Beyond sick. That is how I would classify patients that fit into the scheme of this blog. This is generally a CCT problem in the prehospital world as the patient has been in deep shock for some time before we start having to overcome the problem of vasopressor resistance. We have to figure out a way to keep them alive and something resembling stable in transit to the tertiary care center.
Before anything else, you have to consider the influence of your CUFF pressures on the situation. Oscillometric NIBP is notoriously inaccurate the sicker the patient gets.1 It tends to over-estimate MAP… that’s right it is an ESTIMATION based on a proprietary formula the manufacturer uses. An A-line for placement should be a conversation prior to departure (if your team cannot place them) to ensure you are making decisions based on real and accurate numbers.
Goals: MAP >65, DBP >401
We are typically armed with norepinephrine (Levophed), epinephrine, and vasopressin. These represent our first, second, and third line agents for patients in shock. Their deployment is sometimes dictated by the institution or it is left to the clinical judgement of the individual clinician. But we can all remember a time when the patient was “max triple pressed” and there was still zero traction with their hemodynamics. We call this refractory shock or catecholamine resistant shock.
So what do you troubleshoot when the patient does not respond to escalations in vasopressors. Is it a problem of medication selection? I think if it was that simple then we would have a well established body of evidence that says “for this problem use this medication and for that problem use that medication.” Of course, this would also assume that there is no such thing as vasopressor resistance, catecholamine resistant shock, or any of its cousins. Which we know is not true.
A few flights stick out in my head that collectively taught me a way to approach these cases. I learned to think about Pharmacy, Mico-patho, and the Macro-patho. Thinking through these different pathways might help find the “most right” answer and turn the tide in the battle for perfusion.
Pharmacy
Polypharmacy Problems2
Consider for a minute that the problem is not as bad as it looks, but that there is something also fueling the fire. Patients who are receiving ACE inhibitor therapy or ARB therapy and during the course of their care receive induction drugs or sedation medications post intubation are in a particularly precarious position.
The body’s response system is a cascade of redundancies designed to complement and supplement one another. It starts with the SNS, then the RAS gets involved, and finally the vasopressinergic system. In this case, induction agents + ACEi/ARB therapy leaves the vasopressinergic system carrying the entire load. Which means the system’s response to your exogenous catecholamines will be sluggish at best. With one exception, stay tuned.3,4
Max Dose of Pressors?
This can be debated for hours. What is the maximum dose of levophed? In your organization is this max dose based on policy or physiology? What is in your organization’s guidelines and what is in the literature likely do not mirror each other. “Max dose” is often found to be an institutional policy or a personal limit.5 Personally, I am of the mindset that constantly escalating a single pressor until it is “maxed” is a bit of a foolhardy approach. Adding additional pressors (preferably one that communicates with something other than alpha or beta receptors) and titrating both (or three) up in tandem makes more sense than maxing a single medication.
I cannot do any better to unpack this topic then Dr. Josh Farkas did here at PulmCrit:5 https://emcrit.org/pulmcrit/high-dose-vasopressor/?_login=27f5b43804
The Micro-Patho
Blood Chemistry (pH)
Vasopressors (and really most medications) have a pH limit after which their action is suppressed, generally around a pH of 7.2. It is no shock at all (see what I did there) to find these patients in severe metabolic acidosis. The hypoxia and the body’s compensatory mechanisms leave CCT teams trying to hold a physiologic nightmare together with tools that won’t work as well (or at all) in that environment.6,7
This is one of the first things I considered when I was dealing with a patient that was on multiple pressors that weren’t “working.” I looked at the last gas we had to confirm my suspicion. The right answer as far as what to do about it is “fix the underlying problem,” and the less right answer is to alter the blood chemistry to support the pressors.6,7 Are there certain points in which a bicarb push can attenuate things and create a favorable chemistry for the pressors to work? I think so.1,6,7 Should we routinely push bicarb for patients in shock? No… and not without some ventilator judo to ensure we can increase MV to compensate.1,6,7
Receptor Down Regulation
Adrenergic receptors can eventually lose their ability to respond to exogenous catecholamine stimulation. We can keep escalating our doses of pressors, but we get less and less response over time. The result is soon the opposite of what we want. Instead of more vasoconstriction and therefore better MAPs, we get less vasoconstriction (perhaps even due to vasoplegia) and worse MAPs.4
Adrenal Insufficiency
I did not often consider adrenal insufficiency as a primary driver of badness in some of the refractory shock patients I flew. In my opinion it is not something you will reach for unless you have seen it once or twice or learned of its influence on the clinical picture during a debrief. The patient has been dumping stress hormones into their system almost from start in an attempt to overcome their illness. The supply of hormones (cortisol and aldosterone) can become exhausted to the degree that “stress dose steroids” are necessary to prompt the patient’s system to stay in the fight.
