EKA and Gliflozins

Why do these drugs cause EKA?

#kYJ Euglycaemic KetoAcidosis (EKA)

With the introduction of *Gliflozins as a strategy to target hyperglycaema, and insulin resistance, there has been for the first time real promise that perhaps, we can reverse Type 2 Diabetes.

These drugs (like all) have costs and benefits. They cause increased incidence of UTI as now, sugary urine is a virtual fertiliser for bladder bacteria.
They also cause a rare ketoacidosis where the blood sugar isn’t elevated- euglycaemic KetoAcidosis.
Why??   Read on.

Unlike the older sulphonylureas, Metformin, and even incretin mimics, Januvia and it’s DPP4 inhibitor cousins, the Gliflozins are novel.

These drugs (empagliflozin, dapagliflozin) shut off a protein in your kidneys (SGLT2) responsible for reabsorbing glucose back into the blood.

Block SGLT2, and you pee your glucose out, dropping your blood sugar, and subsequently your insulin secretion.    Less sugar=less  insulin= improved insulin sensitivity.... T2 diabetes fixed (... ok not that simple, but treating Insulin Resistance (IR) is the goal in T2DM.

So ... remember that insulin reduction in blood results from blood glucose reduction.
...
Now insulin.   To fully understand insulin, you need to rearrange what you previously knew about this little hormone.

Insulin is a growth hormone.  It grows fat.
The more insulin a person has, the better they grow fat.

Insulin takes glucose and offers it to cells.  When fat cells are offered glucose, they say “Yes please!!!”, and takes in glucose in to convert it with free fatty acids, to fat.

Now if there is lots of insulin,there is lots of storage.

The FAT house
Think of a house with an open doorway where glucose is streaming in. Insulin keeps that door open, and glucose flushing in.
If insulin is absent or low, then instead of glucose flooding into fat cells, fatty acids flood out.  
Low insulin= free fatty acids  (FFA) released into blood.
...
Are you with me?
...
Insulin = fat cells grow
No insulin = fat cells melt.

Now , when this happens, the FFA, circulated to the liver which converts these FFAs into a group of acids called Ketone Bodies, or just, Ketones.

An accumulation of ketones can only happen when :
Fatty acids are converted to ketones, and this can only happen when insulin is too low.

Summary: low insulin- fat melts-ketones produced.

Now-  back to the side effect of Gliflozins...Euglycaemic KetoAcidosis.
Work it back...
The blood is acidotic because too many ketone acids in the blood.
Ketones are made because fat cells are melting FFA into blood.
Fat is melting because insulin levels fell.
Insulin levels fell because glucose levels fell.
Glucose fell because Kidneys pee all the glucose out (glucosuria)
Glucosuria occurs because
The Gliflozins block glucose reabsorption back to blood.

Less glucose=less insulin= fat melt= ketones and acidosis (Ketoacidodis).

I need a chocolate!

How Vaccination works

How does a vaccine work?

Do you ever remember tasting something or smelling something that takes you back to a childhood memory?

Perhaps it was a tune you heard, and you recognise it from the past.   Well,when you were first exposed to it, your brain chose to store a memory of the taste/smell/sound.

Well it’s not just your brain that remembers stuff.   Your immune system does too.  Special White Blood Cells (leukocytes) called lymphocytes have an incredible capacity to remember chemicals that they’ve been previously exposed to.   Every living and even non living thing is made up of matter that is unique to itself.   

Think of an orange- it looks and tastes and smells like an orange.  An apple looks and tastes and smells like an apple.

To your lymphocytes, they remember how a bacteria,  virus, or parasite/fungus/allergen smell/taste.

On the surface of these organisms, proteins or sugars are present which act as a unique fingerprint called an Antigen.

Once your immune cells have been exposed to an antigen, your lymphocytes remember it for a while.

Lymphocytes that are born and mature in the bone marrow are called B Cells.   They remember the antigens and produce memory jogger chemicals called Immunoglobulins (we commonly call these Antibodies).

Now floating around your blood stream are these Antibodies, and as soon as that virus, or bacteria or threatening allergy producing thing comes into contact with your body again, your immune system can remember it; remember what a threat it was, attack the invader to protect you.

This is happening every minute of every day.  Constant surveillance and defence.  Some diseases are so dangerous (measles, Flu, polio, tetanus (the list goes on)), that it isn’t safe to allow ourselves to be exposed to it.  Your lymphocytes must have first come into contact with the disease before it can make those memory jogging Antibodies.  So vaccination is the strategy.

