Life of an Ambulance Person.

medXclusive Learning

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich’s original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

Individuals with WAS have microthrombocytopenia, which is a decrease in the number and size of blood cell fragments involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising, bloody diarrhea, or episodes of prolonged bleeding following minor trauma. Microthrombocytopenia can also lead to small areas of bleeding just under the surface of the skin, resulting in purplish spots called purpura or rashes of tiny red spots called petechiae. In some cases, the bleeding episodes can be life-threatening.

WAS is also characterized by abnormal or nonfunctional immune system cells known as white blood cells. Changes in white blood cells lead to an increased risk of several immune and inflammatory disorders in people with Wiskott-Aldrich syndrome. These immune problems vary in severity and include increased susceptibility to infection and eczema (an inflammatory skin disorder characterized by abnormal patches of red, irritated skin). People with Wiskott-Aldrich syndrome are at greater risk of developing autoimmune disorders, such as rheumatoid arthritis or hemolytic anemia, which occur when the immune system malfunctions and attacks the body’s own tissues and organs. The chance of developing certain types of cancer, such as cancer of the immune system cells (lymphoma), is also increased in people with Wiskott-Aldrich syndrome.

Over the past five years, there has been a tremendous increase in the number of patients presenting to hospitals with traumatic brain injury. The bulk of these injuries occur in the elderly, and a rapidly growing number of them are taking anticoagulants for management of their medical comorbidities. Although there is a growing body of literature addressing this issue, many practical questions remained unanswered. This is due to the lack of randomized controlled studies of the clinical problems involved. And given the ethical issues of obtaining consent for them, there likely never will be.

An interdisciplinary group of Austrian experts was convened last year to consider the most common questions asked about TBI and concomitant anticoagulant use. They reviewed the existing literature from 2007 to 2018 and combined it with their own expertise to construct some initial answers to those questions.

Over the course of my next few posts, I’ll dig into each of the questions and review their suggested answers. And remember, all these Q&A apply to patients with known/suspected TBI with known/suspected oral anticoagulant use.

Let’s start with some diagnosis questions.

Q1. Should head CT be performed in all patients with known or suspected TBI and suspected or known use of anticoagulants?

Answer: All patients with TBI and potential or known use of anticoagulants should undergo an initial screening CT scan of the head.

A number of systems that predict the utility of head CT already exist (e.g. Canadian head CT rules). However, they do not and cannot take into account the various permutations of drugs and other medical conditions that may influence coagulation status. Vitamin K antagonists (VKA) like warfarin have been clearly shown to increase mortality after TBI. Data involving the use of anti-platelet agents or direct oral anticoagulants (DOAC) are a bit less clear.

Q2. Should a repeat head CT scan be repeated in these patients, and if so, when?

Answer: Patients with intracranial hemorrhage on their initial scan should have a repeat within 6-24 hours, based on the location of the bleed.

The natural course of patients who have an identified intracranial hemorrhage is extremely unpredictable. For that reason, a repeat scan is suggested. However, there are no consistent data that would indicate when this should occur. Indications and potential for progression vary by type of bleed (subarachnoid, subdural, epidural, intraparenchymal). Thus, you must work with your neurosurgeons to arrive at a reasonable repeat interval, and it may be different for a high-risk location (epidural) vs one with low risk (subarachnoid).

Q3. Should a patient with an initial head CT that is negative be admitted for neurologic monitoring?

Answer: Patients taking only aspirin with GCS 15 and initially negative head CT may be discharged. All other patients should be admitted for at least 24 hours for neurologic monitoring as follows (q1 hr x 4 hrs, q2 hr x 8 hrs, q4 hr x 12 hrs). Repeat head CT is indicated if there is any deterioration in neurologic exam.

Multiple papers have described the occurrence of delayed intracranial hemorrhage in patients taking oral anticoagulants other than aspirin. Although some bleeds may develop days or weeks after the initial injury, the majority occur during the first 24 hours. Routine repeat head CT in this group of patients with an initially negative scan has not been found to be helpful.

