Jon: Meghan, thank you for joining me on this post. I’ve wanted to write about the logistics of high dose insulin (HDI) for some time now, but I have a lot of my own biases about where insulin belongs in the ordering of our therapies for sick cardiotoxic overdoses and I thought it would be really helpful to have a second voice that might have some dissenting opinions about HDI and its relative place compared to more traditional therapies.
Meghan: Great to be doing this together. I as well have my own biases, and maybe we should start by letting the readers know where we come from and how we got to our respective fighting corners.
Jon: Excellent idea. I completed fellowship in Minnesota at the Twin Cities Tox Fellowship. The sponsoring institution’s primary hospital is Regions Hospital, and several of my fellowship mentors performed a lot of bench research (mostly pigs) on HDI and other therapies for beta-blocker (BB) and calcium channel-blocker (CCB) poisoning.1–7 They were also early adopters of the clinical use of HDI in both CCB and BB overdoses for bedside consults.8–11 I would say our institutional bias was to be very pro-HDI while being simultaneously skeptical of vasopressors. We almost always started HDI before vasopressors, and if vasopressors were started we routinely prioritized weaning them first over HDI.
Meghan: I completed my med tox fellowship in Phoenix at Banner University Medical Center. Banner is a pretty unique fellowship as it is a tertiary care referral center for extremely sick tox patients around the area. We managed all of our tox patients, including a fair amount of sick CCB and BB cases at the bedside, almost exclusively using vasopressors and inotropes. We published our clinical experience and found this approach to be extremely effective without significant adverse effects.12
Jon: I’ll start with an olive branch if that’s OK with you. While there are some passionate advocates in our field for both vasopressors and HDI (that lead many to believe there is controversy regarding the two therapies), can we agree there is no “one therapy to rule them all?” Given that we’ve all had cases that are barely hanging on with HDI, four vasopressors, methylene blue13, a dose or two of Intralipid®, all while on ECMO14,15, or other mechanical devices like a percutaneous LVAD16,17, is it fair to say there is no magic bullet?
Meghan: I couldn’t agree with that concept more. In fact, that’s a pretty good concept to keep in mind for most medical treatments. In particular, I think our training as medical toxicologists not only equips us but compels us to think about these cases more critically. Relying on dogma or refusing to consider alternative approaches is rarely a good path to go down.
Jon: With that backdrop, let’s start with a brief discussion of each therapy. For the purposes of this post, I’ll primarily discuss HDI; I’m hoping you’ll cover traditional inotropes and vasopressors.
Mechanisms and Clinical Utility of HDI and Vasopressors
The molecular mechanisms of HDI are complex (and covered elsewhere here on Tox & Hound), but the best way to think of the clinical use of insulin is to categorize it the way we do other inotropes and vasopressors. Insulin is a strong inotrope, and also a bit of a vasodilator. It is not a vasopressor.18 I think of it clinically as a slower, more powerful version of dobutamine.
As a quick reminder, recall:
cardiac output (CO) (L/min) = stroke volume (SV) x heart rate (HR)
Insulin’s two therapeutic properties are accomplished via complex cellular pathways that are not specific to a single class of drugs; i.e., insulin is not a specific antidote to CCBs. It causes inotropy by augmenting calcium mediated contractility in cardiovascular tissue, modifying sodium and potassium homeostasis and sodium-calcium exchange, and by increasing the availability of intracellular glucose to maximize ATP production in stressed myocardium.19 HDI causes vasodilation via enhancement of endothelial nitric oxide synthase (eNOS) via activation of the phosphoinositide 3-kinase (PI3K) pathway. This results in a drop in systemic vascular resistance (SVR), and as SVR and cardiac output are inversely proportional if mean arterial pressure (MAP) stays constant (MAP ≈ CO x SVR, see below the discussion of vasopressors), cardiac output then rises (particularly with a concomitant increase in cardiac contractility). The utility of increased inotropy and cardiac output in a BB or CCB overdose is obvious, however the vasodilatory effects of insulin may also be therapeutic as this treats the microvascular dysfunction of cardiogenic shock by enhancing perfusion at the capillary and pre-capillary levels.
