SCCM Resource Library-Treating Pediatric Septic Shock With a Witch's Brew of Potions

Video Transcription

Hello, I'm Lauren Source, and I'd like to welcome you to this session on treating pediatric septic shock with a witch's brew of potions. First up is Dr. Bridget Blowey.  Dr. Blowey is a clinical pharmacy specialist in pediatric intensive care at the Children's Hospital of Philadelphia.  She completed her pharmacy practice residency at Children's Mercy Hospital in Kansas City, Missouri, and a pediatric pharmacy specialty residency at the Medical University of South  Carolina in Charleston, South Carolina. Dr. Blowey's clinical interests include pediatric sepsis management and medication safety.  Dr. Blowey will present, Will You Be Mine by Thiamine or Thiamine. Just had to say it to make it rhyme.  Next up is Dr. Tom Moran, who's manager of clinical pharmacy services at Ann and Robert H. Lurie Children's Hospital of Chicago.  He completed his bachelor's degree at University of Illinois Champaign-Urbana, his master's of science at DePaul University, and his PharmD at the University of Illinois Chicago.  He went on to do a PGY-1 at Kaiser Permanente in Santa Clara. In addition to his administrative role, he spends time working in both the Pediatric  Intensive Care Unit and the Cardiac Intensive Care Unit at Lurie Children's. I would also like to congratulate Dr. Moran, who will be inducted into the American College  of Critical Care Medicine as a fellow at this Congress. Dr. Moran will present, Getting Rid of the Blues with Methylene Blue.  Lastly, Dr. Nelson Sanchez-Pinto, who is an assistant professor of pediatrics of critical  care and preventative medicine, health, and biomedical informatics at Northwestern University Feinberg School of Medicine at Ann and Robert H. Lurie Children's Hospital of Chicago.  He is a pediatric critical care physician, biomedical informatics specialist, and clinical data scientist.  He is interested in discovering and evaluating data-driven phenotypes of critical illness and developing strategies for precision medicine in the acute care setting.  He currently leads an NIH-funded multi-center study collecting electronic health record data from 15 pediatric intensive care units in the U.S. to discover and validate novel  sepsis phenotypes. He also leads the workgroup focusing on large-scale data sharing within the SCCM-ESICM Joint Task Force on Data Science.  Dr. Sanchez-Pinto will present, Don't Forget to Take Your Vitamin C for Pediatric Septic Shock. Thank you for joining our session today. Hi, everyone.  My name is Bridget Blowey, and I am a clinical pharmacist in the pediatric ICU at the Children's Hospital of Philadelphia.  Today, I'm going to be talking about the use of thiamine or vitamin B1 in pediatric septic shock. To start off, I have no financial disclosures.  However, we will be discussing the use of off-label medications throughout this presentation.  Over the next 15 minutes or so, I hope that you take away a few things from this presentation,  including what thiamine is and how it works in the body, what the impact of that mechanism is in pediatric sepsis, and then be able to speak to the available literature, although  limited, to support its potential use in the pediatric population. To really jump right in, I want to first briefly highlight why discussing this topic is so important.  So, sepsis is a huge burden on the healthcare system and a huge impact on patients, and  pediatric sepsis alone has 1.2 million cases per year, with a mortality of 4 to 50%, depending on a variety of factors.  So, despite these high numbers and high mortality, in a variety of studies, the current management  of sepsis includes mostly appropriate antibiotics, appropriate source control, and other supportive care.  Given this, the exploration and study of other therapies that target potentially multiple pathways continues to be important.  I also wanted to touch on two points from within the pediatric sepsis guidelines that were recently published that will be important as we go through the rest of this presentation.  The first, which is lactate, which will be shown to be an important outcome in our future discussions, we know is a surrogate marker for tissue hypoxia, although it is nonspecific.  In limited pediatric studies, increased lactate has been shown to be associated with higher mortality, and a decreased lactate early in therapy has been associated with a decreased  risk for persistent organ dysfunction. When it comes to thiamine administration in sepsis for hyperlactateemia or otherwise,  the current pediatric sepsis guidelines currently do not recommend the routine use in pediatric septic shock.  However, the reason why thiamine administration is of interest in pediatric sepsis and has  been explored throughout the years has to do with its importance in many different metabolic pathways.  So thiamine is an essential intermediate cofactor for enzymes in carbohydrate metabolism and energy production.  And although there are other places in cellular metabolism that thiamine is a cofactor, such  as the pentose phosphate pathway, we're really going to focus on the impact on the pathway that is shown on the slide.  So as you can see, glucose will undergo glycolysis with the end goal of acetyl-CoA entering the Krebs cycle to be able to produce ATP.  One of the rate-limiting steps in the critical pathway of carbohydrate utilization is the oxidation of pyruvate by pyruvate dehydrogenase to acetyl-CoA.  And we cannot use pyruvate dehydrogenase without thiamine or thiamine pyrophosphate, which is its metabolically active form, as a cofactor.  In pediatric septic shock, with the presence of thiamine deficiency leading to an acquired  pyruvate dehydrogenase deficiency, we really lose the ability to undergo aerobic metabolism  and instead undergo anaerobic metabolism through shunting of pyruvate to lactate via lactate dehydrogenase.  This can then lead to the presence of persistent hyperlactateemia, even in the setting of appropriate resuscitation.  