When vaccination occurs a tiny dead (in the case of bacteria) , attenuated (weakened) or inactive virus sample is introduced into the body, stimulating your lymphocytes to learn to recognise it, and make those memory jogging Antibodies.

Now the immune system has been exposed, so should you come into contact with the wild live/active disease, your immune system can whoop it back to primordia.

Memories fade,and so do some antibodies, which is why some diseases need booster shots to remind the immune system what to be vigilant for.

Some organisms mutate so rapidly that they change their antigen.  Kind of like getting a fake ID.  So for diseases like these (Influenza is a great example) we often need an annual immunisation.

Hope this was in some way helpful.   Get your shots!

~Rob.  #ECT4Health 

We cover this stuff in our Fevers and Sepsis sessions 

Check out the website for more details www.ect4health.com.au/whatswww.ect4health.com.au/whats

Virus- alive or not

Is this alive or not?

Coronavirus

News out this week that Australia has “grown” the nCoV virus in a lab and is now “observing the ‘live’ virus in the laboratory to see how it ‘behaves”.

The biocontainment  security facility at CSIRO in Geelong is set to offer valuable information on the Coronavirus.

I thought I’d touch on a bit of misinformation on the internet about this and other viruses.

Point - Viruses are not alive.

The term live virus is a figure of speech that indicates the virus is able to be active or functional.

It is not a living thing,nor is it dead.   It’s undead.   It is a particle of proteins (amino acids) and sugars.

Think of an egg, or a piece of chocolate; it’s not alive or dead, it just ... is.

Now stay with me,

Take a glass.   The type of glass you drink from.  Not alive or dead (because is was never first living), yet that same glass can hold water.

It functions as a tool to hold liquid.  If you think of a glass as a virus, it isn’t living, so you can’t kill it.

In biology something that is living is called ‘biotic’.   A biotic, possesses the ability to reproduce through cell division (mitosis and meiosis).  Viruses are not cells, they can’t reproduce and therefore, are not biotic (alive).   This is the fundamental reason that antibiotics have no effect on viruses.  They’d have to be biotic, for an anti-biotic to have any effect.

So how do we stop viruses?

Well, come back to the analogy of the glass.    The glass functions to hold a drink; and it does this with no need to be living; but it does need to be intact.

If we broke a glass (say, by dropping it), the glass wasn’t killed, but it broke to pieces, so it ceases to function.   Now the same principle is applied to medications that we can use for viruses.   Antivirals break the protein shell that encapsulates a virus’s genetic information.  Alternatively, some antiviral agents break the genes inside a virus.

Currently we don’t have a magic drug available to destroy (break) the novel CoV virus.  The first step in knowing how to break this virus, is to understand the mechanism this virus uses to infect, and the behaviour of these proteins that it is composed from.

Interesting times ahead.   But for now you’d be more correct to think of a virus as active or inactive, rather than live or dead.

How a virus like nCoV works?

First -Out of China

There are concerning (unconfirmed) reports in news channels and social media leaks that Novel CoV has infected now 90000.  This disease first emerged as a new viral pneumonia in seafood market workers in Wuhan China.
The virus is infectious during incubation, and Chinese authorities are now suggesting that where previously this incubation was thought to be  less than a week, it’s now reporting up to 14 days .

Let’s do a recap on how this virus works.

Transmission- droplet and contact, and faecal.

If someone with nCoV sneezes in a shopping centre, like measles, the virus is aerosolised and breathed in or, the virus settles on a surface (eg escalators hand rail, elevator button, coffee table).   Someone touches it, and then touches their own face or eyes, and has at that point become infected.
That is called transmission.

Now the virus starts to invade cells lining the respiratory tree, lungs, throat and nose. It enters the cell using enzymes to invite itself into the cell.
The cell tries to defend itself, by dissolving the virus outer membrane (the envelope) but this is what the virus wants; now the payload is exposed- the genetic instruction sheet called RNA.
Like a recipe book, the lung cell’s own genetic material (DNA) is altered by the virus RNA which now reprograms these cells to to start to make copies of the nCoV .

