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Time Stamps

 

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Show Notes

Pearl 1: General overview: Why Do Red Blood Cells (RBCs) Sickle?  

    1. Sickle cell disease is caused by a mutation in the beta-globin gene, which encodes the beta-globin subunit of hemoglobin. 
      • This mutation alters a charged amino acid into a hydrophobic amino acid.
        • In its oxygenated state, this mutated hemoglobin behaves normally, but in areas that are deoxygenated, acidic, or dehydrated, sickling occurs.
    2. Sickling leads to two major negative outcomes which drive all the sequelae of sickle cell disease
      • Vasoocclusion and microvascular ischemia.
      • Hemolysis secondary to membrane inflexibility of sickled RBCs.
    3. This mutation also makes RBCs inhospitable to malarial parasites, so it has been selected for in areas of the world where malaria is endemic.

Pearl 2: When Should I Transfuse?

  1. Avoid transfusion whenever possible. But what’s so bad about a blood transfusion?
    • Alloimmunization is public enemy #1. 
      • Each unit of blood transfused puts patients at higher risk for development of antibodies to RBC antigens, which can critically limit their transfusion eligibility at a time they may really need it.
      • Be sure to notify your blood bank when caring for a patient with sickle cell disease in the emergency room or inpatient setting. 
    • Hyperhemolytic crisis, or massive hemolysis mediated by antibodies to transfused RBC antigens, can cause fatal acute anemia. 
      1. When working up these patients for acute hemolysis, remember that an undetectable haptoglobin might be their baseline due to chronic hemolysis.
        1. It may be helpful to compare LDH, AST, and indirect bilirubin and compare to their baseline 
    • Iron overload causes chronic end organ dysfunction and is a leading cause of death among older patients with sickle cell disease.
  2. So when DO we transfuse???
    • Symptomatic anemia
      • Compare symptoms to the patient’s baseline. Patients can often tell providers when they feel they need a transfusion for this indication.
    • Aplastic crisis
      • Stressor such as viral infection shuts down the bone marrow and halts RBC production. 
      • Reticulocyte count is lower than expected. 
        • A normal reticulocyte count in sickle cell disease is typically 8-20%! 
      • Hemoglobin might be at baseline, but with no RBC production, baseline hemolysis will lead to acute severe anemia very soon, so we transfuse to get ahead of this. 
    • Do not transfuse for a number in sickle cell disease…BUT if hemoglobin is less than 5 or is 2 or more points less than the patient’s baseline, consider transfusion. 
  3. Simple vs. exchange transfusion 
    • Simple transfusion=just a fancy name for giving your patient a unit of packed RBCs. 
      • One of the benefits of simple transfusion is reduction in the ratio of sickled:total hemoglobin, which decreases the risk of sickled cells coming together and causing vasoocclusion.
      • Favored for treatment of symptomatic anemia, aplastic crisis, or severe worsening anemia. 
    • Exchange transfusion=remove patient’s blood and replace it with packed RBCs.
      • Added benefit: FAST reduction in the ratio of sickled:total hemoglobin without an increase in viscosity. 
      • Favored for treatment of acute end-organ dysfunction such as respiratory failure, stroke, or multi-organ failure. 

Pearl 3: How Do I Diagnose and Treat Pain in Sickle Cell Disease?

  1. The gold standard for the assessment of pain in sickle cell disease is the patient’s report.
    • There are no diagnostic tests to quantify pain or to suggest how much pain a patient should be in. 
  2. Opioids are the mainstay of therapy for vasoocclusive pain crisis. 
    • Acute pain:
      • IV boluses vs Patient Controlled Analgesia (PCA)
        • Patient preference should play a major role in which upfront strategy is used. 
          • Check the medical record for any pain management plan of care agreements with the patient’s outpatient providers, which can be helpful in determining initial dosing. 
        • If selecting a PCA, ensure the patient has a detailed understanding of how the PCA functions. 
      • Watch out for side effects of opioids, including sedation.
      • Expect that higher, more frequent doses of opioids will be needed to treat acute pain in this population given potential altered pain responses and risk of opioid-induced hyperalgesia. 
    • Chronic pain
      • Long-acting opioid therapy such as oxycontin and MS contin can be considered.
      • Increasing evidence suggests that suboxone use can decrease opioid use and acute care utilization.
        • Suboxone should be seriously considered in patients with sickle cell disease on escalating doses of home opioid. 
  3. Adjunctive therapies
    • Ketamine can be trialed for pain unresponsive to opioid therapy.
    • NSAIDs can be considered for a 5-7 day course in addition to opioids.  
      • Weigh risks of NSAID use in each individual patient.
  4. Patients with sickle cell disease face significant barriers to care due to racism and health inequity.
    • This impacts timely evaluation and administration of pain medication. 
    • Be aware of your own biases as a provider. 
    • Specialized centers consisting of interdisciplinary teams familiar with sickle cell disease can improve care.
      1. Improved outcomes include faster administration of pain medication, greater likelihood of rapid reassessment, and lower likelihood of hospitalization.

