Dabigatran template is a prodrug and its active metabolite is a direct thrombin inhibitor. It is a synthetic, reversible, non-peptide thrombin inhibitor. This inhibition of thrombin results in a decrease of fibrin and reduces platelet aggregation.

Drugs like warfarin act by inhibiting the activation of vitamin K-dependent clotting factors. These factors are synthesized by the liver and activated by gamma-carboxylation of glutamate residues with the help of vitamin K. Hydroquinone form of vitamin K is converted to epoxide form in this reaction and regeneration of hydroquinone form by enzyme vitamin K epoxide reductase (VKOR) is required for this activity. Oral anticoagulants prevent this regeneration by inhibiting VKOR, thus vitamin K-dependent factors are not activated. These factors include clotting factors II, VII, IX, and X as well as anti-clotting proteins, protein C and protein S.

Mean, also known as the average, is the most common measure of central tendency. It is the sum of all observed values divided by the number of observation. It is not useful for skewed data, which has an abnormal distribution. It is useful, instead, for numerical data that have symmetric distribution. It reflects the contributions of each data in the group, and are sensitive to outliers.

The median is the value that falls in the middle position when the observations are ranked in order from the smallest to the largest. If the number of observations is odd, the median is the middle number. If it is even, the median is the average of the two middle numbers. Unlike the mean, the median is useful on skewed data, and can be used for ordinal or numerical data if skewed.

The mode is the value that occurs with the greatest frequency in a set of observations, and is utilized for bimodal distribution.

The variance and the standard deviation are not measures of central tendency, but of dispersion.

Dopamine (DA) is a dopaminergic (D1 and D2) as well as adrenergic α and β1 (but not β2 ) agonist.

The D1 receptors in renal and mesenteric blood vessels are the most sensitive: i.v. infusion of a low dose of DA dilates these vessels (by raising intracellular cAMP). This increases g.f.r. In addition, DA exerts a natriuretic effect by D1 receptors on proximal tubular cells.

Moderately high doses produce a positive inotropic (direct β1 and D1 action + that due to NA release), but the little chronotropic effect on the heart.

Vasoconstriction (α1 action) occurs only when large doses are infused.

At doses normally employed, it raises cardiac output and systolic BP with little effect on diastolic BP. It has practically no effect on nonvascular α and β receptors; does not penetrate the blood-brain barrier€”no CNS effects.

Dopamine is used in patients with cardiogenic or septic shock and severe CHF wherein it increases BP and urine outflow.

It is administered by i.v. infusion (0.2€“1 mg/min) which is regulated by monitoring BP and rate of urine formation

The thyroid gland is a gland shaped like a butterfly which lies at the base of the anterior neck. It controls metabolism using hormone secretion.

Iodine is extremely important for the synthesis of hormones within the thyroid. It is internalised into the thyroid follicular cells via the sodium/iodide symporter (NIS).

The parathyroid glands are found posterior to the thyroid gland, with the recurrent laryngeal nerves running posteromedially.

The expected weight of a normal thyroid gland is about 30 grams.

Platelets are fragments of megakaryocytes and they are encapsulated by membrane.

They have no nucleus but are metabolically active and are able to express membrane receptors and release stored substances when triggered. adenosine diphosphate and serotonin are 2 of its content.

Because they have no nucleus, they are not able to produce new proteins. This is why aspirin and other drugs affect function for their entire lifespan after exposure. Its lifespan is approximately 9-10 days in normal individuals.

Platelets does NOT PRODUCE prostacyclin but are able to produce nitric oxide, prostaglandins and thromboxane.

Atrial natriuretic peptide (ANP) is secreted mainly from myocytes of right atrium and ventricle in response to increased blood volume.
It is secreted by both the right and left atria (right >> left).

It is a 28 amino acid peptide hormone, which acts via cGMP
degraded by endopeptidases.

It serves to promote the excretion of sodium, lowers blood pressure, and antagonise the actions of angiotensin II and aldosterone.

Functional residual capacity (FRC) is 1.7 to 3.5L/kg

A capacity is the sum of two or more volumes. The total lung capacity (TLC) is total sum of the volume of gas present in all lung compartments upon maximum inspiration. It is represented mathematically as:

Total lung capacity (TLC) = Vital capacity (VC) + Residual volume (RV)

The residual volume (RV) is the volume of gas still present within the lung post maximum exhalation. It cannot be measured by spirometry, but can be using a body plethysmograph and also with the helium dilution technique.

