cohort study of patients who had in-hospital cardiac arrest. The primary outcome was survival to hospital discharge.

Of 71,615 patients who were intubated in the first 15 minutes, 60% were matched to a patient not intubated in the same minute.

Survival was lower among patients who were intubated 16.3% vs those not intubated 19.4% (RR=0.84; 95% CI 0.81-0.87; p<.001)

So this was a huge study with a pretty p value… so it must be right?!

Wrong.

A few things...

You can’t overpower bias with big numbers.

This study relied on registry data which is notoriously of poor quality. Garbage in, garbage out. No amount of fancy statistics can make up for this.

Once again, this was not a randomized trial so the groups were very likely different from the start. The outcomes could very well be due to one group being sicker than the other. The authors tried to correct for this confounding by some clever propensity matching. But it must be emphasized that this is far from an exact science.

So what’s the take home?

Probably not much. But this study does lay the foundations for a proper randomized trial… hopefully only including geckos.

Covering:

Andersen LW, Granfeldt A, Calloway CW, et al. Association Between Tracheal Intubation During Adult In-Hospital Cardiac Arrest and Survival. JAMA 2017;317(5):494-506.

Trial of Pregabalin for Acute and Chronic Sciatica… Show me the money!

It seems half of the patients I see in the ED are taking Lyrica (pregabalin). Therefore, it was no surprise to me to see it at number 13 on the list of the biggest blockbuster drugs of 2015 making billions of dollars for Pfizer.  

But I was equally surprised to see a negative high quality RCT of pregabalin published in the highest impact journal on the planet!

Surely Pfizer was crazy when they funded and performed this study? Well… of course they weren’t… it was some other crazy authors.

This Australian NHMRC funded double-blind controlled trial randomized 209 participants to either pregabalin or placebo. The primary outcome was a leg-pain intensity score at the 8 week mark.

How much did the pregabalin help?

Zero, zip, zilch, nada…

There was no statistical improvement in the primary or any of the secondary outcomes. About the only thing we are sure of is the incidence of adverse events was significantly higher in the pregabalin group.

Although this was a small study (i.e. risk for Type II error), it probably had adequate power to detect a clinically meaningful difference in pain scores. And the results trended a favour towards placebo anyway.

Of course, no study is perfect. If I was working for Pfizer, I would point out that only a minority of the participants were likely to have neuropathic pain as measured on the PainDETECT score. So of course my drug wouldn’t work… while I sit on my horse made of gold.

As an aside…

I’ve been dubious of these neuopathic pain drugs. A disturbing study published in the NEJM demonstrated what looks like systematic research misconduct with gabapentin which is very closely related to pregabalin. This only was discovered during litigation and release of internal company documents. (This is probably my favourite journal club paper of all time…)

So what’s the take home message for the emergency docs?

Pregabalin probably does not help sciatica. But I would also be sceptical as to the benefits in a wide range of other indications… Especially with industry sponsored research.

Show me the money!

Covering:

Mathieson S, Chiro M, Maher C, et al. Trial of Pregabalin for Acute and Chronic Sciatica. N Engl J Med 2017;376:1111-20.

Risk for Clinically Relevant Adverse Cardiac Events (CRACE) in very low risk chest pain patients admitted to hospital (in the USA)

Move over MACE and say hello to CRACE!

These high profile authors from the USA sought to determine the incidence of short term life threatening events in low risk chest pain patients admitted to hospital.

Their concern was a lack of benefit from admission balanced with the potential harm (false positives, over-diagnosis, hospital acquired infections, VTE, iatrogenic etc.).

They reviewed a large database from 3 hospitals in the US Midwest from 2008-2013. They identified admitted patients that had negative serial biomarkers (old school troponins), normal vital signs and non-ischemic ECGs.

Interestingly, these authors picked a different outcome measure for this study from the traditional MACE that we have seen in many previous studies. They created “CRACE” defined as:

• Life-threatening arrhythmia (VF, symptomatic bradycardia, or treated brady or tachy arrhythmias)
• Inpatient STEMI
• Cardiac or respiratory arrest
• Death

(Noticeably absent from CRACE is non-STEMI or longer term outcomes beyond hospitalization.)