Pearl 4: What Medications Treat Sickle Cell Disease?

  1. Hydroxyurea is the mainstay of therapy.
    • Works through increasing levels of hemoglobin F, which is not dependent on beta-globin to function properly. 
    • Reduces the rate of vasoocclusive crises and reduces mortality in sickle cell disease. 
    • This is the only drug for sickle cell disease that reduces mortality! 
    • Causes an increase in MCV.
      1. If a patient on hydroxyurea is noted to have a normal or low MCV, confirm that they are taking their medication as prescribed. 
    • Can and should be continued while patients are admitted to the hospital for vasoocclusive crisis or other disease-related complications. 
  2. Adjunctive therapies ($$$, and do not reduce mortality like hydroxyurea). 
    1. Voxelotor 
      1. Binds to hemoglobin and reduces sickle hemoglobin polymerization. 
      2. Increases hemoglobin levels, but does not reduce the rate of vasoocclusive crises. 
    2. Crizanlizumab 
      1. P-selectin inhibitor which blocks adhesion of white cells and platelets, which play a key role in sickle cell disease pathphysiology. 
      2. Reduces rate of vasoocclusive crises. 
    3. L-Glutamine
      1. Works through antioxidant action.
      2. Reduces rate of vasoocclusive crises. 
  3. Appropriate immunizations and prophylactic antibiotics are both key in mortality reduction in sickle cell disease.

Pearl 5: Major complications

  1. Any organ can be affected acutely or chronically (see figure 5).
    • Sickle hepatopathy, priapism, pulmonary hypertension, and splenic infarction are just some of the end-organ complications that can occur due to acute or chronic vasoocclusion.
  2. Splenic infarction can predispose patients to infectious complications by encapsulated organisms, such as salmonella osteomyelitis. 
      • Remember to vaccinate!
  3. Stroke can occur secondary to neovascularization with associated AV malformation.
  4. Renal medullary infarction 
    1. The highly concentrated environment at the level of the renal medulla leads to medullary infarction and impairs free water reabsorption, resulting in isosthenuria. 
    2. This in part explains why sickle cell patients might be chronically dehydrated and need IV fluids when coming in with vasoocclusive crisis or complications. 
      • You may see in practice 1/2 NS solution based upon the rationale that sickle cells are slightly dehydrated and so a slightly hypotonic environment might be beneficial by promoting water entry into red cells and thus decreasing the concentration of hemoglobin S and making them slightly more deformable and less prone to Vaso-occlusion. Clinical trials to justify the practice have not been done.
    3. Acute chest syndrome 
      • Acute vasoocclusion in the pulmonary microvasculature. 
      • Diagnosis
        • Pulmonary infiltrates plus 1 of
          • Fever, hypoxemia, tachypnea, intercostal retractions/nasal flaring/use of accessory muscles, chest pain, coughing, wheezing, rales
        • INDISTINGUISHABLE FROM PNEUMONIA!
          • Treat any possible pneumonia in a patient with sickle cell disease as acute chest syndrome until proven otherwise. 
      • Treatment
        • Vasoocclusive crisis management, including pain control
        • Antibiotics for community acquired pneumonia
          • Cover resistant organisms depending on individual patient risk.
        • Transfusion therapy, typically exchange transfusion if progressive respiratory failure. 
      • Prevention
        • Incentive spirometry can reduce the risk of acute chest syndrome in patients admitted with vasoocclusive crisis.
    4. Venous thromboembolism (VTE)
      • Patients with sickle cell disease are at increased risk for VTE.
      • Low threshold for DVT and PE assessment in this population. 

Transcript

PEARL 1: OVERVIEW

L: Ok, so I sat down with Dr. Nancy Berliner, the chief of hematology at Brigham and Women’s Hospital and editor-in-chief of Blood, and just a general legend in all things hematology, to discuss sickle cell disease.

S: That sounds like no big deal but really a pretty big deal. I’m really looking forward to hearing some of all her teaching points.

L: Absolutely! Let’s make sure we are all up to speed on the fundamentals of sickle cell disease.

Nancy Berliner: So sickle cell disease is primarily been selected for because the mutation makes the hemoglobin abnormal and makes the red cell inhospitable to malarial parasites. And so it’s been selected for, in areas of the world where malarias endemic.

S: Wow! I always forget this disease evolved as a way to protect against another disease

L: Yes! This is sometimes referred to as the malaria hypothesis of sickle cell disease. And it’s crazy that just one point mutation drives the whole course of the disease.