Closing capacity (CC) is the volume of gas within the lungs at which small airways close upon expiration. It increases with age and is especially important when it surpasses the FRC as it causes changes in ventilation/perfusion mismatch and hypoxia.
In the supine position, a patient with a normal body mass index and no history of lung pathology, the CC equals the FRC at approximately 44, and at approximately 66 at standing position.

The Delphi is a group facilitation technique that seeks to obtain consensus on the opinions of `experts’ through a series of structured questionnaires (commonly referred to as rounds). By using successive questionnaires, opinions are considered in a non-adversarial manner, with the current status of the groups’ collective opinion being repeatedly fed back. Studies employing the Delphi make use of individuals who have knowledge of the topic being investigated

Dopamine (DA) is a dopaminergic (D1 and D2) as well as adrenergic α and β1 (but not β2 ) agonist.

The D1 receptors in renal and mesenteric blood vessels are the most sensitive: i.v. infusion of a low dose of DA dilates these vessels (by raising intracellular cyclic adenosine monophosphate).

Moderately high doses produce a positive inotropic (direct β1 and D1 action + that due to NA release), but the little chronotropic effect on the heart.

Vasoconstriction (α1 action) occurs only when large doses are infused.

At doses normally employed, it raises cardiac output and systolic BP with little effect on diastolic BP. It has practically no effect on nonvascular α and β receptors; does not penetrate the blood-brain barrier€”no Central nervous system effects.

Dopamine is less arrhythmogenic than adrenaline

Regarding dopamine part of the dose is converted to Noradrenaline in sympathetic nerve terminals.

A higher frequency ultrasound comes with a better resolution of the digital image. Ultrasound with a frequency of 15 MHz is best used in imaging of superficial organs such as the thyroid gland, muscles, tendons and breasts whereas deep organs are better imaged using a lower frequency of 2-7MHz because of its ability for deeper penetration but lower resolution. These low frequency probes are also used to diagnose ascites, pleural effusions or can be used in echocardiography.

The US probe emits and then absorbs a reflected wave. Similar to brightness control, increasing the gain will amplify the return signal which is then attenuated by the tissue. This increases the signal to noise ratio.
A high frame rate, which basically means the number of times an image is updated onto the screen per second, improves the resolution of a moving 3D image which has become more accurate as the computing power has increased.

Widening of the image field can be obtained by altering the penetration depth which is obtained by changing the frequency of the US beam.

The functional residual capacity (FRC) is the volume in the lungs at the end of passive expiration. It is determined by opposing forces of the expanding chest wall and the elastic recoil of the lung. A normal FRC = 1.7 to 3.5 L. It a marker for lung function, and, during this time, the alveolar pressure is equal to the atmospheric pressure.

FRC cannot be measured by spirometry because it contains the residual volume.

Tidal volume, inspiratory reserve volume, forced expiratory volume in 1 second, and vital capacity can be measured directly.

An ankle block is commonly used for anaesthesia and postoperative analgesia when operating on bunions. It results in the selective block of the superficial peroneal, deep peroneal, and posterior tibial nerves.

The deep peroneal nerve supplies sensory input to the web space between the first and second toes (L4-5).

The L2-S1 nerve, often known as the superficial peroneal nerve, is a mixed motor and sensory neuron. It gives sensory supply to the anterolateral region of the leg, the anterior aspect of the 1st, 2nd, 3rd, and 4th toes, and innervates the peroneus longus and brevis muscles (with the exception of the web space between 1st and 2nd toes).

The sensory area of the saphenous nerve (L3-4) in the foot stretches from the proximal portion of the midfoot on the medial side to the proximal part of the midfoot on the lateral side.

The lateral side of the little (fifth) toe is innervated by the sural nerve’s sensory supply (S1-2). The heel, medial (medial plantar nerve), and lateral (lateral plantar nerve) soles of the foot are all served by the posterior tibial nerve.

Ambient pressure has no effect on a volatile agent’s saturated vapour pressure (SVP). At a temperature of 20°C, the SVP of sevoflurane is approximately 21 kPa, or 21% of atmospheric pressure (100 kPa).

The SVP of sevoflurane remains the same when the ambient pressure is doubled to 200 kPa, but the output of the vaporiser is halved, now 21 percent of 200 kPa, equalling 10.5 percent. The vaporiser’s output has increased to 1%, but the partial pressure output has remained unchanged. The splitting ratio will not change because it is determined by temperature changes.

