Human skeletal muscle is composed of a heterogeneous collection of muscle fibre types which differ histologically, biochemically and physiologically.

It can be biochemically classified into 2 groups. This is based on muscle fibre myosin ATPase histochemistry. These are:

Type 1 (slow twitch): Muscle fibres depend upon aerobic glycolytic metabolism and aerobic oxidative metabolism. They are rich in mitochondria, have a good blood supply, rich in myoglobin and are resistant to fatigue.

Type II (fast twitch): Muscle fibres are sub-divided into:
Type IIa – relies on aerobic/oxidative metabolism
Type IIb – relies on anaerobic/glycolytic metabolism.

Fast twitch muscle fibres produce short bursts of power but are more easily fatigued.

Cardiac and smooth muscle twitches are relatively slow compared with skeletal muscle.

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.

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 measurements of GFR are done using renally inert indicators like inulin, where passive rate of filtration at the glomerulus = rate of excretion. Normal value is about 180 litres per day.

GFR is altered by renal blood flow but blood flow does not need to be measured.

The reabsorption of Na leads to a low excretion rate and low urine concentration and therefore its use as an indicator would lead to an erroneously LOW GFR.

If there is tubular secretion of any solute, the clearance value will be higher than that of inulin. This will be either due to tubular reabsorption or the solute not being freely filtered at the glomerulus.

The respiratory quotient (RQ) is the ratio of CO2 produced by the body to O2 consumed in a given amount of time.

CO2 produced / O2 consumed = RQ

CO2 is produced at a rate of 200 mL per minute, while O2 is consumed at a rate of 250 mL per minute. An RQ of around 0.8 is typical for a mixed diet.

The RQ will change depending on the energy substrates consumed in the diet. Granulated sugar is a refined carbohydrate that contains 99.999 percent carbohydrate and no lipids, proteins, minerals, or vitamins.

Glucose and other hexose sugars (glucose and other hexose sugars):
RQ=1

Fats:
RQ = 0.7

Proteins:
Approximately 0.9 RQ

Ethyl alcohol is a type of alcohol.

200/300 = 0.67 RQ

For complete oxidation, lipids and alcohol require more oxygen than carbohydrates.

When carbohydrate is converted to fat, the RQ can rise above 1.0. Fat deposition and weight gain are likely to occur in these circumstances.

The bispectral index (BIS) is one of several systems used in anaesthesiology as of 2003 to measure the effects of specific anaesthetic drugs on the brain and to track changes in the patient’s level of sedation or hypnosis. It is a complex mathematical algorithm that allows a computer inside an anaesthesia monitor to analyse data from a patient’s electroencephalogram (EEG) during surgery. It is a dimensionless number (0-100) that is a summative measurement of time domain, frequency domain and high order spectral parameters derived from electroencephalogram (EEG) signals.

Sleep and anaesthesia have similar behavioural characteristics but are physiologically different but BIS monitors can be used to measure sleep depth. With increasing sleep depth during slow-wave sleep, BIS levels decrease. This correlates with changes in regional cerebral blood flow when measured using positron emission tomography (PET).

BIS shows a dose-response relationship with the intravenous and volatile anaesthetic agents. Opioids produce a clinical change in the depth of sedation or analgesia but fail to produce significant changes in the BIS. Ketamine increases CMRO2 and EEG activity.

BIS is unable to predict movement in response to a surgical stimulus. Some of these are spinal reflexes and not perceived by the cerebral cortex.

BIS is used during cardiopulmonary bypass to measure depth of anaesthesia and an index of cerebral perfusion. However, it cannot predict subtle or significant cerebral damage.

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.

Bilirubin is the tetrapyrrole and a catabolic product of heme. 70-90% of bilirubin is end product of haemoglobin degradation in the liver.

Bilirubin circulates in the blood in 2 forms; unconjugated and conjugated bilirubin.

Unconjugated bilirubin is insoluble in water. It travels through the bloodstream to the liver, where it changes from insoluble into a soluble form (i.e.; unconjugated into conjugated form).

