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.

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.

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.

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.

A mercury barometer can be used to determine absolute pressure. A glass tube with one closed end serves as the barometer. The open end is inserted into a mercury-filled open vessel. The mercury in the container is pushed into the tube by atmospheric pressure exerted on its surface. Absolute pressure is the distance between the tube’s meniscus and the mercury surface.

Pressure is defined as force in newtons per unit area (F) (A). 

Mass of mercury = area (A) × density (ρ) × length (L)
Pressure = ((A × ρ × L) × 9.8 m/s2)/A
Pressure = ρ × L x 9.8
Pressure is proportional to L

The numerator and denominator of the above equation, area (A), cancel out. The constants are density and the gravitational acceleration value.

The length is proportional to the applied pressure.

30 mmol Na+ and 30 mmol Cl- are found in 1 litre of 0.18 percent N. saline with 4% dextrose. Percent (percent) refers to the number of grammes of a compound per 100 mL, so a litre of 4 percent dextrose solution contains 40 grammes.

As a result, a 500 mL bag of 1/5th N. saline and 4% dextrose contains approximately 15 mequivalents of sodium and 20 g of glucose. It is hypotonic due to its osmolarity of 284.

Because of the risk of hyponatraemia, it is no longer considered the crystalloid of choice for fluid maintenance in children.

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.

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.

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 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 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 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.

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

While the brain only weighs 3% of the body weight, 15% of the cardiac output goes towards the brain.

Between mean arterial pressures (MAP) of 60-130 mmHg, autoregulation of cerebral blood flow (CBF) occurs. Exceeding this, the CBF is maintained at a constant level. This is controlled mainly by the PaCO2 level, and the autonomic nervous system has minimal role.

Beyond these limits, the CBF is directly proportional to the MAP, not the systolic blood pressure.

The basal metabolic rate (BMR) is the amount of energy required to maintain basic bodily functions in the resting state. The unit is Watt (Joule/second) or calories per unit time.

Indirect calorimetry measures O2 consumption and CO2 production where gases are collected in a canopy which is the gold standard, Douglas bag, face-mask dilution technique or interfaced with a ventilator.

The BMR can be calculated using the Weir formula:

Metabolic rate (kcal per day) = 1.44 (3.94 VO2 + 1.11 VCO2)

The BMR should be measured while lying down and at rest with the following conditions met:

It should follow a 12 -hour fast
No stimulants ingested within a 12-hour period
It should be done in a neutral thermal environment (between 20°C-25°C)

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 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

Compliance of the respiratory system describes the expandability of the lungs and chest wall. There are two types of compliance: dynamic and static.

Dynamic compliance describes the compliance measured during breathing, which involves a combination of lung compliance and airway resistance. Defined as the change in lung volume per unit change in pressure in the presence of flow.

Static compliance describes pulmonary compliance when there is no airflow, like an inspiratory pause. Defined as the change in lung volume per unit change in pressure in the absence of flow.

For example, if a person was to fill the lung with pressure and then not move it, the pressure would eventually decrease; this is the static compliance measurement. Dynamic compliance is measured by dividing the tidal volume, the average volume of air in one breath cycle, by the difference between the pressure of the lungs at full inspiration and full expiration. Static compliance is always a higher value than dynamic

Static compliance can be computed using the formula:

Cstat = Tidal volume/Plateau pressure – PEEP

Substituting the values given,

Cstat = 800/50-10
Cstat = 20 ml/cmH2O

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.

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.

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.

The following table shows the compartments and their relative oxygen reserve:
Compartment Factors Room air (mL) 100% O2 (mL)
Lung FAO2, FRC 630 2850
Plasma PaO2, DF, PV 7 45
Red blood cells Hb, TGV, SaO2 788 805
Myoglobin 200 200
Interstitial space 25 160

Oxygen reserves in the body, with room air and after oxygenation.

FAO2-alveolar fraction of oxygen rises to 95% after administration of 100% oxygen (CO2 = 5%)
FRC- Functional residual capacity – (the most important store of oxygen in the body) – 2,500-3,000 mL in medium sized adults
PaO2-partial pressure of oxygen dissolved in arterial blood (80 mmHg breathing room air and 500 mmHg breathing 100% oxygen)
DF -dissolved form (0.3%)
PV-plasma volume (3L)
TG-total globular volume (5L)
Hb-haemoglobin concentration
SaO2-arterial oxygen concentration (98% breathing air and 100% when preoxygenated)

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 number of osmoles (Osm) of solute per litre (L) of solution (Osmol/L) is the unit of measurement for solute concentration. The calculated serum osmolality assumes that the primary solutes in the serum are sodium salts (chloride and bicarbonate), glucose, and urea nitrogen.

2 (Na + K) + Glucose + Urea (all in mmol/L) = calculated osmolarity

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

Sodium and potassium ions clearly contribute the most to plasma osmolarity. Glucose and urea, on the other hand, are less so.

The osmolarity of normal serum is 285-295 mOsm/L. Temperature and pressure affect osmolality, and this calculated variable is less than osmolality for a given solution.

The number of osmoles (Osm) of solute per kilogramme (Osm/kg) is a measure of osmolality, which is also a measure of solute concentration. Temperature and pressure have no effect on the value. An osmometer is used to measure it in the lab. Osmometers rely on a solution’s colligative properties, such as a decrease in freezing point or a rise in vapour pressure.

The osmolar gap (OG) is calculated as follows:

OG = osmolaRity calculated from measured serum osmolaLity

Excess alcohols, lipids, and proteins in the blood can all contribute to the difference.

Krebs’ cycle (tricarboxylic acid cycle or citric acid cycle) is a sequence of reactions in which acetyl coenzyme A (acetyl-CoA) is metabolised and this results in carbon dioxide and hydrogen atoms production.

This series of reactions occur in the mitochondria of eukaryotic cells, not the cytoplasm. The cycle requires oxygen and so, cannot function under anaerobic conditions.

It is the common pathway for carbohydrate, fat and some amino acids oxidation and is required for high energy phosphate bond formation in adenosine triphosphate (ATP).

When pyruvate enters the mitochondria, it is converted into acetyl-CoA. This represents the formation of a 2 carbon molecule from a 3 carbon molecule. There is loss of one CO2 but formation of one NADH molecule. Acetyl-CoA is condensed with oxaloacetate, the anion of a 4 carbon acid, to form citrate which is a 6 carbon molecule.

Citrate is then converted into isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate and finally oxaloacetate.

The only 5 carbon molecule in the cycle is alpha-ketoglutarate.

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 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.