Transcript
Speaker: Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: And now, your host, Dr. Sergio Zanotti.
Speaker: Historically, the growth of intensive care units has been closely linked to polymyelitis,
Speaker: and the need its patients has had for prolonged mechanical ventilation support with the iron lung at the initial of these epidemics.
Speaker: With the development of the Salk vaccine, this problem has disappeared from our clinical practice.
Speaker: Today, the Guillain-Barré syndrome and myasthenia gravis account for the majority of patients requiring intensive care admission due to acute neuromuscular weakness.
Speaker: In today's episode of Critical Matters, we will discuss critical care aspects of these acute neuromuscular disorders.
Speaker: Our guest is Dr. Cameron Athar.
Speaker: Dr. Athar is a trained in critical care medicine and neurocritical care.
Speaker: He's a practicing neurointensivist at the Farber Institute of Neuroscience in Philadelphia.
Speaker: Dr. Athar is an assistant professor of medicine and of neurology at the Jefferson School of Medicine in Philadelphia.
Speaker: He has published extensively in the field and is an excellent clinical educator.
Speaker: Cameron, welcome to Critical Matters.
Speaker: Thank you, Sergio, for this kind introduction and thanks for the opportunity to participate in this podcast.
Speaker: So I think that we might start by making a differentiation.
Speaker: Today, most of the patients that have neuromuscular weakness in the ICU have acquired it in the ICU in what we know as critical care-induced myopathy, neuropathy, or neuromyopathy, which is more of a chronic consequence of critical illness.
Speaker: But what we really want to talk about today, Cameron,
Speaker: is those patients who present with acute neuromuscular weakness that require admission to the ICU.
Speaker: So perhaps a great place to start would be for you to give us a little bit of a differential diagnosis of that patient that presents to the ED or to the hospital with acute neuromuscular weakness.
Speaker: Yes, thanks, Sergio.
Speaker: That's a very important question.
Speaker: So the differential diagnosis of acute neuromuscular weakness leading to
Speaker: ICU admission is fairly extensive.
Speaker: The most important conditions to be considered are the acute polyneuropathies of Lyon-Buray syndrome is the most common one for which these patients require admission to the ICU.
Speaker: Other causes of acute polyneuropathies less commonly seen include severe thiamine deficiency, acute arsenic poisoning, Lyme disease, vasculitis,
Speaker: glue sniffing, porphyrias, which typically present with psychiatric manifestations in addition to neuropathy, as well as unexplained GI symptoms.
Speaker: Miller-Fisher syndrome is a subtype or clinical variant of Guillain-Barre syndrome, which is also an acute polyneuropathy that frequently requires ICU admission.
Speaker: In addition, other conditions that should be kept in mind in the differential are neuromuscular disorders, which is myasthenia gravis,
Speaker: Lambert-Eaton syndrome and botulism, penia gravis being the most common of the neuromuscular disorders.
Speaker: In addition, motor neuron disorders such as poliomyelitis, West Nile virus encephalitis, amyotrophic lateral sclerosis, as well as progressive spinal muscle atrophy are also in the differential.
Speaker: In addition, certain brainstem conditions which can mimic Miller-Fisher syndrome
Speaker: should always be on the differential as well.
Speaker: These include brain stem strokes, which typically are acute in onset, as well as brain stem encephalitis.
Speaker: Other conditions affecting spinal cord should also be considered in the differential, such as the acute myelopathy, the most common causes of which are cord compression and transverse myelitis.
Speaker: Typically in these patients on exam,
Speaker: there will be a sensory level as well as involvement of bowel and bladder.
Speaker: In addition, yes.
Speaker: Go ahead.
Speaker: In addition, myopathies such as polymyositis and dermatomyositis are also included in the differential diagnosis of acute neuromuscular weakness.
Speaker: So clearly, Cameron, I mean, a very extensive list of potential causes
Speaker: all of which are very rare for the common practicing intensivist.
Speaker: But I do think that in terms of how you would initiate the workup, are there some basic diagnostic tools that might help the clinician, whether it be in the ED or in the ICU, kind of guide the diagnosis in the right direction?
Speaker: So in addition to the clinical presentation, there are a number of diagnostic modalities available.
Speaker: to us, which in the appropriate clinical setting are helpful in establishing a diagnosis.
Speaker: These include lumbar puncture with analysis of the cerebrospinal fluid, electrodiagnostic studies such as EMG and nerve studies, as well as in the appropriate clinical setting, single fiber EMG, as well as repetitive nerve stimulation testing,
Speaker: And in addition, MRI of the brain and spinal cord can also help in excluding certain other causes of muscle weakness.
Speaker: Serologic testing is also important in certain cases, especially myasthenia gravis and the Miller-Fisher variant of Guillain-Barre syndrome.
Speaker: So in terms of deciding where these patients need to go to an ICU,
Speaker: or another type of setting, what are some of the reasons why patients with acute neuromuscular weakness might benefit from ICU admission, and what are the things that you would recommend our critical care colleagues to have in mind?
Speaker: Yeah, so the most important indication for ICU admission for these patients is typically respiratory failure requiring endotracheal intubation and ventilatory support.
Speaker: Especially in cases of Guillain-Barre syndrome, up to 20 to 30 percent of the patients will need ventilatory support at some point during their disease course.
Speaker: In addition, in some cases, especially in patients with Guillain-Barre syndrome, autonomic dysfunction can occasionally be severe enough that they will require closed ICU monitoring.
Speaker: Additionally, significant bulbar dysfunction
Speaker: in some patients with inability to clear their secretions increase the risk of aspiration.
Speaker: And these patients are also, these patients also require closed monitoring into ICU because they can progress to aspiration pneumonia and progress to respiratory failure.
Speaker: So I think that to recap, the real three big things are potential for respiratory failure, oropharyngeal weakness,
Speaker: and autonomic dysfunction.
Speaker: And I think as we speak more specifically about Guillain-Barré myasthenia gravis, we'll dive into these again.
Speaker: So why don't we go to Guillain-Barré syndrome, like you mentioned earlier, it's one of the most common reasons why patients with acute neuromuscular disease will come to the ICU.
Speaker: And maybe start by telling us a little bit about just how you think about Guillain-Barré in general, its incidence, and maybe what we understand today of its pathophysiology.
Speaker: Right.
Speaker: So Guillain-Barre syndrome is the most common cause of acute neuromuscular weakness.