Nancy Berliner: So sickle cell disease is a point mutation that changes one amino acid in hemoglobin and changes it from a, uh, charge to amino acid, to a neutral amino acid, which means that it makes certain facets of the hemoglobin molecule hydphobic. And when sickle hemoglobin is oxygenated, it behaves pretty normally. But when it is deoxygenated and the confirmation changes, it exposes the hydrophobic face and it tends to make the hemoglobin polymerized and stick together. And then as it goes through the microvasculaturewhere the pH is low and they tend to get dehydrated and the vessels are small and it tends to be hypoxic, you get sickling.

L: I really can’t think of a WORSE place for sickling to occur: the microvasculature of active tissues.

S: Yes! Agreed.

Nancy Berliner: And,  that’s when you get vasoocclusion. So that’s one of the main complications of sickle cell disease is this tendency for the cells to block small vessels and cause ischemia in the microvasculature. In addition, because of the changes in the membrane, the cells less flexible. And so you get hemolysis. And so it’s a combination of the risk of vaso-occlusion and then the risk of chronic hemolysis and everything that comes all of the many, many things that come over the course of the life of someone with sickle cell disease is mostly related to those two things.

S: Wow! It sounds there’s gonna  be lots to unpack but so far let me just recap what I’m hearing – basically, sickling is going to lead to 2 major bad outcomes: (1) vasoocclusion from sickled cells blocking the microvasculature and (2) hemolysis since those RBC membranes are not flexible enough to live through the constant sickling and unsickling.

PEARL 2: TRANSFUSION

S: Now, we can imagine the downstream effect of all that sickling and hemolysis is anemia…and at the same time, we often have this threshold to transfusion for any Hg <7 so how do reconcile that?

L: Such a great question, so I asked Dr. Berliner her thoughts on transfusion in sickle cell disease.

Nancy Berliner: We avoid it. So we never transfuse somebody for a number. And the problem is, is if you do transfuse somebody for a number you will transfuse ’em every time they come into the hospital. And that’s how you end up with a patient with ferritin and a 5,000 and heart disease and liver disease and diabetes and all that stuff.

L: So even if their hemoglobin is like 6.2, we still avoid transfusing?

Nancy Berliner: You look they have scary looking crits, but if you look back, they’ve had that, that same, uh, that same blood count for months and months and months and years and years and years, and really that’s where they live. And you have to have a different mindset about what you think is too low.

S: Okay channeling a different mindset, I’m all about reframing and mindset but jeez, then, when DO we transfuse?

Nancy Berliner: Routine transfusions are only if the patients appear to be symptomatic because of the anemia or they have an aplastic crisis and their crits are going down very quickly. Then obviously you do need to transfuse them.

S: Ok, symptomatic anemia and aplastic crisis — let’s break that down, if we start with symptomatic anemia – my honest reaction to that is to kind of sigh because symptoms of anemia are just so vague, take fatigue for example. Everyone in the hospital is fatigued.

L: Totally, I would say probably including us. You know, all the providers. I definitely hear that. The way I try to work through it is to compare patient’s current symptoms to their baseline; are they MORE fatigued than usual? MORE short of breath? And I’m always humbled to remember that since patients live their whole lives with this disease, they’ll often be able to tell us if they feel like they need a transfusion when things feel really off.

S: Yea, that is a really fair point. I have had plenty of patients tell me that this is a time I need a transfusion. So I appreciate that point. Let’s move on to aplastic crisis as an indication for transfusion.

L: Aplastic crisis happens in the setting of some kind of stress, often a viral infection, which essentially shuts down your bone marrow and stops red blood cell production. So we can expect an acute drop in Hg with an inappropriately low reticulocyte count.

S: And just to compare that for a second, in the usual setting, if there’s an anemia and their bone marrow works, you’d expect the reticulocytes would be ramping up. But here in aplastic crisis, those reticulocytes are inappropriately low.

L: Right, I guess to appreciate what is inappropriately low, we need to know what’s a normal the reticulocyte count is in these patients?

Nancy Berliner: The normal retic site count in a sickle cell patient is usually somewhere between 8-20%. I mean, it’s usually very, very high and that’s because they need to, their red cell, survival is so short that they need to constantly make red cells.

L: Wow, so these patients are constantly making RBCs aren’t they

Nancy Berliner: That’s one of the reasons why patients are usually put on folate chronically because they have that huge demand because they’re making red cells all the time.

L: Gotcha, so if they stop making reticulocytes in aplastic crisis, it’s only a matter of time before their hemoglobin bottoms out.

S:  Right so it really makes sense to transfuse in aplastic crisis … so now I’m wondering besides symptomatic anemia, are there any other situations we’d think of transfusing?

L: Another great question, and something I struggle with too. In sickle cell disease, we’re being told not to transfuse for a number. Dr. Berliner, IS there a number that would change your mind?

Nancy Berliner: And a lot of it, it depends on where they live. If somebody usually has a hemoglobin of six and a half and they go down to six, that’s not so bad if they usually they have a hemoglobin of eight and a half and they go down to six, that’s probably worse. So, I think it it’s sort of a, it, there isn’t a magic number, but there obviously is for every patient, there’s some number where you decide, okay, we got to do something.

