Thursday, 21 May 2020

Early self-proning in awake, non-intubated patients in the ED: A single ED’s Experience during the COVID-19 pandemic


This pilot study was carried out at the crazy Lincoln Medical Center, New York City. Located in the Bronx, it is the third busiest ED in the United States. In the grips of a pandemic, it is the perfect place to study potential treatments of COVID-19.

Awake proning has been shown to be beneficial in patients with ARDS and anecdotal reports have suggested it may be helpful for patients with coronavirus.

This pilot study enrolled a convenience sample of 50 patients who presented to their ED with hypoxia without resolution despite supplemental oxygen and who were capable of self-proning. They excluded patients who were NFR, getting NIV or intubated in the prehospital setting. All were eventually confirmed as COVID positive.

They termed these patients the “happy hypoxemics” as they generally looked quite well without respiratory distress despite having low oxygen saturation.

Results?

The median SpO2 at triage was 80% and this improved to 84% with supplemental oxygen. After 5 minutes of proning the saturation increased to 94%!

18 of the 50 patients eventually required intubation; 13 of those (24%) within the first 24 hours.

This pilot study has lots of limitations; no control group, no idea if proning resulted in meaningful patient-oriented outcomes. Nevertheless, it has adequately raised the hypothesis for a clinical trial.  A search of www.clinicaltrials.gov shows there are now several in progress.

Could there be harm from self-proning? It is possible. But these authors recommend proning until we get better quality evidence to inform practice. They have typical protocols whereby patients are asked to rotate about every 30 to 120 minutes.

Proning support cushions are already being sold in the USA. You can get one for US$164! I would not be surprised if a device manufacturer comes out with a human rotisserie device. No joke… watch this space!


Covering:

Caputo ND, Strayer R, Levitan R. Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED’s Experience during the COVID-19 Pandemic. Acad Emerg Med. 2020;27(5):375-378 [link to full text article]




Intranasal ketamine for analgesia prior to digital nerve block- A double blind RCT!!??


Wow…

This was reportedly a double blind RCT of intranasal ketamine 50mg vs. saline placebo prior to performance of digital nerve blocks at a single centre in Iran. All the blocks were done by one doctor (listed as the third out of seven authors).

The primary outcome was reduction of pain during the block as measured on a visual analogue scale (VAS).

Results?

Exactly 100 patients were enrolled. Block pain was less in the group that got IN ketamine 28mm vs. 47mm (P less than 0.001) on the VAS. Side effects were reported to be “trivial.” This pain reduction persisted at the 45-minute mark at 21mm vs 43mm (P less than 0.001).

The authors conclude, “… IN Ketamine can be effective in reducing pain in patients with acute pain, without adding significant side effects.”

I doubt that many of us would consider giving ketamine prior to a digital nerve block. It does seem rather excessive and puts the patient at risk of side effects. (Reminds me of propofol for migraine) Perhaps we might consider inhaled nitrous oxide or intranasal fentanyl?

Unfortunately, there are a few problems and red flags with this study.

  • The final study methods differ quite substantially from those listed in the trial registry found here.  The primary outcome was different, no power calculation, measuring tool different, etc.
  • Intranasal ketamine burns and tastes bad. This could have unmasked blinding resulting in measurement bias.
  • Data was collected in 2014. Why did it take 5 years to get published? I’m guessing it was rejected for publication from numerous journals.
  • In the manuscript, there are numerous grammatical and spelling errors. What does a sloppy manuscript say about the conduct of the study?
  • Why did patients continue to report substantial pain after the nerve block? Most of these blocks should have been successful at complete analgesia.
  • Side effects were likely under-reported


Regardless of this study's conduct or limitations, I’m not a big fan of intranasal ketamine. Not great bang-for-buck and an undesirable side effect profile. In addition, we have experience with other drugs that are more efficacious.


Covering

Nejati A, Jalili M, Abbasi S, et al. Intranasal ketamine reduces pain of digital nerve block; a double blind randomized clinical trial. Am J Emer Med. 2019;27:1622-1626.






