Insulin Resistance: Its Role in Infertility, DKA and Obesity

When there is insulin resistance the body begins an internal battle between acute survival and longevity. It is a long, subtle conflict that abruptly manifests itself as chronic conditions far beyond just hyperglycemia.

Let me walk you through how we develop insulin resistance and 3 ways it has overwhelmed society via its predominant role is obesity, infertility and diabetic ketoacidosis (DKA).

Insulin and GLUT 4 Transporters

When we eat, the digestive system breaks down complex food into simple molecules like amino acids, glucose and fats. These are then released into the blood stream to support biological processes.

For glucose to be useful to the body it requires the hormone insulin. Insulin binds to insulin receptors on cells. This interaction changes the conformation of the cell in a way that allows them to express the glucose transporter GLUT 4 on the cell surface.

The GLUT 4 transporter provides a entry point for glucose into the cell. It enables cells to take up glucose from the bloodstream.

Illustration showing how the relationship between blood glucose, insulin from the pancreas, expression of glucose transporters and uptake of insulin into cell.

GLUT 4 expression is increased in the presence of insulin and also during muscle contraction (i.e. exercise).

GLUT 4 is expressed largely on muscle, liver and fat cells.

  • In the liver glucose is stored as glycogen
  • In adipose cells glucose is stored as fat
  • In muscle glucose is largely used immediately for energy

The video below explains how insulin facilitates transport of glucose into cells by stimulating GLUT 4 expression.

The Pancreas and Insulin

Insulin is released by beta cells on the pancreas in response to glucose in circulation. There should always be glucose in the circulation, our bodies need a constant supply to survive. The normal range of blood glucose when there is no active consumption (fasting blood glucose) is 70-99mg/dL.

A constant basal release of insulin from the pancreas maintains this narrow range of blood glucose. When we eat, the pancreas responds with “bolus” doses of insulin to maintain post prandial glucose ranges of less than 140mg/dL. The body is in a constant state of receiving and removing glucose from circulation.

Insulin Resistance

When insulin receptors are exposed to high levels of insulin over prolonged periods of time they lose sensitivity (desensitization). There is a decreased physiological response of these receptors to the presence of insulin. The pancreas is able to compensate to some degree by increasing the output of insulin but overtime the pancreas too will not be able to keep up.

A diminished response to insulin means a diminished expression of GLUT 4 transporters.

Illustration showing the corresponding response between glucose levels, insulin, insulin receptors and GLUT 4 receptor expression.

When this happens glucose enters the bloodstream and has no where to go. It just sits there. It is available but the body is no longer able to transfer it out of the bloodstream and into body tissue for use.

While it sits in the circulation it increases the osmolality of plasma, causes electrolyte disturbances, oxidative stress and a host of other disruptions of normal physiological processes.

Left untreated we advance from the development of hyperglycemia to diabetes which creates the potential for many other acute and chronic conditions.

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Glucagon and Alternative Energy

Whether there is a true deficit or a perceived deficit in exogenous glucose the body will kickstart survival pathways starting with the secretion of glucagon to ensure that a source of energy is available.

Glucagon is secreted from the alpha cells in the pancreas in response to low blood glucose. Alpha cells also lose sensitivity to detect glucose when they are exposed to high levels over a prolonged period.

Illustration showing how glucagon responds in insulin resistance

As a result, alpha cells become poorly calibrated for detection of blood glucose levels. Even though the concentration of glucose in circulation is high, they detect low levels and secrete glucagon. This initiates a series of pathways that increases endogenous production of glucose via glycogenesis and gluconeogenesis.

This further worsens the already high levels of glucose the blood stream.

Survival Pathways

The release of glucagon, in an otherwise healthy human, is intended to be a temporary fix to the lack of exogenous glucose until the next meal. It really is a survival situation for the body.

Glucagon release is accompanied by the release of “fight or flight” hormones like epinephrine, cortisol and growth hormone. Together these hormones are preparing the body for what it perceives to be a threat. In this case the threat is a lack of adequate energy.

With insulin resistance, sustained high blood glucose levels also means a sustained “fight or flight” response. Internally the body is in a constant state of stress.

This is why insulin resistance is associated with such a wide variety of syndromes including diabetic ketoacidosis, obesity and polycystic ovarian syndrome.

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1. Diabetic Ketoacidosis and Insulin Resistance

DKA is an acute life threatening condition that can occur in patients with type 1 and type 2 diabetes. DKA occurs when the body does not have enough insulin to take up glucose as a source of energy.

There is usually some trigger, like infection or illness, that offsets the body’s ability to maintain homeostatic glucose levels.

Glucose is available in the bloodstream but it cannot be utilized because the body does not have enough insulin to overcome the resistance the cells have developed.

Gluconeogenesis and glycogenolysis are metabolic processes in the liver and muscles that provide a quick source of glucose in the perceived absence of exogenous sources. The body in now acutely saving itself by providing the immediate energy it needs but simultaneously exacerbating overall hyperglycemia. It is a viscous cycle.

Ketones in DKA

When the body runs out of glucose from gluconeogenesis and glycogenolysis it resorts to the use of ketones as the primary source of energy. Ketones are derived from the body’s breakdown of stored fat.

Again, while trying to save itself the body causes a rapid accumulation of ketones which leads to acidosis, hyperosmolality , dehydration , electrolyte imbalances and cognitive impairment which is the presentation of DKA.

In DKA we must provide exogenous sources of insulin at high doses to overcome insulin resistance.

2. Obesity and Insulin Resistance

If insulin resistance inhibits the uptake of glucose into cells (including fat cells) how could it possibly lead to obesity? Let me explain.

As insulin resistance persists and there is less glucose being taken up from the blood the body interprets this as a survival issue. The body thinks:

“Hey, its been a while since we’ve been able to get glucose from consumption! This could go on for a while. We better increase our storage!”

Illustration explaining how insulin resistance leads to accumulation of fat and potential obesity.

As the body uses the alternative routes of glycogenesis and gluconeogenesis to meet immediate glucose needs it will also produce some glucose for the purpose of long term storage.

Increasing fat increases the “storage space” for glucose. Fat is a building block for glucose via gluconeogenesis and also a direct source of energy in ketogenesis.

This increase in fat is seen predominantly around the abdomen (abdominal fat).

Over time this can progress from weight gain to obesity.

In obesity we can increase the expression of GLUT4 receptors via muscle contraction (exercise). The increase in uptake of glucose from the blood will signal that exogenous glucose is available and there is no need to further increase stores.

3. Infertility and Insulin Resistance

As we’ve established sustaining high levels in glucose in the blood and associated insulin resistance is a stressful condition for the body. In addition to increases in insulin, there is also an increase in the release of glucagon and stress hormones like epinephrine that sends the body into a “fight or flight” response.

Reproduction is not necessary for survival.

While externally we may seem at peace, internally the body is in a battle for viability.

During battle there is no concern for reproduction.

Insulin resistance affects several reproductive pathways beginning with decreased libido and certainly inhibition of conception.

Illustration showing how insulin resistance affects fertility and contributes to the development of polycystic ovarian syndrome

In PCOS women express high levels of the hormone androgen. Androgen is the male sex hormones that is present in relatively low concentrations in otherwise healthy females.

Research has shown that androgen secretion increases in times of stress. Again when there is sustained insulin resistance the body sees this as a threat and activates stress responses. Androgen levels increase causing disruption in menstruations and ovulation with an overall decrease in fertility.

Insulin resistance is a significant public health concern. Our bodies are not designed to remain in prolonged periods of “fight or flight”. What we know for sure is that we can increase our GLUT4 transporter to facilitate uptake exogenous glucose via muscle contraction so let’s get moving!