What did they find?

Of course this group was very low risk… but could you have guessed a CRACE rate of only 0.06% (4 of 7266 patients)!

As is usually the case, there were some methodological issues with this study and the reported rate is probably not a complete reflection of the truth. However this makes a compelling argument that this is an extremely low risk group that may derive more net harm from admission.

The authors are careful to mention that this study does not mean patients derive no utility from further investigation and management after the ED evaluation. But suggest this may be done as an outpatient and might provide a framework for shared decision making.

My guess is the Australians would never admit many of these low risk patients anyway. In addition, these patients would be even lower risk with the high sensitive troponin assays.

Take home? Perhaps we can sleep a little better knowing that low risk patients truly are very low risk. Hope this doesn’t seem to CRACEy…

Covering:

Weinstock MB, Weingart S, Orth F, et al. Risk for Clinically Relevant Adverse Cardiac Events in Patients With Chest Pain at Hospital Admission. JAMA Intern Med. 2015;175(7):1207-1212.

An RCT of Single Dose Dexamethasone vs. 5 days of Prednisone for Acute Adult Asthma... making life simple

Many emergency doctors have traditionally given a 5 day course of prednisone (prednisolone) for acute asthma. However, can the long duration of action (up to 72 hours) of dexamethasone replace a course of prednisone in a single dose? Certainly this would lead to less prescriptions and greater compliance.

The authors from Oakland, California enrolled 376 patients in a single ED with mild to moderate asthma. This was essentially defined as well enough to go home. They were randomized to either a single dose of dexamethasone 12mg or five days of prednisone 60m.

The primary outcome was “relapse” defined as an unscheduled return visit to a health care provider for asthma within 14 days. This was determined by telephone interview.

It was powered to a non-inferiority margin of 8%. In other words, if the results of the two treatment arms were within 8% then they were considered to be equivalent.  Why 8% you ask...? Ok, it’s a bit arbitrary.

Results?

So close...

Relapse rate for dex was 12% and pred was 10%. The absolute difference 2.3%. BUT the 95% confidence interval just scraped above 8%. Therefore this was a statistical fail.

But hold your horses.

There is one important point to emphasize... The study investigators gave the patients the prednisone tablets (or placebo) to take home from the ED. This nullified the prescription filling issue and certainly increased compliance. This biased the study to the prednisone arm.

I think the results are compelling and provide us with ongoing evidence that a single dose of dexamethasone is probably sufficient to treat mild to moderate asthma. This is on the back of numerous similar studies in the pediatric literature. Consistency is a powerful message.

For me, dexamethasone is close enough.

Covering:

Rehrer MW, Liu B, Rodriguez M, et al. A Randomized Controlled Noninferiority Trial of Single Dose of Oral Dexamethasone Versus 5 Days of Oral Prednisone in Acute Adult Asthma. Ann Emerg Med. 2016;68:608-13.

Should we give a lower dose of ketorolac for treating acute pain in the ED?

Ok, ketorolac is a little bit funny...

For some reason, it was never granted TGA approval in Australia for intravenous use although it is used all over the world in this manner. (Therefore it is perfectly fine for giving it IV off-label).

Second, it is probably the only drug where it is recommended to give a lower oral dose (10mg) than parenteral (30mg).

But now that 30mg IV dose is being challenged.

These authors from New York suggest the “ceiling dose” of ketorolac is probably 10mg and postulate that higher doses can cause more harm than good.

They performed a RCT of three different doses of IV ketorolac monotherapy; 10, 15 and 30mg. Inclusion criteria were adults with undifferentiated pain (most had acute flank, abdominal, musculoskeletal pain and headache). They had to have a numerical rating (NRS) of pain >5 not having had any previous pain medication.

The primary outcome was reduction in pain score at 30 minutes.

It was powered to find a 1.3 difference and as such 80 patients in each arm were enrolled.

Results?