L: That’s super helpful. And for the numbers-oriented folks out there– from what I read, numbers to keep in mind for simple transfusion are hemoglobin <5 and a hemoglobin of 2 or more points less than baseline.

S: Nice, I love me some numbers – But Leora, you just dropped the term simple transfusion. So why don’t we think about that term a bit more? I think we hear that term thrown around and it makes me pause for a second. What is a simple transfusion?

L: Simple transfusion is something you are more familiar with than you think. It is what you do when we transfuse patients in clinical practice.

S: Oh simple transfusion is just a regular transfusion that I order for anyone on the floor?

L: Yeah! And I just wanna point out that aside from raising the hemoglobin, one benefit of transfusing patients with sickle cell is that the new RBCs from the transfusion reduce the ratio of sickled/total Hemoglobin– so you have less sickling and less of a chance that two sickle cells are gonna run into each other and block off a capillary.

S: Yes, we do not want that – ok I feel good about a simple transfusion and its indications: aplastic crisis, symptomatic anemia lower than baseline. Now when do we need to kick it up a notch and consider an exchange transfusion? And maybe we should start with what’s the difference between a simple and exchange transfusion.

L: In exchange transfusion, a patient’s blood is removed and replaced with the same blood you’d give in simple transfusion.

S: Wait why do we do that? Why do we need to remove our patient’s blood in the process?

L: The answer is viscosity. With exchange transfusion, I can decrease my proportion of sickle hemoglobin quickly without running into hyperviscosity.

S: Wait these patients that already live at such low hemoglobin can end up with viscosity issues?

L: They can. And that’s the trouble we can run into with simple transfusion– yes, we decrease sickle hemoglobin, but we increase the total hemoglobin and increase risk for hyperviscosity.

S: Yeah, that makes sense – do you have scenario cement hyperviscosity issues with simple transfusion?

L: Let’s say we have a sickle cell disease who lives at a hemoglobin of 6. We give them a few units with simple transfusion and their hemoglobin goes up to 10. Now, under normal circumstances we might be pretty happy with this. We think about our GI bleeders who come in with acute anemia but remember, these patients live at a lower hemoglobin and we are significantly increasing it, almost doubling it in this case. So, that puts these patients at risk for hyperviscosity.

S: I’m glad we put some numbers to that since I could see someone scroll past a Hg 10 since it’s not in red on the CBC panel and not think of hyperviscosity complications. So, with all that in mind, how do we know when to reach for simple or an exchange transfusion?

Nancy Berliner: If you’re transfusing someone because they’re very anemic, cause they have an aplastic crisis or they’re not making red cells for some reason, then that’s a simple transfusion. If you’re treating an acute chest syndrome the practicality of trying to get enough normal red cells in the circulation to prevent ongoing sickling without having a huge rise in the hematocrit and a huge increase in viscosity, it makes sense to exchange people. So that’s we always exchange people when it’s for an acute emergency, like an acute syndrome.

L: So the big takeaway here is if someone is coming in with acute end-organ dysfunction, you don’t have time to slowly decrease their sickled hemoglobin with simple transfusion, so we favor exchange transfusion in situations like respiratory failure, stroke, or multi-organ failure, where you need rapid reduction in sickled hemoglobin and sickling without raising viscosity.

S: Nice! I’m grateful we can sharpen our thresholds for transfusion because particularly with transfusion, we are constantly weighing pros and cons and these transfusions are not without risks.

L: Definitely. Dr. Berliner walked us through some pretty unforgettable stories about transfusion complications.

Nancy Berliner: The most feared complication and what can actually be lethal is, hyper hemolytic syndrome, which can develop, it’s not common, but it does happen.

L: Just to remind ourselves, hyperhemolytic crisis is a sudden severe hemolysis. You’ll find an acute drop in hemoglobin and abnormal hemolysis labs.

S: Wait, but aren’t patients with sickle cell always having a constant low level hemolysis at baseline, how does that work when we trying to diagnose hyperhemolysis?

L: Definitely– an undetectable haptoglobin might be their baseline– that’s where some of these other markers such as AST, indirect bilirubin, and LDH can be helpful as well by comparing these levels in the acute situation to the patient’s baseline levels.

Nancy Berliner: It’s usually associated with certain specific antibodies that are formed. We had one episode of that and it was a real lesson because they didn’t do deep typing on the patient and she ended up getting an antibody that caused a hyper hemolytic episode which she was treated through but it’s very scary. They can get down to a hemoglobin of 2 or 3. It can be lethal.