Q4. What about patients with an initially negative head CT who cannot be examined neurologically (intubation, sedation, dementia)?

Answer: Unexaminable patients should undergo a repeat head CT within 6-24 hours based on the underlying risk factors for development of delayed hemorrhage.

There is no real literature on this topic, but this statement makes sense. Each center should pick a reasonable time interval and include it in their own practice guideline.

In my next post, I’ll review the panel’s recommendations on coagulation tests and target levels for reversal of the various classes of anticoagulants.

Reference: Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 23:62, 2019.

In my previous post, I reviewed recommendations from an Austrian consensus panel addressing patients with TBI on anticoagulants of various types. In this one, I’ll share their statements on coagulation tests and target levels for reversal of the different agents.

Q1. Are platelet function tests capable of detecting and/or ruling out the presence of a platelet inhibitor?

Answer: The three commonly used tests (PFA, Multiplate, and VerifyNow) can detect or rule out the presence of these drugs.

They can also determine whether the amount of platelet inhibition is within therapeutic range for the drug. But they cannot predict if someone with high inhibition will actually bleed, or if a patient with low inhibition will not. And knowing that they have a platelet inhibitor on board probably doesn’t help much because there is not much we can do to reverse them (see next post).

Q2. What is the goal INR after reversing Vitamin K antagonists?

Answer: The INR target value should be < 1.5

This recommendation is not supported by great data. We know that as INR rises above 2, the odds of bleeding in TBI increases by 2.6x. But we don’t now exactly how low it needs to be to ensure no more bleeding occurs. And this probably depends on what is actually bleeding. A subarachnoid hemorrhage probably wouldn’t bleed much at any reasonable INR. A subdural (torn bridging veins) is more likely to at lower INR values. And an epidural (middle meningeal artery laceration) remains at high risk at any INR.

Using related literature, the goal INR is all over the place. So choose a number somewhere around 1.5 and use it. And remember, 4-factor prothrombin complex concentrate (PCC) can bring the INR down below that level, but plasma cannot (see my post What’s The INR Of FFP?)

Q3. Should I use standard coagulation tests (PT, PTT) to detect or rule out direct oral anticoulants (DOACs)

Answer: No

Standard assays like PT and PTT are unreliable with these drugs.

Q4. What test can be used to rule out the direct thrombin inhibitor dabigatran?

Answer: A negative thrombin time (TT) rules out any residual dabigatran anticoagulation.

Of course, this assumes that you know the patient is taking it!

Q5. What test should be used to rule out Factor Xa inhibitors?

Answer: Measuring anti-Factor Xa levels can rule these agents out if calibrated to low molecular weight heparin or the particular -xaban in use.

The major problem is that this is a very specialized test and is not available at all hospitals or at all hours. And it takes some time to run. So the practical answer is really “none.”

In my next post, I’ll review the panel’s recommendations for actual reversal of the various anticoagulant medications.

Reference: Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 23:62, 2019.

My last post covered coagulation tests for oral anticoagulants and antiplatelet agents, as well as target levels of reversal. Today, I’ll share more of the Austrian consensus paper on actual reversal of anticoagulants. I’ll also add a little commentary to some of the answers.

This is a lengthy section in the paper, so I’ll split it into antiplatelet agents and Vitamin K antagonists today, and the direct oral anticoagulants tomorrow.

Q1. Should desmopressin (DDAVP) be administered to reverse the effect of platelet inhibitors?

Answer: No recommendation. (My answer: no)

DDAVP accelerates platelet adhesion. Very few papers have looked at using DDAVP in patients with platelet inhibition, and those that did had low numbers of subjects. The only positive study showed a reduction in hematoma of only 0.5 cc (in hemorrhagic stroke patients, by the way, not trauma). This is not clinically significant. It is likely that the nonfunctional platelets do not really respond to DDAVP, so this drug is not very useful.

