Norepinephrine isn’t work – now what?? (Management of refractory shock)

Most resuscitation is pretty straightforward. No matter how sick the patient is, we select from a fairly limited list of interventions. Hypoxia: does the patient need facemask oxygen, highflow, BiPAP, or intubation? Hypotension: fluids, blood, vasopressors? This basic, well used menu serves us incredibly well for the vast majority of resuscitation. It is simple, which helps manage stress in inherently high stress situations. Unfortunately, sometimes resuscitation does not proceed as planned. Sometimes the patient remains hypotensive despite IV fluids and norepinephrine. How do we manage refractory shock?

When I teach performance under pressure, cognitive stop points are an essential tool. These are moments when you slow down and force yourself to get out of intuitive thinking, and take some time to really think about what is going on. There are natural stop points in any resuscitation, such as when the patient is going to get transferred to the CT scanner. These are excellent times to take a few deep breaths and think. More important, but sometimes harder to recognize, are what I call intuitive stop points. These are moments in a resuscitation when things are not proceeding as you would expect, and your job is to figure out why. Almost all our patients respond to norepinephrine. This patient is not responding. That should be your trigger to stop and think. 

Another important tool that I emphasize if you want to perform well under pressure is the checklist. Cognitive stop points are an excellent time to use checklists. Great trauma centers have a checklist that they use before the patient leaves the trauma bay to get their CTs. This is how excellent trauma teams avoid missing simple things, like antibiotics, tetanus, or TXA.

This post is my personal checklist for the hypotensive patient who is not adequately responding to normal doses of norepinephrine.

I do not include equipment problems in my checklist. The role of arterial lines is highly debated, but I would contend that if you have a patient in shock who is not responding to norepinephrine, you should no longer be using noninvasive blood pressure monitoring. The exact timing varies depending on the patient, but I will start an arterial line on all of these patients.

I also assume that most people will have already performed an ultrasound exam. The RUSH exam precedes, or is performed in conjunction with this checklist. Don’t stop early. One abnormality on the RUSH does not preclude a second. 

1: Have I actually addressed the underlying cause?

We sometimes get so focused on treating numbers that we forget about the patient. If the patient is septic, have you actually achieved source control? Do they need surgery, or some other intervention? Is your antibiotic coverage wide enough? If you are managing PE, do they need thrombolysis or an interventional approach? If it is an overdose, can you remove the agent with dialysis? Before just adding second and third line vasopressors, ensure that you have adequately addressed the underlying pathology. 

2: The metabolic causes – acidosis, calcium, steroids, thyroid, hypothermia

Acidosis

The diagnosis of acidosis should be straightforward: get a VBG on critically ill patients (and remember to pay attention to the most important but often overlooked clinical marker of unexplained tachypnea). 

The management is a lot more difficult. As far as I know, bicarb has never been shown to improve outcomes, but if the patient needs ongoing IV fluids, I would switch to isotonic bicarbonate, especially over normal saline. Ensure the patient is getting adequate respiratory support, so that a relative respiratory acidosis is not complicating the underlying metabolic acidosis.

Consider vasopressin. I usually stick to a combination of norepinephrine and/or epinephrine for almost all my patients. However, catecholamines are less effective when there is significant acidosis, and vasopressin seems to retain its properties.

If acidosis is the primary driver of refractory shock, the main goal should probably be getting the patient to the ICU for continuous renal replacement therapy.

Adrenal insufficiency and steroids

There are a few hints that steroids might be required. Obviously, if the patient is chronically on steroids, they are going to need stress dose steroids. I never get fancy labs back, but a combination of hyperkalemia with hyponatremia is a hint of adrenal insufficiency. However, for the most part, I am not going to make a definitive diagnosis in the ED, and so empiric therapy is required.

My general rule: if the patient requires a second vasopressor, I am giving a stress dose steroid, and the ICU can sort out the details. 

Hydrocortisone 100-200 mg IV

If you are really unsure about the diagnosis, using dexamethasone (6-10mg IV) as the empiric therapy can help the intensivist out, because dexamethasone doesn’t interfere with cortisol levels, and will allow them to perform an ACTH stimulation test later, if indicated. 

Calcium

Hypocalcemia should be relatively easy to diagnose, as long as you send the labs. Technically, you can get a hint in the form of a prolonged QT on the ECG, but realistically, I just don’t think that is how I am going to diagnose hypocalcemia.

The treatment is pretty easy: give some calcium. You can choose between calcium gluconate and calcium chloride depending on your vascular access. 

Thyroid

If your hospital laboratory can provide a rapid TSH and T4 level, this is an easy diagnosis to make (assuming you remember to send it). If you don’t have access to these labs, you are occasionally going to have to treat empirically. Luckily, there is very little downside to an empiric dose of T4.