Speaker: And under Guillain-Barre syndrome are included a number of immune-mediated acute polyneuropathies.
Speaker: And most often it presents as an acute monophasic condition that is typically preceded by an infectious illness.
Speaker: It is recognized now as a heterogeneous condition with several variant forms.
Speaker: And I will mention a little bit about those variant forms in a little bit.
Speaker: In terms of epidemiology, the overall incidence is about one to two per 100,000 population per year.
Speaker: And it's slightly more common in males compared to females.
Speaker: And it's also more common as people get older, right?
Speaker: I mean, there seems to be a spike, I mean, as people get age as well.
Speaker: Is that correct?
Speaker: That is correct.
Speaker: So it has been estimated that there is beyond the first decade of life
Speaker: there is a 10% increase in the incidence for every 10 years beyond the first decade of life.
Speaker: So the incidence definitely increases with age.
Speaker: And you mentioned that often it's preceded by an infectious disease.
Speaker: Very commonly, Campylobacter degeny has been implicated with gastrointestinal, but there's also respiratory and any other
Speaker: viruses or bacteria that are commonly being associated with Guillain-Barre?
Speaker: Yes.
Speaker: So as you mentioned, Sergio, Campylobacteria is the most commonly identified precipitant of Guillain-Barre syndrome.
Speaker: However, certain other viruses, especially cytomegalovirus, HIV, Epstein-Barr virus, and Zika virus, have also been implicated as precipitants for Guillain-Barre syndrome.
Speaker: And that's why it's kind of considered as a post-infectious condition.
Speaker: Cases have also been reported following certain immunizations, and that's always important in the history as well.
Speaker: And as I said, I mean, it's considered as a post-infectious condition, and what happens is that these infectious agents induce antibody production, and these antibodies are then directed against certain components of peripheral nerves because of molecular mimicry.
Speaker: Specifically, these include the ganglioside and glycolipid components of the peripheral nerves,
Speaker: which then results in lymphocytic infiltration, macrophage-mediated stripping of the myelin, and that's why it's kind of considered a demyelinating process.
Speaker: In more severe cases, damage to the axons can occur.
Speaker: And the end result of all of this is that there is defective propagation of electrical impulses resulting in flaccid paralysis.
Speaker: So that, in a nutshell, is sort of the path of physiology of Guillain-Barre syndrome.
Speaker: And I've read a lot about, like, the differentiation
Speaker: of subtypes from a pathophysiology standpoint with the acute inflammatory, demelinating, polyradiocle neuropathy, ADIP, versus acute motor axonal neuropathy, AMAN.
Speaker: Is that mostly in terms of understanding pathogenesis, but ultimately from a clinical perspective, does it have an implication of how we treat them?
Speaker: So in terms of it has more of prognostic significance.
Speaker: The treatment options for all these
Speaker: various subtypes or variants of GBS essentially the same.
Speaker: AIDP or acute inflammatory demyeldening coronary neuropathy, as you mentioned, is the most common variant.
Speaker: In the U.S. and Europe, about 85 to 9% of the cases of Guillain-Barre syndrome are due to AIDP, followed by the Miller-Fisher variant, which accounts for about 10% of the cases in U.S. and Europe.
Speaker: And the classic triad is ophthalmoplegia, ataxia, and areflexia.
Speaker: Acute motor axonal neuropathy and acute sensory axonal neuropathy are more severe forms of injury to the peripheral nerves because the axons are involved.
Speaker: So they typically tend to have more severe weakness, and the time to recovery also tends to be prolonged.
Speaker: And that's why sometimes it's important to differentiate what subtype are we dealing with, which may be important for prognostication purposes.
Speaker: Excellent.
Speaker: And in terms of clinical presentation, you mentioned how one of the variants, very well-known, Miller-Fisher syndrome would present with the ataxia, ariflexia, and apomalplegia, often with diplopia.
Speaker: Why don't you tell us, Cameron, what's a typical clinical presentation of a patient who comes to the hospital because of acute neuromuscular weakness from Guillain-Barre, and how do we usually make that diagnosis initially?
Speaker: Right.
Speaker: So the cardinal feature of Guillain-Barre syndrome clinically is progressive and fairly symmetric muscle weakness along with absent or significantly depressed deep tendon reflexes.
Speaker: And these patients typically present a few days to a week after onset of symptoms and bowel and bladder function usually preserved in GBS.
Speaker: In about 50% of the patients, there is also weakness of the facial muscles,
Speaker: as well as oropharyngeal weakness causing bulbar dysfunction.
Speaker: In about 10% of the patients, the weakness may begin in the arms or facial muscles because typically or classically it is recognized as an ascending paralysis or ascending weakness where the weakness starts in the lower extremities and sort of goes up to involve the respiratory muscles and the upper extremities.
Speaker: As I mentioned earlier, in up to 30% of the patients, the respiratory muscle weakness can be severe enough that they will require endotracheal intubation and mechanical ventilation.
Speaker: Some other features that should also be... Yeah, go ahead.
Speaker: I was going to say that in terms of just recapping, the ascending symmetric paralysis is really something that should make the clinician who's not used to seeing these cases very tuned in that this is probably Guillain-Barre.
Speaker: Correct, and also reflexes, areflexia or significantly depressed, deep tendon reflexes are also kind of point to the diagnosis of Guillain-Barre syndrome.
Speaker: And if you look at the National Institute of Neurological Disorders and Stroke diagnostic criteria, progressive weakness and areflexia are required features, along with other supportive features
Speaker: When you say progressive, can you give me an idea of the timeframe?
Speaker: So if somebody's had weakness for months, probably not going to be right.
Speaker: Right.
Speaker: Yeah.
Speaker: So in the, uh, uh, typically in these patients, after the onset of symptoms, they typically progress over a period of few weeks.
Speaker: And in most patients, about 90% of the patients, the symptoms have reached their nadir by anywhere between two and four weeks.
Speaker: If these patients continue to progress with their weakness or if their symptoms continue to progress beyond that period of time, you should be thinking about other causes of neuromuscular weakness.
Speaker: And, you know, beyond eight weeks, typically we should be thinking more if we have, especially on
Speaker: EMG electrodiagnostic testing, some demyelinating pattern, then we should be probably thinking about a diagnosis of chronic inflammatory demyelinating polyradiculineuropathy.
Speaker: Excellent.
Speaker: And two more questions regarding the diagnosis.