We know that thiamine is essential, as we just discussed, in our everyday cellular metabolism. But why is there such an impact in an acute setting, and why is there a potential role  for acute supplementation? And that really has to do with how thiamine is able to be obtained, and that is only through dietary or supplemental intake.  It also has relatively low total body stores of about 30 milligrams and has a short half-life of about 9 to 18 days.  So this means that someone without appropriate daily intake can become deficient in a very short amount of time.  Patients who are in septic shock also have additional risks for thiamine deficiency that  include potential poor dietary intake prior to admission, increased dextrose intake secondary  to maintenance fluids, which drives glycolysis, potential for increased urinary excretion, and then also an overall increase in metabolic demand.  So this potential for thiamine deficiency in patients admitted for septic shock is really supported by the few studies that have evaluated thiamine deficiency.  It's important to note when we look at these numbers on the slide that there are multiple ways both direct and indirect to evaluate thiamine activity.  So these reported numbers came from studies that all use slightly varying definition of thiamine deficiency and different laboratory tools to assess for its presence.  However, the trends are the same when we look at them. Patients who have septic shock have a relatively high incidence of thiamine deficiency, most  likely from a combination of factors that we mentioned previously. When we look at pediatric patients specifically, the general population from one study reported  was around 7 to 10 percent, but the septic shock patient population has reported incidence up to 28.2 percent.  So about one in four of your pediatric patients that are admitted to your ICU could be thiamine deficient.  Before we move on to the data around IV thiamine administration, I do want to first touch on  the potential risks of therapy, given that the incidences are very low and so not typically focused on in reports.  So the biggest risk for IV thiamine administration is really anaphylaxis or hypersensitivity reactions. And though that's a severe risk factor, the incidence reported is very low.  Additionally, when we discuss the cost of therapy, the average wholesale cost is about $5 per 100 milligrams of IV thiamine.  So if we take a repeatedly reported adult dose of 200 milligrams twice a day, the average intervention would cost you about $20 per day. So we know that thiamine is essential.  We know that thiamine deficiency exists in these patients. And we know that there are relatively low risks and low costs of administration.  So the next question that we can really ask ourselves is, do the adults have it figured out? Do they have the right answer?  And the overall answer to that question is no, they really don't. So you can see here, the adult studies have looked at a wide variety of outcomes from  lactate clearance all the way to mortality. And when you look at these studies and the individual outcomes, you can see there's really  no consensus on the benefit of thiamine administration between smaller studies that are maybe more hypothesis generating and even larger scale studies that looked at mortality.  It's important to mention that the majority of studies that were published later on in 2020 actually evaluated the use of triple therapy of thiamine, hydrocortisone, and ascorbic  acid. And so when looking at those studies and looking at those outcomes, it's really hard to tease out the true impact of thiamine administration alone.  And you can see on this slide that all of the studies that looked at thiamine as its only intervention are marked by an asterisk.  There are, to really get into our pediatric population, there are currently two pediatric  studies available that evaluate the use of thiamine in pediatric sepsis either as a monotherapy or in combination.  However, before those were published, there were actually case reports of this intervention. And some of this identification actually had to do with drug shortages that were going  on at the time. So these case reports are listed, and the biggest takeaways from these publications  or the CDC reports are that TPN-dependent patients became thiamine deficient, secondary to a lack of multivitamin administration.  They developed either neurological or cardiac adverse effects, along with a persistently high lactate.  They were given thiamine as an intervention, and because of that intervention, the lactate went down and symptoms resolved.  So these cases are a great reminder on the impact of thiamine administration, but they don't really touch on our subject of administration in patients with septic shock.  So the first study that we're going to look at was published in 2019 and was one that we completed in the ICU at the Children's Hospital of Philadelphia.  So this study was led by Dr. Weiss, and we completed a retrospective study that compared  patients with sepsis that had received thiamine versus those that did not, matched to a variety of baseline characteristics and illness severity.  The lactate had to be more than or equal to five for study inclusion, which led us to six cases and nine controls.  It's really important to note that because of its retrospective nature, thiamine was given per attending preference for hyperlactectomia.  We did not routinely obtain thiamine concentrations prior to administration, and we did not account for hydrocortisone administration with these patients.  The primary outcome was change in blood lactate at 24 hours, and that starting time was anchored  for cases at the lactate closest to the thiamine administration, and then the anchor time for controls was the maximal recorded lactate.  The dosing scheme that we used was anywhere from one to five mg per kick per day, divided one to two times a day, and our duration was a wide variety of durations up to 30 days.  The primary outcome, as I said, was median change in lactate from time zero to time 24, anchored at those specific points.  