Calculations can be made as follows:

Vaporizer output % (ambient pressure) = % volatile (calibrated) x 100 kPa calibrated pressure/ambient pressure
2% = 2% (dialled) × 100/100
2% of 100 = 2 kPa

Altitude, pressure 50 kPa
4% = 2% (dialled) × 100/50
4% of 50 = 2 kPa

High pressure at 200 kPa
1% = 2% (dialled) × 100/200
1% of 200 = 2 kPa

Sevoflurane has a boiling point of 58°C and, unlike desflurane (which has a boiling point of 22.8°C), does not need to be heated and pressurised with a Tec 6 vaporiser.

Creatinine clearance is a test used to approximate the glomerular filtration rate (GFR) as an assessment of kidney function.

Creatinine is formed during the breakdown of dietary sources of meat and skeletal muscle. It is secreted at a consistent concentration and pace into the body’s circulation, and is easily filtered across the glomerulus without being reabsorbed or metabolized by the kidney.

It is represented mathematically as:
Creatinine clearance (CL) = U x V/P
where,
U: Urinary creatinine concentration (mg/mL)
V: Volume of urine (mL/min)
P: Plasma creatinine concentration (mg/mL)

Therefore, in this case:
CL: 1.25 x 1 = 125mL/min.

The tracheobronchial tree is subdivided into the conducting and the respiratory zones.

The zones from proximal to distal are:

Trachea
Bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar ducts
Alveolar sacs

from the trachea to terminal bronchioles are the conducting zone while the respiratory zone is from the respiratory bronchioles to the alveola sacs.

Randomized controlled trails will be analysed by the intention-to-treat (ITT) approach. It provides unbiased comparisons among the treatment groups. ITT analyses are done to avoid the effects of dropout, which may break the random assignment to the treatment groups in a study.

ITT analysis is a comparison of the treatment groups that includes all patients as originally allocated after randomization.

In order to include such participants in an analysis, outcome data could be imputed which involves making assumptions about the outcomes in the lost participants.

With regards to the autonomic nervous system (ANS)

1. It is not under voluntary control
2. It uses reflex pathways and different to the somatic nervous system.
3. The hypothalamus is the central point of integration of the ANS. However, the gut can coordinate some secretions and information from the baroreceptors which are processed in the medulla.

With regards to the central nervous system (CNS)
1. There are myelinated preganglionic fibres which lead to the
ganglion where the nerve cell bodies of the non-myelinated post ganglionic nerves are organised.
2. From the ganglion, the post ganglionic nerves then lead on to the innervated organ.

Most organs are under control of both systems although one system normally predominates.

The nerves of the sympathetic nervous system (SNS) originate from the lateral horns of the spinal cord, pass into the anterior primary rami and then pass via the white rami communicates into the ganglia from T1-L2.

There are short pre-ganglionic and long post ganglionic fibres.
Pre-ganglionic synapses use acetylcholine (ACh) as a neurotransmitter on nicotinic receptors.
Post ganglionic synapses uses adrenoceptors with norepinephrine / epinephrine as the neurotransmitter.
However, in sweat glands, piloerector muscles and few blood vessels, ACh is still used as a neurotransmitter with nicotinic receptors.

The ganglia form the sympathetic trunk – this is a collection of nerves that begin at the base of the skull and travel 2-3 cm lateral to the vertebrae, extending to the coccyx.

There are cervical, thoracic, lumbar and sacral ganglia and visceral sympathetic innervation is by cardiac, coeliac and hypogastric plexi.

Juxta glomerular apparatus, piloerector muscles and adipose tissue are all organs under sole sympathetic control.

The PNS has a craniosacral outflow. It causes reduced arousal and cardiovascular stimulation and increases visceral activity.

The cranial outflow consists of
1. The oculomotor nerve (CN III) to the eye via the ciliary ganglion,
2. Facial nerve (CN VII) to the submandibular, sublingual and lacrimal glands via the pterygopalatine and submandibular ganglions
3. Glossopharyngeal (CN IX) to lungs, larynx and tracheobronchial tree via otic ganglion
4. The vagus nerve (CN X), the largest contributor and carries ¾ of fibres covering innervation of the heart, lungs, larynx, tracheobronchial tree parotid gland and proximal gut to the splenic flexure, liver and pancreas

The sacral outflow (S2 to S4) innervates the bladder, distal gut and genitalia.

