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).

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

Carbonic anhydrase is an enzyme which contains zinc and can be found in:
1. Erythrocytes
2. Pulmonary endothelium
3. The intestine
4. Pancreas
5. Cardiac muscle and skeletal muscle.

To date, there have been seven isoenzymes identified. Of note, isoenzyme IV is found in the brush border of the proximal convoluted tubule and isoenzyme II is found within the luminal cells.

Acetazolamides a carbonic anhydrase inhibitor and is used as prophylaxis against mountain sickness and in glaucoma management.

Spironolactone is a potassium diuretic and is an aldosterone antagonist.

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.

Smoking is a major risk factor associated with perioperative respiratory and cardiovascular complications. Evidence also suggests that cigarette smoking causes imbalance in the prostaglandins and promotes vasoconstriction and excessive platelet aggregation. Two of the constituents of cigarette smoke, nicotine and carbon monoxide, have adverse cardiovascular effects. Carbon monoxide increases the incidence of arrhythmias and has a negative ionotropic effect both in animals and humans.

Smoking causes an increase in carboxyhaemoglobin levels, resulting in a leftward shift in which appears to represent a risk factor for some of these cardiovascular complications.

There are two mechanisms responsible for the leftward shift of oxyhaemoglobin dissociation curve when carbon monoxide is present in the blood. Carbon monoxide has a direct effect on oxyhaemoglobin, causing a leftward shift of the oxygen dissociation curve, and carbon monoxide also reduces the formation of 2,3-DPG by inhibiting glycolysis in the erythrocyte. Nicotine, on the other hand, has a stimulatory effect on the autonomic nervous system. The effects of nicotine on the cardiovascular system last less than 30 min.

Systemic vascular resistance (SVR), also known as total peripheral resistance (TPR), is the amount of force exerted on circulating blood by the vasculature of the body. Three factors determine the force: the length of the blood vessels in the body, the diameter of the vessels, and the viscosity of the blood within them. The most important factor that determines the systemic vascular resistance (SVR) is the tone of the small arterioles.

These are otherwise known as resistance arterioles. Their diameter ranges between 100 and 450 µm. Smaller resistance vessels, less than 100 µm in diameter (pre-capillary arterioles), play a less significant role in determining SVR. They are subject to autoregulation.

Any change in the viscosity of blood and therefore flow (such as due to a change in haematocrit) might also have a small effect on the measured vascular resistance.

Changes of blood temperature can also affect blood rheology and therefore flow through resistance vessels.

Systemic vascular resistance (SVR) is measured in dynes·s·cm-5

It can be calculated from the following equation:

SVR = (mean arterial pressure − mean right atrial pressure) × 80 cardiac output

In situations of poisoning or drug overdose with acid dugs like salicylates and barbiturates, forced alkaline diuresis may be used.

With regards to overdose with alkaline drugs, forced acid diuresis is used.

By changing the pH of the urine, the ionised portion of the drug stays in the urine, and this prevents its diffusion back into the blood. Charged molecules do not readily cross biological membranes.

The process involves the infusion of specific fluids at a rate of about 500ml per hour. This requires monitoring of the central venous pressure, urine output, plasma electrolytes, especially potassium, and blood gas analysis.

The fluid regimen recommended is:
500ml of 1.26% sodium bicarbonate (not 200ml of 8.4%)
500ml of 5% dextrose and
500ml of 0.9% sodium chloride.

CBF is defined as the blood volume that flows per unit mass per unit time in brain tissue and is typically expressed in units of ml blood/100 g tissue/minute. The normal average CBF in adults human is about 50 ml/100 g/min, with lower values in the white matter (,20 ml/100 g/min) and greater values in the gray matter (,80 ml/100 g/min).

Low CBF levels between 30-40 ml/100 g/min may begin to show poor prognostic EEG. EEG findings consistently associated with a poor outcome are isoelectric EEG, low voltage EEG, and burst suppression (specifically burst suppression with identical bursts), as well as the absence of EEG reactivity.

The respiratory quotient is the ratio of CO2 produced to O2 consumed while food is being metabolized:

RQ = CO2 eliminated/O2 consumed

Most energy sources are food containing carbon, hydrogen and oxygen. Examples include fat, carbohydrates, protein, and ethanol. The normal range of respiratory coefficients for organisms in metabolic balance usually ranges from 1.0-0.7.

Granulated sugar is a refined carbohydrate with no significant fat, protein or ethanol content.

The RQ for carbohydrates is = 1.0

The RQ for the rest of the compounds are:

Fats RQ = 0.7
The chemical composition of fats differs from that of carbohydrates in that fats contain considerably fewer oxygen atoms in proportion to atoms of carbon and hydrogen.

Protein RQ = 0.8
Due to the complexity of various ways in which different amino acids can be metabolized, no single RQ can be assigned to the oxidation of protein in the diet; however, 0.8 is a frequently utilized estimate.