The clinical clue is the pan-lows: hypotension, hypothermia, a relative bradycardia, and low (altered) mental status. 

The empiric treatment is T4 400 mcg IV. 

Hypothermia

I am not sure if hypothermia needs to be included on a checklist of occult causes of shock. That being said, hypothermia will cause persistent hypotension, and can be overlooked (or even caused) in a chaotic resus setting. Critically ill patients should have core temperatures measured, and patients should be kept warm as part of good supportive care. I will admit that I have occasionally found a low temperature slightly later in a resuscitation than I would consider ideal, and so I decided to include it on my checklist.

3: Consider anaphylaxis

Sometimes you misdiagnose this on arrival, and they had anaphylaxis the whole time. However, even if they didn’t have anaphylaxis as their primary complaint, by the time you are considering refractory shock you have probably given half a dozen medications the patient could be allergic to. Multiple times in my career a septic patient suddenly got worse, and it was because of anaphylaxis to piperacillin-tazobactam. These secondary presentations of anaphylaxis can be really tricky to pick up in patients who are already intubated and in shock. Carefully repeating your head to toe exam is essential in patients who are not improving. You might find a subtle rash as the only indication of a new allergy. 

Personally, I try to keep my approach simple. I use epinephrine routinely as my second line vasopressor. Therefore, even if I miss the diagnosis of anaphylaxis, I will have it covered. If you aren’t routinely using epinephrine, you will have to be a lot more vigilant about searching for signs of allergy. 

4: Toxins

Obviously, there is a massive list of toxins that can cause hypotension and shock. When I see a patient with unexplained hypotension, overdose is always near the top of my differential. However, it is also important to remember toxins as a secondary cause of shock. Patients might just be taking their usual dose of beta-blocker or calcium channel blocker, but now they are septic, have acute renal failure, and are retaining their normal antihypertensive. (Such as in BRASH syndrome.)

The management of most toxins is just good supportive care, which you are already providing. The key is to consider the short list of toxins that have a specific therapy:

• Calcium channel blockers: calcium and high dose insulin
• Beta-blockers: high dose insulin
• Digoxin: digibind
• Sodium channel blockers: sodium bicarbonate or hypertonic saline
• Cyanide: hydroxocobalamin

For all refractory shock that may be related to toxins, consider the role of intralipid, dialysis, ECMO, and of course get your toxicologist on the phone as soon as possible. 

5: Occult bleeding

This is the geriatric special: the patient comes in with clear urosepsis, but because of their delirium also had a fall resulting in significant traumatic injury. Or, you have the patient with cirrhosis who presents with sepsis, but also has a significant undiagnosed GI bleed. 

Most patients with refractory shock are going to need a trip to the CT scanner. Remember to look for traumatic injuries. Look for bleeding in those places that are not always clinically evident: the retroperitoneal bleeds. And be liberal with repeat labs. 

6: Obstructive shock

Obstructive shock is hard to treat with vasopressors. If the patient remains undifferentiated, now is the time to go back to step one, and consider whether you might be missing an obstructive cause as their primary reason for being hypotensive. Use ultrasound to assess for tamponade and tension pneumothorax. Think about massive PE. Obstructive shock needs specific therapy, not just supportive care. 

When I hear obstructive shock, I automatically think of tension pneumothorax, tamponade, and pulmonary embolism. I don’t really need to add those diagnoses to my checklist. However, there are a few rare causes of obstructive shock that I could potentially forget:

Auto-PEEP

In asthmatic patients who have been ventilated, we need to be very careful about auto-PEEP. Even in the absence of auto-PEEP, if the patient has refractory shock you should keep the PEEP as low as the patient’s oxygenation tolerates.  

Abdominal compartment syndrome

Although more commonly an ICU presentation, we need to consider abdominal pressures carefully in patients with abdominal pathology, such as severe pancreatitis, significant ascites, recent abdominal surgery, or bowel obstruction. You make the diagnosis by measuring the bladder pressure through a foley catheter. (The diagnosis requires a pressure above 20 resulting in organ failure.) 

Management is to drain any fluid you can (paracentesis for ascites; NG tube for bowel contents) and involve surgery to consider surgical decompression. 

Dynamic left ventricular outflow tract obstruction

Dynamic left ventricular outflow tract obstruction is an important consideration in a patient who seems to be getting worse despite multiple vasopressors. In the simplest possible terms, LVOTO occurs when the mitral valve gets pulled forward by fast flowing blood, restricting cardiac output. A full discussion is probably beyond the scope of this article, so I will share my more lengthy notes in an accompanying post. 