The American Diabetes Association (ADA) and Centers for Disease Control (CDC) have a host of helpful resources whether you are a healthcare professional, diabetic or a caregiver of someone with insulin resistance.

If you’ve found this unit helpful I would love to hear from you! Leave a comment or question below.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

Blood Glucose: 4 Ways The Body Generates Energy

Where there is no energy, there is death. A fundamental requirement for maintaining our physical existence is the ability to generate energy for the body. Let’s talk about all the sources our body uses to create energy.

Let me walk you through 4 metabolic processes that the body uses to create energy. Energy is so crucial to survival that the body has redundant systems in the event of failure of any one system.

When we understand how the body generates energy we can manipulate this information to inform diet, lifestyle and medication choices, if necessary, to optimize blood glucose levels.

4 Energy Generating Processes

Diagram illustrating the four ways the body generates energy: consumption, glycogenolysis, gluconeogenesis, and ketogenesis.

Glucose as Energy

The body’s primary source of energy is glucose. To support biological processes there should be glucose in the bloodstream at all times.

When we eat (consumption) the digestive tract breaks down complex food into simple molecules. Glucose is derived from the metabolism of carbohydrates in the diet. Once absorbed into the bloodstream the body is in a constant process of maintaining a strict concentration of blood glucose.

After we eat (post prandial) the normal concentration of blood glucose, in an otherwise healthy adult, should be less than 140mg/dL.

When there is no consumption (fasting) the normal blood glucose is maintained at 70-99mg/dL.

This delicate balance of receiving and eliminating glucose is maintained by insulin and glucagon.

Illustration showing how insulin and glucose work together to maintain the body's energy sources

Insulin: How the Body Recognizes Glucose

Glucose is useless to the body without insulin. Your blood could literally be saturated with glucose yet your cells could be starved if there is not enough insulin present (as we see in diabetes).

Glucose is the body’s energy source but insulin allows access to create energy.

Illustration showing how the body uses insulin to process glucose. Insulin enables the expression of GLUT4 transporters in muscle, fat cells and liver. This allows glucose to be taken up by those cells out of systemic circulation,

Insulin is a hormone that is secreted by the beta cells of the pancreas in response to the presence of glucose in the blood.

Since there needs to be a constant presence of glucose in the bloodstream there is also a constant, basal release of insulin from the pancreas.

When we eat, blood glucose levels increase. The pancreas will also increase its release of insulin to maintain those ideal blood glucose concentrations.

Insulin binds to insulin receptors on cells changing their conformation in a way that allows them to express the glucose transporter GLUT 4 on the cell surface. This makes it possible for cells to take up glucose from the bloodstream. The glucose transporter GLUT4 is found primarily in muscle, adipose and liver cells. Without insulin, glucose will not enter these cells.

This is why insulin resistance is also harmful to the body.

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3 Pathways of Glucose

When glucose is available the body will meet its immediate energy needs and store any extra glucose for later use as either glycogen or fat.

  1. Immediate use in muscle
  2. Stored in liver as glycogen
  3. Stored in adipose cells as fat

Glucagon: The Low Glucose Alarm

There can be an actual lack of glucose being supplied to the body in cases of starvation or a perceived lack of glucose when there is glucose in the bloodstream but the body is unable to utilize it (insulin absence or resistance).

Regardless of the cause, the body will activate one of its many redundant systems for creating energy starting with an increase in the release of glucagon (also from the pancreas) when blood glucose is too low.

This article provides an in depth look into the relationship between insulin and glucagon in regulating the body’s energy sources.

Illustration showing how the pancreas response with insulin or glucagon in response to changes in blood glucose

Like glucose there is a basal release of glucagon even when blood glucose is normal. Normal blood glucagon level is a very low: “pico” concentration (25-50pg/ml).

Increased glucagon concentration initiates a series of energy generating processes, the first being glycogenesis.

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Glycogenesis

Any “extra” glucose not needed for immediate use by the body is first stored as glycogen in the liver.

The body is limited in the amount of glycogen it can store. The average person can store about 500grams of glycogen which translates to ~2000 calories. The average caloric need per day ranges from 1600-3000 kcal.

Illustration showing the process of glycogenolysis where the liver converts glucose that was stored as glycogen back to glucose. Glycogenolysis as a source of energy.

Glucagon will signal the liver to convert stored glycogen into glucose to generate energy in the body. This is glycogenolysis. Glycogenolysis will maintain blood glucose concentrations in the absence of consumption.

Once we have depleted glycogen stores the body’s secondary response will be gluconeogenesis as a source of energy.

Gluconeogenesis

Gluconeogenesis is the formation of new glucose molecules from non- carbohydrate sources including fatty acids, certain insulin sensitive amino acids, glycerol and lactate.

Image showing the process of gluconeogenesis. The liver makes new molecules of glucose from non carbohydrate sources like fats and amino acids.

It occurs primarily in the liver and too a lesser extent in the kidneys.

If gluconeogenesis is prolonged the body will start to breakdown fat tissue (lipolysis) to access more fatty acids so that the body can continue to use it in gluconeogenesis as an energy source. Gluconeogenesis is the basis of a calorie deficit diet for weight loss which allows the body to create energy from fat instead of getting it from food consumption.

Ketogenesis

If there continues to be an absence of exogenous glucose the body will transition from using fatty acids as a substrate for glucose production to using fatty acids as a direct source of energy.

In ketosis, fatty acids are broken down by the liver into ketones that are released into the bloodstream and used instead of glucose to generate energy in the body.

Illustration showing the process of ketogenesis where the body uses fast as a direct source of energy in the form of ketones.

Survival Pathways

Insulin ensures that blood glucose is not too high, glucagon ensures that blood glucose is not too low. This is why glucagon is referred to as counterregulatory to insulin.

These alternative sources of energy for the body (glycogenesis, gluconeogenesis and ketogenesis) are intended to be temporary buffers for maintaining blood glucose levels. These metabolic processes keep us alive until we can get to back to the obtaining glucose from exogenous sources. They are survival pathways.

When glucose levels are low our bodies go into “fight or flight” mode. In addition to glucagon other counterregulatory hormones like cortisol, vasopressin and adrenaline as also released. These are stress hormones.

Our bodies are not designed to function in these pathways for prolonged periods of time. In healthy adults short periods of ketosis has been used as a strategy for weight loss. In patients with diabetes, prolonged ketosis as an energy source leads to acute and life threatening ketoacidosis.

If you’ve found this unit helpful, I would love to hear from you. Leave a question or comment below.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

3 Habits to Maximize Productivity as a Medical Professional

The healthcare field is challenging because of the variability from day to day but that is also what makes it so enjoyable. If you haven’t intentionally examined your workflow to optimize your performance you probably struggle to meet or even better, stay ahead of expectations. Let me walk you through 3 habits that will set you up to increase productivity.

1. Orient Your Day, Don’t Let the Day Orient You

As you head into work you should know the framework of your entire day. A clear framework can increase productivity significantly, as it avoids expending unnecessary energy.

Your framework consists of those tasks that must get done every day. These are broad categories like vancomycin consults, warfarin consults, patient work up for team rounds, hospitalist patient workups, renal dosing review, daily huddles, lunch etc.

How to increase productivity by building a framework for your day

When you build your framework you are not only considering what should be done but in what order. This helps to increase productivity.

Which sequence of these core events will minimize redundancies?

Where will each of these tasks be completed?

If you don’t have clear answers to these questions, you are expending energy every single day working through these unnecessary decisions. It is a loss of time and energy.

What to Include in Your Framework

Your framework should account for social engagement. How much time can you spend talking with coworkers without compromising your productivity. This is not to discourage you from interacting at work, this is a necessary part of the profession so build it into your framework.