S: Sounds like it is pretty important for whoever is ordering transfusions to be in close touch with the blood bank…

Nancy Berliner: It is important to do extended typing on those patients because of the rate at which they develop antibodies and you can actually and you can actually prevent many of the antibodies that are formed by having extended typing and being very careful how you crossmatch patients. So we had a patient who was often in the hospital who had one or two antibodies that had developed very early on. And she was always, she always had extended typing. And then she went to another hospital where they did not do extended typing and got, that was matched for the two known antibodies, but otherwise was not nearly as carefully matched. And she then had 15 antibodies and became untransfusable. And she ultimately developed bone marrow necrosis and went down to a hemoglobin of 2 or 3, and we ultimately had to transfuse her with the best blood that we could, that was cross-match negative and treat her with all kinds of other things to try to get her through. We gave her eculizumab so she wouldn’t have complement-mediated red cell destruction. We did all kinds of things. We got her through it the first time it happened. We didn’t get her through it the second time.

L: Wow, that sounds like an incredibly challenging case.

S: Yes, will absolutely be ensuring my due diligence with the blood bank to let know a patient has sickle cell disease and send that T&S on admission so they can take their time to do that careful extended typing.

L: And last thing that Dr. Berliner also walked me through other major complications of transfusion we should be thinking about.

Nancy Berliner: Iron overload is a major problem. And is in fact, I think a leading cause of death among older patients with, with sickle cell disease. It’s hard to unload people who have, um, anemic disorder because you can’t phlebotomies ’em the way we do people with hemochromatosis. So they have to be on chelators.

L: Yet another humbling reminder about the harms of transfusion if we can avoid it.

S: So to recap, sounds like in sickle cell we throw out the idea of transfusion to a number goal and instead do simple transfusions for symptomatic anemia, aplastic crisis or if ther is an acute change from their baseline and to think of exchange transfusion when there is some acute end-organ damage. And regardless of which transfusion we order, we have to make sure we work with our pathologist colleagues to make sure extended typing happens to prevent lethal antibodies.

PEARL 3: PAIN MANAGEMENT

S: I’m glad we talked about when to transfuse, the other thing we are often navigating in vasoocclusive crisis is pain management.

Nancy Berliner: An acute vaso-occlusive crisis? It’s virtually impossible to do anything but give narcotics.

S: Yep, not a time we should be trialing only that high dose Tylenol TID only.

L: Exactly, I asked Dr. Berliner her thoughts on what to initially put patients on – whether that’s intermittent IV boluses or PCAs?

Nancy Berliner: So that’s highly dependent on the sort of the psyche of the patient. If the patient wants a PCA pump, you should give to them. The issue is to make it as much patient controlled as possible. I’m a great proponent of PCAs in having patients control is that you can’t push the PCA button if you’re asleep. And me, one of the most horrifying experiences I had very very long ago was someone who was in a room far away from the nurses in the days when the wards were not nearly as open as they are now and were not as easily accessible who got over medicated and aspirated and died. Um, and, uh, because, so it it’s the real, um, things that make me nervous.  And the other thing is is that if you stop breathing, when you have sickle cell disease and you become hypoxic, then that just makes everything worse. So I think it’s important to be liberal enough with narcotics, that the patients are made comfortable, but it’s always a juggling act. And that’s one of the reasons that I think that, uh, patient control anesthesia is the way to go. 

S: I hear that and that’s powerful case for a PCAs but it also humbling to see that we as team didn’t check how they were using PCA or explain it well in the beginning to set them for success.

Nancy Berliner: You know, they, they wait until they’re miserable and then they push it five times and they get one dose and then they say, it’s not working or they don’t know to push it. They really don’t. And, and some of them know that they come in and they, you say, do you want a PCA pump? They say, no, they don’t work for me. And those people, you have to give intermittent bonuses.

L: On top of the challenges of being in severe uncontrolled pain, these patients often face stigma for the amount of pain medications that they require.

Nancy Berliner: Yeah. And I think a lot of the problems with sickle cell patients feelings about the medical system is that, that, um, they feel like they are viewed as being, um, drug seeking and that they are, you know, that they’re not taken seriously and tend to be, um, put in a position where they feel they’re being undertreated. And so I think it’s very important to listen to the patient for the most part when the patients come in, they are in really terrible pain. It’s probably as bad as anything that anyone has ever had to deal with. And you have to, um, you have to let them drive the ship and, um, eventually try to get them to the point where they’re, they are ready to step back and, and decrease it.

L: I can’t agree more. We as clinicians are so used to driving that ship and titrating pain meds as we see fit– sometimes not even telling patients that we did it– but best practice in sickle cell is really letting patients drive that ship.

S: Agreed. And maybe a part of us taking over pain management plans is probably our own feeling of helplessness because they’re on such high doses of pain meds and they’re still not getting pain relief.

Nancy Berliner: The patients who don’t get enough adequate relief either because they’re chronically on so much narcotics that it doesn’t really work is when you start trying things like ketamine. And, um, that’s something that has become more common.

L: Ketamine is definitely not something we regularly reach for, so it’s good to know we have that in our back pocket.

S: The other thing I’ve also seen used is NSAIDS from time to time but I worry about giving it too because I don’t want to cause kidney injury and worsening sickling.