Speaker: One related to the physical exam and obviously grading the amount of weakness is going to be very important in triage and understanding what treatments have to be implemented.
Speaker: What is the commonly accepted scale?
Speaker: I think that I've read that the British Medical Research Council scale is what people recommend for muscle strength.
Speaker: Could you just review that for our listeners very quickly, Cameron?
Speaker: Sure, yeah.
Speaker: So the British Medical Research Council graded system for muscle strength is widely used.
Speaker: And what the examiner does is he assesses the patient's ability to move the muscle against resistance, which is provided by the examiner.
Speaker: And the patient's effort is graded on a scale of zero to five.
Speaker: So grade five is that the muscle contracts normally against full resistance.
Speaker: Grade four is when the muscle strength is reduced.
Speaker: However, muscle contraction can still move the joint against resistance.
Speaker: Grade three is when muscle strength is reduced to the point that the joint can be moved only against gravity with the examiner's resistance completely removed.
Speaker: Grade two is the muscle can only move if the resistance of gravity is removed.
Speaker: And in grade one, only a trace or flicker of movement is seen or felt in the muscle, or you can observe, or you may observe the circulations in the muscle.
Speaker: And grade zero is when there is absolutely no movement in the muscle.
Speaker: So in terms of considering severe weakness, anything below three, three or below would be considered severe weakness acutely?
Speaker: That is correct, yes.
Speaker: And that's how it is when we say mild, moderate, severe forms of Deandre syndrome.
Speaker: That's kind of what the, it's based on the muscle grading, strength grading system.
Speaker: So anything below three is considered as severe.
Speaker: And the second question you had mentioned earlier in the differential diagnosis and diagnostic tools, the use of an LP.
Speaker: So that is something obviously that's available immediately.
Speaker: Imaging, I understand, would be useful to exclude other causes but not to make the diagnosis of Guillain-Barre.
Speaker: But could you comment on the CSF that we find with Guillain-Barre typically?
Speaker: So the classic finding on CSF analysis in patients with Guillain-Barre syndrome is what we call albuminocytological dissociation, where you have an elevated CSF protein with a normal WBC, a white blood cell count, typically left in five cells per millimeter cube.
Speaker: as many as 66 or two-thirds of the patients by week one will have this finding on CSF.
Speaker: And by week three, more than 75 to 80 percent of the patients will have albuminopsychological dissociation on examination of their CSF.
Speaker: There was a series, prospective series, done at Mass General Hospital of 110 patients where they looked at their CSF profile, and what they found was that
Speaker: 87% of these patients had a cell count of less than 5, and another 9% of the patients had a cell count between 5 and 10.
Speaker: So this is a finding that is fairly often seen, and it's classic for patients with Guillain-Barre syndrome.
Speaker: So high protein and no cells or very low cells is what we're looking for.
Speaker: And also, I guess it allows us to differentiate or test for other potential differential diagnosis.
Speaker: which I think is always important.
Speaker: That is correct, yes.
Speaker: Now, in terms of once we see the classical presentation, we make some initial diagnosis, let's say that we feel comfortable with a Guillain-Barré syndrome patient, what would prompt you in your practice, Cameron, to say this patient needs to go to the ICU?
Speaker: Yeah, it's a very important question because, you know, these patients, when they come in, initial triage is important.
Speaker: Some studies have actually looked at clinical predictors in these patients of the need for under-tratubation and mechanical ventilation.
Speaker: And so, as I mentioned earlier, you know, in addition to... So some of these parameters are based on bedside assessments of respiratory muscle strength or spirometry.
Speaker: So patients who have a vital capacity
Speaker: of less than 20 mL per kg.
Speaker: These are patients who are likely or will likely need endotracial intubation and cataclysmal ventilation.
Speaker: This is what we call sort of the 20, 30, 40 rule.
Speaker: So on spirometry, you assess your vital capacity, negative inspiratory force or maximal inspiratory force, and maximum inspiratory pressures.
Speaker: So a number of retrospective studies have shown that a vital capacity less than 20, a negative instaurary force less than 30, or a maximum instaurary pressure less than 40 is likely going to result in the need for endotracheal intubation and mechanical ventilation.
Speaker: And so these are some of the criteria that we use to initiate intubation and mechanical ventilation in these patients.
Speaker: And I think that this is very important because, like you mentioned, the 20-30-40 rule with bedside spirometry is very important in predicting who will need intubation.
Speaker: But I would imagine that way before you get there, you want to put them in an ICU so that you're monitoring them, right?
Speaker: So these numbers that you mentioned would be more in terms of crossing the threshold for intubation as opposed to crossing the threshold for let's put this patient in the ICU for close monitoring.
Speaker: Correct, yeah, and actually there is one fairly large study that actually has looked at very early predictors of the need for mechanical annihilation.
Speaker: And this was from the French cooperative group on plasma exchange and Guillain-Barre syndrome.
Speaker: And what they looked at were 700 plus patients with Guillain-Barre syndrome who were enrolled in trials for Guillain-Barre.
Speaker: And the main outcome variable that they looked at was need for mechanical ventilation.
Speaker: And in the cohort, 43% of the patients required mechanical ventilation.
Speaker: And when they looked at the multivariate model, they identified six predictors that predicted the need for an intubation.
Speaker: One was time of onset to admission of less than seven days, which kind of goes on to shows you that these patients have a more aggressive course.
Speaker: patients who are unable to cough, unable to stand, unable to lift the elbows above the bed, unable to lift their head.
Speaker: And then for some reason, they found that liver enzyme increase in this multivariate model.
Speaker: All these six variables were predictive of the need for endotracheal intubation and mycanal ventilation.
Speaker: And what they found was that if a patient at the time of presentation had four out of these six predictors, more than 85% of the time, they required
Speaker: mechanical methylation.
Speaker: And they also looked at a subgroup.
Speaker: Yeah, go ahead.
Speaker: But I was just going to say that we really should have a very low threshold when we see a patient who is acutely admitted and has the early phases of their syndrome because we don't know how they're going to respond to treatment or how they may deteriorate over the next couple of days, right?
Speaker: Yes, that's correct.
Speaker: And these six variables that they identified, they're very, very simple
Speaker: bedside exam, bedside maneuvers that you can do to kind of triage patients.
Speaker: You know, very, very simple bedside tests.
