Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest – Part I

 
Also to be posted on ResearchBlogging.org when they relaunch the site.

The results are in from the only completed Adrenaline (Epinephrine in non-Commonwealth countries) vs. Placebo for Cardiac Arrest study.
 


 

Even I overestimated the possibility of benefit of epinephrine.

I had hoped that there would be some evidence to help identify patients who might benefit from epinephrine, but that is not the case.

PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) compared adrenaline (epinephrine) with placebo in a “randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest”.

More people survived for at least 30 days with epinephrine, which is entirely expected. There has not been any controversy about whether giving epinephrine produces pulses more often than not giving epinephrine. As with amiodarone (Nexterone and Pacerone), the question has been whether we are just filling the ICUs and nursing home beds with comatose patients.
 

There was no statistical evidence of a modification in treatment effect by such factors as the patient’s age, whether the cardiac arrest was witnessed, whether CPR was performed by a bystander, initial cardiac rhythm, or response time or time to trial-agent administration (Fig. S7 in the Supplementary Appendix). [1]

 

The secondary outcome is what everyone has been much more interested in – what are the neurological outcomes with adrenaline vs. without adrenaline?

The best outcome was no detectable neurological impairment.
 

the benefits of epinephrine that were identified in our trial are small, since they would result in 1 extra survivor for every 112 patients treated. This number is less than the minimal clinically important difference that has been defined in previous studies.29,30 Among the survivors, almost twice the number in the epinephrine group as in the placebo group had severe neurologic impairment.

Our work with patients and the public before starting the trial (as summarized in the Supplementary Appendix) identified survival with a favorable neurologic outcome to be a higher priority than survival alone. [1]

 


Click on the image to make it larger.
 

Are there some patients who will do better with epinephrine than without?

Maybe (I would have written probably, before these results), but we still do not know how to identify those patients.

Is titrating tiny amounts of epinephrine, to observe for response, reasonable? What response would we be looking for? Wat do we do if we observe that response? We have been using epinephrine for over half a century and we still don’t know when to use it, how much to use, or how to identify the patients who might benefit.

I will write more about these results later

We now have evidence that, as with amiodarone, we should only be using epinephrine as part of well controlled trials.

Also see –

How Bad is Epinephrine (Adrenaline) for Cardiac Arrest, According to the PARAMEDIC2 Study?

Footnotes:

[1] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMoa1806842. [Epub ahead of print]
PMID: 30021076

Free Full Text from NEJM

All supplementary material is also available at the end of the article at the NEJM site in PDF format –

Protocol

Supplementary Appendix

Disclosure Forms

There is also an editorial, which I have not yet read, by Clifton W. Callaway, M.D., Ph.D., and Michael W. Donnino, M.D. –

Testing Epinephrine for Out-of-Hospital Cardiac Arrest.
Callaway CW, Donnino MW.
N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMe1808255. [Epub ahead of print] No abstract available.
PMID: 30021078

Free Full Text from NEJM

.

Too Much Oxygen, Too Many Backboards


 

This week on EMS Office Hours, Jim Hoffman, Josh Knapp, and I discuss a variety of topics – quality in EMS, respect for EMS, the value of research and whether we should teach people to use research in EMS.
 

Too Much Oxygen, Too Many Backboards
 

Spinal immobilization can be done in many different ways. Strapping a curved spine to a flat piece of lumber/plastic is not the only way to do it and not even the only way that it is done in the US, nor in the rest of the world.
 


 

Long spine board immobilization is continuing to be replaced by the lateral trauma position in Norway.[1],[2]
 

What about in America?

Going back to 2008 (the earliest protocols available on line, all of Pennsylvania has had spinal clearance.
 

Immobilize the entire spine3,4 in any trauma patient who sustains an injury with a
mechanism having the potential for causing spinal injury and who has at least one of
these clinical criteria:5
a. Altered mental status (including any patient that is not completely alert and oriented)
b. Evidence of intoxication with alcohol or drugs
c. A distracting painful injury (including any suspected extremity fracture)
d. Neurologic deficit (including extremity numbness or weakness- even if resolved)
e. Spinal pain or tenderness (in the neck or back)
[3]

 

Without altered mental status, evidence of intoxication, a distracting painful injury, neurologic deficit, and/or spinal pain or tenderness spinal immobilization is a violation of protocol in Pennsylvania.