HDI does have an additional therapeutic benefit in CCB poisoning. Because part of the final common pathway of insulin release from beta-islet cells in the pancreas involves calcium entry into the cell via a calcium channel, CCB poisoning can result in blockade of this channel and impairment of insulin release.20 Clinically (at least in verapamil and diltiazem poisoning), we see this manifest as hyperglycemia.21 HDI thus specifically targets the endocrine dysfunction seen in CCB poisoning.
Because of the diabetogenic effects of CCBs, and because insulin was first studied for the treatment of poison-induced shock in CCB toxicity (mostly verapamil)22–24, it is commonly thought that HDI is primarily a treatment for CCB poisoning, though there is now a similar amount of supportive data for beta-blockers too (mostly propranolol).2,4,6,25
Clinically with HDI, regardless of the offending poison, we see the increase in inotropy/cardiac output comes primarily from an increase in stroke volume (SV) / ejection fraction (EF). We’ve observed this both in the lab and with patients.2
If you’re a visual person, here is an echo of a patient who took a massive metoprolol+amlodipine overdose who is on 10 U/kg/hr. Note the relatively slow rate coupled with the ejection fraction of 75%.
Meghan: Now onto vasopressors. Norepinephrine (NE) and epinephrine (EPI) are both endogenous catecholamines and pharmaceutical agents that act directly on our adrenergic receptors, namely the α-adrenergic and β-adrenergic G-protein coupled receptors (GPCRs).
Starting with the α receptor, there are two main types: α-1 and α-2 (I’ll spare you the subtypes). Peripherally, α-1 receptors are found on the postsynaptic side of the synaptic cleft, and when stimulated on vascular tissue result in vasoconstriction. We typically think of α-2 receptors as mediators of negative feedback and preventing further release of NE, however there is also some evidence that peripheral α-2 stimulation may also lead to vasoconstriction. So when we give exogenous NE or EPI (direct acting agonists at the adrenergic receptors) in the setting of hypotension secondary to CCB vasoplegia, we vasoconstrict, increase systemic vascular resistance (SVR) and raise the mean arterial pressure (MAP).
MAP ≈ CO x SVR
Regarding the vasodilatory effects of insulin being beneficial due to improved microvascular circulation, I’m not totally sold. Though there is likely something to the importance of microvascular dysfunction, with these acutely dying patients, I think we are much more concerned about keeping vital organs like the brain perfused. Cerebral perfusion pressure (CPP) is directly proportional to MAP, not necessarily microcirculation.
CPP = MAP – ICP
For now I think we have to keep the vasodilatory effects of HDI in the “negatives” column.
The β receptors include β-1, β-2, and β-3. The β-1 receptors are primarily localized to the heart and β-2 receptors are on both the heart and the vasculature. We aren’t very interested in β-3 receptors for this discussion. Stimulation of β-1 receptors results in increased inotropy and chronotropy whereas β-2 receptor stimulation can cause vasodilation.
Norepinephrine has higher relative α-1 activity but also acts on β-1 receptors, while epinephrine has more effect on β-1 and β-2 receptors compared to its α-1 activity.
In particular when you recall that the pathophysiology of CCBs is dominated by vasoplegia (blockade of L-type calcium channels on the vasculature augmented by release of NO), using an agent that increases vascular tone makes sense. The β agonist effects of epinephrine in particular combats the accompanying myocardial depression from L-type calcium channel and β-1 receptor blockade in the heart from CCBs and BBs, respectively..
Now onto the good stuff…..
The Initial Approach
Jon: First, do you agree in general that crystalloid fluids (titrated to euvolemia via your definition of choice), atropine, and IV calcium are first-line therapies? And, that calcium is generally under-dosed?26 If I have time, I usually give 2 g calcium chloride every 10-15 minutes until the steady state calcium level is 1.5x the upper limit of normal, though some argue to be even more aggressive.26
Meghan: Sure. And we should definitely emphasize initial fluid resuscitation. Not all people who present after taking a little extra of the cardioactive meds are going to need the Full Monty. I definitely start with fluid resuscitation, but for the real deal, we don’t expect this to be our definitive therapy. Atropine and calcium are rarely effective but are worth a try. Personally, I also like glucagon for your BB-lite toxicity, but perhaps we can discuss that in another post. I’ll admit it’s not a popular choice, and the literature isn’t very supportive of glucagon.