The Macro-Patho
LV Failure
All of the pressor support in the entire drug bag will not yield results without a functioning left ventricle. A number of maladies can affect LV function like an MI or chronic heart failure. Some of the aforementioned issues can also negatively impact inotropy like acidosis. In sepsis there is such thing as sepsis induced cardiomyopathy where all of the badness circulating in the body exerts a negative inotropic influence on the heart.6-9
However, this can sometimes be an easily correctable issue on our part. I got caught more than a few times working the pressor angle and neglected to think of the need for volume resuscitation. I was naive to think sometimes that the patient had been adequately fluid resuscitated prior to the CCT team’s arrival. I can remember one flight in my training period where my preceptor watched me squirm for a bit before he nodded over to our flight nurse partner who pulled out a bag of fluid, hooked it up, squeezed a little volume in for a bit… and well, the ending was predictable. Volume resuscitation is a reversible cause of vasopressor resistant shock and should be a focus for the team.8
Vasoplegic Shock Syndrome2
The team that finds the patient in vasoplegic shock syndrome has a tall order to restore perfusion. The patient has lost their vasomotor function. Generally, this is due to endotheliopathy that often accompanies shock (also known as Shock Induced Endotheliopathy or SHINE).2,8,9 The inflammatory mediators and cytokines released as a result of cellular damage and hypoxia damage and destroy the endothelial glycocalyx and damage endothelial cells. These surfaces are essential to vasomotor control and the maintenance of perfusion.
This is often associated with the polypharmacy issue seen above. The key is to remember that the patient is catecholamine resistant, the RAS system is blocked (if they are on ACEi/ARB therapy) and this leaves the vasopressinergic system carrying the entire load of maintaining perfusion. Once aVP or arginine vasopressin (your endogenous vasopressin stores aka anti-diuretic hormone) supplies are exhausted there is nothing left to stimulate vasomotor action. The ensuing vasodilation is occurring nearly unopposed.
How do you know that you have a vascular tone problem? Look at the DBP. The target we like is around 40, but we should be acting to correct it long before the patient arrives here.1
This is sometimes referred to as the “final common pathway” of shock.
Response Options
What are the options for us once we learn that the patient is not responding to pressor support? I think it sometimes depends on your care setting and what is available to your team. Some teams have just about anything you could wish to have in these situations (like methylene blue) while others have to take more of a “make do with what ya got” approach.
The Ones You Need to Know
Early vasopressin or the “Broad Spectrum Vasopressor” Approach:2,3,8,10 I rarely went to epi as my second line pressor, I preferred vasopressin. Vasopressin acts on a completely different set of receptors and tends to behave a little better when the patient is acidotic.1 It does take a little bit of time to get on board and start working so start it early if you see that you are constantly escalating levophed doses. In one organization I was with, the trigger to add vasopressin was once the levophed reached 15mcg/min without favorable response. The strategy for “broad spectrum vasopressor” therapy is to quickly initiate multi-modal, non-overlapping vasopressor support, early.