The PNS has long preganglionic and short post ganglionic fibres.
Preganglionic synapses, like in the SNS, use ACh as the neuro transmitter with nicotinic receptors.
Post ganglionic synapses also use ACh as the neurotransmitter but have muscarinic receptors.

Different types of these muscarinic receptors are present in different organs:
There are:
M1 = pupillary constriction, gastric acid secretion stimulation
M2 = inhibition of cardiac stimulation
M3 = visceral vasodilation, coronary artery constriction, increased secretions in salivary, lacrimal glands and pancreas
M4 = brain and adrenal medulla
M5 = brain

The lacrimal glands are solely under parasympathetic control.

With respect to oxygen transport in cells, almost all oxygen is transported within erythrocytes. There is limited solubility and only 1% is carried as solution. Thus, the amount of oxygen transported depends upon haemoglobin concentration and its degree of saturation.

Haemoglobin is a globular protein composed of 4 subunits. Haem is made up of a protoporphyrin ring surrounding an iron atom in its ferrous state. The iron can form two additional bonds – one is with oxygen and the other with a polypeptide chain.
There are two alpha and two beta subunits to this polypeptide chain in an adult and together these form globin. Globin cannot bind oxygen but can bind to CO2 and hydrogen ions.
The beta chains are able to bind to 2,3 diphosphoglycerate. The oxygenation of haemoglobin is a reversible reaction. The molecular shape of haemoglobin is such that binding of one oxygen molecule facilitates the binding of subsequent molecules.

The oxygen dissociation curve (ODC) describes the relationship between the percentage of saturated haemoglobin and partial pressure of oxygen in the blood.
Of note, it is not affected by haemoglobin concentration.

Chronic anaemia causes 2, 3 DPG levels to increase, hence shifting the curve to the right

Haldane effect – Causes the ODC to shift to the left. For a given oxygen tension there is increased saturation of Hb with oxygen i.e. Decreased oxygen delivery to tissues.
This can be caused by:
-HbF, methaemoglobin, carboxyhaemoglobin
-low [H+] (alkali)
-low pCO2
-ow 2,3-DPG
-ow temperature

Bohr effect – causes the ODC to shifts to the right = for given oxygen tension there is reduced saturation of Hb with oxygen i.e. Enhanced oxygen delivery to tissues. This can be caused by:
– raised [H+] (acidic)
– raised pCO2
-raised 2,3-DPG
-raised temperature

The magnitude of x determines the rate of change of x. First-order drug kinetics is a good example. Most drugs’ plasma levels are controlled by an exponential process. The rate of change in drug metabolism is proportional to the current plasma concentration (so-called non-linear kinetics).

A tear-away function is just one type of exponential relationship (y = ex), in which e is Euler’s number, x is the power, and e is the base. Natural logarithms rely on Euler’s number.

Euler’s number is a mathematical constant, not a mathematical principle. It’s referred to as an irrational number. This is a number that cannot be expressed as a simple fraction or a ratio.

A line or curve that acts as the limit of another line or curve is known as an asymptote. A washout exponential curve, for example, where the value y represents the plasma concentration of a drug in a single compartment model against time on the x axis. This descending curve approaches but never touches the x axis. This curve is asymptotic to the x axis, which is the curve’s asymptote. An asymptote isn’t just a characteristic of exponential curves.

A patient presenting with symptomatic asthma should be assessed for severity to determine appropriate management options. Indications of acute severe asthma are:

Peak expiratory flow rate (PEFR): 33-50% best/predicted
Respiratory rate: ‰¥25/min
Heart rate: ‰¥110/min
Inability to finish a complete sentence in a single breath.

Oxygen saturation should be measured. Any measurement of an oxygen saturation of 92% or less, either on air or on oxygen, indicates severe, life threatening asthma, and requires an arterial blood gas (ABG) to detect normo- or hypercarbia.

A chest x-ray would not be routine as it will not provide any relevant information. It is only required in specific cases, including:
Diagnosis of a subcutaneous emphysema
Indications of a unilateral pneumothorax
Indications of a lobar collapse of consolidation
Treatment-resistance life-threatening asthma
If mechanical ventilation is indicated

A peak expiratory flow rate (PEFR) can provide relevant information to help distinguish between acute, moderate, severe and life threatening asthma. However, it is not necessary as other parameters exist that can also help make the same distinction.

An ECG is indicated in this case as the patient has tachycardia and tachypnoea which are indicative of acute severe asthma. The ECG would indicate if arrhythmia is also present which would suggest life-threatening asthma.