In your head your framework should be so clear that you know that 15 minutes in the morning, 15 minutes in the afternoon and 10 minutes in the late afternoon, however you slice up those time slots is about all you can spare for socialization to execute your tasks and make it out on time.

You should write out your framework. You will have to refer to it when you first implement it. This is a one-time build. It may require adjustments here and there as your roles or expectations change but this framework is essentially set in stone. After a while, it becomes second nature. I guarantee that sticking to an overarching framework will improve your proficiency and increase your productivity.

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2. Make a Dynamic List

Your dynamic list organizes those tasks that create the fickle nature of healthcare. You don’t have to be a slave to the variability of the days.

Unlike your framework, you quickly generate your dynamic list every day and update throughout the day to increase productivity.

These tasks on the dynamic list vary from day to day.

Because they are not part of your routine they can be easily forgotten.

Review your dynamic list to quickly reorient yourself to what needs to be executed between the framework of your day.

How to increase productivity even when your day is variable.

While there is a specific spot in the framework to review vancomycin consults, the vancomycin level pending for 13:00 will be on your dynamic list. There is a big difference between anticipating and responding to a level versus a nursing hunting around trying to find you for a decision on whether to give the next dose. With the dynamic list, YOU initiate the call. You remain a step ahead. This builds trust among your peers.

The antibiotic stewardship meeting that occurs once every 3 months would be on your dynamic list for that day. The baby shower in the breakroom will be on your dynamic list.

The few minutes required to create your dynamic list is well worth the increase in productivity and mental relief you will experience.

3. Do the Hardest Thing First

Whenever possible, place the hardest things on the top of your list. Rip the Band-Aid off, get it out of the way.

Would you walk around all day with a large rock in your hand? You would set it down as soon as possible. Your hardest tasks of the day are a mental rock. It makes everything else you have to do, however simple, more difficult and less enjoyable.

Particularly in healthcare, you never know what lies ahead. There could be many additions to your dynamic list throughout the day. Give yourself the bandwidth to successfully tackle challenges throughout the day by handling the hardest tasks first whenever possible.

It sets great momentum for dominating the day by achieving something difficult early.

I hope that you can visualize the high level of execution and efficiency these strategies enable. No more bouncing around from one event to another all the while worried about all the things you haven’t done but need to get done. All these uncertainties in your day are mentally exhausting and produce poor results. Aim to increase productivity by incorporating these strategies.

All experts agree that intentional time management skills are one of the prominent keys of success. These 3 strategies tell you how to accomplish that.

For more strategies to increase your productivity check out the posts on getting the most out of your study session and how to increase your recommendation acceptance rate. As well as these life-changing books: Atomic Habits and Smarter, Faster, Better.

If you’ve found this unit helpful, I would love to hear from you. Tell us what strategies you use to optimize your work day and increase productivity.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

How to Dose Vancomycin: When Protocols Fail

Standard vancomycin dosing will not work for every patient. Let me walk you through 3 often overlooked patient characteristics that suggests the need for closer scrutiny and off-protocol dosing.

This isn’t a post about how to perform detailed vancomycin calculations. It’s about learning how anticipate and be responsive to the body mechanics of patients to prevent both surpratherpaeutic and subtherapeutic dosing of vancomycin and maximize patient outcomes.

The Knowledge Gap

Despite the availability of algorithms, protocols and calculators, vancomycin dosing still remains a challenge for many. A knowledge gap exist when there is a dissociation between the components of a calculation and the patient variables they connect to.

Let’s close the gap. These are 3 red flags that should make you pause and reconsider the use of standard vancomycin dosing protocols.

Illustration summarizing 3 scenarios where standard vancomycin dosing protocols will often lead to improper dosing: quadriplegia, paraplegia, ascites and assumptions about about "normal: renal function.
  1. paraplegia/quadriplegia
  2. “normal” renal function
  3. ascites

I have seen dosing errors occur in each of these situations multiple times in my career. Let me help you to never make these mistakes.

Benefits of Vancomycin Dosing Protocols

Vancomycin protocols are developed with good intentions. They are helpful.

In general protocols allow for standardization of care which is useful when different providers see the patient from day to day. There is an inherent understanding of what as done and why when a protocol is followed.

Vancomycin dosing protocols are usually well vetted and based on evidenced based guidelines which can translate to better patient outcomes.

Protocols are a great starting point and every institution should have one for vancomycin dosing.

It lays out an approach for vancomycin dosing that will likely be successful for the majority of patients.

Illustration summarizing the benefits of vancomycin dosing protocols including: standardization. broad applicability, good starting point for dosing, evidence based and convenient

However, no protocol replaces clinical judgement. No protocol can account of every clinical scenario. Which is why we must also know when to stray away from vancomycin dosing protocols.

The Problem with Vancomycin Protocols

All protocols make assumptions. They have to do this if they are to be applied broadly. They often make linear correlations between patient characteristics and how vancomycin will be processed by the body.

Most vancomycin protocols rely heavily on 2 patients factors: their weight and renal function. Weight is used to estimate the dose and renal function to determine the frequency of dosing.

Within the boundaries of weight and renal function set by the protocol there are many patient variables that influence how the body will process vancomycin.

Illustration showing the limitations of vancomycin dosing protocols. There are patient variables within the variables that are used by those. It would be very hard to any protocol to account for all of the scenarios that can occur within the boundaries of the protocol.

Variables of Weight

A patient’s weight is a function of muscle, fat and fluid. Variations the relative amounts of these will affect how vancomycin will be processed. 2 patients weighing 72kg may have very different body compositions and therefore process vancomycin differently.

Variables of Renal Function

Renal function is estimated by creatinine clearance (CrCl). CrCl is calculated using Scr, weight and age. 2 patients with a CrCl of 45ml/min can vary significantly in each of these variables but have an overall similar calculated value. They will process vancomycin differently because of these variabilities.

It would be very difficult for any protocol for account for all these patient variables. The first step is being aware of the limitations of vancomycin dosing protocols. Then we need to actively seek out what would make our patients ineligible for protocol dosing. We should be looking to rule out protocol use. This starts with a thorough chart review.

1. Quadriplegia & Paraplegia

I’ve seen this error multiple times in my career.

Always read the patient’s history prior to dosing vancomycin. If quadriplegia, paraplegia or really any spinal cord injury is documented, veer off the protocol. Here’s why.

Paraplegia refers to paralysis of the legs, quadriplegia is paralysis of both arms and legs.

Patients with spinal cord injury, acute or chronic, have a substantially higher risk of renal failure compared to the general population.

Graphic showing the difference between paraplegia and quadriplegia. Paraplegia refers to paralysis of the legs, quadriplegia is paralysis of both arms and legs.

Renal deterioration can occur at any time after injury. Routine assessment of renal function is required.

Estimating Renal Function in Paralyzed Patients

The issue is further complicated by the use of creatinine clearance as an estimate of renal function in this population. Most vancomycin dosing protocos rely on this calculation to determine the frequency of dosing.

Illustration showing how serum creatinine is produced. The liver creates creatine from protein in our diet, Creatine is then stored in muscle where it is used to create energy is the form of ATP. Once energy is expended creatine is released, it degrades into creatinine which is released by the muscle and cleared by the kidneys.

Creatinine is a waste product of creatine degradation.

Our bodies derive creatine from protein metabolism and uses it to store energy in muscle as creatine-phosphate.

Once creatinine-P has donated it phosphate stores to make energy in the muscle, it once again becomes creatine. Creatine will naturally degrade overtime to become creatinine which is released from muscle then cleared from the body by the kidneys.

In a non paralyzed patients serum creatinine works are a measure of renal function because the muscles are constantly releasing it and the kidneys then clear it.