Wednesday, 20 May 2020

Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm


The literature regarding cooling of comatose survivors of cardiac arrest is mixed. But even more controversial is the role of therapeutic hypothermia in the group of patients with non-shockable rhythm.

Enter the HYPERION trial published in the high impact New England Journal of Medicine.

This mammoth effort was an open-label pragmatic RCT comparing hypothermia (33 degrees) vs normothermia (37 degrees) in comatose survivors of cardiac arrest with non-shockable rhythms (PEA or asystole).

As if PEA and asystole were not bad enough, they excluded the sicker patients who would have highly likely died anyway- regardless of cooling or no cooling. These were patients who had no CPR for >10 minutes, CPR for more than 60 minutes, those with high vasopressor requirements etc.

The primary outcome was a good one; survival with a favorable day-90 neurologic outcome. This was defined as independent & able to perform ADL’s (CPC score 1-2). Unfortunately, it was possibly poorly determined by a single blinded psychologist by phone interview.

Results?

Over 4 years, 581 patients were included from 25 French ICU’s. On day 90, 10.2% of the hypothermia group vs. 5.7% of the normothermia had a good outcome (difference 4.5% 95%CI 0.1 to 8.9; P=0.04 and a NNT of 22.) Overall mortality did not differ between the groups at 80%.

Cooling wins!?

Despite the results, I am a bit less enthusiastic about this one.

The literature is still conflicting, and this is far from overwhelming data.

The primary result has a fragility index of 1. If only one of the patients that did well in the hypothermia group were reclassified as unfavorable at 90 days, the results would not have been statistically significant… we would be talking about a negative trial.

There are other issues with the measurement of the primary outcome, external validity and a few other things.

In the end, it is probably fine if your ICU wants to cool these patients. But please make sure it does not distract & get in the way of providing adequate resuscitation and supportive care. Stay cool (or not) and do the right things first.


Covering:

Lascarrou JB, Merdji H, Le Gouge, A, et al. Targeted Temperature Management for Cardiac Arrest with Non-Shockable Rhythm. New Engl J Med; 2019: 381:2327-2337. [link to article]


Friday, 24 April 2020

Compassionate use of Remdesivir for Patients with Severe Covid-19


It is a sign of the times when an article of such low-quality evidence is published in the New England Journal of Medicine. We are obviously desperate to get some information regarding therapy for Covid-19.

Compassionate use, or properly termed “expanded use,” is when patients can request a not yet FDA approved drug outside of a clinical trial.

This industry funded and written study reports on 53 patients with severe Covid-19 that got expanded use remdesivir in the USA, Europe and Japan.

Short answer… they got it and they got better.

Of course, we have no idea if remdesivir did anything. This was not a trial. There was no control group, no randomization, no blinding, nothing, zip, nada.

But fear not. Gilead Sciences, the manufacturer of remdesivir, is currently conducting a large phase 3 randomized clinical trial. They plan to enroll 6000 patients at 179 sites and have it finished by a “holy shit fast” May 2020!

Fortunately, most of their recruiting sites are based in the USA where there is plenty of patients to study. (Thanks Donald). Studies out of China have now been suspended or terminated due to low patient numbers.

A search of www.clinicaltrails.gov indicates the primary outcome of the phase 3 trial is an odds ratio of improvement on a 7-point ordinal scale. This type of analysis has incredible statistical efficiency. Along with 6000 patients, this study will have the power to demonstrate miniscule differences in patient outcomes.

Do you know what else Gilead Sciences developed?

Tamiflu.

Gilead licensed the drug to Roche in 1996 on return for royalties. Despite hardly any evidence of efficacy, it was a blockbuster that saw the world stockpile billions worth during H1N1.

Now if there was just some other global scare that might sell remdesivir? Hmmmm….

Ok, I am being paranoid. But I do think we need to be careful when this study is soon published and not let emotions & politics trump science. (Pun intended.)

Nevertheless, I genuinely hope this drug works. We have antivirals that have cured hepatitis C. We’ve put the brakes on HIV. In theory, remdesivir looks quite promising. It is an RNA polymerase inhibitor specifically designed to treat coronaviruses. Perhaps there is some hope.