The cardiac action potential has several phases which have different mechanisms of action as seen below:
Phase 0: Rapid depolarisation – caused by a rapid sodium influx.
These channels automatically deactivate after a few ms

Phase 1: caused by early repolarisation and an efflux of potassium.

Phase 2: Plateau – caused by a slow influx of calcium.

Phase 3 – Final repolarisation – caused by an efflux of potassium.

Phase 4 – Restoration of ionic concentrations – The resting potential is restored by Na+/K+ATPase.
There is slow entry of Na+into the cell which decreases the potential difference until the threshold potential is reached. This then triggers a new action potential

Of note, cardiac muscle remains contracted 10-15 times longer than skeletal muscle.

Different sites have different conduction velocities:
1. Atrial conduction – Spreads along ordinary atrial myocardial fibres at 1 m/sec

2. AV node conduction – 0.05 m/sec

3. Ventricular conduction – Purkinje fibres are of large diameter and achieve velocities of 2-4 m/sec, the fastest conduction in the heart. This allows a rapid and coordinated contraction of the ventricles

The following is the Advanced Trauma Life Support (ATLS) classification of haemorrhagic shock:

Class I haemorrhage:
It has blood loss up to 15%. There is very less tachycardia, and no changes in blood pressure, RR or pulse pressure. Usually, fluid replacement is not required.

Class II haemorrhage:
It has 15-30% blood loss, equivalent to 750 – 1500 ml. There is tachycardia, tachypnoea and a decrease in pulse pressure. Patient may be frightened, hostile and anxious. It can be stabilised by crystalloid and blood transfusion.

Class III haemorrhage:
There is 30-40% blood loss. It portrays inadequate perfusion, marked tachycardia, tachypnoea, altered mental state and fall in systolic pressure. It requires blood transfusion.

Class IV haemorrhage:
There is > 40% blood volume loss. It is a preterminal event, and the patient will die in minutes. It portrays tachycardia, significant depression in systolic pressure and pulse pressure, altered mental state, and cold clammy skin. There is need for rapid transfusion and surgical intervention.

The half life of Retinol binding protein (RBP) is 10-12 hours and therefore reflects more acute changes in protein metabolism than any of these proteins. Therefore it is not commonly used as a parameter for nutritional assessment.

The half life of Transthyretin (thyroxine binding pre-albumin) is only one to two days and so levels are less sensitive and this protein is not an albumin precursor. 15 mg/dL represents early malnutrition and a need for nutritional support.

Albumin levels have been frequently as a marker of nutrition but this is not a very sensitive marker. It’s half life more than 30 days and significant change takes some time to be noticed. Also, synthesis of albumin is decreased with the onset of the stress response after burns. Unrelated to nutritional status, the synthesis of acute phase proteins increases and that of albumin decreases.

A more accurate indicator of protein stores is transferrin. It’s response to acute changes in protein status is much faster. The half life of serum transferrin is shorter (8-10 days) and there are smaller body stores than albumin. A low serum transferrin level is below 200 mg/dL and below 100 mg/dL is considered severe. Serum transferrin levels can also affect serum transferrin level.

Fibronectin is used a nutritional marker but levels decrease after seven days of starvation. It is a glycoprotein which plays a role in enhancing the phagocytosis of foreign particles.

The ions found in higher concentrations intracellularly than outside the cells are:

ATP
AMP
Potassium
Phosphate, and
Magnesium Adenosine diphosphate (ADP)

Sodium is a primarily extracellular ion.

The guidelines for the management of cardiac arrest in hypothermic patients published by the UK Resuscitation Council differ slightly from the standard algorithm.

In a patient with a core temperature of less than 30°C, do the following:

If you’re on the shockable side of the algorithm (VF/VT), you should give three DC shocks.
Further shocks are not recommended until the patient has been rewarmed to a temperature of more than 30°C because the rhythm is refractory and unlikely to change.
There should be no drugs given because they will be ineffective.

In a patient with a core temperature of 30°C to 35°C, do the following:

DC shocks are used as usual.
Because they are metabolised much more slowly, the time between drug doses should be doubled.

Active rewarming and protection against hyperthermia should be given to the patient.

Option e is false because there is insufficient information to determine whether resuscitation should be stopped.

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.

Osmolarity refers to the osmotic pressure generated by the dissolved solute molecules in 1 L of solvent. Measurements of osmolarity are temperature dependent because the volume of the solvent varies with temperature. The higher the osmolarity of a solution, the more it attracts water from an opposite compartment.

Osmolarity can be computed using the following formulas:

Osmolarity = Concentration x number of dissociable particles; OR
Plasma osmolarity (Posm) = 2([Na+]) + (glucose in mmol/L) + (BUN in mmol/L)

Posm = 2 (144) + 3.5 + 9.5 = 301 mOsm/L

Suppose there is electrical neutrality, the formula will double the cation activity to account for the anions.

