Vasopressor Receptors

Different vasopressors have different functions and these functions dictate why we choose certain pressors at certain times. We’re all familiar (hopefully) with the fact that epinephrine is a positive inotrope as well as a vasopressor while phenylephrine is pure vasoconstrictor. This is why we choose epi over phenylephrine when we need inotropy and why phenylephrine will actually make hypotension secondary to cardiogenic shock worse.

These differences in function are dictated by the different receptors on which the pressor drugs act. In addition to different functions, some vasopressors with the same general effect (vasoconstriction) act on different targets (catecholamine vs non-catecholamine) and so can have a synergistic effect. Adding vasopressin to norepinephrine for a patient in septic shock, for example, can help even beyond the fact that norepi is at its limit. This is why adding vasopressin before maxing out norepi is often beneficial. Additionally, vasopressin is less affected by blood pH, so it will work in patients with extreme acidosis where norepi will not.

Eddy Joe Gutierrez has a great Instagram post on this with a nice slide showing how the different pressors work.

Calcium in MTP

Transfusing a lot of blood presents a lot of problems (not the least of which being that the patient needs a lot of blood to begin with!). Chief among those is likely the coagulopathy that results from a depletion of coagulation factors due to losing whole blood (PRBCs, plasma, and platelets) but only getting PRBCs back. Massive transfusion protocols (MTP) helps to address this by transfusing additional products in some sort of “proper” ratio (what that ratio IS is up for debate), but even if you transfuse PRBCs, FFP, and platelets in proper balance, you can still run into another life threatening complication. And I’m not talking about TACO (although that certainly is a problem). It’s one that may not be as readily recognized or remembered, but one that can wreak havoc with your resuscitation. Hypocalcemia.

Banked blood contains citrate as a preservative for storage. Citrate binds calcium and renders it inactive. Giving lots of banked blood can result in hypocalcemia. Hypocalcemia can cause all sorts of problems including hypotension (probably ALREADY a problem in someone requiring MTP) and seizures.

Pharmbythegram has a really nice post summarizing the role of calcium administration during MTP. Hopefully, you’ll now always remember to give calcium along with PRBCs, FFP, and platelets.

Bicarb in Metabolic Acidosis

The Resuscitationist has a great Instagram post about sodium bicarb in cardiac arrest, does it help or hurt? I’d expand this to just about any metabolic acidosis. IVP sodium bicarb used to be commonly given in these stations, especially during a cardiac arrest. It makes sense intuitively. Metabolic acidosis causes all sorts of cardiovascular problems including increased arrhythmias and poor contractility. Additionally, most vasopressors (vasopressin being the notable exception) won’t work in severe acidosis. So that just worsens things as the patient gets more hypotensive and you go up and up on the pressors to no effect.

So, it stands to reason that giving some bicarb would correct the acidosis (pH and HCO3 are inversely related in metabolic processes, after all) and fix all of our problems. So, why would you not want to give a couple of amps of bicarb?

Firstly, there isn’t any real evidence that it helps. Two studies mentioned in the IG post are pretty conflicting with one showing bicarbonate administration during cardiac arrest associated with earlier ROSC, but the other showing worse neurological outcomes. It may be beneficial in certain populations, including patients with severe metabolic acidosis and stage 2 or 3 AKI, some poisonings/overdoses (i.e. sodium channel blockers, TCA, salicylates, some toxic alcohols), and hyperkalemia (although a recent study question that as well).

So, there’s no real evidence it helps, but what’s the harm in trying? Well, firstly, I would argue that there’s always risk in medicine and so we shouldn’t be doing stuff “just because” if there is no evidence that it helps. But in the case of bicarb, it can actually hurt. Sodium bicarbonate (NaHCO3) gets metabolized and one of the byproducts is CO2. In a lot of cases, this isn’t really a big deal, but if your patient already has a respiratory acidosis (or is at risk for one), this is a really bad idea. It can also drop the ionized calcium, which again would be pretty bad in a critically ill patient.

So, no real evidence of benefit outside of certain situations. Possible harm. The better thing to do in most cases is to treat the cause of the metabolic acidosis. Having said that, I will sometimes give bicarb in a severe metabolic acidosis (pH < 7.2) in an unstable patient in order to buy some time. But, I’m cautious about it.

Spontaneous ICH

Spontaneous Intracranial Hemorrhage (ICH) is one of the more common things we see in the Neuro ICU. This is most commonly caused by hypertension, and so blood pressure management is usually a key part of ICU care in these patients. There is a fine line to walk between proper brain perfusion and increasing further bleeding. The other major pharmacological question involves reversal of oral anticoagulants that the patient may be taking. Although it’s not usually the cause of the bleed (again, hypertension, possibly in concern with anticoagulants is most likely; other causes include aneurysm rupture, vascular malformation, and malignancy), they can certainly exacerbate the bleeding.