This conjugated bilirubin travels from the liver into the small intestine and the gut bacteria convert bilirubin into urobilinogen and then into urobilin (not urobilin to urobilinogen). A very small amount passes into the kidneys and is excreted in urine.

Approximately 25% of phase-1 drug reactions is made responsible by CYP2D6.

As much as a 1,000-fold difference in the ability to metabolise drugs by CYP2D6 can happen between phenotypes, and this may result in adverse drug reactions (ADRs).

The metabolism of antiemetics, beta-blockers, codeine, tramadol, oxycodone, hydrocodone, tamoxifen, antidepressants, neuroleptics, and antiarrhythmics is also as a result of CYP2D6.

Patients who take drugs that are metabolised by CYP2D6 but have poor CYP2D6 metabolism are more likely to have ADRs. People with ultra-rapid CYP2D6 metabolism may have a decreased drug effect due to low plasma concentrations of these drugs.

All the other CYP enzymes are subject to genetic polymorphism. Variants are less likely to lead to adverse drug reactions.

Such a high rise of end-tidal CO2 (EtCO2) in a patient who is spontaneously breathing is often encountered.

Close observation should occur for further rises in EtCO2 and other signs of malignant hyperthermia. If this were to rise even more, it might be wise to ensure that ventilatory support is available.

A lot would depend on whether surgery was almost completed. At this stage of anaesthesia, it would be inappropriate to administer opioid antagonists or respiratory stimulants.

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 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

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 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.

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.

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.

A major source of caloric expenditure and oxygen consumption in the body is work of breathing (WOB) and 70% of this is to overcome elastic forces. The remaining 30% is for flow-resistive work

In a normal patient breathing normally, the total area of hysteresis pressure volume curve represents the flow-resistive WOB.

The area of the expiratory resistive work increases during an asthma attack making the compliance curve larger in area. The larger the area the greater the work required to breathe.

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.

Prostaglandins do not play a major role in regulating RBF in healthy resting individuals. However, during pathophysiological conditions such as haemorrhage and reduced extracellular fluid volume (ECVF), prostaglandins (PGI2, PGE1, and PGE2) are produced locally within the kidneys and serve to increase RBF without changing GFR. Prostaglandins increase RBF by dampening the vasoconstrictor effects of both sympathetic activation and angiotensin II. These effects are important because they prevent severe and potentially harmful vasoconstriction and renal ischemia. Synthesis of prostaglandins is stimulated by ECVF depletion and stress (e.g. surgery, anaesthesia), angiotensin II, and sympathetic nerves.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, potently inhibit prostaglandin synthesis. Thus administration of these drugs during renal ischemia and hemorrhagic shock is contraindicated because, by blocking the production of prostaglandins, they decrease RBF and increase renal ischemia. Prostaglandins also play an increasingly important role in maintaining RBF and GFR as individuals age. Accordingly, NSAIDs can significantly reduce RBF and GFR in the elderly.

When there is capillary leakage as seen in dependent oedema or ascites, oncotic pressure becomes a problem.

The intracellular sodium concentration is very sensitive to the extracellular sodium concentrations. When there is an imbalance, osmosis occurs resulting in shifts in water between the two compartments.

The microvascular endothelium relies upon osmosis and other processes as it is not freely permeable to water.

For the local anaesthetic base to be stable in solution, it is formulated as a hydrochloride salt. As such, the molecules exist in a quaternary, water-soluble state at the time of injection. However, this form will not penetrate the neuron. The time for onset of local anaesthesia is therefore predicated on the proportion of molecules that convert to the tertiary, lipid-soluble structure when exposed to physiologic pH (7.4).

The ionization constant (pKa) for the anaesthetic predicts the proportion of molecules that exists in each of these states. By definition, the pKa of a molecule represents the pH at which 50% of the molecules exist in the lipid-soluble tertiary form and 50% in the quaternary, water-soluble form. The pKa of all local anaesthetics is >7.4 (physiologic pH), and therefore a greater proportion the molecules exists in the quaternary, water-soluble form when injected into tissue having normal pH of 7.4.

Furthermore, the acidic environment associated with inflamed tissues favours the quaternary, water-soluble configuration even further. Presumably, this accounts for difficulty when attempting to anesthetize inflamed or infected tissues; fewer molecules exist as tertiary lipid-soluble forms that can penetrate nerves.