In paralyzed patients serum creatinine is low not because the kidneys are clearing well but because it is not being produced. A calculation cannot discern this difference, we must be able to recognize the risk and adjust our calculations and dosing.

Graphic illustration showing how creatinine clearance is overestimated in patients with paralysis. Diminishing muscle mass means decreased release of serum creatinine which increases the calculated value. It is not a true reflection of the kidneys ability to clear creatinine.

These patients have very restricted mobility so they lose muscle mass quickly. Diminishing muscle mass results in low levels of serum creatinine, consequent overestimation of renal function by creatinine clearance calculations and masking of any renal dysfunction.

Impaired renal function leads to reduced drug clearance and vancomycin accumulation. I have seen this happen multiple times in my career when creatinine clearance is taken at face value in paralyzed patients.

Vancomycin Dosing Interval in Paralyzed Patients

When dosing vancomycin in quadriplegic and paraplegics, extend the dosing interval beyond what the calculated creatine clearance suggests. They will require an extended window for drug clearance. Most times, it appears they can tolerate Q8H dosing. I assure you, they cannot.

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2. “Normal” Renal Function

Never dose on a single value, always dose on a trend.

The trend we are most concerned about is serum creatinine. This is the lab value that will be used in the estimation of renal function. Most practitioners understand the importance of stable renal function but can underestimate what stability really means.

What is normal serum creatinine?

Normal serum creatinine in the general population ranges anywhere from 0.6-1.2mg/dL. Normal serum creatinine for YOUR patient is dependent on their baseline. Though a value between 0.6-1.2 mg/dL is considered normal, a value of 1mg/dL can signal renal impairment for your patient. Here’s how.

Acute kidney injury is defined as an increase in serum creatinine greater than 0.3mg/dL within 48 hours. This means that a patient whose serum creatinine is normally 0.7mg/dL would have renal impairment if they presented with a serum creatinine of 1.1mg/dl even though they would still fall within the “normal” range.

Sample Patient

Illustration showing how small changes in Scr reflect big changes in the calculated clearance by the kidneys. Both values of Scr are "normal" values. This highlights the importance of considering the trend in serum creatinine for individual patients rather than focusing on 1 value because it is "normal" on presentation.

There is a significant difference in the rate of filtration even though both are “normal” values. If we simply assume that if serum creatinine at presentation is “normal” because it falls within the normal range we would miss the opportunity to proactively guard against drug accumulation.

Most patients who are being treated for less than 5 days with vancomycin may not require a level but a patient like this may require assessment of levels and more frequent monitoring of renal function.

Vancomycin Dosing with “Normal” Renal Function

Whenever possible, always compare the serum creatinine at the time of dosing with prior labs even when values fall within the “normal” range.

3. Ascites

A patient’s weight should be assessed from a perspective of body composition: fat versus muscle versus fluid weight.

Again, always read the patient’s full history and chief complaint before dosing vancomycin.

Illustration showing ascites as the accumulation of fluid in the abdominal cavity.

If ascites is mentioned, raise the red flag.

Ascites occurs when fluid accumulates in the abdomen usually secondary to cirrhosis, cancers, alcoholism, viral infections among other things.

Vancomycin is hydrophilic (water loving) but it has a large volume of distribution (~0.7L/kg). This means that it distributes widely throughout different tissues in the body which is why we can effectively use it to treat skin infections, brain infections, bone infections, bloodstream infections and ascitic infections.

A patient who is volume overloaded due to ascites can have a significant amount of their reported weight influenced by fluid accumulation in the abdomen.

When a patient presents with large volume ascites, part of the treatment plan is to alleviate this fluid congestion. High volume paracentesis may be performed removing usually more than 5L via a catheter.

High Volume Paracentesis

A patient with severe ascites requiring large volume paracentesis can have anywhere from a 10-44 lb (4.5-20kg) difference in weight after fluid has been removed from the abdomen.

Vancomycin is dosed at 10-15mg/kg. That is a potential 45mg-300mg difference in the dose used. This accumulation can be significant with repeated dosing.

Infographic showing how ascites affects the body in ways that require changes in vancomycin dosing. This includes significant changes in body weight and Vd after large volume paracentesis and low levels of creatinine resulting in an overestimation of renal function.

Vancomycin dosing in patients with cirrhosis is further complicated by the reduced production of creatinine.

This can result in an overestimation of renal function via creatinine clearance equations as we discussed above.

Because vancomycin is able to penetrate ascitic fluid when that large volume has been removed it may reduce the volume of distribution of vancomycin further increasing the risk of accumulation.

If a patient continues to receive the dose calculated with their pre-paracentesis weight there are a multiple factors that places them at risk for supratherapeutic dosing.

Vancomycin Dosing with Ascites

If severe ascites is mentioned in a patient’s chart it should raise an alert. Investigate the degree of ascitic accumulation and monitor for any recommendations for paracentesis.

Vancomycin dosing protocols are a valuable resource that can be accurately applied to a vast majority of patients. Because of this the best approach is to use them with skepticism. We are trying rule out our patient’s eligibility for protocol dosing via a thorough chart review.

As you read any mention of paraplegia, quadriplegia, ascites, paracentesis should trigger an internal alert. Strict protocol dosing is probably not the best approach for these patients. Assessing renal function relative to the individual patient’s baseline rather than population parameters of “normal” is also best practice.

If you’ve found this unit helpful I would love to hear from you. Leave a question or comment below.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

How to Use 5 Blood Products from Whole Blood

Every 2 seconds a blood transfusion is needed in the United States. Let me walk you through what you need to know about how we derive and how we use blood products.

We give transfusions as a way to supplement blood loss, maintain hemostasis and oxygenation in a wide range of scenarios: major blood loss due to trauma, anticoagulation, childbirth and major surgeries. As well as chronic conditions like cancers and sickle cell disease.

5 Blood Products from Whole Blood

From whole blood we can derive:

  1. Packed Red Blood Cells (PRBC)
  2. Fresh Frozen Plasma (FFP)
  3. Platelets
  4. Cryoprecipitate
  5. Prothrombin Complex Concentrate (PCC)
Illustration showing the blood products that are derived from whole blood. Packed red blood cells, plasma, fresh frozen plasma, platelets, cryoprecipitate and prothrombin complex concentrate

How is Donated Blood Processed?

Image showing the centrifuge that is used to process whole blood received from blood donors.

When a donor gives blood, the sample collected is referred to as whole blood. Whole blood is spun in a centrifuge.

A centrifuge will spin blood at a high rate causing it to separate into different blood components.

Red Blood Cells

Image showing red blood cells and plasma derived from initial spin of whole blood in centrifuge.

With the initial spin whole blood will separate into red blood cells and platelet-rich plasma.

The separated red blood cells are referred to as packed red blood cells (PRBCs).

We refer to them as “packed” because each unit of PRBCs has twice the hematocrit (oxygen carrying capacity) as whole blood.

PRBCs will provide oxygen to tissues during a bleed. They can achieve tissue perfusion with less volume than giving whole blood.

Each unit (250ml) will raise hemoglobin by 1-2g/dL.

The recipient and donor blood must be ABO matched for whole blood transfusions. In the blood compatibility unit, I explain three easy steps to match blood recipients and donors.

Plasma

Along with PRBCs, whole blood separates into plasma when centrifuged.

A donor can directly provide plasma via plasmapheresis. A apheresis machine can derived whole blood from the donor, separate the plasma and return red blood cells and platelets back to the patient.

Plasma is the liquid part of blood after removing all cells (red and white blood cells and platelets). It has few cells and contains proteins, mainly clotting factors.

Image showing blood products that are derives from a sample of plasma: fresh frozen plasma and platelets

Plasma is then used to create fresh frozen plasma and to isolate platelets.

