The major action of ADH is to increase reabsorption of osmotically unencumbered water from the glomerular filtrate and decreases the volume of urine passed. The osmolarity of urine is increased to a maximum of four times that of plasma (approx. 1200 mOsm/kg) by Increasing water reabsorption.

Chronic water loading, Lithium, potassium deficiency, cortisol and calcium excess, all blunt the action of ADH. This leads to nephrogenic diabetes insipidus.

ADH’s primary site of action is the distal tubule and collecting duct.

During fetal development, blood oxygenated by the placenta flows to the foetus through the umbilical vein, bypasses the fetal liver through the ductus venosus, and returns to the fetal heart through the inferior vena cava.

Blood returning from the inferior vena cava then enters the right atrium and is preferentially shunted to the left atrium through the patent foramen ovale. Blood in the left atrium is then pumped from the left ventricle to the aorta. The oxygenated blood ejected through the ascending aorta is preferentially directed to the fetal coronary and cerebral circulations.

Deoxygenated blood returns from the superior vena cava to the right atrium and ventricle to be pumped into the pulmonary artery. Fetal pulmonary vascular resistance (PVR), however, is higher than fetal systemic vascular resistance (SVR); this forces deoxygenated blood to mostly bypass the fetal lungs. This poorly oxygenated blood enters the aorta through the patent ductus arteriosus and mixes with the well-oxygenated blood in the descending aorta. The mixed blood in the descending aorta then returns to the placenta for oxygenation through the two umbilical arteries.

When drugs are bound to proteins, drugs cannot cross membranes and exert their effect. Only the free (unbound) drug can be absorbed, distributed, metabolized, excreted and exert pharmacologic effect. Thus, when amide local anaesthetics are bound to ?1-glycoproteins, their duration of action are reduced.

The potency of local anaesthetics are affected by lipid solubility. Solubility influences the concentration of the drug in the extracellular fluid surrounding blood vessels. The brain, which is high in lipid content, will dissolve high concentration of lipid soluble drugs. When drugs are non-ionized and non-polarized, they are more lipid-soluble and undergo more extensive distribution. Hence allowing these drugs to penetrate the membrane of the target cells and exert their effect.

Tissue pKa and pH will determine the degree of ionization.

Secreted T4 and T3 circulate in the bloodstream almost entirely bound to proteins. Normally only about 0.03% of total plasma T4 and 0.3% of total plasma T3 exist in the free state. Free T3 is biologically active and mediates the effects of thyroid hormone on peripheral tissues in addition to exerting negative feedback on the pituitary and hypothalamus. The major binding protein is thyroxine-binding globulin (TBG), which is synthesized in the liver and binds one molecule of T4 or T3. About 70% of circulating T4 and T3 is bound to TBGl 10% to 15% is bound to another specific thyroid-binding protein called transthyretin (TTR). Albumin binds 15% to 20%, and 3% to lipoproteins. Ordinarily only alterations in TBG concentration significantly affect total plasma T4 and T3 levels.

Two important biological functions have been ascribed to TBG. First, it maintains a large circulating reservoir of T4 that buffers any acute changes in thyroid gland function. Second, binding of plasma T4 and T3 to proteins prevents loss of these relatively small hormone molecules in urine and thereby helps conserve iodide. TTR transports T4 in CSF and provides thyroid hormones to the CNS.

The minimal alveolar concentration (MAC) is the concentration of an inhalation anaesthetic agent in the lung alveoli required to stop a response to the surgical stimulus in 50% of the patient.

Following factors don’t affect the MAC of the inhaled anaesthetic agents:

Gender, acidosis, alkalosis, hypothyroidism, hyperthyroidism, body weight, serum potassium level, and the duration of the anaesthesia.

MAC increase in children, elevated temperature, high metabolic rate, sympathetic increase and chronic alcoholism.