You can see on this graph here that shows lactate in absolute values over time that there was no difference in median change, with a decrease in cases of nine and a decrease  in controls of 7.2, with a p-value of .78, and although we did not see a difference in median change, there was a very rapid decline in both groups over 24 hours from our initial  anchored lactate measurement. When looking at the secondary outcomes, we also found no difference in changes at lactate  at 48 or 72 hours, time to lactate normalization, or a variety of other secondary outcomes that included both length of stay and hospital mortality.  As you can see here, the graph shown is, again, the primary outcome graph of lactate over time.  However, when we analyzed our data, we noticed that there was a significant difference in the duration of hyperlactectomia between the controls and the cases, and as you can see  here, the duration of hyperlactectomia in the controls was 3.4 hours prior to that maximal  lactate, versus in the case group, the hyperlactectomia was for 39 hours prior to thiamine administration,  and this maybe suggests that those two populations may be different, and what I mean by that is that the group that received thiamine had a lactate profile that suggested it was not  responding to normal care, versus the control group demonstrated an improvement that would have been expected with normal sepsis management.  So the question is, are these populations somehow different in that one group responded appropriately to normal care, versus one did not?  Did we get lucky in our timing of thiamine administration, where we would have seen a dramatic decrease in lactate regardless of intervention, and if the control group had  patients with similar prolonged hyperlactectomia, would we have seen a clinically significant difference in time to lactate normalization?  So those were the questions we asked ourselves, but based on our primary endpoint, our conclusion  that the benefit of thiamine administration over usual care really could not be inferred from this study.  However, the duration of prolonged hyperlactectomia with a dramatic decrease in our intervention group really is thought-provoking and probably warrants further exploration.  The second study that I'm going to talk about was published in early 2020 by Walden Colleagues out in Chicago, and I'm not going to go too much into depth in this study as  it will most likely probably be discussed later on in this session. However, this study included an impressive amount of pediatric patients with an N of  557 with patients with septic shock, and included thiamine as part of a triple therapy that included hydrocortisone, ascorbic acid, and thiamine.  That was started within 24 hours of vasopressor initiation. So it's really hard to separate thiamine from the combination therapy when evaluating  the outcome, which was 30-day mortality. However, given their impressive data and decrease in 30-day mortality that you can see by the  Kaplan-Meier survival curve when compared to the control group and the hydrocortisone-only  matched patients, it just suggests that thiamine may play a role in that significant outcome that was found.  So as I kind of alluded to before, there is limited literature to support the use of thiamine in pediatric patients, as demonstrated by the two studies that I presented.  However, I hope that given our discussion of the role of thiamine in the body, how it affects patients in septic shock, and the limited literature I shared with you, that  we can at least knowledge that the true impact of thiamine in administration is probably still unknown, that the benefits most likely outweigh the risk in the right patient.  And I really urge you to, that if you're going to include thiamine in your patients or consider  giving thiamine in your patients, that you protocolize your decision within your unit. So what cohort are you going to treat? What regimen will you prescribe?  So what dose, what duration? Will you prescribe monotherapy or will you include hydrocortisone and ascorbic acid in your regimen? And then how will you monitor for benefit and risk?  So what outcomes will you look at to show that we're improving patient care? And on that ending note, I would just like to thank everyone who took the time out of  their day to listen. And I hope I made you want to think a little bit more about the importance of thiamine in your day-to-day practice. Well, thank you very much for having me.  I'm Nelson Sanchez-Pinto. I'm an assistant professor of pediatrics and critical care at Northwestern University and a critical care physician at Robert Lurie Children's Hospital.  And I'm going to be talking about vitamin C in pediatric sepsis. Is it a panacea or a snake oil? So I have no relevant funding, some NIH funding that's not relevant to this talk.  So vitamin C, also known as ascorbic acid, has pleiotropic effects which are relevant to the sepsis pathobiology.  This is a review article by Muskowitz and colleagues on the topic and I encourage all of you who are interested to look at it, it's a very nice article.  It points out sort of this pleiotropic effects in this figure of all the parts of the sepsis pathobiology where there's some relevant effects of ascorbic acid or vitamin C.  Most important and most relevant are the effects, the antioxidant effects and effects on reducing  the potential damaging effects of the reactive oxygen species that occur during sepsis as well as enhancing the production of catecholamines.  So two key parts of sepsis pathobiology in which vitamin C or ascorbic acid has a potentially beneficial effect.  So the end effects that are known within sepsis pathobiology which ascorbic acid or vitamin  C has an effect include as I was saying the catecholamine synthesis, it has some bacteriostatic  effects, enhancement of neutrophil function as well as a reduction in microvascular dysfunction,  cellular apoptosis, a reduction in endothelial dysfunction and a reduction in basal dilation, all of which sort of the net effects are sort of beneficial for, potentially beneficial  for the recovery from sepsis and the reduction of organ dysfunction in the setting of sepsis.  