@emergencymeded has a great post on Instagram covering the basics of pharmacological management of these patients. They point out that BP targets are controversial. I think controversial may be too strong, the guidelines generally recommend SBP < 140, but they do point out 2 large trials, INTERACT II and ATACH 2 both suggest that there is no increase in negative outcomes by allowing SBP up to 180. For management, labetalol and nicardipine are the mainstays of therapy. I generally start with 10-20mg labetalol IVP q1h PRN. If that is insufficient or if there are contraindications to beta blocker therapy, you can add 10-20mg hydralazine IVP q1h PRN (although this is rarely sufficient). If you’re still not able to get good control, or if you’re having to give lots of PRNs, a nicardipine gtt is the next best step. Although, be aware that due to it’s longer half-life, nicardipine isn’t really truly titratable. Once you get BP in range, it’s a good idea to back off a little on the dose to avoid overshooting. Clevidipine is probably a better option, but it’s pretty expensive so not as readily available. With a half-life of around 1 min, clevidipine is a truly titratable drug. Be aware that it is a lipid emulsion and can easily be confused with propofol in intubated patients.

When it comes to reversing oral anticoagulation drugs, the first question to ask is, “should we reverse?” Patients are on these drugs for a reason, after all. This is a decision that needs to be made after a careful risk:benefit assessment. In most cases though, you’ll end up reversing these drugs to prevent worsening of the bleed. There are 2 different strategies to reverse these drugs, targeted and non-targeted. Targeted involves giving an “antidote,” that is a specific reversal agent. Vitamin K for warfarin (although it doesn’t work fast enough and you’ll want to give FFP or 4-PCC as well), idarucizamab for dabigitran, and andexanet for the Xa inhibitors. Andexanet is not widely available due to cost and questions of efficacy. Non-targeted involves giving clotting factors that reverse all drugs. This is predominately 4-factor prothrombin complex concentrate (4-PCC) as FFP won’t reverse the Xa inhibitors and 4-PCC has been shown to do a better job of reversing warfarin than FFP. I’ll do a whole post soon on reversing anti-coagulation drugs.

Melatonin for the Prevention of ICU Delirium

Delirium is a common problem in the ICU. The reason is usually multi-modal, but sleep deprivation and alterations in the sleep-wake cycle are often a big part of it. so, if we ensure that patients get good sleep, that should prevent delirium, or at least SOME cases, right? to that end, we often will start patients who we deem at-risk for ICU delirium on melatonin in order to help them sleep and thereby prevent delirium. But does it actually work?

Pharmacy Joe looks at a recent study examining the efficacy of melatonin as a preventative strategy for ICU delirium and the results were not what I was hoping to see. The study was a multi-center RCT of around 800 patients in ICUs across Australia. Patients in the study group were all given 4mg of melatonin every night during their ICU stay. All patients were assessed twice daily using the CAM-ICU for delirium. There was no significant differences between the study group and the control group in terms of delirium.

One thing that isn’t clear is if 4mg might not be enough. Although I typically start with 3mg, I will often escalate it to 6mg pretty quickly if 3mg doesn’t seem to effective. I also typically don’t start melatonin until either the patient or the nurse complains of poor sleep. Further study is needed to determine if melatonin plays any role in delirium prevention.

For right now, it seems that the best strategy to prevent delirium (and we know that prevention is superior to treatment) is to focus on the nonpharmacological interventions. Maintaining a normal sleep-wake cycle is key. I encourage lights on during the day and having the TV on if there are no visitors to converse with the patient. It’s ok for patients to nap, but they shouldn’t be sleeping all day. If able, ambulation in the hallway or at least being up to the chair are beneficial as well.

Likewise, minimizing disturbances at night are important. Often patients are very ill and staff need to be in and out of the room frequently, but if possible, minimize these disturbances. Lights should be left off or low as much as possible. Don’t leave the TV on all night in the room. And, remember that sedation does not = sleep. I was a night shift ICU nurse for 10 years and often saw that the same care not to disturb day/night cycle was not observed in patients who were sedated.

The biggest pharmacological therapy you can do for prevention is to avoid the use of drugs known to cause or exacerbate delirium. The big offenders here are benzodiazepines. Benzo drips should almost never be used except in the case of status epilepticus. They were also found to be helpful in some cases of COVID back in 2020-2021 when nothing else would keep patients sedated, but they should be avoided in most cases.

The Critical Illness, Brain Dysfunction, and Survivorship (SIBS) Center has some great resources on delirium prevention and treatment.

TXA for SAH?

Tranexamic acid (TXA) is an antifibrinolytic drug that stabilizes clots and helps to control bleeding. It is often used in acute trauma and of cases of massive hemorrhage. It is not prothrombotic, so it can help to control bleeding while not increasing clotting like some other drugs. So, is there a place for it in the initial management of aneurysmal subarachnoid hemorrhage?