Alameda County, California; Xenia, Ohio; and all of Connecticut are doing away with backboards.

Spinal clearance has been in place in many more places in various forms for years, or even for decades.

Don’t let local attitudes fool you. this is not new or limited to isolated areas.
 

Spinal immobilization is witchcraft. There is no evidence of benefit.
 

Oxygen was also discussed.

There is a lot to discuss about the absence of good evidence that supplemental oxygen improves outcomes when there is no known hypoxia.
For heart attack patients, why do we want to give a drug (oxygen) that causes vasoconstriction, when our goal is vasodilation?

If the goal is to improve blood supply, and oxygen decreases blood supply, then why are we giving oxygen in the absence of evidence of hypoxia?

Supplemental oxygen without evidence of hypoxia is also witchcraft.

Footnotes:

[1] The lateral trauma position: what do we know about it and how do we use it? A cross-sectional survey of all Norwegian emergency medical services.
Fattah S, Ekås GR, Hyldmo PK, Wisborg T.
Scand J Trauma Resusc Emerg Med. 2011 Aug 4;19:45.
PMID: 21816059 [PubMed – in process]

Free Full Text from PubMed Central with links to PDF Download

[2] The Lateral Trauma Position: What do we know about it and how do we use it
Sun, 04 Dec 2011
Rogue Medic
Article

[3] Spinal Immobilzation – 261
2008 Pennsylvania Protocols
PEHSC
Page with links to protocols in PDF format.

[4] More Oxygen Can’t Hurt…Can It?
by William E. “Gene” Gandy, JD, LP and Steven “Kelly” Grayson, NREMT-P, CCEMT-P
Created: MAY 1, 2013
EMS World
Article

.

Will IV Oxygen Save Lives?

ResearchBlogging.org
Image credit.
 

Intravenous oxygen delivery that works?

Maybe temporary oxygenation, but not yet.

Will this change the approach to CICV (Can’t Intubate, Can’t Ventilate) patients?

No, but it may change the approach to CICO (Can’t Intubate, Can’t Oxygenate) patients.

The distinction is important. If we can deliver oxygen without ventilation, we can avoid some of the problems of hypoxia, but we will still have to deal with the acidosis that results from the inability to eliminate CO2 (Carbon DiOxide).
 

In the early 1900s, intravenous administration of oxygen gas was used in attempts to relieve refractory cyanosis (4–7). Most reported that spontaneously breathing, cyanotic animals exhibited signs of pulmonary embolism at infusion rates in excess of 0.2 to 1 ml/kg per minute and required frequent pauses in the infusion (4, 5); . . . None of these studies documented an increase in oxygen content in the blood as a result of the intervention.[1]

 

Try walking up several flights of stairs while only breathing through your nose. You will become short of breath very quickly.

Unless you are in truly horrible shape, it is not a lack of oxygen that is causing you to become short of breath. It is the inability to remove CO2 (Carbon DiOxide) that is the problem.

Most of us breathe because of a buildup of CO2, not because of a lack of oxygen.
 

The reflexive response of some people might be to give the anti-acidosis drug NaHCO3 (sodium bicarbonate). We will ignore the sodium, which at 5.8% in NaHCO3 is over 6 times the concentration of the NSS (Normal Saline Solution – 0.9% sodium) we routinely give. The sodium in NaHCO3 may be effective for treating sodium channel blocking drugs, such as antidepressnts, antiseizure medications, antiarrhythmics, and antivirals.[2]

The sodium is not the real danger. The bicarbonate (HCO3) is the problem. When binding with the excess hydrogen ions to neutralize metabolic acidosis, CO2 is produced.
 

HCO3 + H+

Produces:

CO2 + H2O
 

a patient with complex airway anatomy and difficulty maintaining oxygenation using basic airway maneuvers could avert a hypoxemic crisis during a prolonged intubation attempt. To date, safe and effective intravascular delivery of oxygen gas has not been realized.[1]

 

In the cute little bunnies used in the study (7 LOM [Lipidic Oxygen–containing Microparticles] and 6 Control), these were the results.
 


Click on images to make them larger.
 