We also know that vitamin C levels are depleted during sepsis and that we can replete them with IV administration.  So this is a phase I safety trial done by Fowler and colleagues a few years ago in which we can see that patients who had sepsis and received placebo had this persistently very  low plasma levels of vitamin C. In fact at a level which would be considered sort of scurvy levels in many situations and we know that the administration of IV vitamin C both  at low doses and high doses are able to replete those levels at least to normal levels and in the case of high dose to very effective therapeutic levels or higher levels.  But does this make a difference? We know that vitamin C has pleiotropic effects. We know that those levels are low when patients have sepsis and that we can replete them with  IV administration, but does that make a difference? In multiple small single center randomized controlled trials and observational studies,  vitamin C appears to have an association with improved outcomes. This is a meta-analysis published a few years ago on the effects of vitamin C in different conditions.  Here in the middle is a forest plot for studies particularly in sepsis patients and as you can see the net effect tends to favor the use of vitamin C in patients with sepsis  which is not the case in other types of patients. For example, burn patients does not seem to be beneficial in that situation.  Vitamin C studies, it's included in the study by Paul Merrick and colleagues, so-called HAT therapy, before-after study which started a lot of the most recent surge in interest  in vitamin C in the last few years in critical care. This was, as I was saying, a before and after study.  It's called HAT therapy because it was the combination of vitamin C with both hydrocortisone and thiamine, so hydrocortisone, ascorbic acid, and thiamine, so-called HAT treatment  in patients with severe sepsis and septic shock. In this study, Paul Merrick and colleagues enrolled, prospectively enrolled 47 patients,  actually treated 47 consecutive patients with severe sepsis and septic shock with this protocol  that included the administration of hydrocortisone, vitamin C, and thiamine and observed their outcomes.  Then they compared this with a historical control, 47 patients, historic controls, and were able to show that in the treatment patients in the after implementation, those  patients had significantly lower mortality compared to historic controls. Paul Merrick then went ahead and presented this at national conferences, including critical  care reviews, and several locations said that he had cured sepsis, which, as you can imagine, was not well received by the community, which is extremely skeptical, naturally wanting  to see this in a more sort of prospective, randomized fashion to be able to ascertain that this was truly an effective therapy.  And that's sort of probably the start of a lot of controversy around the use of vitamin C. In the case of pediatrics, septic shock. We also have some evidence of effectiveness.  This is a study that our research team published, first author is Eric Wald, and what we found  in our study was that HAT therapy, the use of hydrocortisone, ascorbic acid, and thiamine in kids with pediatric septic shock seemed to have an associated improvement in outcomes.  This was a propensity score match analysis in which we, after the implementation of the HAT therapy protocol in our institution in 2017, we had 43 patients who received this  therapy after presenting with septic shock in the first 24 hours of admission, and those patients were matched to historic controls, both those who had only hydrocortisone and  those who had no hydrocortisone or obviously no HAT therapy, and in both cases, both comparisons  show that the patients that had HAT therapy had an associated improvement in outcomes of lower mortality, 9% mortality versus 30% mortality at 30 days, so a significant improvement  associated there. Of note, the average patient in our cohort that received HAT therapy had a moderate level ARDS by PF ratio.  So this is an important piece that will come up here soon and why we think that was important. This is the Kaplan-Meier curve of mortality, and you can see here the top line is the  HAT therapy patients who had a significantly reduced mortality, but of note here, the biggest difference occurred in this difference on early deaths.  So we saw that the administration of HAT therapy seemed to have an associated improvement in outcomes, particularly by preventing some of these very early deaths within the first  three, four days of ICU admission. On top of that, there was a multicenter randomized controlled trial where the use of high dose  vitamin C on isolation without hydrocortisone or thiamine, just the vitamin C, was associated with lower mortality in patients with sepsis and ARDS, adult patients.  This was the Citrus Alley randomized clinical trial, and as we can see here in this survival  and this mortality figure, we can see that the patients with vitamin C had a lower mortality compared to those who received placebo, and most of the separation of these mortality  curves occurred within the first 96 hours, which was the treatment period when the vitamin C was being administered.  So again, an improvement in reduction in those early deaths was mostly what happened in this trial. This mortality was a secondary outcome in this trial.  The primary outcome was reduction in organ dysfunction and reduction in biomarkers, and on a secondary analysis of that, when accounting for those patients who died, indeed there  was also a reduction in organ dysfunction. This is a subsequent analysis that was done as in the first analysis of not taking into  account those patients who had died in the organ dysfunction analysis. But again, a little bit of signal here that there seemed to be a benefit, at least in  the sepsis patients with ARDS. However, after the Citrus Alley study, there's been two additional multicenter randomized  control trials published, the VITAMINS trial and the ACTS trial. These are trials of HAP therapy, so again, vitamin C with hydrocortisone and thiamine,  and in both cases there was no difference in outcomes. In the case of the VITAMINS trial, this was comparing vitamin C against hydrocortisone  only patients, and the outcome was median time alive and free of vasopressure administration.  