Jon: It has become fashionable to bash glucagon, that’s for sure. Besides the vomiting and tachyphylaxis, now the average wholesale price of glucagon is $337/mg, so…
Meghan: Certainly no one is ever happy when you put someone on a glucagon drip and drain the hospital’s supply! But back to our main discussion…
The Data Paradox: Controlled Animals vs. Uncontrolled Human Case Experience
Jon: So for the patient who is now euvolemic and hypotensive despite atropine and IV calcium at a healthy dose, I generally start HDI next, regardless of whether I think it’s a BB or CCB causing the shock. And the primary reason I do that is that the large-animal literature (e.g., dogs and pigs) shows HDI to have both a hemodynamic and mortality advantage over almost every other common vasopressor or inotrope.1,4,6,22,23,25,27 Our most recent data suggest that, in an isolated lethal propranolol (pig) model, vasopressors may have even worse outcomes than placebo. As you can see from the graphs below, vasopressors look good right out of the gate, but after about 100 minutes all the pigs treated with vasopressors died, whereas only half the pigs who got placebo died.
The next figure shows visually how HDI works as an inotrope – slow out of the gait but builds steadily over time.
Admittedly this is where both my fellowship’s institutional bias and my own internal bias comes through. If Dan is going to Rat Hell then I am well on my way to Pig Purgatory. I spent a substantial amount of time in my fellowship in the lab poisoning pigs with big doses of propranolol (and a little bit of nifedipine).2,5,7 For roughly six months every Wednesday I watched a large mammal with every invasive monitor and catheter in place you can think of reach the brink of death, and then frequently get rescued with insulin. BTW – if you ever need a Swan-Ganz catheter on a pig, I’m your guy.
Meghan: I do have to say I have a little bit of fangirl feelings about the Minnesota program. You guys are doing impressive animal research work and always come correct to our national meetings with great ideas and opinions. In particular, the strong female presence is formidable (no offense).
Jon: None taken. We have no shortage of strong toxicologic women (or men) up here. One of the most opinionated, of course, was Kristin Engebretsen, a pharmacist and toxicologist who was a driving force behind our animal work who has since passed.28 I learned so much from her, and I miss her. She pushed the envelope with many things, including HDI.
Meghan: I had the pleasure of debating her on this exact topic at NACCT a few years ago. She was such a force and will certainly be missed.
With regards to the animal research in this area, I do want to push back a little and highlight some of the concerns raised by @MedToxFellowshp on Twitter. On the surface, the animal data is pretty compelling. But there are a few issues here that caution me against blind acceptance.
First, methodologic limitations in many animal studies significantly limit clinical translatability. For example, many of these studies are not blinded and one described here uses post hoc data. We would be pretty critical of similarly designed studies in humans and would be very hesitant to change practice based on their results. Additionally, we always have to be cognizant of relying too heavily on animals to fully represent disease processes as they occur in humans. Examples of this fallacy include discordant results for the benefit (or lack thereof) of corticosteroids for head trauma.29 In general, translating animal data to human clinical practice has significant limitations and should be approached with extreme caution and skepticism.30
Second, we should talk about the small numbers and dropouts. The number of pigs in these studies is extremely small, typically 4-5 per treatment arm. The beneficial findings with regards to HDI are compelling, however the risk of false positives with such small numbers is very real. Additionally, within these small numbers used in the studies, some animals inevitably die early. Imputation is then used to fill in the missing values. This is, of course, a valid statistical method for dealing with missing data. However, when numbers are so low and such a relatively large percentage of it is essentially made up, things get a little shaky. To be clear, your research is rigorous and reputable, and some of the best we have in tox, but, it is important to keep these very real limitations in mind as we use data in our clinical decision making.
One last thing, many of the initial animal studies showing inferiority of vasopressors to HDI used much lower doses than we would recommend in sick BB or CCB toxicity. Your recent papers looking at BB toxicity have gotten those doses up pretty high, but it’s just another piece to pay attention to when looking at this data.