Oxygen saturation remained between 40% and 60% with the LOM, but that was much better than the less than 20% for the controls. since the study animals received LOMs titrated to an arterial oxygen tension of greater than 30 mmHg, this is not a surprise. The controls just received fluid at a similar rate.
 


 

CO2 more than doubled for both groups.

Providing oxygen does nothing to remove CO2.
 


 

When CO2 increases, the pH will decrease (acidosis will increase).

Sodium bicarbonate will not decrease the acidosis for these patients.

Sodium bicarbonate will increase the acidosis for these patients.

Sodium bicarbonate produces CO2, which must be removed by ventilation. If we are giving LOM to patients we can adequately ventilate, maybe we do not understand what we are doing.

We should only give sodium bicarbonate to a patient who is well ventilated – unless we are trying to kill the patient.
 


 

In (F) and (G), data are means ±SEM. The blue lines end at 10.2 min because no animals treated as controls had spontaneous circulation after that time and received chest compression–only cardiopulmonary resuscitation (CPR) during the remainder of asphyxia. (H) Kaplan-Meier plot of animals experiencing cardiac arrest during asphyxia (left; P =0.0002, log-rank test), restoration of mechanical ventilation (shaded box), and subsequent recovery and observation (right).[1]

 


 

None of the bunnies reported any near-death experiences.

Consider the time involved. Many in the media have been reporting this as a way to provide half an hour of apneic oxygenation. That is ridiculously optimistic. This will be something that might provide an extra 5-10 minutes to manage a hypoxic patient, if the patient has not already died due to the hypoxia.

5-10 minutes can be the difference between life and death.

Don’t believe me?

Hold your breath for 10 minutes. Just stop breathing and hold your breath.[3]

Without LOMs, all of the bunnies were pulseless after a little more than 10 minutes, but at 15 minutes, when ventilation was resumed, almost all of the LOM bunnies still had pulses (6 out of 7).

LOMs are not just to make it possible to deliver a patient with a pulse to the hospital, so that we can say that They didn’t die in the ambulance.

That is not changing anything.

LOMs are to provide time for us to provide an airway – if this ever demonstrates safety and efficacy in humans.

Footnotes:

[1] Oxygen gas-filled microparticles provide intravenous oxygen delivery.
Kheir JN, Scharp LA, Borden MA, Swanson EJ, Loxley A, Reese JH, Black KJ, Velazquez LA, Thomson LM, Walsh BK, Mullen KE, Graham DA, Lawlor MW, Brugnara C, Bell DC, McGowan FX Jr.
Sci Transl Med. 2012 Jun 27;4(140):140ra88. doi: 10.1126/scitranslmed.3003679.
PMID: 22745438 [PubMed – indexed for MEDLINE]

Free Full Text Download in PDF format from medlive.cn
 

At the end of the asphyxial period, mechanical ventilation was restored with 100% oxygen until return of pulsations (in animals receiving chest compressions) and then titrated downward to achieve arterial saturations of >92%. Animals achieving return of spontaneous circulation after relief of asphyxia were treated with standard intensive care management, including inotropic support (dopamine, 2 to 10 mg/kg per minute, intravenous infusion) to maintain MABP of at least 40 mmHg during the follow-up period. Hyperthermia was avoided by passive ambient cooling (goal, 34 to 35° C). Animals were sacrificed 90 min after the end of asphyxia for lab and histology sampling.

Everyone seems to be using therapeutic hypothermia and trying to avoid giving too much oxygen.

[2] Management of sodium-channel blocker poisoning: the role of hypertonic sodium salts.
Di Grande A, Giuffrida C, Narbone G, Le Moli C, Nigro F, Di Mauro A, Pirrone G, Tabita V, Alongi B.
Eur Rev Med Pharmacol Sci. 2010 Jan;14(1):25-30. Review.
PMID: 20184086 [PubMed – indexed for MEDLINE]

Free Full Text in PDF format from EuropeanReview.org
 

As more substances having sodium-channel blocking properties become available, the incidence of this poisoning may be expected to increase, and clinician, particularly the emergency physician, should be familiar with this potential fatal condition.

A little evidence supports the treatment with hypertonic sodium salts, and current recommendations have not been based on randomized clinical trials.

[3] Longest time breath held voluntarily (male)
Guinness World Records
Web page.
 

