Making-A-Pressor by Tom Latosek

Whether you are a brand-new paramedic or nurse or a seasoned critical care provider, chances are you have started or maintained a patient on vasopressors.  They are considered to be one of the hallmark drugs of resuscitation and what we consider to be “life support” drugs.  There are a few key drugs on the market that have fallen into/out of favor over the years for various reasons but there remains a significant amount of controversy on what the “best” agent is to use in a given situation. 
In this article, we step out of the clinical context of what the preferred vasopressor is for a given clinical situation, but instead take a look at the scientific concepts underlying their administration and efficacy as key players in resuscitation.  Specifically, we will look at those vasopressors derived from tyrosine and phenylalanine, though many of the biological concepts presented here extend to many other drugs as well.  It is my hope that by reading on you gain a better understanding of these agents to better apply them in your clinical practice, and that you learn or refresh your knowledge of biology and chemistry along the way.
Let’s dive in…
The Making of a Vasopressor
Above is what looks like a complicated synthesis pathway, a dreaded topic among many students in organic chemistry courses.  In this context, our goal is just to understand how our vasopressors are made in the body, and we can break down this complex pathway into more digestible components. 
First, looking at the picture above we can see that the process of forming the vasopressors: dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine).
Phenylalanine and tyrosine are both amino acids that are considered to be a part of the 20 essential amino acids the body requires to carry out many of our necessary reactions, and as the building blocks for other compounds (like nerdy legos). 
Both tyrosine and phenylalanine fall into the class of amino acids referred to as aromatics (literally because these enzymes have a sweet odor..).  Let’s talk a little bit of painless organic chemistry and the concept of an aromatic structure.
Aromatic ring structures are considered to be a very versatile form of an organic molecule. One of the most common structures is benzene, an aromatic ring of six carbons forming a hexagon.  The intersecting lines of the hexagons above each represent a carbon
Anytime you observe a second line, it indicates that there are two bonds attaching the carbons.  On most organic structures you will not see hydrogens, but they exist to satisfy a total of 4 bonds made by each carbon.  In this case, there is 1 additional H assumed to be attached to each carbon.
Why do we care so much about this?
It is a basic building block for adding things and moving other groups around, or forming new compounds. This is what makes these aromatic rings so versatile.  Ok, now let’s address how they apply to our vasopressors above.
If we start at tyrosine and we want to get to the compound L-Dopa, we need the compound tyrosine hydroxylase (the finger below) to make that happen.  If we break down the words, anything that contains “-ase” is an enzyme, and hydroxyl groups are the -OH groups you see on many of the molecules above. Legos don't build themselves. You need an enzyme to stack those puppies up!
The basic concept here, to go from tyrosine to L-Dopa we need to add a hydroxyl group (an -OH) to tyrosine.  Once that happens the new compound has different biological characteristics than the previous compound.  Because of the chemistry of the -OH group on L-Dopa it can now bind receptors differently and it reacts differently at physiological conditions inside the body.  
For example, Parkinson’s patients are often administered L-Dopa as part of their treatment regimen to replace needed dopamine in the brain.  L-Dopa can cross the blood brain barrier more readily, so it is administered in the L-Dopa form and converted to dopamine once inside the brain.   Another important point to consider is what we consider “vasopressors” derived from tyrosine, are also neurotransmitters that function within the brain carrying out other functions.
Back to the chemistry… to get from L-Dopa to dopamine, we need to do some rearrangement, and, in the process, we get rid of carbon dioxide. There is a loss of 1 carbon molecule and 2 oxygen molecules and we move the NH2group, called an amino group, to the end of the molecule.  Again, this rearrangement changes how this molecule will interact at different pH levels, with different receptors, and with different membranes.  The molecules are very similar, but the groups attached to them (NH2, OH, etc) change their functional abilities.  
In going from dopamine to noradrenaline (norepinephrine) and from noradrenaline to adrenaline (epinephrine) take a look above to see what’s added and what is re-arranged.  Then look at the arrows and see if you can make sense of the names of the enzymes, or reaction intermediates, that were needed to make those changes occur.  I would explain them here, but I think it would be more beneficial for you to see for yourself how that change occurs now that you have the education to decipher what just a few minutes ago may have looked extremely complex.
Now that the molecule is made, let’s discuss how they work in Part 2! Stay Tuned..
-Tom Latosek

Tom is a practicing paramedic and EMS educator who is interested in EMS research, and advancing the profession of EMS through education.  Tom has practiced in a variety of EMS clinical settings and teaches a variety of courses for a healthcare education company.  Tom holds an MS in neuroscience and a bachelor’s degree in biology and psychology and is currently a first-year medical student.


Cardiac Arrest Management to Pre-ROSC Management - Time to Change the Mindset

Every cardiac arrest you choose to begin resuscitating, has the potential to achieve ROSC.

 A Change in Mindset

Most of us in the EMS profession are used to managing the adult out of hospital cardiac arrest. When I was a paramedic student, the ability to terminate resuscitation in the field was just beginning to make its way into my area and was met with both trepidation as well as an unusual excitement. One of the most startling reasons I heard was “we will only have to work an arrest for 20 minutes and then we can call it.” 

 It is all about the mindset we walk into the scene with. 

 Each cardiac arrest you are dispatched to is someone’s family member.They are relying on you to do the best you can to restore them back to their previous level of functioning (our true goal in resuscitation). We should treat every one of the patients who we make the decision to begin resuscitating in the field as someone who has the potential to achieve ROSC.