Speaker: In addition, also an important feature of Guillain-Barre syndrome that kind of just differentiates it from myasthenia is that some of these patients, a lot of these patients can actually, from a respiratory standpoint, may remain fairly stable.
Speaker: However, sudden respiratory decline is not uncommon.
Speaker: in these patients, which again argues for close monitoring in a more intensive care setting for these patients because then these patients will require or may require emergent intubation.
Speaker: And in terms of once they come to the ICU, obviously the monitoring is with serial spirometry since I presume that ABGs would be too late in terms of determining the need for intubation once they're hypoxemic and hypercapnic.
Speaker: we probably passed the time when we should have intubated that patient.
Speaker: Is that correct?
Speaker: Yeah, that is correct because, you know, if you have hypoxemia and hypercarbia on ABG, then that already sort of indicates established respiratory failure as a result of respiratory muscle weakness.
Speaker: So that's kind of late in the game.
Speaker: And that's why these early predictors are important.
Speaker: Clinical variables as well as bedside spirometry testing
Speaker: And the trends in these numbers, the bed size parameter testing, are more important.
Speaker: And also, they have to be interpreted in the appropriate clinical setting, looking at the whole big picture as well.
Speaker: And also, take into account bulbar dysfunction, ability to handle secretions, and all those things as well.
Speaker: Yeah.
Speaker: So then, it's not only the absolute number, like you mentioned, with the 20, 30, 40 rule, but like
Speaker: rapidly falling vinal capacity might be as good as an indicator that the patient needs to be intubated as a vinal capacity below 20, right?
Speaker: That is correct.
Speaker: Always, you know, these numbers should be interpreted in the appropriate clinical setting, taking into account, as I said, the big picture clinical clues like signs of respiratory muscle involvement or distress, as well as trend in these measures.
Speaker: They have to be.
Speaker: And also, one must also keep in mind that these numbers, although important, there are caveats because some patients who have facial muscle weakness may not be able to make a good seal.
Speaker: And sometimes these numbers can be, in those cases, misleading as well.
Speaker: So they're not perfect tests.
Speaker: And patient effort and also quality of the testing, I guess, also can impact the numbers.
Speaker: So I think those are great points, Cameron, to
Speaker: to make sure that people are aware of.
Speaker: So since we're talking about intubation and mechanical ventilation, let's just go down this rabbit hole a little bit more, and then I want to go backwards and talk about other treatment modalities.
Speaker: So once the patient's intubated, obviously, like you mentioned, the course, especially the very severe cases, can be prolonged.
Speaker: The good news is that the majority of patients will improve at one point, and many will get back, I mean, maybe to normal function.
Speaker: So you might be in for the long run.
Speaker: How do you think about weaning these patients?
Speaker: And when did you start thinking about trichostomy in these patients, Cameron, in your practice?
Speaker: Yeah, so while these patients are intubated, we should be following their, again, their bedside pulmonary function test or spirometry values closely.
Speaker: And again, decision to initiate weaning
Speaker: and precede vental liberation should be individualized for each patient.
Speaker: You could consider these patients as ready for vental liberation if they have objective evidence of improving respiratory muscle strength, because that is the most important clinical feature, which would be shown by an improvement in their vital capacity.
Speaker: as well as an improvement in their negative inspiratory force or maximal inspiratory pressure.
Speaker: So if the vital capacity is improving, it's about 20 cc per kg, and the negative inspiratory force is more negative than negative 30, the patients on a spontaneous breathing trial, they do not appear fatigued, they're breathing comfortably, there are no signs of respiratory distress, their ABGs are relatively normal.
Speaker: These are some of the patients whom you could
Speaker: a critter activation trial.
Speaker: And also, again, a lot of it depends upon clinicians' individual experience with this type of patient population.
Speaker: There is no perfect way to proceed with weaning in these patients, but some of the rules to remember are that weaning should proceed in a manner that prevents respiratory muscle fatigue and it allows for adequate rest between weaning trials.
Speaker: Excellent.
Speaker: And in terms of tracheostomy,
Speaker: A lot of these patients will be on mechanical ventilation for a long period of time, so early tracheostomy makes sense if we can identify those patients.
Speaker: How do you approach this decision?
Speaker: So vent liberation, the assumption is that those patients that are going to respond to therapy and are going to start the recovery process in a
Speaker: sort of reasonable amount of time, their respiratory muscle will improve, strength will improve, that will allow us to liberate these patients from the ventilator.
Speaker: If that is not happening and the PFTs, pulmonary function testing, those numbers are not improving, probably after 10 days or so, 10 to 14 days is sort of a cutoff, these patients should probably be considered for tracheostomy
Speaker: this patient population is likely going to have a much longer recovery time.
Speaker: However, if you see trends that show improvement over a period of time, those 10 to 14 day cutoff is not set in stone.
Speaker: You could, if you see a positive trend, maybe wait a few more days to allow more time for recovery of respiratory muscle strength and then attempt mental liberation
Speaker: and maybe possibly avoid tracheostomy.
Speaker: So that's kind of like our general approach to these patients.
Speaker: And you mentioned treatment.
Speaker: So why don't we talk a little bit about what are the currently accepted treatments for Guillain-Barré?
Speaker: There's been obviously a lot of discussion back and forth regarding plasma exchange versus IVIG and permutations of this.
Speaker: Why don't you just tell us what would be current state-of-the-art treatment and how you think about it?
Speaker: So...
Speaker: The treatment options available for Gabri syndrome are plasmapheresis or plasma exchange.
Speaker: And the other option available is intravenous immunoglobulin.
Speaker: A number of studies have looked at IVIG versus PLEX.
Speaker: And really, what we have found from all these trials is that they're equally efficacious.
Speaker: And the choice essentially between this and the number of factors
Speaker: of local availability, patient preference, if there are contraindications to one treatment modality versus the other, patient risk factors.
Speaker: So all those are factors that have to be taken into account.
Speaker: But in terms of efficacy, both are equally efficacious.
Speaker: And in terms of differentiating, I guess, with plasma exchange, obviously, the question is you have to put a dialysis catheter, so it's an invasive procedure.
Speaker: But it might be available in certain settings where IVIG is not available.
Speaker: IVIG has an increased expense of the drug.
Speaker: There's been some call-out, not call-outs, there's been like a limited availability of IVIG in certain situations.
Speaker: And in some institutions, it might not be something that is readily available.