Patients who received vitamin C had a reduction, HAP therapy, sorry, had a reduction of just .6 hours median, and this was not significant.  And then in the case of the ACTS trial, they were looking at a change in the SOFA score, and they did find about a point difference in the SOFA score reduction in the patients  who received vitamin C, HAP therapy versus placebo, but this was not statistically significant either. So in both cases, no difference in outcomes.  One thing to note is in both cases this was all comers, patients with septic shock, not specifically patients with ARDS. So is it a panacea or is it a snake oil?  Again, some considerations, obviously for the observational studies, both the pediatric and the Merrick study, the biggest problem obviously is the confounding by indication  in these observational studies and some other confounders that might not have been adjusted between the comparison of historic controls and intervention patients.  In the RCTs, things to consider are the exclusion criteria as well as the time to intervention.  So in all of these trials, the patients who were very sick and were considered to be imminent death were excluded from the trial.  So the question is whether in a prospective implementation in which that exclusion is not there and you just try this intervention, whether some of those who were considered  to be imminent death would actually have benefited and potentially not died is a question that remains unanswered. And then the time to intervention is a big issue.  As we mentioned both in our findings in our study as well as in the Citrus Alley, a lot of the prevention of bad outcomes was very early on in that first day, two, three days  of disease. So the earlier you start these interventions, the better. In both the ACTS and in the vitamins trial, initiation of therapy was somewhat delayed  anywhere from 12 hours to 30 hours or so from presentation to actual getting the intervention or placebo. So this may have been an issue, although that remains to be uncovered.  However, I think in my opinion, this is my opinion, I think the biggest difference is heterogeneity of treatment effect and the fact that there might be a subset of patients  who benefit from this therapy but not necessarily all patients and I think that's sort of the key difference here is this whole idea of phenotypes. So maybe it's not panacea.  Definitely I don't think it's a snake oil. I think it's somewhere in the middle. So the question is do we need to identify the right phenotype of sepsis that may benefit  from this intervention and think about the pathobiology of how this intervention of vitamin C may help patients with sepsis and whether we can identify that subset of patients.  This is a very nice figure from a paper by Natalia Ostansky and Hector Wong on this idea of prognostic and predictive enrichment in sepsis and the idea going from the left to  the right is that sepsis is a heterogeneous disease, lots of different pathways activated in patients who have sepsis, different types of organ dysfunction and patients are going  to behave differently. We know this already. Prognostic enrichment is the process of stratifying patients into high-risk patients and low-risk  patients and assuming that we're only using this therapy in the high-risk patients, we can then think about this second stage which is the predictive enrichment phase in which  high-risk patients are stratified based on their underlying pathobiology and the mechanisms underlying the disease process.  In this case we may have a hypothesis by which the, for example, patients who have ARDS may identify a subset of patients whose mechanism of disease is a little bit different than  those with sepsis but no ARDS. In the case of vitamin C, things relevant to this might be things like the hyperinflammatory  state associated with the worst types of ARDS phenotypes as well as things like the fact that we're giving extrinsic FiO2 to this patient so we're both having internal oxidants, the  reactive oxygen species that are created through the pathobiology of sepsis as well as the  oxygen, the supplement oxygen that we're administering through the mechanical ventilation that can  also exacerbate that oxidative stress and perhaps a therapy like vitamin C that has a big role in antioxidant effects, maybe that's where it actually works.  So maybe the answer here is that yes, in patients with sepsis ARDS it will be an effective therapy  whereas in other all-comers it might not and this might be a difference between the Citrus Alley trial which showed a benefit in mortality and the vitamins and the ACTS trials which  enrolled all-comers and where only a small minority of those patients had ARDS, about 20 to 30% of those patients and hence showed no difference since the majority of patients  did not have this ARDS phenotype. So this is a question, this is a hypothesis that obviously will need to be tested but maybe the answer here.  In conclusion, sepsis is associated with low vitamin C levels. Vitamin C has pleiotropic effects which are important to sepsis.  Several small RCTs and observational studies have shown a benefit associated with either  high-dose vitamin C or HAT therapy in patients with sepsis, particularly sepsis with ARDS.  Two multicenter RCT trials in all-comers septic shock patients did not show a benefit of HAT  therapy and will further phenotyping of sepsis help identify a subset of patients that will  benefit more from this therapy is the question that remains open and I think we need to answer it definitely in the pediatric population.  So we're looking forward to potentially doing that and seeking partners to do that trial. So thank you very much and happy to answer questions in the Q&A session. Hello.  