Q2. Should TXA be used in patients receiving platelet inhibitors?

Answer: No recommendation. (My answer: no)

There are few, if any, studies that address this. A CRASH-2 subset with TBI showed no significant difference in intracranial hematoma size after TXA. Only one very small (80 patient) study showed a decreased total hematoma after TXA administration (2cc vs 4cc). I’m not sure how clinically significant this is. CRASH-3 did not address it. Overall there is too little data to make a decision regarding this one. It’s value, if any, is very subtle.

Q3. Should platelet concentrate be administered to reverse the effect of platelet inhibitors?

Answer: No

There are no studies that have shown any clear benefit to giving units of platelets to these patients. And a meta-analysis showed no survival benefit. Giving platelets sounds like a good idea, but remember that the drug that poisoned the patient’s platelets is still circulating. It can and does poison the new platelets as well. So adding more platelets that are destined to stop functioning doesn’t seem like a good idea.

In my next post, I’ll dig into the recommendations for reversing Vitamin K antagonists (warfarin).

Reference: Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 23:62, 2019.

In my last post, I started reviewing the anticoagulant reversal section of the Austrian consensus statement on TBI patients taking anticoagulants. Due to its length, I covered only anti-platelet agents. Today I’ll discuss their findings on reversing  Vitamin K antagonists.

Q1. Should Vitamin K antagonists (VKAs) be reversed in case of hemorrhagic TBI?

Answer: That’s simple. Yes!

Q2. Should Vitamin K be administered to reverse the effects of VKAs?

Answer: Yes, as an adjunct to other reversal agents. The usual dose is 5-10mg IV.

Adjuncts must always be used, because Vitamin K only enables the liver to produce factors II, VII, IX, and X. This is not an immediate process, and may take up to 24 hours for the INR to fall to reasonable levels. Additional treatment is needed to raise these factor levels quickly.

Q3. Should prothrombin complex concentrate (PCC) and/or plasma be used for reversal of VKAs?

Answer: Four-factor PCC is the treatment of choice, and is preferred over plasma. 

Reversal of VKAs with plasma requires administration of large volumes, and each unit is given over one to two hours. This results in a slower correction when compared to PCC, which occurs in less than 30 minutes. And many elderly patients with comorbidities cannot tolerate the colloid volume administered with multiple units of plasma. Multiple studies have shown that patients treated with PCC achieve their target INR significantly faster and have less hematoma progression than those treated with plasma.

Q4. Should recombinant activated factor VII (rFVIIa) be used for reversal of VKAs?

Answer: No.

This drug was the darling in trauma care around the turn of the century, but has since fallen into disuse. The few studies available show that there may be INR rebound and more frequent hematoma expansion compared to PCC.

Next post: Recommendations for reversal of DOACs.

The central nervous system (which includes the brain and spinal cord) is made up of two basic types of cells: neurons and glia. 

Neurons are information messengers. 

Use electrical impulses and chemical signals to transmit information between different areas of the brain, and between the brain and the rest of the nervous system. 

Supported by glial cells called astrocytes and oligodendrocytes

Within the cell body is a nucleus: controls the cell’s activities and contains the cell’s genetic material. 

Axon transmits messages from the cell. 

Dendrites receive messages for the cell. 

Neurons communicate sending neurotransmitters across a tiny space, (synapse) between the axons and dendrites of adjacent neurons.

There are three classes of neurons:

Sensory neurons carry information from the sense organs (such as the eyes and ears) to the brain.

Motor neurons control voluntary muscle activity such as speaking.

All the other neurons are  interneurons.

Birth

The extent to which new neurons are generated in the brain is a controversial subject. 

Mmajority of neurons are already present at birth

There is evidence to support that neurogenesis (creation of neurons) is a lifelong process.

Neurons are created in areas of the brain that are rich in concentrations of neural precursor cells (also called neural stem cells). These cells have the potential to generate most, if not all, of the different types of neurons and glia found in the brain.