Speaker: So I guess those are things or factors that might go into the decision-making as well, correct?
Speaker: That is correct.
Speaker: Yes, absolutely.
Speaker: And, you know, although it's not as common, patients with eye deficiency, if they are given IVIG, they could develop an anaphylaxis.
Speaker: So that would be a contraindication.
Speaker: In addition, I mean, IVIG is also, there's a cost factor that you mentioned.
Speaker: Also, it has some side effects or adverse events as well.
Speaker: Acute kidney injury, septic meningitis, and sometimes intractable headaches.
Speaker: And also, it can sort of occasionally induce a prothrobotic state.
Speaker: So all these factors have to be taken into account in terms of choice between plasma exchange and IVIG.
Speaker: And my understanding of the literature, Cameron, I just want to make sure that, correctly if I'm wrong, is that both IVIG and the plasma exchange, when studied against placebo and controlled studies, have shown to improve outcomes.
Speaker: That is correct.
Speaker: Go ahead.
Speaker: Yes, what the studies have shown is that they both shorten disease duration and they hasten recovery.
Speaker: So the time to recovery from the condition is shortened.
Speaker: So in some ways, they sort of shorten the disease course.
Speaker: And again, addition of IVIG after plasma exchange
Speaker: or vice versa, at least in studies, has not been shown to confer any significant extra benefit.
Speaker: And what about, and the studies that you said earlier, when they compare one against the other have shown no difference in favor of one in particular, but what about combining them for very severe cases?
Speaker: Is there any thoughts or studies on that?
Speaker: Some studies have looked at a combination approach as well, and found is that, and the studies that were done, IVIG was used after plasma exchange treatments had been done.
Speaker: And the addition of IVIG did not actually confer any extra benefit in terms of recovery time and disease progression.
Speaker: So really no benefit, as far as we know, in combining them.
Speaker: And I guess what I have understood from some of my neuro critical care and neurology colleagues is that in very severe cases, what they might do is they might extend the treatment period with the modality they were using a little bit longer.
Speaker: But that is not based on any particular randomized trial, just kind of an expert opinion.
Speaker: That is correct.
Speaker: And, you know, again, it's sort of based on expert opinion, as you said, and also, you know, experience of the clinician, you know, after patients, clinicians who take care of a lot of these patients,
Speaker: and have more experience.
Speaker: And, you know, so some of these decisions are based on their clinical experience.
Speaker: So is there any role for corticosteroids in Yambara?
Speaker: So that's a good question.
Speaker: And a number of systematic reviews and a meta-analysis that have looked at trials that used corticosteroids for patients with Yambara syndrome have shown that
Speaker: steroids do not hasten recovery from DeAndre syndrome or affect the long-term outcome.
Speaker: And actually, there are a number of smaller trials which have shown that actually oral corticosteroids given to these patients may, in some cases, delay recovery.
Speaker: So as of now, the way things stand, corticosteroids have no role in the management of patients with DeAndre syndrome.
Speaker: And what about, we talked about, obviously, the most important
Speaker: Likely reason they will require critical care is mechanical ventilation support.
Speaker: But autonomic dysfunction can also cause severe problems and even mortality in these patients.
Speaker: Could you give us some comments on autonomic dysfunction and how you go about it in the ICU?
Speaker: Yes.
Speaker: Autonomic dysfunction or dysautonomia is a fairly well-recognized feature of Guillain-Barre syndrome.
Speaker: And it can be a cause of significant morbidity and mortality.
Speaker: And it can be seen in up to 70% of the patients with Guillain-Barre.
Speaker: The typical medications are tachycardia, the most common sinus tachycardia.
Speaker: In addition, these patients can have urinary retention, widely fluctuating blood pressures, alternating from hypertension to hypotension.
Speaker: They can also have orthostasis, bradycardia, other cardiac arrhythmias, conduction abnormalities.
Speaker: In addition,
Speaker: Ilias and loss of sweating has also been seen in these patients due to the dysautonomia.
Speaker: In about 20% of the patients, the autonomic disturbances can be severe.
Speaker: And this is typically in patients who have more profound muscle weakness and or respiratory failure.
Speaker: And in these patients, they actually can be threatening the autonomic disturbances.
Speaker: And that's why these patients need to be very closely monitored in the intensive care setting.
Speaker: Their fluid status, their hemodynamics, their vital signs, and of course, their cardiac rhythms.
Speaker: These should be monitored very closely.
Speaker: What's the prognosis of these patients, Cameron, overall?
Speaker: Yeah, so, you know, the outcomes for these patients, in spite of the fact that, you know, they may look very sick when they come in,
Speaker: patient with severe GPS, especially at the nature of their disease, are actually reasonably good.
Speaker: 80% of the patients will be able to walk independently in six months.
Speaker: And the number goes up to about 85% by one year.
Speaker: As much as 60% of the patients by one year, there will be full recovery of motor strength.
Speaker: However, a small subset, about 15% of the patients, severe motor problems can persist.
Speaker: In terms of ventilator dependency, about 5% to 10% of the patients will become ventilator dependent.
Speaker: And these are the patients who obviously have more severe form of disease and have more severe weakness.
Speaker: The mortality is about 5% at one year.
Speaker: However, patients who become ventilator-dependent, the mortality, as expected, would be higher, and that is about 20%.
Speaker: And in addition, relapse can happen in about 10% of the patients.
Speaker: This occurs, and these are typically treated with an course of IVIG or plasmapheresis.
Speaker: And I think it's an important point because we usually have a very narrow view of patients in the ICU.
Speaker: And in this particular case, even though the road would be long with rehab and support, but the outcomes are quite good overall in terms of improvement and for many even getting back to a normal life.
Speaker: So I think it's important for intensivists when they talk about goals of care and when they talk with patients and counsel them on what to expect.
Speaker: That is correct.
Speaker: And that's a very important point.
Speaker: You know, you have to sort of...
Speaker: make it clear to the family as well as the patient that they may look really, really bad from a clinical standpoint in terms of their weakness at the height of their disease or condition when they're at the ICU.
Speaker: However, the road to recovery may be long and requiring a lot of physical therapy rehab, but most patients will recover fairly well, reasonably well, over the course of the next six months to a year.
Speaker: Excellent.
Speaker: So why don't we switch topics and talk a little bit about myasthenia gravis, which as you mentioned, is a neuromuscular plate disease that is also commonly seen in acute patients with neuromuscular disorders in the ICU.
