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Management Of Anaphylaxis
15 Plays4 years ago
In this episode of Critical Matters, we will discuss the critical care management of the patient with anaphylaxis.
Our guest is Dr. Guha Krishnaswamy. Dr. Krishnaswamy is a Professor of Medicine in the Section of Pulmonary, Critical Care, Allergy and Immunology and the Section of Infectious Diseases in the Wake Forest School of Medicine. He is also chief, of the Section of Allergy, Asthma and Immunology at the Bill Hefner VA Hospital and Affiliated Clinics in Salisbury, NC.
Additional Resources:
Critical Care Management of the Patient with Anaphylaxis: A Concise Definitive Review: https://bit.ly/3zfkA58
Anaphylaxis- Practice Parameter Update: https://bit.ly/3ctbGaG
American College of Allergy, Asthma and Immunology Website: https://bit.ly/3zcKvL6
Hereditary Alpha-Tryptasemia: A Commonly Inherited Modifier of Anaphylaxis: https://bit.ly/3w5tJLZ
Books Mentioned in this Episode:
Everyday Zen: Love and Work by CJ Beck: https://amzn.to/3g5U9Ye
Jonathan Livingston Seagull by Richard Bach: https://amzn.to/3w9FCjR
The Wasteland by TS Elliot: https://amzn.to/3gjcDDA
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Transcript
Introduction
00:00:06
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Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:14
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Sound provides comprehensive critical care programs to hospitals across the country.
00:00:19
Speaker
To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Critical Care Management of Anaphylaxis
00:00:26
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And now your host, Dr. Sergio Zanotti.
00:00:32
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In today's episode of Critical Matters, we will discuss the critical care management of the patient with anaphylaxis.
00:00:38
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Our guest is Dr. Guha Krishnaswamy.
00:00:41
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Dr. Krishnaswamy is a professor of medicine in the section of pulmonary critical care, allergy and immunology, and the section of infectious diseases in the Wake Forest School of Medicine.
00:00:51
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He is also chief of the section of allergy, asthma, and immunology at the Bill Hefner VA Hospital and Affiliated Clinics in Salisburg, North Carolina.
00:01:00
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He is board certified in internal medicine and allergen clinical immunology.
00:01:04
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His research interests include primary immune deficiencies in adults, anaphylaxis, angioedema, among other topics.
00:01:12
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Dr. Krishnaswamy has published over 160 manuscripts that have appeared in numerous peer-reviewed journals, including Critical Care Medicine, the New England Journal of Medicine, JAMA, Chest, and Science.
00:01:24
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He is the author of two books and has contributed to over 30 book chapters in the area of inflammation biology.
00:01:30
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It's a real pleasure and honor to have him today to talk about this important topic.
00:01:34
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Guha, welcome to Critical Matters.
00:01:37
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Sergio, thank you for having me.
00:01:39
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Appreciate it.
Understanding Anaphylaxis and Its Implications
00:01:41
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So it's always very encouraging to talk about topics that are not related to COVID lately, although obviously anaphylaxis also came to the forefront in the news with the first COVID vaccination.
00:01:53
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So I guess we'll have to touch on COVID at one point, no matter what.
00:01:57
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But I really wanted to start, Guha, with maybe
00:02:00
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a general definition of anaphylaxis and some specific criteria in terms of diagnostics?
00:02:08
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So the definition of anaphylaxis has evolved over time.
00:02:15
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It's an ancient disease.
00:02:16
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And in the last couple of decades, there have been meetings of minds, if you will, across the world and large conferences dedicated to defining and developing a consensus
00:02:30
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over asthma guidelines and much of our presentation today will be a glimpse into this, Sergio.
00:02:37
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So the definition, a good definition of anaphylaxis is it's an acute onset illness characterized by involvement of skin
00:02:47
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respiratory GI and cardiovascular systems in various combinations.
00:02:52
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So that's an important thing to remember.
00:02:55
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And that raises two caveats.
00:02:58
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One is that cardiopulmonary involvement is often the cause of fatality.
00:03:03
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whether it's angioedema of the airways or whether it's hypovolemia, distributive shock, a mixed shock leading to pump failure and organ dysfunction, almost like a multi-organ dysfunction syndrome that you see in stage in fatal anaphylaxis cases.
Anaphylaxis Classifications and Challenges
00:03:20
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The second aspect is that there are patients where you don't have skin involvement.
00:03:25
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So up to 10 to 20% of patients don't have pruritis, don't have hives, don't have itching, don't have the skin lesions.
00:03:32
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And so the diagnosis might present with just hypertension or severe bronchospasm that's being seen in food anaphylaxis cases.
00:03:40
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And so that caveat needs to be kept in mind.
00:03:44
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The second aspect of the definition is the mechanistic definition.
00:03:48
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And it is a result of a massive and rapid release of mediators
00:03:54
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from perivascular resident cells around the blood vessels called mast cells, discovered initially by Paul Ehrlich.
00:04:02
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And mast cells came from the word mastos, meaning breast.
00:04:05
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So they were very laden with granules.
00:04:08
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And now we know that these granules contain a variety of mediators that result in the manifestations we see as clinical anaphylaxis.
00:04:21
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When we think of classifying anaphylaxis, I know a lot of times
00:04:24
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We've had people talk about the recurrence of symptoms or the phases, the severity.
00:04:30
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What are the current classifications that you think are most useful to have as a framework clinically?
00:04:36
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So if you look at the presentation of anaphylaxis,
00:04:42
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You can classify it by severity.
00:04:45
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And many patients, the majority of patients come into the ER, they're being stung by a bee or the mother brings the patient, a child in, very anxious because the child ate a peanut sandwich by mistake and is known to be allergic to peanuts.
00:05:00
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and he was complaining of feeling a little warm and flushed, and he was developing some hives, and she brought him to the ER.
00:05:07
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So a lot of them are acute anaphylaxis, but relatively mild.
00:05:13
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But it can go along a cascade of events to fulminant or fatal anaphylaxis.
00:05:19
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severe refractory anaphylaxis.
00:05:20
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So the initial classification for purposes of management would be, is this a mild anaphylaxis or is this more severe disease with lung and heart involvement and hypertension or near-fatal anaphylaxis where the patient is hypoxemic and close to moribund or cardiorespiratory
Managing Severe Anaphylaxis
00:05:38
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arrest?
00:05:38
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So that's the first classification.
00:05:40
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The second classification that evolved over the last two decades is that when clinicians observed the presentation in the hospitals and emergency rooms, they noticed that some people got better on their own in a couple of hours, probably three to six hours, they were observing the ER, and the ER doc came by in six hours and said, hey, you're all fine, Harry, I think you can go home now.
00:06:04
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and gave him a prescription for an EpiPen and some instructions to go and see the PCP after they got discharged, sent him home on some steroids perhaps.
00:06:14
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And this is called uniphasic anaphylaxis.
00:06:17
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or monophasic enaphylaxis where if you think of it as a peak it's a single peak so boo mediators are released patient comes in itchy hyvee complaining of some sore throat hoarseness dinophagia difficulty swallowing
00:06:35
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and starts developing a little wheeze.
00:06:37
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He gets a couple of dose of epinephrine, some Benadryl.
00:06:39
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He gets a breathing treatment.
00:06:41
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He gets some bolus of fluids, and he's sitting up and he's asking the ER doc, when can I go home?
00:06:46
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So that's the uniphasing or monophasing.
00:06:49
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Now, people started noticing that in allergic responses, even in asthma, you'll find what's called a late phase response.
00:06:57
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And this happens several hours after the initial event.
00:07:01
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So they started describing a phenomenon known as biphasic anaphylaxis.
00:07:05
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And biphasic anaphylaxis initially was thought to be 30, 40, 50% of all cases.
00:07:10
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And then as we got more and more data, we started looking across the wider swaths of the population.
00:07:16
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We realized that the incidence is probably between 4 and 20%.
00:07:20
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In some studies, as low as 3% incidence of biphasic.
00:07:23
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And what is biphasic?
00:07:25
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Biphasic is a second wave of media to release that happens after the first event.
00:07:31
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sometimes six hours after the first event, but in the absence of the inciting allergens.
00:07:37
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So the allergen does not have to be there, but the mast cells still go through a second wave of immediate release.
00:07:43
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The danger of that is, and this is what we, in education, when we talk to the ERs and we talk and we give lectures to residents and fellows who are going out and practice, we tell them,
00:07:53
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If you have a significant anaphylactic event and there's urticaria, angioedema, lip swelling, alterations and hypovolemia manifestations, blood pressure manifestations, then it's safest to keep the patient in for a longer period for observation, either a 24-hour admit or keep the patient in the ER if you don't have beds in the hospital for at least 12 hours because the second wave, if this were to happen at 2 a.m.
00:08:19
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at night,
00:08:20
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and result in a fulminant airway obstruction, the patient probably might die in sleep or might not be able to get to the hospital in time.
00:08:29
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And that's a very important point, I guess, Guha, I just want to emphasize, right?
00:08:32
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Because we don't have good tools to predict who's at risk for a secondary phase.
00:08:38
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So ultimately we base it on severity and that's the type of patients that usually will come to the ICU for a 24 hour or overnight observation.
00:08:46
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Very true, Sergio.
00:08:48
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And some data suggesting that delayed administration of epinephrine, we'll come back to this as a theme.
00:08:55
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One of the failures
Research and Statistics on Anaphylaxis
00:08:56
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in anaphylaxis management and why they land up with you guys is that the diagnosis is not made early or it's misdiagnosed as an acute allergic reaction and not classified as anaphylaxis that happens almost in 30 to 40%.
00:09:13
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of some large ER emergency room studies
00:09:17
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or the epinephrine is given late into the illness and Benadryl and steroids given promptly.