Plasma osmolarity (Posm) = 2([Na+] + [K+]) + (glucose in mmol/L) + (BUN in mmol/L)

Posm = 2 (144 + 6) + 3.5 + 9.5 = 313 mOsm/L

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.

Hypoxic Pulmonary vasoconstriction (HPV) reflects the constriction of small pulmonary arteries in response to hypoxic alveoli (.i.e.; PO2 below 80-100mmHg or 11-13kPa).

These blood vessels become independent of the nerve stimulus, when blood with a high PO2 flows through the lung which contains a low alveolar PO2.

Thus a low PO2 within the alveoli has been shown to impact on hypoxic pulmonary vasoconstriction (HPV) more than a low PO2 within the blood.

HPV results in the blood flow being directed away from poorly ventilated areas of the lung and helps to reduce the ventilation/perfusion mismatch (not increase).

In animals, volatile anaesthetic agents can diminish HPV, while in adults, the evidence proves less persuading, in spite of the fact that it certainly doesn’t strengthen the effects.

HPV response will be suppressed by 20 parts per million (ppm) of nitric oxide.

Heme a exists in cytochrome a and heme c in cytochrome c; they are both involved in the process of oxidative phosphorylation. 5′-Aminolevulinic acid synthase (ALA-S) is the regulated enzyme for heme synthesis in the liver and erythroid cells.

There are two forms of ALA Synthase, ALAS1, and ALAS2.

Body fluid compartments in a 70kg male:
Total volume=42L (60% body weight)
Intracellular fluid compartment (ICF) =28L
Extracellular fluid compartment (ECF) = 14L

ECF comprises:
Intravascular fluid (plasma) = 3L
Extravascular fluid = 11L

Extravascular fluids comprises:
Interstitial fluid = 10.5L
Transcellular fluid = 0.5L

The ‘ideal’ alveolar PO2 minus arterial PO2 is the alveolar-arterial (A-a) oxygen difference.

The ‘ideal’ alveolar PO2 is derived from the alveolar air equation and is the PO2 that the lung would have if there was no ventilation-perfusion (V/Q) inequality and it was exchanging gas at the same respiratory exchange ratio as real lung.

The amount of oxygen in the blood is measured directly in the arteries.

The A-a oxygen difference (or gradient) is a useful measure of shunt and V/Q mismatch, and it is less than 2 kPa in normal adults breathing air (15 mmHg). Because the shunt component is not corrected, the A-a difference increases when breathing 100 percent oxygen, and it can be up to 15 kPa (115 mmHg).

An abnormally low or abnormally high V/Q ratio within the lung can cause an increased A-a difference, though the former is more common. Atelectasis, which results in a low V/Q ratio, is the most likely cause of an A-a difference in a healthy adult breathing 100 percent oxygen.

Hypoventilation may cause an increase in alveolar (and thus arterial) CO2, lowering alveolar PO2 according to the alveolar air equation.

The alveolar PO2 is also reduced at high altitude.

Healthy people are unlikely to have a right-to-left shunt or an oxygen transport diffusion defect.

Glycolysis occurs in the cytoplasm of the cell. It converts 1 glucose molecule (6-carbon) to pyruvate (two 3-carbon molecules) and produces 4 ATP molecules and 2NADH but uses 2 ATP in the process with an overall net energy production of 2 ATP.

Pyruvate is then oxidised to acetyl coenzyme A (generating 2 NADH per pyruvate molecule). This takes place in the mitochondria and then enters the Krebs cycle (citric acid cycle). It produces 2 ATP, 8 NADH and 2 FADH2 per glucose molecule.

Electron transport phosphorylation takes place in the mitochondria. The aim of this process is to break down NADH and FADH2 and also to pump H+ into the outer compartment of the mitochondria. It produces 32 ATP with an overall net production of 36ATP.

In anaerobic respiration which occurs in the cytoplasm, pyruvate is reduced to NAD producing 2 ATP.

Awareness during general anaesthesia is a frightening experience, which may result in serious emotional injury and post-traumatic stress disorder.

The incidence of awareness during general anaesthesia with current anaesthetic agents and techniques has been reported as 0.2-0.4% in nonobstetric and noncardiac surgery, as 0.4% during caesarean section, and as 1.5% in cardiac surgery.

The incidence during major trauma surgery is higher. Incidence of recall has been reported to be as high as 11-43% in major trauma cases.

The oxygen content of arterial blood can be calculated by the following equation:
(10 x haemoglobin x SaO2 x 1.34) + (PaO2 x 0.0225).
This is the sum of the oxygen bound to haemoglobin and the oxygen dissolved in the plasma.