Jon: Many of those criticisms apply to our work.7 Our group did several studies before3,5,6 we began to blind and randomize treatment arms.2,4 And because of ethical and financial reasons, we used study designs with a relatively lethal model but smaller number of animals so we could make multiple observations on each pig to increase our power for the hemodynamic parameters.2 These are all substantial limitations. And then of course, there’s the problem that humans rarely overdose on just one thing. Even if HDI really is better in an isolated propranolol overdose, is it still better if you chase that propranolol with a whopping dose of lisinopril? There’s no way to know for sure based on our data.
Meghan: Yes that is a major limitation with research in toxicology. Polyingestions are the rule, not the exception, which throws everything on its head. Data limitations are real, but I don’t believe that means we ignore it, especially when it is the best we have. We equally have to be careful not to bury our heads in the sand waiting for that perfect double blinded RCT that will never arrive for most tox ingestions.
Jon: Absolutely fair. Constant vigilance is needed when you introduce a new therapy. At the same time though, the evidence for vasopressors (other than tradition) is less than compelling in poisoning, no? One of Kristin’s final projects was a systematic review of the utility of vasopressors in BB/CCB poisoning, and essentially what the published data show is a somewhat bizarre mixed picture where the animal data are dismal but human case experience shows mostly success.31 There are, of course, no human trials of vasopressors (or HDI) for CCB or BB poisoning.
Meghan: Yes that’s true. The paper’s conclusions were conflicting in that sense. And in a way that supports my argument above! So for me, in these cases I would favor the limited human data over limited animal data. I also think vasopresor efficacy suffers from publication bias. No one is going to fund a study or try to report on successful use of a therapy that has been standard of care for decades. It’s like trying to publish a case report on giving dextrose for hypoglycemia and showing it works. The Phoenix group did publish a retrospective study looking at outcomes in all CCB cases over 25 years.12 They found that ALL patients survived their toxicity and almost no one got insulin. I will concede that this is retrospective single center data, but there are several atypical strengths worth mentioning:
- Humans, not pigs
- This is not Poison Center or other registry data. Full clinical data was available to the study investigators.
- These were SICK patients! 50% verapamil & 41% intubated
- Unlike most toxicology case reports or series, these patients had GCMS confirmation of their CCB overdose. This is HUGE. (Oh how I miss this tox lab!)
Safety in Numbers? Adverse Events and Pitfalls of HDI and Vasopressors
Meghan: Perhaps now is a good point to discuss the downsides of the therapies. Advocates of HDI often describe vasopressors as a murder weapon, citing horror stories of boxed kidneys and necrosed digits as reasons to avoid their use. In the Phoenix paper discussed above, they really did not see these complications, even at very high doses (up to 100 mcg/min for norepinephrine and 150 mcg/min for epinephrine).12
Jon: We’ve certainly contributed some to that. In the lab we observed vasopressors to look really great in the first 60 minutes of resuscitation, only to have cardiac output, SVR, and blood pressure fall rapidly resulting in death shortly thereafter.7 In our first case series of HDI patients10, the only death was in a case where HDI was stopped in favor of norepinephrine and the patient suddenly experienced PEA arrest – similar to what we observed in the lab when the pigs received vasopressors. The usual rules about post hoc ergo propter hoc apply of course, as with all single cases. The Levine paper is a remarkable collection of well-documented verapamil and diltiazem poisonings, but for all it’s strengths, 48 patients is still probably too small to draw firm conclusions about safety. The 95% confidence interval (CI) of a null-event study with n=48 is 0-7.5%. And for ischemic complications, the 95% CI of 10% would be 3-23%. Just because a therapy is time-tested, doesn’t mean there aren’t problems with it, or that we shouldn’t challenge its acceptance. Kayexalate® was a standard therapy for hyperkalemia, but if we had not challenged this dogma, we wouldn’t have realized its efficacy is questionable32 and that it has some important side effects.33 Nevertheless, I concede vasopressors are a time-honored therapy.