Endovascular coiling or surgical clipping is the preferred management of bleeding cerebral aneurysms, but could TXA be useful in situations where surgical management is not readily available? Pharmacy Joe looks at a new study by Long and Gottlieb in Academic Emergency Medicine that seeks to answer that question.

The review of the literature included 13 studies of nearly 3000 patients and essentially concluded that there was no real benefit. Although there was no difference in adverse events between placebo and TXA, there was no difference in mortality or functional outcomes either. There did appear to be a benefit when it came to rebleeding. The study found 8.7% reduction in rebleeding among patients treated with TXA. So, there may be some benefit in reducing further complications, but more study is needed.

Check out Pharmacy Joe’s episode for all the details and links to the relevant evidence.

Best Vasopressor in TBI?

What vasopressor do you routinely use in the management of traumatic brain injury patients? Admittedly, in my neurocritical care practice, I don’t manage a lot of true TBI patients. In our system, the only neurotrauma patients that come to the neuro ICU are isolated neurotrauma (brain and/or spine without other major trauma). Polytrauma patients go to the trauma service and are comanaged in the TICU along with neurosurgery.

But, in my limited experience, I typically use norepinephrine. I might have formerly said phenylephrine, as that used to be the vasopressor of choice in the neuro ICU. This was mostly due to the fact that at one point, we were mostly using vasopressors to augment BP in order to increase perfusion to the brain or spine, a practice that has largely fallen out of favor. In these cases, the patients often just needed short runs of low dose pressor and so phenylephrine was considered safer to run without a central line, making it appealing in this subset.

But, in the past few years, we’ve gradually shifted away from this to favoring norepinephrine. I think this is largely because we’ve seen a steady increase in the overall acuity of the patients and now those who need pressors typically need them for actual shock, not just to drive MAPs. In that case, central access is typically needed anyway, eliminating the one benefit of phenylephrine.

In this episode of the Elective Rotation podcast, Pharmacy Joe covers a recent study in Anesthesia and Analgesia that seems to favor the use of phenylephrine as the first line vasopressor in TBI patients. It was a rather large retrospective study that showed a statistically significant increase in in-hospital mortality in patients who received norepinephrine as compared to those who received phenylephrine. The study found that norepinephrine was much more common in sicker patients (higher ISS, use of ICP monitoring, comorbidities, etc.), but the authors used propensity-matching statistical analysis to account for this.

Overall, it is an interesting study but there are number of issues including incomplete data regarding shock states. Despite the propensity-matching analysis, I think it’s reasonable to assume that there is probably some bias with patients receiving norepinephrine instead of phenylephrine being sicker at baseline which may account for the difference to a greater degree than is appreciated.

What about you? What is your practice regarding vasopressors in TBI? After reading this study and/or listening to the podcast episode, will you change your practice?

Low-Concentration Peripheral Norepinephrine

We’ve talked before about norepinephrine as a powerful and commonly used vasopressor in the ICU. This is often my go-to pressor for all types of shock, unless it’s cardiogenic shock or I’ve got reason to suspect that contractility is part of the problem. But, historically it has to be infused through a central venous catheter because of the potential risks of infiltration.

It used to be my practice to use phenylephrine when I needed a little bit of vasopressor but wanted to avoid a central line or the need for pressors was too urgent to wait for central line placement. This might be in the face of rapidly progressing, life-threatening shock when even the few minutes it would take to place a central line would be an unacceptable delay in pressor administration. Or, maybe the patient just needs a time-limited run of pressors, while recovering from anesthesia/procedural sedation, for example.

But, while phenylephrine is generally thought of as safe for peripheral administration, it’s really not the optimal vasopressor. I do use push doses of phenylephrine for transient hypotension associated with endotracheal intubation, for example. But, a phenylephrine drip is almost never what I want. If my patient needs a drip, they probably need norepinephrine.

In this episode of the Elective Rotation, Pharmacy Joe discusses the safety and efficacy of using low-concentration norepinephrine through peripheral venous access. Low-concentration norepinephrine has decreased risks in cases of infiltration as compared to standard-dose. Additionally, Tyler Jones has a great post over at Critical Care now discussing more broad use of peripheral vasopressors.

Either way, I think if a patient is sick enough to require norepinephrine at higher doses and/or longer periods of time, the risk of peripheral administration outweighs the risks associated with central venous access. So, put in the central line.


Earlier, we discussed epinephrine. Now, Rishi Kumar has another great post about another vasopressor, norepinephrine. When I was first starting out as a nurse, norepi had quite the reputation, and not in a good way. Known by the brand name Levophed, it was often called “Leave-em-dead.” These days, norepi is the go-to pressor for just about any type of shock except cardiogenic. It’s a good all around drug, causing mainly vasoconstriction, but also having some positive inotropic/chronotropic effects as well.