When millions of copies are made- the new viruses then burst out of the slave cell, killing it, and showering a spread of millions of virus particles to neighbouring cells.
The process repeats until so many cells have been damaged that the immune system responds.
This lag from Transmission to symptoms is called incubation time.
In Flu it’s 1-3 days, but this nCoV is now believed to be up to 14 days.  All that time, a person is shedding and spreading virus, and has no idea they were even infected or infectious.

Mutation:
The concerning issue at hand is that this virus is thought to have mutated in to a second generation- meaning it can be passed from human to human.  Previously it was thought to be purely zoonotic, transmitted by an animal to human only in its first generation.

As a virus mutates, it undergoes minor changes called Drift, but major changes like second mutations, are referred to as Shift.  This causes the host (is in this case) to not recognise the virus from one mutation to another.   Very difficult to pin down this virus yo produce a vaccine.

#ncov
Official death toll (reported) is currently at 80.
Cases in China, Japan, France, USA, Australia and no doubt third world nations with limited capacity to contain or report.
Written at 8am on 27th Jan 2020.

Differentiating AV Blocks

Tropes and Pressors - Part 2 of a 3 part series.

Tropes and Pressors  -A 3 part series.

Part 2 of 3  # KYJ (Knowing your jargon)

This episode – The Pressors

Recap from yesterday …

Vasopressors are drugs we give to squeeze arteries (and veins) to increase SVR (Afterload and Blood pressure, and subsequently MAP.

Inoptopes :more correctly – positive inotropes, are drugs we give to increase the force of the cardiac contraction. This increases SV, and CO which of course increases MAP.  Its all about that MAP!!.

So when are each indicated?

God I wish it was that simple, but it comes down to etiology (cause) and type of shock occurring in the patient.

If you didn’t already view the post on shock, or watch my Video on shock;  then perhaps that might be a good place to refresh.

Remembering there are 4 main types of shock: hypovolemic, distributive, cardiogenic, and obstructive. Vasopressors and inotropes may be indicated for all types, and though most of the medications can be used in each type, we do need to tackle the specifics of each one.

So….here goes.

The major vasopressors include phenylephrine, norepinephrine, vasopressin and Metaraminol.

Drugs like Adrenaline and Dopamine are vasopressors, but they also exert inotrope properties.

Then  out on a limb (good choice of words really) Dobutamine and Milrinone are obligate inotropes.

So Last bit of FIZZ (physiology before we dive into the drugs)

Receptors to consider for this post :

Adrenergic - Alpha 1 – Cause Vasoconstriction

Adrenergic - Beta 1  - Causes increase Chronotropy and Inotropy

Vasopressin Receptors – V1 = vasoconstriction, V2= reduced urine output.

The Vasopressors

By redistributing blood back to the heart, vasopressors help increase CO directly with an increase in blood return to the heart (Preload), and  and increase in SVR. through arterial vasoconstriction peripherally. There are  main groups are catecholamines, Smooth Muscle and dopaminergic receptors

The Vasopressors are ‘Boss of the Pit’ when distributive shock (Sepsis, Neurogenic disruption or anaphylaxis) is the dominant cause of drop in Cardiac output.  The goal of vasopressors is to increase the SVR by direct constriction of the vessels.

Two distinct physiologies are happening in distributive shock.  

First a loss of nerve messages to blood vessel walls  causes them to relax – dilate, and blood pools in the peripheries.  With the maldistribution of volume between central and peripheral circulation, (blood stuck out in the veins of Arms and legs), there is little perfusing the core vital organs.  Remember at any given moment in time your 5.5 litres of blood is parked 30% in your arteries, and 70% in your veins.  Increases in that venous pooling causes a dramatic drop in arterial flow/volume and of course, pressure (SVR and MAP).

Secondly, as blood in peripheral areas pools, and causes congestion, this vasodilation extends to the capillaries, and these little guys are super leaky.   As they congest, and spill their plasma into the peripheral tissues, you see oedema forming and drop in blood volume, which is now becoming thick and viscous as plasma leaves, the haemoconcentrated blood now has a tenacious sticky vibe going on.  Bad bad bad.   You can see why we fluid resuscitate these people.  In fact, a fluid load, is frequently the First line treatment; and only after some sauce is given to we then squeeze the pie – ok bad visual.

Note to Americans – in Australia we eat real pies with meat inside – sauce “dead horse”  or what you mob call “ketchup” is a must have.