The diagnosis will require a bedside echo. There is obviously a huge range of skill when it comes to echo in the emergency department, but my focus is on the very basics: things that even I should be able to identify. A very large septum, or a very small left ventricular systolic volume, will trigger me to try to look at the mitral valve more closely, and suggest that I should involve the experts early.

The key management steps for LVOTO are treating the underlying cause, increasing afterload, avoiding inotropes, and potentially controlling tachycardia with beta-blockers. 

(You can read more on the Internet Book of Critical Care, and there are a bunch of videos on echocardiography and LVOTO linked below)

7: Cardiogenic shock

You might have missed cardiac dysfunction as the primary cause, or the patient might have secondary cardiac dysfunction caused by their sepsis. Either way, if you have not already done an echo, every patient in refractory shock deserves an ultrasound probe on their chest.

If there are signs of cardiac dysfunction, start an inotrope. Although the classic ICU inotropes are dobutamine and milrinone, I try to keep this simple in the emergency department, and stick with epinephrine, considering that I want both its vasopressor and inotropic effects in cardiogenic shock patients.

The key question in these patients is: am I missing a surgical problem? An acute valve issue needs a cardiac surgeon, not just an inotrope. 

8: A second diagnosis

This whole exercise has been about looking for secondary causes of shock. Maybe this bullet point is unnecessary. However, I have been burnt by premature closure or anchoring bias too many times in my career, so I like to give myself a second kick in the ass.

Forget about Occam’s razor. Focus on Hickam’s Dictum: “A patient can have as many diseases as they damn well please”. Early in my career, I was managing a very sick patient with an upper GI bleed. The diagnosis was obvious – there was blood and melena on my shoes. But about 90 minutes into the resuscitation, we got a chest x-ray that showed a tension pneumothorax. We hadn’t placed any lines in the area, nor had we performed chest compressions. It wasn’t clearly iatrogenic. I have no idea if it was there the entire time, or if it had developed over the course of his resuscitation. However, I do know that as soon as I opened his chest, his vital signs normalized.

The patient can have as many diagnoses as they damn well please.

If the patient is not responding to your treatment as you expect, go back to the beginning and start again. Do a thorough head to toe exam. Remember to turn the patient – the only sign of anaphylaxis might be a rash on their back. Grab the ultrasound again and repeat your RUSH protocol. Don’t close your mind too early. 

9: Do I have access to ECMO or other fancy interventions?

No matter what the underlying cause, if it is potentially reversible and the patient has a reasonable chance of survival, ECMO is always a consideration, even if it remains inaccessible to almost all of us.

The point of this post is to act as a checklist for actions for the average community emergency doctor. There are a number of heroic interventions for refractory shock, such as ECMO, intra-aortic balloon pumps, LVADs, etc, that are simply not available to most of us. If you work in an institution with fancy therapies, get these teams involved early.

There are a number of other therapies that have been tried, and are sometimes suggested, in refractory shock. Methylene blue, thiamine, vitamin C, and hydroxocobalamin are all options with reasonable theory but basically no evidence. In my mind, those are ICU interventions that I won’t be considering in the emergency department, but how far you get into this algorithm might depend on the environment in which you work. 

Summary

Perhaps the most important lesson is that vasopressors are not the treatment for hypotension. (With the exception, I suppose, of epinephrine in anaphylaxis.) You need to find and treat the underlying pathology. If things are not going as you expect, start again from the beginning. Repeat your head to toe exam. Dig into the history. Use the RUSH exam. Ensure that you have effectively treated the primary cause of shock, but don’t forget that hey patient may also have a secondary diagnosis. 

Other FOAMed

EMCrit: The RUSH exam

IBCC: Approach to shock & refractory shock

IBCC: Dynamic left ventricular outflow tract obstruction

First10EM: Dynamic left ventricular outflow tract obstruction

IBCC: Abdominal compartment syndrome

References

Jentzer JC, Vallabhajosyula S, Khanna AK, Chawla LS, Busse LW, Kashani KB. Management of Refractory Vasodilatory Shock. Chest. 2018 Aug;154(2):416-426. doi: 10.1016/j.chest.2017.12.021. Epub 2018 Jan 9. PMID: 29329694

Nandhabalan P, Ioannou N, Meadows C, Wyncoll D. Refractory septic shock: our pragmatic approach. Crit Care. 2018 Sep 19;22(1):215. doi: 10.1186/s13054-018-2144-4. PMID: 30231909

Ornato JP. Optimal vasopressor drug therapy during resuscitation. Crit Care. 2008;12(2):123. doi: 10.1186/cc6824. Epub 2008 Mar 31. PMID: 18394182