Fresh Frozen Plasma

Plasma is rapidly frozen to create fresh frozen plasma that will have a shelf life of 1 year from the date collected.

FFP has a lot of clotting factors which is helpful for bleeding when normal blood clotting is affected, such as in warfarin toxicity and severe liver disease.

Administration of FFP requires compatibility between the donor and receiver. Compatibility is not the same between blood groups for red blood cell transfusions and plasma transfusions.

Image showing the ABO compatibilities between receiver and donor when fresh frozen plasma is transfused
  • Patients with type A blood can receive A or AB FFP
  • Patients with type B blood can receive B or AB FFP
  • Patients with type AB blood can receive AB FFP
  • Patients with type O blood can receive A, B, AB, or O FFP

Rhesus (Rh) factor matching is not essential for FFP transfusion but some facilities may require it.

Cryoprecipitate

Fresh frozen plasma can be further separated to create cryoprecipitate. When fresh frozen plasma is thawed, the precipitate from that is cryoprecipitate.

It is concentrated with clotting factor VIII, XIII, fibrinogen and Von Willebrand factor.

Cryoprecipitate has very specific uses because it contains very specific clotting factors.

Patients with:

  1. hemophilia A (factor VIII deficiency)
  2. Von Willebrand disease (deficiency in carrier for factor VIII)
  3. fibrinogen deficiency …

are the usual candidates for cryoprecipitate transfusions

Image sowing the blood product that is derived from fresh frozen plasma: cryoprecipitate

Rh factor compatibility is not required with cryoprecipitate transfusions.

Cryoprecipitate is acellular (like the plasma it is derived from). It has no red blood cells and very little plasma. ABO antigens are found on the cells and in body fluids. So there is very low potential for the presence of antigens that can induce infusion reactions. It is possible, especially with larger volume transfusions but unlikely with typical use of cryoprecipitate.

For this reason, ABO compatibility for cryoprecipitate transfusions are not always performed. It tends to be more of an institution based policy if it is required or not.

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Platelets

Platelet infusions are used in patients who present with bleeding and thrombocytopenia (abnormally low platelet counts ie, platelet count <20,000/μL). Because platelets play a major role in clotting, thrombocytopenia places a patient at risk for bleeding.

Patients on certain chemotherapeutic agents are at risk for thrombocytopenia because these agents attack rapidly dividing cells (like cancers) but also those of the bone marrow which is where platelets are made.

Other drug that can cause thrombocytopenia include linezolid and carbamazepine.

The Problem with Platelet Transfusions and ABO Matching

Every 15 seconds someone is the US needs a platelet transfusion.

Platelets can be specifically extracted from donors (plateletpheresis) or they can be separated from whole blood donations. Once extracted they are stable for only 5 days. Supply is very limited.

If we ABO matched platelets, this would further limit the supply.

We avoid the need for ABO matching, donor plasma (in which platelets are suspended) is replaced with plasma additive solution (PAS).

PAS minimizes the risk of hemolysis between mismatched ABO groups because it reduces the amount of plasma protein including antigens by 65%.

Illustration showing the difference between 100% plasma and platelets suspended in a Plasma Additive Solution

Because of this substitution of plasma with PAS, ABO matching is not required for platelets. Studies show that PAS platelets transfusions have a lower incidence of allergic transfusion reactions compared to 100% plasma.

If we use 100% plasma, the donor should be ABO matched with the recipient’s red blood cells.

Platelets do not expressed Rh antigens, Rh compatibility is not required unless specified by your institution.

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Prothrombin Complex Concentrate

Cryoprecipitate can be further separated into prothrombin complex concentrate (PCC). This is done via ion-exchange chromatography to isolate 3-factor, 4-factors or activated PCC (aPCC). This process creates a product that is 25 times more concentrated in clotting factors that fresh frozen plasma.

Illustration showing the different formulations of prothrombin complex concentrates and the clotting factors that each contains.

Whichever PCC you choose. they will always contain factors II, IX and X.

Factor 4 and PCCa also contain factor VII in an inactive and activated form respectively.

They all contain varying amounts of the naturally occurring anticoagulants protein C and S and well as unfractionated heparin.

PCCs are used for used for reversal of antithrombotic agents in acute major bleeding or when reversal is needed prior to an urgent surgery or invasive procedure.

Compared to donated blood products, PCCs are advantageous because we can get treatment to patients faster:

  1. Immediate availability: simple reconstitution of PCC rather than thawing blood products and awaiting delivery from lab
  2. No ABO matching
  3. Smaller infusion volumes: the faster drug gets to patients the faster it will work

PCCs are also advantages in terms of product longevity:

  1. Simple Storage: Stored in non-refrigerated vials instead of refrigerated or frozen bags of blood products.
  2. Long Shelf Life: Some PCCs can last up to 36 months, unlike the shorter lifespan of donated blood products.

PCCs are also advantageous in terms of safety:

  1. Transfusion Related Lung Injury is not a concern with the administration of PCCs because antibodies are removed from the product
chart comparing prothrombin complex concentrate (PCC) to donated blood products

Risk of Blood Product Infusion

Administration of these blood components are not without significant risk. Transfusion reaction is a broad term we use to refer to any number of events that can occur as a direct result of the infusion of blood or its components. Those events can be mild with non specific symptoms like chills, fever, rashes or tachycardia. But they can also be as severe as hemolysis, sepsis or transfusion related lung injury (TRALI).

To further complicate things, these infusion reactions can occur during infusion or days to weeks later. It can be the results of etiologies including immunologic responses to antibodies in donor blood, blood contamination during processing or volume overload from the infusion. Because of these complexities transfusion reactions can be hard to diagnose.

The American Red Cross has a comprehensive resource on practice guidelines for all the infusions we’ve discussed.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

Blood Compatibility: What You Need to Know Before Transfusion

Blood compatibility is a matter of life and death. What blood type a patient can receive is a decision that has to made quickly and accurately every time. I’ll walk you through 3 simple steps to make the right call every time when matching blood types and provide quick reference charts of blood compatibilities.

Understanding Blood Type Matching

Red blood cell transfusions require matching the donor’s blood type to the recipient’s blood type. Blood types are determined by the presence or absence of antigens on the surface of red blood cells.

There are 4 possible combinations of antigens on a patients red blood cells.

  1. Antigen A only
  2. Antigen B only
  3. Both Antigen A and B
  4. Neither Antigen A nor B

An antigen is a substance that triggers an immune response.

The ABO system is used to categorize blood types based on which of the 4 combinations of antigens are present on a patient’s red blood cells.

The Rh System is used to further specify the ABO blood type as either positive or negative for the presence of the Rh protein on the surface of the red blood cell.

A patient who has the Rh protein is protein is Rh positive (Rh+).

A patient without the Rh protein is Rh negative (Rh-).

Together, the ABO and Rh system makes up a person’s blood type.

Illustration showing the categories of the blood types based on the ABO system and the surface antigens they carry.

Blood Type O: has no surface antigens

Blood Type A: has surface antigen A

Blood Type B: has surface antigen B

Blood Type AB: has both antigen A and antigen B

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The Immune System Produces Antibodies to Foreign Antigens

Illustration showing the different ABO categories. The antigens present with each type and the antibodies that it will produce.

Blood Type O

The immune system of the receiver will produce antibodies against whatever antigens are absent on the receivers red blood cells.

A patient with blood type O has no antigens and so will produce antibodies against antigens A and B if exposed.

This means that if a patient with blood type O is exposed to A or B antigens (blood type A, B or AB) the immune system will identify it as foreign and produce antibodies against it to destroy it.

A patient with type O blood can only receive type O blood.

Blood Type A

A patient with blood type A has A antigens. B antigens are absent so the immune system will produce antibodies against B antigens if exposed.