00:09:25
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And so a gentleman called Novak, a physician up in, who ran a cluster of emergency rooms up in the East coast, he did a study where he went and educated people in all his ERs.
00:09:36
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He had about 12 ERs in a large hospital system and told them about late phase reactions, biphasic reactions,
00:09:44
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and the use of, early use of EpiPen.
00:09:46
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And what they found, he did this as a study and pre and post education, there was a dramatic drop in biphasic disease, dramatic drop in hospitalization, a dramatic increase in the use of EpiPen as the first medication introduced and a great drop in Benadryl and steroids, which became second tier medications and the outcomes were very good.
00:10:10
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So it's a very important point to keep in mind, Sergio.
00:10:14
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The third important aspect is that a very small fraction, these are the ICU flyers, and these are the patients who have what we regard as malignant or fulminant anaphylaxis or severe anaphylaxis.
00:10:31
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And a subset of these severe anaphylaxis patients will evolve into what's called refractory anaphylaxis almost seamlessly.
00:10:37
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And this happens during the transition and the management and the handing over.
00:10:42
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The patient is not responding to two or more doses of EpiPen, and you call them refractory anaphylaxis.
00:10:49
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They're often in the ICU.
00:10:51
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Many of them get intubated, or many of them go on pressers or even ECMO.
00:10:57
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Sergio?
00:10:57
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Excellent.
00:10:58
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And we talked about...
00:11:00
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some of the definitions, obviously introductory classification, but can we dive a little bit more, Guha, into the epidemiology of anaphylaxis that ends up coming to the ICU?
00:11:10
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And specifically, I don't really know about the numbers, but I do presume that every one of our listeners has seen an anaphylaxis case recently, and it's something that we see every year, obviously maybe not every day or every week, but certainly see these cases.
00:11:24
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But I'm more interested maybe in the causes that lead to anaphylaxis,
00:11:29
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risk factors for severe anaphylaxis requiring the ICU.
00:11:32
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And I think you already identified a very important one, which is failure to institute epinephrine treatment early, right?
00:11:38
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But there might be others.
00:11:40
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And then also, if you could make specific comments on perioperative anaphylaxis, which seems to be obviously a topic that comes to the ICU very frequently.
00:11:50
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Yes.
00:11:51
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So if you look at anaphylaxis in general, it's increasing globally.
00:11:55
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Every country has demonstrated increases in the incidence and the prevalence of anaphylaxis in their populations.
00:12:03
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Now, one could be a better understanding of the disease, better diagnosis, and also better recognition of the disease.
00:12:10
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But also remember that we have more drugs.
00:12:13
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A lot of patients are getting outpatient IV infusions, home
Recognizing and Responding to Anaphylaxis
00:12:18
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therapies.
00:12:19
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and new biologicals, transgenic foods.
00:12:23
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So a lot of changes have happened in the last 20 years that could explain the spike.
00:12:28
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Now, in general, anaphylaxis is set to occur in one in 300% persons.
00:12:36
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But at some point in life, you would say probably 0.5% of the population would have had
00:12:45
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and introduction or experience of systemic anaphylaxis where they get severe disease requiring emergency room visits.
00:12:53
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And if you look at the number of deaths, about almost a couple of thousand people die in the US every year.
00:12:59
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And some of them are due to venom anaphylaxis and they had never recognized they were allergic to venom or very sadly, food anaphylaxis that Hugh Sampson recorded
00:13:10
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in schools where things went awfully wrong.
00:13:15
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Either the EpiPen was outdated, the EpiPen was missing when the child went to look for it, or the nurse who knew how to administer the EpiPen was off that particular day and the new nurse came on board and who had no idea how to operate the EpiPen and within minutes, their life was lost.
00:13:31
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So anaphylaxis can be pretty severe and common in certain settings like schools.
00:13:39
Speaker
Now it occurs in about 1% of all emergency department visits is what is, you know, positive to happen.
00:13:47
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And if you look at the mortality rate of all cases of anaphylaxis, probably less than 2% of all patients will die.
00:13:53
Speaker
And a subset of them, as you said earlier, are severe anaphylaxis cases requiring ICU admissions.
00:14:04
Speaker
Now, severe anaphylaxis,
00:14:07
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is easy to recognize in the emergency room and in the hospital.
00:14:12
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These people are usually hypotensive, defined as blood pressure less than 90 millimeters of mercury or less than 30% of the patients early baseline in adults.
00:14:21
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And there are child-specific, age-specific blood pressure measures that you'll find in reviews.
00:14:29
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The second thing is hypoxemia with saturation less than 92 percent.
00:14:33
Speaker
And the most important prognostic and ominous indicators are confusion, loss of consciousness, and fecal urinary incontinence.
00:14:42
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When that happens, when there's bladder and bowel incontinence, that often is a sign of very severe anaphylaxis.
00:14:49
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If you look at the ICU admissions, here's some interesting data.
00:14:55
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A study from London showed
00:14:57
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in about five years when they looked at their larger collection of hospitals in their NHS system,
00:15:05
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They found that 1,300 patients were admitted to the ICU for anaphylaxis, but the optimistic finding was over 90% did survive with good ICU management and good care.
00:15:22
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And we'll discuss those aspects of intra-hospital care as we proceed with this podcast.
00:15:29
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Modus, you look at 38,000 patients in the emergency department, and what he found was 11% roughly.
00:15:38
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One in 10, you can say, required hospitalization.
00:15:42
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And out of that 1 in 10, 11%, about 5%, a small fraction of that landed up in the ICU.
00:15:50
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And less than 2% of those patients were admitted to the hospital, landed up being intubated.
00:15:57
Speaker
And with less than 0.5% being fatal.
00:15:59
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So if you look at it, there's a general dilution of these.
00:16:03
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So relatively common emergency room visits.
00:16:09
Speaker
a small fraction, a tenth of them get into the hospital and a smaller fraction of them, 120 of them get into the ICU and a very, very small fraction, like we said, over 90% will survive and less than 10% of them will die of the disease.
00:16:24
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Now, risk factors for simianaphylaxis, I'll very quickly go through this.
00:16:28
Speaker
And this would be the predictive markers that a clinician would look at when he's evaluating the patient.
00:16:35
Speaker
Did the person or the patient just get a parental allergen, an IV drug?
00:16:40
Speaker
And so just to remind you, the time from administration of the IV drug to full cardiorespirator rest in fulminant anaphylaxis is only five minutes.
00:16:50
Speaker
Because remember, it's given IV.
00:16:52
Speaker
And both mass cells, tissue-derived mass cells, as well as basophils can get recruited into a massive anaphylactic reaction with an outburst of mediators, resulting in rapid cardiopulmonary burst and fatality.
00:17:05
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Whereas with something like venoms, like a bee sting or a yellow jacket sting, it's said to be 15 minutes according to Femfrey in his fatal anaphylaxis studies in London.
00:17:18
Speaker
And if you look at the time
Medications and Risk Factors
00:17:20
Speaker
to fatal anaphylaxis and cardiorespiratory rest with foods, it's about 30 minutes because it goes through the GI tract processes
00:17:28
Speaker
gets into the bloodstream but of course 30 minutes is an average and there are some children who can be very sick very quickly so what is the type of allergen in the route in which it was administered secondly
00:17:42
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patients who are on two groups of drugs, beta blockers and ACE inhibitors.
00:17:47
Speaker
And we are very, very conscious as allergists and as practicing physicians to immediately call the PCP and make sure that they change the ACE inhibitor and the beta blocker for two reasons.
00:17:57
Speaker
One, ACE inhibitors, as we know, angiotensin-conviting enzyme is involved in bradykinin breakdown.
00:18:03
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And so you get hyperbradykininemia.
00:18:06
Speaker
And bradykinin binding to bradykinin receptors can lead to capillary leak and lead to a worsening of distributive shock and angioedema.
00:18:14
Speaker
So that is one major aspect to remember.
00:18:17
Speaker
If they're on an ACE inhibitor, that needs to be stopped right away and switched to a calcium channel blocker safest in acute settings.
00:18:25
Speaker
And long-term, with caution, you can switch the patient to an ARB, such as low serotonin, for example.
00:18:33
Speaker
The second drug is the beta blocker.
00:18:36
Speaker
Now, beta blocker is important because endogenous catecholamins are a physiological mechanism to hypovolemia and shock.
00:18:47
Speaker
And if you've got a beta blocker on board, of course, the endogenous catecholamins are not able to bind to their receptor, the beta-1, beta-2 receptor.
00:18:56
Speaker
So you get negative inotrophic effects and you get effects of myocardial depression.
00:19:02
Speaker
as well as bronchospasm.
00:19:04
Speaker
But the most important thing is when the beta-adrenergic antagonist is sitting in the beta-adrenergic receptor and blocking it, your adenalin is not going to work.
00:19:15
Speaker
So these people often land up getting fairly progressive pulmonid anaphylaxis, and the beta blocker has to be stopped, and there's going to be a half-life for the beta blocker.
00:19:25
Speaker
So this is going to be a pretty dicey situation when you're in the ICU managing these patients.
00:19:30
Speaker
And we'll have a couple of caveats as we go through this podcast.
00:19:34
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as what options we have in these scenarios.
00:19:37
Speaker
The other risk factors are poorly controlled asthma, poorly controlled heart disease.
00:19:40
Speaker
So, cardiopulmonary disease are definitely factors.
00:19:44
Speaker
And impaired cognition has been a risk factor, including for a hypercapnic respiratory failure because of impaired recognition of hypoxemia, dyspnea, or the hypovolemia and dizziness.
00:19:59
Speaker
So, the patient might not be able to complain to a caregiver that something is happening.