Neural stem cells increase by dividing in two and producing either two new stem cells, or two early progenitor cells, or one of each.

Stem cell divides to produce another stem cell = self-renew. 

Stem cell divides to produce an early progenitor cell = differentiate. -> the new cell is more specialized in form and function. 

An early progenitor cell does not have the potential of a stem cell to make many different types of cells. It can only make cells in its particular lineage.

Early progenitor cells can self-renew or go in either of two ways. One type will give rise to astrocytes. The other type will ultimately produce neurons or oligodendrocytes.

Migration

Neurons use at least two different methods to travel to the area they need to work in:

Some neurons migrate by following the long fibers of cells called radial glia. These extend from the inner layers to the outer layers of the brain. 

Neurons also travel by using chemical signals. Adhesion molecules on the surface of neurons bind with similar molecules on nearby glial cells or nerve axons. These chemical signals guide the neuron to its final location.

Only a third reach their destination. Some cells die during the process of neuronal development. Some neurons survive the trip, but end up where they shouldn’t be. Mutations in the genes that control migration create areas of misplaced or oddly formed neurons that can cause disorders such as childhood epilepsy. 

Differentiation

In the developing brain, a neuron depends on molecular signals from other cells, such as astrocytes, to determine its shape and location, the kind of transmitter it produces, and to which other neurons it will connect. These freshly born cells establish neural circuits - or information pathways connecting neuron to neuron - that will be in place throughout adulthood.

Death

Although neurons are the longest living cells in the body, large numbers of them die during migration and differentiation.

The lives of some neurons can take abnormal turns. Some diseases of the brain are the result of the unnatural deaths of neurons.

- In Parkinson’s disease, neurons that produce the neurotransmitter dopamine die off in the basal ganglia, an area of the brain that controls body movements. This causes difficulty initiating movement.

- In Huntington’s disease, a genetic mutation causes over-production of a neurotransmitter called glutamate, which kills neurons in the basal ganglia. As a result, people twist and writhe uncontrollably.

- In Alzheimer’s disease, unusual proteins build up in and around neurons in the neocortex and hippocampus, parts of the brain that control memory. When these neurons die, people lose their capacity to remember and their ability to do everyday tasks. Physical damage to the brain and other parts of the central nervous system can also kill or disable neurons.

- Blows to the brain, or the damage caused by a stroke, can kill neurons outright or slowly starve them of the oxygen and nutrients they need to survive.

- Spinal cord injury can disrupt communication between the brain and muscles when neurons lose their connection to axons located below the site of injury. These neurons may still live, but they lose their ability to communicate.

Yesterday, I posted a series of sodium levels that were drawn daily. There was no change in clinical status as the levels varied from 131 to 125 and back up.

Now let me give you a bit more information. The patient was actually getting serial checks every 6 hours (or more)! Here’s the updated chart:

Day/Time Na Treatment NaCl per day Day 1 18:30 131 Day 1 22:54 132 0.9% NS @ 125/hr 3G Day 2 05:59 133 continues 3G Day 2 12:19 129 continues Day 2 17:50 129 continues Day 3 07:18 127 continues Day 3 12:09 127 continues Day 3 17:58 126 continues Day 3 23:53 126 continues Day 4 07:45 125 continues Day 4 11:38 122 2% NS @ 25/hr 6G Day 4 15:25 125 continues Day 4 19:31 125 continues Day 5 00:06 122 continues 6G Day 5 04:04 126 continues Day 5 08:01 122 continues Day 5 11:50 132 stop Day 5 16:14 126 Day 5 19:26 127 Day 6 00:20 129 9.2G Day 6 04:42 127 2% NS @ 40/hr Day 6 08:30 124 continues Day 6 12:29 127 stop Day 6 16:16 127 Salt tabs 2G tid Day 6 20:28 132 continues Day 7 05:22 134 Salt tabs 2G qid 8G Day 7 12:33 135 continues Day 8 07:02 131 stop None Day 8 13:33 136

Confused? Me, too! This poor person had 30 blood draws in 8 days, with 6 per day for two of those days. Carefully look at the amount of salt given in each 24 hour period, and look at the sodium levels for that day.