This means if a person with type A is exposed to type B blood, the body will attack those B antigens resulting in agglutination (clumping of the cells). The body will identify these clumped red blood cells as foreign substances that needs to be eliminated.

Since O has no antigens, it will not induce an immune response when administered to a patient with A antigens.

Blood Type B

Likewise, a patient blood type B has B antigens. It does not have A antigens so it will produce antibodies against A antigens if exposed.

This means if a person with type B blood is exposed to any blood with A antigens (A or AB) the immune system will identify it as foreign to the receiver, triggering an immune response, agglutination and elimination.

Since O has no antigens, it will not induce an immune response when administered to a patient with B antigens.

Blood Type AB

A patient with blood type AB has both A antigens and B antigens. Therefore it will not produce antibodies against either A or B.

This means that if a patient with AB blood is exposed to blood that contains A antigens or B antigens (A, B or AB), there would be no immune response.

Since O has no antigens, it will also not induce an immune response when administered to patients with both A and B antigens.

This is why AB patients are referred to as universal receivers: they can receive blood from all the blood groups.

We will organize all of this into charts of blood compatibilities for quick recall.

How Rh System Turns 4 ABO Groups into 8 Blood Types

In addition to the ABO type matching, blood must be match for Rh factor before transfusion.

Rh is antigen that is either present (+) or absent ( – ) on the surface of the red blood cell. A blood donor or receiver is either Rh positive or Rh negative. The Rh status is the +/- designation included in a person’ blood type e.g. A+, B-.

If a patient is Rh antigen negative they will develop antibodies if exposed to Rh positive blood. This will result in a transfusion reaction.

An Rh+ patient can receive Rh+ or Rh- blood.

An Rh- patient can only receive Rh- blood.

Diagram showing Rh compatibilities between groups. A Rh+ patient can receive Rh+ or Rh- blood. An Rh- patient can only receive Rh- blood.

Rh Factor and Pregnancy

In pregnancy, Rh status is crucial. Mother and child may have differing Rh status.

Cross section of a pregnant female showing a fetus with Rh+ red blood cells and mother with Rh- red blood cells.

If mother is Rh- and the fetus is Rh+, mom’s immune system will identify the baby as foreign and produce antibodies that will cross the placenta and attack the baby’s red blood cells.

This can cause fatal hemolysis for the current baby and even future Rh+ babies.

Fortunately, mom can be given RhoGAM [Rho(D)] which will prevent the mother from developing antibodies against baby’s red blood cells.

8 Blood Types

With the combinations of 4 ABO types and 2 Rh types there are 8 possible blood types.

Illustration showing the 8 possible blood types that result from the combination of 4 different ABO groups and 2 Rh groups.

Donating versus Receiving Blood

Blood donation and receiving blood are not reciprocal. A person may be able to donate blood to a blood group but will not be able to receive it from that same blood group.

A donor with blood type O can donate to blood type A. A type A donor could not donate to blood type O. This is because donors induce antibodies, receivers produce antibodies.

Illustration showing that blood donation and receiving blood are not reciprocal. A person can donate blood to a differing blood group but also not be able to receive from that same group.

A blood type O donor has no antigens and so it will not induce the receiver to produce any antibodies.

A blood type O receiver has no antigens and so will produce antibodies against any donor antigens it is exposed to.

From a healthcare provider’s perspective, it is more useful to think of compatibility from the perspective of the recipient. The predominant scenario will be that you have a patient in need a transfusion and you need to know what blood type will be compatible.

How to Divide 8 Blood Group into 2 Categories to Determine Compatibility

A simple way to remember compatibility among the 8 different blood groups is to consider them in 2 groups based on ABO letter matching between donor and recipient. Let’s consider compatibility from the perspective of a patient needing to be matched with a donor.

Diagram showing an overview of how we determine the compatibility of blood types. We can place a patient in 1 of 2 categories to determine whether exact or atleast partial ABO letter compatibility is required. Then we further categorize based on Rh factor status

The 2 groups are:

  1. Single Letter Receiver: A, B or O
  2. AB Receiver

Each of these group will then be matched based on Rh status.

If the donor is Rh-, the recipient must also be Rh-. If the donor is Rh+ then the Rh status of the recipient does not matter.

Refer to this chart of blood compatibilities often and it will soon become second nature.

Blood Compatibility for Single Letter Receivers

Chart showing blood compatibility of single letter (A, B and O) receivers.

When your patient is any of the single letter blood groups (A, B, or O) the donor must be an exact letter match or group O.

Once we’ve matched blood based on the ABO letters we then consider the Rh status.

If the receiver is Rh+, the donor blood can either Rh+ or Rh-. If the receiver is Rh- donor blood must be Rh-.

If you learn by observing patterns, you will notice that the chart of blood compatibilities above forms a series of triangles. This can be a helpful way to derive compatibilities for blood type matching.

Chart showing blood compatibility of single letter (A, B and O) receivers. It forms a triangular pattern which can help in deriving compatibilities.

Blood Compatibility for AB Receivers

Chart showing blood compatibility of AB group receivers.

When a patient is AB blood type, the donor blood must be atleast a partial letter match or O. The donor can therefore be of any of the the 8 blood groups. Once we have the ABO types matched we can then consider the Rh status.

If the receiver is Rh+, the donor blood can either Rh+ or Rh-. If the receiver is Rh- donor blood must be Rh-.

You can see that a patient with AB+ blood can receive any and all donor types. AB+ patients referred to as universal receivers.

AB- patient also can receive from all the donor types but they are limited to the Rh- groups.

There is a clear triangular pattern to be observed here, much like the table for the single letter group.

I structured all these charts of blood compatibilities in the same way so that they are easy to replicate from memory.

3 Steps to Matching Blood Types

Infographic showing 3 simple steps for determining blood compatibility

With these 3 simple steps you can derive the compatible blood types for any patient. Let’s walk through some examples below.

Blood Compatibility: Example Questions

Questions showing how to use 3 simple steps to determine what blood types a patient can receive.
Questions showing how to use 3 simple steps to determine what blood types a patient can receive.

The American Red Cross makes it easy to donate blood/blood products or support others who donate.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

Everything You Need to Know: Edoxaban

Edoxaban is an oral anticoagulant. It belongs to the drug class: direct oral anticoagulants (DOAC) and the subclass: Xa inhibitor.

Diagram showing the classification of direct oral anticoagulants (direct thrombin inhibitors and Xa inhibitors) and the drugs included in each class

Mechanism of Action

Edoxaban works by interrupting the sequence of clotting factor activations in the common pathway of the coagulation cascade via factor Xa. This halts thrombin activation and the conversion of fibrin to fibrinogen.

If you have any questions about the process of hemostasis and the coagulation cascade the unit What You Need to Know: Hemostasis provides an excellent overview.

Illustration showing where in the coagulation cascade edoxaban works to prevent thrombin activation and therefore clot formation.

Indications

Edoxaban is indicated for use in:

  • atrial fibrillation/flutter
  • venous thromboembolism.

The ENGAGE Trial

Image of the the ENGAGE trial that compared edoxaban to warfarin for the prevention of stroke and systemic embolism in patients in atrial fibrillation.

The ENGAGE trial compared edoxaban to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

Efficacy was determined by the rate occurrence of stroke and systemic embolism in each group.

Safety was determined by the rate of major bleed in each group.

Edoxaban was found to be non inferior to warfarin in preventing stroke or systemic embolism and caused less bleeding.

Administration & Availability

Edoxaban is available as an oral tablet. For patients who are unable to swallow whole tablets, edoxaban tablets may be crushed and mixed with 60 to 90ml of water and immediately administered by mouth or through a gastric tube.