The longest time holding the breath underwater was 22 min 00 sec by Stig Severinsen (Denmark) at the London School of Diving in London, UK, on 3 May 2012.

Stig was allowed to hyperventilate with oxygen prior to the attempt, and did this for 19 minutes and 30 seconds.

Kheir, J., Scharp, L., Borden, M., Swanson, E., Loxley, A., Reese, J., Black, K., Velazquez, L., Thomson, L., Walsh, B., Mullen, K., Graham, D., Lawlor, M., Brugnara, C., Bell, D., & McGowan, F. (2012). Oxygen Gas-Filled Microparticles Provide Intravenous Oxygen Delivery Science Translational Medicine, 4 (140), 140-140 DOI: 10.1126/scitranslmed.3003679

.

Comment on With Conflicting Evidence, What Should We Do? – Oxygen

 

In the comments to With Conflicting Evidence, What Should We Do? – Oxygen is the following from Dr. Brooks Walsh.
 

The importance of this study is that it may suggest that hyperoxia may be beneficial at different points in critical illness, and that we need to be careful before acting too broadly.

 

The way to find out what works is with prospective studies.

We do not have any shortage of cardiac arrests to study. We only have a shortage of research and therefore a shortage of understanding.

We should not attempt to make up for that ignorance with wishful thinking.

Homeopathy, epinephrine, chiropractic, oxygen, Reiki, amiodarone, prayer, lidocaine, acupuncture, vasopressin, et cetera. There is no shortage of possible treatments that lack evidence of benefit.

Where do we start?

Homeopathy probably has more research than all of the other treatments combined.

Howevere, homeopathy is just playing the numbers. There is no real treatment, but if we study a placebo enough times, there will be some statistically significant results.

This is just the same as flipping a coin. If we flip a coin enough times, we will produce a series of heads that is so long that it will have a p value that has an impressive bunch of zeroes in it.
 


Image credit. Click on image to make it larger. Below is the mouse-over text from this – xkcd 882.

So, uh, we did the green study again and got no link. It was probably a–‘ ‘RESEARCH CONFLICTED ON GREEN JELLY BEAN/ACNE LINK; MORE STUDY RECOMMENDED!

 

The important point is to pretend that the other studies do not matter. Except that the other studies do matter. All that is being done is throwing feces at a wall and hoping that something sticks.

We have been pretending that, with our understanding of physiology, we are too smart to have too study oxygen.

We have been very arrogant and very stupid.

We haven’t even bothered to find out how dangerous our treatments are.
 

Perhaps there is an analog to the past studies that looked at the treatment of sepsis. Initial studies of sepsis therapy, using aggressive fluid resus and pressors, were conducted in the ICU, hours after admission. Although these studies were based on strong physiologic evidence, the clinical studies were negative. However, when these same interventions were started in the ED, minutes after arrival, we found a huge drop in mortality. Timing matters.

 

I should have linked to an mp3 recording of Dr. Mervyn Singer pointing out that hypoxemia is probably not as dangerous as we have been told.[1]

Dr. Singer also has a presentation pointing out the problems with catecholamines in sepsis and questioning the research showing benefit from dopamine.[2]

Dr. Singer raises some interesting questions. the only way to find out the answers is to do the research, not to claim that a lack of proof of harm is evidence of benefit.

Very few treatments have been proven to be harmful, so we could use anything. If enough people follow suit, we have a standard of care that probably is much more harmful than we image and probably not helpful at all.
 

And so it may be with oxygen. It doesn’t help that most of the studies out there are retrospective, and so are suggestive, but they require confirmation with prospective trials. Some “common-sense” changes in practice have already been implemented, but we need to be careful before extending this reasoning to all clinical situations.

 

We do not have any high-quality data of benefit. We have a lot of anecdotes of kitchen sink treatment.

When we throw the kitchen sink at the patient, sometimes the patient dies and sometimes the patient lives. We cannot tell if there is any benefit from the kitchen sink, or from any element of the kitchen sink, but we don’t let that stop us.

Our ignorance is unstoppable.

We already have an avalanche of excuses for continuing to harm patients.

We need to stop making excuses and figure out what we are doing.