See the variability, even when getting high doses of sodium chloride? What does this tell you? Was the salt administration helpful? Was seeing the lab value every 4-6 hours valuable?

Tell me what you think. Leave comments or tweet your opinions. Next, I’ll discuss the known variability of the serum sodium assay, and give you my opinion on the value of serial testing.

Boerhaave syndrome, a transmural perforation of the esophagus, should be distinguished from Mallory-Weiss syndrome, a nontransmural esophageal tear that is also associated with vomiting. Because it is often associated with emesis, Boerhaave syndrome usually is not truly spontaneous.

In my last two posts, I detailed the serum sodium measurements in a hypothetical patient two ways. The first was a listing of daily values, and the second provided values obtained every six hours or so. It also showed the sodium supplementation that was ordered based on those values. (I’ve included the table at the bottom of this post)

What did you think? Did the extra determinations help you decide what, if any, treatment was needed? Did the therapies ordered help?

Here are my thoughts:

Overall, there was not a huge or rapid decline in sodium values. Given the initial values, I would not have started a saline infusion on day 1, just watched a few daily values and the patients physical exam. The infusion only provided 3gm of salt per day, and the serum Na remained fairly stable for the first 3 days.

There was a significant amount of intra-day variation seen on the six hour table. You need to know the normal “within-person ” variation for any lab test you order. If two assays on specimens drawn at the same time can vary by 5%, you must factor this in to your decision making. If the value is 3% lower than the previous draw, the difference could represent normal variation. Obtaining more frequent assays exacerbates the amount of variation you see and my be confusing.

From day 5 to 6, the sodium appeared to be rising without any salt supplementation! But then a higher dose was given, and one of the intra-day values dropped to 124. What’s up with that? More variation?!

Is the morbidity of frequent blood draws worth it if there is no clinical change in the patient’s exam? What morbidity, you ask? Sleep disturbances, with all the cascading problems like delirium, sundowning, administration of additional meds to compensate, and on and on. Unnecessary medication or interventions. Plus it does not promote patient or family satisfaction at all.

Bottom line: Unless your patient has a clinical problem that may deteriorate rapidly, serial lab determinations are probably not of much value. The example patient was many days out from a TBI with some extra-axial blood. So yes, he could develop hyponatremia, but it would have probably surfaced earlier. Know your within-person  variability, which for sodium is roughly +2 meq. Is your new value within that limit? Then it is statistically the same as the first value unless you see a trend over several measurements. And as always, if you note a marked change in just one value, repeat it immediately before beginning any more drastic interventions.

Reference: Biological variation of laboratory analytes based on the 1999-2002 national health and nutrition examination survey. Natl Health Statistic Reports 21:March 1, 2010.

Day/Time Na Treatment NaCl per day Day 1 18:30 131 Day 1 22:54 132 0.9% NS @ 125/hr 3G Day 2 05:59 133 continues 3G Day 2 12:19 129 continues Day 2 17:50 129 continues Day 3 07:18 127 continues Day 3 12:09 127 continues Day 3 17:58 126 continues Day 3 23:53 126 continues Day 4 07:45 125 continues Day 4 11:38 122 2% NS @ 25/hr 6G Day 4 15:25 125 continues Day 4 19:31 125 continues Day 5 00:06 122 continues 6G Day 5 04:04 126 continues Day 5 08:01 122 continues Day 5 11:50 132 stop Day 5 16:14 126 Day 5 19:26 127 Day 6 00:20 129 9.2G Day 6 04:42 127 2% NS @ 40/hr Day 6 08:30 124 continues Day 6 12:29 127 stop Day 6 16:16 127 Salt tabs 2G tid Day 6 20:28 132 continues Day 7 05:22 134 Salt tabs 2G qid 8G Day 7 12:33 135 continues Day 8 07:02 131 stop None Day 8 13:33 136

Nephrotic syndrome results from a problem with the kidneys’ filters, called glomeruli. Glomeruli are tiny blood vessels in the kidneys that remove wastes and excess fluids from the blood and send them to the bladder as urine.