Inotropic Support: Does the LV need some help? Dobutamine is perhaps one of the more overlooked medications that we can access.8,9 Yes, there is some risk of an initial drop in pressure due to the vasodilatory effects, but they are known to be short lived and if we already have two other pressors on at high doses then we can more than mitigate the risk of vasodilation and hypotension.8,9 We can sometimes forget that as we are working to increase MAP/SVR that the LV has to generate enough force to clear it against that increased SVR. If additional volume resuscitation does not move the needle for you, at least consider some inotropic support. This can be accomplished with the addition of an epi infusion added third line, however, it is not without some added considerations (like HR or arrhythmias).1,8,11
The Ones that are Nice to Know
Methylene Blue:1-3,8 Part of the problem with vasodilation and vasoplegia is the presence of iNOS, nitric oxide, which as we know is an incredibly potent vasodilator. If the patient has reached a point where they can no longer respond to catecholamine stimulation, then perhaps there is a role for methylene blue (MB). MB acts by inhibitng iNOS and improving the conditions for vasoconstriction to occur. It shows some positive physiologic effects in the literature, but has not proven to be a windfall for mortality. Which should surprise no one since we are studying this in a patient population that is quite in extremis.
Stress Dose Steroids:8 A common intervention performed for these patients in the ICU. Some services make room for this modality in their guidelines, but there is a catch. Just like when we are giving steroids for respiratory patients, the desired effect is not immediate. Steroids work over the ensuing hours to help the patient generate vascular tone. Having said that, the earlier they are administered, the better.
Close Out
If the standard vasopressors are getting close to their “max allowable” dose and are still failing to move the needle, we are likely not dealing with a deficiency in milligrams of levophed. The patient’s condition has progressed to the point that the whole environment we would normally easily manipulate to great effect is completely deranged, rendering most of our options ineffective.
You are at the edge of the evidence and your guidelines here. You have to pivot away from the guideline directed approach and bring more brains to the problem (read: collaborate with physician support) to generate effective solutions.
References
Bernardoni B, Sayre M, Roginski M, et al. Vasodilatory shock-from initial resuscitation to rescue therapies: narrative review and considerations for critical care transport. Air Med J. 2025;44(6):539-547. doi:10.1016/j.amj.2025.08.009
Heyman HM, Serrano RA. Vasoplegic syndrome and noncatecholamine therapies. In: StatPearls. StatPearls Publishing; 2025. Accessed August 15, 2026. https://www.ncbi.nlm.nih.gov/books/NBK599553/
Shear T, Greenberg S. Vasoplegic syndrome and renin-angiotensin system antagonists. APSF Newsl. 2012;27(1). Accessed August 15, 2026. https://www.apsf.org/article/vasoplegic-syndrome-and-renin-angiotensin-system-antagonists/
Wieruszewski PM, Khanna AK. Vasopressor choice and timing in vasodilatory shock. Crit Care. 2022;26(1):76. doi:10.1186/s13054-022-03911-7
Farkas J. PulmCrit- High dose vasopressors: never surrender. EMCrit Project. Published June 4, 2018. Accessed August 15, 2026. https://emcrit.org/pulmcrit/high-dose-vasopressor/?_login=27f5b43804
Drumheller BC, Sabolick EE. Hemodynamic instability and abnormal vasopressor responsiveness in the setting of severe metabolic acidosis treated with adapted alkalinization and continuous renal replacement therapy in the emergency department. J Emerg Med. 2020;60(1):67-72. doi:10.1016/j.jemermed.2020.09.022
Kimmoun A, Novy E, Auchet T, et al. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside. Crit Care. 2016;19:175. doi:10.1186/s13054-015-0896-7
Bassi E, Park M, Azevedo LC. Therapeutic strategies for high-dose vasopressor-dependent shock. Crit Care Res Pract. 2013;2013:654708. doi:10.1155/2013/654708
Innocenti F, Palmieri V, Pini R. Fluids, vasopressors, and inotropes to restore heart–vessel coupling in sepsis: treatment options and perspectives. Anesth Res. 2024;1(2):128-145. doi:10.3390/anesthres1020013
Demiselle J, Fage N, Radermacher P, Asfar P. Vasopressin and its analogues in shock states: a review. Ann Intensive Care. 2020;10(1):9. doi:10.1186/s13613-020-0628-2
See E, Chawla L. Redefining the modern paradigm of vasopressor therapy for vasodilatory shock. Crit Care Resusc. 2025;27:100148. doi:10.1016/j.ccrj.2025.100148