00:20:04
Speaker
The other risk factors are more are management related, delayed administration of epinephrine, a poor diagnosis of anaphylaxis or misdiagnosis of anaphylaxis, calling anaphylaxis an asthma attack or an acute allergic reaction and not classifying it as anaphylaxis so that proper treatment can be initiated right away.
00:20:28
Speaker
Excellent.
00:20:29
Speaker
And I think that just as a, as a,
00:20:32
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summary of some of the pearls that you shared in terms of clinicians when they're facing these cases in the early phases is really to recognize, like you said, in addition to the usual respiratory and cardiopulmonary symptoms that we can all recognize as intensivists, the loss of bowel and bladder continence is a big sign.
00:20:54
Speaker
Altered cognition, another big sign of severity.
00:20:57
Speaker
And risk factors that we should really be tuned into are the use of ACE inhibitors and beta blockers.
00:21:03
Speaker
And then from the perspective, what we control as physicians, and I think there's going to be a recurrent theme like you mentioned earlier, Guha, it's delays in administration of epinephrine.
00:21:13
Speaker
That's a time-sensitive intervention that really, I mean, we need to emphasize over and over again.
00:21:19
Speaker
That's very true.
00:21:21
Speaker
And just to touch on this point very quickly so I don't forget it, when they look at outpatient administration of epinephrine and IPPEN devices were getting to be expensive, and there was a time when they were in fact short supply for the last few years, we were asked to instruct patients to train them in drawing adrenaline from a vial or an ampoule.
00:21:46
Speaker
And they found that there was enormous delays and mistaken administration of doses when this was given using syringe and needle.
00:21:56
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That's number one.
00:21:57
Speaker
The second point to be remembered is the dose of epinephrine is 0.5 cc or 0.5 milligram of the 1 in 1,000 doses.
00:22:09
Speaker
concentration of epinephrine weight per volume.
00:22:12
Speaker
And so what is important is that the epinephrine auto-inject only administers 0.3 milligrams.
00:22:22
Speaker
And so you're short of about 0.2 milligrams in very severe cases.
00:22:27
Speaker
And if you look at some of the UK data and some of the data coming from the US,
00:22:32
Speaker
Children about 12 years can tolerate 0.5 milligrams of epipen or epinephrine acutely without having an adverse effect.
00:22:41
Speaker
So it's actually a very, very safe drug to use in systemic aphylaxis.
00:22:45
Speaker
So I just wanted to raise that point that without delay and even drawing it in the syringe, they found that experienced nurses draw it faster than doctors and doctors draw the epinephrine dose faster than patients do.
00:22:58
Speaker
So in that sequence.
00:23:01
Speaker
Well, I think this is a great segue to talk about the management of anaphylaxis
Diagnosis and Symptoms Differentiation
00:23:05
Speaker
in the ICU.
00:23:06
Speaker
And perhaps we could start, Guha, with diagnosis.
00:23:10
Speaker
And the two things that I'm always interested in is establishing a diagnosis when it's not clear.
00:23:16
Speaker
Sometimes it's very obvious that somebody had anaphylactic reaction.
00:23:19
Speaker
But like you said, sometimes there are delays in treatment because we don't recognize it.
00:23:23
Speaker
Or the other part is that there might be
00:23:26
Speaker
that present like anaphylaxis that are not anaphylaxis.
00:23:30
Speaker
We're also talking about that differential diagnosis.
00:23:33
Speaker
Yes.
00:23:33
Speaker
So we'll touch on three things, Sergio, a couple of things I forgot to mention earlier on.
00:23:38
Speaker
One is the diagnostic criteria for anaphylaxis.
00:23:42
Speaker
And the criteria for anaphylaxis has also been modified.
00:23:46
Speaker
The first,
00:23:48
Speaker
lovely criteria that has a great sensitivity and specificity for the diagnosis was created by the second meeting of the NIAID and the Food Allergy Anaphylaxis Network.
00:23:59
Speaker
And basically, they came up with three criteria for anaphylaxis.
00:24:03
Speaker
But to make it simple, the Europeans have changed it and made it more simple.
00:24:07
Speaker
So bottom line is, one, is if you have mucocutaneous findings,
00:24:13
Speaker
high skin rashes, flushing, itching with lip swelling or tongue swelling combined with any two of either respiratory, cardiac, or GI manifestations, you make the diagnosis of anaphylaxis.
00:24:29
Speaker
So if you have eucocutaneous findings with, for example, wheezing, hypertension, refractory nausea, vomiting, or diarrhea, you can make the diagnosis of anaphylaxis.
00:24:43
Speaker
or a combination of any two of those.
00:24:45
Speaker
If you have cutaneous, pulmonary, cardiovascular, and GI, and any two of those in a fairly established pattern,
00:24:56
Speaker
and then you diagnose anaphylaxis.
00:24:58
Speaker
But skin findings alone will not diagnose anaphylaxis sufficiently enough.
00:25:04
Speaker
That's the first point I wanted to make in terms of the diagnostic criteria of anaphylaxis.
00:25:10
Speaker
Second is very quickly, we're going into the endotype and phenotype, which we didn't mention.
00:25:16
Speaker
I'll go through this very briefly.
00:25:17
Speaker
And in the review that I wrote for critical care medicine, if anybody wants to refer to those,
00:25:25
Speaker
But endotype is a mechanism.
00:25:27
Speaker
Phenotype is the presentation of anaphylaxis.
00:25:31
Speaker
The commonest cause, as we know, is allergy, IgE, immediate, and anaphylaxis.
00:25:35
Speaker
That is by far the commonest.
00:25:37
Speaker
And typically, it happens when somebody has exposure to a food, latex, bee sting, medication, certain hormone, or...
00:25:51
Speaker
a drug that they're known to be allergic to and they have it accidentally ingested accidentally or get introduced accidentally and they develop anaphylactic reaction.
00:26:02
Speaker
So that's the immune mediated, IgA mediated anaphylaxis.
00:26:06
Speaker
Now that is characterized by mass cells releasing histamine and platelet activating factor and tryptase, which is a protease, very important marker for anaphylaxis, which we'll discuss later in terms of diagnosis.
00:26:19
Speaker
and they also release apletorocytokines.
00:26:22
Speaker
The second type of immune anaphylaxis is IgG-mediated anaphylaxis.
00:26:27
Speaker
Now, IgG-mediated anaphylaxis is not that commonly seen.
00:26:31
Speaker
It's mainly mediated by gamma globulin infusions, blood transfusions in certain susceptible individuals,
00:26:40
Speaker
Certain chimeric monoclonal antibodies, such as Rituxan, for example, and administration of aprotinine or dextran volume expanders have been linked to acute anaphylactic reactions mediated by IgG.
00:26:54
Speaker
In this case, they don't get as much histamine production as more platelet-activating factor, which medias capillary leakability and hypovolemia.
00:27:05
Speaker
Now, there are three or four other classifications of anaphylaxis or causes.
00:27:09
Speaker
I won't go into great detail, and Sergio, we can discuss these in detail later if there's time.
00:27:16
Speaker
But the most important thing of these are what's called a contact system or bradykinin-mediated anaphylaxis.
00:27:22
Speaker
And we know that when the contact system, the clotting system is activated, factor 12 gets activated, and it activates bradykinin, and bradykinin binds to bradykinin receptor and causes capillary leak.
00:27:35
Speaker
Classic example was this was with the contaminated heparin in 2007, 2008, Chinese heparin.
00:27:43
Speaker
And I don't know, Sergio, if you remember that, there was a clustering of anaphylactic events across the country, across Europe, UK, Australia, US, across countries, across the world.
00:27:53
Speaker
And what they found was that the heparin was contaminated with a oversulfated chondroitin sulfate.
00:28:00
Speaker
And the OSCS, as it's called,
00:28:03
Speaker
was activating anaphylaxis by a very fascinating mechanism.
00:28:08
Speaker
It was activating the clotting cascade, which then activated the kinin system and then caused the anaphylactic-like presentation.
00:28:18
Speaker
So it's almost like IgG-mediated anaphylaxis.
00:28:21
Speaker
You get this is bradykinin-mediated.
00:28:23
Speaker
So you have the histamine.
00:28:24
Speaker
and tryptase and the cytokine-mediated anaphylaxis with IgE.
00:28:30
Speaker
Then you have the platelet-activating factor-mediated anaphylactic reactions with IgG and dextran and volume expanders.
00:28:37
Speaker
And then you have the contact clinton system anaphylaxis
00:28:41
Speaker
with certain forms of chondroitin sulfate and other material.
00:28:46
Speaker
And then we have the complement activated anaphylaxis, which is known as CARPA, complemented activation related pseudo-allergic reaction, or pseudo-anaphylaxis, where the complement product actually directly binds to mast cells and releases mediators.
00:29:06
Speaker
Now,
00:29:07
Speaker
There's a whole host of mast cell disorders and cytokine-mediated anaphylactic disorders.
00:29:13
Speaker
I won't go into great detail in those.
00:29:14
Speaker
They're highly specialized, but the cytokine release syndrome or the cytokine storm reaction we see with COVID can occur with a variety of drugs, chemotherapeutics and multiple antibodies.
00:29:28
Speaker
and they're present with capillary leak and wheezing and pulmonary edema and hypovolemia, hypertension, very similar presentation.
00:29:38
Speaker
However, they will have an acute phase response combination.
00:29:42
Speaker
They'll have fever and chills and myalgia complicating the presentation.
00:29:47
Speaker
So when you have that, think of a cytokine-mediated
Anaphylaxis in Surgery
00:29:51
Speaker
reaction.
00:29:52
Speaker
And these reactions do respond to, like, for example, as we know with COVID inhibition of the IL-6 pathway or glucocorticoids or dexamethasone, as we do for COVID pneumonia.