As blood passes through healthy kidneys (pic above), the glomeruli filter out the waste products and allow the blood to retain cells and proteins the body needs. However, proteins from the blood, such as albumin, can leak into the urine when the glomeruli are damaged. In nephrotic syndrome, damaged glomeruli allow 3 grams or more of protein to leak into the urine when measured over a 24-hour period, which is more than 20 times the amount that healthy glomeruli allow.

Mnemonic: Protein LEAC (LEAK): Proteinuria Lipid up Edema Albumin down (losing protein) Cholesterol up

[Pic: Micrographs (x200) of the (A.) outer airway wall, between the airway smooth muscle (ASM) layer and the airway adventitia (dashed line) showing adipose tissue and mucous glands and (B.) inner airway wall (submucosa), between the basement membrane and ASM layer (dashed line) in a case of fatal asthma stained with haematoxylin and eosin. Inflammatory cells were counted within the inner airway wall.

Credit: European Respiratory Journal]

We already know how fatty build-ups in the arteries can increase the chances of developing heart problems, but now scientists have found early evidence the same sort of clogging could happen in the lungs – and it might be linked to asthma.

Asthma is known to be more common in obese people. Scientists analyzed lung samples from 52 people post-mortem. They found the amount of fat in the vital organ increased alongside the deceased’s BMI.

Sir Charles Gairdner Hospital and the University of Western Australia in Perth found that excess adipose tissue swelled the thickness of the airway walls and caused them to become inflamed. Of these lungs, 15 belonged to people who did not suffer asthma, 21 who had asthma but died of other causes, and 16 who died of asthma. A total of 1,373 airways were examined under the microscope using dyes to expose any fatty tissue.

Muscle tissue is made from a collection of highly specialised muscle fibres, formed by the fusion of individual muscle cells (myocytes).

All muscles are contractile and excitable and contain the proteins myosin and actin, which are responsible for contraction. 

Skeletal muscles 

Voluntary muscles

Attached to bones via tendons

Muscle tissue is surrounded by supporting and protecting bands of fibrous connective tissue called fascia

Plentiful nerve and blood supplies which an active muscle requires are located within fascia.

The muscle cells fuse into fibres and contain the contractile proteins actin and myosin, arranged in myofibrils, giving skeletal muscle its histological, striated appearance. 

Within a myofibril, actin and myosin are interleaved, producing the characteristic striated (striped) appearance, which can be seen under the microscope and is shown schematically in the figure below. When a muscle contracts the actin and myosin slide across each other, causing the striations to bunch up.

Energy is required to relax the muscle 

The default condition is contraction

When a muscle runs out of energy it contracts, as occurs in cramp and rigor mortis.

Overlapping proteins actin and myosin produce the characteristic pattern of striations in skeletal muscle. 

Smooth and Cardiac Muscle 

In contrast to skeletal muscle, both cardiac and smooth muscle are involuntary muscles, meaning that we cannot voluntarily control their contraction. 

In cardiac muscle the myocytes form a network, with crosslinks and intercalated discs between the cells. They have striations comparable to those in skeletal muscle.

Smooth muscle is found in the wall of blood vessels and many hollow organs, including the uterus, the bladder and along all parts of the gastrointestinal tract.

Divided into two subgroups; the single-unit (unitary) and multiunit smooth muscle. 

Within single-unit cells, the whole bundle or sheet contracts as a syncytium.

Smooth muscle cells are also present in the eyes and are able to change the size of the iris and alter the shape of the lens.