Right Back to it…

Remembering that that Magic MAP of 60 to 65 mm Hg is required to perfuse organs (American College of Critical Care Medicine (ACCM) guidelines). If fluid resuscitation doesn’t get that MAP up to 60 mm Hg, it is recommended that vasopressors be next in line.

So what do we select? 

Norad (Noradrenaline) / Norepinephrine

The first of our Catecholamines, and a favourite in the Sepsis world (Surviving Sepsis Campaign recommendation).

We follow this with Adrenaline (epinephrine) or Vasopressin  as a back up plan

Norepinephrine is recommended as the initial pressor for  because it lights up those Alpha  receptors.  In blood vessels, these receptors act like switches that open Calcium gateways into the smooth muscle cells lining the vessel walls.   As they get turned on, Calcium rushes in, causing the muscles to contract (constrict) pushing up the pressure, and squeezing the blood out of those naughty veins, back to the heart and central core circulation.   By increasing the venous return, then you increase the Preload, and the heart now has volume it can use to pump with.  They also act on the arteries (remember that constriction here increases SVR and MAP)  … And that is the game changer.

Metaraminol

Metaraminol is trade named Aramine, and Metaramin.  It is a potent alpha 1 stimulant, with weak Beta effects.  It tends to be used in spinal cord injuries that result in distributive neurogenic shock, and to bring up BP in a perianaesthetic scenario.  RFDS in Australia use it as a first line "rescue drug" for increasing BP that can occasionally plummet when performing rapid sequence induction (emergency intubation).   Dose is usually up to 10mg diluted to 20 ml and given in a good secure IV line as a slow push over 1-2 mins

Vasopressin

Vasopressin is a natural hormone also known as ADH (Antidiuretic Hormone) normally secreted from the Pituitary gland.

It fires up specific Vasopressin 1 and 2 receptors.  Remember V-1 receptors to stimulate smooth muscle contraction of the vessels , and the V-2 receptors in the kidneys stop urine production hence increased blood volume, and increased CO and MAP.

It wont cause the patient to increase heart rate, or increase force of contraction.

Phenylephrine

This is another pressor that occasionally gets bandied around, but caution in use is advised because it tends to cause a reflex bradycardia.

Ironically, as much as it fires off those alpha receptors to cause vasoconstriction, The sudden increase in BP can trigger off the vagus nerve (Parasympathetic) which is actually the nerve that tells the heart to “Go Slow – this is a school zone”.  So BP goed up, parasympathetic response kicks in and a reflex bradycardia loses the ground you gain.  Some docs love it- Im not convinced.  Many of you will know of Phenylephrine as the why bother replacement for pseudoephedrine in the old cold and flu tablets.

Phenylephrine is a pure alpha-1 agonist, inducing peripheral arterial vasoconstriction. Reflex bradycardia may occur due to selective vasoconstriction and elevation of blood pressure.

Adrenaline

Also known as Epinephrine, this hormone has essentially equivocal activity on alpha-1 and beta -1 receptors. So Epinephrine increases SVR through the Alpha 1, and the Beta effects on increasing Inotropy and  HR, boost cardiac output on both sides of the equation (CO=SVxHR).

Dopamine is a precursor of norepinephrine and epinephrine (catecholamines).  So it essentially does the same thing.  All good pies need a reliable base, so as a precursor to the catecholamines, the effects are both vasopressor and inotropic.

Controversy exists around whether differing doses of Dopamine affect different tissues. Many readers will recall that low doses increase renal perfusion(5 to 15 micrograms/kg/min), and higher doses (>15 micrograms/kg per minute), are more peripherally vasopressor.

Giving Pressors

IV.   Say it out loud.  IV.   These drugs are for intravenous (IV) use only.   They are fast acting, short duration, and epically destructive if an IV cannula through which these drugs are given, should extravasate (tissue).

It’s a brave clinician that will settle for a peripheral IV line, so as soon as possible these patients should have a central access (either CVL or PICC).  Doses are dependent on presentation but always via a pump, and the patient should be very closely monitored – especially heart rate and BP, but also Sats, JVP and breath sounds.  As BP can rise dramatically with pressors, complications like heart failure can declare itself with a surprise ankle swelling, pulmonary oedema, and breathlessness.

Next part of our series will tackle the other class of drugs, looking deeper at the Beta 1 receptor meds  - the inotropes.