The crushed tablets may also be mixed into applesauce and immediately administered orally.

Edoxaban can be given without regard to meals.

Missed Dose

If a dose of edoxaban is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule.

Dosing

Edoxaban is dosed at 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min.

Edoxaban is unique among the Xa inhibitors in that it cannot be used in patients with a high creatinine clearance (>95ml/min).

At high renal clearance there is an increased risk of ischemic stroke compared to warfarin.

Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min.

Avoid use with CrCl<15ml/min and in hemodialysis.

Illustration showing an overview of edoxaban dosing. Where to start (standard dosing), when to dose adjust and when to avoid.

Drug Interactions

With edoxaban the interaction with P-gp transporters is more significant than CYP enzymes. There is minimal engagement with cytochrome enzymes but it is a substrate of P-gp transporters.

The only P-gp inducer that is listed as a significant interaction with edoxaban is rifampin. It is recommended to avoid edoxaban and rifampin coadministration because of decreased serum concentration and risk of thromboembolic events.

For all other clinically relevant P-gp inducers the recommendation is to monitor therapy or consider alternate therapies.

No dose reduction is recommended for concomitant P-gp inhibitor use. Clinical experience from the ENGAGE trial showed dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

Everything You Need to Know: Dabigatran

Dabigatran changed the landscape and set a new standard for oral anticoagulation in 2010. It was the first oral alternative to warfarin and the inaugural member of the drug class Direct Acting Oral Anticoagulants (DOACs).

It is still the only oral anticoagulant in the subclass of Direct Thrombin Inhibitor. Let me walk you through everything you need to know to use dabigatran safely and effectively.

Illustration showing the categories of direct acting anticoagulants and they drugs in each category.

How Dabigatran Works

Dabigatran is absorbed as an inactive prodrug that is converted into active drug by hepatic enzymes (in the liver).

Dabigatran inhibits thrombin in the common pathway of the coagulation cascade.

Thrombin activates the conversion of fibrinogen to fibrin during the coagulation cascade. Fibrin is the structural protein that forms the mesh network of a clot. Therefore inhibiting thrombin will prevent the formation of fibrin and in turn, a stable clot.

Illustration showing the where in the coagulation cascade dabigatran works, dabigatran inhibits thrombin in the common pathway of the coagulation cascade. This prevents the series of clotting factor activations that leads to the formation of fibrin that is needed to form a clot.

When is Dabigatran Needed

Indications

  • Atrial fibrillation
  • Venous thromboembolism (treatment & prevention)

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How to Use Dabigatran

Chart showing the unique features of dabigatran in terms of storage and availability.

Dabigatran has unique storage requirements.

Dabigatran is available as capsules and oral pellets.

The approved indications and intended age groups are not the same for the different dosage forms.

The oral bioavailability of dabigatran increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule.

Therefore the capsules should not be broken, chewed, or opened before administration. The formulations are not interchangeable.

Dabigatran should be dispensed and stored in the manufacturer’s bottle and used within 4 months of being opened. Advise patients not to store this medication in their pill organizers. The drug is easily hydrolyzed by humidity which reduces it’s potency. The capsules are available is unit dose blister packs as well.

The Evidence for Dabigatran

Illustration showing the RE-LY trial as the landmark trial comparing warfarin and dabigatran in patients with atrial fibrillation for the prevention of stroke and systemic embolism.

Dabigatran was evaluated in the RE-LY trial compared with dose-adjusted warfarin. Efficacy was assessed by the rate of stroke and systemic embolism. Safety was assessed as the rate of major bleed.

Dabigatran showed superiority over warfarin for prevention of stroke and systemic embolism. There was a non-significant difference in major bleed at the higher dose (150mg BID) and a significantly lower risk of major bleed at the lower dose (110mg BID).

How to Dose Dabigatran

The standard dosing of dabigatran is 150mg BID. It requires renal dose adjustment, consideration of drug interactions and should be avoided in patients with significant renal impairment including dependence on hemodialysis.

Illustration showing the key takeaways for dabigatran dosing. Where to start (standard dosing), when to adjust and when to avoid.

Drug Interactions with Dabigatran

Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes.

Dabigatran is a substrate of the efflux transporter P-gp. Learn more about the clinical significance of this class of interactions in the Cytochrome and P Glycoprotein unit.

P-gp are efflux pumps, they will pump drugs out of cells.

Therefore, if the pump’s activity is induced, more drug will be pumped out resulting in the possibility of reduced clinical effect i.e. increased risk of thrombosis.

Illustration showing the clinically significant drug interactions for dabigatran

Avoid Combination: dabigatran + PGP Inducers

Clinically significant P-gp inducers: carbamazepine, fosphenytoin, green tea, lorlatinib, phenytoin, rifampin, St John’s Wort.

Theoretically, inhibition of P-gp efflux pumps would increase serum concentrations of dabigatran and therefore increase the risk of toxicity. However, what has been observed in a large retrospective cohort is that concurrent use of ketoconazole (a strong P-gp inhibitor) was not associated with a significant increase in risk for major bleeding.

Consider Therapy Modification/Monitor Therapy: dabigatran + P-gp Inhibitors

The recommendations for the use of dabigatran with P-gp inhibitors is indication and patient specific and should always be reviewed.

Clinically significant PGP inhibitors: ketoconazole, itraconazole, posaconazole, ritonavir, erythromycin, clarithromycin, grapefruit.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.

Rivaroxaban: What You Need to Know to Maximize Patient Outcomes

2 million people use rivaroxaban each year. The benefits are proven, the risks are manageable. Let me what you through what you need to know to minimize risk and optimize efficacy.

Rivaroxaban is an oral anticoagulant. It belongs to the drug class: Direct Oral Anticoagulant (DOAC).

DOACs were introduced in 2010 as an alternative to warfarin. They address alot of the complexities associated with the use of warfarin.

Warfarin is effective within a very narrow therapeutic range. This window of efficacy is easily disrupted by many drug interactions, food interactions and acute illness.

Because of this, warfarin requires regular and often frequent monitoring of blood levels to ensure that patients are anticoagulated enough to prevent thrombosis but not too much that they are high risk for a major bleed. The unit on WARFARIN provides an in depth analysis of the drug.

Image showing the benefits of direct oral anticoagulants. Compared to warfarin they are more efficacious and safer. More convenient, have fewer interactions ad a faster onset.

In comparison, DOACs including rivaroxaban have a better safety and efficacy profile with a more rapid and predictable onset compared to warfarin.

They do not require frequent blood monitoring and there are very few drug and food interactions.

There are 2 subcategories of DOAC based on the mechanism of action: direct thrombin inhibitors and Xa inhibitor. Rivaroxaban is a Xa inhibitor.

Diagram showing the different categories of direct oral anticoagulants. They are classified based on the mechanism of action. Direct thrombin inhibitors or Xa inhibitors. Apixaban is a Xa inhibitor.

How Rivaroxaban Works

Rivaroxaban is a factor Xa inhibitor. It inhibits clotting factor Xa, the first factor activated in the common pathway of the coagulation cascade.

The mechanism of action of rivaroxaban cannot be understood without knowledge of the coagulation cascade. The unit What You Need to Know: Hemostasis covers the coagulation cascade in detail.

The diagram below illustrates where in the coagulation cascade rivaroxaban works.

Illustration showing where in the coagulation cascade rivaroxaban works. It works by inhibitor factor Xa at the beginning of the coagulation cascade. This prevents the series of factor activations that leads to the formation of the clot.

When is Rivaroxaban Needed?