Meghan: And HDI certainly isn’t without its negative side effects correct? Hypokalemia and hyperglycemia have been higher in more recent HDI studies if I’m not mistaken. Citing one of your first author papers here.34
Jon: Absolutely. Well played using my own data against me. As noted above, bigger n studies (even observational retrospective studies) allow for a better assessment of adverse events. In 2018 there were two new, larger studies on HDI that both showed metabolic complications were problematic. An Australian study of 22 patients found hypoglycemia (73%) and hypokalemia (82%) were quite common.35 That same year, as you note above, we published our Poison Center’s experience with HDI, which totalled 199 cases, and found similar results (hypoglycemia 31%, hypokalemia 29%).18 The hypoglycemia is a very fixable problem provided you stay vigilant with point-of-care glucose measurements and dextrose infusions. The hypokalemia (in my opinion) is a more important reason to be cautious with insulin. Hypokalemia causes QT prolongation and increases the risk of Torsades des Pointes (TdP)36 . . . as does bradycardia. This is particularly important with certain drugs, such as sotalol, as sotalol itself also prolongs the QT interval.37 In our HDI study, we only had 2 sotalol overdoses, but one of them developed V-tach and had a cardiac arrest. HDI, by exacerbating hypokalemia and prolonging the QT interval, certainly could have contributed to this arrest. If your patient is at high risk for TdP, make sure HDI is really indicated, and be vigilant with potassium replacement. We typically recommend only replacing potassium if it gets below 2.8 mEq/L since the hypokalemia is intracellular shifting and not whole body potassium depletion. Overly aggressive replacement could result in hyperkalemia once recovery occurs and the insulin infusion is weaned, particularly if there is concomitant acute kidney injury. In a patient at high risk for TdP that required HDI, I would be a bit more aggressive with potassium replacement, but putting an exact number to titrate to would be an educated guess at best. Remember, insulin can shift magnesium and phosphorus too, so complete and frequent electrolyte monitoring is important.
Meghan: That’s a really important observation. I completely agree regarding the importance of hypokalemia being more important than hypoglycemia clinically here. I’d even go as far as to consider avoidance of HDI if there are any QT concerns.
Jon: One important finding from this dive into our Poison Center data was that hypoglycemia was a lot less common if we used concentrated dextrose solutions (not surprising of course).34 We actually recommend using stock D70 now to keep fluids concentrated. While not FDA-approved for use in this fashion, D70’s primary risk is its osmolarity (3,535 mOsm). While high, this is still far lower than the osmolarity of other medications used in critical care, such as 23% hypertonic saline (8,008 mOsm/L). D70 should only be infused via a central line. Using concentrated dextrose is critical not only to prevent hypoglycemia but also to concentrate fluids to minimize the risk of pulmonary edema – a complication of CCB poisoning that is made far worse with volume overload.38
Meghan: Pulmonary edema is a very underappreciated complication of CCB overdose! As someone who managed these patients until death or discharge, we always found the process of getting them off the vent very difficult if they had been over volume resuscitated. But I digress . . .
Jon: We recommend placing a central line immediately upon the decision to use HDI, and concentrating dextrose to D50 or D70 to minimize the risk of both hypoglycemia and pulmonary edema. For prevention of volume overload, we also recommend using a higher concentration of insulin for the infusion compared to the DKA concentration of 1 U/mL. We use 10 U/mL in most patients, though on at least one occasion in a very high risk patient we used the 100 U/mL concentration as an infusion. Insulin is stable concentrated at 16 U/ml for up to 14 days, which should help allay stability concerns.39 Patients on HDI require a lot of attention to all their infusions to avoid complications, especially volume overload.
Meghan: Man, this insulin thing sure is starting to sound a lot more complicated than our old friend epinephrine!
Jon: Very true – HDI patients typically require a 1:1 nursing ratio, at least at first. Not to pile on insulin here, but there are other circumstances where insulin may be problematic as well. Remember insulin’s therapeutic effects are inotropy and vasodilation. Vasodilation always occurs, but there’s no inotrope in the world that can fix an old MI or a heart that’s sick at baseline. If you have ischemic cardiomyopathy with a baseline EF of 10%, HDI is not going to magically fix your scarred heart and restore you to an EF of 60%. It will, however, vasodilate you, which might make things worse. Other structural heart problems that don’t tolerate inotropes are important too. We saw a patient with hypertrophic cardiomyopathy that we treated with insulin worsen after the infusion started.8 Baseline cardiac function is extremely helpful to know before starting HDI.