00:30:04
Speaker
And then the mast cell mediated disorders are a whole plethora of clustering of disorders categorized by mast cell mediated disorders.
00:30:16
Speaker
autonomous function where the mast cells are very trigger happy and release mediators and minor triggers or even without triggers automatically
00:30:25
Speaker
And these patients are very prone to direct release, for example, opiates and certain drugs like vancomycin and the redneck syndrome, for example, radio contrast media can directly release mediators from mast cells and lead to histamine and gradykinin and platelet activating factor release with the resulting effects.
00:30:47
Speaker
So in terms of the differential diagnosis of anaphylaxis, which was raised,
00:30:53
Speaker
The differential diagnosis of anaphylaxis is wide.
00:30:58
Speaker
The important thing to remember is that in the emergency room or in the ICU, if you meet the criteria for anaphylaxis, somebody has hives, lipid edema, starts wheezing, drops blood pressure, there's no doubt in your mind that's anaphylaxis.
00:31:13
Speaker
If they came out of the operating room and the anesthesiologist is weaning the patient into the ICU and tells them that the patient dropped their blood pressure as soon as he introduced a rocoronium, and you know that's a rocoronium anaphylaxis, and there's no doubt in those cases.
00:31:29
Speaker
So they meet the criteria for anaphylaxis.
00:31:31
Speaker
Now, the question comes when you have atypical presentations or it's not as clear or like we said before, the skin manifestations are absent and then you go to a wider group of differential diagnosis.
00:31:44
Speaker
Of these, the most important would be something like a vasovagal episode, something like a pheochromocytoma, carcinoid syndrome, pulmonary embolism.
00:31:53
Speaker
And we, in the subspecialized world, see Munchausen-Streuter and somatiform anaphylaxis, where it's more of a psychosomatic disease and so on.
00:32:05
Speaker
But you still think of these things, pulmonary embolism, microinfarction, they can present with pulmonary edema and capillary leak and with hypoxemia and wheezing and can present with an anaphylaxis-like presentation.
00:32:22
Speaker
And so that's a thing to keep in mind.
00:32:24
Speaker
And I think, Sergio, you asked about the perioperative anaphylaxis.
00:32:29
Speaker
Very quickly, perioperative anaphylaxis is one of the most common reasons for ICU admissions.
00:32:34
Speaker
And the thing to keep in mind is perioperative anaphylaxis
00:32:38
Speaker
occurs probably in one in 10,000 cases.
00:32:42
Speaker
And in some situations, it's associated with high mortality.
00:32:45
Speaker
Older patients, people with cardiopulmonary disease, those on beta blockade may not do as well with intraoperative or perioperative anaphylaxis.
00:32:54
Speaker
The commonest causes include muscle relaxants, chlorhexidine, and the NMDA group of drugs, such as rocoronium, the neuromuscular blocking agent.
00:33:07
Speaker
When we admit a patient with a presumptive diagnosis of anaphylaxis in the ICU, are there any diagnostic tests that you would recommend that we consider?
00:33:18
Speaker
A lot of times we have a diagnosis and we treat them and we just do the usual test, but for general ICU diagnostic criteria, but is there anything specific that could help with the management of anaphylaxis down the road?
00:33:31
Speaker
Yes, it's very important to draw a tryptase level.
00:33:35
Speaker
The reason for the tryptase level, it's going to come back to you three days later.
00:33:39
Speaker
It helps you in two ways.
00:33:40
Speaker
One, if the patient is not responding, is getting progressively worse, and it's getting into cardiopulmonary failure and is on ECMO, it would be nice to have tryptase that was elevated, even if it's two or three days into the illness, so that you confirm its endopholysis and your management is titrated towards the
00:34:01
Speaker
management of anaphylaxis and you're not worrying about the capilar leak or a clonction syndrome or some other so it can be confusing in scenarios like that the second important thing is post-hoc diagnosis so after the patient is discharged and sent home if the patient lands up with the allergist hopefully he'll be referred to an allergist for further
00:34:21
Speaker
elaboration of the history, diagnostic testing, and figuring out if it's intraoperative, what was the drug that caused it?
00:34:28
Speaker
Was it chlorhexidine?
00:34:30
Speaker
Was it rocoronium?
00:34:32
Speaker
Was it latex?
00:34:33
Speaker
Was it the antibiotic the patient got in the operating room?
00:34:36
Speaker
Or was it a food or a venom reaction the patient had before he came into the emergency department?
00:34:43
Speaker
The allergist would like to have a triptase level.
00:34:45
Speaker
And the triptase level is a very specific marker for mast cells.
00:34:50
Speaker
It's a
00:34:51
Speaker
You just ordered tryptase.
00:34:52
Speaker
It measures total tryptase, alpha and beta tryptase.
00:34:56
Speaker
The tryptase is very elevated during an anaphylactic event.
00:34:59
Speaker
Then the physician and the outpatient will draw another tryptase level.
00:35:03
Speaker
The tryptase level drops back to the normal range of six weeks later.
00:35:07
Speaker
It tells you there was an acute anaphylactic degranulation of mast cells.
00:35:11
Speaker
And so that confirms your diagnosis.
00:35:14
Speaker
And then the allergist just has to figure out what triggered this reaction.
00:35:17
Speaker
So there's a lot of clearing of the air, if you will.
00:35:21
Speaker
And the diagnosis becomes, making the diagnosis becomes a more specific and clarified task.
00:35:28
Speaker
The second important caveat is if the triptase level goes up and doesn't really come back to normal, but stabilize to the high level, let's say the normal triptase level is up to be 11.4, which is what we accept as normal.
00:35:43
Speaker
If the level of triptase is 20 to 23, these people greater than 20 most likely have a mast cell disorder, malignant disorder or clonal disorder mast cells.
00:35:53
Speaker
We call it systemic mastocytosis.
00:35:55
Speaker
and various variants of cystic mastocytosis.
00:35:58
Speaker
So that is something to keep in mind.
00:36:00
Speaker
But a very fascinating discovery just five years ago by a group at NIH where they were getting referrals of anaphylaxis of uncertainty theology from across the country and across the world, and they had a cluster of patients.
00:36:16
Speaker
They found a small group of patients had a
00:36:21
Speaker
a condition known as hereditary alpha tryptosemia.
00:36:24
Speaker
Now, it's a hereditary condition, it's autosomal dominant disorder, and these people have struck just two tryptase genes, have three or four tryptase genes, so they have gene duplication.
00:36:36
Speaker
So as a result, they have more anaphylactic potential,
Treatment Protocols
00:36:40
Speaker
and now this is considered a huge marker and a huge predisposition
00:36:46
Speaker
for anaphylaxis of any kind, whether you're in the ICU, the operating room, whether you're allergic to penicillin and you get the antibiotic or whether you're allergic to bee stings.
00:36:56
Speaker
Now it's called HAT syndrome or H-A-T-S.
00:36:59
Speaker
And this gives me a great opportunity to introduce this syndrome to you guys.
00:37:04
Speaker
And I hope some of you will go back and read about it.
00:37:06
Speaker
Fascinating syndrome.
00:37:08
Speaker
And it is very testable because there are several companies now commercially that can just do a Google search for HATS or heterotry alpha tryptosemia testing and you'll get the companies and it's about $120 to do, but it will define a genetic basis in these people.
00:37:26
Speaker
So,
00:37:27
Speaker
I wanted to raise all those points to you guys.
00:37:30
Speaker
And important to remember is that a patient can have an ongoing HATS plus mastocytosis, HATS plus bee sting allergy, HATS plus a complement mediated anaphylactic event, HATS plus a kinin response, or HATS plus a cytokine mediated response.
00:37:48
Speaker
And so those people will be doubly sick and more likely, we believe, to guarantee the ICU settings or have paid lymphoma.
00:37:55
Speaker
And this is obviously a very relevant point from a patient-centered perspective, because like you mentioned, getting this level is not going to help us maybe immediately in most cases in the ICU, but has tremendous value for the allergist when they follow up and really defining what happened and what needs to happen in the future to prevent a recurrent anaphylactic reaction.
00:38:20
Speaker
So that's a great point, Guha.
00:38:22
Speaker
Thanks for really sharing that with us.
00:38:24
Speaker
And I will definitely include
00:38:25
Speaker
not only the excellent review that you did for critical care medicine and the show notes as a link, but also something on Hatt syndrome, which is something that I am not familiar with and definitely will read upon.
00:38:38
Speaker
Sure.
00:38:39
Speaker
And then just to mention, if you don't think it's anaphylaxis, it's best to contact an endocrinologist who can look for weird syndromes, metanephrines and calcitonin and medullary carcinoma of the thyroid and carcinoid syndrome, which will require its own evaluation.
00:39:01
Speaker
Excellent.
00:39:02
Speaker
So why don't we step now into the realm of treatment, which, like everything in medicine,
00:39:08
Speaker
Sometimes people have a very simplistic view that might not be based on science as we learn more and more.
00:39:15
Speaker
And as also you have shared with us already, the layers, right, of the immune background gets more complicated and maybe not every case reacts the same to the same medications.
00:39:28
Speaker
But there is a general therapeutic approach for most of these anaphylactic cases that come to the ICU.
00:39:33
Speaker
And why don't you tell us your framework and start there, Guha?
00:39:37
Speaker
Yes.
00:39:38
Speaker
So I have a little algorithm in the review that I wrote, but I want to first talk a little bit about epinephrine or adrenaline.
00:39:51
Speaker
It's an endogenous hormone, as we all know.
00:39:53
Speaker
It's the original fear fight flight hormone, and that's what makes your heart race and your blood pressure go up when you have an anxiety reaction.