My name is Tom Moran. I'm the manager of clinical pharmacy services at Anna Robert H. Lurie Children's Hospital of Chicago.  Welcome to my talk today entitled Getting Rid of the Blueies with Methylene Blue. As you can see, I have nothing to disclose.  I will, however, be discussing the off-label uses of medications. The objectives for our talk today are to briefly discuss nitric oxide as it relates to sepsis,  describe the mechanism of action of methylene blue, and discuss the application of methylene blue in vasopressor-affected pediatric septic shock.  Last year at this time, we were discussing the new pediatric sepsis guidelines published in Pediatric Critical Care Medicine.  They define septic shock in children as a severe infection leading to cardiovascular dysfunction which may include hypertension, need for treatment with vasoactive medication,  impaired perfusion, and sepsis-associated organ dysfunction. There are roughly 1.2 million cases of childhood septic shock each year and we all use the  same tools to treat it, fluid boluses, antibiotics, vasoactive agents including epinephrine and norepinephrine, and corticosteroids.  Despite our best efforts, however, sepsis still leads to significant mortality. What can we do when our best tools fail?  Today I'm here to talk to you about methylene blue as a potential option. Methylene blue is a very old chemical with many reported uses, including the ones listed  here, most of which are considered off-label. It is dark blue in solution, and it comes as, even though it comes as a light, dark green powder.  Another use for methylene blue not listed above is as a treatment for vasoplegia or persistent hypertension refractory depressors.  In order to understand how methylene blue works for vasoplegia, we need to understand more about nitric oxide and its role in vascular tone.  Many people have devoted their careers to studying nitric oxide. We only have time for the briefest of overviews, however. So I'll look at my rudimentary drawings here.  Nitric oxide has many functions, including regulating gene transcription, mRNA translation, and vascular tone.  It has even been described as the endothelial-derived relaxing factor, EDRF. There are a few different enzymes that produce nitric oxide in mammals, nitric oxide synthase,  neuronal nitric oxide synthase, endothelial nitric oxide synthase. As seen here, the precursor of nitric oxide is L-arginine, which in combination with calcium  and nitric oxide synthase leads to nitric oxide production. Nitric oxide has both a constitutive expression and inducible expression.  Inducible expression of nitric oxide is also formed from L-arginine by response to inflammatory  cytokines or bacterial endotoxins, and will lead to two to three times the amount of nitric oxide produced.  Now that we have a brief understanding of where nitric oxide comes from, let's look at why it's important. One of nitric oxide's role in the body is to produce vascular relaxation.  It does this by binding to guanylate cyclase, the GC here in the picture. Binding to guanylate cyclase catalyzes production of cyclic GMP.  Cyclic GMP production results in dephosphorylation of the myosin light chains, which leads to muscle relaxation and vasodilation.  I can't emphasize enough how basic this overview has been, but this basic overview of how nitric  oxide is made and how it can affect our bodies, let's look back at methylene blues and rolling vascular tone.  Pictured here is methylene blue's proposed mechanism of action as it pertains to nitric oxide. As you can see here, methylene blue binds to the soluble guanylate cyclase, the SGC  pictured there, inhibiting nitric oxide's ability to bind. Binding a methylene blue to guanylate cyclase essentially stops the nitric oxide-induced  production of cyclic GMP, blocking nitric oxide's action on vascular smooth muscle. This inhibition of nitric oxide activity can lead to a decrease in vasoplegia caused  by nitric oxide. As a pharmacist, I think about the pharmacokinetics and pharmacodynamics of drugs quite often. Methylene blue is no different.  However, for as old as methylene blue is, the pharmacokinetic data is a little uncertain. It has a relatively quick onset of action, it has a large volume of distribution, it  is excreted in bile, urine, and feces, and due to its ability to inhibit monoamine oxidase, it can interact with serotonergic drugs like SSRIs.  It is generally well-tolerated with the most common side effects being blue discoloration of the skin and urine.  Paradoxically, even though it is used as a treatment for methemoglobinemia, it can cause methemoglobinemia at higher doses.  Now that we've had some background of nitric oxide and methylene blue and their mechanisms of action and how they relate, it's time to look at methylene blue in sepsis.  Overall, there is precious little data on methylene blue in pediatric septic shock. There is, not surprisingly, more data in adults.  And before we move on to discussing pediatric data, I want to summarize a few adult studies. Looking at the adult literature, I chose a few random papers with bigger ends.  This group is not necessarily representative of the entire body of adult literature, but it does give us an idea of how methylene blue is used.  In this first citation, in 2002, Memes et al. had a prospective double-blind randomized placebo-controlled study with 30 patients.  Their methylene blue intervention was 0.5 mcpk per hour IV infused over six hours. They had an increase in mean arterial pressure in the methylene blue group, but there was  no difference in mortality. In 2001, Kirov et al. had a prospective randomized controlled open-label pilot study with 20 patients.  The result was a 2 mcpk dolus of methylene blue followed by an infusion with a titratable rate.  That meaning that they started the infusion at 0.25 mcpk per hour and increased the rate of the infusion based upon the hemodynamic parameters of the patient.  The study found methylene blue led to a significant increase in mean arterial pressure, but led to no difference in mortality.  