Rivaroxaban has a growing list of indications including:

  • Reduction of risk for stroke and pulmonary embolism in non valvular atrial fibrillation
  • Treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE)
  • Prevention of DVT and PE in hip and knee replacement and acutely ill patients
  • Reduction of risk of major cardiovascular events in patients with coronary artery disease

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ROCKET-AF Trial: The Evidence

Illustration showing the landmark Rocket AF trial that compared rivaroxaban to warfarin. It showed that rivaroxaban was non inferior to warfarin for the prevention of stroke and systemic embolism. There was no significant difference in the rates of bleeding.

The Rocket-AF trial compared rivaroxaban to warfarin in patients with atrial fibrillation in need of anticoagulation.

Efficacy was determined by the rate of stroke or systemic embolism. Safety was compared as the rate of major bleed in each group.

Rivaroxaban was found to be non-inferior (not worse than) to warfarin with no significant difference in major bleed.

How to Use Rivaroxaban

Rivaroxaban is available as an oral tablet and oral 1mg/ml suspension for pediatric patients.

Adult patients who are not able to swallow whole tablets can crush them and mix with applesauce right before administration. Rivaroxaban can also be crushed and suspended in 50cc of purified water for administration via nasogastric and gastric tube. Flush tubes with 15cc before and after. Crushed tablets are stable in applesauce and water for up to 4 hours.

Administration with food increases the bioavailability of rivaroxaban. Doses > 15mg should be administered with meals to achieve a bioavailability of >80%.

This includes doses that are crushed and administered with apple sauce or suspended in water. The recommendation is to take rivaroxaban with the evening meal when it is dosed daily. Lower doses (<15mg) may be administered without regard to meals.

Missed Doses

For patients on a 15mg twice daily regimen who miss a dose, the missed dose should be taken immediately to ensure that the total dose received that day is 30mg. 30mg can be taken as a single dose to achieve this.

Twice daily dosing should resume the next day. For all other twice daily dosing regimens, if a dose is missed, the patient should resume dosing at the next scheduled administration.

For once daily dosing, if missed, take the dose as soon as possible and resume therapy the following day as previously taken.

Drug Interactions with Rivaroxaban

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp transporters. See the study unit on Cytochrome P450 and P-Glycoproteins to grasp the clinical significance of this group of interactions.

Infographic showing the some of the major drug combinations that should be avoided when using rivaroxaban based on cytochrome and P glycoprotein interactions.

Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding.

Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Avoid combined P-gp and strong CYP3A inhibitors and inducers.

Avoid combined P-gp and moderate CYP3A inducers in patients with renal impairment.

Use of Rivaroxaban in Significant Renal Impairment

The manufacturer’s labeling for rivaroxaban reads:

Systemic exposure to rivaroxaban administered as a single 15 mg dose in ESRD subjects dosed 3 hours (post-dialysis) is 56% higher when compared to subjects with normal renal function. The systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session…is 47% higher compared to those with normal renal function.

The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure.

In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.

It is important to note that patients with a creatinine clearance of <15ml/min were excluded from the clinical trials. The recommendations above for use in dialysis is based on a single dose pharmacokinetic study that did not evaluate clinical outcomes.

Rivaroxaban is excreted via urine (66% primarily via active tubular secretion ,~36% as unchanged drug; 30% as inactive metabolites); feces (28%,<7% as unchanged drug; 21% as inactive metabolites)

Most drug references, including Lexicomp, recommends against the use of rivaroxaban in patients with a CrCl<15ml/min or on hemodialysis based on expert opinion for the reasons noted above.

How to Dose Rivaroxaban

The standard dosing of rivaroxaban is 20mg once daily in atrial fibrillation. DVT and PE require higher initial doses.

Illustration showing an overview of rivaroxaban dosing. Where to start (standard dosing), when to adjust and when to avoid.

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Everything You Need to Know: Apixaban

Apixaban is an oral anticoagulant. It belongs to the drug class: Direct Oral Anticoagulant (DOAC).

DOACs were introduced in 2010 as an alternative to warfarin. They address alot of the complexities associated with the use of warfarin.

Warfarin is effective within a very narrow therapeutic range. This window of efficacy is easily disrupted by many drug interactions, food interactions and acute illness.

Because of this, warfarin requires regular and often frequent monitoring of blood levels to ensure that patients are anticoagulated enough to prevent thrombosis but not too much that they are high risk for a major bleed. The study unit on WARFARIN provides an in depth analysis of the drug.

Image showing the benefits of direct oral anticoagulants. Compared to warfarin they are more efficacious and safer. More convenient, have fewer interactions ad a faster onset.

In comparison DOAC including apixaban have a better safety and efficacy profile with a more rapid and predictable onset compared to warfarin.

They do not require frequent blood monitoring and there are very few drug and food interactions.

There are 2 subcategories of DOAC based on the mechanism of action: direct thrombin inhibitors and Xa inhibitor. Apixaban is a Xa inhibitor.

Diagram showing the different categories of direct oral anticoagulants. They are classified based on the mechanism of action. Direct thrombin inhibitors or Xa inhibitors. Apixaban is a Xa inhibitor.

Mechanism of Action

Apixaban is a factor Xa inhibitor. It inhibits clotting factor Xa, the first factor activated in the common pathway of the coagulation cascade.

The mechanism of action of apixaban cannot be understood without knowledge of the coagulation cascade. The unit What You Need to Know: Hemostasis covers the coagulation cascade in detail.

The diagram below illustrates where in the coagulation cascade apixaban works.

Illustration showing where on the coagulation cascade apixaban works. Apixaban inhibits factor X at the start of the common pathway of the coagulation cascade.

Indications

Apixaban also has a growing list of indications that include:

  • atrial fibrillation
  • heparin induced thrombocytopenia
  • treatment and prevention of DVT and PE
  • prophylaxis against DVT/PE post hip/knee surgery

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The Aristotle Trial

Illustration showing the landmark Aristotle trial that compared warfarin to apixaban. It showed that apixaban was more efficacious and safer than warfarin in patients with atrial fibrillation requiring anticoagulation.

The Aristotle trial compared apixaban to warfarin in patients with atrial fibrillation in need of anticoagulation.

Efficacy was determined by the occurrence of stroke and systemic embolism in each group.

Safety was determined by the rate of major bleed in each group.

Apixaban was found to be superior to warfarin in preventing stroke or systemic embolism and caused less bleeding.

Availability & Administration

Apixaban is available as oral tablets. It can be given without regard to meals. If the patient is unable to swallow whole tablets, they can be crushed and suspended in 60cc of water, D5W, apple juice or mixed with applesauce. The preparation should be administered immediately but is stable for up to 4 hours.

Missed Doses

If a dose is missed, the dose should be taken as soon as possible on the same day and twice daily administration should be resumed. The dose should not be doubled to make up for a missed dose.

Dosing

The standard dosing of apixaban is 5mg twice daily. Higher dosing is required in the initial treatment of DVT and PE.

Illustration showing an overview of apixaban dosing. Where to start (standard dosing), when to adjust and when to avoid.

Renal dosing of apixaban is unique in that it is based on 3 patient characteristics: age, body weight and serum creatinine. A dose reduction to 2.5mg is recommended if a the patient meets any 2 of these criteria.

serum creatinine > 1.5mg/dL + (>80 yo OR <60kg) = 2.5mg BID

serum creatinine <1.5mg/dL = (> 80yo AND <60kg) = 2.5mg BID

Drug Interactions

Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban. The recommendation is to reduce apixaban dose to 2.5 mg or avoid concomitant use. Clinically relevant inhibitors include cobicistat, itraconazole, ketoconazole, ritonavir and posaconazole.

Simultaneous use of strong inducers of CYP3A4 and P-gp reduces blood levels of apixaban. For inducers, the recommendation is to avoid concomitant use. Clinically relevant inducers include carbamezapine, fosphenytoin, phenytoin and rifampin.

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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.