Speaker: And just tell us a little bit about what's the incidence, what is myasthenia gravis, and we can start there.
Speaker: Yeah.
Speaker: So myasthenia gravis, you know, it's an acquired autoimmune disorder.
Speaker: It's the most common disorder of neuromuscular transmission.
Speaker: Classic clinical features are weakness of the scalpel muscles and fatigability on exertion.
Speaker: And in terms of incidence, the annual incidence is 7 to 20 new cases per million population.
Speaker: The prevalence anywhere from 70 to 320 cases per population.
Speaker: And the prevalence actually has been increasing over the last 60 to 70 years, and that is primarily because of the increased recognition of this condition.
Speaker: aging population and also patients with myasthenia gravis are living longer so the prevalence obviously has increased in the last 60 to 70 years or so in terms of what age group can it affect it can affect patients in any age however there's a biomodal distribution to the age of onset there's an early peak which is seen in the second and third decade of life and
Speaker: And typically, these patients tend to be females.
Speaker: So there's a female predominance in this subgroup patient.
Speaker: Then there's another late peak that is seen in the sixth to eighth decade of life with a more male predominance.
Speaker: And in terms of pathophysiology, you mentioned autoimmune disease.
Speaker: Can you just give us a little more details in terms of what are the antibodies that occur and what happens
Speaker: Yes, so as I said earlier, it's an acquired autoimmune disorder, and it's characterized by production of autoantibodies to the acetylcholine receptors, as well as the acetylcholine receptor-associated protein on the post-synaptic muscle membrane.
Speaker: This leads to blockage or prevents binding of acetylcholine to the receptors.
Speaker: In addition, these autoantibodies also induce
Speaker: sort of what we call complement-mediated degradation of the acetylcholine receptors.
Speaker: The result of all of this is that these muscle weakness develops.
Speaker: And in addition, over time, the synaptic cleft widens in these patients, and also the number of postsynaptic muscle membrane folds decreases, which is what we expect in a patient where the number of acetylcholine receptors available to the neurotransmitter is decreased.
Speaker: And in terms of diagnosis, how do you diagnose myasthenia gravis?
Speaker: So the diagnosis is suspected on clinical grounds.
Speaker: And other diagnostic modalities available are serological testing to check for or look for acetyl-coating receptor antibodies or muscle-specific receptor, tri-parison kinase receptor antibodies.
Speaker: And in very occasional cases, lipoprotein receptor-related protein 4 can also be seen.
Speaker: And in addition to serological testing, electrodiagnostic testing can also be helpful.
Speaker: These include single fiber EMG and repetitive nerve stimulation.
Speaker: The repetitive nerve stimulation, typically you would see a decremental action potential with repeated nerve stimulation, whereas single fiber EMG is probably the most sensitive test for diagnosis.
Speaker: However, it's technically quite, it's technically a little difficult, but it's also in the, you know, if you have the expertise available, it does help establishing the diagnosis.
Speaker: And I think that my impression, correct me if I'm wrong, Cameron, is that most patients that we see as intensivists with myasthenia gravis will have a diagnosis of myasthenia gravis made.
Speaker: And we usually see them in the context of a myasthenia gravis crisis or in the context of they are undergoing surgery or other critical illness and they come to the ICU.
Speaker: So it's not very common that we do a de novo diagnosis in the ICU.
Speaker: Is that true?
Speaker: That is correct, yeah.
Speaker: Most that will present to the ICU will come with what we call a myasthenic crisis, which essentially is defined as neuromuscular weakness to the point that these patients need some sort of ventilatory support, which could be either intubation and mechanical ventilation or noninvasive ventilation, or muscle weakness that delays recovery after surgery.
Speaker: or prolongs recovery or delays extubation after surgery.
Speaker: So these patients, I agree, most of the time already have established diagnosis of myasthenia gravis.
Speaker: And one of the features in terms of diagnosis that is very common, I guess, is ptosis or weakness in the eyelid.
Speaker: And I remember, I mean, as a resident, we would talk about the ice pack test.
Speaker: Could you tell us a little bit about that?
Speaker: The test is essentially based on the principle that neuromuscular transmission improves at lower muscle temperatures.
Speaker: And if you, in patients with myasthenia, ptosis can be overcome by application of direct cooling to the eyelid muscle.
Speaker: That's what the ice pack test is.
Speaker: It's very simple.
Speaker: What you do is you take a surgical glove, fill it with ice, and place it on the closed eyelid for two minutes.
Speaker: And then when the ice is removed, the extent of ptosis is immediately assessed and in ptosis is considered a positive test result.
Speaker: It's a very simple bedside test.
Speaker: And I think that those are probably much more safe than doing neostigmine or endonoculum injections at the bedside, correct?
Speaker: That is correct.
Speaker: And actually, as of, I think, 2016 or 2017, hydrofonium is actually no longer available in the U.S.
Speaker: So it essentially has pretty much gone out of favor, that Adrophonian test.
Speaker: And just to go back to the ice pack test, the sensitivity is approximately 80% for the test.
Speaker: And I think that one of the things that you were mentioning was obviously the characteristic of articability or the fact that with repetitive contractions, the weakness comes up.
Speaker: How does that impact your evaluation of respiratory weakness?
Speaker: perhaps you do vital capacity and it's normal, right?
Speaker: So it doesn't really give you a clear indication of how to follow these patients.
Speaker: Yes.
Speaker: So, again, in these patients, you know, in patients with generalized myasthenia, that's where you will have variable sort of combination of bulbar, limb, and respiratory muscle weakness.
Speaker: And in some cases, the muscle weakness, respiratory muscle weakness, can be severe enough to necessitate some sort of ventilatory support.
Speaker: And again, the initial assessment of these patients would require some basic clinical bedside testing so you can ask them to
Speaker: start counting, so single breath, how many numbers they can count.
Speaker: You can look at any evidence of respiratory muscles fatigue.
Speaker: And again, if you want to get more objective, you can do bedside spirometry testing, including assessment of vital capacity, negative respiratory force, and or maximum expiratory pressures in these patients.
Speaker: And one of the differences that I think is important to highlight for the audience
Speaker: and you mentioned it briefly, but I want you to dive in a little bit more, Cameron, is that in general, for Guillain-Barré syndrome, noninvasive positive pressure ventilation is not recommended.
Speaker: So usually when they have issues, we go directly to endopracheal intubation.