In 2005, Park et al. had a single-center prospective observational study with 20 patients. Their intervention was a 1 mcpk IV bolus, where two patients received an infusion after  the bolus. Methylene blue significantly increased mean arterial pressure in these patients, and one  of the other markers for the study was looking at how methylene blue affected cytokine levels, and they found that no cytokine levels were different between the methylene blue group  and the placebo group. Back in 1995, Pryzor et al. had a study which was prospective observational of 14 patients.  They did a 2 mcpk bolus in 6 patients, 2 mcpk bolus, where 6 patients received a second bolus after 90 minutes.  Again, the mean arterial pressure was significantly increased in the methylene blue group. However, in this study, 11 of 14 patients died.  You may be starting to see a bit of a trend here, that methylene blue is working well to increase mean arterial pressure in these patients, but there is not necessarily a difference  in mortality between standard therapy and methylene blue therapy. Moving on to pediatric literature, there are far fewer papers to choose from, with the  vast majority of them being case reports or case studies. This year, in 2020, Bitterman et al. had a case series of 7 pediatric patients ranging age from newborn to 4 1⁄2 year.  All patients had clinical features of vasoplegia and were unresponsive to at least 2 vasopressors and steroids.  The intervention Bitterman et al. had was to use a 1 mcpk bolus in methylene blue, followed by an infusion of 0.25 mcpk per hour.  Six of the 7 patients had a favorable hemodynamic response, i.e., an increased MAP pressure and a decrease in vasopressor requirements, but 3 of the 7 patients eventually died.  In 2015, Rutledge et al. had a case report of a 22-month-old girl with Newnan syndrome. This patient was on norepinephrine, dopamine, vasopressin, all at relatively high doses.  Methylene blue was infused at 1 mcpk, followed by a continuous infusion of 0.25 mcpk per hour.  For this patient, the systolic blood pressure increased by 33 points, the diastolic blood  pressure increased by 20 points, and the patient was weaned off of inotropes, eventually gone home.  In 2011, Bala et al. had a case report of a 5-year-old female post-heart transplant. This patient was post-surgery but was brought to the ICU, and they were on high-dose inotropes  including dopamine, dobutamine, milrinone, norepinephrine, and vasopressin. What appeared to be a last-ditch effort to save this patient, the team gave them a 1  mcpk bolus of methylene blue, and astonishingly, the mean arterial pressure increased from 30 to 60 over 10 minutes, post-methylene blue bolus, and all of the inotropes were weaned  off within 12 hours, again with the patient being discharged home successfully. In 1995, Driscoll et al. had a case series of five neonates over the course of one year,  where they were all admitted with hypotension unresponsive to volume, dopamine, epinephrine, and in three cases, dobutamine.  Methylene blue was given as a 1 mcpk bolus infused over one hour, with three patients receiving a second bolus.  Again, the mean arterial pressure was increased in each patient with each methylene blue bolus. Three of the five patients survived and were discharged home.  In 2016, Abdelazim et al. had a study entitled Methylene Blue Compared to Norepinephrine and the Management of Vasoplegic Syndrome in Pediatric Patients After Cardiopulmonary  Bypass, a randomized controlled study. They had 40 pediatric patients who developed vasoplegia after cardiac bypass.  All patients, all 40 patients, received norepinephrine 0.5 mcpk per minute for five minutes without improvement.  They were then identified and put into one of two groups, the methylene blue group or the norepinephrine group.  Methylene blue group received a 1.5 mcpk bolus of methylene blue in addition to the norepinephrine that they were currently on.  However, the norepinephrine was titrated to produce mean arterial pressures. And the norepinephrine group, group N, they just continued on norepinephrine alone, titrating  to beneficial effect for the patient. This study had impressive results. They had the norepinephrine dose was lower in the methylene blue group, i.e. the people  who received methylene blue needed less norepinephrine. The mean arterial pressure was higher in the methylene blue group. The heart rate was lower in the methylene blue group.  The CVP was higher in the methylene blue group. The cardiac output and the cardiac index were higher in the methylene blue group.  And the SVR index was higher in the methylene blue group. Overall, these are impressive results.  The study, however, had a small N, and all patients were post-bypass CV surgery patients, not patients with sepsis.  So these results would support the use of methylene blue in vasoplasia, but not necessarily sepsis-induced vasoplasia.  An important thing to remember for all these studies is that not all these studies were performed on patients who were in sepsis.  So the vasoplasia-induced bisepsis could be affected differently by methylene blue than the vasoplasia in CV surgery patients.  Overall, the evidence in pediatrics for using methylene blue in vasoplasia is not strong, and the evidence for using methylene blue in sepsis-induced vasoplasia is even less so.  Dosing in the literature has a wide range, but many studies seem to land on a bolus of one to two mg per kg, followed by an effusion or a repeat bolus.  Methylene blue should be considered as a salvage therapy for vasoplasia unresponsive to conventional  therapy, but I would recommend weighing the potential risks and benefits for your patient. In conclusion, nitric oxide is an important factor in regulating hemodynamics.  Methylene blue represents a novel approach to treating vasoplasia by limiting nitric oxide's effect on vascular tone.  However, more studies are needed to further define the role of methylene blue in treating vasoplasia-induced biopediatric sepsis. Thank you very much for listening.