MAC decrease in low temperature, low oxygen level, old age, hypotension (<40 mmHg), depressant drugs e.g. opioids and low level of catecholamines; alpha methyl dopa. Carbon dioxide O2 at the pressure > 120mmHg is being used in anesthetic-Hinkman as an additive effect to decrease MAC, however, increase concentration of CO2 activates the sympathetic system resulting the MAC increases.

During glycolysis, 2,3-diphosphoglycerate (2,3-DPG) is
created in erythrocytes by the Rapoport-Luebering shunt.

The production of 2,3-DPG increases for several conditions
in the presence of decreased peripheral tissue O2 availability.
Some of these conditions include hypoxaemia, chronic lung
disease anaemia, and congestive heart failure. Thus,
2,3-DPG production is likely an important adaptive mechanism.

High levels of 2,3-DPG cause a shift of the curve to the right.
Low levels of 2,3-DPG cause a shift of the curve to the left,
as seen in states such as septic shock and hypophosphatemia.

The toxicity of organophosphorus (OP) nerve agents is manifested through irreversible inhibition of acetylcholinesterase (AChE) at the cholinergic synapses, which stops nerve signal transmission, resulting in a cholinergic crisis and eventually death of the poisoned person. Oxime compounds used in nerve agent antidote regimen reactivate nerve agent-inhibited AChE and halt the development of this cholinergic crisis.

A preplanned preinduction strategy includes the consideration of various interventions designed to facilitate intubation should a difficult airway occur. Non-invasive interventions intended to manage a difficult airway include, but are not limited to: (1) awake intubation, (2) video-assisted laryngoscopy, (3) intubating stylets or tube-changers, (4) SGA for ventilation (e.g., LMA, laryngeal tube), (5) SGA for intubation (e.g., ILMA), (6) rigid laryngoscopic blades of varying design and size, (7) fibreoptic-guided intubation, and (8) lighted stylets or light wands.

Most supraglottic airway devices (SADs) are designed for use during routine anaesthesia, but there are other roles such as airway rescue after failed tracheal intubation, use as a conduit to facilitate tracheal intubation and use by primary responders at cardiac arrest or other out-of-hospital emergencies. Supraglottic airway devices are intrinsically more invasive than use of a facemask for anaesthesia, but less invasive than tracheal intubation. Supraglottic airway devices can usefully be classified as first and second generation SADs and also according to whether they are specifically designed to facilitate tracheal intubation. First generation devices are simply ‘airway tubes’, whereas second generation devices incorporate specific design features to improve safety by protecting against regurgitation and aspiration.

The concentration of solute particles per litre (mosm/L) = the osmolarity of a solution. Changes in water content, ambient temperature, and pressure affects osmolarity. The osmolarity of any solution can be calculated by adding the concentration of key solutes in it.

Individual manufacturers of crystalloids and colloids may have different absolute values but they are similar to these.

0.45% N. Saline with 5% glucose:
Tonicity – hypertonic
Osmolarity – 405 mosm/L
Kilocalories (kCal) – 107

0.9% N. Saline:
Tonicity – isotonic
Osmolarity – 308 mosm/L
Kilocalories (kCal) – 0

5% Dextrose:
Tonicity – isotonic
Osmolarity – 253 mosm/L
Kilocalories (kCal) – 170

Gelofusine (154 mmol/L Na, 120 mmol/L Cl):
Tonicity – isotonic
Osmolarity – 274 mosm/L
Kilocalories (kCal) – 0

Hartmann’s solution:
Tonicity – isotonic
Osmolarity – 273 mosm/L
Kilocalories (kCal) – 9

The following is the alveolar gas equation:

PAO2 = PiO2 − PaCO2/R

Where:

PAO2 is the partial pressure of oxygen in the alveoli.
PiO2 is the partial pressure of oxygen inhaled.
PaCO2 stands for partial pressure of carbon dioxide in the arteries.
The amount of carbon dioxide produced (200 mL/minute) divided by the amount of oxygen consumed (250 mL/minute) equals R = respiratory quotient. With a normal diet, the value is 0.8.