Meghan: In all seriousness, the above discussion highlights my biggest beef with HDI. All EM physicians and nurses know how to use and titrate norepinephrine and epinephrine. We are firmly in our wheelhouse with those drugs. How many EM physicians are comfortable using doses of insulin that approach 10 U/kg/hr? What kind of barriers are you going to run into with nursing when you place that order? How many pharmacists have prepared these specialized concentrated drips? What happens to these patients at smaller community centers that see severe CCB or BB overdoses once every few years? Sure they will be watching for hypoglycemia, but will they remember to stay on top of the potassium? How many people reading this post had potassium in their mind as the biggest issue with HDI?
Jon: It’s true – using a novel therapy for a rapidly declining patient is not easy to do. But that’s exactly the point of publishing our PCC’s HDI experience – the majority of those 199 cases occurred at hospitals outside the main toxicology centers in Minnesota (and the Dakotas). While there are some stubborn emergency docs out there, one point of our paper was that emergency physicians can use HDI even if they are not immediately familiar with it. It just takes an experienced toxicologist (or poison center) to guide them through the pitfalls.
Meghan: As my olive branch, we could also argue that this is a reason for us to all get more comfortable with new promising therapies. You can’t get good at what you don’t do.
I’d like to add one more important point on my contrarian rant. On top of all the barriers I mentioned, it takes real time before you see clinical effects from insulin (if indeed pig hearts turn out to be closer to mine than I would like). Quite the opposite, epinephrine rapidly improves hemodynamics. So for that crashing patient, I am not holding off while multiple managers wrap their heads around my zebra of an HDI order. Instead, I’m grabbing my vasopressor of choice and titrating it up rapidly.
Jon: You are correct. While it has a tremendous ability to increase inotropy, HDI is not a fast-onset therapy. Metabolic effects occur in seconds to minutes, but hemodynamic effects don’t start for 10 minutes or more.40 As Jeff Kline (yes, THAT Jeff Kline41,42) so aptly put it:
Adrenergic agents convert the heart into a drag racer able to produce a showy start but with poor endurance, whereas insulin converts the heart into a diesel engine with a slow start but able to pull the heavy load for the long haul.”40
Meghan: If you are a believer in HDI, I might consider it akin to phenobarbital for EtOH withdrawal. It’s role can be significant, but it is not my standard first-line agent, and I would never use it in a situation where I needed immediate results.
The most interesting question is how do we decide when to use our various treatment options, particularly in the very sick and dying patients.
Should we even be thinking of this as a hierarchical order or should we instead use a more informed and nuanced approach? If most overdoses are polysubstance and can have variable hemodynamic derangements that don’t fit our textbook presentations or pig heart models, perhaps we should simply be evaluating the patient in front of us and tailoring the management based on what we see.
Jon: Agreed. One-size-fits-all therapeutic choices make for mediocre medicine.
So to summarize the available literature, HDI seems very promising with a huge treatment effect size in small n animal studies, with real-world experience showing a high risk of (relatively manageable) metabolic abnormalities, while vasopressors have tepid supporting evidence in controlled animal studies while uncontrolled real-world case reports and clinical experience are relatively positive.
Mehgan: That’s fair, keeping in mind all the factors that would go into biasing the literature already discussed.
Putting it All Together and the Only Real Controversy
Jon: With all that in mind, the only real controversy (to me) isn’t which therapy to choose, it’s WHEN to choose each therapy. With that in mind, here’s how I make my choices, acknowledging my bias toward insulin.
In a BB/CCB patient refractory to fluids, calcium, and atropine, I use bedside echocardiography to make my decision. I am no master of the echo machine, but I (and I believe most emergency and critical care physicians) can use bedside echocardiography to make a judgment about cardiac contractility. I tend to trichotomize it into bad squeeze, OK squeeze (“eucardia”), and super-powerful squeeze. If the patient is hypotensive and squeeze is either bad or OK but with bad blood pressure (or some other indication of shock), I reach for HDI before vasopressors, and I give a bolus of 1 U/kg/hr and start a drip at 1 U/kg/hr. Frequently I titrate all the way up to 10 U/kg/hr after that, but the most critical step is the initial bolus and infusion.