Video Summary

This video features three speakers who discuss the potential use of different medications in the treatment of pediatric septic shock. Dr. Bridget Blowey discusses thiamine (vitamin B1) and its impact on carbohydrate metabolism and energy production. She explains that thiamine deficiency is relatively common in pediatric septic shock patients and that thiamine administration could potentially have a positive impact on lactate levels and overall outcomes. However, more research is needed to fully understand the benefits and risks of thiamine administration in this population.<br /><br />Dr. Nelson Sanchez-Pinto discusses the use of vitamin C in pediatric septic shock. He explains that vitamin C has pleiotropic effects that could be beneficial in the treatment of sepsis, including reducing oxidative stress and enhancing the production of catecholamines. While there is limited evidence in pediatric patients specifically, some studies suggest that vitamin C administration may improve outcomes in sepsis patients with ARDS. However, further research is needed to identify specific patient populations that could benefit from vitamin C therapy.<br /><br />Dr. Tom Moran discusses the potential use of methylene blue in pediatric septic shock. Methylene blue works by inhibiting the action of nitric oxide, which can cause vasodilation and contribute to hypotension in septic shock patients. Although there is limited evidence in pediatric patients, some studies suggest that methylene blue can increase mean arterial pressure and decrease vasopressor requirements. However, more research is needed to determine the appropriate dosing and patient populations that would benefit from methylene blue therapy.<br /><br />Overall, while there is some evidence to support the use of thiamine, vitamin C, and methylene blue in pediatric septic shock, more research is needed to fully understand their effectiveness and determine the best approach for their use in this population.

Asset Subtitle

Pediatrics, Sepsis, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Review pharmacology and the role of thiamine to reverse refractory pediatric septic shock with elevated lactate levels
Describe the novel application of methylene blue in vasopressor-refractory pediatric septic shock
Discuss the role and benefits of vitamin C in the treatment of pediatric septic shock

Will You Be Mine, Thine Thiamine?
Bridget L. Blowey

Don't Forget to Take Your Vitamin C for Pediatric Septic Shock!
L. Nelson Sanchez-Pinto

Getting Rid of the Blues with Methylene Blue

Thomas J. Moran

Meta Tag

Content Type Presentation

Knowledge Area Pediatrics

Knowledge Area Sepsis

Knowledge Level Advanced

Membership Level Select

Tag Shock

Tag Monitoring

Year 2021

Keywords

medications

pediatric septic shock

thiamine

vitamin C

methylene blue

outcomes

oxidative stress

arterial pressure

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.