I challenge you to remove the term “cardiac arrest” from your mental mindset when responding to and working these resuscitations and replace it with thinking of all of these patients as being pre-ROSC. Each and every one of them should receive care that is focused on optimizing their ability to both achieve return of spontaneous circulation, but also make a meaningful recovery. Do we necessarily need to go out and change the textbooks and guidelines? I would argue that it is unnecessary, what we do need to do as a profession is instill a mindset in ourselves and our colleagues that focuses on a common goal with these patient’s, the achieving ROSC. When you alter your mindset around what phase of this goal you are in, it has the potential to alter your management priorities and decision making.

 Pre-ROSC Optimization

Shifting your mindset from managing a cardiac arrest to managing a pre-ROSC patient allows you to consider all of that factors that will help you optimize the patient for when they achieve ROSC and those crucial few minutes, the “intra-ROSC” phase where the patient may remain extremely unstable due to the many processes that are trying to recover from such dysregulation (more on that later).

First and foremost, good high-quality chest compressions to optimize the patient’s perfusion. Many consider this to be a simple and routine part of resuscitation, but the effectiveness of chest compressions in your pre-ROSC patient will often mean the difference between moving from the intra- ROSC phase and never reaching that point. As the team leader, employ the use of feedback devices in this task if available and make sure you have a system for rotating fatigued compressors. It could be as simple as starting a practice where someone sets a metronome and gives feedback to the person currently doing compressions and monitors them for fatigue or drop in compression quality. Gone are the days of “I can keep going for a few more rounds”, we owe our patients to do better than that. Simple actions like chest compression quality and defibrillation are the two methods we know work for achieving ROSC.

Do you routinely just apply defibrillation/pacing pads to these patients? Often times in a well-managed resuscitation we find ourselves anticipating next steps and looking for tasks that need to be completed. This may be a good time to apply monitoring electrodes as well as precordial electrodes to the patient as well as your other monitoring like NIBP and pulse oximetry. When you reach ROSC, you are now a few keystrokes on your monitor away from that initial 12-lead ECG and valuable blood pressure that will guide the next steps in your resuscitation. If done early in the resuscitation you also won’t be hastily looking to get these tasks done and your management of wires and good electrode placement can make for a better tracing and more organized resuscitation while you are task saturated in the crucial next few minutes.

What drugs do you anticipate needing for the intra-ROSC phase? Are your narcotics locked away in the truck if this patient requires post-arrest sedation and analgesia? Often times when we need to mix a vasopressor infusion we are looking for key components like a pump, calculating dosing, and looking for the right sized bag to mix with (depending on how your organization is within your system). If you are deliberate in your post arrest planning a lot of the preparation for these tasks or even mixing an infusion can be accomplished ahead of time. This allows you to focus on your decisions and management and employ management strategies earlier once ROSC is achieved.

If you approach this patient as “we are going to resuscitate for 20 minutes then re-evaluate if we should continue”, and the patient achieves ROSC 15 minutes into the resuscitation, you are caught in a situation where it may adversely impact the patient’s outcome.

Management of the Intra-ROSC Phase.

So now that you have achieved ROSC and you consider yourself the resuscitation master, you can just kick back, pour yourself a cup of your beverage of choice and watch the rest of the show, right? Your monitor does have a 10-foot therapy cable for a reason.

Those initial first few minutes after achieving ROSC can make the difference between the patient who walks out of the hospital neurologically intact, the patient who spends their remaining days on a ventilator, or the patient who re-arrests. But no worries, you have prepared for this phase throughout the entire resuscitation and your patient is optimized for it. Within 30 seconds, you have a 12-lead ECG tracing in your hand, the initial post-ROSC blood pressure has been obtained, your medications are ready to go, and if your patient needs to be paced you have the electrodes in place to do that. If your patient is intubated and begins to wake up agitated, your sedatives and analgesics are easily within reach and ready to go.

Instead of the “post-arrest phase” that we are used to calling this, I challenge you to change your terminology to the intra-ROSC phase of the resuscitation. This is not a game where you have unlocked an achievement by making it to this phase and it’s smooth sailing from here. This is a phase where your patient is incredibly physiologically vulnerable to any of your actions and they have the potential to return to pre-ROSC or make major improvements in their condition in a matter of seconds with or without your actions.

Remember that these patients are often incredibly metabolically deranged, many of their normal physiological functions are extremely dysregulated, both at the level you can observe (breathing, non- invasive monitoring) but also on the cellular level as well as there are fluid shifts, ion shifts, and other reactions occurring. Your job here is to support the restoration of homeostasis and guide the patient

into the next phase of their recovery, whether it be the preparation and transport to a PCI center or a stay in the ICU that is their next step, you have to support their physiological functions to get them there.

 A Shift in the Research Paradigm

We have a lot of data that takes a look at all comers for cardiac arrest and evaluates the effect of our intra-arrest interventions on the overall outcome of the patient such as their survival to hospital discharge and what their functional status is. One area we do not seem to have great data on is how our care both during the initial resuscitation as well as the specific care we render in the intra-ROSC period impacts patient outcomes. This is going to be far more challenging to study (see The EMS Research Conundrum) but there may be the possibility of some very savvy researchers within our field who may be able and willing to take on the task of looking at some new variables and new sub-groups of patients. Shifting the mindset of the clinicians may also shift the mindset of some of the researchers to focus on how to make our care even better.

Armed with a new mindset and new ideas, I wish you all the best in managing your next pre-ROSC patient!

Tom is a practicing paramedic and EMS educator who is interested in EMS research, and advancing the profession of EMS through education.  Tom has practiced in a variety of EMS clinical settings and teaches a variety of courses for a healthcare education company.  Tom holds an MS in neuroscience and a bachelor’s degree in biology and psychology and is currently a first-year medical student.


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