Speaker: But you did mention the Guillain-Barré, sorry, in the myasthenia gravis population that noninvasive ventilation might be helpful.
Speaker: It might be a way of supporting them early on.
Speaker: Could you mention that a little bit more, please?
Speaker: Yes.
Speaker: Again, as, Sergio, you mentioned, in patients with Guillain-Barre syndrome, noninvasive ventilation, as things stand out now today, really has no role because there are very small case series that have shown that patients who were tried on noninvasive ventilation in Guillain-Barre syndrome required emergent intubation because after staying stable for a while, these patients developed sudden respiratory deterioration.
Speaker: However, in patients with myasthenia gravis, again, there are small case series where noninvasive ventilation has been used as a bridge to prevent or avoid intubating these patients, sort of as a bridge to recovery.
Speaker: And also, patients who are intubated and you want these patients to be liberated from the ventilator, it has also been used as a bridge to ventral liberation.
Speaker: So there is some limited literature on that, which again kind of points to the fact that myasthenia and Guillain-Barre syndrome are two somewhat different conditions that can present both with respiratory failure, but the pathophysiology is different.
Speaker: So in small case series in patient myasthenia, where non-invasive isolation was tried as an initial ventilatory strategy,
Speaker: Well, the factors that predicted BIPAP failure or non-invasive ventilation failure were baseline hypercapnia, which means that by the time these patients start to get hypercapnia, that probably you would not be able to bridge them to recovery just using non-invasive ventilation.
Speaker: So the key point is that if you do want to try non-invasive ventilation, try it early.
Speaker: While at the same time, other treatment modalities are being administered,
Speaker: to hasten recovery in these patients.
Speaker: So why don't we talk about the treatment modalities that are commonly utilized for myasthenia gravis.
Speaker: And I think that there's a distinction between maintenance therapy for myasthenia gravis, this is a chronic disease, as opposed to acute Guillain-Barré, versus how we treat the myasthenia gravis crisis.
Speaker: So why don't you tell us a bit more about that, Cameron?
Speaker: Yeah, so my stenic crisis, in addition to assessment of the need for ventilatory support, other medical therapies available to us include immunomodulating treatments, and these can be subdivided into rapid modulating treatments, which include the plasma exchange or plasmapheresis and the venous immunoglobulin or IVIG.
Speaker: In addition, chronic immunomodulating treatments include
Speaker: glucocorticoids, or other immunosuppressive drugs, which in most cases should be initiated at the same time because the effect of the rapid immunomodulating treatment typically lasts for about three to six weeks.
Speaker: In addition, anticholinesterase agents are typically used for symptomatic treatment, and patients who are in a myasthenic crisis
Speaker: it is still somewhat controversial whether these patients in the midst of a myasthenic crisis should be on anticholinerous rate agents or not.
Speaker: Some people argue that because they do provide some symptomatic improvement, that they may be helpful as long as patients are able to handle their secretions, and secretions is not a major or significant factor in these patients.
Speaker: So in terms of rapid immunomodulating treatments, again,
Speaker: IVIG and Plex are the two therapeutic modalities.
Speaker: Typically, the onset of their action can take anywhere from a few days to up to a week, and the maximal effect takes up to three weeks or can take up to three weeks.
Speaker: And the effect of these therapies lasts anywhere from three to six weeks.
Speaker: The dose for IVIG is 0.4 grams per kg per day.
Speaker: for five days for a total dose of two grams per kg.
Speaker: And for plasma exchange, typically four to six sessions are given over a period of eight to ten days.
Speaker: And in terms of patients that you mentioned, so here another distinction is that corticosteroids do have a very prominent role in the treatment of Mycenae Gravis both
Speaker: chronically, but also in crisis, we initiate them because their effects will occur later, correct?
Speaker: That is correct.
Speaker: And generally, the gluocorticoids are started initially at relatively high doses, anywhere from 60 to 80 milligrams daily preptone.
Speaker: And their onset of action is relatively later, about two to three weeks from the initiation of the medication, and peaks at about five to six months.
Speaker: And although, as you mentioned, Sergio, transient weakness or worsening of symptoms can be seen in these patients, which can be actually significant in as many as 50% of the patients, what you do want is the glucocorticoids to be initiated because after the effects of the plasmapheresis and IVIG, which typically, as I said, lasts for three to six months,
Speaker: wears off, these patients can have a rebound of their symptoms.
Speaker: And what you want is to be on an immunosuppressive agent to suppress the production of autoantibodies.
Speaker: And also, in terms of the worsening of symptoms, typically the period where you can have worsening secondary to
Speaker: initiation of corticosteroid is five to 10 days after the initiation.
Speaker: And that worsening can last anywhere from five to seven days.
Speaker: So be very cognizant of that time period when glucocorticoids are initiated and should be in terms of worsening of symptoms that could be related to the use of glucocorticoids.
Speaker: Excellent.
Speaker: And the next question I have for you, Cameron, relates to when these patients are in mechanical ventilation,
Speaker: They are receiving, obviously, acute treatment for their crisis.
Speaker: The regular life or the regular time frame of these diseases is different than Guillain-Barre, right?
Speaker: So, in theory, these patients should have a lower proportion of prolonged mechanical ventilation and tracheostomy.
Speaker: Could you talk about the weaning of these patients?
Speaker: So, again, weaning for patients with myasthenia gravis
Speaker: The general principles are similar, however, in terms of which is that if you have serial measurements of bedside spirometry showing trends in the right direction, improving respiratory muscle strength,
Speaker: In addition, if these patients, while on the ventilator, on spontaneous breathing trial, they do not have any signs of significant respiratory distress or fatigue, these patients should be concerned for mental liberation.
Speaker: And there's one clinical rule of thumb, especially in myasthenic patients, that ready to wean when they can actually hold their head above the bed.
Speaker: That's a very significant sign that the muscle strength is improving.
Speaker: And again, you know, there is also the option in these patients, just because the way the disease course is in patients with myasthenia gravis, that of putting these patients on non-invasive mammylation following extubation as a bridge to recovery.
Speaker: So the percentage of patients who require tracheostomy in this patient population is definitely less than the patients with Guillain-Barre syndrome.
Speaker: And again, a lot of this kind of like
Speaker: goes back to clinicians' experience with these patients, how comfortable they are with trying non-invasive ventilation as a bridge to recovery or as a bridge to ventricular duration.