Oxygen content x cardiac output = The amount of oxygen delivered to the tissues in unit time which is known as the oxygen flux.

Any factor that increases the metabolic demand will encourage oxygen offloading from the haemoglobin in the tissues and this causes the oxygen dissociation curve (ODC) to shift to the right. This subsequently reduced the oxygen content of arterial blood.

Conditions like fever, metabolic or respiratory acidosis lowers the oxygen content and shifts the ODC to the right.
A low level of 2,3 diphosphoglycerate (2,3-DPG) is usually related to an increased oxygen content as there is less offloading, and so the ODC is shifted to the left.

So for a given PaO2, a high blood oxygen content is related to any factors that can shift the ODC to the left and not to the right.

A low haematocrit usually means that there is a decreased haemoglobin concentration, and therefore is associated with decreased oxygen binding to haemoglobin.

Glucose transport is a highly regulated process accomplished mostly by facilitated diffusion using carrier proteins to cross cell membranes.

There are many transporters, but the most important are known as glucose transporters (GLUTs).

Stresses in various form of acute and chronic forms affect the activity of glucose transporters.
They are responsive to many types of metabolic stress, including hypoxia, injury, hypoglycaemia, numerous metabolic inhibitors, stress hormones, and other influences such as growth factors.

Numerous signalling pathways appear to be involved in transporter regulation.

New evidence suggests that stresses regulating GLUTs are not only acute biological stresses. In addition, chronic low-grade inflammation, and their associated chronic diseases also lead to altered glucose transport. These include obesity, type 2 diabetes, cardiovascular disease, and the growth and spread of many tumours that are affected by altered glucose transporters. Some of these glucose transport effects are compensatory, while others are pathogenic.

Ultimately, deliberate manipulation of GLUTs could be used as treatment for some of these chronic diseases.

Sodium concentration for different fluids
3% N saline 513 mmol/L
5% N saline 856 mmol/L
0.9% N saline 154 mmol/L
Hartmann’s solution 131 mmol/L
0.45% N saline with 5% glucose 77 mmol/L

This means that:

500 mL 5% N saline contains 428 mmol of sodium
1000 mL 3% N saline contains 513 mmol of sodium
3500 mL 0.9% N saline contains 539 mmol of sodium
4000 mL Hartmann’s contains 524 mmol of sodium
6000 mL 0.45% N saline with 5% glucose contains 462 mmol of sodium.

Crystalloids recommended for fluid resuscitation include 0.9% N saline and Hartmann’s solution(a physiological solution). 0.9% N. saline is not a physiological solution for the following reasons:

Compared with the normal range of 98-102 mmol/L, its chloride concentration is high (154 mmol/L)
It lacks calcium, magnesium, glucose and potassium
It does not have bicarbonate or bicarbonate precursor buffer necessary to maintain plasma pH within normal limits

There is a difference in the activity (concentration) of strong ions at a physiological pH. This imbalance can explain abnormalities of acid base balance. A normal strong ion difference (SID) is in the order of 40.

SID = ([Na+] + [K+] + [Ca2+] + [Mg2+]) – ([Cl-] + [lactate] + [SO42-])

This imbalance is made up with the weaker anions to maintain electrical neutrality.
Administration of a large volume of 0.9% normal saline during resuscitation results in excessive chloride administration and this impairs renal bicarbonate reabsorption. The SID of 0.9% normal saline is 0 (Na+ = 154mmol/L and Cl- = 154mmol/L = 154 – 154 = 0). A large volume of NS will decrease the plasma SID causing an acidosis.

Other causes of a hyperchloremic acidosis are:

Diabetic ketoacidosis
Total Parenteral Nutrition
Overdose of ammonium chloride and hydrochloric acid
Gastrointestinal losses of bicarbonate like in diarrhoea and pancreatic fistula
Proximal renal tubular acidosis with failure of bicarbonate reabsorption

Sixty-seven percent of filtered water is reabsorbed in the proximal tubule. The driving force for water reabsorption is a transtubular osmotic gradient established by reabsorption of solutes (e.g., NaCl, Na+-glucose).

Henle’s loop reabsorbs approximately 25% of filtered NaCl and 15% of filtered water. The thin ascending limb reabsorbs NaCl by a passive mechanism, and is impermeable to water. Reabsorption of water, but not NaCl, in the descending thin limb increases the concentration of NaCl in the tubule fluid entering the ascending thin limb. As the NaCl-rich fluid moves toward the cortex, NaCl diffuses out of the tubule lumen across the ascending thin limb and into the medullary interstitial fluid, down a concentration gradient as directed from the tubule fluid to the interstitium. This mechanism is known as the counter current multiplier.

The distal tubule and collecting duct reabsorb approximately 8% of filtered NaCl, secrete variable amounts of K+ and H+, and reabsorb a variable amount of water (approximately 8%-17%).