L: Definitely– NSAIDS do have associated risks, but ASH guidelines suggest that NSAIDS can be used as an adjunct for pain for 5-7 days. Of course, we want to look at each patient individually and weigh the risks and benefits and safety of NSAID use, but if there are no major contraindications, you can consider them.

S: Good to know but of course proceed with caution with NSAIDs – the other pain point is when acute pain management becomes more of chronic pain management.

Nancy Berliner: The real problem is not acute pain management, but chronic pain management. And I, we, we actually do try pretty hard to keep people off chronic, long acting narcotics. A lot of patients come to us on them and some patients require them, but, um, in the long run, I think part of the problem is, is that there’s only so many opioid receptors that you can have. And so I, it’s a mystery to me how all these enormous doses, um, really do anything, but make people hyperalgesic and make them have more pain.

S: Ok so tough balance to strike with keeping them off of narcotics long-term and if they do need it, balancing if they’ve have not crossed over to being hyperalgesic.

Nancy Berliner: It’s also true that, um, sickle cell disease is associated with abnormal pain responses. So there have been studies so that if you give a painful stimulus in the hand in the hand and you look for changes in vascular, uh, tone and, and vasoconstriction in a normal person, you get an immediate vasoconstriction reaction. And as you repeatedly give that stimulus, it decreases, you sort of get used to it. in sickle cell disease. It increases. So they have, um, have altered, uh, neural responses.

L: I think that abnormal pain response is really important for us to understand because many of us are not used to giving such high doses of narcotics, but this really helps provide context for the pain and suffering these patients experience and why they need these doses of medication.

Nancy Berliner: We have started using a lot more Suboxone for there are some patients who are unwilling to accept it. There are other patients say it transforms their lives. And why, why haven’t I been on this all along?  And I think for people who are, who, um, are requiring more and more narcotics because they are on chronically so many narcotics, it can be very helpful to do something like transition them to suboxone mostly because then when they come in in acute crisis, the narcotics work again.

S: Ah, that sounds such a happy ending if our patient responds well to suboxone.

L: Yeah, agreed. Though even with pain control, these patients still face so many barriers.  – I asked Dr. Berliner to share her thoughts on this, especially since the vast majority of patients are African American, and it’s well-established that this population faces a lot of barriers in healthcare.

Nancy Berliner: I know that there are huge barriers to care for African Americans whether they sickle cell disease or not. I think that the level of racism and, and health inequity is very high, um, even in places where maybe even, especially in places where they think that it isn’t and where, where people think they’re very conscious of these issues. And then the sickle cell population, because their main interaction with the healthcare system is when they’re in pain. And I think it’s also, um, very difficult because it derails their lives. I mean, a lot of the patients, you know, they can’t keep a job because they’re in the hospital or they, you know they didn’t finish school because they spend so much time at home and, and things like that.

L: This brings up why it’s so important for us as clinicians to be as knowledgeable. It’s interesting because certain hospitals have specialized units for patients with sickle cells and so the interdisciplinary teams in these units get to know these patients really well and ultimately we see faster administration of pain medication, greater likelihood of rapid reassessment, and lower likelihood of hospitalization.

S: So it sounds like the big takeaways from this section are when patients come in with vasooclusive crisis, reach for PCA and IV bolus of opioids with a slight preference to PCAs giving the patient control and coaching them how to use it. Ketamine and short-term NSAIDS are also options. Suboxone can be a helpful to transition if someone is on chronic opioids. I think we to recognize this is a terrible disease on top of the many other barriers these patients often face in their medical care.

L: And we should do our best to not add to those barriers by being sympathetic to their pain, treating it adequately, and on a systems-level, organizing specialized units with staff that are well-versed in helping patients through a pain crisis. If we take nothing else away from this episode, the most important thing is that the gold standard for assessment of pain in sickle cell disease is the patient’s report.

PEARL 4: TREATMENT

S: Leora I’m curious what you learned about from Dr. Berliner about the overall treatment for sickle cell. The one I remember the most is hydroxyurea.

L: Yeah, I think that one stands out in a lot of our minds… Dr. Berliner made a good case as to why it’s the best drug we have.

Nancy Berliner: Hydroxyurea was really the only drug that was demonstrate to have a real impact on long term survival. And they had a big trial and it was extremely effective in raising hemoglobin F levels. So you increased the number of F cells and it had a profound effect on the rate of crises. So Hydrea has turned out to be a great, a great drug. And, um, they initially did it in people who had lots of crises, and then they started using it in almost everybody. And then they started giving it to little kids. And actually, there are children who are started as toddlers on Hudrea and they don’t know what a sickle cell crisis is. They do great. The one thing you have to watch is, you know, it’s a, it’s a tough disease to live with and patients don’t always take all the things you give them. So one of the thing markers of taking Hydrea is it makes your red cells really big. It causes megaloblastic changes. And so they get a very high MCV. 