Speaker: And I think that the other thing that is commonly associated with myasthenia gravis is worsening of symptoms due to drug interactions.
Speaker: And obviously, in today's ICU, we really appreciate the input of our pharmacy colleagues
Speaker: in all these critical ill patients, but are there any specific drugs in the ICU that we should avoid in myasthenia gravis patients?
Speaker: Yeah, so the list of medications that can actually worsen myasthenic symptoms is fairly long.
Speaker: And, you know, and I was actually looking at some of these medications, and some very commonly used medications can actually exacerbate myasthenic symptoms.
Speaker: Antibiotics, including aminoglycosides, are well known to do that.
Speaker: some of the fluoroquinolones, and some of the beta-lact antibiotics, anthocelin, and then macrolides such as azithromycin, clarithromycin, and erythromycin, they can all exacerbate myasthenic symptoms.
Speaker: Some of the commonly used cardiovascular drugs, such as beta blockers and calcium channel blockers, they can also make symptoms worse.
Speaker: In addition, prednisone we already talked about.
Speaker: Patients can get worse before they get better, so that is well recognized.
Speaker: Some of the antipsychotic agents, such as lithium and chlorpromazine, some anticonvulsants like dilantin and gabapentin.
Speaker: So these are some of the medications that can make symptoms of myasthenia worse.
Speaker: So I think just, I mean, a word of caution for our listeners when you're dealing with a myasthenic patient is to be very cognizant
Speaker: that several drugs that we commonly utilize can exacerbate symptoms and understand where we stand with that and really, I mean, look into this as we treat these patients.
Speaker: I think, Cameron, that this has been a phenomenal conversation.
Speaker: I really appreciate, I mean, a lot of the insight that you have on these patients.
Speaker: Like you said earlier, Guillain-Barre is the most common cause of neuromuscular weakness in the ICU acutely.
Speaker: I think that every clinician has seen these.
Speaker: maybe not in great numbers, but I think that most of our intensivist colleagues have treated these patients or have heard of people who had a Guillain-Barré, so clearly something that happened.
Speaker: And as you said, the incidence of Myasthenia Gravis continues to increase, so it's more likely that we will see them post-surgically or with crises as they come to the ICU.
Speaker: We'd like to finish the podcast by asking our guests a couple of questions not related to the clinical topic we discussed.
Speaker: Would that be okay, Cameron?
Speaker: Yes, sure, absolutely.
Speaker: So my first question is, what book or books have influenced you the most or what books have you gifted most often to others?
Speaker: Yeah, that's an interesting question.
Speaker: Not recently, but maybe three years ago, I read this book.
Speaker: I've read others since then, but I think that book kind of made an impact on me.
Speaker: And it's fairly well known.
Speaker: but it's called How Doctors Think by Jerome Groopman, who is an oncologist and chair of Medicine at Harvard Medical School.
Speaker: And it's actually based on his experiences as an oncologist and also based on his interviews with other prominent physicians.
Speaker: And it's kind of like, I found it very interesting because it's not a very technical book.
Speaker: It's very easy reading.
Speaker: And it just kind of gives you a window into the mind of physicians.
Speaker: and kind of like, you know, explores, you know, some of the top processes, some of the forces behind the decisions that we as physicians make on a daily basis.
Speaker: And I think it's kind of why I found it kind of helped me in sort of analyzing myself in terms of my decision-making process every day as I see patients and, you know,
Speaker: and the way the risks benefit, pros and cons of each decision, clinical decision that we make on a daily basis.
Speaker: Excellent.
Speaker: I would recommend that book actually.
Speaker: I have not read it, but I'll definitely pick it up, and I definitely will include it in the show notes so our audience, our listeners can take a look at it.
Speaker: The second question relates to what do you believe to be true in medicine or life that most other people don't believe?
Speaker: Yeah, I think that over time as you sort of age, mature, gain more experience, I'm kind of like becoming more and more convinced that in medicine, a lot of times, not in all cases, but a lot of times, and it's a well-known dictum, that less is more, and that more is not always better.
Speaker: We're kind of like sold this idea that all these technological advances, they're all good, they all help, they all make a difference.
Speaker: Whereas the truth in a lot of the cases is different.
Speaker: So I think that we should be advocates for application of the right amount of medicine.
Speaker: And sometimes the age-old age that may actually be the right approach.
Speaker: I'm kind of realizing more and more as time goes on.
Speaker: And I think that even though some people have heard that dictum,
Speaker: It's not something that people frequently practice on a regular basis, right?
Speaker: And I think that the recognition at all levels that sometimes less not only is more, but it's better is, I think, very valuable from design to how we offer treatment to patients.
Speaker: I think very powerful.
Speaker: And clearly, I think that most people do not behave in a way that would support this.
Speaker: So I think it's very, very, very great insight, Cameron.
Speaker: And my final question is,
Speaker: What would you like or want every intensivist and advanced practice provider who's listening to this podcast to know?
Speaker: Would it be a quote or a fact?
Speaker: I think that in the ICU, we deal with a lot of life issues, end-of-life decisions.
Speaker: And I think that what I'm sort of realizing more and more, it's very, very important to
Speaker: understand and respect what the priorities, what the goals, what the needs of our patients who may be dying in the ICU are, and to sort of minimize suffering as much as possible.
Speaker: Because I think that in our quest to do more and our quest to help patients, sometimes we'll forget that
Speaker: Dying with dignity is also a basic human right.
Speaker: So that's kind of what I would say about sort of what I've learned and the message that I would pass on to my color intensers.
Speaker: I think it's a great place to stop, Cameron.
Speaker: I think that it's something that we've all very acutely aware of as we experience this wonderful profession.
Speaker: But definitely, I mean, listening to the voice of our patients
Speaker: to their preferences, and respecting that, I think, is of utmost importance, especially in patients who are dying.
Speaker: So, again, thank you so much for a wonderful conversation.
Speaker: I learned a lot, and I'm sure this will be very valuable for our audience.
Speaker: And we hope to have you back to talk about other neurocritical care topics.
Speaker: Thank you so much, Sergio, again, for having me and for the opportunity to participate in this podcast.
Speaker: Thank you.
Speaker: Thanks again for listening to Critical Matters.
Speaker: Make sure to subscribe to this podcast on iTunes or Google Play.
Speaker: You can also listen at www.soundphysicians.com backslash podcast.