00:40:02
Speaker
Now epinephrine is life-saving in anaphylaxis.
00:40:05
Speaker
So to administer epinephrine 1, you have to have a concrete diagnosis.
00:40:09
Speaker
You're very firm in your diagnosis and you're not wishy-washy and you know this is anaphylaxis based on criteria.
00:40:17
Speaker
You made the diagnosis.
00:40:18
Speaker
Number two, when you give epinephrine, there are two aspects of epinephrine administration.
00:40:23
Speaker
One is epinephrine when it's given in the field, when it's given in the emergency department,
00:40:28
Speaker
Or a naive patient who's rushed in from the operating room with intraoperative hypotension and cardiorespiratory collapse.
00:40:37
Speaker
And the anesthesiologist basically wheels the patient and said, I haven't done anything for this patient.
00:40:42
Speaker
Guys, get started right away.
00:40:44
Speaker
I think it's anaphylaxis.
00:40:46
Speaker
That scenario, that's the first scenario where you're going to give the first dose of epinephrine in the naive patient.
00:40:51
Speaker
And how much do you give?
00:40:53
Speaker
The dose is one in 1,000 milligrams per milliliter.
00:40:57
Speaker
And it used to be in ratios before, but because of confusion, the FDA, NIAID, and other players in this decision-making process
00:41:12
Speaker
decided to go to a milligram per milliliter which is easier to understand and follow so the vial that you need is one milligram per milliliter
00:41:23
Speaker
okay and that's you you're going to give point family grants im in the outer aspect of the thai the vastus lateralis and that's the place where the studies have shown the absorption is greatest because of the large muscle mass as well as the vascularity is going to access the circulation right away now two caveats one is we never use subcutaneous ap anymore we used to do this about
00:41:46
Speaker
15, 20 years ago, but over the last decade has changed and we give only IM epinephrine.
00:41:50
Speaker
Second, if you don't have 0.5 milligrams, you don't have the one in 1000 epi, and you don't have time to measure out and break the ampule or draw the vial, just use the EpiPen auto injector, which is present in most acute care settings.
00:42:08
Speaker
If you don't, I would encourage you guys to have the pharmacy
00:42:13
Speaker
give you a small anaphylaxis kit that can be with a head nurse or a place where you guys can access very easily.
00:42:19
Speaker
That's what I do.
00:42:20
Speaker
We as allergists do lots of challenges to drugs and medications.
00:42:24
Speaker
and we make sure that this is readily available.
00:42:26
Speaker
So you need that 1 in 1,000 epinephrine.
00:42:29
Speaker
If you can't, you need the EpiPen, which injects 0.3 milligrams.
00:42:33
Speaker
In today's world, IM directly into the pie, and little kids are going to get 0.15 milligrams.
00:42:40
Speaker
Okay, that's the first point I want to make.
00:42:43
Speaker
The second point I want to make is that in some cases, the epinephrine might not work.
00:42:48
Speaker
And why would it not work?
00:42:49
Speaker
One,
00:42:49
Speaker
for the patient's hypovolemic in shock and cardiorespiratory rest distributive or make shock and he's not got enough circulation so the epinephrine that you give in the peripheral muscle is not reaching the circulation fast enough in those scenarios sergio uh you would consider giving iv epinephrine now um as some of the early guidelines talked about bolus epinephrine uh we don't believe in boluses anymore except in as part of an aclis protocol for
00:43:19
Speaker
cardiorespirator
Post-ICU Management and Education
00:43:20
Speaker
arrest.
00:43:21
Speaker
But giving IV epinephrine, which is basically one milligram epinephrine, one ml diluted in thousand milliliters of 0.5 dextrose, 5% dextrose, D5 normal saline, can be run IV at the rate of about one to 10 micrograms per minute.
00:43:41
Speaker
And that can replace the
00:43:45
Speaker
sub-QFP if you're not able to get the sub-QFP to work, the IMFP to work.
00:43:50
Speaker
Second thing is when they're on a beta blocker and we'll talk about what we do when there's a beta blocker on board and there are options we have.
00:43:58
Speaker
The third thing to remember is in very obese people, the needle might not reach far enough and there's a lot of discussion on the length of the needle and the dose.
00:44:07
Speaker
So you're going to need the higher dose for obese or large-billed people up to 0.4 milligrams.
00:44:14
Speaker
So that's the first aspect of the management, Sergio.
00:44:17
Speaker
So when you give the IV epinephrine, it's important not to piggyback it because you want a very carefully titrated dose and you want to make sure that it's run at the 0.5 to 1 milliliters per kilogram per hour or 1 to 10 micrograms per minute dose.
00:44:37
Speaker
when they go through it.
00:44:38
Speaker
The second aspect of this is giving high flow oxygen.
00:44:43
Speaker
And oxygen is important to keep a saturation of about 94 to 98%.
00:44:48
Speaker
And this ICU nurses and doctors and critical care intensivists are pretty familiar with, I'm not going to go into detail there.
00:44:57
Speaker
And then assisting the airway is important, can be done either by nasopharyngoscopy or
00:45:04
Speaker
other forms of aerial visualization, getting anesthesia or ENT to help you if you need help.
00:45:11
Speaker
And going in for early intubation, if you think the airway is occluded and there's massive angioedema, which could make it very difficult.
00:45:19
Speaker
Now, if intubation is not possible, you're going to go to something like front of the neck airway, a cricotomy or tracheostomy to maintain oxygenation.
00:45:31
Speaker
The second aspect is, this is the oxygen part.
00:45:34
Speaker
The third aspect is the bronchospasm.
00:45:36
Speaker
And for that, intermittent continuous albuterol can be given.
00:45:41
Speaker
And the posture is important.
00:45:42
Speaker
One caveat about posture, Sergio, is I present case studies with posture because there are cases where
00:45:53
Speaker
Dr. The patient comes in in a pretty prominent anaphylaxis to the ICU and the doctors order the FBE, two doses have been given, the IV has been started, the oxygen was given, albutrol nebulizer, concus albutrol nebulization started.
00:46:10
Speaker
And the nurse and the patient says he needs to urinate.
00:46:13
Speaker
And the nurse comes by and you're sitting and writing notes in
Compassion in Medical Practice
00:46:17
Speaker
the room next door.
00:46:18
Speaker
And the nurse has the hospital bed moved up.
00:46:24
Speaker
The patient has moved up to a sitting position and she's trying to put the Foley catheter.
00:46:28
Speaker
And the patient goes into cardiac standstill.
00:46:30
Speaker
And what happens is the so-called empty heart syndrome is
00:46:33
Speaker
And these people are so massively hypovolemic due to capillary leak and postcapillary venular endothelial dilatation because of the gap junctions and the endurance junctions opening up that all the fluid has leaked out into the extravascular space.
00:46:48
Speaker
So they're massively hypopolemic.
00:46:50
Speaker
and they're just hanging on by a thread with endogenous catecholamins and your IV fluids and the adrenaline you gave.
00:46:58
Speaker
And when you sit them upright, that puts them into complete cardiac stansyl.
00:47:03
Speaker
And they've been fatalities from free as recorded, many fatalities.
00:47:06
Speaker
So the posture is very important and keeping them recumbent, very important.
00:47:11
Speaker
If they're pregnant, you move them to one side.
00:47:13
Speaker
So that's the third aspect of management in the ICU.
00:47:17
Speaker
And the fourth aspect is the use of Benadryl and glucocorticoids.
00:47:22
Speaker
Like we said before, Sergio, in many ERs, as a reflex, doctors who haven't kept up with some of the guidelines will immediately administer Benadryl and will give a dose of Solimedrol, start a Albutrol nebulizer, give some oxygen, and go in to see the next patient and fail to give the epinephrine.
00:47:42
Speaker
So we believe that that's the biggest failure in anaphylaxis management.
00:47:47
Speaker
And as I promised, we came back to this fact.
00:47:50
Speaker
And if you look at the study that Wood did, Bob Wood worked with him at Johns Hopkins a couple of decades ago, very smart man.
00:48:01
Speaker
He's done many studies in these areas and food related anaphylaxis.
00:48:06
Speaker
And what he found in a telephone study, random study of a thousand patients
00:48:11
Speaker
who had no history of anaphylaxis and then 1,000 patients with a history of anaphylaxis, what they found is that less than half of them were prescribed an epinephrine autoinjector even though they had a history of anaphylaxis.
00:48:24
Speaker
And those who had a history of anaphylaxis, only about 20% of them gave themselves the epinephrine because they themselves self-misdiagnosed their case
00:48:33
Speaker
or they did not recognize the fact that they were going into a full-blown anaphylaxis syndrome and waited until it was too late.
00:48:42
Speaker
So this is an important point is to, it's epinephrine, epinephrine, epinephrine.
00:48:47
Speaker
That's it.
00:48:48
Speaker
And right up front, every five minutes, you're going to give the 0.3 to 0.5 cc's IM, and that's going to be important.
00:48:55
Speaker
These are adjunct devices.
00:48:56
Speaker
So when you use steroids and when you use Benadryl and Femotidine,
00:49:01
Speaker
Now, right now, I would promise you that 90% of the ICUs, 90% of emergency departments in the country will give epinephrine.
00:49:10
Speaker
And if there's a deserted area, there's hypertension, they're going to start the H1H2 block and they're going to start dexamethasone.
00:49:17
Speaker
Does dexamethosin help with biphasic reaction reduction?
00:49:21
Speaker
Studies have shown no.
00:49:23
Speaker
If you give steroids, we used to think that one reason to give IV steroids is to decrease the biphasic reaction that occurs six hours later.
00:49:30
Speaker
Remember, we talked about the uniphasic, biphasic, and the protracted malignant anaphylaxis.