By subtracting the partial pressure exerted by water vapour at body temperature, the PiO2 can be calculated:

PiO2 = 0.21 × (100 kPa − 6.3 kPa)
PiO2 = 19.8

Substituting:
PAO2 = 19.8 − 10/0.8
PAO2 = 19.8 − 12.5
PAO2 = 7.3k Pa

Total body water (TBW) is about 50% to 70% in adults depending on how much fat is present. ECF is relatively contracted in an obese person.

The simple rule is 60-40-20. (60% of weight = total body water, 40% of body weight is ICF and 20% is ECF)

For this woman, the total body water is 36 litres (0.6 × 60). ECF is 12 litres (1/3 of TBW) and 24 litres (2/3 of TBW) is intracellular fluid .

Sodium concentration is approximately 135-145 mmol/L in the ECF.

The ECF is made up of both intravascular and extravascular fluid and plasma proteins is found in both.

Krebs’ cycle (tricarboxylic acid cycle or citric acid cycle) is a sequence of reactions to release stored energy through oxidation of acetyl coenzyme A (acetyl-CoA). Some of the products are carbon dioxide and hydrogen atoms.

The sequence of reactions, known collectively as oxidative phosphorylation, only occurs in the mitochondria (not cytoplasm).

The Krebs cycle can only take place when oxygen is present, though it does not require oxygen directly, because it relies on the by-products from the electron transport chain, which requires oxygen. It is therefore considered an aerobic process. It is the common pathway for the oxidation of carbohydrate, fat and some amino acids, required for the formation of adenosine triphosphate (ATP).

Pyruvate enters the mitochondria and is converted into acetyl-CoA. Acetyl-CoA is then condensed with oxaloacetate, to form citrate which is a six carbon molecule. Citrate is subsequently converted into isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate and finally oxaloacetate.

The only five carbon molecule in the cycle is Alpha-ketoglutarate.

The response of cerebral blood flow (CBF) to hyperoxia (PaO2 >15 kPa, 113 mmHg), the cerebral oxygen vasoreactivity is less well defined. A study originally described, using a nitrous oxide washout technique, a reduction in CBF of 13% and a moderate increase in cerebrovascular resistance in subjects inhaling 85-100% oxygen. Subsequent human studies, using a variety of differing methods, have also shown CBF reductions with hyperoxia, although the reported extent of this change is variable. Another study assessed how supra-atmospheric pressures influenced CBF, as estimated by changes in middle cerebral artery flow velocity (MCAFV) in healthy individuals. Atmospheric pressure alone had no effect on MCAFV if PaO2 was kept constant. Increases in PaO2 did lead to a significant reduction in MCAFV; however, there were no further reductions in MCAFV when oxygen was increased from 100% at 1 atmosphere of pressure to 100% oxygen at 2 atmospheres of pressure. This suggests that the ability of cerebral vasculature to constrict in response to increasing partial pressure of oxygen is limited.

Increases in arterial blood CO2 tension (PaCO2) elicit marked cerebral vasodilation.

CBF increases with general anaesthesia, ketamine anaesthesia, and hypoviscosity.

In the neonatal stage, the tongue is usually large and comes to the normal size at the age of 1 year. The vocal cords lie inverse C4 and as it reaches the grown-up position inverse C5/6 by the age of 4 (not 1 year).

Due to the immature cricoid cartilage, the larynx lies more anterior in newborn children. That’s why the cricoid ring is the narrowest part of the paediatric respiratory tract, while in the adults the tightest portion of the respiratory route is vocal cords. The epiglottis is generally expansive and slants at a point of 45 degrees to the laryngeal opening.

The carina is the ridge of the cartilage in the trachea at the level of T2 in newborn (T4 in adults), that separates the openings of right and left main bronchi.

Neonates have a comparatively low number of alveoli and then this number gradually increases to a most extreme by the age of 8 (not 3 years).

Neonates are obligatory nose breathers and any hindrance can cause respiratory issues (e.g., choanal atresia).