L: So if a patient comes in and they’re supposed to be on hydroxyurea, BUT their MCV is normal, we should double-check if they’re actually taking their medication as prescribed.

S: I’ll definitely be looking out for that when doing admissions! Speaking of admitting patients on hydroxyurea– is it safe to keep the medication going inpatient with a vasoocclusive crisis or should we say restart in a few days or when they are discharged?

L: Definitely keep it going in the hospital. Safe and appropriate to do so.

Nancy Berliner: So Hydrea is sort of the mainstay upper-level treatment. And for years, and years and years, there was nothing else. It was supportive care. And then in the last few years, there have been two new drugs that have been introduced. Um, one is voxelotor, which is a drug that shifts the oxygen dissociation curve. So it makes the, um, the hemoglobin hang on the oxygen, hang on to the hemoglobin longer. There’s been an ongoing controversy as to, um, whether it does that at the expense of oxygen delivery. And so there is a huge back and forth about it because the clinical trial and the basis by which they approved Voxelotor was actually based on an increase in hemoglobin and not on a reduction in sickle cell crises. And in fact, there was no change in the rate of sickle cell crises, despite the fact that people had better hemoglobins.  I think the jury is still allowed as to whether it’s really gonna turn out to be such a good drug.

S: Gotcha, so cool pathophysiology and sounds like voxelotor stabilize the hemoglobin, but won’t protect our patients against vasoocclusive crisis and doesn’t reduce mortality like hydroxyurea.

L: Exactly. Dr. Berliner had one more new drug she mentioned that you may see patients on.

Nancy Berliner: The other drug is a biologic agent, um, called crizanlizumab, a mouthful, which is a P selectin inhibitor, which, uh, as we’ve learned more about sickle cell disease, turns out that adhesion of white cells and platelets have an important part to place, not just the red cells that are causing the problem. And it’s they create an inflammatory response. And there’s a lot of, um, of involvement of white cells and, and, and platelets in the pathophysiology of crises and of sickle cell disease. And so this is an antibody that blocks adhesion to endothelial cells.

L: Another cool drug and yes, crizanlizumab does decrease sickle crisis, but again does not reduce mortality like hydroxyurea. One other drug to be aware of is L-glutamine, an oral agent that works through antioxidant action and does reduce sickle crises as well.

S: Are there any other downsides to the novel drugs? I bet they’re expensive.

L: They sure are Shreya! So you can imagine it’s challenging getting them on formulary in major hospitals.

S: So it sounds like the major theme here is hydroxyurea is really the mainstay of treatment, and then things like voxelotor or crizanlizumab serve as adjunctive therapy.

L: While these are great drugs to treat these patients with and there is a lot more coming on the horizon, unfortunately, we just can’t prevent all the complications of this disease.

PEARL 5: COMPLICATIONS OF SICKLE CELL DISEASE

S: Let’s move on to the complications. I feel like this can feel a bit like a laundry list of things we should be looking out for and its hard for me to remember all of it

L: Yeah its going to feel like that because unfortunately, in sickle cell basically any organ, you name it, can be affected acutely or chronically from sickling

S: thats so humbling to think about about – give me some examples

L: In the liver, sinusoidal obstruction by sickled RBCs can lead to sickle hepatopathy. At the level of the penis, vasoocculusion can cause priapism; this is an emergency which often prompts exchange transfusion. In the lungs, Microvascular obstruction can lead to pulmonary hypertension. Even the spleen, early on in life sickle cell leads to vascular obstruction 

Nancy Berliner: Of course, nobody has a spleen. And then there are multiple infectious complications based on the fact that they are asplenic. So, um, osteomyelitis and the thing that’s sort of characteristically considered, um, something that is unique amongst Sickles of patients is that is the prominence of salmonella now as an infecting organism in osteomylitis. Although I get plenty of staph too

S: gosh what a refreshing throwback to an association we all memorized some time ago. so that’s the spleen, what about the brain

Nancy Berliner: They tend to be related to neovascularization in the brain. And they’re basically AV malformation type lesions and they can bleed and people can get devastating strokes. So patients who have that tend to get exchanged transfused based on what we know in pediatrics.

S: Ok will definitely be on high alert for strokes in this population.

L: Absolutely. I think of kidney disease as a big issue as well.

Nancy Berliner: Renal failure can be a major problem. If you have a cell in a very hypertonic environment, then it will water moves out of the cell and the concentration of hemoglobin rises. And so the concentration of unoxygenated hemoglobin rises and the cell is more likely to sickle. So almost all sickle cell patients have infarcted the medulla of the kidney. And so by the time they’re adults, they can no longer concentrate their urine because they’ve lost the inner medulla which is where all of the concentrating mechanisms, uh, take place.

L: This can lead to patients peeing out A LOT of extra free water and becoming pretty dehydrated. For those interested, the term for this is isosthenuria.