The pain score dropped about 2.5 in both the 10 & 15mg doses of ketorolac. It dropped by 3.0 in the 30mg dose. This was not statistically significant.

The authors boldly conclude, “The results of our study provide a basis for changes in practice patterns and guidelines in ED care, supporting use of the 10mg intravenous ketorolac dose.”

Unfortunately this conclusion is inappropriate.

Despite the decent design and blinding of this study, there were significant problems such that one cannot make any decent conclusions.

Any time one does not see a dose response with a particular drug then one must seriously consider if it is having any effect at all. This is pharmacology 101. I very much imagine that placebo (i.e. a ketorolac dose of zero) would have given similar results in this heterogeneous group of patients with these study methods.

I give ketorolac in patients in whom I think it will have a greater benefit. This is usually part of a cocktail of medications and not monotherapy. It works extremely well in patients with renal colic but less so in those with abdominal pain and headache. So extrapolating the results of this study to the individual patient is problematic.

A key foundation of this study is predicated on the theoretical harm with a higher dose of ketorolac. Otherwise this whole discussion is moot. I would seriously question if a single dose at the higher range would cause clinically important problems. In addition, we can pick and choose which patients get higher doses. An 85 year old 40kg woman with chronic renal failure would probably never get ketorolac in the first place.

In summary, we don’t know if a lower dose of ketorolac is appropriate at the moment. A single administration of ketorolac at the standard dose would be extremely unlikely to cause clinically significant problems.

It is always wise to be sceptical of small single centre studies. In the end they are often proven wrong. Nevertheless, this study could provide foundation for future study and clinical equipoise for inclusion of a placebo dose of ketorolac.

Watch this space but don’t change you dose of ketorolac just yet.

(Addendum: Please see lead authors reply to this post under the comments section)

Covering:

Motov S, Yasavolian M, Likourezos A, et al. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. 2016 Dec 16. pii: S0196-0644(16)31244-6. doi:10.1016/j.annemergmed.2016.10.014. [Epub ahead of print]

Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation in the ED. An Australian RCT

What is the best drug for treatment of acute agitation in the ED?

Generally speaking we know the real answer to such questions is, “it depends...” And this is often followed by an emphatic explanation of the clinician’s beliefs based on eminence based medicine.

This study at least makes an attempt to enter some high quality evidence into the discussion.

This randomized, controlled, double blind, triple-dummy (who you callin’ dummy?) clinical trial enrolled adult patients requiring IV sedation for acute agitation in 2 ED’s. They randomized 349 patients to either:

·         Group 1: Midazolam 5mg + Droperidol 5mg or

·         Group 2: Droperidol 10mg or

·         Group 3: Olanzapine 10mg

If patients were not adequately sedated by five minutes they could get further pre-specified study drug.

The primary outcome was adequate sedation by 10 minutes.

If you have any knowledge of pharmacodynamics of the study drugs, you can probably guess the results.

Yes, the midazolam group did better. By the 10 minute mark, about 75% were adequately sedated vs. 50% in the groups that got monotherapy with droperidol or olanzapine.

Once again, the results of this study are not a surprise. Intravenous midazolam works within seconds of IV administration whereas the antipsychotics take several minutes.

I personally (eminence based medicine anyone?) rapidly titrate midazolam in combination with a single dose of antipsychotic. I have most of this done well before the 10 minute mark with the attendants already wiping the sweat off their brow.

Of course we have made no mention of safety. This study was not powered for safety outcomes. Nevertheless it is quite clear that drugs in combination require extra care; especially benzodiazepines.

What’s the take-home point?

Combination therapy with IV midazolam plus an antipsychotic is probably the best strategy if the goal is rapid sedation of the acutely agitated patient. But really, therapy should be tailored to the individual patient and adequate precautions taken.

This is a great triple dummy RCT... but whatever you do, “don’t call me stupid.”

Covering:

Taylor DM, Yap CL, Knott JC, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2016 Oct 10. pii: S0196-0644(16)30456-5. doi: 10.1016/j.annemergmed.2016.07.033