These clinical signs suggest that 15-30% of circulating blood volume has been lost.

Pelvic fractures are associated with significant haemorrhage (>2000 ml) that can be concealed. This may require aggressive fluid resuscitation which is initially with crystalloids and then blood. What is also important is including stabilisation of the fracture(s) and pain relief.

The Advanced Trauma Life Support (ATLS) classification of haemorrhagic shock is as follows:

Class I haemorrhage (blood loss up to 15%):
<750 ml of blood loss
Minimal tachycardia
No changes in blood pressure, RR or pulse pressure
Patients do not normally not require fluid replacement as will be restored in 24 hours, but in trauma, this needs to be correct.

Class II haemorrhage (15-30% blood volume loss):
Uncomplicated haemorrhage requiring crystalloid resuscitation
Represents about 750 – 1500 ml of blood loss
Tachycardia, tachypnoea and a decrease in pulse pressure (due to a rise in diastolic component due action of catecholamines).
There are minimal systolic pressure changes.
There may be associated anxiety, fright or hostility

Class III haemorrhage (30-40% blood volume loss):
Complicated haemorrhagic state – crystalloid and probably blood replacement are required
There are classical signs of inadequate perfusion, marked tachycardia, tachypnoea, significant changes in mental state and measurable fall in systolic pressure.
Almost always require blood transfusion, but decision based on patient initial response to fluid resuscitation.

Class IV haemorrhage (> 40% blood volume loss):
Preterminal event patient will die in minutes
Marked tachycardia, significant depression in systolic pressure and very narrow pulse pressure (or unobtainable diastolic pressure)
Mental state is markedly depressed
Skin cold and pale.
Needs rapid transfusion and immediate surgical intervention.

A blood loss of >50% results in loss of consciousness, pulse and blood pressure.

Fluid resuscitation following trauma is a controversial area.

This clinical scenario points to a 15-30% blood loss. However, further crystalloid and blood replacement may be required after assessing the clinical situation. There is increasing evidence to suggest that transfusion of large volumes of crystalloid in the hospital setting are likely to be deleterious to the patient and hypotensive resuscitation and judicious blood and blood product resuscitation is a more appropriate option. A ratio of 1 unit of plasma to 1 unit of red blood cells is used to replace fluid volume in adults.

This patient does not require immediate transfusion of O negative blood and there is time for a formal crossmatch. The argument about colloids versus crystalloids has existed for decades. However, while they have a role in fluid resuscitation, they are not first line.

There is a risk of anaphylaxis, Hypernatraemia, and acute renal injury with colloidal solutions.

The derived unit of energy, work or amount of heat is joule (J). It is defined as the amount of energy expended if a force of one newton (N) is applied through a distance of one metre (N·m)

J = 1 kg·m/s2·m = 1 kg·m2/s2 or 1 kg·m2·s-2

Kinetic energy (KE) = ½ MV2

An object with a mass of 1500 kg moving at 30 m/s correlates to 675 kJ:

KE = ½ (1500) × (30)2 = 750 × 900 = 675 kJ

Total energy released when 1 kg fat is metabolised to CO2 and water is 37 MJ. 1 g fat produces 37 kJ/g, therefore 1 kg fat produces 37,000 × 1000 = 37 MJ.

Raising the temperature of 1 kg water from 0°C to 100°C correlates to 420 kJ. The amount of energy needed to change the temperature of 1 kg of the substance by 1°C is the specific heat capacity. We have 1 kg water therefore:

4,200 J × 100 = 420,000 J = 420 kJ

In order to calculate the energy involved in raising a 100 kg mass to a height of 1 km against gravity, we need to calculate the potential energy (PE) of the mass:

PE = mass × height attained × acceleration due to gravity
PE = 100 kg × 1000 m × 10 m/s2 = 1 MJ

The heat generated when a direct current of 10 amps flows through a heating element for 10 seconds when the potential difference across the element is 1000 volts can be calculated by applying Joule’s law of heating:

Work done (WD) = V (potential difference) × I (current) × t (time)
WD = 10 × 10 × 1000 = 100 kJ

Changes in the osmolality of body fluids (changes as minor as 1% are sufficient) play the most important role in regulating AVP secretion. The receptors that monitor changes in osmolality of body fluids (termed osmoreceptors) are distinct from the cells that synthesize and secrete AVP, and are located in the organum vasculosum of the lamina terminalis (OVLT) of the hypothalamus. The osmoreceptors sense changes in body osmolality by either shrinking or swelling. When the effective osmolality of the plasma increases, the osmoreceptors send signals to the AVP synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus, and AVP synthesis and secretion are stimulated. Conversely, when the effective osmolality of the plasma is reduced, secretion is inhibited. Because AVP is rapidly degraded in the plasma, circulating levels can be reduced to zero within minutes after secretion is inhibited.

In this scenario, the osmolality of the plasma will decrease to an estimate of 2.5%, hence inhibition of AVP.

Stimulation of atrial stretch receptors is incorrect because the increase in plasma volume is still below the threshold for its activation.

Osmotic diuresis is incorrect because 5% dextrose is isotonic, hence osmotic diuresis is not probable.

Renin is inhibited when an excess of NaCl in the tubular fluid is sensed by the macula densa.

Second messengers relay signals to target molecules in the cytoplasm or nucleus when an agonist interacts with a receptor on the cell surface. They also amplify the strength of the signal. The most ubiquitous and abundant second messenger is calcium and it regulates multiple cellular functions in the body.

These include:
Muscle contraction (skeletal, smooth and cardiac)
Exocytosis (neurotransmitter release at synapses and insulin secretion)
Apoptosis
Cell adhesion to the extracellular matrix
Lymphocyte activation
Biochemical changes mediated by protein kinase C.

cAMP is either inhibited or stimulated by G proteins.

The receptors in the body that stimulate G proteins and increase cAMP include:

Beta (?1, ?2, and ?3)
Dopamine (D1 and D5)
Histamine (H2)
Glucagon
Vasopressin (V2).

The second messenger for the action of nitric oxide (NO) and atrial natriuretic peptide (ANP) is cGMP.

The second messengers for angiotensin and thyroid stimulating hormone are inositol triphosphate (IP3) and diacylglycerol (DAG).

After the carotid body, the thyroid gland is the second most richly vascular organ in the body.

The global blood flow to the thyroid gland can be measured using:
1. Colour ultrasound sonography
2. Quantitative perfusion maps using MRI of the thyroid gland using an arterial spin labelling (ASL) method.

This table shows the blood flow to various organs of the body at rest:
Organ Blood Flow(ml/minute/100g)
Hepatoportal 58
Kidney 420
Brain 54
Skin 13
Skeletal muscle 2.7
Heart 87
Carotid body 2000
Thyroid gland 560

Skeletal muscle blood flow is in the range of 1-4 ml/min per 100 g when at rest. Blood flow can reach 50-100 ml/min per 100 g during exercise. With maximal vasodilation, blood flow can increase 20 to 50 times.

The adrenal medulla releases catecholamines and increases neural sympathetic activity during exercise. Normally, alpha-1 and alpha-2 would cause vasoconstriction in the muscle groups being used, but vasodilatory metabolites override these effects, resulting in a so-called functional sympathectomy. Local hypoxia and hypercarbia, nitric oxide, K+ ions, adenosine, and lactate are some of the stimuli that cause vasodilation.

However, the splanchnic and cutaneous circulations, which supply inactive muscles, vasoconstrict.

Sympathetic cholinergic innervation of skeletal muscle arteries is found in some species (such as cats and dogs, but not humans). Vasodilation is induced by stimulating smooth muscle beta-2 adrenoreceptors, but at rest, the alpha-adrenoreceptor effects of adrenaline and noradrenaline predominate. During exercise, the skeletal muscle pump promotes venous emptying, but it does not necessarily increase blood flow.