The latest lab data though, especially for really sick patients, suggests that the question isn’t vasopressors OR insulin, it’s “why not both?” Kate Katzung, one of our fellowship graduates, just published a study comparing a combination of norepinephrine + epinephrine vs. HDI vs. HDI + norepinephrine in a very sick propranolol model (pigs again).4 To bolster the methodology I believe she sought counsel from the folks in Phoenix on dosing of the vasopressors to most closely approximate their practice. As has been the case with our lab, vasopressors were found to be ineffective, however, the study showed the combination of HDI and norepinephrine was superior to HDI alone, both in terms of mortality…
. . . and in terms of cerebral oxygenation.
To me this jibes with what we’ve all seen on those heroic cases where someone pulls through on 4 pressors, HDI, and the rest of the kitchen sink – that there’s likely synergism with HDI and vasopressors. So after looking at the available data, that’s where I’ve landed. I use echo to confirm inadequate contractility, then I start insulin, followed quickly by norepinephrine if I think there is inadequate perfusion.
Meghan: So you’re saying we need each other? Better together?
Jon: That’s exactly right. Where the conflicting animal data and human case experience now agree is that in a really sick overdose, these therapies are complimentary.
Meghan: I agree, using squeeze on echo is a great way to guide therapy. Norepinephrine alone is not going to work for a failing heart. In that instance, we need to either reach for an agent with more beta agonism like epinephrine or isoproterenol (if you can afford it at an average wholesale price of $1,766/mL) or, dare I say it, HDI at that point. In general, I would start with the basics as you mentioned and quickly get your vasopressor (or two) of choice on board and titrated up up up. If the patient isn’t improving and you see poor squeeze on echo, I think it’s reasonable to reach for HDI at that point. As an aside, our anecdotal experience in Phoenix was that the squeeze on echo was often good in CCB overdoses, further supporting our preference for pressors. I want to stress, however, that you should never hold off on using epinephrine or norepinephrine when faced with a hypotensive patient in this setting. If you’d like to add HDI later or even simultaneously, be my guest. Just don’t hold onto dogma from either camp while you watch a sick patient get worse.
Jon: Sage advice. Often when you’re starting HDI, you need something to bridge the resuscitation until HDI takes effect. Even in our center where we frequently use HDI without vasopressors, in 58% of our 199 cases a norepinephrine drip was also used.
As others have noted, vasopressors and HDI really are different tools for different problems. HDI is a slow but effective treatment for cardiogenic shock. It does nothing for vasoplegia and in fact might make it worse. Vasopressors give you immediate response in terms of MAP and HR, but monitoring for ischemic complications is critical. Regardless of which therapy is started first, as long as the complications of each therapy are properly monitored for and the synergism of HDI and vasopressors is utilized in a timely manner, experience tells us patients are likely to do well.
Meghan, thank you for joining me on this post. This was really fun to write together, and your skepticism kept me honest.
Meghan: Same! Great to get to spend time with you and as always, it was a learning experience.
Jon: And thank you to all our Twitter friends who sent us questions. We did our best to answer all of them, though some will have to wait for future posts. We’re lucky to have such thoughtful, engaged colleagues. Even the ones who write moderately bizarre fan fiction.
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- 2.Cole J, Stellpflug S, Ellsworth H, et al. A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock. Clin Toxicol (Phila). 2013;51(4):201-207. doi:10.3109/15563650.2013.770152
- 3.Holger J, Engebretsen K, Obetz C, Kleven T, Harris C. A comparison of vasopressin and glucagon in beta-blocker induced toxicity. Clin Toxicol (Phila). 2006;44(1):45-51. doi:10.1080/15563650500394795
- 4.Katzung K, Leroy J, Boley S, Stellpflug S, Holger J, Engebretsen K. A randomized controlled study comparing high-dose insulin to vasopressors or combination therapy in a porcine model of refractory propranolol-induced cardiogenic shock. Clin Toxicol (Phila). 2019;57(11):1073-1079. doi:10.1080/15563650.2019.1580372
- 5.Engebretsen K, Morgan M, Stellpflug S, Cole J, Anderson C, Holger J. Addition of phenylephrine to high-dose insulin in dihydropyridine overdose does not improve outcome. Clin Toxicol (Phila). 2010;48(8):806-812. doi:10.3109/15563650.2010.521753
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