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

In contrast to the arterial system, which contains 15% of the circulating blood volume, the body’s veins contain 70% of it.

In severe haemorrhage, when sympathetic stimulation causes venoconstriction, venous tone is important in maintaining the return of blood to the heart.

Because the liver receives about 30% of the resting cardiac output, it is a very vascular organ. The hepatic vascular system is dynamic, which means it can store and release blood in large amounts – it acts as a reservoir within the general circulation.

In a normal situation, the liver contains 10-15% of total blood volume, with the sinusoids accounting for roughly 60% of that. The liver dynamically adjusts its blood volume when blood is lost and can eject enough blood to compensate for a moderate amount of haemorrhage.

In the portal venous and hepatic arterial systems, sympathetic nerves constrict the presinusoidal resistance vessels. More importantly, sympathetic stimulation lowers the portal system’s capacitance, allowing blood to flow more efficiently to the heart.

Net transcapillary absorption of interstitial fluid from skeletal muscle into the intravascular space compensates for blood loss effectively during haemorrhage. The decrease in capillary hydrostatic pressure (Pc), caused by reflex adrenergic readjustment of the ratio of pre- to postcapillary resistance, is primarily responsible for fluid absorption. Within a few hours of blood loss, these fluid shifts become significant, further diluting haemoglobin and plasma proteins.

Albumin synthesis begins to increase after 48 hours.

The juxtamedullary complex releases renin in response to a drop in mean arterial pressure, which causes an increase in aldosterone level and, eventually, sodium and water resorption. Increased antidiuretic hormone (ADH) levels also contribute to water retention.

The patient in the case has a fluid volume requirement of 30 mL/kg/day. His basic electrolyte requirement per day is:

Sodium at 2 mmol/kg/day x 110 = 220 mmol/day
Potassium at 1 mmol/kg/day x 110 = 110 mmol/day

His energy requirement per day is:

35 kcal/kg/day x 110 kg = 3850 kcal/day

One gram of glucose in fluid can provide approximately 4 kilocalories.

The following are the electrolyte components of the different intravenous fluids:

Fluid Na (mmol/L) K (mmol/L)
0.9% Normal saline (NSS) 154 0
0.45% NSS + 5% dextrose 77 0
0.18% NSS + 4% dextrose 30 0
Hartmann’s 131 5
5% dextrose 0 0

1000 mL of 5% dextrose has 50 g of glucose

Option B is inadequate for his sodium and caloric requirements (30 mmol of Na+ and 560 kcal). It is adequate for his K+ requirement (120 mmol of K+).

Option C is in excess of his Na+ requirement (462 mmol of Na+). Moreover, it does not provide any K+ replacement.

Option D is inadequate for his caloric requirement (600 kcal) and K+ requirement (60 mmol of K+). Moreover it does not provide any Na+ replacement.

Option E is in excess of his Na+ requirement (393 mmol of Na+), and is inadequate for his potassium requirement (15 mmol of K+)

Option A has adequate amounts for his Na+ (231 mmol of Na+) and K+ (120 mmol of K+) requirements. It is inadequate for his caloric requirement (600 kcal).

If there is no change in preload and myocardial contractility, there will be decrease in end-diastolic volume and stroke volume. So there must be increase in end-systolic volume.

A decrease in the functional residual capacity (FRC) is the most important physiologic change to consider for such patients.

FRC is the sum of the expiratory reserve volume and the residual volume. It is the resting volume of the lung, and is an important marker for lung function. During this time, the alveolar pressure is equal to the atmospheric pressure. When morbidly obese individuals lie supine, the FRC decreases by as much as 40% because the abdominal contents push the diaphragm into the thoracic cavity.

Chest wall compliance is expected to reduce because of fat deposition surrounding adjacent structures.

Inspiratory reserve volume (IRV) is expected to increase, and peak expiratory flow is expected to decrease, however the decrease in FRC is more important to consider because of the risk of hypoxia secondary to premature airway closure and ventilation-perfusion mismatch.

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.