So, watch this space.

But be skeptical.


Covering

Grein J, Ohmagari N, Shin D, et al. Compassionate use of Remdesivir for Patients with Severe Covid-19. N Engl J Med 2020 [E pub ahead of print] [link to full text]

Hydroxychloroquine in patients with COVID-19: an open-label un-peer reviewed RCT


We want to rapidly know as much as we can about COVID-19. In the current pandemic, researchers are rushing to complete studies and often prematurely release the results on MedRxiv (pronounced “med-archive”) before they have even undergone a process of peer review.


Of course, this can be good news for rapid dissemination of information, but it can also be rather harmful if bad studies get pushed without proper scrutiny.

This multicenter RCT from china included 150 patients with COVID-19. They got hydroxychloroquine (open label) vs. standard care. The primary outcome was clearance of the virus at 28 days.

They concluded, “…adding hydroxychloroquine to the current standard-of-care in patient with COVID-19 does not increase virus response but accelerate the alleviation of clinical symptoms.” (Yes, you read that correctly).

They go on to say that the alleviation of symptoms may due to the anti-inflammatory properties of hydroxychloroquine and less lymphopenia. The authors suggest clinicians might consider it in symptomatic patients with elevated CRP and or lymphopenia because it might prevent disease progression in high risk patients.

Unfortunately, this conclusion is wrong.

Their primary outcome was negative, but at with such small numbers was at risk of a Type I error. Hidden in the manuscript, the authors mention that they wanted to enroll close to 400 patients but had to give up when recruitment fell short.

The median time from symptom onset to getting hydroxychloroquine was 16 days. For most antivirals to work, they need to be given early.

But what about the claim that the medication reduces clinical symptoms?

This comes from one of fourteen post-hoc subgroup analysis in 28 patients that was “statistically significant” with hazard ratio 95%CI of 1.09 to 71.3.

Peer reviewers will easily spot this inappropriate claim that came about through a process known as data dredging or P-hacking. 

What should we conclude?

Unfortunately, nothing.  

This was an underpowered biased study that made some silly claims based on an unadjusted post-hoc subgroup analysis.

We still don't know if hydroxychloroquine helps or harms.


Covering:

Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. MedRxiv [link to un-peer reviewed manuscript]

Sunday, 16 February 2020

Conservative vs interventional Treatment for Spontaneous Pneumothorax: Don’t just do something… stand there!


This study in the New England Journal of Medicine is going to change how we treat spontaneous pneumothorax. If you haven’t read it, you should.

(Disclaimer: the lead author, Dr Simon Brown is a colleague of mine at the Royal Hobart Hospital. He is bigger than me and knows where I live. Hmmmm….)

By way of background, there are conflicting guidelines regarding the treatment of primary spontaneous pneumothorax. The Americans are quite aggressive with intervention, the British less so. Any time you see such variation, it usually means there is no high-quality evidence to inform practice.

Fortunately, we now have that evidence.

The Primary Spontaneous Pneumothorax (PSP) trial was a prospective randomised open-label non-inferiority study that enrolled 316 patients in 39 hospitals in Australia & New Zulund over 6 years.

They included stable patients between the ages of 14-50 with at least a 32% (sum of interpleural distance greater than 6cm) primary spontaneous pneumothorax.

Those randomised to intervention had a <12 French Seldinger style chest tube placed. They got a repeat chest x-ray in one hour. If the lung was re-expanded and there was no air leak, they clamped the tube. Another x-ray was taken 4 hours later. If all was fine, the tube was pulled and the patient discharged. If not, they got admitted.

The conservative” arm was observed for 4 hours and a repeat chest x-ray was taken. If they did not require oxygen and they were walking around comfortably, they could be discharged. However, intervention could be allowed for if the patient had clinically significant symptoms despite adequate analgesia, couldn’t walk, unwilling to continue, became unstable or if the chest x-ray was getting worse.

The primary outcome was full lung expansion by 8 weeks. There were lots of arguably more important secondary outcomes.

Results?