Footnotes:

[1] Permissive hypoxaemia – the way forward
2011, Critical Care, Manchester Critical Care Conference
2011-04-28 at 09:30
Dr. Mervyn Singer
Free Emergency Medicine Talks
Free page with link to free mp3 of presentation.

[2] Catecholamines Should Be Banned
2009, Critical Care, Manchester Critical Care Conference
2009-04-24 at 15:45
Dr. Mervyn Singer
Free Emergency Medicine Talks
Free page with link to free mp3 of presentation.

.

With Conflicting Evidence, What Should We Do? – Oxygen

 

Dr. Brooks Walsh writes about a recent paper on the amount of oxygen in the blood of resuscitated.[1] This paper appears to show benefit from high oxygen concentrations.[2] This is contrary to almost all the previous papers looking at the effects of supplemental oxygen.

How do we decide what to believe?

Does this paper mean that the people who claim that science constantly reverses itself are right?

Let me answer the second question first.

No. Science does not constantly reverse itself. The media does report oversimplified mistaken explanations of the results of research. When that media-reported inaccuracy is corrected, that does not mean that the original research made any of the claims the media reported. A reversal of a media misrepresentation is not a scientific reversal.

Science does continually modify previous understanding, but that is how we learn. We do not learn by making exaggerated claims on limited evidence.

So, how do we decide what to believe?

First, we need to understand what conclusions are actually being stated in the research. Reading a news article is not the same as understanding the original paper.

Second, we need to understand how the conclusions were arrived at and how the acknowledged limitations affect the results, as well as the effects of limitations that even the authors may not be aware of.

One limitation is the intervention and how the authors decide what the intervention is.

The intervention is the treatment that must be demonstrated to be safer and more effective than providing a placebo or even safer and more effective than doing nothing.

In these studies of supplemental oxygen, the intervention is supplemental oxygen. If we think of the intervention as withholding supplemental oxygen, we are looking at things backwards.

As with any drug, and oxygen certainly is a drug, the dose should also be taken into consideration. We should not administer unproven treatments in the highest dose possible, just because we can. We should have evidence that the intervention is beneficial and that the dose is safe and effective.

Where is that evidence?

The evidence against supplemental oxygen is the stronger evidence.

Stressing the hearts of cardiac patients leads to slower recovery and evidence of more ischemia with supplemental oxygen than with room air. Ischemia is supposed to be prevented by supplemental oxygen.[3]

This study was tiny, but it was prospective, double-blinded. The new study reviewed by Dr. Walsh has larger numbers, but everything else about the study is too poorly controlled to be considered good science. Over 60 years have gone by and we still do not have any studies that provide good evidence that supplemental oxygen is safe and improves outcomes for patients who are not hypoxic.

Dr. Walsh writes –

 

As the authors note, “Reasons for the benefit of higher oxygen tensions during CPR can more easily be hypothesized than explained.” Given the conflicting data, it might behoove us to proceed cautiously in modifying the targets for oxygen delivery in cardiac arrest.[1]

 

But which caution is appropriate?

Should we be cautious about giving too much of an unproven treatment?

Or –

Should we be cautious of evidence that we are harming patients with an unproven treatment?

Dr. Walsh is not telling us that there is clear evidence of benefit.

This is the history of a lot of medical treatment is that we harm patients with unproven traditional treatments.
 


Image credit.
 

How well do we understand the pathophysiology on which we base our treatment decisions?

We think we understand the way the body works. We start to use a treatment based on that misunderstanding. Somebody eventually studies the treatment. We admit that our misunderstanding misled us to harm patients. We still do not admit that we should have studied the treatment before making it a standard of care.
 

Until there is good evidence that supplemental oxygen improves outcomes, we should not be aggressive with this unproven traditional treatment.

Will we ever have good evidence of benefit? History continually provides more evidence that traditional treatments are harmful – not evidence that these traditional treatments have been neglected.

Oxygen is a drug. Drugs should be used when indicated by our assessment. Drugs should not be used out of a belief that drugs cannot hurt.

The intervention is the risk, the danger, the threat to the patient until there is evidence of safety and benefit.

It is rare that we ever have that evidence, because we keep unreasonably expecting each treatment to be magically beneficial.