Now the physiology and Jargon is out the way, stay tuned for Part 2 as we dive into the deep dark world of the "Tropes and Pressors"

 Who is Rob Timmings and ECT4Health?   Follow on Facebook

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Tropes and Pressors - Part 1 of a 3 part series

Tropes and Pressors 

Part 1 of 3  # KYJ (Knowing your jargon)

To kick off this KYJ  we first need to unpack a bit of terminology.  So this is Part 1 of 3

Shock  is a state of  oxygen deficit (hypoxia) to tissues; all tissues – and of particular concern, vital organs (heart , brain, lungs, kidneys). Shock is global cellular hypoxia.  Whilst shock can be caused by a lack of oxygen in the blood itself, most shock is actually a drop in perfusing pressure of what blood is available.  SHOCK VIDEO

MAP is Mean arterial pressure.  It is, in its most basic of descriptors the average blood pressure (mean) that perfuses vital organs.  A low MAP will therefore be consistent with shock, irrespective of how oxygenated the blood is.  Magic MAP number to aim for is 60 mmHg.  Below 60, and we struggle to perfuse our Kidneys.

MAP is determined by two things.

Cardiac output, and Systemic vascular resistance.

Cardiac output is the volume of blood you pump out in any given minute (normally 4200-7000ml).  It is made up of how much you heart pumps in one beat (Stroke volume (SV)) x the number of times/in that you beat (Heart Rate (HR)).  

The maths looks like this:  CO = SV x HR.

MAP VIDEO

Stroke Volume

Your ventricles are a muscular bag of blood.  When they contract (systole), blood is ejected in a volume called a stroke volume (SV).  We don’t eject all of our blood with every contraction, infact your heart fills with about 100ml, and pumps out 70ml. 

This stroke volume represents 70% of the ventricle’s filling volume.  That percentage (70%) is called an ejection fraction (EF). 

Stroke volume (SV) is determined by a few factors. 

·         Strength of your heart beat,  (Inotropy)

·         how much blood was in your heart, (Preload)

·         the pressure inside the artery that your heart is pumping into (Systemic Vascular Resistance – also called Afterload) and,

·         the stiffness of the ventricle. (Compliance)

CARDIAC OUTPUT & STROKE VOLUME VIDEO

Inotropy

This is a concept that refers to the strength of a heart’s contraction. 

So what if I could give you a drug that increased the force of your contraction?   Then you’d fill with 100ml, but pump out a greater SV by increasing your EF.  That drug is therefore referred to as a positive Inotrope.

Positive Inotropes are hormones or drugs that increase the strength (force) of the heart contraction (Inotropy).   Typical Inotropes include Dopamine, digoxin, adrenaline, dobutamine and others; we will discuss in detail in Part 2.

Loss of inotropy occurs after infaction, ischaemia, or with an aging stiff heart.   Collectively this is called Heart Failure.

Preload

Fundamentally, preload is about the filling and the stretching of your ventricles.  Passively the Left ventricle fills up to about 70 ml, then the atria contracts squeezing (pushing ) in another 25-30 ml.  Like, you’re your suit case is full, but some muppet says, “hey Dad, can you fit my jacket in”?   so you are there squeezing a jacket into an already full case.     The case isn’t full its now Preloaded.   It is stretched and bulging.   Preload in the heart is determined by a couple of factors.  The force of an atrial contraction (lost in AF or flutter), and the volume of blood returning to the left heart from the lungs.  So, atrial arrythmias, and hypovolaemia can dramatically lead to a reduced SV, CO, MAP and subsequently shock.

Systemic Vascular Resistance (Afterload)

As a pipe carrying fluid is compressed (narrowed), the pressure inside the pipe increases. Thus, squeezing blood through a narrower artery leads to increased in pressure.  This is called systemic vascular resistance (SVR). Increasing the SVR leads to increased blood pressure, mean arterial pressure (MAP) and increased perfusion to organs.  

Vasopressors are natural hormones, or drugs that cause an increase vasoconstriction.  Commonly these are just referred to as “pressors”.  Common drugs that fall into these categories include Noradrenaline(norepinephrine), Metaraminol, phenylephrine, vasopressin, and good old adrenaline

Now the physiology and Jargon is out the way, stay tuned for Part 2 as we dive into the deep dark world of the "Tropes and Pressors"

 Who is Rob Timmings and ECT4Health?   Follow on Facebook

Robs     Courses  -  Cruises  -   Videos   and Seminar Dates