As expected, patients were generally young, male and thin. Half were smokers.

Mean pneumothorax size was 65%! Holy crap… that’s big.

For the primary outcome, 98% of the intervention arm had full lung re-expansion at 8 weeks vs. 94% in the conservative arm. This was within their prespecified non-inferiority margin of -9% as such, this is a positive study.

However, even more impressive are the secondary outcomes in favour of a conservative approach.

85% of patients randomised to conservative management got no intervention. The intervention arm had many more adverse events (26% vs. 8%) mostly related to the chest tube. Mean time to resolution of symptoms was 15 days in both groups. Recurrent pneumothorax was double in the intervention arm; 16% vs. 8%.

Median hospital length of stay was 3.8 days in the intervention group compared to 0.2 in the conservative arm!

All of this is quite a good argument for us to change our practice.

For what it is worth, the manuscript goes into length regarding the limitations of loss to follow-up. Even going so far as to perform an analysis assuming all of them were treatment failures making this study “fragile.” While perhaps technically correct, I think this was overzealous peer review that was ultimately biased.

A 26-year-old male, who got no treatment and feels fine is probably less likely to follow up as directed. However, patients in the intervention arm (who got painful tubes and spent 4 days in hospital) were more likely to return for the 8-week visit.

What’s the take home point?

Looks like we’ll be doing less chest tubes in stable patients with primary spontaneous pneumothorax.
 
Bummer… I like putting in chest tubes.


Covering:

Brown S.G.A, Ball E.L, Perrin K, Conservative versus Interventional Treatment for Spontaneous Pneumothorax. N Eng J Med. 2020;382:405-15. [link to article]





Diagnosis of PE with D-Dimer Adjusted to Clinical Probability- A game changer!


Image result for game changer


Intern, “the D-dimer just came back at 0.6… what should I do?”

Me, “… faaaaaaaaaaaaaaaaaaaaaaaaarrrrrrrk!”

Fortunately, this study is probably a game changer.

These Canadian’s conducted a prospective study in which PE was considered to be ruled out if the pretest clinical suspicion was low (Well’s score0-4) and a D-dimer of less than 1.0mg/L or if the clinical suspicion was moderate (Well’s score 4.5-6) and D-dimer less than 0.5mg/L.

Just over two thousand patients were enrolled. Their overall rate of PE was 7.4%.

Of the 1325 patients with low or moderate clinical suspicion for PE and a negative D-dimer (as above), NONE (95%CI 0.0 to 0.29%) of them had venous thromboembolism during the 3-month follow up.   

This is amazing.

Once again, two-thirds of all patients were excluded from imaging and the diagnostic performance of this strategy was perfect.

Furthermore, this publication from the NEJM is one in line of papers supporting the notion of adjusting D-dimer thresholds. Consistency in the literature is reassuring.

Slam dunk?

Ok… no studies are perfect. What were the two major limitations?

The quality of a study looking at diagnostic performance of a test is only as good its gold standard. Unfortunately, patients that were ruled out by this strategy did not have definitive imaging. This study relied on 3-month follow up (sometimes by telephone) and may have led to the underdiagnosis of PE.

Secondly, there were 34 deaths during follow-up.

Yikes!

But they claim, “no deaths were attributed by the central adjudication committee to pulmonary embolism.” Table S5 in the supplementary appendix shows that most died of cancer or cardiovascular disease. I very much doubt many (if any) of the deaths had autopsy performed. We all know PE can be quite tricky to diagnose. I still wonder if some of these deaths were due to missed PE.

Despite these limitations, I still think adjusting D-dimer thresholds makes sense. And now it is supported by numerous studies published in high impact journals.

Intern, “the D-dimer just came back at 0.6… what should I do?”

Me, “Never order a D-dimer without asking me first!”

Oh… I meant, “send them home…” And hopefully they don’t die of “cancer.”


Covering:

Kearon C, de Wit, Parpia S, et al. Diagnosis of Pulmonary Embolism with D-dimer Adjusted to Clinical Probability. N Engl J Med 2019;381:2125-34. [link to article]