Footnotes:

[1] Hyperoxia during CPR associated with improved survival
Wednesday, April 3, 2013
Mill Hill Ave Command
Article

[2] Increasing arterial oxygen partial pressure during cardiopulmonary resuscitation is associated with improved rates of hospital admission.
Spindelboeck W, Schindler O, Moser A, Hausler F, Wallner S, Strasser C, Haas J, Gemes G, Prause G.
Resuscitation. 2013 Jan 17. doi:pii: S0300-9572(13)00042-7. 10.1016/j.resuscitation.2013.01.012. [Epub ahead of print]
PMID: 23333452 [PubMed – as supplied by publisher]

[3] One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris.
RUSSEK HI, REGAN FD, NAEGELE CF.
J Am Med Assoc. 1950 Sep 30;144(5):373-5. No abstract available.
PMID: 14774103 [PubMed – indexed for MEDLINE]
 

In five patients with angina pectoris the administration of 100 per cent oxygen did not favorably influence the onset or duration of pain or the electrocardiographic alterations induced by standard exercise. On the contrary, oxygen therapy actually appeared responsible for more pronounced and persistent electrocardiographic changes in several patients.

.

Does an Oxygen Saturation of 100% Mean an Overdose?


 

Are we harming patients with oxygen?[1]

This will offend many in the oxygen religion, but we should start thinking of oxygen overdose.

What is our use of oxygen for everything based on?

Received wisdom from authority figures. We need to stop using authority and tradition as excuses to harm people.

Tom Bouthillet, Kelly Arashin, and Mike McEvoy discuss the harms of oxygen and the evidence of harm.
 

Go listen to the podcast, or watch the video.
 

Then reconsider your answer to my question.

Are we overdosing our patients, when we raise their oxygen saturation to 100%?

What if the original oxygen saturation was 94%?

What if the original oxygen saturation was 74%?

What if the original oxygen saturation was 54%?

Does the original oxygen saturation matter?
 

Would we have the same worries if the drug (oxygen is a drug) is morphine, NTG, midazolam, or even amiodarone?

Why do we grant the beliefs of the religion of oxygen such immunity from examination?

 

According to Mike McEvoy, the goal is 92% to 96%.

Not 97%.

98% is worse.

99% is much worse.

100% is as bad as it can get – even worse than hypoxia.

 

Go listen to the podcast, or watch the video.
 

A couple of points. Mike McEvoy states that the intensive care community has been familiar with this since the 1990s. This has been studied, and there has been evidence of harm since at least as early as 1950.
 

The administration of 100 per cent oxygen may actually be contraindicated in patients in whom oxygen saturation of arterial blood is normal.[2]

 

This was a decade before we found out that internal mammary artery ligation is nothing more than a placebo surgery.[3] That extremely popular procedure was done away with so quickly, that few people even remember the use of internal mammary artery ligation as a treatment for angina?

Oxygen has tradition behind it encouraging us to keep killing patients.

We should have been smart enough to reconsider our devotion to received wisdom and authority in 1950.

Many of us still refuse to learn.

This is why we need evidence before applying treatments to everyone.

How many hundreds of thousands of patient have we killed with oxygen and our refusal to require evidence of improved outcomes?
 


 

Go listen to the podcast, or watch the video.
 

Footnotes:

[1] EMS 12-Lead podcast – Episode #11 – Are we harming patients with oxygen?
EMS 12 Lead Podcast
EMS 12 Lead
Page with podcast and video podcast.

[2] One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris.
RUSSEK HI, REGAN FD, NAEGELE CF.
J Am Med Assoc. 1950 Sep 30;144(5):373-5. No abstract available.
PMID: 14774103 [PubMed – indexed for MEDLINE]
 

In five patients with angina pectoris the administration of 100 per cent oxygen did not favorably influence the onset or duration of pain or the electrocardiographic alterations induced by standard exercise. On the contrary, oxygen therapy actually appeared responsible for more pronounced and persistent electrocardiographic changes in several patients.

[3] An evaluation of internal-mammary-artery ligation by a double-blind technic.
COBB LA, THOMAS GI, DILLARD DH, MERENDINO KA, BRUCE RA.
N Engl J Med. 1959 May 28;260(22):1115-8. No abstract available.
PMID: 13657350 [PubMed – indexed for MEDLINE]

.