00:49:36
Speaker
But no, steroids don't seem to block it.
00:49:38
Speaker
The only thing that blocks biphasic disease is early administration of epinephrine.
00:49:42
Speaker
So epinephrine is a theme of today's presentation.
00:49:45
Speaker
If there's any one take-home point,
00:49:47
Speaker
When do you give steroids?
00:49:48
Speaker
Steroids are best given when they have steroid-responsive angioedema of the airways, severe urticaria, or poorly controlled asthma.
00:49:58
Speaker
If a patient has a history of prior asthma, comes in with severe bronchospasm,
00:50:03
Speaker
He's going to dramatically respond to prednisone in a few hours, and that might forestall his intubation, mechanical ventilation, barotoma, and all the consequences of ventilating these very sick patients.
00:50:15
Speaker
So that's a scenario where he would give steroids.
00:50:18
Speaker
When the patient has pro-asthema, the patient has urticaria, or has tongue or lip swelling or angioedema of the throat, you could do that.
00:50:26
Speaker
The angiolimum of the throat is another indication for nebulized epinephrine that seems to be effective.
00:50:32
Speaker
Racemic epinephrine 0.5 milliliters to 0.75 milliliters can be put in a nebulizer and that also makes your intubation a little easier.
00:50:42
Speaker
Just a little caveat or side trick if you will.
00:50:45
Speaker
And then when you give H1H to block it.
00:50:50
Speaker
A couple of the doctors I worked with at Johns Hopkins are trained at NIAID.
00:50:56
Speaker
And at that time, just a decade before I trained with them, there was a study where they injected endotoxin and created shock.
00:51:05
Speaker
and they found that when they gave H1H to block it, they were able to normalize blood pressures better.
00:51:12
Speaker
And of course, no, we don't do those studies anymore.
00:51:15
Speaker
However, that study has stood the test of time, and for a long period of time,
00:51:21
Speaker
H1H2 blockade, steroids, which followed the administration of epinephrine and fluids and oxygen was the scenario that we followed for anaphylaxis.
00:51:32
Speaker
But now we know that H1H2 blockade does nothing to anaphylaxis in terms of cardiopulmonary disease, does nothing in terms of hypertension,
00:51:43
Speaker
hypoxemia, and doesn't really help with the correction of the vascular parameters.
00:51:48
Speaker
However, when a patient has diffuse erythema, extensive pruritus, extensive urticaria, or what we refer to as histaminergic angioedema.
00:51:58
Speaker
These are people who have angioedema that's very responsive to histamine.
00:52:01
Speaker
These are typical allergic patients who have anaphylactic reaction, an allergic reaction to bee sting, or an allergic reaction to food and they're present with lip or tongue swelling.
00:52:10
Speaker
They are more histaminergic and respond to antihistamines as opposed to bradykininergic angioedema, which is due to like an ACE inhibitor.
00:52:20
Speaker
They are usually resistant to epinephrine and to antihistamines.
00:52:24
Speaker
So antihistamines is a consideration, but it's a third-tier drug.
00:52:30
Speaker
After you're given fluids, oxygen and posture and IV fluids and epinephrine right up front,
00:52:38
Speaker
you're going to give H1H to block it at that point for these other indications we talked about.
00:52:44
Speaker
And then we come to the refractory patient.
00:52:48
Speaker
Sergio, do you want me to go to the refractory patient now?
00:52:50
Speaker
Yeah, actually, I was going to ask you about that.
00:52:52
Speaker
You did mention that refractory cases are those who don't respond to appropriate dosing and administration of epinephrine.
00:53:00
Speaker
But clearly, that is a case, I think, that we would like to discuss in terms of what are other management options that we have and maybe mention some of the special drugs
00:53:08
Speaker
that can also be utilized in these cases?
00:53:10
Speaker
Yes.
00:53:11
Speaker
So when you've done all this right, and so the patient is transferred to the ICU, the patient is on oxygen, he's got a mask that's delivering high flow oxygen, he's breathing a little better, his blood pressures are responding, and his systolic is, mean ocular pressure is now slowly increasing.
00:53:36
Speaker
and patients looking a little bit more comfortable and you say, okay, I think we can now watch him.
00:53:44
Speaker
All of a sudden he begins to deteriorate again, either due to biface response or because he has reached a point in his body
00:53:53
Speaker
Ketakalamin protective mechanism where there's a failure of the endogenous mechanisms and the hypovolemia takes over and as a result, it goes into pump failure, myocardial depression.
00:54:07
Speaker
And there are two complications you have with these people.
00:54:10
Speaker
One is known as the Kuhnus syndrome, which is a vasospasm of the coronary arteries that leads to myocardial ischemia.
00:54:17
Speaker
And the Tarkotsubo cardiomyopathy, as you folks in the ICU probably know, which is a reversible ischemic dysfunction of the myocardium leading to either anterior or inferior, depending on Tarkotsubo or the reverse Tarkotsubo.
00:54:34
Speaker
All these things can happen, pump failure due to leukotrienes and cytokines.
00:54:40
Speaker
depressive cytokines and depressive mechanisms, they go into worsening hypovolemia.
00:54:46
Speaker
How do you manage this patient?
00:54:48
Speaker
You've already given them the epinephrine IM, you give them oxygen fluids and all that, and they're deteriorating.
00:54:55
Speaker
So two things to quickly look at.
00:54:57
Speaker
One, are they on blood pressure pills, ACE inhibitors, and beta blockers?
00:55:02
Speaker
Like I said, this is the first thing to look at as you look at these cofactors in these patients.
00:55:08
Speaker
And the beta blocker needs to be stopped.
00:55:11
Speaker
ACE inhibitor needs to be stopped.
00:55:12
Speaker
But these drugs have half-life.
00:55:13
Speaker
So what are you going to do now?
00:55:15
Speaker
So two things you can do.
00:55:17
Speaker
One is you can use glucagon to bypass the beta adrenoid receptor.
00:55:23
Speaker
which directly activates cyclic AMP.
00:55:25
Speaker
Glucagon is present in the insulin hypoglycemia kits that are readily available.
00:55:29
Speaker
One to five milligrams can be given in these people and will buy you time until the beta blockers watch out of the system.
00:55:36
Speaker
And you can also start IV pressors.
00:55:38
Speaker
The second thing you can do is IV pressors.
00:55:40
Speaker
We talked about the IV epinephrine, one milliliter and 1,000 milliliters of D5 or normal saline.
00:55:48
Speaker
And remember that it's one in 1,000.
00:55:50
Speaker
You take one milliliter and dilute it to 1,000.
00:55:54
Speaker
And so it's a very dilute solution.
00:55:56
Speaker
And you give one to 10 micrograms titrated to a mean actual pressure of 65 millimeters.
00:56:01
Speaker
So that can be done.
00:56:03
Speaker
Now, if you have something like intraoperative anaphylaxis, where the anesthesiologist tells you that this happened as soon as he injected the rocuronium and he didn't have time and he brought the patient over and leaves him in your care, you can use this drug called Sugamadex, 4 milligrams per kilogram IV,
00:56:23
Speaker
Specifically, the cyclodextrin is called a relaxant binder and basically quickly reverses the effects of bronchoronium, the neuromuscular blocking agent.
00:56:35
Speaker
So that can be done very quickly.
00:56:38
Speaker
And if you continue to have hypotension and refractory hypotension, that's when a salvage mechanisms come into play.
00:56:46
Speaker
By this time, you've been battling this patient for probably last four, six, eight hours.
00:56:51
Speaker
And the patient is now slowly tending to go downhill.
00:56:55
Speaker
And you have some options to bring him back.
00:56:58
Speaker
One is there have been studies, anecdotal studies.
00:57:01
Speaker
Again, I got to stress right up front.
00:57:05
Speaker
Because of the formative nature of anaphylaxis, the dramatic nature of the syndrome, the rapid evolution of the disease and the rapid onset and progression to cardiorespiratory arrest, there has not been good randomized trials, and you can realize why.
00:57:21
Speaker
As a result, we've developed only experience-based recommendations, case cohort-based recommendations,
00:57:32
Speaker
And in rare studies, outpatient studies, or randomized studies that we extract some of the information.
00:57:39
Speaker
But now we have a lot of pressors and there have been some increasing data on the literature recently on the use of vasopressin.
00:57:47
Speaker
And vasopressin you guys use in the ICU, I'm sure, but it binds to the AVP receptors in both the blood vessels as well as the other sites
00:58:02
Speaker
causing vasoconstriction and reversal of some of the findings that you have in refractory hypervolemia and hypertension and pump failure.
00:58:11
Speaker
So the AVP receptor binding to the vasopressin result in reversal and synergy in some cases with epinephrine.
00:58:21
Speaker
So you can have an epinephrine drip and or add a vasopressin drip at the
00:58:27
Speaker
at appropriate rates, I read rates of 0.01 to 0.04 units per minute, but you guys would know those doses much better and can be given.
00:58:38
Speaker
And that seems to, in some studies, almost 40, 50% of the patients quickly normalized their blood pressures after vasopressin was given.
00:58:49
Speaker
Again, these anecdotal reports in small case clusters.
00:58:52
Speaker
Now, there is a rule for methylene blue
00:58:56
Speaker
There have been reports, a lot of reports, probably 50, 60 across various journals and across various countries where Methyl in Blue rapidly reverses anaphylaxis.
00:59:09
Speaker
And what Methyl in Blue does is it salvages nitric oxide.
00:59:13
Speaker
We didn't discuss this upfront, but what happens is when you have an allergic reaction,
00:59:18
Speaker
The allergen binds the IGE, IGE then binds the FCER1 receptor, causes what's called cross-linking.