Nancy Berliner: We do have patients who are actually on dialysis, but in general, the, um, the loss of concentrating ability does not affect glomerulus so that most of the other functions of the kidney are, are still intact. So they don’t develop end stage renal disease. What they do is they get very predisposed to becoming dehydrated and dehydration is very bad for sickle cell patients. That’s one of the reasons why every patient who comes in the hospital, sickle cell disease is put on fluids sometimes to their detriment because as they get older, they tolerate the fluids less well. We tend to drown them, which is not good either, but, um, in general, at least conceptually it makes sense that you would want to make sure that they work through you well, hydrated.

S: And then which type of fluids to prevent dehydration is interesting. You’ll see some people whose practice is to always give hypotonic fluids like ½ NS the idea being that sickle cells are slightly dehydrated and so a slightly hypotonic environment might be beneficial for promoting water entry into the red cells.

L: Or at least that’s the idea in theory. We will need a large scale prospective clinical trial to tell which fluid will give the optimal environment for these cells and what the associated clinical outcomes will be.

S: Ah, I am so surprised there isn’t a trial like that yet but it is good to know in theory but hasn’t panned out in studies yet. But either way, the takeaway here is that patients are going to lose a lot of fluid and we want to prevent that vicious cycle of dehydration and more sickling in the kidney.

L: And this sickling in the renal medulla can similarly drive dysfunction in many other organs. You name it, sickle cell disease can affect it.

S: Give us some examples Leora.

L: In the liver, sinusoidal obstruction by sickled RBCs can lead to sickle hepatopathy and ultimately cirrhosis in some of these patients. At the level of the penis, vasoocculusion can cause priapism. This is an emergency you wan’t to look out for and often prompts exchange transfusion. Pulmonary hypertension can happen to from microvascular obstruction.

S: And the same concept applies to the spleen. This is where at a very early age these patients get splenic infarction from all the sickle cells leading to vascular occlusion.

Nancy Berliner: Of course, nobody has a spleen. And then there are multiple infectious complications based on the fact that they are asplenic. So osteomyelitis and the thing that’s sort of characteristically considered, um, something that is unique amongst Sickles of patients is that is the prominence of salmonella as an infecting organism in osteomyelitis. Although I get plenty of staph too.

L: The last big complication in sickle cell disease is acute chest syndrome- this is from acute vasoocclusion in the pulmonary microvasculature. The tough thing about diagnosing an acute chest is it’s virtually indistinguishable from pneumonia.

S: Yeah, its tough diagnosis because the criteria is basically pulmonary infiltrates plus 1 of following: fever, hypoxemia, tachypnea, use of accessory muscles of respiration, chest pain, coughing, wheezing, or rales. The things we would expect with pneumonia.

L: So you really have to treat any possible pneumonia in a patient with sickle cell disease as acute chest until proven otherwise. Management includes antibiotics, plus consideration of simple transfusion if it’s mild vs exchange transfusion if their presentation is severe. And last but not least, assess for possible PE and venous thromboembolism.

Nancy Berliner: Something that I think we underappreciated until actually relatively recently is the significance of thrombotic disease in this population. If they have really striking pleurtic chest pain, um, you need to make sure they don’t have PE. We used to be very frightened about doing PECTs on people, because if someone’s in the middle of a crisis, giving them dye is not a good thing to do, dehydrate their red cells a little more. We have become much more conscious of the fact that you can get D VTS and PEs and very easily in these patients.

S: While we are talking about management, we should give some space to talk about prevention. Leora you gave a talk to your co-residents about this and I don’t think I had known how compelling the data is for incentive spirometry to prevent acute chest.

L I’m so glad you brought that up. One of the studies that helped me cement how important this was was a small prospective RCT in 1995 published in the New England Journal of Medicine. It showed that patients acute chest or back pain above the diaphragm. Incentive spirometry significantly reduced the risk of acute chest syndrome.

Nancy Berliner: So that’s, that’s a major complication and, um, what organ have I left out?

L: That’s my favorite in the whole interview!

S: That’s a good place to recap then! In terms of complications, we are going to be looking out for strokes, particularly bleeds in adults. With kidney failure it is more so that they aren’t able to concentrate urine, so these patients will be peeing out a ton. What was that word you used?

L: Isosthenuria. Again, we need the nephrologist here. Don’t quote me on the pronunciation.

S: To prevent the complications of isosthenuria, we have to make sure our patients are geting enough fluid to prevent dehydration and sickling.

L: And lastly we talked about acute chest, which is hard to distinguish from pneumonia but we need to be on high alert for it and talk to our hematology colleagues if we have concern for it.

S: And that’s a wrap for today’s episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on instagram or facebook page. Thank you to our peer reviewer Drs. Jonathan Berry,  Yang Jiang MD, Jason Freed MD, Ram Reddy MD

Thank you to Daksh Bhatia for the audio editing and Dr. Samuel Woodworth for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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