00:59:25
Speaker
That gives a signal to the mast cell.
00:59:28
Speaker
The mast cell goes through signaling cascade, releases calcium.
00:59:31
Speaker
Calcium causes degranulation as well as activation of the nitric oxide expression in endothelial blood vessels.
00:59:42
Speaker
The granules and the granular contents like TNF and histamine bind to TNF receptors, PATH receptors, and histamine receptors on the blood vessel wall and the endothelium.
00:59:53
Speaker
And this signal transduction leads to activation of enos.
00:59:56
Speaker
And enos then elaborates nitric oxide.
00:59:59
Speaker
And nitric oxide is responsible for part of the capillary leak and the hypovolemia and the hypotension vasodilatation that you see.
01:00:07
Speaker
And it looks like methylene blue is a good salvage mechanism
01:00:11
Speaker
mechanism by activating a guanil cyclic AMP and negating the effects of the cascade created by nitric oxide.
01:00:23
Speaker
So, Methyl in Blue is infused in doses, half the dose of Sugamidex is basically 2 mg per kg body weight.
01:00:31
Speaker
Sugamidex is a 4 mg per kg body weight.
01:00:34
Speaker
So, that's how you do this.
01:00:36
Speaker
And these are all salvaged protocols and ultimately if all else fails, the patient will end up with the ultimate treatment in the ICU, which is extracorporeal life support systems and
01:00:51
Speaker
And then a slow management after that based on, you know, various parameters and, you know, and getting them out of that.
01:01:02
Speaker
That's totally an ICU intensivist regulated area.
01:01:08
Speaker
So, Sergio, I will start.
01:01:09
Speaker
Absolutely.
01:01:09
Speaker
I'm going to go to you.
01:01:11
Speaker
Yeah, absolutely.
01:01:12
Speaker
And I think that, Guha, obviously a lot of interesting salvage therapies, like you said, obviously,
01:01:21
Speaker
are based mostly on anecdotal reports, but that we have utilized with success of very extreme cases.
01:01:27
Speaker
And I think are important things to have in the back of our mind for those refractory cases that despite appropriate initial treatment continue to deteriorate because they might actually help patients.
01:01:38
Speaker
And specifically, I think with the glucagon and the sugamidex, right, which are directed at specific drugs that might be present, it's important for all the intensivists to have this
01:01:50
Speaker
in their armamentarium for treating patients with anaphylaxis.
01:01:55
Speaker
I do believe that it's worth emphasizing one more time, epinephrine, epinephrine, epinephrine, and that this is a time-sensitive intervention.
01:02:04
Speaker
And like you said, it is not uncommon to see people giving glucocorticoids, giving histamine blockers, yet failing to give the appropriate doses of epinephrine for these cases.
01:02:14
Speaker
So just important to always start with what really works and
01:02:18
Speaker
and make sure that the most important thing that patients need is given appropriately.
01:02:21
Speaker
So a lot of great information there.
01:02:24
Speaker
The last thing I wanted to ask you about acute treatment, Gruha, before we kind of start wrapping up, is could you make any comments on patients with stroke who receive TPA and then have an anaphylactic reaction, which is not common but can be quite dramatic?
01:02:39
Speaker
Yes, so, you know, when the patient comes in with an acute need for an ICU care and then gets a secondary anaphylactic event due to intervention, that of course is a nightmare scenario.
01:02:54
Speaker
None of us want to be handling that, but it really happens.
01:02:58
Speaker
Now, those who are admitted for stroke, a small fraction of these people, less than 2%, one in 50 people who get TPA will anaphylax to TPA and develop a massive angioedema response, even as they're undergoing thrombolosis.
01:03:16
Speaker
And a lot of this might be mediated by the kinin cascade.
01:03:20
Speaker
Now, I'm going to tell you that probably in the next few years, we're going to have more studies on kinin inhibition, platelet-active factor inhibition, and we'll have new drugs in that sequence and cascade to control those reactions.
01:03:37
Speaker
But right now,
01:03:40
Speaker
The best we can do is to discontinue the TPA and administer antihistamine steroids, epinephrine.
01:03:48
Speaker
And if they've been intubated, make sure that with the TPA that you avoid hematomas and bleeding into the airway because they've already been thrombolyzed.
01:03:59
Speaker
So it is a hairy scenario, no good answers.
01:04:05
Speaker
But I just want to put it out there that this is something to keep in mind that patients who come in for one event could anaphylax to the intervention for that event.
01:04:14
Speaker
And you have a secondary consequence that's more severe than the primary event itself.
01:04:20
Speaker
and requires stopping of the drug.
01:04:22
Speaker
That's the first thing you do in all of these anaphylaxis cases, whether it's an antibiotic or rocuronium or it's the IBIG or a blood transfusion product, you're going to stop that drug, number one.
01:04:37
Speaker
And number two, you're going to do all the management of anaphylaxis, realizing
01:04:42
Speaker
that the primary disorder that you are treating might actually get worse.
01:04:46
Speaker
What if you had a patient with infection and you give an antibiotic, the anaphylax to the antibiotic, and you've got to give them steroids, for example.
01:04:54
Speaker
All these scenarios are difficult scenarios.
01:04:57
Speaker
But this is just presenting a broad framework, Sergio, just to keep this in mind.
01:05:04
Speaker
And probably in the future, we'll have bradykinin inhibitors.
01:05:06
Speaker
We already have three drugs available in the market for C1 inhibitor and the bradykinin pathway that we use for heterotia angioedema.
01:05:15
Speaker
They have not been studied in anaphylaxis and in situations like these complicated patients with TPA reactions.
01:05:23
Speaker
which might be kinin-mediated, and so we might have more drugs in the future.
01:05:28
Speaker
Calicrine, bradykinin pathway inhibitors might be available in the future.
01:05:33
Speaker
Excellent.
01:05:34
Speaker
And I would like to ask you if you could give us some advice and comments on post-ICU management, and mostly Guha from the perspective that I recently had a young female who had an aphylactic, severe aphylactic reaction during an orthopedic surgery, probably to the antibiotics.
01:05:51
Speaker
obviously being young and a kind of a low risk case, it caused a tremendous stress for the anesthesia team.
01:05:58
Speaker
She did well and she was discharged home.
01:06:01
Speaker
And that's one of the few cases or situations where we might discharge people from the ICU 24 hours later.
01:06:07
Speaker
But what are the things that we should be making sure that they get, obviously starts with allergy and immunology referral, but are there any other things?
01:06:16
Speaker
And you also mentioned some of the
01:06:18
Speaker
the drugs, some of the diagnostic tests, such as the tripe disc level, that might be very helpful for our patient management.
01:06:24
Speaker
But what are recommendations in that area?
01:06:26
Speaker
So one is when they get discharged, the patient has been through a pretty morbid event, right?
01:06:37
Speaker
So it's a pretty scary situation.
01:06:39
Speaker
When anaphylaxis happens, we call it a sense of impending doom.
01:06:42
Speaker
It's not like anything else anybody has ever experienced before because very rapidly the whole body is going out of whack.
01:06:51
Speaker
The flushing happens, the hives happen, the itching furiously, the tongue begins to swell, they can't breathe, the neck tightens up and they start getting dizzy and some of them actually pass out and lose consciousness.
01:07:03
Speaker
So it's a very traumatic event for them and they leave the hospital with a sense of fear, almost like our COVID patients do, leave with great dread.
01:07:13
Speaker
So one is educate them about anaphylaxis, very briefly direct them towards the Quad AI website, the Anaphylaxis Food Allergy Anaphylaxis Network website, NIDID website, and the Mayo Clinic.
01:07:29
Speaker
A lot of these places will give very useful information
01:07:32
Speaker
that a sibling or a kid or a distant relative can pull up for them as they're recuperating at home.
01:07:39
Speaker
The second thing is to have some sort of an anaphylaxis management plan until they see their primary care and definitely get referred to an allergist.
01:07:46
Speaker
In some studies, when they're discharged from the ICU, less than 20% get referred to an allergist and less than 40% are given Epipen autoinjectors.
01:07:56
Speaker
So giving the Epipen autoinjector is one aspect of this discharge.
01:08:01
Speaker
The second aspect is describing how they use it.
01:08:03
Speaker
Now you can get pharmacy involved.
01:08:05
Speaker
You guys are busy in the ICU and pharmacists are always ready to do this.
01:08:09
Speaker
So this education about how to use EpiPen is important.
01:08:13
Speaker
The EpiPen auto injectors and the generic EpiPens that are now available, you take it out of the case, make sure that it's viable and the expiry date is not exceeded.
01:08:24
Speaker
And the patient has to remove the gray cap in the back and the blue cap in front.
01:08:30
Speaker
And basically, with one big movement, strike it against the thigh, and it will inject the 0.3 milligrams of epinephrine.
01:08:38
Speaker
and you hold it down for about 10 seconds, you pull it out, and then you massage the area so that you allow the medicine to spread evenly into the muscle and the tissue.
01:08:50
Speaker
And a second dose can be given if they're far away from the emergency room, realizing that a small fraction of them, 20 to 30% of them, will get symptomatic again as they're heading to the ER and will need a second dose.
01:09:05
Speaker
So that education is important and you can recruit your pharmacist to do that, but make sure that the education is done and have some sort of an alphalaxis management plan because of they go home after ICU care and somebody, a caregiver, somebody has to be educated on what to do if there's a relapse of these events and when to do allergy blocking drugs and use EpiPen and go back to the hospital
01:09:34
Speaker
And the reference to an allergist is important.
01:09:37
Speaker
Is there any value, Guha, in sending them home with a steroid taper?
01:09:42
Speaker
I've seen people do that.
01:09:44
Speaker
Or more antihistamines?
01:09:47
Speaker
So if you have a full-blown anaphylactic event, the patient's being discharged at or to carry out their angioedema, I think that it's reasonable.
01:09:56
Speaker
I don't see any harm in sending them home, even though the current guidelines don't really recommend it, but the evidence is weak for that surgery.
01:10:04
Speaker
So we don't have great evidence for or against this process.
01:10:08
Speaker
They're recommending against it, but they say the evidence is weak to make a decision.
01:10:15
Speaker
As a result, I would say that's reasonable to send them home on a five-day or a seven-day prednisone taper H1H to block it so that the transition home is a lot smoother.
01:10:27
Speaker
Excellent.
01:10:28
Speaker
So very important in terms of educating people on the use of the EpiPen once they leave, but also making sure that they have proper follow-up with allergy and immunology.
01:10:39
Speaker
Guha, thanks so much for all your expertise and sharing such wonderful pearls in terms of managing this fascinating disease, which is anaphylaxis.
01:10:50
Speaker
We'd like to close the podcast by asking our guests some questions unrelated to the clinical topic.
01:10:56
Speaker
Would that be okay?
01:10:58
Speaker
Yes, Sergio.
01:11:00
Speaker
So my first question relates to books that have influenced you the most or books that you have gifted most often to others.
01:11:07
Speaker
So I'll tell you a book that I read a lot.
01:11:11
Speaker
And so I've dealt in spirituality because medicine is a chaotic practice and our day-to-day life is difficult.
01:11:21
Speaker
And as a balance, I use music and exercise, but I also use spirituality, not religion as much as spirituality.
01:11:30
Speaker
And there was a beautiful book called Everyday Zen that I used to read a lot.
01:11:33
Speaker
And the book begins, the first page begins,
01:11:37
Speaker
Jo'Kobek, she's no more.
01:11:38
Speaker
She passed away three years ago.
01:11:40
Speaker
I actually went and met her in San Diego where she had the Zen Center of San Diego.
01:11:45
Speaker
And she ran that center.
01:11:47
Speaker
Very beautiful, calm person and calm demeanor.
01:11:51
Speaker
And I used to talk to her on the phone and then I went and met her.
01:11:54
Speaker
And so I gave that book to many people.
01:11:57
Speaker
The first page begins with this line.
01:11:59
Speaker
It says,
01:12:01
Speaker
my dog doesn't worry about tomorrow, but I do, you know.
01:12:06
Speaker
And that's the conundrum we have as human beings because we do worry, regret the past and worry about the future.
01:12:17
Speaker
And with medicine being a tough field and we come back to our lives, I think we need a calming influence.
01:12:22
Speaker
So I use that.
01:12:23
Speaker
Another favorite book of mine I used to read was Jonathan Livingston's Sekel by Richard Bach.
01:12:28
Speaker
It's a beautiful book.
01:12:30
Speaker
about how to overcome your limitations and Fletcher Segal and the way he moves out of his wingtip wingtip mentality into infinitude.
01:12:40
Speaker
He moves, you know, beyond the limitations of the mind framework.
01:12:46
Speaker
And as a poet, I've read a lot of Indian poetry, but...
01:12:50
Speaker
The point that influenced me the most was T.S.
01:12:52
Speaker
Eliot in the Wasteland.
01:12:53
Speaker
And I've read a lot, written during the chaos of World War II, when England was being bombed and there was no food and they were at the throes of the end of World War II.
01:13:05
Speaker
And he wrote the Wasteland, which won the Nobel Prize.
01:13:08
Speaker
And he was an Indologist and he quotes a lot of Indian spirituality in the Upanishads there.
01:13:13
Speaker
So that, those are some of the books that come to mind.
01:13:17
Speaker
There were a lot more, Sergio, but I just thought I'd throw those out to you.
01:13:21
Speaker
Excellent.
01:13:21
Speaker
I think it's a nice, it's a nice group and we'll put links in the, in the show notes.
01:13:27
Speaker
And I've heard other people talk about everyday Zen.
01:13:30
Speaker
I definitely want to pick it up.
01:13:32
Speaker
I have read, I mean, a little bit of T.S.
01:13:34
Speaker
Eliot.
01:13:35
Speaker
And I also, I have not read the Richard Bach book.
01:13:37
Speaker
So I'm definitely interested in always picking up new, new reads.
01:13:41
Speaker
So thanks for sharing that.
01:13:44
Speaker
The second question, Guha, relates to something that you believe to be true in medicine or in life that many other people don't believe or don't act like they believe.
01:13:55
Speaker
So, you know, I listened to a talk, Sergio, I think almost 18, 20 years ago.
01:14:03
Speaker
It was a psychologist being interviewed on a very nice channel from California.
01:14:11
Speaker
And it was Saturday afternoon.
01:14:12
Speaker
I used to listen to that channel a lot.
01:14:14
Speaker
And the psychologist was asked the question, do you believe in empathy?
01:14:20
Speaker
You know?
01:14:22
Speaker
And so the psychologist said, actually, there's empathy and there's compassion, you know.
01:14:27
Speaker
And in medical school, we're always asked to teach empathy, right, to students and residents and fellows training with you.
01:14:34
Speaker
And empathy is to feel like the patient would feel so that when you talk to the patient, you hone in your bedside manners and
01:14:44
Speaker
your demeanor, your words, the way you speak to the patient all reflect your empathy.
01:14:51
Speaker
But she said, actually, empathy is not sufficient.
01:14:53
Speaker
She says a higher order of empathy is compassion.
01:14:57
Speaker
Okay.
01:14:58
Speaker
And then I said, wait a minute, what is this?
01:15:00
Speaker
And so she said, even somebody who tortures somebody, you know, in North Korea or some horrendous regimes where torture was done, like in Vietnam, when Senator McCain, you know, was tortured for years and we've seen movies of torture.
01:15:19
Speaker
And she said that even the torturer has empathy.
01:15:22
Speaker
He knows that if he pulls the nail, that person is going to have pain.
01:15:27
Speaker
Compassion is wanting to alleviate the pain, you know?
01:15:30
Speaker
want to actually go and relieve that pain.
01:15:33
Speaker
And that is the higher degree of empathy.
01:15:38
Speaker
Compassion would be what you would reach for as a physician, especially in the ICU.
01:15:46
Speaker
Compassion for yourself is important too, I would say, by the way.
01:15:50
Speaker
Compassion for other caregivers around you, nurses and respiratory techs and guys who manage the ventilators.
01:15:58
Speaker
and the phlebotomist, but compassion most of all for the patient who's actually undergoing the disease.
01:16:03
Speaker
And I wanna briefly tell a very quick story from the Buddhist archives, Sergio.
01:16:10
Speaker
So Buddha had his cousin took care of him.
01:16:13
Speaker
His cousin's name was Ananda.
01:16:15
Speaker
It was his cousin's sister's son who went to live the homeless life and learn about love and compassion from the great master Buddha, 2,700 years ago now.
01:16:28
Speaker
And so Ananda asked Buddha once, sir, you keep saying compassion, compassion.
01:16:36
Speaker
You said everything about life is compassion.
01:16:39
Speaker
is compassion your main teaching?
01:16:42
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And the Buddha looks at him, smiles and says, no, Ananda, compassion is not my main teaching.
01:16:48
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Ananda shocked his jaw drops.
01:16:49
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He said, but I thought you always say compassion.
01:16:52
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And you say, everybody needs to have compassion.
01:16:54
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Is that not your main teaching?
01:16:56
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And the Buddha looks at him, smiles and says, Ananda, compassion is not the main teaching.
01:17:01
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It's the only teaching.
01:17:04
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And so the important thing to understand is that
01:17:08
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a skilled physician, diagnostic skills, all that is great, but you complete the circle with compassion.
01:17:17
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So the second aspect I wanted to mention, Sergio, is something that people don't understand, and that too in this world that we live in is, you know, that we are on the web of life, and I truly believe it.
01:17:31
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The plankton in the oceans, the earthworm in the mud,
01:17:37
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the bird that's raising his little chicks and a nest in the tree, the bee that's got a nest, you, me, the deer in the forest, we're all connected, the trees, the mountains, we're all connected in a web of life, you know.
01:17:53
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And so, you know, Chief Seattle, a very wise man going to the Native Americans many, 300, 400 years ago,
01:18:06
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He said that what we do to the web of light, we do to ourselves.
01:18:10
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And I firmly believe that with the pandemics and all that we're having, a man has destroyed the habitat, destroyed the caves and the dwellings and invaded rivers and streams and polluted the oceans.
01:18:26
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As a result,
01:18:27
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the intermediary hosts for these viruses have gotten extinct, bats and pangolins and all of those, you know, intermediary hosts.
01:18:36
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And therefore, by the need to survive, the virus has mutated.
01:18:44
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And the ecosystem destruction has been cited very often recently in the spread of pandemics.
01:18:51
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And so as human beings, we have to look at the world differently.
01:18:55
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We have to understand
01:18:56
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but we live in an interconnected universe and we're not just individual people living individual lives.
01:19:02
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So those were the two things I wanted to raise, Sergio.
01:19:06
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Excellent.
01:19:06
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And I think that obviously, like you mentioned, very relevant to our lives on an everyday basis, but also with the distinction between empathy and compassion and the need to be compassionate to ourselves and to others, I think really goes to the fiber of what we do at the bedside.
01:19:23
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Guha, it's really been a pleasure to talk with you.
01:19:26
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I learned a lot today and I want to thank you for your generosity with your knowledge and with your time and look forward to talking to you on the podcast again soon.
01:19:37
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Thank you, Sergio.
01:19:37
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Thank you for having me today.
01:19:41
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01:19:44
Speaker
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01:19:50
Speaker
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01:19:55
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